Guidelines for the Use of Antiretroviral Agents in

Pediatric HIV Infection

Developed by the HHS Panel on Antiretroviral Therapy and Medical

Management of Children Living with HIV—A Working Group of the
NIH Office of AIDS Research Advisory Council (OARAC)

How to Cite the Pediatric Antiretroviral Guidelines:

Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV. Guidelines for the Use of
Antiretroviral Agents in Pediatric HIV Infection. Department of Health and Human Services. Available at
https://clinicalinfo.hiv.gov/en/guidelines/pediatric-arv. Accessed (insert date) [include page numbers, table
number, etc., if applicable].

It is emphasized that concepts relevant to HIV management evolve rapidly. The Panels have a mechanism to
update recommendations on a regular basis, and the most recent information is available on the Clinicalinfo
website (https://clinicalinfo.hiv.gov/).
Table of Contents
What’s New in the Guidelines .......................................................................................................................... vii
Guidelines Panel Members .............................................................................................................................. xii
Financial Disclosure ........................................................................................................................................ xiv
Introduction......................................................................................................................................................A-1
Table 1. Outline of the Guidelines Development Process ..............................................................................................A-3
Table 2. Rating Scheme for Recommendations .............................................................................................................A-6
Pregnancy and Postpartum HIV Testing and Identification of Perinatal and Postnatal HIV
Exposure ..........................................................................................................................................................B-1
Overview ........................................................................................................................................................................B-2
HIV Testing During the Postpartum Period ....................................................................................................................B-7
Other Issues ...................................................................................................................................................................B-8
Infant Feeding for Individuals With HIV in the United States .......................................................................C-1
Overview of Counseling and Management ................................................................................................................... C-3
Factors Affecting Decisions About Infant Feeding ........................................................................................................ C-7
Safety of Antiretroviral Drugs During Breastfeeding ...................................................................................................... C-9
Diagnosis of HIV Infection in Infants and Children.....................................................................................C-18
Timing of Diagnostic Testing in Infants With Perinatal HIV Exposure ......................................................................... C-20
Table 3: Recommended Virologic Testing Schedules for Infants Who Were Exposed to HIV According to Risk of
Perinatal Acquisition ................................................................................................................................................... C-23
Diagnostic Testing in Children With Perinatal HIV Exposure in Special Situations ..................................................... C-24
Diagnostic Testing in Children With Nonperinatal HIV Exposure or Children With Perinatal
HIV Exposure Aged >24 Months ................................................................................................................................. C-26
Virologic Assays to Diagnose HIV Infection in Infants Younger Than 18 Months With
Perinatal HIV-1 Exposure ............................................................................................................................................ C-27
Other Issues ................................................................................................................................................................ C-28
Clinical and Laboratory Monitoring of Pediatric HIV Infection ....................................................................D-1
Clinical and Laboratory Monitoring of Children With HIV .............................................................................................. D-2
Table 4. Characteristics and Requirements for In-Person Clinic Visits vs. Telemedicine Visits ....................... D-4
Immunologic Monitoring in Children: General Considerations ...................................................................................... D-6
Table 5. CD4 Cell Counts and Percentages in Healthy Children: Distribution by Age ..................................... D-6
HIV RNA Monitoring in Children: General Considerations ............................................................................................ D-7
Genetic Testing for Management of HIV ....................................................................................................................... D-8
Table 6. Sample Schedule for Clinical and Laboratory Monitoring of Children Before
and After Initiation of Antiretroviral Therapy ..................................................................................................... D-8

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection i

 Table 7. Primary U.S. Food and Drug Administration–Approved Assays for Monitoring Viral Load ............... D-10
When to Initiate Therapy in Antiretroviral-Naive Children ........................................................................... E-1
What to Start: Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children .................. F-1
Criteria Used for Recommendations .............................................................................................................................. F-1
Factors to Consider When Selecting an Initial Regimen ................................................................................................ F-2
Choosing an Initial Antiretroviral Regimen for Children With HIV ................................................................................... F-3
Integrase Strand Transfer Inhibitor-Based Regimens .................................................................................................... F-4
Non-Nucleoside Reverse Transcriptase Inhibitor-Based Regimens .............................................................................. F-6
Protease Inhibitor–Based Regimens .............................................................................................................................. F-8
Selection of Dual-Nucleoside Reverse Transcriptase Inhibitor Backbone as Part of Initial
Combination Therapy ................................................................................................................................................... F-10
Figure 1. Preferred Regimen by Age, Weight, and Drug Class ....................................................................... F-13
Table 8. Antiretroviral Regimens Recommended for Initial Therapy for HIV Infection in Children .................. F-14
Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended for
Initial Therapy in Children ............................................................................................................................... F-18
What Not to Start: Regimens Not Recommended for Use in Antiretroviral-Naive Children.................... F-38
Antiretroviral Drugs and Drug Combinations Not Recommended for Initial Therapy in Children ................................ F-38
Antiretroviral Drugs and Combinations With Insufficient Data to Recommend for Initial Therapy in Children ............. F-40
Table 10. Antiretroviral Regimens or Components That Are Not Recommended for Initial
Treatment of HIV Infection in Children and Adolescents ................................................................................. F-43
Table 11. Antiretroviral Regimens or Components That Are Never Recommended for
Treating HIV in Children and Adolescents ...................................................................................................... F-44
Antiretroviral Management of Newborns With Perinatal HIV Exposure or HIV ......................................... G-1
General Considerations for Antiretroviral Management of Newborns Exposed to HIV or
Born With HIV ............................................................................................................................................................... G-2
Table 12. Neonatal Antiretroviral Management According to Risk of HIV Infection in the Newborn ................. G-3
Table 13. Antiretroviral Drug Dosing Recommendations for Newborns ........................................................... G-6
Recommendations for Antiretroviral Drugs in Specific Clinical Situations ................................................................... G-10
Table 14. Infant Antiretroviral Prophylaxis for Newborns of Mothers With Sustained Viral Suppression
Who Breastfeed ............................................................................................................................................. G-12
Special Considerations for Antiretroviral Therapy Use in Adolescents With HIV .....................................H-1
Background ................................................................................................................................................................... H-1
Timing and Selection of Antiretroviral Therapy ............................................................................................................. H-2
Dosing of Antiretroviral Therapy for Adolescents With HIV ........................................................................................... H-2
Adherence Concerns in Adolescents ............................................................................................................................ H-2
Mental Health and Substance Use Concerns in Adolescents ....................................................................................... H-3

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection ii

 Sexually Transmitted Infections in Adolescents ............................................................................................................ H-4
Contraception, Pregnancy, and Antiretroviral Therapy ................................................................................................. H-5
Special Considerations for Adolescents With HIV Who Are Sexual Minorities.............................................................. H-6
Transitioning Adolescents Into Adult HIV Care Settings ............................................................................................... H-6
Adherence to Antiretroviral Therapy in Children and Adolescents With HIV.............................................. I-1
Background ..................................................................................................................................................................... I-1
Specific Adherence Issues in Children ............................................................................................................................ I-2
Adherence Assessment and Monitoring.......................................................................................................................... I-2
Strategies to Improve and Support Adherence ............................................................................................................... I-3
Regimen-Related Strategies ........................................................................................................................................... I-3
Patient/Family-Related Strategies ................................................................................................................................... I-4
Health Care Provider–Related Strategies ....................................................................................................................... I-6
Table 15. Approaches for Monitoring Medication Adherence ............................................................................. I-7
Table 16. Strategies to Improve Adherence to Antiretroviral Medications .......................................................... I-8
Management of Medication Toxicity or Intolerance...................................................................................... J-1
Medication Toxicity or Intolerance .................................................................................................................................. J-1
Management .................................................................................................................................................................. J-2
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Central Nervous System Toxicity .................................................................................................. J-8
Table 17b. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Dyslipidemia ............................................................................................................................... J-11
Table 17c. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Gastrointestinal Effects ............................................................................................................... J-18
Table 17d. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Hematologic Effects .................................................................................................................... J-23
Table 17e. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Hepatic Events............................................................................................................................ J-29
Table 17f. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Insulin Resistance, Asymptomatic Hyperglycemia, and Diabetes Mellitus ................................. J-36
Table 17g. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Lactic Acidosis ............................................................................................................................ J-41
Table 17h. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Lipodystrophies and Weight Gain ............................................................................................... J-46
Table 17i. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Nephrotoxic Effects ..................................................................................................................... J-54
Table 17j. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Osteopenia and Osteoporosis .................................................................................................... J-60
Table 17k. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Rash and Hypersensitivity Reactions ......................................................................................... J-67

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection iii
Management of Children Receiving Antiretroviral Therapy .........................................................................K-1
Modifying Antiretroviral Regimens in Children With Sustained Virologic Suppression on
Antiretroviral Therapy .....................................................................................................................................................K-1
Table 18. Examples of Changes in Antiretroviral Regimen Components for Children With
Sustained Virologic Suppression....................................................................................................................... K-5
Recognizing and Managing Antiretroviral Treatment Failure ....................................................................K-20
Categories of Treatment Failure.................................................................................................................................. K-20
Table 19. Discordance Among Virologic, Immunologic, and Clinical Responses ............................................ K-24
Management of Virologic Failure................................................................................................................................. K-24
Therapeutic Options to Achieve Complete Virologic Suppression After Virologic Failure ........................................... K-26
Management Options When Two Fully Active Agents Cannot Be Identified or Administered ..................................... K-28
Table 20. Options for Regimens With at Least Two Fully Active Agents to Achieve Virologic Suppression
in Patients With Virologic Failure and Evidence of Viral Resistance ............................................................... K-29
Antiretroviral Treatment Interruption in Children With HIV........................................................................K-39
Unplanned Treatment Interruptions............................................................................................................................. K-39
Structured Treatment Interruptions ............................................................................................................................. K-40
Short-Cycle Therapy Strategies .................................................................................................................................. K-41
Conclusion .................................................................................................................................................................. K-42
Appendix A: Pediatric Antiretroviral Drug Information ................................................................................ L-1
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors ........................................................................ L-3
Abacavir ............................................................................................................................................................ L-4
Emtricitabine ................................................................................................................................................... L-17
Lamivudine ...................................................................................................................................................... L-25
Tenofovir Alafenamide .................................................................................................................................... L-37
Tenofovir Disoproxil Fumarate ........................................................................................................................ L-56
Zidovudine ...................................................................................................................................................... L-70
Non-Nucleoside Analogue Reverse Transcriptase Inhibitors ....................................................................................... L-80
Doravirine ........................................................................................................................................................ L-81
Efavirenz ......................................................................................................................................................... L-88
Etravirine ....................................................................................................................................................... L-103
Nevirapine ..................................................................................................................................................... L-109
Rilpivirine ...................................................................................................................................................... L-119
Protease Inhibitors ..................................................................................................................................................... L-129
Atazanavir ..................................................................................................................................................... L-130
Darunavir ...................................................................................................................................................... L-141

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection iv

 Lopinavir/Ritonavir ........................................................................................................................................ L-153
Entry and Fusion Inhibitors......................................................................................................................................... L-169
Fostemsavir................................................................................................................................................... L-170
Ibalizumab ..................................................................................................................................................... L-174
Maraviroc ...................................................................................................................................................... L-178
Integrase Inhibitors ..................................................................................................................................................... L-183
Bictegravir ..................................................................................................................................................... L-184
Cabotegravir.................................................................................................................................................. L-194
Dolutegravir ................................................................................................................................................... L-202
Elvitegravir .................................................................................................................................................... L-217
Raltegravir ..................................................................................................................................................... L-231
Pharmacokinetic Enhancers....................................................................................................................................... L-247
Cobicistat ...................................................................................................................................................... L-248
Ritonavir ........................................................................................................................................................ L-254
Fixed-Dose Combinations .......................................................................................................................................... L-260
Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or
as a Co-packaged Formulation, by Drug Class ............................................................................................. L-261
Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations:
Minimum Body Weights and Considerations for Use in Children and Adolescents ....................................... L-264
Archived Drugs.......................................................................................................................................................... L-264
Didanosine .................................................................................................................................................... L-265
Enfuvirtide ..................................................................................................................................................... L-270
Fosamprenavir .............................................................................................................................................. L-274
Indinavir ........................................................................................................................................................ L-279
Nelfinavir ....................................................................................................................................................... L-284
Saquinavir ..................................................................................................................................................... L-290
Stavudine ...................................................................................................................................................... L-295
Tipranavir ...................................................................................................................................................... L-304
Appendix B: Acronyms .................................................................................................................................. M-1
Appendix C: CDC Pediatric HIV CD4 Cell Count/Percentage and HIV-Related Diseases
Categorization..................................................................................................................................................N-1
Table A. HIV Infection Stage Based on Age-Specific CD4 Count or Percentage.......................................................... N-1
Table B. HIV-Related Symptoms and Conditions ......................................................................................................... N-1

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection v

Appendix D: Supplemental Information ....................................................................................................... O-1
Table A. Likelihood of Developing AIDS or Death Within 12 Months, by Age and CD4
T-Cell Percentage or Log 10 HIV-1 RNA Copy Number in HIV-Infected Children Receiving
No Therapy or Zidovudine Monotherapy ....................................................................................................................... O-1
Table B. Death and AIDS/Death Rate per 100 Person-Years by Current Absolute CD4 Cell
Count and Age in HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy
(HIV Paediatric Prognostic Markers Collaborative Study) and Adult Seroconverters (CASCADE Study) ..................... O-1
Table C. Association of Baseline Human Immunodeficiency Virus (HIV) RNA Copy Number
and CD4 T-Cell Percentage With Long-Term Risk of Death in HIV-Infected Children .................................................. O-3
Figure A. Estimated Probability of AIDS Within 12 Months by Age and CD4 Percentage in
HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy ................................................................... O-3
Figure B. Estimated Probability of Death Within 12 Months by Age and CD4 Percentage in
HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy ................................................................... O-4
Figure C. Death Rate per 100 Person-Years in HIV-Infected Children Aged 5 Years or Older
in the HIV Paediatric Prognostic Marker Collaborative Study and HIV-Infected Seroconverting Adults From
the CASCADE Study ..................................................................................................................................................... O-4
Figure D. Estimated Probability of AIDS Within 12 Months of Age and HIV RNA Copy
Number in HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy ................................................. O-5
Figure E. Estimated Probability of Death Within 12 Months of Age and HIV RNA Copy
Number in HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy ................................................. O-5

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection vi

What’s New in the Pediatric Guidelines
Updated: January 31, 2024
Reviewed: January 31, 2024

January 31, 2024

The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the
Panel) has reviewed and updated one section of the Guidelines for the Use of Antiretroviral Agents in
Pediatric HIV Infection that is developed in collaboration with the Panel on Treatment of HIV
During Pregnancy and Prevention of Perinatal Transmission. The changes are highlighted in yellow
in the PDF version of the guidelines.

Pregnancy and Postpartum HIV Testing and Identification of Perinatal and

Postnatal HIV Exposure
• This section has been retitled to align with updates in other sections, with revisions and updates
made to bulleted recommendations and throughout the text to provide added detail, new data, and
clarification.
• The Panel recommends that when acute HIV infection is suspected during pregnancy, the
intrapartum period, or while breastfeeding, a plasma HIV RNA assay should be performed in
conjunction with an antigen/antibody immunoassay.

April 11, 2023

When to Start
• The section summary has been revised to clarify that rapid initiation of antiretroviral
therapy (ART), defined as therapy initiated immediately or within days of HIV diagnosis, is
recommended except for children with cryptococcal meningitis, disseminated Mycobacterium
avium Complex Disease, or Mycobacterium tuberculosis. Because of concerns regarding the risk
of immune reconstitution inflammatory syndrome, ART initiation may be deferred until the
optimal timing relative to treatment of the opportunistic infection. Timing of ART initiation in
these cases should be discussed with a pediatric HIV specialist. See the Guidelines for the
Prevention and Treatment of Opportunistic Infections in Children With and Exposed to HIV and
the World Health Organization Updated Recommendations on HIV Prevention, Infant Diagnosis,
Antiretroviral Initiation, and Monitoring, March 2021.

Clinical and Laboratory Monitoring of Pediatric HIV Infection

• The section now describes several methods to obtain regular weight and height measurements in
addition to HIV clinic visits. Cooperative children can be weighed and height measured at home
if a scale and measuring tape are available, with simple instructions for continuity, or directly
observed during a synchronous visit or obtained from recent pediatric or other specialty in-office
visit.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection vii
• Table 5. CD4 Cell Counts and Percentages in Healthy Children: Distribution by Age has been
added to the section.
• Table 6. Sample Schedule for Clinical and Laboratory Monitoring of Children Before and After
Initiation of Antiretroviral Therapy has been updated.
• Initial laboratory screening for infants and children now includes HLA-B*5701 testing to allow
for possible abacavir initiation. An alternative ARV drug should be used if the HLA-B*5701 test
result is positive.
• The Panel has added guidance about viral load monitoring for adolescents initiating long-acting
cabotegravir and rilpivirine (LA-CAB and RPV).
• To address issues related to biologic variability in HIV RNA (viral load), the Panel has added
clarification of clinically significant plasma viral load changes in infants aged <2 years
(>0.7 log10 copies/mL, a fivefold difference) and in children aged ≥2 years
(>0.5 log10 copies/mL, a threefold difference).

What Not to Start: Regimens Not Recommended for Use Antiretroviral-Naive

Children
• Content regarding some drugs that are not recommended for initial therapy has been reorganized.

Special Considerations for Antiretroviral Therapy Use in Adolescents With HIV

• The Panel noted that LA-CAB and RPV could be considered to improve or support ART
adherence in adolescents aged ≥12 years and weighing ≥35 kg who are virally suppressed and
also noted that data about the use of LA-CAB and RPV in those with adherence concerns are still
emerging.
• Based on recent data about a higher prevalence of attempted suicide in adolescents with HIV
compared to HIV-exposed but uninfected adolescents, providers who are caring for adolescents
with HIV should incorporate screening for suicidality into other mental health and psychiatric
screenings, referring patients to age-appropriate services as needed.

Adherence to Antiretroviral Therapy in Children and Adolescents With HIV

• The Panel points out that the growing use of telemedicine visits, which allow remote and often
face-to-face contact, provides new opportunities to support families and visualize ART handling
and swallowing, as well as to conduct directly observed therapy in the home setting.
• Table 16. Strategies to Improve Adherence to Antiretroviral Medications has been updated to
address monitoring adherence, specific barriers to adherence, and strategies that may help to
improve adherence, such as participation in camp programs and referrals to counseling and
mental health programs.

Management of Medication Toxicity or Intolerance

• Tables for Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations have been reviewed with updates regarding associated ARVs, onset and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection viii
 clinical manifestations, estimated frequency, risk factors, prevention and monitoring, and
management where indicated.
o Table 17a. Central Nervous System Toxicity. The table now includes neuropsychiatric
symptoms and other central nervous system manifestations associated with cabotegravir.

Management of Children Receiving Antiretroviral Therapy

• Modifying Antiretroviral Regimens in Children With Sustained Virologic Suppression on
Antiretroviral Therapy and Table 18. Examples of Changes in Antiretroviral Regimen
Components for Children With Sustained Virologic Suppression have been updated to
incorporate the most recent switch options in line with pediatric ARV drug approvals and Panel
recommendations.
• While oral two-drug regimens are not approved for use in children or for initial therapy, the Panel
notes that they may be considered for when simplification of ART or avoidance of nucleoside
reverse transcriptase inhibitors is needed. Because adolescents may have difficulties adhering to
therapy, close monitoring with viral load testing is recommended.
• Recognizing and Managing Antiretroviral Treatment Failure and Table 20. Options for Regimens
With at Least Two Fully Active Agents to Achieve Virologic Suppression in Patients With
Virologic Failure and Evidence of Viral Resistance have been updated to incorporate new data
and ARV options in the context of treatment failure.

Appendix A: Pediatric Antiretroviral Drug Information

Drug sections and fixed-dose combination (FDC) Table 1. Antiretrovirals Available in Fixed-Dose
Combination Tablets or as a Co-packaged Formulation, by Drug Class and Table 2. Antiretroviral
Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and
Considerations for Use in Children and Adolescents in this appendix were reviewed and updated to
include recent pediatric data, dosing and safety information, and U.S. Food and Drug Administration
approvals of new formulations and FDCs. Significant changes are summarized below:

• The Bictegravir section was updated to include additional information related to splitting,
dissolving, or crushing bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) tablets;
crushing tablets is not recommended.
• The Panel notes that the current raltegravir dosing regimen with two dose changes in the first
month of life may be challenging for some families; the Raltegravir section now includes
guidance from some experts on simplifying medication teaching and minimizing dosing changes.
January 31, 2023
Infant Feeding for Individuals with HIV in the United States
Updated recommendations for infant feeding are now included as a shared section in the Perinatal
Guidelines.
The Panel recommends that people with HIV receive evidence-based, patient-centered counseling to
support shared decision-making about infant feeding. Counseling about infant feeding should begin
prior to conception or as early as possible in pregnancy; information about and plans for infant

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection ix

feeding should be reviewed throughout pregnancy and again after delivery (AIII). During
counseling, people should be informed that—
• Replacement feeding with properly prepared formula or pasteurized donor human milk from
a milk bank eliminates the risk of postnatal HIV transmission to the infant (AI).
• Achieving and maintaining viral suppression through antiretroviral (ARV) therapy during
pregnancy and postpartum decreases breastfeeding transmission risk to less than 1%, but not
zero (AI).
Replacement feeding with formula or banked pasteurized donor human milk is recommended to
eliminate the risk of HIV transmission through breastfeeding when people with HIV are not on
antiretroviral therapy (ART) and/or do not have a suppressed viral load during pregnancy (at a
minimum throughout the third trimester) and at delivery (AI).
Individuals with HIV who are on ART with a sustained undetectable viral load and who choose to
breastfeed should be supported in this decision (AIII).
Individuals with HIV who choose to formula feed should be supported in this decision; potential
barriers to formula feeding should be identified and addressed (AIII).
Content about counseling and management of individuals who choose to breastfeed was updated,
with added content on situations in which to consider stopping or modifying breastfeeding.

Diagnosis of HIV Infection in Infants and Children

This section now provides additional guidance about HIV diagnostic testing for infants with perinatal
HIV exposure who are being breastfed, with time points for testing listed in Table 3. Recommended
Virologic Testing Schedules for Infants Who Were Exposed to HIV According to Risk of Perinatal
HIV Acquisition at and After Birth.

A subsection was added with information about HIV testing for infants who were being breastfed at
the time of maternal HIV diagnosis.

Antiretroviral Management of Newborns with Perinatal HIV Exposure or HIV

Infection
When the criteria for low risk of perinatal HIV transmission are met, the Panel now recommends that
infants receive 2 weeks of zidovudine (ZDV) prophylaxis (BII), rather than 4 weeks (see Table 12.
Neonatal Antiretroviral Management According to Risk of HIV Infection in the Newborn).

o The criterion for viral suppression was further defined as at least two consecutive tests with
HIV RNA levels <50 copies/mL obtained at least 4 weeks apart.
Infants born to individuals who do not meet criteria for low risk for perinatal HIV transmission but
who have a viral load <50 copies/mL at or after 36 weeks should receive ZDV for 4 to 6 weeks (BII).

The Panel clarified the duration of ARVs for newborns at high risk of perinatal acquisition.
Presumptive HIV therapy with three-drug regimens should be administered from birth for 2 to
6 weeks (see Tables 12 and 13); if the duration of the three-drug regimen is shorter than 6 weeks,
ZDV should be continued alone to complete a total of 6 weeks of prophylaxis.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection x

All premature infants <37 weeks gestation who are not at high risk of perinatal acquisition of HIV
should receive ZDV for 4 to 6 weeks (BII).

New subsections and Table 14. Infant Antiretroviral Prophylaxis for Newborns of Mothers with
Sustained Viral Suppression Who Breastfeed were added to address ARV prophylaxis for newborns
at low risk of perinatal HIV transmission who are breastfed and to provide information about
breastfeeding in newborns at high risk of perinatal HIV acquisition.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection xi

Members of the HHS Panel on Antiretroviral Therapy
and Medical Management of Children Living With HIV
Updated: April 11, 2023
Reviewed: April 11, 2023

Panel Executive Secretary

Rohan Hazra, MD National Institutes of Health, Bethesda, MD

Panel Co-Chairs
Ann J. Melvin, MD, MPH Seattle Children’s Hospital, University of Washington, Seattle, WA

Mary E. Paul, MD Baylor College of Medicine, Houston, TX

Theodore D. Ruel, MD University of California, San Francisco, San Francisco, CA

Members of the Panel

Elaine J. Abrams, MD Columbia University, New York, NY

Lisa Abuogi, MS, MD University of Colorado Denver, Denver, CO

Ben Banks, MPH, BSW Ashland, VA

Kristina M. Brooks, PharmD University of Colorado Anschutz Medical Campus, Aurora, CO

Megan Brundrett, MD, MPH, FACP, FAAP The Ohio State University College of Medicine, Columbus, OH

Ellen G. Chadwick, MD Feinberg School of Medicine, Northwestern University, Chicago, IL

Rana Chakraborty, MD, MS, PhD Mayo Clinic College of Medicine, Rochester, MN

Diana F. Clarke, PharmD Boston Medical Center, Boston, MA

Patricia M. Flynn, MD St. Jude Children’s Research Hospital, Memphis, TN

Alka Khaitan, MD Indiana University School of Medicine, Indianapolis, IN

Linda Lewis, MD Clinton Health Access Initiative, Bethesda, MD

James B. McAuley, MD, MPH, DTM&H Rush University Medical Center, Chicago, IL

Lynne M. Mofenson, MD Elizabeth Glaser Pediatric AIDS Foundation, Washington, DC

Jeremiah Momper, PharmD, PhD Skaggs School of Pharmacy and Pharmaceutical Sciences, University of
California, San Diego, La Jolla, California

Mark Mirochnick, MD Boston University Chobanian & Avedisian School of Medicine, Boston, MA

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection xii
 Anne Neilan, MD, MPH Harvard Medical School, Boston, MA

Kathleen (Kate) Powis, MD, MPH, MBA Massachusetts General Hospital, Boston, MA

Murli Purswani, MD BronxCare Health Systems, Bronx, NY

Natella Rakhmanina, MD, PhD Children’s National Medical Center, Washington, DC

Leslie Raneri, MSSW, MPH, LCSW Texas Children’s Hospital West Campus, Houston, TX

George K. Siberry, MD, MPH United States Agency for International Development, Washington, DC

Summer Drake, DO Los Angeles, CA

Richard M. Rutstein, MD Children’s Hospital of Philadelphia, Philadelphia, PA

Geoffrey A. Weinberg, MD University of Rochester School of Medicine and Dentistry, Rochester, NY

Members From the U.S. Department of Health and Human Services

Yodit Belew, MD U.S. Food and Drug Administration, Silver Spring, MD

Mindy Golatt, MPH, MA, RN, CPNP Health Resources and Services Administration, Rockville, MD

Patrick Jean-Philippe, MD National Institutes of Health, Bethesda, MD

Steve Nesheim, MD Centers for Disease Control and Prevention, Atlanta, GA

Mary Tanner, MD, FAAP Centers for Disease Control and Prevention, Atlanta, GA

Franklin Yates, MD National Institutes of Health, Bethesda, MD

Dwight Yin, MD, MPH National Institutes of Health, Bethesda, MD

Non-Voting Observers
Adam Bartlett, MBBS, MPHTM, PhD Sydney Children’s Hospital, Randwick, NSW, Australia Australasian Society
for HIV, Viral Hepatitis, and Sexual Health Medicine

Jason Brophy, MD, MSc, DTM&H Children’s Hospital of Eastern Ontario, Ottawa, ON

Deborah Storm, MSN, PhD Fairfield, CA. Formerly, François-Xavier Bagnoud Center, Rutgers School of
Nursing, Rutgers, The State University of New Jersey, Newark, NJ

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection xiii
HHS Panel on Antiretroviral Therapy and
Medical Management of Children Living With HIV
Financial Disclosure
Updated: April 11, 2023
Reviewed: April 11, 2023

Name Panel Status Company Relationship

Abrams, Elaine J. M Merck Data Monitoring Committee

Abuogi, Lisa M Gilead Sciences Research Support

Banks, Ben M None N/A

Bartlett, Adam NVO Gilead Sciences Research Support

Belew, Yodit M None N/A

Brooks, Kristina M. M None N/A

Brophy, Jason NVO Abbott Laboratories Research Support

Brundrett, Megan M None N/A

Chadwick, Ellen G. M AbbVie/Abbott Laboratories Stockholder

Chakraborty, Rana M None N/A

Clarke, Diana F. M 1. ViiV Healthcare 1. Research Support

2. Gilead Sciences 2. Research Support

Drake, Summer M None N/A

Flynn, Patricia M. M 1. Merck 1. Safety Monitoring Committee

2. Janssen 2. Research Support

Golatt, Mindy HHS None N/A

Hazra, Rohan ES None N/A

Khaitan, Alka M None N/A

Jean-Philippe, Patrick HHS None N/A

Lewis, Linda M None N/A

McAuley, James B. M None N/A

Melvin, Ann J. CC Merck Research Support

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection xiv
 Name Panel Status Company Relationship
Mirochnick, Mark M 1. Merck 1. Research Support
2. ViiV Healthcare 2. Research Support
3. Gilead Sciences 3. Research Support
4. AstraZeneca 4. DSMB
5. Merck 5. Consultant

Mofenson, Lynne M. M ViiV Healthcare Research Support

Momper, Jeremiah M Gilead Sciences Research Support

Neilan, Anne M None N/A

Nesheim, Steve M None N/A

Paul, Mary E. CC None N/A

Powis, Kathleen (Kate) M None N/A

Purswani, Murli M None N/A

Rakhmanina, Natella M 1. Merck 1. Research Support

2. Gilead Sciences 2. Research Support

Raneri, Leslie M None N/A

Ruel, Theodore D. CC None N/A

Rutstein, Richard M. M None N/A

Siberry, George K. M None N/A

Storm, Deborah NVO 1. Eli Lilly and Company 1. Stockholder

2. Merck 2. Stockholder
3. Roche 3. Stockholder

Tanner, Mary M None N/A

Weinberg, Geoffrey A. M Merck Honoraria

Yates, Franklin M None N/A

Yin, Dwight M None N/A

Key: C = Chair; CC = Co-Chair; DSMB = Data Safety Monitoring Board; ES = Executive Secretary; HHS = Member From the
U.S. Department of Health and Human Services; M = Member; N/A = Not Applicable; NVO = Non-Voting Observer

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection xv

Introduction
Updated: April 11, 2023
Reviewed: April 11, 2023

The Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (Pediatric Guidelines)
address the diagnosis of HIV infection in infants and children and the use of antiretroviral
therapy (ART) in children with HIV, including adolescents with sexual maturity ratings (SMRs,
formerly Tanner staging) 1 to 3. Note that the Guidelines for the Use of Antiretroviral Agents in
Adults and Adolescents with HIV, developed by the Panel on Antiretroviral Guidelines for Adults
and Adolescents, are suitable for the care and management of adolescents in late puberty
(SMRs 4–5).

The Pediatric Guidelines also include recommendations for managing adverse events that are
associated with the use of antiretroviral (ARV) drugs in children and a detailed review of information
about the safety, efficacy, and pharmacokinetics (PKs) of ARV agents in children. The Department
of Health and Human Services (HHS) Panel on Antiretroviral Therapy and Medical Management of
Children Living with HIV (the Panel), a working group of the Office of AIDS Research Advisory
Council (OARAC), reviews new data on an ongoing basis and regularly updates the guidelines. The
guidelines are available on the Clinicalinfo website. These guidelines are developed for the United
States and may not be applicable in other countries. The World Health Organization provides
guidelines for resource-limited settings.

The Pediatric Guidelines and the Perinatal Guidelines contain some closely related content that can
overlap. To ensure that information is consistent across the guidelines and that users can easily find
the information they need, the Panels that publish these two sets of guidelines have developed a
process to jointly produce sections for shared content areas. The development of these sections is led
by a group composed of members from both Panels; the sections are discussed separately and voted
on by each full Panel. Jointly produced sections include—

• Maternal HIV Testing and Identification of Perinatal HIV Exposure

• Diagnosis of HIV Infection in Infants and Children
• Antiretroviral Management of Newborns with Perinatal HIV Exposure or HIV Infection
• Infant Feeding for Individuals with HIV in the United States

Since the guidelines were first developed in 1993 (with the support of the François-Xavier Bagnoud
Center, Rutgers, The State University of New Jersey), advances in medical management have
dramatically reduced both the number of new pediatric HIV infections and the morbidity and
mortality in children with HIV in the United States. The widespread use of ARV drugs in people
with HIV during pregnancy and the use of ARV prophylaxis in infants who have been exposed to
HIV have reduced the annual rate of perinatally acquired HIV infection1,2 from a peak of 43.1 per
100,000 births in 1992 to 1.0 per 100,000 births in 2020. Racial and ethnic disparities are evident in
annual rates of new perinatal infection; in 2020, perinatal infections occurred in Black or African
American infants (3.8 per 100,000 births) at annual rates of 4 and 13 times those of Hispanic/Latinx
(0.9 per 100,000 births) and White infants (0.3 per 100,000 births), respectively.1 Since the
introduction of ART, mortality in children with perinatal HIV infection has decreased by about 90%,
and the incidence of opportunistic infections and other infections in these children has significantly
declined.3,4 ARV drug-resistance testing has made it easier for clinicians to choose effective initial
and subsequent regimens. Treatment strategies focus on early initiation of potent ARV regimens that

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A-1
are capable of maximally suppressing viral replication, which can prevent disease progression,
preserve or restore immunologic function, reduce the size of viral reservoirs, and prevent the
development of drug resistance.5,6 In addition, the availability of new drugs and drug formulations
has led to more potent regimens with lower toxicity, lower pill burden, and less frequent medication
administration—all factors that can improve adherence and outcomes. However, delays in the
development and testing of pediatric formulations continue to limit the availability of optimal ARV
regimens for children, especially infants.7

Children with HIV in the United States are increasingly born outside the United States8; they may be
members of immigrant families or they may have been adopted by U.S. residents. These children
may have non-B subtypes of HIV, incomplete medical and treatment histories, an increased risk of
tuberculosis and other infections that are endemic in their countries of origin, and legal and
psychosocial needs related to immigration.9,10

Finally, as children with HIV grow older, new challenges arise related to adherence, drug resistance,
reproductive health planning, transition to adult medical care, and the potential for long-term
complications from HIV and its treatments.11-13

The pathogenesis of HIV infection and the virologic and immunologic principles underlying the use
of ART are generally similar for all individuals with HIV. However, unique considerations exist for
infants, children, and adolescents with HIV, including—

• Acquisition of infection through perinatal exposure for most children with HIV;
• In utero and neonatal exposure to ARV drugs in most children with perinatal HIV infection14;
• The need to use HIV virologic tests to diagnose perinatal HIV infection in infants younger than
18 months;
• Age-specific interpretations of CD4 T lymphocyte (CD4) cell counts;
• Higher plasma viral loads in infants with perinatal HIV infection than in adolescents and adults
with non-perinatal HIV infection;
• Age-related changes in PK parameters that are caused by the continuing development and
maturation of organ systems involved in drug absorption, distribution, metabolism, and
clearance15;
• Differences in the clinical manifestations and treatment of HIV in growing, immunologically
immature individuals; and
• Special considerations associated with adherence to ARV treatment in infants, children, and
adolescents.

The care of children with HIV is complex and evolves as results of new research are reported, new
ARV drugs are approved, and new approaches to treatment are recommended. As new drugs become
available, a critical need exists for clinical trials that define appropriate drug doses and identify
possible toxicities in infants, children, and adolescents. As additional ARV drugs are approved and
optimal strategies for the use of these drugs in children become better understood, the Panel will
modify these guidelines.

The recommendations in these guidelines are based on the current state of knowledge regarding the
use of ARV drugs in children. Evidence is drawn primarily from published data regarding the
treatment of HIV in infants, children, adolescents, and adults; however, when no such data are
available, unpublished data and the clinical expertise of the Panel members are also considered.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A-2
These guidelines are only a starting point for medical decision-making and are not meant to
supersede the judgment of clinicians who are experienced in the care of children with HIV. Because
of the complexity of caring for children with HIV, health care providers with limited experience in
the care of these patients should consult a pediatric HIV specialist. The HIV/AIDS Management
Clinician Consultation Center is an excellent resource for telephone consultation. The Center can be
contacted at 1-800-933-3413, 9 a.m. to 8 p.m. ET, Monday through Friday.

Table 1. Outline of the Guidelines Development Process

Topic Comment
Goal of the Guidelines The guidelines provide guidance to HIV care practitioners in the United States on the
optimal use of antiretroviral (ARV) agents when treating infants, children, and
adolescents in early to mid-puberty (sexual maturity rating [SMR] 1–3) with HIV.
Panel Members The Panel on Antiretroviral Therapy and Medical Management of Children Living With
HIV (the Panel) is composed of approximately 30 voting members who have expertise
in the management of HIV infection in infants, children, and adolescents. Members
include representatives from the Committee on Pediatric AIDS of the American
Academy of Pediatrics and community representatives with knowledge of pediatric HIV
infection (e.g., parents and caregivers of children and youth with HIV). The Panel also
includes at least one representative from each of the following Department of Health
and Human Services (HHS) agencies: the Centers for Disease Control and
Prevention, the U.S. Food and Drug Administration (FDA), the Health Resources and
Services Administration (HRSA), and the National Institutes of Health (NIH). A
representative from the Canadian Paediatric and Perinatal HIV/AIDS Research Group
and a representative from the Australasian Society for HIV, Viral Hepatitis, and Sexual
Health Medicine participate as nonvoting, ex officio members of the Panel. The U.S.
government representatives are appointed by their respective agencies;
nongovernmental members are selected after an open announcement to call for
nominations. Each member serves on the Panel for a 3-year term with an option for
reappointment. A list of current members can be found in the Guidelines Panel
Members.
Financial Disclosure All members of the Panel submit an annual financial disclosure statement in writing,
reporting any association with manufacturers of ARV drugs or diagnostics used to
manage HIV infections. A list of the latest disclosures is available on the Clinicalinfo
website.
Users of the Guidelines Providers of care to infants, children, and adolescents with HIV in the United States
Developer Panel on Antiretroviral Therapy and Medical Management of Children Living with
HIV—a working group of the Office of AIDS Research Advisory Council (OARAC)
Funding Source NIH Office of AIDS Research and HRSA
Evidence Collection A standardized review of recent, relevant literature related to each section of the
guidelines is performed by a technical assistance consultant (through funding from
HRSA) and provided to individual Panel working groups. The recommendations
generally are based on studies published in peer-reviewed journals. The Panel may
occasionally use unpublished data to revise the guidelines, particularly when the new
information relates to dosing or patient safety. These data come from presentations at
major conferences or from the FDA and/or drug manufacturers.
Recommendation Grading Described in Table 2

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A-3
 Topic Comment
Method of Synthesizing Data Each section of the guidelines is assigned to a small group of Panel members with
expertise in the area of interest. The members synthesize the available data and
propose recommendations to the Panel. The Panel discusses all proposals during
monthly teleconferences. Proposals are modified based on Panel discussion and then
distributed with ballots to all Panel members for concurrence and additional
comments. If there are substantive comments or votes against approval, the
recommended changes and areas of disagreement are brought back to the full Panel
(by email or teleconference) for additional review, discussion, and further modification
to reach a final version that is acceptable to all Panel members. The recommendations
in these final versions represent endorsement from a consensus of members and are
included in the guidelines as official Panel recommendations.
Other Guidelines These guidelines focus on infants, children, and adolescents in early to mid-puberty
(SMR 1–3) with HIV. Guidelines for the treatment of adolescents in late puberty (SMR
4–5) are provided by the Panel on Antiretroviral Guidelines for Adults and
Adolescents.
Separate guidelines outline the use of antiretroviral therapy (ART) during pregnancy
and interventions to reduce perinatal HIV transmission, including maternal and infant
interventions to prevent perinatal transmission (the Perinatal Guidelines); ART for
nonpregnant adults and postpubertal adolescents with HIV; and ARV prophylaxis for
those who experience occupational or nonoccupational exposure to HIV. These and
other HIV guidelines are also available on the Clinicalinfo website.
Update Plan The full Panel meets monthly by teleconference to review data that may warrant
modification of the guidelines. Smaller working groups of Panel members hold
additional teleconferences to review individual drug sections or other specific topics
(e.g., What to Start: Initial Combination Antiretroviral Regimens for People with HIV).
Updates may be prompted by new drug approvals (or new indications, formulations, or
frequency of dosing), new safety or efficacy data, or other information that may have a
significant impact on the clinical care of patients. In the event of significant new data
that may affect patient safety, the Panel may issue a warning announcement and post
accompanying recommendations on the Clinicalinfo website until the guidelines can be
updated with appropriate changes. All sections of the guidelines are reviewed at least
once a year, with updates as appropriate.
Public Comments A 2-week public comment period follows the release of the updated guidelines on the
Clinicalinfo website. The Panel reviews these comments to determine whether
additional revisions to the guidelines are indicated. The public may also submit
comments to the Panel at any time via the Contact Us webpage.

Basis for Recommendations

Recommendations in these guidelines are based on scientific evidence and expert opinion. Each
recommendation includes a letter (A, B, or C) that represents the strength of the recommendation and
a Roman numeral (I, II, or III) that represents the quality of the evidence that supports the
recommendation.

When approving drugs for use in children, the U.S. Food and Drug Administration (FDA) often
extrapolates efficacy data from adult trials, in addition to using safety and PK data from studies in
children.16 Because of this, recommendations for use of ARV drugs in children often rely, in part, on
data from clinical trials or studies in adults. Because the course of HIV disease and the effects of
ARV drugs in pediatric and adult populations are expected to be similar enough to permit
extrapolation of adult efficacy data to pediatric patients, it is appropriate to base approval of ARV
drugs for children on evidence from adequate and well-controlled investigations in adults if—

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A-4
• Supplemental data exist on the PKs of the drug in children, indicating that systemic exposure in
adults and children is similar; and
• Studies are provided that support the safety of using the drug in pediatric patients.17-19

If a concern exists that concentration–response relationships might be different in children than in

adults, then pediatric drug approval should include evidence from studies that relate drug activity to
drug levels (pharmacodynamic data) in children. In many cases, the evidence from studies on the use
of ARV drugs in adults (especially from randomized clinical trials) is much more substantial and
higher in quality than the available evidence from studies in children. Therefore, for pediatric
recommendations, the following rationale has been used when the evidence from studies in children
is limited or of lower quality:

Quality of Evidence Rating IRandomized Clinical Trial Data

• Quality of Evidence Rating I will be used if there are data from large randomized trials in
children with clinical and/or validated laboratory endpoints.
• Quality of Evidence Rating I* will be used if there are high-quality randomized clinical trial data
in adults with clinical and/or validated laboratory endpoints and pediatric data from well-
designed, nonrandomized trials or observational cohort studies with clinical outcomes that are
consistent with the adult studies. A rating of I* may be used for quality of evidence if, for
example, a randomized Phase 3 clinical trial in adults demonstrates that a drug is effective in
ARV-naive patients, and data from a nonrandomized pediatric trial demonstrate adequate and
consistent safety and PK data in the pediatric population.

Quality of Evidence Rating IINonrandomized Clinical Trials or Observational

Cohort Data
• Quality of Evidence Rating II will be used if there are data from well-designed, nonrandomized
trials or observational cohorts in children.
• Quality of Evidence Rating II* will be used if there are well-designed, nonrandomized trials or
observational cohort studies in adults with supporting and consistent information from smaller,
nonrandomized trials or cohort studies with clinical outcome data in children. A rating of II* may
be used for quality of evidence if, for example, a large observational study in adults demonstrates
a clinical benefit to initiating treatment at a certain CD4 cell count, and data from smaller
observational studies in children indicate that treatment initiation at a similar CD4 cell count is
associated with clinical benefit.

Quality of Evidence Rating IIIExpert Opinion

• The criteria do not differ for adults and children.

In an effort to improve the quality of evidence available to guide the management of HIV infection in
children, clinicians are encouraged to discuss participation in trials with children and their caregivers.
Information about clinical trials for adults and children with HIV can be obtained from the
Clinicalinfo website or by telephone at 1-800-448-0440.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A-5
Table 2. Rating Scheme for Recommendations

Strength of Recommendation Quality of Evidence for Recommendation

A: Strong recommendation for the I: One or more randomized trials in childrena with clinical outcomes and/or
statement validated laboratory endpoints
B: Moderate recommendation for I*: One or more randomized trials in adults with clinical outcomes and/or validated
the statement laboratory endpoints, plus accompanying data in childrena from one or more well-
designed, nonrandomized trials or observational cohort studies with clinical
C: Optional recommendation for the
outcomes
statement
II: One or more well-designed, nonrandomized trials or observational cohort studies
in childrena with clinical outcomes
II*: One or more well-designed, nonrandomized trials or observational cohort studies
in adults with clinical outcomes, plus accompanying data in childrena from one
or more smaller nonrandomized trials or cohort studies with clinical outcome data
III: Expert opinion
aThese are studies that include children or children and adolescents, but not studies that are limited to postpubertal
adolescents.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A-6
References

1. Centers for Disease Control and Prevention. Monitoring selected national HIV prevention
and care objectives by using HIV surveillance data united states and 6 dependent areas, 2019.
2021. Available at: https://www.cdc.gov/hiv/library/reports/hiv-surveillance/vol-26-no-
2/index.html.

2. Nesheim SR, Wiener J, Fitz Harris LF, Lampe MA, Weidle PJ. Brief report: estimated
incidence of perinatally acquired HIV infection in the United States, 1978–2013. J Acquir
Immune Defic Syndr. 2017;76(5):461-464. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28991886.

3. Kapogiannis BG, Soe MM, Nesheim SR, et al. Mortality trends in the U.S. Perinatal
AIDS Collaborative Transmission Study (1986–2004). Clin Infect Dis. 2011;53(10):1024-1034.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22002982.

4. Mirani G, Williams PL, Chernoff M, et al. Changing trends in complications and

mortality rates among U.S. youth and young adults with HIV infection in the era of combination
antiretroviral therapy. Clin Infect Dis. 2015;61(12):1850-1861. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26270680.

5. Payne H, Chan MK, Watters SA, et al. Early ART-initiation and longer ART duration
reduces HIV-1 proviral DNA levels in children from the CHER trial. AIDS Res Ther.
2021;18(1):63. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34587974.

6. Garcia-Broncano P, Maddali S, Einkauf KB, et al. Early antiretroviral therapy in neonates

with HIV-1 infection restricts viral reservoir size and induces a distinct innate immune profile.
Sci Transl Med. 2019;11(520). Available at: https://www.ncbi.nlm.nih.gov/pubmed/31776292.

7. Penazzato M, Gnanashanmugam D, Rojo P, et al. Optimizing research to speed up

availability of pediatric antiretroviral drugs and formulations. Clin Infect Dis. 2017;64(11):1597-
1603. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29190337.

8. Nesheim SR, Linley L, Gray KM, et al. Country of birth of children with diagnosed HIV
infection in the United States, 2008–2014. J Acquir Immune Defic Syndr. 2018;77(1):23-30.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29040167.

9. Fair CD, Alger S. Prepared but unprepared: a qualitative study of provider perspectives
on the preparation and adjustment of U.S. families who internationally adopt children with HIV.
AIDS Care. 2021;33(10):1363-1367. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32741214.

10. Shetty AK. Infectious diseases among refugee children. Children (Basel). 2019;6(12).
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31783605.

11. Committee on Pediatric AIDS. Transitioning HIV-infected youth into adult health care.
Pediatrics. 2013;132(1):192-197. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23796739.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A-7
12. Cervia JS. Addressing the needs of youth with HIV infection in the era of combination
antiretroviral therapy. Clin Infect Dis. 2016;62(7):947. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26743091.

13. Flynn PM, Abrams EJ. Growing up with perinatal HIV. AIDS. 2019;33(4):597-603.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30531318.

14. Little KM, Taylor AW, Borkowf CB, et al. Perinatal antiretroviral exposure and
prevented mother-to-child HIV infections in the era of antiretroviral prophylaxis in the United
States, 1994–2010. Pediatr Infect Dis J. 2017;36(1):66-71. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27749662.

15. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE.
Developmental pharmacology-drug disposition, action, and therapy in infants and children. N
Engl J Med. 2003;349(12):1157-1167. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/13679531.

16. FDA-ICH Harmonized Guidelines. The International Council of Harmonisation of

Technical Requirements of Pharmaceuticals for Human Use overview. 2022. Available at:
https://www.fda.gov/media/165161/download.

17. Dunne J, Rodriguez WJ, Murphy MD, et al. Extrapolation of adult data and other data in
pediatric drug-development programs. Pediatrics. 2011;128(5):e1242-1249. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22025597.

18. Murphy D. Extrapolation of efficacy in the pediatric population. 2012.

19. E11(R1) addendum: clinical investigation of medicinal products in the pediatric

population guidance for industry [package insert]. Food and Drug Administration. 2018.
Available at:
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
UCM530012.pdf.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A-8
 Pregnancy and Postpartum HIV Testing and
Identification of Perinatal and Postnatal HIV
Exposure
Updated: January 31, 2024
Reviewed: January 31, 2024

Panel’s Recommendations
• HIV testing is recommended for all sexually active people and should be a routine component of pre-pregnancy care (AII).
• All pregnant people should receive opt-out HIV testing as early as possible during each pregnancy (see Laboratory Testing
for the Diagnosis of HIV Infection: Updated Recommendations and 2018 Quick Reference Guide: Recommended
Laboratory HIV Testing Algorithm for Serum or Plasma Specimens from the Centers for Disease Control and Prevention
[CDC]) (AII).
• Partners of all pregnant people should be referred for HIV testing when their status is unknown (AIII).
• Repeat HIV testing in the third trimester is recommended for pregnant people with negative initial HIV tests who are at
increased risk of acquiring HIV, including those receiving care in facilities that have an HIV incidence of ≥1 case per 1,000
pregnant people per year, those who reside in jurisdictions (states or counties) with elevated HIV incidence among females
aged 15 to 45 years (>17 per 100,000 females aged 15–45 years), or those who reside in states or territories that require
third-trimester testing (AII). Annual state and county-level HIV diagnosis rates are available at CDC’s National Center for
HIV, Viral Hepatitis, Sexually Transmitted Diseases, and Tuberculosis Prevention AtlasPlus webpage.
• Repeat HIV testing is recommended for pregnant people with a sexually transmitted infection, with signs and symptoms of
acute HIV infection, or with ongoing exposure to HIV (AIII). Initiation of pre-exposure prophylaxis (PrEP) is recommended if
HIV testing is negative (AIII). See Pre-Exposure Prophylaxis (PrEP) to Prevent HIV During Periconception, Antepartum,
and Postpartum Periods for more information.
• Expediteda HIV testing should be performed during labor or after delivery for people with undocumented HIV status and for
those who tested negative early in pregnancy but are at increased risk of HIV infection and were not retested in the third
trimester (AII). HIV antigen/antibody testing should be available 24 hours a day, and results should be available within
1 hour. If results of expediteda HIV testing are positive, intrapartum intravenous zidovudine prophylaxis should be initiated
immediately (AI); see Intrapartum Care for People with HIV.
• When acute HIV infection is suspected during pregnancy or the intrapartum period or while breastfeeding, a plasma HIV
RNA assay should be performed in conjunction with an antigen/antibody immunoassay (AIII).
• When a person has a positive HIV test result during labor and delivery or postpartum, an HIV-1/HIV-2 antibody
differentiation assay and an HIV RNA assay should be performed on the birthing parent (AI). In these situations, an HIV
nucleic acid test (NAT) should be performed on the infant, with immediate initiation of presumptive HIV therapy appropriate
for an infant at high risk of perinatal HIV transmission (AI); see Diagnosis of HIV Infection in Infants and Children for
additional information.
• If HIV test results of the birthing parent are unavailable at birth, the newborn should be tested using an expediteda antibody
test to identify perinatal HIV exposure (AI). If positive, an HIV NAT should be performed on the infant, and the birthing
parent should be offered standard HIV diagnostic testing as soon as possible (AI).
o In this situation, presumptive HIV therapy appropriate for infants who are at high risk of perinatal HIV transmission
should be initiated immediately (AI). See Antiretroviral Management of Newborns with Perinatal HIV Exposure or HIV
Infection for guidance.
o For people with an initial positive HIV test during labor or delivery or immediately postpartum who were planning to
breastfeed, the Panel recommends against breastfeeding. Breast milk should be expressed and stored appropriately
until all supplemental HIV tests are reviewed and are negative (AI).
• For postpartum people at increased risk of HIV acquisition, HIV testing and PrEP should be offered. If the parent is
breastfeeding, consult an HIV specialist regarding frequency of HIV testing for the breastfeeding parent and/or infant (AIII).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-1
 • HIV test results of the birthing parent should be documented in the newborn’s medical record and communicated to the
newborn’s primary care provider (AIII).
• To identify perinatal HIV exposure and possible HIV infection, HIV testing is recommended for infants and children in foster
care and adoptees for whom the HIV status of the birthing parent is unknown (AIII) (see Diagnosis of HIV Infection in
Infants and Children).
a The term “expedited” is used to designate HIV testing performed in situations when a very short turnaround time is
optimal. Expedited testing is dependent on the available HIV tests in each facility and may include antigen/antibody
immunoassays or antibody-only assays; see Approved HIV Tests in the text below.

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints;
I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying
data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical
outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term
outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical
outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical
outcome data; III = Expert opinion
†Studies that include children or children and adolescents, but not studies limited to postpubertal adolescents

Overview
Incident HIV infection during pregnancy or postpartum among people who are breastfeeding
represents a period of high viremia and significantly increased risk of infant HIV acquisition.
Similarly, entering pregnancy without knowledge of HIV infection also presents a high risk of
perinatal transmission. This section addresses HIV testing in pregnancy, during labor and delivery,
and postpartum. The section also addresses HIV testing to identify HIV perinatal and postnatal
exposure in infants. For guidance on diagnosis of HIV in infants and children, see Diagnosis of HIV
in Infants and Children.

Approved HIV Tests and Recommended HIV Testing Algorithm

There are multiple U.S. Food and Drug Administration (FDA)–approved tests available for the
diagnosis of HIV infection. Clinicians should familiarize themselves with the testing available at
their facilities, including the turnaround time for receiving results and test performance
characteristics (e.g. sensitivity, specificity). For the purposes of this section, three types of testing are
discussed: antigen/antibody immunoassays; antibody-only immunoassays; and HIV nucleic acid tests
(NATs).

• Antigen/antibody immunoassays: Most routine laboratory testing for HIV currently uses
antigen/antibody tests. Because these tests also detect HIV p24 antigen, they can detect acute
HIV infection as early as 1 to 2 weeks after appearance of HIV RNA and before appearance of
HIV antibody. These tests also detect HIV-2 infection. Laboratory-based tests require trained
laboratory staff, and results can be available within 1 hour, but in some hospitals the test may not
be readily available 24 hours a day. One FDA-approved antigen/antibody test can be performed
at the point of care (POC), provides results after 20 minutes, and must be read before
30 minutes. Using timed seroconversion panels, this POC antigen/antibody test has been shown
to detect HIV infection just 1 day later than laboratory-based antigen/antibody tests. However, it
has lower specificity than laboratory-based antigen/antibody tests; therefore, false positive results
are more likely than with laboratory-based tests.1

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-2
• Antibody-only immunoassays: Many antibody-only immunoassays in current use can be
performed using blood from a finger stick or oral fluid and provide results within 30 minutes.
Because of this very short turnaround time, they are often referred to as rapid tests. Many of these
tests are also approved by the FDA for POC usage. Because these tests detect only antibody,
acute HIV infection may be missed.
• HIV NAT: HIV-1 NAT detects HIV viral nucleic acid in blood. Depending on the type of HIV
NAT, it may detect acute HIV infection, help diagnose HIV infection, and assess response to
HIV therapy. The HIV RNA assay is the preferred NAT for possible acute infection and
perinatally acquired infection. Different laboratories may have varying turnaround times for HIV
NAT; some require several days before results are available.

• In this section, the term expedited is used to designate testing performed in situations when a
very short turnaround time is optimal, such as when the individual is in labor but HIV status is
undocumented. Expedited testing should be available in all delivery units 24 hours a day, and
results should be available within 1 hour. Expedited testing is dependent on the available HIV
tests in each facility and may include any of the three test types. In a setting with low HIV
prevalence and/or frequent testing, false positive initial test results will be common. Expedited
and/or concurrent NAT can be helpful in managing an initial positive HIV test result. An
HIV-1/HIV-2 antibody differentiation assay may be helpful if an antibody response has been
mounted.

The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV and the
Panel on Treatment of HIV During Pregnancy and Interventions to Reduce Perinatal HIV
Transmission (the Panels) recommend that clinicians initiate HIV testing with an immunoassay
that can detect HIV-1 antibodies, HIV-2 antibodies, and HIV-1 p24 antigen (referred to as an
HIV antigen/antibody immunoassay). The Panels’ recommendations for HIV testing are based on
the Centers for Disease Control and Prevention’s (CDC’s) 2014 Laboratory Testing for the Diagnosis
of HIV Infection: Updated Recommendations.2

Individuals with a reactive antigen/antibody immunoassay should be tested further with an

HIV-1/HIV-2 antibody differentiation assay (referred to as supplemental testing). Individuals
with a reactive antigen/antibody immunoassay and a nonreactive differentiation test should be tested
with an FDA-approved plasma HIV RNA assay to assess for acute HIV infection (see the CDC’s
2018 Quick Reference Guide: Recommended Laboratory HIV Testing Algorithm for Serum or
Plasma Specimens).

In some clinical settings, initial testing may be conducted with a rapid HIV test, which may detect a
combination of antigen and antibodies or only HIV antibodies. Positive results on POC rapid tests
should be followed first by a laboratory-based antigen/antibody assay using serum or plasma and
when reactive, followed by a differentiation assay.3

Clinicians should assess a pregnant person’s risk of acute HIV infection, particularly late in
pregnancy, because people may receive a negative result for HIV immunoassays when they are in the
window period (the time between infection and when the infection can be detected by a specific
laboratory test). The antigen/antibody immunoassay may detect infection as early as 18 days after
infection; antibody-only assays may not detect infection until as long as 45 days post-infection.
However, during this period, the person with acute HIV will be viremic,4 with a high risk of perinatal
transmission. The HIV RNA assay can detect the presence of HIV as early as 10 days post-infection.
When acute HIV infection is suspected during pregnancy, during the intrapartum period, or while
breastfeeding, a plasma HIV RNA assay should be performed in conjunction with an
antigen/antibody immunoassay. See Early (Acute and Recent) HIV Infection for more information.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-3
Discordant or False Positive HIV Tests
Discordant HIV testing results can occur, requiring careful evaluation and often repeat tests. Early in
HIV infection, before HIV seroconversion, the test combination of a positive antigen/antibody
screen, negative HIV-1/HIV-2 antibody differentiation assay, and positive HIV RNA assay may be
seen. This combination of results can occur because the immunoglobulin G–based antibody
differentiation assay is positive later in infection than the antigen capture or the immunoglobulin M
result in the antigen/antibody screen.

False positive results do occur with HIV testing. The frequency of false positive HIV testing is
dependent both on the specificity of the assay and the prevalence of HIV in the population, so
frequency may vary considerably. In a large urban hospital in Dallas, 21,163 women were screened
using a combination antigen/antibody immunoassay. Reactive initial screens were followed by
supplemental testing recommended by the CDC algorithm. Of the 190 who tested positive, 28 were
determined to have a false positive HIV test, yielding a positive predictive value of 83% (95%
confidence interval [CI], 77% to 88%) and a false positive rate of 0.16% (95% CI, 0.11% to 0.22%),
using the ARCHITECT HIV Ag/Ab assay.5 For women screened a second time in pregnancy, the
rate of false positive results relative to true positive results may be higher, as it depends on the
community risk of HIV acquisition over a short time period (i.e., the 6 months between first- and
third-trimester testing).

For any positive HIV screen late in pregnancy, during labor, or immediately postpartum, an HIV
RNA assay should be done at the same time as the supplemental HIV-1/HIV-2 antibody
differentiation assay. The HIV RNA assay will be needed to resolve questions raised by discordant
results between the antigen/antibody screen and the antibody differentiation assay.

The combination of a positive HIV antigen/antibody screen with a negative supplemental

HIV-1/HIV-2 antibody differentiation assay and a negative HIV RNA assay is seen in people without
HIV who have a false positive antigen/antibody screen.

Timing and Benefits of HIV Testing Prior to Conception or During Pregnancy

HIV infection should be identified before pregnancy (see Prepregnancy Counseling and Care for
Persons of Childbearing Age with HIV) or as early as possible in pregnancy. In the United States,
approximately 20% to 34% of infants with perinatal HIV exposure were born to people whose HIV
diagnosis was not known before pregnancy.6 Early diagnosis provides the best opportunity to
improve the pregnant person’s health and pregnancy outcomes and to prevent infant acquisition of
HIV. Universal voluntary HIV testing is recommended as the standard of care for all pregnant people
in the United States by the Panels, CDC, American Academy of Pediatrics, American College of
Obstetricians and Gynecologists, and U.S. Preventive Services Task Force.7-11 For pregnant people,
HIV testing should be performed wherever a person seeks care (including emergency departments
and prenatal clinics) to avoid missed opportunities to identify HIV infection. Repeat HIV testing
should be performed in the third trimester for people who are at increased risk of acquiring HIV or
who are living in areas of high HIV incidence. Repeat testing is also recommended when pregnant
individuals are diagnosed with sexually transmitted infection (STI), or when they show symptoms
and signs of acute HIV infection. Pregnant people with unknown or undocumented HIV status who
present to care in labor should be tested before delivery or as soon as possible after delivery.12-15
Because women are more susceptible to HIV acquisition during pregnancy and the postpartum
period,16 HIV testing provides an opportunity for clinicians to initiate a discussion about preventive
interventions, including educating and counseling about pre-exposure prophylaxis (PrEP) for a
pregnant person who is at risk for acquiring HIV. See Pre-exposure Prophylaxis (PrEP) to Prevent

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-4
HIV During Periconception, Antepartum, and Postpartum Periods and guidance available on CDC’s
Pre-exposure Prophylaxis (PrEP) page for more information.

Determining an individual’s HIV status before they become pregnant or during the antenatal period
enables:

• People with HIV to receive appropriate antiretroviral therapy (ART) and prophylaxis against
opportunistic infections;
• Initiation of treatment to maintain and improve health and to decrease risk of perinatal HIV
transmission and transmission to partners7,17,18;
• Referral of partners for testing, providing an opportunity for treatment initiation by partners
testing positive, PrEP initiation by serodifferent partners testing negative, and counseling on
other preventive measures (see Pre-exposure Prophylaxis (PrEP) to Prevent HIV During
Periconception, Antepartum, and Postpartum Periods);
• Counseling of pregnant people with HIV about recommended modes of delivery based on
individualized risks of perinatal transmission of HIV19-21;
• Provision of an appropriate antiretroviral (ARV) prophylaxis regimen to the newborn to reduce
risk of infant HIV acquisition (see Antiretroviral Management of Newborns with Perinatal HIV
Exposure or HIV Infection);
• Shared decision-making on infant feeding choice, specifically breastfeeding or use of
replacement feeding (see Infant Feeding for Individuals with HIV in the United States); and
• Early diagnostic evaluation of infants exposed to HIV, as well as testing of other children, to
permit prompt initiation of ART and any indicated prophylaxis measures (see Diagnosis of HIV
Infection in Infants and Children, Antiretroviral Management of Newborns with Perinatal HIV
Exposure or HIV Infection, and Table 6. What to Start: Initial Antiretroviral Regimens During
Pregnancy for People Who Are Antiretroviral-Naive).8,22,23
Finally, all HIV testing should be performed in a manner that is consistent with state and local
regulations. The CDC recommends the “opt-out” approach, which is allowed in many jurisdictions
and involves notifying a pregnant person that HIV testing will be performed as part of routine care
unless they choose not to be tested.7 The “opt-in” approach involves obtaining specific consent
before testing, and this approach has been associated with lower testing rates.24,25 Despite the
guidelines for universal HIV screening of pregnant people, recent studies indicate that fewer than
80% of women report having been tested for HIV during pregnancy.26,27 The mandatory newborn
HIV testing approach, which has been adopted by several states, involves testing newborns with or
without consent of the birthing parent. In some areas, this applies to all newborns; in others, it applies
only when the birthing parent of the newborn has declined prenatal or intrapartum testing.

Repeat HIV Testing in the Third Trimester

Repeat HIV testing during the third trimester, before 36 weeks of gestation, is recommended for
people with negative results on their initial HIV tests during pregnancy who:

• Are at high risk of acquiring HIV (i.e., those who inject drugs or have sex with people who inject
drugs, those who exchange sex for money or drugs, those who have a sex partner with HIV who
has a detectable or unknown HIV viral load, those who have had a new sex partner or more than
one sex partner during the current pregnancy,7 those who have a suspected or diagnosed STI
during pregnancy,10 those who have recently immigrated from a high-burden HIV setting, or

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-5
 those who have a partner who either recently immigrated from a high-burden HIV setting or
recently traveled to such a setting); or
• Are receiving health care in facilities where prenatal screening identifies one or more pregnant
people with HIV per 1,000 screened or reside in a jurisdiction (state or county) that has an
elevated incidence rate of HIV in females aged of 15 to 45 years. An annual HIV diagnosis rate
≥17 per 100,000 females aged 15 to 45 years can be used as a proxy for elevated HIV incidence.
Annual state- and county-level HIV diagnosis rates by age are available at the CDC’s National
Center for HIV, Viral Hepatitis, Sexually Transmitted Diseases, and Tuberculosis Prevention
AtlasPlus webpage7,10; or
• Reside in states or territories with statutes or regulations that require third-trimester testing. In a
2020 article, these included Arizona, Connecticut, Delaware, Florida, Georgia, Illinois,
Louisiana, Maryland, Nevada, New Jersey, North Carolina, Tennessee, Texas, Virginia, and
West Virginia.28 Clinicians should check current requirements in their jurisdictions; or
• Have signs or symptoms of acute HIV (e.g., fever, lymphadenopathy, skin rash, myalgia,
headaches, oral ulcers, leukopenia, thrombocytopenia, elevated transaminase levels).7,10,29,30

• In addition, third-trimester testing should be offered to pregnant people who perceive themselves
as being at increased risk for HIV infection (regardless of whether or not they fit any of the above
criteria). Pregnant people who decline testing earlier in pregnancy should be offered testing again
during the third trimester.
An antigen/antibody immunoassay should be used for third-trimester testing because these tests have
a higher sensitivity in the setting of acute HIV infection than older antibody tests.2,31 If acute HIV
infection is suspected, a plasma HIV RNA assay should be performed in conjunction with an
antigen/antibody immunoassay. See Early (Acute and Recent) HIV Infection for more information.

Providers should be proactive in assessing a pregnant person’s HIV acquisition risk and
implementing third-trimester HIV retesting when indicated. A study in Baltimore found that only
28% of women were retested for HIV despite the high incidence of HIV in Maryland and a high
frequency of clinical risk factors.15 A study of data from 2007 to 2014 on children in Florida with
perinatal HIV exposure found that perinatal HIV transmission was associated with poor or late
prenatal care, diagnosis of HIV during labor and delivery or after birth, and, in some cases, acute
maternal infection (as indicated by negative results for initial tests).32

HIV Testing During Labor in People with Unknown HIV Status

People in labor whose HIV status is undocumented and those who tested negative early in pregnancy
but are at increased risk of HIV infection and were not retested in the third trimester should undergo
expedited HIV testing.7-9,22,33,34

• Perform an expedited HIV test—either an antigen/antibody immunoassay that can provide results
within 1 hour or the most sensitive rapid test (includes rapid POC tests) available for people in
labor. An HIV RNA assay should also be performed for individuals with suspected acute HIV
infection. In a setting with low prevalence and/or frequent testing, false positive initial test results
will be common. Expedited and/or concurrent NATs can be helpful in managing an initial
positive HIV test result.35
• If the initial HIV test result is negative (nonreactive), no further testing is required unless acute
HIV infection is suspected (see Acute HIV Infection During Pregnancy or Breastfeeding below).2

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-6
• A positive antigen/antibody immunoassay or rapid HIV test result must be immediately followed
by a supplemental HIV-1/HIV-2 antibody differentiation assay, as well as an HIV RNA assay for
the birthing parent and an HIV NAT for the infant.2 If possible, contact the laboratory to
prioritize results.
• For delivery units, every effort should be made to have the ability to run a confirmatory
supplemental test (HIV-1/HIV-2 antibody differentiation assay) seven days a week. If possible,
results of HIV RNA assays should be available in 24 hours or less.
• For individuals with a positive HIV test result or suspected acute HIV infection during labor,
provide counseling about HIV test results and implications for care.
o Initiate IV zidovudine during labor (see Intrapartum Care for People with HIV).
o Immediately initiate presumptive HIV therapy appropriate for infants who are at high risk of
perinatal HIV transmission (see Antiretroviral Management of Newborns with Perinatal HIV
Exposure or HIV Infection or contact the National Clinician Consultation Center Perinatal
HIV/AIDS hotline).
o For individuals who were planning to breastfeed, the Panel strongly advises against initiating
breastfeeding given the high risk of perinatal transmission. Breast milk should be expressed
and stored appropriately until all supplemental HIV test results are reviewed and determined
to be negative (see Infant Feeding for Individuals with HIV in the United States).

HIV Testing During the Postpartum Period

People who have not been tested for HIV during pregnancy or labor should be offered expedited
testing during the immediate postpartum period. Postpartum HIV testing should be done using the
antigen/antibody immunoassay to screen for established and acute HIV; results should be obtained in
<1 hour. If acute HIV infection is a possibility, then a plasma HIV RNA test should be sent as well.
When the birthing parent is unavailable for testing, their newborn should receive HIV testing using
an antigen/antibody immunoassay to assess perinatal HIV exposure, understanding that the results
reflect the HIV status of the birthing parent. For infants testing positive, an HIV NAT should be sent
immediately (see Diagnosis of HIV Infection in Infants and Children).8,22

Postpartum individuals who request HIV testing or are at increased risk of HIV acquisition
(e.g., those who inject drugs or have sex with people who inject drugs, those who exchange sex for
money or drugs, those who have a sex partner with HIV who has a detectable or unknown HIV viral
load, those who have had a new sex partner or more than one sex partner during the current
pregnancy,7 those who have a suspected or diagnosed STI during pregnancy,10 those who have
recently immigrated from a high-burden HIV setting, or those who have a partner that either recently
immigrated from a high-burden HIV setting or recently traveled to such a setting) should be offered
HIV testing and PrEP. See Pre-exposure Prophylaxis (PrEP) to Prevent HIV During Periconception,
Antepartum, and Postpartum Periods for more information. If the parent is breastfeeding, consult an
HIV specialist regarding frequency of HIV testing in the birthing parent and/or infant.

When an initial HIV test is positive in birthing parents or infants, it is strongly recommended that
clinicians initiate presumptive HIV therapy appropriate for infants who are at high risk of perinatal
HIV transmission, ideally ≤6 hours after birth (see Antiretroviral Management of Newborns with
Perinatal HIV Exposure or Perinatal HIV). The birthing parent should be counseled against
breastfeeding pending the results of supplemental testing, which should include a plasma HIV RNA
assay. Breast milk can be expressed while HIV diagnostic testing is being completed, but it should
not be given to the infant until testing confirms that the birthing parent is HIV negative. If

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection

B-7
supplemental test results are negative and acute HIV is excluded, infant ARV drugs can be
discontinued. In the absence of ongoing HIV exposure in the birthing parent, breastfeeding can be
initiated. Consultation with a pediatric HIV specialist is strongly recommended if questions remain
about the potential for acute infection in the birthing parent or ongoing infant risk of HIV exposure.

Infant HIV Testing When the Birthing Parent’s HIV Test Results Are
Unavailable
When the birthing parent’s HIV test results are unavailable (e.g., they declined testing during
pregnancy, infant or child is in foster care) or their accuracy cannot be evaluated (e.g., for
internationally adopted infants and children), HIV testing of these infants or children is indicated to
identify HIV exposure and possible infection.8 If the birthing parent’s HIV test results are
unavailable at birth, the newborn should be tested using an expedited antibody test to identify
perinatal HIV exposure. If positive, an HIV NAT should be performed on the infant, presumptive
HIV therapy appropriate for infants at high risk for perinatal HIV transmission should be initiated
immediately (see Antiretroviral Management of Newborns with Perinatal HIV Exposure or HIV
Infection for guidance), and the birthing parent should be offered standard HIV diagnostic testing as
soon as possible. For older infants and children, the choice of test will vary based on the age of the
child (see Diagnosis of HIV Infection in Infants and Children).

Acute HIV Infection During Pregnancy or Breastfeeding

Pregnancy and the early postpartum period are times of increased risk for HIV infection.36 Risk of
HIV exposure should be assessed in all people who are considering becoming pregnant, as well as in
all pregnant and postpartum people who previously tested negative for HIV, including those who are
breastfeeding. People with risk factors for HIV acquisition before, during, and after pregnancy
should receive prevention counseling and appropriate interventions, including PrEP if indicated36,37
(see Prepregnancy Counseling and Care for Persons of Childbearing Age with HIV and Pre-Exposure
Prophylaxis [PrEP] to Prevent HIV During Periconception, Antepartum, and Postpartum Periods for
more information). People who have acute HIV during pregnancy or lactation have an increased risk
of perinatal transmission; acute HIV also increase risk for sexual transmission of HIV (see Early
[Acute and Recent] HIV Infection).38-42 The antigen/antibody immunoassay will detect acute HIV
infection earlier than other immunoassays—within approximately 18 days of acquisition. When acute
HIV infection is suspected, a plasma HIV RNA test should be sent as well as the antigen/antibody
test, because virologic tests can detect the presence of HIV approximately 5 days earlier than the
antigen/antibody immunoassay. People with possible acute HIV infection who are breastfeeding
should cease breastfeeding immediately until HIV infection is confirmed or excluded.43 Breast milk
can be expressed while HIV diagnostic testing is completed. Breastfeeding can resume if HIV
infection is excluded and there is no ongoing risk. Care of pregnant or breastfeeding people with
acute or early HIV, and their infants, should follow the recommendations in the Perinatal Guidelines
(see Early [Acute and Recent] HIV Infection, Antiretroviral Management of Newborns with Perinatal
HIV Exposure or HIV Infection, and Infant Feeding for Individuals with HIV in the United States).

Other Issues
Clinicians should be aware of public health surveillance systems and regulations that may exist in
their jurisdictions for reporting infants who have been exposed to HIV; this is in addition to
mandatory reporting of people with HIV, including infants. Reporting infants who have been
exposed to HIV allows the appropriate public health functions to be accomplished.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-8
References

1. Delaney KP, Hanson DL, Masciotra S, et al. Time until emergence of HIV test reactivity
following infection with HIV-1: implications for interpreting test results and retesting
after exposure. Clin Infect Dis. 2017;64(1):53-59. Available at:
https://pubmed.ncbi.nlm.nih.gov/27737954.

2. Branson BM, Owen SM, Wesolowski LG, et al. Laboratory testing for the diagnosis of
HIV infection: updated recommendations. 2014. Available at:
http://stacks.cdc.gov/view/cdc/23447.

3. Centers for Disease Control and Prevention. Technical update : Use of the Determine
HIV 1/2 Ag/Ab combo test with serum or plasma in the laboratory algorithm for HIV
diagnosis. 10/4/2017 2017.Available at: https://stacks.cdc.gov/view/cdc/48472.

4. Centers for Disease Control and Prevention and Association of Public Health
Laboratories. Laboratory testing for the diagnosis of HIV infection: updated
recommendations. June 27, 2014 2014.Available at:
http://dx.doi.org/10.15620/cdc.23447. Accessed.

5. Adhikari EH, Macias D, Gaffney D, et al. Diagnostic accuracy of fourth-generation

ARCHITECT HIV Ag/Ab Combo assay and utility of signal-to-cutoff ratio to predict
false-positive HIV tests in pregnancy. Am J Obstet Gynecol. 2018;219(4):408 e401-408
e409. Available at: https://pubmed.ncbi.nlm.nih.gov/29913173.

6. Nesheim SR, FitzHarris LF, Mahle Gray K, Lampe MA. Epidemiology of perinatal HIV
transmission in the United States in the era of its elimination. Pediatr Infect Dis J.
2019;38(6):611-616. Available at: https://pubmed.ncbi.nlm.nih.gov/30724833.

7. Branson BM, Handsfield HH, Lampe MA, et al. Revised recommendations for HIV
testing of adults, adolescents, and pregnant women in health-care settings. MMWR
Recomm Rep. 2006;55(RR-14):1-17; quiz CE11-14. Available at:
https://pubmed.ncbi.nlm.nih.gov/16988643.

8. Chadwick EG, Ezeanolue EE, Committee On Pediatric A. Evaluation and management of

the infant exposed to HIV in the United States. Pediatrics. 2020;146(5). Available at:
https://pubmed.ncbi.nlm.nih.gov/33077537.

9. Chou R, Cantor AG, Zakher B, Bougatsos C. Screening for HIV in pregnant women:
systematic review to update the 2005 U.S. Preventive Services Task Force
recommendation. Ann Intern Med. 2012;157(10):719-728. Available at:
https://pubmed.ncbi.nlm.nih.gov/23165663.

10. American College of Obstetricians Gynecologists, Committee on Obstetric Practice HIV

Expert Work Group. ACOG committee opinion no. 752: prenatal and perinatal human
immunodeficiency virus testing. Obstet Gynecol. 2018;132(3):e138-e142. Available at:
https://pubmed.ncbi.nlm.nih.gov/30134428.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-9
11. U.S. Preventive Services Task Force, Owens DK, Davidson KW, et al. Screening for
HIV infection: US preventive services task force recommendation statement. JAMA.
2019;321(23):2326-2336. Available at: https://pubmed.ncbi.nlm.nih.gov/31184701.

12. Whitmore SK, Taylor AW, Espinoza L, et al. Correlates of mother-to-child transmission
of HIV in the United States and Puerto Rico. Pediatrics. 2012;129(1):e74-81. Available
at: https://pubmed.ncbi.nlm.nih.gov/22144694.

13. Ezeanolue EE, Pharr JR, Hunt A, et al. Why are children still being infected with HIV?
Impact of an integrated public health and clinical practice intervention on mother-to-child
HIV transmission in Las Vegas, Nevada, 2007–2012. Ann Med Health Sci Res.
2015;5(4):253-259. Available at: https://pubmed.ncbi.nlm.nih.gov/26229713.

14. Taylor AW, Nesheim SR, Zhang X, et al. Estimated perinatal HIV infection among
infants born in the United States, 2002-2013. JAMA Pediatr. 2017;171(5):435-442.
Available at: https://pubmed.ncbi.nlm.nih.gov/28319246.

15. Liao C, Golden WC, Anderson JR, Coleman JS. Missed opportunities for repeat HIV
testing in pregnancy: implications for elimination of mother-to-child transmission in the
United States. AIDS Patient Care STDS. 2017;31(1):20-26. Available at:
https://pubmed.ncbi.nlm.nih.gov/27936863.

16. Thomson KA, Hughes J, Baeten JM, et al. Increased risk of HIV acquisition among
women throughout pregnancy and during the postpartum period: a prospective per-coital-
act analysis among women with HIV-infected partners. J Infect Dis. 2018;218(1):16-25.
Available at: https://pubmed.ncbi.nlm.nih.gov/29514254.

17. Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early
antiretroviral therapy. N Engl J Med. 2011;365(6):493-505. Available at:
https://pubmed.ncbi.nlm.nih.gov/21767103.

18. Baggaley RF, White RG, Hollingsworth TD, Boily MC. Heterosexual HIV-1
infectiousness and antiretroviral use: systematic review of prospective studies of
discordant couples. Epidemiology. 2013;24(1):110-121. Available at:
https://pubmed.ncbi.nlm.nih.gov/23222513.

19. Jamieson DJ, Read JS, Kourtis AP, et al. Cesarean delivery for HIV-infected women:
recommendations and controversies. Am J Obstet Gynecol. 2007;197(3 Suppl):S96-100.
Available at: https://pubmed.ncbi.nlm.nih.gov/17825656.

20. Tubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-to-child

transmission of HIV-1 despite a maternal viral load <500 copies/ml at delivery: a case-
control study nested in the French Perinatal Cohort (EPF-ANRS CO1). Clin Infect Dis.
2010;50(4):585-596. Available at: https://pubmed.ncbi.nlm.nih.gov/20070234.

21. Townsend CL, Cortina-Borja M, Peckham CS, et al. Low rates of mother-to-child
transmission of HIV following effective pregnancy interventions in the United Kingdom

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-10
 and Ireland, 2000–2006. AIDS. 2008;22(8):973-981. Available at:
https://pubmed.ncbi.nlm.nih.gov/18453857.

22. Havens PL, Mofenson LM, American Academy of Pediatrics Committee on Pediatric A.
Evaluation and management of the infant exposed to HIV-1 in the United States.
Pediatrics. 2009;123(1):175-187. Available at:
https://pubmed.ncbi.nlm.nih.gov/19117880.

23. Hegazi A, Forsyth S, Prime K, Bashh Adolescent Special Interest Group. Testing the
children of HIV-infected parents: 6 years on from 'Don't forget the children'. Sex Transm
Infect. 2015;91(2):76-77. Available at: https://pubmed.ncbi.nlm.nih.gov/25316913.

24. Boer K, Smit C, van der Flier M, et al. The comparison of the performance of two
screening strategies identifying newly-diagnosed HIV during pregnancy. Eur J Public
Health. 2011;21(5):632-637. Available at: https://pubmed.ncbi.nlm.nih.gov/21051473.

25. Yudin MH, Moravac C, Shah RR. Influence of an "opt-out" test strategy and patient
factors on human immunodeficiency virus screening in pregnancy. Obstet Gynecol.
2007;110(1):81-86. Available at: https://pubmed.ncbi.nlm.nih.gov/17601900.

26. Olakunde BO, Pharr JR, Adeyinka DA. HIV testing among pregnant women with
prenatal care in the United States: An analysis of the 2011–2017 National Survey of
Family Growth. Int J STD AIDS. 2020;31(7):680-688. Available at:
https://pubmed.ncbi.nlm.nih.gov/32538331.

27. Koumans EH, Harrison A, House LD, et al. Characteristics associated with lack of HIV
testing during pregnancy and delivery in 36 U.S. states, 2004–2013. Int J STD AIDS.
2018;29(12):1225-1233. Available at: https://pubmed.ncbi.nlm.nih.gov/29969977.

28. Salvant Valentine S, Caldwell J, Tailor A. Effect of CDC 2006 revised HIV testing
recommendations for adults, adolescents, pregnant women, and newborns on state laws,
2018. Public Health Rep. 2020;135(1_suppl):189S-196S. Available at:
https://pubmed.ncbi.nlm.nih.gov/32735201.

29. Sansom SL, Jamieson DJ, Farnham PG, et al. Human immunodeficiency virus retesting
during pregnancy: costs and effectiveness in preventing perinatal transmission. Obstet
Gynecol. 2003;102(4):782-790. Available at: https://pubmed.ncbi.nlm.nih.gov/14551009.

30. Richey LE, Halperin J. Acute human immunodeficiency virus infection. Am J Med Sci.
2013;345(2):136-142. Available at: https://pubmed.ncbi.nlm.nih.gov/23095473.

31. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in adults and adolescents with HIV. 2023. Available at:
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-
arv/whats-new.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-11
32. Trepka MJ, Mukherjee S, Beck-Sague C, et al. Missed opportunities for preventing
perinatal transmission of human immunodeficiency virus, Florida, 2007–2014. South
Med J. 2017;110(2):116-128. Available at: https://pubmed.ncbi.nlm.nih.gov/28158882.

33. Yee LM, Miller ES, Statton A, et al. Sustainability of statewide rapid HIV testing in labor
and delivery. AIDS Behav. 2018;22(2):538-544. Available at:
https://pubmed.ncbi.nlm.nih.gov/28986656.

34. Scott RK, Crochet S, Huang CC. Universal rapid human immunodeficiency virus
screening at delivery: a cost-effectiveness analysis. Infect Dis Obstet Gynecol.
2018;2018:6024698. Available at: https://pubmed.ncbi.nlm.nih.gov/29731602.

35. Wesolowski LG, Delaney KP, Lampe MA, Nesheim SR. False-positive human
immunodeficiency virus enzyme immunoassay results in pregnant women. PLoS One.
2011;6(1):e16538. Available at: https://pubmed.ncbi.nlm.nih.gov/21304592.

36. Thomson KA, Hughes J, Baeten JM, et al. Increased risk of HIV acquisition among
women throughout pregnancy and during the postpartum period: a prospective per-coital-
act analysis among women with HIV-infected partners. J Infect Dis. 2018;218(1):16-25.
Available at: https://pubmed.ncbi.nlm.nih.gov/29514254.

37. Graybill LA, Kasaro M, Freeborn K, et al. Incident HIV among pregnant and breast-
feeding women in sub-Saharan Africa: a systematic review and meta-analysis. AIDS.
2020;34(5):761-776. Available at: https://pubmed.ncbi.nlm.nih.gov/32167990/.

38. Lockman S, Creek T. Acute maternal HIV infection during pregnancy and breast-
feeding: substantial risk to infants. J Infect Dis. 2009;200(5):667-669. Available at:
https://pubmed.ncbi.nlm.nih.gov/19627246.

39. Taha TE, James MM, Hoover DR, et al. Association of recent HIV infection and in-utero
HIV-1 transmission. AIDS. 2011;25(11):1357-1364. Available at:
https://pubmed.ncbi.nlm.nih.gov/21572305.

40. Humphrey JH, Marinda E, Mutasa K, et al. Mother to child transmission of HIV among
Zimbabwean women who seroconverted postnatally: prospective cohort study. BMJ.
2010;341:c6580. Available at: https://pubmed.ncbi.nlm.nih.gov/21177735.

41. Drake AL, Wagner A, Richardson B, John-Stewart G. Incident HIV during pregnancy
and postpartum and risk of mother-to-child HIV transmission: a systematic review and
meta-analysis. PLoS Med. 2014;11(2):e1001608. Available at:
https://pubmed.ncbi.nlm.nih.gov/24586123.

42. Birkhead GS, Pulver WP, Warren BL, et al. Acquiring human immunodeficiency virus
during pregnancy and mother-to-child transmission in New York: 2002-2006. Obstet
Gynecol. 2010;115(6):1247-1255. Available at:
https://pubmed.ncbi.nlm.nih.gov/20502297.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-12
 43. Committee on Pediatric AIDS. Infant feeding and transmission of human
immunodeficiency virus in the United States. Pediatrics. 2013;131(2):391-396. Available
at: https://pubmed.ncbi.nlm.nih.gov/23359577.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection B-13
Infant Feeding for Individuals with HIV in the
United States
Updated: January 31, 2023
Reviewed: January 31, 2023

Panel’s Recommendations
• People with HIV should receive evidence-based, patient-centered counseling to support shared decision-making about
infant feeding. Counseling about infant feeding should begin prior to conception or as early as possible in pregnancy;
information about and plans for infant feeding should be reviewed throughout pregnancy and again after delivery (AIII).
During counseling, people should be informed that—
o Replacement feeding with properly prepared formula or pasteurized donor human milk from a milk bank eliminates the
risk of postnatal HIV transmission to the infant (AI).
o Achieving and maintaining viral suppression through antiretroviral therapy (ART) during pregnancy and postpartum
decreases breastfeeding transmission risk to less than 1%, but not zero (AI).
• Replacement feeding with formula or banked pasteurized donor human milk is recommended to eliminate the risk of HIV
transmission through breastfeeding when people with HIV are not on ART and/or do not have a suppressed viral load
during pregnancy (at a minimum throughout the third trimester), as well as at delivery (AI).
• Individuals with HIV who are on ART with a sustained undetectable viral load and who choose to breastfeed should be
supported in this decision (AIII).
• Individuals with HIV who choose to formula feed should be supported in this decision. Providers should ask about potential
barriers to formula feeding and explore ways to address them (AIII).
• Engaging Child Protective Services or similar agencies is not an appropriate response to the infant feeding choices of an
individual with HIV (AIII).
• Clinicians are encouraged to consult the national Perinatal HIV/AIDS hotline (1-888-448-8765) with questions about infant
feeding by individuals with HIV (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One
or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert
opinion

In this document, the term “breastfeeding” is used to describe feeding a child one’s own milk (either
direct feeding or with expressed milk). When counseling individuals with HIV about infant feeding, it
is important to assess and use their preferred terminology; some transgender men and gender-
diverse individuals may prefer using the term “chestfeeding” rather than “breastfeeding.” We urge
providers to consult community-based resources for more information about inclusive, affirming
language around gender in health care settings.

Counseling about infant feeding is an integral component of care for pregnant and postpartum people
with HIV. Ideally, this counseling should begin before pregnancy, continue during pregnancy, and be
reviewed again after delivery. Patient-centered counseling should assess an individual’s opinions and
plans about infant feeding, engage them in shared decision-making, and assist them in implementing
their plans for infant feeding. Replacement feeding with properly prepared formula or banked,
pasteurized donor human milk has been recommended for individuals with HIV in the United States
because it is generally available and eliminates any risk of HIV transmission through breastfeeding.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-1
However, breastfeeding provides certain benefits to the mother and infant that are not possible with
formula feeding. In addition, the risk of transmission through breastfeeding is very low, but not zero,
for women on antiretroviral therapy (ART) with an undetectable HIV viral load.1-3 Multiple experts
and community organizations have called for a patient-centered approach to infant feeding decision
making and for parents with HIV to have access to the information, support, and tools necessary to
make informed infant feeding decisions.4-12 As part of the shared decision-making process, providers
and parents should discuss the possible use of infant antiretroviral (ARV) prophylaxis during
breastfeeding in addition to the ARV prophylaxis recommended for all infants with perinatal HIV
exposure; these conversations need to take place during pregnancy as well as after delivery (see
Antiretroviral Management of Newborns With Perinatal HIV Exposure or HIV Infection and Table
12. Infant Antiretroviral Prophylaxis for Newborns of Mothers With Sustained Viral Suppression
Who Breastfeed.)

Most of the data on HIV transmission via breastmilk come from low- and middle-income countries.
Interest in and experience with breastfeeding for people with HIV in higher resource settings have
been explored in a small number of studies. In a survey of 15 treatment centers in Germany, the
number of women with HIV who breastfed increased over time from 0 to 2 women per year in 2009
to 2016 to 9 to 13 women per year in 2017 through 2019.13

In five small case series that reported on breastfed infants in higher-resource countries, all mothers
were on ART and almost all were virally suppressed. A group in Toronto described three breastfed
infants with no transmission via breastfeeding.14 Nine women with 10 pregnancies successfully
breastfed at one site in the United States,15 and eight women breastfed at a U.S. second site16; there
were no cases of HIV transmission. Thirteen women, described in a prospective study conducted in
Italy, also had no transmissions of HIV through breastfeeding.17 In Germany, among 30 women with
HIV who breastfed, there were no cases of breastfeeding transmission of HIV, although only 25
women had optimal viral suppression. Four of the five women not considered to be optimally
suppressed had viral loads of 50 to 70 copies/mL at some point postpartum, and two had had a
detectable viral load early in pregnancy and, therefore, did not meet the authors’ criteria for optimal
suppression.18 Of note, the approaches to infant prophylaxis ranged from 4 weeks of zidovudine
(ZDV) to three-drug ARV regimens using therapeutic doses for the duration of breastfeeding.

The Panel on Treatment of HIV in Pregnancy and Prevention and Perinatal Transmission and the
Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (Panels)
recommend that clinicians engage parents in patient-centered counseling and shared decision-making
regarding infant feeding. Among 93 U.S. clinicians who provide specialty care to women with HIV,
one-third of the providers were aware that women in their care breastfed their infants after being
advised not to do so.19 Open communication that involves the parent in shared decision-making
provides an opportunity for providers to understand their patients’ values and infant feeding
preferences, thus allowing individuals who choose to breastfeed, and their infants, to receive
appropriate care and support.

Clinicians who are caring for people with HIV who have questions about infant feeding or are
considering breastfeeding should consult with an expert and/or the national Perinatal
HIV/AIDS hotline (1-888-448-8765).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-2
Overview of Counseling and Management
For people with HIV who are not on ART and/or do not have a suppressed viral load at delivery,
replacement feeding with formula or banked pasteurized donor human milk is recommended to
eliminate the risk of HIV transmission. However, it is important to recognize that accessing an
adequate supply of formula may be difficult for some people, and there may be cost and access
barriers to obtaining donor milk. For anyone with HIV who chooses replacement feeding, systems of
care should ensure supportive access to clean water, safe formula, and banked human milk, if
available.

Individuals with HIV on ART with a consistently suppressed viral load during pregnancy (at a
minimum during the third trimester) and at the time of delivery should be counseled on the options of
formula feeding, banked donor milk, or breastfeeding. Community-based organizations have
developed patient-facing materials to assist pregnant individuals in considering their infant feeding
options.20

• The infant feeding options that eliminate the risk of HIV transmission are formula and
pasteurized donor human milk.
• Fully suppressive ART during pregnancy and breastfeeding decreases breastfeeding transmission
risk to less than 1%, but not zero.
• If breastfeeding is chosen, exclusive breastfeeding up to 6 months of age is recommended over
mixed feeding (i.e., breast milk and formula), acknowledging that there may be intermittent need
to give formula (e.g., infant weight loss, milk supply not yet established, mother not having
enough stored milk). Solids should be introduced as recommended at 6 months of age, but not
before.21
• The postpartum period, which can be difficult for all parents, can present several challenges to
medication adherence and engagement in care. Ensuring that parents have access to both a
supportive clinical team and peer support in the postpartum period is beneficial in promoting
medication adherence and viral load monitoring (see Postpartum Follow-up for Individuals With
HIV).
• Access to a lactation consultant or lactation support provider with expertise in supporting
breastfeeding by individuals with HIV is beneficial.
• As most studies of breastfeeding in mothers with HIV were conducted in resource-limited
settings, more information is needed about the risk of HIV transmission through breastfeeding in
high-resource settings and when individuals are adherent to ART with sustained viral suppression
starting early in pregnancy.
• Breastfeeding provides numerous health benefits to both the infant (e.g., reduction in asthma,
gastroenteritis, and otitis media) and the parent (e.g., reduction in hypertension; type 2 diabetes;
and breast and ovarian cancers).21

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-3
Special Concerns
Engaging Child Protective Services or similar agencies is not an appropriate response to the
infant feeding choices of an individual with HIV.

Numerous pregnant people with HIV have reported that after expressing their interest/intention to
breastfeed, their providers threatened to report them to Child Protective Services or actually did so.
Such engagements can be extremely harmful to families; can exacerbate the stigma and
discrimination experienced among people with HIV; and are disproportionately applied to
minoritized individuals, including Black, Indigenous, and other people of color.22-24

Approach to Counseling
Health care providers who care for individuals with HIV who are pregnant or planning a pregnancy
should initiate conversations about infant feeding early in pregnancy, or even prior to the pregnancy,
and the discussion should continue during the pregnancy.

One approach is to say, “Have you thought about how you would like to feed your baby? Formula
feeding eliminates the risk of HIV transmission through breastmilk. Less than 1 of 100 breastfed
infants would be expected to acquire HIV through breastmilk when the breastfeeding parent is taking
ART and has an undetectable viral load, but the risk is not zero. What information can I provide to
help you decide?”

For individuals with HIV who are considering breastfeeding, providers should engage them in
patient-centered, evidence-based counseling about infant feeding, allowing for shared decision-
making. It should be a private, nonjudgmental conversation to understand the motivations for
breastfeeding (e.g., bonding, health benefits for lactating parents and their infants) and potential
barriers to formula feeding (e.g., concern about formula feeding, inadvertently disclosing HIV status,
barriers to accessing formula, cultural concerns). Factors such as resource accessibility, the need for
informed lactation support, and history of medication adherence should be considered when making
these decisions. The conversation should also include information about the risks of HIV
transmission during breastfeeding, the importance of sustained viral suppression, and common
challenges to ART adherence during the postpartum period.

Transgender and Gender-Diverse People Who Desire to Chestfeed

Transgender and gender-diverse people may desire to feed their infants their own milk (e.g.,
breastfeeding, chestfeeding, or body feeding), although some may find it dysphoric.25 All pregnant
individuals with HIV, regardless of gender identity, should be counseled about infant feeding
options, as discussed in this section. There are no evidence-based guidelines on timing of restarting
testosterone after giving birth or while breast/chestfeeding. In one published case report of restarting
testosterone 13 months postpartum while still lactating, the calculated milk-to-plasma ratio was under
1.0, and the calculated relative infant dose was under 1%, the infant had no observable side effects,
and the infant serum testosterone concentrations remained undetectable.26

Approach to Management
If a parent decides to breastfeed, several measures should be taken to reduce the possibility of HIV
transmission. Care of the parent and infant should be coordinated prior to delivery among the

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-4
maternity care provider, HIV provider, infant provider, lactation consultant, and social worker, all of
whom may need education about new approaches to infant feeding among people with HIV.
Counseling should include the importance of adherence to ART, viral suppression during pregnancy
and breastfeeding, and engagement in postpartum care for both the lactating parent and infant. Some
providers and/or institutions have chosen to have individuals sign a written agreement
acknowledging the risks of HIV transmission via breastfeeding; others have felt this practice is too
stigmatizing. Recommendations include the following:

• Support the parent’s ART adherence and engagement in care throughout pregnancy and
breastfeeding.
o Provide case management and/or social work support from individual(s) with perinatal
support experience.
o Provide early active referral to a supportive lactation consultant knowledgeable in concerns
regarding HIV transmission and the situations in which to consider stopping or temporarily
interrupting breastfeeding. (Refer to the next section on Situations in which to Consider
Stopping or Modifying Breastfeeding.)
o Screen and provide support for postpartum depression and other mental health conditions that
are highly prevalent among new parents and may affect ART adherence. Postpartum
depression occurs more frequently in individuals with HIV compared to those without HIV.27
• Document sustained viral suppression before delivery and throughout breastfeeding.
o No data exist to inform the appropriate frequency of viral load testing for the breastfeeding
parent. One approach is to monitor the plasma viral load of the parent every 1 to 2 months
during breastfeeding.15,16
o Decide which clinician (e.g., prenatal care provider or primary care HIV clinician) is
responsible for following viral loads of the parent postpartum and continuing
counseling/education around breastfeeding.
o If the parent’s viral load becomes detectable, consult an expert in breastfeeding and HIV
immediately and consider the options provided in the section Situations to Consider Stopping
or Modifying Breastfeeding below.
o Recommend exclusive breastfeeding in the first 6 months of life, followed by the
introduction of complementary foods with continued breastfeeding, if desired.21 Some people
may choose to breastfeed for fewer than 6 months.
o In pre-ART studies, exclusive breastfeeding was associated with lower rates of HIV
transmission compared to mixed feeding (a term used to describe infants fed breast milk plus
other liquid or solid foods, including formula).28,29 The highest risk in these studies was from
very early introduction of solids (before 2 months of age).30,31
o In the context of parental ART and viral suppression, it is not known whether formula
supplementation increases the risk of HIV acquisition in the breastfed infant.
• Administer appropriate ARV prophylaxis starting at birth as described in Antiretroviral
Management of Newborns With Perinatal HIV Exposure or HIV Infection.
• Provide guidance on good breast care, including strategies to avoid and promptly resolve over-
production of breastmilk, milk stasis, and breast engorgement, which can lead to sore nipples,
mastitis, or breast abscess. Promptly identify and treat mastitis, thrush, and cracked or bleeding

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-5
 nipples. These conditions may increase the risk of HIV transmission through breastfeeding,
although the impact of these conditions in the context of ART and viral suppression is unknown.
• Develop a joint plan for weaning with family and providers. Since very rapid weaning was
associated with increased risk of HIV shedding into breast milk and risk of transmission in the
pre-ART era,32-34 weaning over a 2- to 4-week period might be safer, paying special attention to
good breast care and avoidance of breast engorgement and milk stasis.
• There is little evidence to guide the infant HIV testing schedule during breastfeeding, and there
have been transmissions detected many weeks or even months after reported cessation of
breastfeeding.35 Information about HIV testing for infants who are being breastfed is available in
Diagnosis of HIV Infection in Infants and Children, see Table 13. Recommended Virologic
Testing Schedules for Infants Who Were Exposed to HIV According to Risk of Perinatal HIV
Acquisition at and After Birth.

Situations to Consider Stopping or Modifying Breastfeeding

Situations may arise in which there is a need to stop or modify breastfeeding, such as the
breastfeeding parent having a detectable viral load or developing mastitis or bleeding nipples. If the
situation is temporary, some options to consider until the condition has resolved or viral load
becomes undetectable include: (1) giving previously stored expressed milk from a date when person
was virally suppressed while encouraging pumping and discarding breastmilk to ensure that
breastfeeding can resume; (2) pumping and flash heating breastmilk before feeding it to the baby; (3)
providing replacement feeding with formula or pasteurized donor human milk; or (4) permanent
cessation of breastfeeding. Flash heating, which has been documented to eliminate HIV from
breastmilk, involves placing a sample of milk in a glass container within a small pot of water, heating
the water to a boil, and immediately removing the milk from the heated water when the water has
boiled.36,37 Once cooled to room temperature, milk can be given to the baby via bottle or cup.

In the case of mastitis or bleeding nipples, pump and either flash heat or discard milk from the
affected breast while continuing to feed or pump from the unaffected breast.

In the case of a detectable viral load in a breastfeeding parent, the Panels recommend that
breastfeeding be temporarily stopped, using one of the above options, while the viral load is repeated.
If the repeat viral load is undetectable, breastfeeding may resume. This is also an opportunity to
provide positive feedback and review the risks and benefits of continued breastfeeding, adherence
strategies, and other considerations. If the repeat viral load remains detectable, providers should
urgently discuss and counsel about the significant elevation in risk of vertical transmission conferred
by ongoing breastfeeding. Due to the high risk of postnatal transmission associated with viremia
during breastfeeding, the Panels advise immediate cessation of breastfeeding; this guidance is more
directive than counseling for individuals on suppressive ART. In situations where viremia is low and
an addressable cause has been identified, the added risk of short term continued breastfeeding would
be less. No studies have evaluated different approaches to ARV prophylaxis in this specific clinical
scenario, but the Panels recommend that infants with newly identified exposure to breastmilk from a
person with viremia be managed using the ARV prophylaxis approach of an infant identified at high
risk of transmission (see Breastfeeding in Newborns at High Risk of Perinatal HIV Acquisition in
Antiretroviral Management of Newborns With Perinatal HIV Exposure or HIV Infection). Diagnosis
of HIV Infection in Infants and Children provides guidance about HIV diagnostic testing for infants
who are being breastfed. If after counseling, a breastfeeding parent with viremia chooses to continue
to breastfeed, the parent and provider should remain engaged; the provider should offer guidance on

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-6
ARV prophylaxis and testing for the infant and assist the parent to rapidly regain and maintain
virologic suppression. Consultation with an expert or the National Perinatal HIV/AIDS hotline (1-
888-448-8764) is recommended.

Infant HIV Infection

If an infant has a positive NAT result, it should be confirmed with a repeat NAT as soon as possible
(see Diagnosis of HIV Infection in Infants and Children). Antigen–antibody combination
immunoassays are not recommended for diagnosis in infants because of the transplacental transfer of
HIV antibodies during pregnancy.

In the event of HIV transmission via breastfeeding, consult a pediatric HIV specialist and promptly
initiate a full ART regimen for the infant (see What to Start: Regimens Recommended for Initial
Therapy of Antiretroviral-Naive Children in the Guidelines for the Use of Antiretroviral Agents in
Pediatric HIV Infection). If an infant acquires HIV, breastfeeding may be continued. Drug-resistance
testing should be done on the infant’s viral isolate. If resistance is identified, the ARV regimen can
be adjusted appropriately.

Factors Affecting Decisions About Infant Feeding

Several factors affect parents’ decisions about infant feeding. Patient-centered counseling should be
conducted in a manner that supports the family by sharing the risks and benefits of feeding options;
listening to beliefs, values, and interests of parents; addressing concerns; and engaging in shared
decision-making to identify and support each family’s infant feeding decision.

Benefits of Breastfeeding
In general, breastfeeding is widely considered to be the healthiest infant feeding option for both
parents and infants in the general population (see CDC, Recommendations and Benefits:
Breastfeeding). Breastfeeding is associated with improved neonatal immune status and a lower risk
of infants developing asthma, obesity, type 1 diabetes, severe lower respiratory disease, otitis media,
sudden infant death syndrome, gastrointestinal infections, and necrotizing enterocolitis. In addition to
bonding with their infant and avoiding the monetary costs of formula, benefits to the breastfeeding
parent include decreased risk of hypertension; type 2 diabetes; and breast, endometrial, and ovarian
cancers.21 An exclusive focus on the risk of perinatal HIV transmission via breastfeeding fails to
acknowledge the health benefits to lactating parents and their infants that may be lost by prohibiting
breastfeeding for individuals with HIV.

Equity Considerations
Black women are disproportionately affected by HIV. People of color and their infants also
experience a greater burden of many health conditions that research has shown may be alleviated by
breastfeeding.38 These inequities are largely driven by the effects of structural racism, poverty, and
segregation. Research has also shown that systemic racism contributes to lower uptake and
continuation of breastfeeding among Black individuals without HIV.39 These inequities and health
disparities should be considered as part of counseling and support for infant feeding decisions for
people with HIV in the United States. It is also important to recognize that, even in the United States,
some people have limited access to safe water and/or difficulty obtaining formula. It is estimated that

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-7
17% of the U.S. population relied on privately owned wells for water in 2010; these are not regulated
and are not subject to Environmental Protection Act standards.40

Cultural Considerations
Pregnant individuals may face environmental, social, familial, and personal pressures to consider
breastfeeding.4,11,38,41-46 Qualitative studies of mothers with HIV in Canada found that many factors
affected a woman’s decision to breastfeed her infant; these included social, cultural, and emotional
factors and concerns about HIV-related stigma.42

Some women, especially those from a country or cultural background where breastfeeding is the
norm, feared that not breastfeeding would lead to disclosure of their HIV status.4,45,46 Focus groups
held in Canada elucidated the importance of discussing infant feeding options and motivations to
breastfeed, especially among women who had immigrated from other countries where they had been
encouraged to breastfeed.12

Risk of HIV Transmission

Both the evidence regarding the risk of HIV transmission via breastfeeding and the strategies to
reduce this type of transmission come from studies conducted in low- and middle-income countries,
where rates of infant mortality are high and many families do not have access to safe water and
affordable formula. Without maternal ART or infant ARV prophylaxis, the risk of an infant acquiring
HIV through breastfeeding is 15% to 20% over 2 years.47,48 The mechanisms of HIV transmission by
breastfeeding are not fully understood.49,50 This lack of current knowledge, and the fact that rare HIV
transmissions during breastfeeding have occurred from individuals with undetectable breast milk
and/or plasma HIV viral load, complicate decision-making.51,52

Studies have shown that maternal ART throughout pregnancy and breastfeeding or infant ARV
prophylaxis during breastfeeding can reduce, but not eliminate, the risk of breast milk–associated
HIV transmission.53-57 However, in most of these studies, ART was initiated late in pregnancy, and
ARV medications for women or infants were only provided for 6 months after birth, with limited
data on maternal plasma HIV viral load during breastfeeding.

As ART has become more widely available for women during pregnancy and the postpartum period,
studies have evaluated HIV transmission during breastfeeding among women who continued ART
longer than women in previous studies. Among more than 500 mothers who were on ART in the
Mma Bana study, two cases of HIV transmission via breastfeeding occurred. In these cases, maternal
plasma and breast milk HIV RNA levels were <50 copies/mL at 1 month and 3 months postpartum.58
Two cases of HIV transmission during breastfeeding were reported among 186 infants born during a
study in Tanzania; the first occurred in the infant of a mother who had a high viral load 1 month after
delivery, and the second occurred after a mother discontinued ART. No cases of HIV transmission
were reported among infants who were born to virally suppressed mothers who remained in care.59

In a secondary analysis of the Breastfeeding, Antiretrovirals, and Nutrition (BAN) study, increased
maternal ART adherence was associated with lower breast milk and plasma viral loads. Higher breast
milk and plasma viral loads were associated with increased breast milk transmission. Where maternal
plasma viral load remained <100 copies/mL during breastfeeding, there were no occurrences of
infant HIV acquisition.52

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-8
The PROMISE (Promoting Maternal and Infant Survival Everywhere Study) trial, which included
more than 2,400 women with CD4 T lymphocyte cell counts ≥350 cells/mm3, compared the efficacy
of prolonged infant ARV prophylaxis with NVP to maternal ART in preventing HIV transmission
during breastfeeding. Both treatments continued through cessation of breastfeeding or 18 months
postpartum, whichever came first. This study reported estimated transmission rates of 0.3% at
6 months and 0.6% at 12 months in both arms.1 Both maternal HIV RNA load and maternal HIV
drug resistance were independently associated with breastfeeding transmission.60 A secondary
analysis of the PROMISE trial demonstrated an association between maternal viral load and HIV
transmission among mother–baby pairs in the maternal ART arm but not in the infant ARV
prophylaxis arm. Two infants in the maternal ART arm acquired HIV despite maternal viral load
measured as not detected or detected but less than 40 copies/mL on the date that the infants’ first
samples tested positive for HIV RNA.51

In the 72-week analysis of the DolPHIN-2(Dolutegravir in Pregnant HIV Mothers and Their
Neonates) study, comparing dolutegravir- and efavirenz-based ART started in the third trimester,
there was one breastfeeding HIV transmission reported in the efavirenz group.2 This infant
transmission was diagnosed at 72 weeks of life and occurred despite maternal plasma viral load <50
copies per mL at 12, 24, 48, and 72 weeks postpartum. The infant tested HIV DNA negative at birth
and 6 weeks and 12 weeks postpartum. Infant visits at 24 or 48 weeks were missed; however,
subsequent analysis of stored specimens was negative. The mother had undetectable viral loads at
each visit. The infant was exclusively breastfed until 24 weeks, followed by introduction of
complementary foods; breastfeeding stopped at 48 weeks postpartum. No history of maternal mastitis
was recorded throughout the postpartum period.

In all these studies, maternal ART was initiated in the second or third trimester or postpartum. No
studies have systematically evaluated the risk of HIV transmission through breastfeeding when
maternal ART is started before pregnancy or in the first trimester and continued throughout
breastfeeding.

In the Tshilo Dikotla Study (Botswana), frequent monitoring of HIV viral load occurred in pregnancy
and postpartum while breastfeeding was ongoing, counseling was offered on adherence to ARV
medications for both mothers and infants, and infant virologic diagnostic tests were performed
routinely. Women were maintained on ART and infants received 4 weeks of prophylactic ZDV or
NVP. If a woman had a detectable viral load, she was encouraged to switch to formula feeding but
shared decision-making was employed. Among 247 participants, 19 had detectable viral loads at
some point during breastfeeding. Twelve chose to stop breastfeeding, and 7 continued to breastfeed
with ongoing counseling and frequent viral load checks. There were no cases of HIV transmission
via breastfeeding.61

Safety of Antiretroviral Drugs During Breastfeeding

Parents are often concerned about infant exposure to ARV drugs through breast milk. The non-
nucleoside reverse transcriptase inhibitors (NNRTIs) NVP, efavirenz, and etravirine have been
detected in breast milk; however, the levels of these ARV drugs that have been detected in breast
milk are lower than those seen in maternal plasma. Among protease inhibitors (PIs), lopinavir,
ritonavir, and atazanavir have been found in very low concentrations in breast milk, with little to no
drug detectable in the blood of the breastfed infant.62 Nucleoside reverse transcriptase inhibitors
(NRTIs) show more variability than PIs and NNRTIs. Tenofovir concentrations from tenofovir
disoproxil fumarate (TDF) are very low in breast milk, and the drug is undetectable in the blood of

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-9
the breastfed infant.62-64 Emtricitabine and lamivudine (3TC) have more accumulation in breast milk
and can sometimes be detected in the blood of the breastfed infant (in 19% and 36% of infants,
respectively).62 A sub-analysis of the BAN study confirmed higher levels of the NRTIs ZDV and
3TC in breast milk than in maternal plasma, in contrast to NNRTIs and PIs. The study demonstrated
that higher drug concentrations in the maternal plasma and breast milk compartments were associated
with lower levels of the virus in both compartments and a lower incidence of viral transmission
during breastfeeding.65 Data on the transfer of integrase strand transfer inhibitors to breast milk in
humans are limited; data do show that dolutegravir is found in breast milk at levels that are about 3%
of those seen in maternal plasma.66 For more details on the passage of ARV drugs into breast milk,
see the individual drug sections in Appendix B: Supplement: Safety and Toxicity of Individual
Antiretroviral Agents in Pregnancy.

A systematic data review showed a decrease in maternal bone mineral content among breastfeeding
mothers who were receiving TDF-based ART compared to mothers who received no ART, but
whether this persisted after discontinuation of breastfeeding was not known.67 The clinical
significance of the reduced bone mineral density is uncertain. Subsequent studies in Africa have
shown TDF-based ART to be associated with a decrease in bone mineral density during lactation. In
one study, bone mineral density decline through 74 weeks postpartum was greater in breastfeeding
women with HIV receiving TDF than in those receiving ZDV-based ART.68 A second study
comparing bone mineral density in women with HIV receiving TDF-based ART to women without
HIV showed accelerated loss during lactation, with only partial recovery by 3 months after cessation
of lactation.69

In infants, serious adverse events that are associated with the use of ART by breastfeeding mothers
appear to be relatively uncommon. In two studies that compared the efficacy of maternal ART
(ZDV-based ART in one study and TDF-based ART in the other) to infant NVP prophylaxis with no
maternal ART during breastfeeding for prevention of postnatal HIV transmission, no significant
differences in adverse events were observed between study arms.1,54 An infant who acquires HIV
while breastfeeding is at risk for developing ARV drug resistance due to subtherapeutic drug levels
in breast milk.60,70,71

Likewise, the rates of serious adverse events among infants who receive extended ARV prophylaxis
during breastfeeding are low. In one study, the rate of adverse events in infants receiving 6 months of
NVP was not significantly different from the rate in infants receiving placebo.54 Studies to date have
examined only short-term adverse events, and few data are available on whether there might be long-
term consequences of these drug exposures.

Clinicians who are caring for people with HIV and who have questions about infant feeding
should consult with an expert and/or the national Perinatal HIV/AIDS hotline
(1-888-448-8765).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-10
References
1. Flynn PM, Taha TE, Cababasay M, et al. Prevention of HIV-1 transmission through
breastfeeding: efficacy and safety of maternal antiretroviral therapy versus infant nevirapine
prophylaxis for duration of breastfeeding in HIV-1-infected women with high CD4 cell count
(IMPAACT PROMISE): a randomized, open-label, clinical trial. J Acquir Immune Defic
Syndr. 2018;77(4):383-392. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29239901.

2. Malaba TR, Nakatudde I, Kintu K, et al. 72 weeks post-partum follow-up of dolutegravir

versus efavirenz initiated in late pregnancy (DolPHIN-2): an open-label, randomised
controlled study. Lancet HIV. 2022;9(8):e534-e543. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35905752.

3. Behrens GMN, Aebi-Popp K, Babiker A. Close to zero, but not zero: what is an acceptable
HIV transmission risk through breastfeeding? J Acquir Immune Defic Syndr. 2022;89(4):e42.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/34897228.

4. Yudin MH, Kennedy VL, MacGillivray SJ. HIV and infant feeding in resource-rich settings:
considering the clinical significance of a complicated dilemma. AIDS Care. 2016;28(8):1023-
1026. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26881474.

5. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine dosed
every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a randomised,
multicentre, open-label, phase 3b, non-inferiority study. Lancet. 2021;396(10267):1994-
2005. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33308425.

6. Morrison P, Israel-Ballard K, Greiner T. Informed choice in infant feeding decisions can be

supported for HIV-infected women even in industrialized countries. AIDS.
2011;25(15):1807-1811. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21811145.

7. Johnson G, Levison J, Malek J. Should providers discuss breastfeeding with women living
with HIV in high-income countries? an ethical analysis. Clin Infect Dis. 2016;63(10):1368-
1372. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27572099.

8. Kahlert C, Aebi-Popp K, Bernasconi E, et al. Is breastfeeding an equipoise option in

effectively treated HIV-infected mothers in a high-income setting? Swiss Med Wkly.
2018;148:w14648. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30044473.

9. British HIV Association. British HIV association guidelines for the management of HIV in
pregnancy and postpartum 2018 (2020 third interim update). 2020. Available at:
https://www.bhiva.org/file/5f1aab1ab9aba/BHIVA-Pregnancy-guidelines-2020-3rd-interim-
update.pdf.

10. Gostin LO, Kavanagh MM. The ethics of breastfeeding by women living with HIV/AIDS: a
concrete proposal for reforming department of health and human services recommendations.
J Law Med Ethics. 2019;47(1):161-164. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30994078.

11. The Well Project and the International Community of Women Living With HIV- North
America. Expert consensus statement on breastfeeding and HIV in the United States and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-11
 Canada. 2020. Available at: https://www.thewellproject.org/hiv-information/expert-consensus-
statement-breastfeeding-and-hiv-united-states-and-canada.

12. Khan S, Kennedy VL, Loutfy M, et al. “It’s not easy”: infant feeding in the context of HIV in
a resource-rich setting: strengths, challenges and choices, a qualitative study. J Assoc Nurses
AIDS Care. 2021;32(1):105-114. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33177433.

13. Haberl L, Audebert F, Feiterna-Sperling C, et al. Not recommended, but done: breastfeeding
with HIV in Germany. AIDS Patient Care STDS. 2021;35(2):33-38. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33571048.

14. Nashid N, Khan S, Loutfy M, et al. Breastfeeding by women living with human
immunodeficiency virus in a resource-rich setting: a case series of maternal and infant
management and outcomes. J Pediatric Infect Dis Soc. 2020;9(2):228-231. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30753640.

15. Yusuf HE, Knott-Grasso MA, Anderson J, et al. Experience and outcomes of breastfed
infants of women living with HIV in the United States: findings from a single-center
breastfeeding support initiative. J Pediatric Infect Dis Soc. 2022;11(1):24-27. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34888664.

16. Koay WLA, Rakhmanina NY. Supporting mothers living with HIV in the United States who
choose to breastfeed. J Pediatric Infect Dis Soc. 2022;11(5):239. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35238385.

17. Prestileo T, Adriana S, Lorenza DM, Argo A. From undetectable equals untransmittable
(U=U) to breastfeeding: is the jump short? Infect Dis Rep. 2022;14(2):220-227. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35447879.

18. Weiss F, von Both U, Rack-Hoch A, et al. Brief report: HIV-positive and breastfeeding in
high-income settings: 5-year experience from a perinatal center in Germany. J Acquir
Immune Defic Syndr. 2022;91(4):364-367. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35944107.

19. Tuthill EL, Tomori C, Van Natta M, Coleman JS. “In the United States, we say, ‘no
breastfeeding,’ but that is no longer realistic”: provider perspectives towards infant feeding
among women living with HIV in the United States. J Int AIDS Soc. 2019;22(1):e25224.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30657639.

20. The Well Project. Overview of infant feeding options for parents living with HIV. 2022.
Available at: https://www.thewellproject.org/hiv-information/overview-infant-feeding-
options-parents-living-hiv.

21. Meek JY, Noble L, Section on Breastfeeding. Policy statement: breastfeeding and the use of
human milk. Pediatrics. 2022;150(1). Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35921640.

22. Putnam-Hornstein E, Ahn E, Prindle J, Magruder J, Webster D, Wildeman C. Cumulative

rates of child protection involvement and terminations of parental rights in a California birth

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-12
 cohort, 1999–2017. Am J Public Health. 2021;111(6):1157-1163. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33856882.

23. Roberts D. THE COLOR OF CHILD WELFARE. Vol. ed.: 2002.

24. Wall-Wieler E, Roos LL, Nickel NC, Chateau D, Brownell M. Mortality among mothers
whose children were taken into care by Child Protection Services: a discordant sibling
analysis. American Journal of Epidemiology. 2018;187(6):1182-1188. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29617918.

25. MacDonald T, Noel-Weiss J, West D, et al. Transmasculine individuals’ experiences with

lactation, chestfeeding, and gender identity: a qualitative study. BMC Pregnancy Childbirth.
2016;16:106. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27183978.

26. Oberhelman-Eaton S, Chang A, Gonzalez C, Braith A, Singh RJ, Lteif A. Initiation of

gender-affirming testosterone therapy in a lactating transgender man. J Hum Lact.
2022;38(2):339-343. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34490813.

27. Zhu QY, Huang DS, Lv JD, Guan P, Bai XH. Prevalence of perinatal depression among
HIV-positive women: a systematic review and meta-analysis. BMC Psychiatry.
2019;19(1):330. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31666033.

28. Coovadia HM, Rollins NC, Bland RM, et al. Mother-to-child transmission of HIV-1 infection
during exclusive breastfeeding in the first 6 months of life: an intervention cohort study.
Lancet. 2007;369(9567):1107-1116. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17398310.

29. Coutsoudis A, Pillay K, Spooner E, Kuhn L, Coovadia HM. Influence of infant-feeding

patterns on early mother-to-child transmission of HIV-1 in Durban, South Africa: a
prospective cohort study. South African vitamin A study group. Lancet. 1999;354(9177):471-
476. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10465172.

30. Becquet R, Ekouevi DK, Arrive E, et al. Universal antiretroviral therapy for pregnant and
breast-feeding HIV-1-infected women: towards the elimination of mother-to-child
transmission of HIV-1 in resource-limited settings. Clin Infect Dis. 2009;49(12):1936-1945.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19916796.

31. Iliff PJ, Piwoz EG, Tavengwa NV, et al. Early exclusive breastfeeding reduces the risk of
postnatal HIV-1 transmission and increases HIV-free survival. AIDS. 2005;19(7):699-708.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15821396.

32. Kuhn L, Aldrovandi GM, Sinkala M, et al. Effects of early, abrupt weaning on HIV-free
survival of children in Zambia. N Engl J Med. 2008;359(2):130-141. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18525036.

33. Thea DM, Aldrovandi G, Kankasa C, et al. Post-weaning breast milk HIV-1 viral load, blood
prolactin levels and breast milk volume. AIDS. 2006;20(11):1539-1547. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16847409.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-13
34. Kuhn L, Kim HY, Walter J, et al. HIV-1 concentrations in human breast milk before and
after weaning. Sci Transl Med. 2013;5(181):181ra151. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23596203.

35. King CC, Kourtis AP, Persaud D, et al. Delayed HIV detection among infants exposed to
postnatal antiretroviral prophylaxis during breastfeeding. AIDS. 2015;29(15):1953-1961.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/26153671.

36. Israel-Ballard K, Chantry C, Dewey K, et al. Viral, nutritional, and bacterial safety of flash-
heated and pretoria-pasteurized breast milk to prevent mother-to-child transmission of HIV in
resource-poor countries: a pilot study. J Acquir Immune Defic Syndr. 2005;40(2):175-181.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/16186735.

37. Israel-Ballard K, Donovan R, Chantry C, et al. Flash-heat inactivation of HIV-1 in human

milk: a potential method to reduce postnatal transmission in developing countries. J Acquir
Immune Defic Syndr. 2007;45(3):318-323. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17514015.

38. Gross MS, Taylor HA, Tomori C, Coleman JS. Breastfeeding with HIV: an evidence-based
case for new policy. J Law Med Ethics. 2019;47(1):152-160. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30994076.

39. Hinson TD, Skinner AC, Spatz DL. Subject matter experts identify health equity concerns in
breastfeeding for African American women. J Perinat Neonatal Nurs. 2021;35(2):160-168.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/33346570.

40. Murray A, Hall A, Weaver J, Kremer F. Methods for estimating locations of housing units
served by private domestic wells in the United States applied to 2010. J Am Water Resour
Assoc. 2021;57(5):1-16. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34987281.

41. Levison J, Weber S, Cohan D. Breastfeeding and HIV-infected women in the United States:
harm reduction counseling strategies. Clin Infect Dis. 2014;59(2):304-309. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24771330.

42. Greene S, Ion A, Elston D, et al. “Why aren’t you breastfeeding?”: how mothers living with
HIV talk about infant feeding in a “breast is best” world. Health Care Women Int.
2015;36(8):883-901. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24527767.

43. Tariq S, Elford J, Tookey P, et al. “It pains me because as a woman you have to breastfeed
your baby”: decision-making about infant feeding among African women living with HIV in
the UK. Sex Transm Infect. 2016;92(5):331-336. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26757986.

44. Freeman-Romilly N, Nyatsanza F, Namiba A, Lyall H. Moving closer to what women want?
A review of breastfeeding and women living with HIV in the UK and high-income countries.
HIV Med. 2020;21(1):1-8. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31825556.

45. Etowa J, Babatunde S, Hannan J, et al. Motherhood among Black women living with HIV: a
“north-south” comparison of sociocultural and psychological factors. Health Care Women
Int. 2021;42(3):304-322. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33600277.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-14
46. Etowa J, Nare H, Kakuru DM, Etowa EB. Psychosocial experiences of HIV-positive women
of African descent in the cultural context of infant feeding: a three-country comparative
analyses. Int J Environ Res Public Health. 2020;17(19). Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33003622.

47. Nduati R, John G, Mbori-Ngacha D, et al. Effect of breastfeeding and formula feeding on
transmission of HIV-1: a randomized clinical trial. JAMA. 2000;283(9):1167-1174. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/10703779.

48. World Health Organization. HIV Transmission through breastfeeding: a review of available
evidence; 2007 update. 2008. Available at:
http://apps.who.int/iris/bitstream/10665/43879/1/9789241596596_eng.pdf.

49. Weinberg GA, Nachman S. Breastfeeding by women living with HIV in the United States:
are the risks truly manageable? J Pediatric Infect Dis Soc. 2022;11(3):92-93. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34939650.

50. Waitt C, Low N, Van de Perre P, Lyons F, Loutfy M, Aebi-Popp K. Does U=U for
breastfeeding mothers and infants? Breastfeeding by mothers on effective treatment for HIV
infection in high-income settings. Lancet HIV. 2018;5(9):e531-e536. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29960731.

51. Flynn PM, Taha TE, Cababasay M, et al. Association of maternal viral load and CD4 count
with perinatal HIV-1 transmission risk during breastfeeding in the PROMISE postpartum
component. J Acquir Immune Defic Syndr. 2021;88(2):206-213. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34108383.

52. Davis NL, Miller WC, Hudgens MG, et al. Maternal and breastmilk viral load: impacts of
adherence on peripartum HIV infections averted—the Breastfeeding, Antiretrovirals, and
Nutrition Study. J Acquir Immune Defic Syndr. 2016;73(5):572-580. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27846071.

53. White AB, Mirjahangir JF, Horvath H, Anglemyer A, Read JS. Antiretroviral interventions
for preventing breast milk transmission of HIV. Cochrane Database Syst Rev.
2014(10):CD011323. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25280769.

54. Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to
reduce HIV-1 transmission. N Engl J Med. 2010;362(24):2271-2281. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20554982.

55. Coovadia HM, Brown ER, Fowler MG, et al. Efficacy and safety of an extended nevirapine
regimen in infant children of breastfeeding mothers with HIV-1 infection for prevention of
postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind, placebo-controlled
trial. Lancet. 2012;379(9812):221-228. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22196945.

56. Nagot N, Kankasa C, Tumwine JK, et al. Extended pre-exposure prophylaxis with lopinavir-
ritonavir versus lamivudine to prevent HIV-1 transmission through breastfeeding up to 50
weeks in infants in Africa (ANRS 12174): a randomised controlled trial. Lancet.
2016;387(10018):566-573. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26603917.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-15
57. Kesho Bora Study Group, de Vincenzi I. Triple antiretroviral compared with zidovudine and
single-dose nevirapine prophylaxis during pregnancy and breastfeeding for prevention of
mother-to-child transmission of HIV-1 (kesho bora study): a randomised controlled trial.
Lancet Infect Dis. 2011;11(3):171-180. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21237718.

58. Shapiro RL, Hughes MD, Ogwu A, et al. Antiretroviral regimens in pregnancy and breast-
feeding in Botswana. N Engl J Med. 2010;362(24):2282-2294. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20554983.

59. Luoga E, Vanobberghen F, Bircher R, et al. Brief report: No HIV transmission from virally
suppressed mothers during breastfeeding in rural Tanzania. J Acquir Immune Defic Syndr.
2018;79(1):e17-e20. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29781882.

60. Boyce CL, Sils T, Ko D, et al. Maternal human immunodeficiency virus (HIV) drug
resistance is associated with vertical transmission and is prevalent in infected infants. Clin
Infect Dis. 2022;74(11):2001-2009. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34467974.

61. Volpe LJ, Powis KM, Legbedze J, et al. A Counseling and Monitoring Approach for
Supporting Breastfeeding Women Living With HIV in Botswana. J Acquir Immune Defic
Syndr. 2022;89(2):e16. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34723927.

62. Waitt C, Olagunju A, Nakalema S, et al. Plasma and breast milk pharmacokinetics of
emtricitabine, tenofovir and lamivudine using dried blood and breast milk spots in nursing
African mother-infant pairs. J Antimicrob Chemother. 2018;73(4):1013-1019. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29309634.

63. Mugwanya KK, Hendrix CW, Mugo NR, et al. Pre-exposure prophylaxis use by
breastfeeding HIV-uninfected women: a prospective short-term study of antiretroviral
excretion in breast milk and infant absorption. PLoS Med. 2016;13(9):e1002132. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/27676257.

64. Palombi L, Pirillo MF, Marchei E, et al. Concentrations of tenofovir, lamivudine and
efavirenz in mothers and children enrolled under the option B-plus approach in Malawi. J
Antimicrob Chemother. 2016;71(4):1027-1030. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26679247.

65. Davis NL, Corbett A, Kaullen J, et al. Antiretroviral drug concentrations in breastmilk,
maternal HIV viral load, and HIV transmission to the infant: results from the BAN Study. J
Acquir Immune Defic Syndr. 2019;80(4):467-473. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30570527.

66. Waitt C, Orrell C, Walimbwa S, et al. Safety and pharmacokinetics of dolutegravir in

pregnant mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1
study). PLoS Med. 2019;16(9):e1002895. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31539371.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-16
67. Mofenson LM, Baggaley RC, Mameletzis I. Tenofovir disoproxil fumarate safety for women
and their infants during pregnancy and breastfeeding. AIDS. 2017;31(2):213-232. Available
at. https://pubmed.ncbi.nlm.nih.gov/27831952/.

68. Stranix-Chibanda L, Tierney C, Sebikari D, et al. Impact of postpartum tenofovir-based

antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a
randomized clinical trial. PLoS One. 2021;16(2):e0246272. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33544759.

69. Nabwire F, Prentice A, Hamill MM, et al. Changes in bone mineral density during and after
lactation in Ugandan women with HIV on tenofovir-based antiretroviral therapy. J Bone
Miner Res. 2020;35(11):2091-2102. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32573842.

70. Fogel J, Li Q, Taha TE, et al. Initiation of antiretroviral treatment in women after delivery
can induce multiclass drug resistance in breastfeeding HIV-infected infants. Clin Infect Dis.
2011;52(8):1069-1076. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21460326.

71. Zeh C, Weidle PJ, Nafisa L, et al. HIV-1 drug resistance emergence among breastfeeding
infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral
prophylaxis for prevention of mother-to-child transmission: a secondary analysis. PLoS Med.
2011;8(3):e1000430. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21468304.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-17
Diagnosis of HIV Infection in Infants and Children
Updated: January 31, 2023
Reviewed: January 31, 2023

Panel’s Recommendations

• Virologic assays (HIV RNA or HIV DNA nucleic acid tests [NATs]) that directly detect HIV must be used to diagnose HIV in
infants and children aged <18 months with perinatal and postnatal HIV exposure; HIV antibody and HIV antigen/antibody
tests should not be used (AII).
• Plasma HIV RNA or cell-associated HIV DNA NATs are generally equally recommended (AII). However, the results of
plasma HIV RNA NAT or plasma HIV RNA/DNA NAT can be affected by maternal antiretroviral therapy (ART), or by
antiretroviral (ARV) drugs administered to the infant as prophylaxis or presumptive HIV therapy.
• An assay that detects HIV non-B subtype viruses or Group O infections (e.g., an HIV RNA NAT or a dual-target total
DNA/RNA test) is recommended for use in infants and children who were born to mothers with known or suspected non-B
subtype virus or Group O infections (AII).
• Virologic diagnostic testing (see Table 3 below) is recommended for all infants with perinatal HIV exposure at the following
ages:
o 14 to 21 days (AII)
o 1 to 2 months (AII)
o 4 to 6 months (AII)
• For infants who are at high risk of perinatal HIV infection, additional virologic diagnostic testing is recommended at birth
(AII) and at 2 to 6 weeks after ARV drugs are discontinued (BII).
• For infants with perinatal HIV exposure who are being breastfed, virologic diagnostic testing is recommended at birth, 14 to
21 days, 1 to 2 months, and 4 to 6 months of age (AII). An additional virologic test should be performed between the 1-to-
2-month and 4-to-6-month time points if the gap between tests is greater than 3 months. See Infant Feeding for Individuals
With HIV in the United States.
o Virologic diagnostic testing should be performed every 3 months during breastfeeding (BII);
o After cessation of breastfeeding, irrespective of when breastfeeding ends, virologic diagnostic testing should be
performed at 4 to 6 weeks, 3 months, and 6 months after cessation (BII).
• A positive virologic test should be confirmed as soon as possible by a repeat virologic test (AII).
• Definitive exclusion of HIV infection in non-breastfed infants is based on two or more negative virologic tests, with one
negative test obtained at age ≥1 month (and at least 2 -6 weeks after discontinuation of multi-drug ARV
prophylaxis/presumptive HIV therapy) and one at age ≥4 months, or two negative HIV antibody tests from separate
specimens that were obtained at age ≥6 months (AII).
• Additional HIV testing (e.g., HIV RNA or HIV DNA NAT, HIV antibody, HIV antigen/antibody) is not needed routinely for
non-breastfed infants who meet the criteria for definitive exclusion of HIV and who have had no known or suspected HIV
exposure after birth.
• Infants with potential HIV exposure after birth (e.g., from maternal HIV diagnosis during breastfeeding, premasticated
feeding, sexual abuse, contaminated blood products, percutaneous exposure) who are aged <18 months require
additional testing using HIV RNA/DNA NAT assays to establish their HIV status. Infants aged ≥18 months who have these
potential exposures require HIV antigen/antibody testing.
• Age-appropriate HIV testing also is recommended for infants and children with signs and/or symptoms of HIV, even in the
absence of documented or suspected HIV exposure.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-18
 • For children aged >24 months and for children aged 18 to ≤ 24 months with non-perinatal HIV exposure only, HIV antibody
(or HIV antigen/antibody) tests are recommended for diagnostic testing (AII).
• When acute HIV infection is suspected, additional testing with an HIV NAT may be necessary to diagnose HIV infection
(AII).

Note: The National Clinician Consultation Center- Perinatal HIV/AIDS provides consultations on issues related to the
management of perinatal HIV infection, including diagnostic testing (1-888-448-8765; 24 hours a day, 7 days a week).

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints;
I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying
data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical
outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term
outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical
outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical
outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to post-pubertal adolescents

Diagnosis of HIV in Infants and Children

HIV can be diagnosed definitively by virologic testing in most non-breastfed infants with perinatal
HIV exposure by age 1 to 2 months and in almost all perinatally-exposed infants by age 4 to 6
months. Antibody tests, including antigen/antibody combination immunoassays (sometimes referred
to as fourth- and fifth-generation tests), do not establish the presence of HIV in infants because of
transplacental transfer of maternal HIV antibodies; therefore, a virologic test must be used.1,2 Positive
virologic tests (i.e., nucleic acid tests [NATs]—a class of tests that includes HIV RNA and HIV
DNA polymerase chain reaction [PCR] assays and related RNA qualitative or quantitative assays)
indicate likely HIV infection. Plasma HIV RNA and HIV DNA NATs are generally equally
recommended. However, both tests can be affected by maternal antiretroviral therapy (ART) through
transplacental transfer of antiretroviral (ARV) drugs from the pregnant person to the fetus or by ARV
drugs administered to the infant as prophylaxis or presumptive HIV therapy. In general, qualitative
HIV proviral DNA PCR assays from whole blood detecting cell-associated virus are less affected by
ARVs.

A positive HIV test result should be confirmed as soon as possible by repeat virologic testing,
because false-positive results can occur with both RNA and DNA assays.3 For additional information
on the diagnosis of Group M non-subtype B infections, Group O HIV-1 infections, and HIV-2
infections, see the relevant sections below and the HIV Sequence Database. Newer real-time HIV
RNA PCR assays and the qualitative diagnostic RNA assay are better at detecting non-subtype B
HIV infection and Group O strains than older RNA assays.4-9 (See Clinical and Laboratory
Monitoring of Pediatric HIV Infection.) One example is the COBAS® AmpliPrep/COBAS®
TaqMan-HIV-1 qualitative test (a dual-target DNA/RNA, sometimes called total nucleic acid or
TNA test), which also can identify non-subtype B and Group O infections.10-12

Antigen/antibody combination immunoassays that detect HIV-1/2 antibodies and HIV-1 p24 antigen
are not recommended for diagnosis of HIV infection in infants. In the first months of life, the
antigen component of antigen/antibody tests is less sensitive than an HIV NAT, and antibody tests
should not be used for HIV diagnosis in infants and children <18 months of age.13-15 Children with
perinatal HIV exposure who are aged 18 to 24 months occasionally have residual maternal HIV

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-19
antibodies; definitive confirmation of HIV infection in children in this age group who remain HIV
antibody–positive should be based on a NAT (see Diagnostic Testing in Children With Perinatal HIV
Exposure in Special Situations below). Diagnosis in children aged >24 months relies primarily on
HIV antibody and antigen/antibody tests (see Diagnostic Testing in Children with Non-Perinatal HIV
Exposure or Children With Perinatal HIV Exposure Aged >24 Months below).1

An infant who has a positive HIV antibody test but whose mother’s HIV status is unknown (see
Maternal HIV Testing and Identification of Perinatal HIV Exposure) should be assumed to have been
exposed to HIV. The infant should undergo HIV diagnostic testing, as described in Timing of
Diagnostic Testing in Infants with Perinatal HIV Exposure below,16 and receive ARV prophylaxis or
presumptive HIV therapy as soon as possible. For ARV management of newborns who have been
exposed to HIV and newborns with HIV infection (including those who do not yet have confirmed
infection), see Antiretroviral Management of Newborns With Perinatal HIV Exposure or HIV
Infection.

Timing of Diagnostic Testing in Infants With Perinatal HIV Exposure

Confirmation of HIV infection is based on the results of positive virologic tests from two separate
blood samples in infants and children younger than 18 months. Table 3 below summarizes the timing
of recommended virologic diagnostic testing for infants based on HIV transmission risk. Infants at
high risk of perinatal HIV transmission, may require additional virologic testing, given the increased
risk of infection and concern that ARV prophylaxis, particularly combination ARV prophylaxis or
presumptive HIV therapy, may reduce the sensitivity of diagnostic testing. The risk of transmission is
determined based on whether a mother is receiving ART and virally suppressed.

HIV infection can be presumptively excluded in non-breastfed infants with two or more negative
virologic tests (one at age ≥2 weeks and one at age ≥4 weeks) or one negative virologic test at age ≥8
weeks at least 2 weeks after discontinuing multi-drug ARV prophylaxis/presumptive therapy, or one
negative HIV antibody test at age ≥6 months.1,16

Definitive exclusion of HIV infection in non-breastfed infants is based on two or more negative
virologic tests, with one negative test obtained at age ≥1 month (and at least 2 -6 weeks after
discontinuation of multi-drug ARV prophylaxis/presumptive therapy) and one at age ≥4 months, or
two negative HIV antibody tests from separate specimens that were obtained at age ≥6 months. For
both presumptive and definitive exclusion of HIV infection, a child must have no other laboratory
evidence (i.e., no positive virologic test results or low CD4 T lymphocyte cell count/percentage) or
clinical evidence of HIV infection and must not be breastfeeding. No additional HIV testing of any
kind (e.g., NAT, antibody, antigen/antibody) is needed routinely for non-breastfed infants who meet
the criteria for definitive exclusion of HIV and who have had no known or suspected HIV
exposure after birth.

Pneumocystis jirovecii pneumonia (PCP) prophylaxis is recommended for infants with

indeterminate HIV infection status starting at age 4 to 6 weeks until they are determined to be
definitively or presumptively without HIV infection.17 Thus, PCP prophylaxis can be avoided or
discontinued if HIV infection is presumptively excluded (see Initial Postnatal Management of the
Neonate Exposed to HIV and Pneumocystis jirovecii Pneumonia in the Pediatric Opportunistic
Infection Guidelines).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-20
Virologic Testing at Birth for Newborns at High Risk of Perinatal HIV
Transmission
Virologic testing at birth should be considered for newborns who are at high risk of perinatal HIV
transmission,18-23 such as infants born to women with HIV who—

• Did not receive prenatal care;

• Received no antepartum ARVs or only intrapartum ARV drugs;
• Initiated ART late in pregnancy (during the late second or third trimester);
• Received a diagnosis of acute HIV infection during pregnancy or in labor; and/or
• Had detectable HIV viral loads (≥50 copies/mL) close to the time of delivery, including those
who received ART and did not have sustained viral suppression.

All infants at high risk of perinatal HIV transmission should have specimens obtained for HIV testing
at birth before initiating an ARV drug regimen; however, presumptive HIV therapy should not be
delayed.

Blood samples from the umbilical cord should not be used for diagnostic evaluation because of the
potential for contamination with maternal blood.

Virologic testing at birth is critical for early HIV diagnosis (see When to Initiate Therapy in
Antiretroviral-Naive Children in the Pediatric Antiretroviral Guidelines). Infants who have a positive
virologic test result at or before age 48 hours are considered to have early (intrauterine) infection,
whereas non-breastfed infants who have a negative virologic test result during the first week of life
and subsequently have positive test results are considered to have late (intrapartum) infection.18,19,24
Testing at birth also might be considered in instances when there are concerns that a newborn at low
risk of perinatal HIV transmission may be lost to follow-up without testing.

Virologic Testing at Age 14 to 21 Days

The diagnostic sensitivity of virologic testing increases rapidly by age 2 weeks,16 and early
identification of infection permits transition from presumptive HIV therapy to treatment doses of
ART (see When to Initiate Therapy in Antiretroviral-Naive Children in the Pediatric Antiretroviral
Guidelines).

Virologic Testing at Age 1 to 3 Months

Testing performed at age 1 to 3 months is intended to maximize the likelihood of detecting HIV
infection in perinatally exposed infants. In the HIV Prevention Trials Network 040 study, 93 of 140
infants with HIV (66.4%) were identified at birth. Infants who received negative test results in the
first 7 days of life received an HIV diagnosis when the next diagnostic test was performed at 3
months of age.25 For infants at high risk of perinatal HIV transmission, the Panel on Antiretroviral
Therapy and Medical Management of Children Living with HIV and the Panel on Treatment of HIV
During Pregnancy and Interventions to Reduce Perinatal Transmission suggests performing an
additional virologic test 2 to 6 weeks after ARV drugs are discontinued (i.e., at age 8–12 weeks),
given the increased risk of infection and concern that ARV prophylaxis, particularly combination
ARV prophylaxis or presumptive HIV therapy, may reduce the sensitivity of diagnostic testing.25,26

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-21
In these situations, many experts recommend one test at age 4 to 6 weeks to allow prompt diagnosis
of HIV in infants with an additional test at 8 to 12 weeks of life (i.e., 2–6 weeks after cessation of
prophylaxis or presumptive HIV therapy) to capture additional cases (see Table 3 below). For infants
at low risk of HIV transmission, a single test obtained at 1 to 2 months of age may be timed to occur
2 to 4 weeks after cessation of ARV prophylaxis.

An infant with two negative virologic test results (the first at age ≥14 days and the other at age
≥4 weeks), or one negative test result at age ≥8 weeks at least 2 weeks after discontinuing multi-drug
ARV prophylaxis/presumptive therapy, can be viewed as presumptively HIV uninfected, assuming
the child has not had a positive prior virologic test result or clinical evidence indicative of HIV
infection and is not breastfed.

Virologic Testing at Age 4 to 6 Months

Infants with HIV exposure who have had negative virologic assays at age 14 to 21 days and at age
1 to 2 months, who have had no positive virologic tests, who have no clinical evidence of HIV
infection, and who are not breastfed should be retested at age 4 to 6 months for definitive exclusion
of HIV infection.

Virologic Testing for Infants With Perinatal HIV Exposure Who Are Being
Breastfed.
Some individuals with HIV may choose to breastfeed their infants (see Infant Feeding for Individuals
With HIV in the United States). Infants with perinatal HIV exposure who are being breastfed should
have virologic diagnostic testing at the standard time points: 14 to 21 days, 1 to 2 months, and 4 to
6 months (see Table 3 below). In addition, a virologic test at birth is recommended. In some cases, an
additional virologic test should be performed between the 1-to-2 month and 4-to-6-month time points
if the gap between tests is greater than 3 months. Infants continuing to be breastfed beyond 6 months
of age should have virologic diagnostic testing every 3 months during breastfeeding. At cessation of
breastfeeding, virologic diagnostic testing should be performed at 4 to 6 weeks, 3 months, and 6
months after breastfeeding has ended, regardless of the age of the child when breastfeeding is
discontinued. If an infant’s virologic test result is positive, a repeat test should be performed as soon
as possible and ART should be initiated.

Maternal viral load monitoring is recommended every 1 to 2 months during breastfeeding. Additional
infant virologic testing, including immediate NAT testing, is indicated if maternal viral load becomes
detectable during breastfeeding. If the mother has a detectable viral load and continues breastfeeding,
some Panel members would recommend monthly virologic testing of the infant as an approach to
early detection of HIV infection during ongoing exposure. After cessation of breastfeeding, virologic
testing should be performed at least 2 weeks after cessation of presumptive HIV therapy or ARV
prophylaxis (see Antiretroviral Management of Newborns of Newborns With Perinatal HIV
Exposure or HIV Infection) and at 4 to 6 weeks, 3 months, and 6 months after cessation of
breastfeeding. Consultation with an expert and/or the Perinatal HIV Hotline (888-448-8765) is
recommended in these situations and for questions about HIV diagnostic testing for infants with
perinatal HIV exposure who are being breastfed. For additional information see Infant Feeding for
Individuals With HIV in the United States.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-22
Table 3. Recommended Virologic Testing Schedules for Infants Who Were Exposed to HIV
According to Risk of Perinatal HIV Acquisition at and After Birtha

Infants at High Risk

Criteria for Infants at High Risk Age at HIV NATb Testing for Infants at High Risk
Infants born to mothers with HIV who— Birth
• Did not receive prenatal care; 14–21 days
• Received no antepartum ARVs or only intrapartum ARV 1–2 months
drugs; 2–3 monthsc
• Initiated ART late in pregnancy (during the late second or 4–6 months
third trimester);
All infants at high risk of perinatal HIV transmission should
• Received a diagnosis of acute HIV infection during have specimens obtained for HIV testing at birth before
pregnancy or in labor; and/or initiating an ARV drug regimen; however, presumptive HIV
therapy should not be delayed.
• Had detectable HIV viral loads (≥50 copies/mL) close to
the time of delivery, including those who received ART but If an infant’s NAT test result is positive, a repeat test should
did not achieve sustained viral suppression be performed as soon as possible and ART should be
initiated.

Infants at Low Risk

Criteria for Infants at Low Risk Age at HIV NATb Testing for Infants at Low Risk
Infants born to mothers who— 14–21 days
• Received ART during pregnancy; 1–2 monthsd
• Had sustained viral suppression (usually defined as 4–6 months
<50 copies/mL); and
• Were adherent to their ARV regimens

Infants With Perinatal HIV Exposure Who Are Being Breastfed

Age at HIV NATb Testing for Infants With Perinatal HIV Exposure Who Are Being Breastfed
Birth
14–21 days
1–2 months
2–4 monthse
4–6 months

If breastfeeding continues beyond 6 months of age, NAT testing should be performed every 3 months during breastfeeding.

In addition to the standard time points after birth, NAT testing also should be performed at 4 to 6 weeks, 3 months, and
6 months after cessation of breastfeeding, regardless of the age at when breastfeeding ends.

Consultation with an expert is recommended to determine additional testing time points that may be needed for infants with
risk factors for HIV acquisition at birth who are being breastfed.

Prompt NAT testing of the infant is indicated if maternal viral load becomes detectable during breastfeeding.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-23
 If the mother has a detectable viral load and continues breastfeeding, some Panel members would recommend monthly
virologic testing of the infant as an approach to early detection of HIV infection during ongoing exposure.

See Infant Feeding for Individuals With HIV in the United States. Consultation with an expert and/or the Perinatal HIV Hotline
(888-448-8765) is recommended for questions about HIV diagnostic testing for infants with perinatal HIV exposure who are
being breastfed.
a Thistable summarizes standard time points for HIV virologic diagnostic testing of infants according to risk of perinatal
acquisition.
b HIV RNA or HIV DNA NATs that directly detect HIV.
c For high-risk infants, virologic diagnostic testing is recommended at birth. For infants treated with multiple ARVs in the first 2 to
4 weeks of life, additional virologic testing is recommended 2 to 6 weeks after ARV drugs are discontinued (i.e., at 8–12 weeks
of life).
d For low-risk infants, testing may be timed to occur at least 2 weeks after cessation of ARV prophylaxis.
e An additional virologic test should be performed at age 2 to 4 months if the gap between the tests at ages 1 to 2 months and
4 to 6 months is greater than 3 months.
Key: ART = antiretroviral therapy; ARV = antiretroviral; NAT = nucleic acid test

Antibody Testing at Age 6 Months and Older

Two or more negative results of HIV antibody tests that were performed in non-breastfed infants at
age ≥6 months also can be used to exclude HIV infection definitively in children with no clinical or
virologic laboratory-documented evidence of HIV infection.27,28

Antibody Testing at Age 18 to 24 Months to Document Seroreversion

In general, no additional HIV testing of any kind (e.g., NAT, antibody, antigen/antibody) is needed
routinely for non-breastfed infants who meet the criteria for definitive exclusion of HIV and who
have had no known or suspected HIV exposure after birth. However, infants with potential HIV
exposure after birth (e.g., maternal diagnosis during breastfeeding, premasticated feeding, sexual
abuse, contaminated blood products, percutaneous exposure) who are aged <18 months require
additional testing using HIV RNA/DNA NAT assays to establish their HIV status. Infants aged
≥18 months who have these potential exposures require HIV antigen/antibody testing.

In a study from 2012, the median age at seroreversion was 13.9 months.29 Although the majority of
infants who do not have HIV will serorevert by age 15 months to 18 months, late seroreversion after
18 months has been reported (see Diagnostic Testing in Children With Perinatal HIV Exposure in
Special Situations below). Factors that might influence the time to seroreversion include maternal
disease stage and assay sensitivity.29-32

Diagnostic Testing in Children With Perinatal HIV Exposure in Special Situations

Breastfeeding at the Time of New Maternal HIV Diagnosis
Infants may be exposed to HIV through breastfeeding if the mother develops acute or primary HIV
infection or when pre-existing maternal HIV infection was not diagnosed during pregnancy or
immediately postpartum.33 People who are diagnosed with HIV during breastfeeding should be
counseled to discontinue breastfeeding immediately to reduce the risk of postnatal transmission to the

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-24
infant, see Situations to Consider Stopping or Modifying Breastfeeding in Infant Feeding for
individuals With HIV in the United States. In these situations, infant virologic diagnostic testing by
HIV DNA or RNA PCR is recommended as soon as possible with the schedule for subsequent tests
affected by the infant’s age when breastfeeding is discontinued. Virologic tests should be conducted
at ages 14 to 21 days, 1 to 2 months, and 4 to 6 months. A virologic test also should be performed at
least 2 weeks after cessation of ARV prophylaxis or presumptive HIV therapy (see Antiretroviral
Management of Newborns With Perinatal HIV Exposure or HIV Infection) and at 4 to 6 weeks, 3
months, and 6 months after cessation of breastfeeding. Duplicate tests are not needed if some of these
time points overlap. For additional information, consult the Perinatal HIV Hotline (1­888­448­8765).

Late Seroreversion (Aged ≤24 Months)

Non-breastfed children with perinatal HIV exposure, no other HIV transmission risk factor, and no
clinical or virologic laboratory evidence of HIV infection may have residual maternal HIV antibodies
up to age 24 months. These children are called late seroreverters.29-32 In one study, 14% of children
with HIV exposure who did not have HIV infection seroreverted after age 18 months.29 More recent
data from Thailand associated late seroreversion with the antenatal use of protease inhibitors in
pregnant women with HIV. In this study, late seroreversion also was associated with the use of
fourth-generation combination antigen/antibody immunoassays.34 These children may have had
positive immunoassay results, but supplemental antibody test results indicated indeterminate HIV
status. In such cases, repeat antibody testing at a later date confirmed seroreversion. Due to the
possibility of residual maternal HIV antibodies, virologic testing is necessary to definitively exclude
or confirm HIV infection in children with perinatal HIV exposure who have a positive HIV antibody
(or antigen/antibody) test at age 18 months to 24 months. Virologic testing will distinguish late-
seroreverting children who do not have HIV but have residual antibodies from children who have
antibodies due to underlying HIV infection. Age-appropriate HIV testing also is recommended for
infants and children with signs and/or symptoms of HIV, even in the absence of documented or
suspected HIV exposure.

Postnatal HIV Infection in Children With Perinatal HIV Exposure and Prior
Negative Virologic Test Results for Whom There Are Additional HIV
Transmission Risks
In contrast to late seroreverters, in rare situations, postnatal HIV infections have been reported in
children with HIV exposure who had prior negative HIV virologic test results. This occurs in
children who acquire HIV through an additional risk factor after completion of testing (see
Diagnostic Testing in Children With Non-Perinatal HIV Exposure or Children with Perinatal HIV
Exposure Aged >24 Months below).

Suspicion of HIV-2 or Non-Subtype B HIV-1 Infections With False-Negative

Virologic Test Results
Children with non-subtype B HIV-1 and children with HIV-2 may have false-negative virologic tests
but persistent positive immunoassay results.35-37 The diagnostic approach in these situations is
discussed below in Virologic Assays to Diagnose Group M Non-Subtype B and Group O HIV-1
Infections and in Virologic Assays to Diagnose HIV-2 Infections.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-25
Diagnostic Testing in Children With Non-Perinatal HIV Exposure or Children With
Perinatal HIV Exposure Aged >24 Months
Premastication
Receipt of solid food that has been premasticated or prewarmed (in the mouth) by a caregiver with
HIV is associated with risk of HIV transmission.38-43 If this occurs in children with perinatal HIV
exposure aged ≤24 months with prior negative virologic tests, it will be necessary for such children
to undergo virologic diagnostic testing because they may have residual maternal HIV antibodies (see
Diagnostic Testing in Children With Perinatal HIV Exposure in Special Situations above).

Additional Routes of HIV Transmission

Additional routes of HIV transmission in children include sexual abuse, receipt of contaminated
blood products, and needlestick with contaminated needles. It may be difficult to obtain a history of
HIV exposure. Therefore, age-appropriate HIV testing is recommended for infants and children with
signs and/or symptoms of HIV infection, even in the absence of documented or suspected perinatal
or non-perinatal HIV exposure. Acquisition of HIV in older children is possible through accidental
needlestick injuries, sexual transmission, or injection drug use. Medical procedures performed in
settings with inadequate infection control practices may pose a potential risk; although tattooing or
body piercing presents a potential risk of HIV transmission, no reported cases of HIV transmission
from these activities have been documented.44

Diagnostic Testing
Diagnosis of HIV-1 infection in infants and children with non-perinatal HIV exposure only or in
children with perinatal HIV exposure who are aged >24 months relies primarily on HIV antibody and
antigen/antibody tests.1,45 U.S. Food and Drug Administration (FDA)-approved diagnostic tests
include the following:

• Antigen/antibody combination immunoassays, which detect HIV-1/2 antibodies and HIV-1 p24
antigen. These tests are recommended for initial testing to screen for established infection with
HIV-1 or HIV-2 and for acute HIV-1 infection. However, p24 antigen from HIV-1 non-B strains,
HIV-1 non-M strains, and HIV-2 strains may not be detected.46 Recent data suggest that the use
of immunoassays and rapid diagnostic test combination algorithms that have limited HIV antigen
breadth may not be adequate for diagnosis of HIV infection in children following early treatment
with ART.47
• HIV-1/HIV-2 antibody differentiation immunoassay, which differentiates HIV-1 antibodies from
HIV-2 antibodies. This immunoassay is recommended for supplemental testing.
• HIV-1 NAT. A NAT always is indicated as an additional test to diagnose acute HIV infection.

The diagnosis of HIV-2 in children with non-perinatal exposure only or in children with perinatal
exposure aged >24 months relies on the 2014 Centers for Disease Control and Prevention
(CDC)/Association of Public Health Laboratories laboratory testing guidelines. These guidelines
recommend using an HIV-1/HIV-2 antibody differentiation immunoassay that distinguishes between
HIV-1 and HIV-2 antibodies for supplemental testing. When used as a supplemental test, the results
of the HIV-1 Western blot are more ambiguous than those of the HIV-1/HIV-2 antibody

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-26
differentiation immunoassay; >60% of individuals with HIV-2 are misclassified as having HIV-1 by
the HIV-1 Western blot.1,48 All HIV-2 cases should be reported to the HIV surveillance program of
the state or local health department; additional HIV-2 DNA PCR testing can be arranged by a local
public health laboratory or by CDC if an HIV-1/HIV-2 antibody differentiation immunoassay is
inconclusive. HIV-2 DNA PCR testing may be necessary for definitive diagnosis, although this assay
is not commercially available.49,50

Virologic Assays to Diagnose HIV in Infants Younger Than 18 Months With Perinatal
HIV-1 Exposure
HIV RNA Assays
HIV quantitative RNA assays detect extracellular viral RNA in plasma. Their specificity has been
shown to be 100% at birth and at ages 1 month, 3 months, and 6 months and is comparable to the
specificity of HIV DNA PCR.26 Testing at birth will detect HIV RNA in infants who acquire HIV
in utero and not in those who acquire HIV from exposure during delivery or immediately before
delivery (i.e., during the intrapartum period). Studies have shown that HIV RNA assays identify 25%
to 58% of infants with HIV infection from birth through the first week of life, 89% at age 1 month,
and 90% to 100% by age 2 months to 3 months. These results are similar to the results of HIV DNA
PCR for early diagnosis of HIV.3,26,51

The sensitivity of HIV RNA assays is affected by maternal antenatal ART or ARV drugs
administered to the infant as prophylaxis or presumptive therapy.52 In one study, the sensitivity of
HIV RNA assays was not associated with the type of maternal ART or infant ARV prophylaxis, but
HIV RNA levels at 1 month were significantly lower in infants with HIV who were receiving
multidrug prophylaxis. In contrast, the median HIV RNA levels were high by age 3 months in both
groups after stopping prophylaxis.26 Between 2010 and 2016, a significant decline in baseline
viremia was noted in South Africa’s Early Infant Diagnosis program, with loss of detectability
documented among some infants with HIV. This decline may have reflected the administration of
various prophylactic ARV regimens during those years.53 Further studies are necessary to evaluate
the sensitivity of HIV RNA assays during receipt of multidrug ARV prophylaxis or presumptive HIV
therapy in infants whose mothers also received antenatal ART.

An HIV quantitative RNA assay can be used as a confirmatory test for infants who have an initial
positive HIV DNA PCR test result. In addition to providing virologic confirmation of infection
status, an HIV RNA measurement assesses baseline viral load. An HIV genotype can be performed
on the same sample to guide initial ARV treatment in an infant with HIV. HIV RNA assays may be
more sensitive than HIV DNA PCR for detecting non-subtype B HIV (see Virologic Assays to
Diagnose Group M Non-Subtype B and Group O HIV-1 Infections below).

The HIV qualitative RNA assay (APTIMA HIV-1 RNA Qualitative Assay) is an alternative
diagnostic test that can be used for infant testing. It is the only qualitative RNA test that is approved
by the FDA.24,54-57

HIV DNA PCR and Related Assays

HIV DNA PCR is a sensitive technique that is used to detect intracellular HIV viral DNA in
peripheral blood mononuclear cells. The specificity of the HIV DNA PCR is 99.8% at birth and
100% at ages 1 month, 3 months, and 6 months. Studies have shown that HIV DNA PCR assays

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-27
identify 20% to 55% of infants with HIV infection from birth through the first week of life, with the
same caveat as for RNA testing—testing at birth detects only in utero HIV infection and not
infection in those infants who acquire HIV during the intrapartum period. This percentage increases
to >90% by age 2 weeks to 4 weeks and to 100% at ages 3 months and 6 months.24,26,51

Two studies provided data on diagnostic testing at different time points in infants with confirmed
HIV infection, including those who had negative test results at birth. One study noted that among
47 infants with HIV infection who had negative DNA PCR test results at birth, 68% were identified
during the period of neonatal ARV prophylaxis at 4 to 6 weeks; by 3 months, all 47 infants were
identified.25 Another study from Cape Town evaluated the sensitivity of HIV DNA assays within
8 days of life during and after initiating ART in infants with HIV. The infants had been exposed to a
combination of maternal ART in utero and ARV drugs for prophylaxis and treatment. In seven
infants who achieved virologic suppression (defined as a continuous downward trend in plasma HIV
RNA, with <100 copies/mL after 6 months), total HIV DNA continued to decay over 12 months. The
authors noted that one infant had undetectable HIV DNA after 6 days on treatment, another had
undetectable HIV DNA after 3 months, and a third had undetectable HIV DNA after 4 months,
suggesting that rapid decline of HIV-1 RNA and DNA may complicate definitive diagnosis.58 More
recent studies from the same authors suggest that ART initiation within the first week of life reduces
persistence of long-lived infected cells and that delaying ART initiation is associated with slower
decay of infected cells.59 A data set of 38,043 infants from the Western Cape province of South
Africa who were tested at a median age of 45 days showed that infants who received the World
Health Organization Option B+ ARV regimen had fewer indeterminate DNA PCR results than
infants who were receiving older ARV regimens.60 Another group of South African investigators
reported similar findings in a study of a cohort of 5,743 neonates from Johannesburg who were
exposed to HIV.61

The AMPLICOR® HIV-1 DNA test has been used widely for diagnosis of HIV in infants born to
mothers with HIV-1 infection since it was introduced in 1992. However, it is no longer commercially
available in the United States. The sensitivity and specificity of noncommercial HIV-1 DNA tests
that use individual laboratory reagents may differ from the sensitivity and specificity of an FDA-
approved commercial test. The COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 version 2.0
qualitative test (which detects both HIV-1 RNA and proviral DNA in plasma, whole blood, and dried
blood spots) may be used for early HIV diagnosis in infants, but it is not approved by the FDA.10,11,61
These considerations underscore the importance of testing with HIV NATs at 4 months—well after
neonatal ARV prophylaxis or presumptive HIV therapy has stopped.

Other Issues
Virologic Assays to Diagnose Group M Non-Subtype B and Group O HIV-1
Infections
Although HIV-1 Group M subtype B is the predominant viral subtype found in the United States,
multiple subtypes and recombinant forms also are found in the United States.62 Data from the CDC
National HIV Surveillance System (NHSS) showed that the number of non-U.S.-born children with
HIV has exceeded the number of U.S.-born children with HIV since 2011, with 65.5% of non-
U.S.-born children with HIV born in sub-Saharan Africa and 14.3% in Eastern Europe.63 In an
evaluation of infants who received a perinatal HIV infection diagnosis in New York State in 2001
and 2002, 16.7% of infants had acquired a non-subtype B strain of HIV, compared with 4.4% of
infants born in 1998 and 1999.64 Among a group of 40 children who visited a pediatric HIV clinic in

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-28
Rhode Island between 1991 and 2012, 14 (35%) acquired HIV with non-B HIV-1 subtypes. All 14
children were either born outside the United States or their parents were of foreign origin.65 In an
analysis of 1,277 unique sequences collected in Rhode Island from 2004 to 2011, 8.3% were non-B
subtypes (including recombinant forms). Twenty-two percent of participants with non-B subtypes
formed transmission clusters, including individuals with perinatally acquired infection.66 In an
analysis of 3,895 HIV-1 sequences that were collected between July 2011 and June 2012 in the
United States, 5.3% were determined to be non-B subtypes (including recombinant forms).

Evolving immigration patterns may be contributing to local and regional increases in HIV-1 subtype
diversity. Non-subtype B viruses predominate in other parts of the world, such as subtype C in
regions of Africa and India and subtype CRF01 in much of Southeast Asia. Group O HIV strains are
seen in West-Central Africa.67 Non-subtype B and Group O strains may be seen in countries with
links to these geographical regions.68-72 The geographical distribution of HIV groups is available at
the HIV Sequence Database.

Real-time HIV RNA PCR assays and the qualitative diagnostic RNA assay are better at detecting
non-subtype B HIV infection and the less-common Group O strains than older RNA assays4-9 (see
Clinical and Laboratory Monitoring of Pediatric HIV Infection). An example includes the COBAS®
AmpliPrep/COBAS® TaqMan® HIV-1 qualitative test (a dual-target DNA/RNA test), which also can
identify non-subtype B and Group O infections.10,11

Thus, a real-time PCR assay, qualitative RNA assay, or a dual-target total DNA/RNA test should be
used for infant testing instead of a DNA PCR assay when evaluating an infant born to a mother
whose HIV infection is linked to an area that is endemic for non-subtype B HIV or Group O strains,
such as Africa or Southeast Asia. Another indication is when initial testing is negative using an HIV
DNA PCR test and non-subtype B or Group O perinatal exposure is suspected. Two negative HIV
antibody test results obtained at age ≥6 months provide further evidence to rule out HIV infection
definitively. Clinicians should consult with an expert in pediatric HIV infection; state or local public
health departments or CDC may be able to assist in obtaining referrals for diagnostic HIV testing.

Chimeric Antigen Receptor T-Cell and Lentiviral-Based Gene Therapy May Give
Rise to False-Positive HIV NAT Results
Chimeric antigen receptor (CAR) T-cell immunotherapy is a major advancement in cancer
therapeutics, including for pediatric B-cell acute lymphoblastic leukemia. Reprogramming of T cells
is achieved by using gammaretroviral or lentiviral vectors. Recent reports indicate that these vectors
may interfere with long terminal repeat genomes in HIV NAT results and, thus, produce false-
positive results. As CAR T-cell therapy becomes more widely available for multiple indications, it
will be important for clinicians to recognize that routine HIV-1 NAT results may give rise to false
results. In addition, lentiviral vector–based gene therapy as treatment for severe combined
immunodeficiency can give rise to false-positive HIV NAT results. Laboratories should, therefore,
have appropriate alternate HIV-1 NAT resulting platforms made available for this emerging patient
population.73-77

Virologic Assays to Diagnose HIV-2 Infections

HIV-2 infection is endemic in Angola; Mozambique; West African countries, including Benin,
Burkina Faso, Cape Verde, the Gambia, Ghana, Guinea, Guinea-Bissau, Ivory Coast, Liberia, Mali,
Mauritania, Niger, Nigeria, Sao Tome, Senegal, Sierra Leone, and Togo; and parts of India.78-80

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-29
HIV­2 infection also is well documented in France and Portugal, which have large numbers of
immigrants from these regions.81,82 HIV-1 and HIV-2 coinfection may occur, but this rarely is
described outside areas where HIV-2 is endemic. HIV-2 is rare in the United States. Although
accurately diagnosing HIV-2 can be difficult, it is clinically important because HIV-2 strains are
resistant to several ARV drugs that were developed to suppress HIV-1.83-85 (See HIV-2 Infection and
Pregnancy.)

A mother should be suspected of having HIV-2 if her infection is linked to an area that is endemic for
HIV-2 infection or if her HIV test results are suggestive of HIV-2 infection (i.e., the mother has a
positive initial HIV 1/2 immunoassay test result and HIV-1 RNA viral loads that are at or below the
limit of detection in the absence of treatment). The current recommendation is to use an HIV-1/HIV-
2 antibody differentiation immunoassay for supplemental testing.1 Between 2010 and 2017, an
increase in the number of HIV­1/HIV-2 differentiation test results was reported to the CDC’s NHSS.
More than 99.9% of all HIV infections identified in the United States were categorized as HIV-1, and
the number of HIV-2 diagnoses (mono-infection or dual-infection) remained extremely low (<0.03%
of all HIV infections).86

Infant testing with HIV-2–specific DNA PCR tests should be performed at time points similar to
those used for HIV-1 testing when evaluating an infant born to a mother with known or suspected
HIV-2 infection. HIV-2 DNA PCR testing can be arranged by the HIV surveillance program of the
state or local health department through their public health laboratory, or the CDC, because this assay
is not commercially available.49,50 Clinicians should consult with an expert in pediatric HIV infection
when caring for infants with suspected or known exposure to HIV-2.78,87

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-30
References
1. Centers for Disease Control and Prevention and Association of Public Health Laboratories.
Laboratory testing for the diagnosis of HIV infection: updated recommendations. June 27,
2014. Available at: http://dx.doi.org/10.15620/cdc.23447.

2. Donovan M, Palumbo P. Diagnosis of HIV: challenges and strategies for HIV prevention and
detection among pregnant women and their infants. Clin Perinatol. 2010;37(4):751-763, viii.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/21078448.

3. Read JS, Committee on Pediatric AIDS, American Academy of Pediatrics. Diagnosis of

HIV-1 infection in children younger than 18 months in the United States. Pediatrics.
2007;120(6):e1547-1562. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18055670.

4. Church D, Gregson D, Lloyd T, et al. Comparison of the RealTime HIV-1, COBAS TaqMan
48 v1.0, Easy Q v1.2, and Versant v3.0 assays for determination of HIV-1 viral loads in a
cohort of Canadian patients with diverse HIV subtype infections. J Clin Microbiol.
2011;49(1):118-124. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21084515.

5. Cobb BR, Vaks JE, Do T, Vilchez RA. Evolution in the sensitivity of quantitative HIV-1
viral load tests. J Clin Virol. 2011;52 Suppl 1:S77-82. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22036041.

6. Katsoulidou A, Rokka C, Issaris C, et al. Comparative evaluation of the performance of the

abbott realtime HIV-1 assay for measurement of HIV-1 plasma viral load on genetically
diverse samples from Greece. Virol J. 2011;8:10. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21219667.

7. Gueudin M, Leoz M, Lemee V, et al. A new real-time quantitative PCR for diagnosis and
monitoring of HIV-1 group O infection. J Clin Microbiol. 2012;50(3):831-836. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22170927.

8. Xu S, Song A, Nie J, et al. Comparison between the automated Roche COBAS

AmpliPrep/COBAS TaqMan HIV-1 test version 2.0 assay and its version 1 and Nuclisens
HIV-1 EasyQ version 2.0 assays when measuring diverse HIV-1 genotypes in China. J Clin
Virol. 2012;53(1):33-37. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22051503.

9. Muenchhoff M, Madurai S, Hempenstall AJ, et al. Evaluation of the NucliSens EasyQ v2.0
assay in comparison with the Roche Amplicor v1.5 and the Roche CAP/CTM HIV-1 Test
v2.0 in quantification of C-clade HIV-1 in plasma. PLoS One. 2014;9(8):e103983. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/25157919.

10. Mossoro-Kpinde CD, Jenabian MA, Gody JC, et al. Evaluation of the upgraded version 2.0
of the Roche COBAS® AmpliPrep/COBAS® TaqMan HIV-1 qualitative assay in Central
African Children. Open AIDS J. 2016;10:158-163. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27857825.

11. Templer SP, Seiverth B, Baum P, Stevens W, Seguin-Devaux C, Carmona S. Improved

sensitivity of a dual-target HIV-1 qualitative test for plasma and dried blood spots. J Clin

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-31
 Microbiol. 2016;54(7):1877-1882. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27194686.

12. Hans L, Allmen NV, Edelmann A, et al. Early diagnosis of HIV-1 and HIV-2 using COBAS
HIV-1/HIV-2 Qualitative Test: a novel qualitative nucleic acid amplification test for plasma,
serum, and dried blood spot specimens. J Acquir Immune Defic Syndr. 2021;87(5):1187-
1195. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33883470.

13. Tamhane M, Gautney B, Shiu C, et al. Analysis of the optimal cut-point for HIV-p24 antigen
testing to diagnose HIV infection in HIV-exposed children from resource-constrained
settings. J Clin Virol. 2011;50(4):338-341. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21330193.

14. Wessman MJ, Theilgaard Z, Katzenstein TL. Determination of HIV status of infants born to
HIV-infected mothers: a review of the diagnostic methods with special focus on the
applicability of p24 antigen testing in developing countries. Scand J Infect Dis.
2012;44(3):209-215. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22074445.

15. Bhowan K, Sherman GG. Performance of the first fourth-generation rapid human
immunodeficiency virus test in children. Pediatr Infect Dis J. 2013;32(5):486-488. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/23190776.

16. Chadwick EG, Ezeanolue EE, Committee on Pediatric AIDS. Evaluation and management of
the infant exposed to HIV in the United States. Pediatrics. 2020;146(5). Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33077537.

17. Panel on Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Guidelines

for the prevention and treatment of opportunistic infections in HIV-exposed and HIV-
infected children. 2019. Available at: https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-
guidelines-pediatric-opportunistic-infections/whats-new-guidelines.

18. Lilian RR, Kalk E, Technau KG, Sherman GG. Birth diagnosis of HIV infection on infants to
reduce infant mortality and monitor for elimination of mother-to-child transmission. Pediatr
Infect Dis J. 2013;32(10):1080-1085. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23574775.

19. Jourdain G, Mary JY, Coeur SL, et al. Risk factors for in utero or intrapartum mother-to-
child transmission of human immunodeficiency virus type 1 in Thailand. J Infect Dis.
2007;196(11):1629-1636. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18008246.

20. Tubiana R, Le Chenadec J, Rouzioux C, et al. Factors associated with mother-to-child

transmission of HIV-1 despite a maternal viral load <500 copies/ml at delivery: a case-
control study nested in the French perinatal cohort (EPF-ANRS CO1). Clin Infect Dis.
2010;50(4):585-596. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20070234.

21. Katz IT, Shapiro DE, Tuomala R. Factors associated with lack of viral suppression at
delivery. Ann Intern Med. 2015;162(12):874-875. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26075762.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-32
22. Momplaisir FM, Brady KA, Fekete T, Thompson DR, Diez Roux A, Yehia BR. Time of HIV
diagnosis and engagement in prenatal care impact virologic outcomes of pregnant women
with HIV. PLoS One. 2015;10(7):e0132262. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26132142.

23. Mandelbrot L, Tubiana R, Le Chenadec J, et al. No perinatal HIV-1 transmission from

women with effective antiretroviral therapy starting before conception. Clin Infect Dis.
2015;61(11):1715-1725. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26197844.

24. Lilian RR, Kalk E, Bhowan K, et al. Early diagnosis of in utero and intrapartum HIV
infection in infants prior to 6 weeks of age. J Clin Microbiol. 2012;50(7):2373-2377.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22518871.

25. Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to
prevent intrapartum HIV infection. N Engl J Med. 2012;366(25):2368-2379. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22716975.

26. Burgard M, Blanche S, Jasseron C, et al. Performance of HIV-1 DNA or HIV-1 RNA tests
for early diagnosis of perinatal HIV-1 infection during anti-retroviral prophylaxis. J Pediatr.
2012;160(1):60-66 e61. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21868029.

27. Kuhn L, Schramm DB, Shiau S, et al. Young age at start of antiretroviral therapy and
negative HIV antibody results in HIV-infected children when suppressed. AIDS.
2015;29(9):1053-1060. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25870988.

28. Payne H, Mkhize N, Otwombe K, et al. Reactivity of routine HIV antibody tests in children
who initiated antiretroviral therapy in early infancy as part of the Children With HIV Early
Antiretroviral Therapy (CHER) trial: a retrospective analysis. Lancet Infect Dis.
2015;15(7):803-809. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26043884.

29. Gutierrez M, Ludwig DA, Khan SS, et al. Has highly active antiretroviral therapy increased
the time to seroreversion in HIV exposed but uninfected children? Clin Infect Dis.
2012;55(9):1255-1261. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22851494.

30. Gulia J, Kumwenda N, Li Q, Taha TE. HIV seroreversion time in HIV-1-uninfected children
born to HIV-1-infected mothers in Malawi. J Acquir Immune Defic Syndr. 2007;46(3):332-
337. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17786126.

31. Alcantara KC, Pereira GA, Albuquerque M, Stefani MM. Seroreversion in children born to
HIV-positive and AIDS mothers from Central West Brazil. Trans R Soc Trop Med Hyg.
2009;103(6):620-626. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19339030.

32. Sohn AH, Thanh TC, Thinh le Q, et al. Failure of human immunodeficiency virus enzyme
immunoassay to rule out infection among polymerase chain reaction-negative Vietnamese
infants at 12 months of age. Pediatr Infect Dis J. 2009;28(4):273-276. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19289981.

33. Swain CA, Kaufman S, Miranda W, et al. Postpartum mother-to-child transmission of HIV in
a breastfeeding infant. Pediatrics. 2022;149(2). Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35043205.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-33
34. Chatpornvorarux S, Maleesatharn A, Rungmaitree S, et al. Delayed seroreversion in HIV-
exposed uninfected infants. Pediatr Infect Dis J. 2019;38(1):65-69. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30239474.

35. Kline NE, Schwarzwald H, Kline MW. False negative DNA polymerase chain reaction in an
infant with subtype C human immunodeficiency virus 1 infection. Pediatr Infect Dis J.
2002;21(9):885-886. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12380591.

36. Zaman MM, Recco RA, Haag R. Infection with non-B subtype HIV type 1 complicates
management of established infection in adult patients and diagnosis of infection in newborn
infants. Clin Infect Dis. 2002;34(3):417-418. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11774090.

37. Obaro SK, Losikoff P, Harwell J, Pugatch D. Failure of serial human immunodeficiency
virus type 1 DNA polymerase chain reactions to identify human immunodeficiency virus
type 1 clade A/G. Pediatr Infect Dis J. 2005;24(2):183-184. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15702052.

38. Centers for Disease Control and Prevention. Premastication of food by caregivers of HIV-
exposed children—nine U.S. sites, 2009–2010. MMWR Morb Mortal Wkly Rep.
2011;60(9):273-275. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21389930.

39. Gaur AH, Freimanis-Hance L, Dominguez K, et al. Knowledge and practice of

prechewing/prewarming food by HIV-infected women. Pediatrics. 2011;127(5):e1206-1211.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/21482608.

40. Hafeez S, Salami O, Alvarado M, Maldonado M, Purswani M, Hagmann S. Infant feeding

practice of premastication: an anonymous survey among human immunodeficiency virus-
infected mothers. Arch Pediatr Adolesc Med. 2011;165(1):92-93. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21199989.

41. Maritz ER, Kidd M, Cotton MF. Premasticating food for weaning African infants: a possible
vehicle for transmission of HIV. Pediatrics. 2011;128(3):e579-590. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21873699.

42. Ivy W, 3rd, Dominguez KL, Rakhmanina NY, et al. Premastication as a route of pediatric
HIV transmission: case-control and cross-sectional investigations. J Acquir Immune Defic
Syndr. 2012;59(2):207-212. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22027873.

43. Gaur AH, Cohen RA, Read JS, et al. Prechewing and prewarming food for HIV-exposed
children: a prospective cohort experience from Latin America. AIDS Patient Care STDS.
2013;27(3):142-145. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23477456.

44. Centers for Disease Control and Prevention. HIV transmission 2018. Available at:
https://www.cdc.gov/hiv/basics/transmission.html.

45. Alexander TS. Human immunodeficiency virus diagnostic testing: 30 years of evolution. Clin
Vaccine Immunol. 2016;23(4):249-253. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26936099.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-34
46. Ly TD, Plantier JC, Leballais L, Gonzalo S, Lemee V, Laperche S. The variable sensitivity of
HIV Ag/Ab combination assays in the detection of p24Ag according to genotype could
compromise the diagnosis of early HIV infection. J Clin Virol. 2012;55(2):121-127.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22795598.

47. Puthanakit T, Ananworanich J, Akapirat S, et al. Pattern and frequency of seroreactivity to

routinely used serologic tests in early-treated infants with HIV. J Acquir Immune Defic
Syndr. 2020;83(3):260-266. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31917751.

48. Centers for Disease Control and Prevention. HIV-2 infection surveillance—United States,
1987–2009. MMWR Morb Mortal Wkly Rep. 2011;60(29):985-988. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21796096.

49. Shanmugam V, Switzer WM, Nkengasong JN, et al. Lower HIV-2 plasma viral loads may
explain differences between the natural histories of HIV-1 and HIV-2 infections. J Acquir
Immune Defic Syndr. 2000;24(3):257-263. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10969350.

50. Damond F, Benard A, Balotta C, et al. An international collaboration to standardize HIV-2

viral load assays: results from the 2009 ACHI(E)V(2E) quality control study. J Clin
Microbiol. 2011;49(10):3491-3497. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21813718.

51. American Academy of Pediatrics Committee on Pediatric AIDS. HIV testing and prophylaxis
to prevent mother-to-child transmission in the United States. Pediatrics. 2008;122(5):1127-
1134. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18977995.

52. Saitoh A, Hsia K, Fenton T, et al. Persistence of human immunodeficiency virus (HIV) type
1 DNA in peripheral blood despite prolonged suppression of plasma HIV-1 RNA in children.
J Infect Dis. 2002;185(10):1409-1416. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11992275.

53. Mazanderani AH, Moyo F, Kufa T, Sherman GG. Brief report: declining baseline viremia
and escalating discordant HIV-1 confirmatory results within South Africa’s Early Infant
Diagnosis Program, 2010–2016. J Acquir Immune Defic Syndr. 2018;77(2):212-216.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29084045.

54. Food and Drug Administration. APTIMA HIV-1 RNA qualitative assay. 2006. Available at:
https://www.fda.gov/vaccines-blood-biologics/aptima-hiv-1-rna-qualitative-assay.

55. Pierce VM, Neide B, Hodinka RL. Evaluation of the gen-probe aptima HIV-1 RNA
qualitative assay as an alternative to Western blot analysis for confirmation of HIV infection.
J Clin Microbiol. 2011;49(4):1642-1645. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21346052.

56. Fiscus SA, McMillion T, Nelson JA, Miller WC. Validation of the gen-probe aptima
qualitative HIV-1 RNA assay for diagnosis of human immunodeficiency virus infection in
infants. J Clin Microbiol. 2013;51(12):4137-4140. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24088864.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-35
57. Nelson JA, Hawkins JT, Schanz M, et al. Comparison of the Gen-Probe Aptima HIV-1 and
Abbott HIV-1 qualitative assays with the Roche Amplicor HIV-1 DNA assay for early infant
diagnosis using dried blood spots. J Clin Virol. 2014;60(4):418-421. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24929752.

58. Veldsman KA, Maritz J, Isaacs S, et al. Rapid decline of HIV-1 DNA and RNA in infants
starting very early antiretroviral therapy may pose a diagnostic challenge. AIDS.
2018;32(5):629-634. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29334551.

59. Veldsman KA, Janse van Rensburg A, Isaacs S, et al. HIV-1 DNA decay is faster in children
who initiate ART shortly after birth than later. J Int AIDS Soc. 2019;22(8):e25368. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/31441231.

60. Maritz J, Maharaj JN, Cotton MF, Preiser W. Interpretation of indeterminate HIV-1 PCR
results are influenced by changing vertical transmission prevention regimens. J Clin Virol.
2017;95:86-89. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28898704.

61. Technau KG, Mazanderani AH, Kuhn L, et al. Prevalence and outcomes of HIV-1 diagnostic
challenges during universal birth testing - an urban South African observational cohort. J Int
AIDS Soc. 2017;20(Suppl 6):21761. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28872276.

62. Pyne MT, Hackett J, Jr., Holzmayer V, Hillyard DR. Large-scale analysis of the prevalence
and geographic distribution of HIV-1 non-B variants in the United States. J Clin Microbiol.
2013;51(8):2662-2669. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23761148.

63. Nesheim SR, Linley L, Gray KM, et al. Country of birth of children with diagnosed HIV
infection in the United States, 2008–2014. J Acquir Immune Defic Syndr. 2018;77(1):23-30.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29040167.

64. Karchava M, Pulver W, Smith L, et al. Prevalence of drug-resistance mutations and non-
subtype B strains among HIV-infected infants from New York State. J Acquir Immune Defic
Syndr. 2006;42(5):614-619. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16868498.

65. Rogo T, DeLong AK, Chan P, Kantor R. Antiretroviral treatment failure, drug resistance, and
subtype diversity in the only pediatric HIV clinic in Rhode Island. Clin Infect Dis.
2015;60(9):1426-1435. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25637585.

66. Chan PA, Reitsma MB, DeLong A, et al. Phylogenetic and geospatial evaluation of HIV-1
subtype diversity at the largest HIV center in Rhode Island. Infect Genet Evol. 2014;28:358-
366. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24721515.

67. Bush S, Tebit DM. HIV-1 group O origin, evolution, pathogenesis, and treatment: unraveling
the complexity of an outlier 25 years later. AIDS Rev. 2015;17(3):147-158. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26450803.

68. Auwanit W, Isarangkura-Na-Ayuthaya P, Kasornpikul D, Ikuta K, Sawanpanyalert P,

Kameoka M. Detection of drug resistance-associated and background mutations in human
immunodeficiency virus type 1 CRF01_AE protease and reverse transcriptase derived from

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-36
 drug treatment-naive patients residing in central Thailand. AIDS Res Hum Retroviruses.
2009;25(6):625-631. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19500016.

69. Deshpande A, Jauvin V, Pinson P, Jeannot AC, Fleury HJ. Phylogenetic analysis of HIV-1
reverse transcriptase sequences from 382 patients recruited in JJ Hospital of Mumbai, India,
between 2002 and 2008. AIDS Res Hum Retroviruses. 2009;25(6):633-635. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19534630.

70. Chaix ML, Seng R, Frange P, et al. Increasing HIV-1 non-B subtype primary infections in
patients in France and effect of HIV subtypes on virological and immunological responses to
combined antiretroviral therapy. Clin Infect Dis. 2013;56(6):880-887. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23223603.

71. Hemelaar J, Gouws E, Ghys PD, Osmanov S, WHO-UNAIDS Network for HIV Isolation
Characterisation. Global trends in molecular epidemiology of HIV-1 during 2000–2007.
AIDS. 2011;25(5):679-689. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21297424.

72. Dauwe K, Mortier V, Schauvliege M, et al. Characteristics and spread to the native
population of HIV-1 non-B subtypes in two European countries with high migration rate.
BMC Infect Dis. 2015;15:524. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26572861.

73. Hauser JR, Hong H, Babady NE, Papanicolaou GA, Tang YW. False-positive results for
human immunodeficiency virus type 1 nucleic acid amplification testing in chimeric antigen
receptor T cell therapy. J Clin Microbiol. 2019;58(1):e01420-01419. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31694968.

74. Laetsch TW, Maude SL, Milone MC, et al. False-positive results with select HIV-1 NAT
methods following lentivirus-based tisagenlecleucel therapy. Blood. 2018;131(23):2596-
2598. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29669777.

75. Ariza-Heredia EJ, Granwehr BP, Viola GM, et al. False-positive HIV nucleic acid
amplification testing during CAR T-cell therapy. Diagn Microbiol Infect Dis.
2017;88(4):305-307. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28610774.

76. Milone MC, O'Doherty U. Clinical use of lentiviral vectors. Leukemia. 2018;32(7):1529-
1541. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29654266.

77. De Ravin SS, Gray JT, Throm RE, et al. False-positive HIV PCR test following ex vivo
lentiviral gene transfer treatment of X-linked severe combined immunodeficiency vector.
Mol Ther. 2014;22(2):244-245. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24487563.

78. Torian LV, Eavey JJ, Punsalang AP, et al. HIV type 2 in New York City, 2000–2008. Clin
Infect Dis. 2010;51(11):1334-1342. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21039219.

79. Campbell-Yesufu OT, Gandhi RT. Update on human immunodeficiency virus (HIV)-2
infection. Clin Infect Dis. 2011;52(6):780-787. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21367732.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-37
80. Prince PD, Matser A, van Tienen C, Whittle HC, Schim van der Loeff MF. Mortality rates in
people dually infected with HIV-1/2 and those infected with either HIV-1 or HIV-2: a
systematic review and meta-analysis. AIDS. 2014;28(4):549-558. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23921613.

81. Barin F, Cazein F, Lot F, et al. Prevalence of HIV-2 and HIV-1 group O infections among
new HIV diagnoses in France: 2003–2006. AIDS. 2007;21(17):2351-2353. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18090288.

82. Thiebaut R, Matheron S, Taieb A, et al. Long-term nonprogressors and elite controllers in the
ANRS CO5 HIV-2 cohort. AIDS. 2011;25(6):865-867. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21358376.

83. Menendez-Arias L, Alvarez M. Antiretroviral therapy and drug resistance in human

immunodeficiency virus type 2 infection. Antiviral Res. 2014;102:70-86. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24345729.

84. Tchounga BK, Inwoley A, Coffie PA, et al. Re-testing and misclassification of HIV-2 and
HIV-1&2 dually reactive patients among the HIV-2 cohort of the West African database to
evaluate AIDS collaboration. J Int AIDS Soc. 2014;17:19064. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25128907.

85. Balestre E, Ekouevi DK, Tchounga B, et al. Immunologic response in treatment-naive HIV-
2-infected patients: the IeDEA West Africa cohort. J Int AIDS Soc. 2016;19(1):20044.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/26861115.

86. Peruski AH, Wesolowski LG, Delaney KP, et al. Trends in HIV-2 diagnoses and use of the
HIV-1/HIV-2 differentiation test - United States, 2010–2017. MMWR Morb Mortal Wkly
Rep. 2020;69(3):63-66. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31971928.

87. Burgard M, Jasseron C, Matheron S, et al. Mother-to-child transmission of HIV-2 infection

from 1986 to 2007 in the ANRS French Perinatal Cohort EPF-CO1. Clin Infect Dis.
2010;51(7):833-843. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20804413.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection C-38
Clinical and Laboratory Monitoring of Pediatric
HIV Infection
Updated: April 11, 2023
Reviewed: April 11, 2023

Panel’s Recommendations
• Absolute CD4 T lymphocyte (CD4) cell count and plasma HIV RNA (viral load) should be measured at the time of HIV
diagnosis, and, if a child is not started on antiretroviral therapy (ART) after diagnosis, this monitoring should be repeated at
least every 3 to 4 months thereafter (AIII).
• Absolute CD4 count is recommended for monitoring immune status in children with HIV of all ages, with CD4 percentage
as an alternative for children aged <5 years (AII).
• Antiretroviral (ARV) drug-resistance testing is recommended at the time of HIV diagnosis, before initiation of therapy in all
ART-naive patients, and before switching regimens in patients with treatment failure (AII). Genotypic resistance testing is
preferred for this purpose (AIII).
• After initiation of ART or after a change in ARV regimen, children should be evaluated for clinical adverse effects and
should receive support for treatment adherence within 1 week to 2 weeks; laboratory testing for toxicity and viral load
response is recommended at 2 to 4 weeks after treatment initiation or change in ARV regimen and every 3 to 4 months
thereafter (see Table 6 below) (AIII).
• Children on ART should be monitored for therapy adherence, effectiveness, and toxicities routinely (every 3–4 months)
(see Table 6 below) (AII*). See the sections on Adherence to Antiretroviral Therapy in Children and Adolescents With HIV
and Management of Medication Toxicity or Intolerance.
• Additional CD4 count and plasma viral load monitoring should be performed to evaluate children with suspected clinical,
immunologic, or virologic deterioration or to confirm an abnormal value (AIII). CD4 count can be monitored less frequently
(every 6–12 months) in children and adolescents who are adherent to therapy, who have sustained virologic suppression
and CD4 count values that are well above the threshold for opportunistic infection risk, and who have stable clinical status
(AII). Viral load measurement every 3 to 4 months is generally recommended to monitor ART adherence (AIII).
• Phenotypic resistance testing should be considered (usually in addition to genotypic resistance testing) for patients with
known or suspected complex drug resistance mutation patterns, which generally arise after a patient has experienced
virologic failure on multiple ARV regimens (CIII).
• Review the history of all previously used ARVs and available resistance test results when making decisions about the
choice of new ARVs because mutations may not be detected once the prior drugs have been discontinued (AII).
• Viral co-receptor tropism assays are recommended whenever a CCR5 antagonist is being considered for treatment (AI*).
The use of tropism assays also should be considered for patients who demonstrate virologic failure while receiving therapy
that contains a CCR5 antagonist (AI*).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints;
I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying
data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical
outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term
outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical
outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical
outcome data; III = Expert opinion
†Studies that include children or children/adolescents, but not studies limited to postpubertal adolescents

Laboratory monitoring of children living with HIV poses unique and challenging issues. In
particular, the normal ranges of CD4 T lymphocyte (CD4) counts and plasma HIV RNA

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-1
concentrations (viral loads) can vary significantly by age. The CD4 counts and viral load values that
predict the risk of disease progression also change as a child ages. This section will address
immunologic, virologic, general laboratory, and clinical monitoring of children with HIV, with
information that is relevant to both those who have recently received an HIV diagnosis and those
who are receiving antiretroviral therapy (ART).

Clinical and Laboratory Monitoring of Children With HIV

Initial Evaluation of Children Who Recently Received an HIV Diagnosis,
or Entering or Transferring to a New Care Setting
Children who have recently received an HIV diagnosis should have their CD4 counts and plasma
viral loads measured. Their growth and development should be evaluated for signs of HIV-associated
abnormalities, and a complete physical examination should be performed to identify physical
findings of HIV disease (e.g., lymphadenopathy, hepatosplenomegaly, hyperreflexia, ankle clonus).
Testing also should be performed to assess for HIV-associated conditions, including anemia,
leukopenia, thrombocytopenia, hypoalbuminemia, nephropathy (urinalysis), hyperglycemia, hepatic
transaminitis, and renal insufficiency (creatinine). In addition, children with HIV should have a
complete, age-appropriate medical history and physical examination (see Table 6 below).
Opportunistic infection (OI) monitoring should follow the guidelines that are appropriate for the
child’s exposure history and clinical setting (see the Pediatric Opportunistic Infection Guidelines).
Children with HIV who are relocating from outside the United States may benefit from additional
evaluations—such as screening for tuberculosis, gastrointestinal parasites, hepatitis infection, lead
level, and thyroid function. See Centers for Disease Control and Prevention International Adoption.1

Laboratory confirmation of HIV infection should be obtained when available documentation is

incomplete (see Diagnosis of HIV Infection in Infants and Children). Genotypic resistance testing
should be performed, even if ART is not initiated immediately. In addition, a full antiretroviral
(ARV) drug history should be obtained; this history should include any exposure to ARV drugs for
the prevention of perinatal HIV transmission (see Drug-Resistance Testing in the Adult and
Adolescent Antiretroviral Guidelines). HLA-B*5701 testing should be conducted on initial
laboratory screening to allow for possible abacavir (ABC) initiation, and an alternative ARV drug
should be used if the HLA-B*5701 test result is positive2 (see the Abacavir section in Appendix A:
Pediatric Antiretroviral Drug Information).

Before initiating therapy or making changes to a patient’s ARV regimen, a clinician and
multidisciplinary team members (where available) should assess potential barriers to adherence and
discuss the importance of adherence with the patient and/or their caregiver (see Adherence to
Antiretroviral Therapy in Children and Adolescents With HIV).

If a child does not initiate ART after receiving an HIV diagnosis, the child’s CD4 count and plasma
viral load should be monitored at least every 3 to 4 months.

Evaluation at Initiation of Antiretroviral Therapy

At the time of ART initiation, a physical examination should be performed, including assessment of
weight and height, and baseline labs for CD4 count and plasma viral load should be obtained to
monitor ART response (see Table 6 below). To set the baseline for monitoring ART toxicity (see
Management of Medication Toxicity or Intolerance), a complete blood count, urinalysis, and serum
chemistry panel (including levels of electrolytes, creatinine, glucose, and hepatic transaminases)
should be performed (see Table 6 below). The levels of serum lipids (cholesterol and triglycerides)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-2
also should be measured. For information about the adverse effects (AEs) associated with a specific
ARV drug, see Appendix A: Pediatric Antiretroviral Drug Information for complete information on
each drug. Tables 17a–17k in Management of Medication Toxicity or Intolerance provide
information about specific toxicities associated with ARV drugs (e.g., osteopenia and osteoporosis,
lipodystrophies and weight gain, nephrotoxic effects) and include guidance for prevention,
monitoring, and management.

Clinical and Laboratory Monitoring After Initiating or Changing an

Antiretroviral Regimen
Children who start ART or who change to a new regimen should be monitored to assess the
effectiveness, tolerability, and AEs of the regimen and to evaluate medication adherence. Clinicians
and multidisciplinary teams should schedule frequent clinical in-person and/or telemedicine visits to
monitor patients closely during the first few months after initiating a new ARV regimen.
Telemedicine visits and telehealth communication platforms are particularly relevant to the care of
adolescent patients based on their technology access and habits.3,4 Additional check-ins via telephone
and/or telehealth (emails, text messaging, app-based communications) may support adherence and
early identification of medication side effects. The continuity of patient and caregiver interactions is
an opportunity for clinicians and the multidisciplinary team to provide support and discuss adherence
with patients and their caregivers.

A recent systematic review of randomized controlled trials from the last 10 years that used a
telemedicine approach as a study intervention or assessed telemedicine as a subspecialty of pediatric
care found that telemedicine services for the general public and pediatric care are comparable to or
better than in-person services.5 Use of telemedicine as remote, technology-based access to clinical
services in HIV care is growing and has been shown to achieve similar outcomes as those associated
with in-person care.6 People with HIV on ART achieve similar clinical responses to therapy,
adherence to treatment, quality-of-life scores, and psychological and emotional status, whether
treated through telemedicine or in person.7-9 When selecting the format for clinical follow-up, it is
important to recognize differences and similarities between in-person and telemedicine visits (see
Table 4 below). The benefits of telemedicine visits include patient and caregiver convenience, lack of
travel, flexibility, and ability to visualize ART handling/swallowing and conduct directly observed
therapy in the home setting. Telemedicine visits, however, require technological access and capacity
and limit the provider’s ability to conduct physical examinations and obtain laboratory testing on
site,6-8 as well as to perform periodic measurements of body weight, which are important for dose
modification in rapidly growing infants, and to monitor for excessive weight gain as a possible AE of
some ARVs. Cooperative children can be weighed and have their height measured at home if a scale
and measuring tape are available, with simple instructions for continuity, or directly observed during
a synchronous visit or obtained from a recent pediatric or other specialty in-office visit.10
Additionally, providers need to arrange and coordinate access to the laboratory testing and be
familiar with state and local requirements for carrying out, documenting, and billing telemedicine
visits. Although both in-person and telemedicine visits involve considerations for stigma, privacy,
and confidentiality, these considerations differ between health care and home/community-based
settings. For example, the caregiver who has not disclosed the HIV and ART status of the child at
home might prefer in-person visits at the clinic or specific hours and/or alternative locations for a
telemedicine visit.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-3
Table 4. Characteristics and Requirements for In-Person Clinic Visits vs.
Telemedicine Visits

In-Person Visits Telemedicine Visits

Patient/caregiver convenience 
Flexibility (time and locations) of appointments 
Confidentiality concerns  
Directly observed therapy in home settings 
Physical assessment (e.g., skin rashes)  
Physical exam, including weight and height  a
Adherence support and counseling  
Mental health assessment and counseling  
Multidisciplinary support (assessment and coordination of nutritional
and social services)  

Laboratory testing on site 

Travel to clinic 
Technology requirements (internet access, equipment, skills) 
Legal and administrative guidelines for visit documentation and
billing  

a Cooperative children can be weighed and have their height measured at home if a scale and measuring tape are available,
with simple instructions for continuity, or directly observed during a synchronous visit or obtained from a recent pediatric or other
specialty in-office visit.

The first few weeks of ART can be particularly difficult for children and their caregivers; they must
adjust their schedules to allow consistent and routine administration of medication doses. Children
also may experience the AEs of medications, and both children and their caregivers need assistance
to determine whether the effects are temporary and tolerable or more serious or long term, requiring a
clinical visit. It is critical that providers communicate with caregivers and children in a supportive,
nonjudgmental manner and use plain language. This approach promotes interactive reporting and
ensures that providers can have a productive dialogue with both children and their caregivers,
particularly in situations where medication adherence is reported to be inconsistent.

Within 2 Weeks of Initiating Antiretroviral Therapy

Within 2 weeks of initiating ART, children should be evaluated either in person, through
telemedicine, or by telephone. During this evaluation, clinicians should identify clinical AEs and
provide support for adherence. Many clinicians plan additional contacts (in person, through
telemedicine, by telephone, or via email/texts/apps) with children and caregivers to support
adherence during the first few weeks of therapy.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-4
Two to 4 Weeks After Initiating Antiretroviral Therapy

Most experts recommend performing laboratory testing at 2 to 4 weeks (but no later than 8 weeks)
after initiating ART to assess virologic response and laboratory toxicities, although this
recommendation is based on limited data. The laboratory chemistry tests that a patient requires will
depend on the ARV regimen that the patient is receiving (see Table 6 below). Plasma viral load
monitoring is important as a marker of response to ART because a decline in viral load suggests that
the patient is adherent to the regimen, that the appropriate doses are being administered, and that the
virus is susceptible to the drugs in the regimen. Some experts favor measuring viral load at 2 weeks
to ensure that viral load is declining. A significant decrease in viral load should be observed 4 to
8 weeks after initiation of ART.

Clinical and Laboratory Monitoring for Children Who Are Stable on Long-Term
Antiretroviral Therapy
After the initial phase of ART initiation (1–3 months), clinicians should assess a patient’s adherence
to the regimen and the regimen’s effectiveness (as measured by CD4 count and plasma viral load)
every 3 to 4 months. Additionally, clinicians should review a patient’s history of drug toxicities and
evaluate each patient for any new AEs using physical examinations and the relevant laboratory tests.
Generally, if laboratory evidence of toxicity is identified, testing should be performed more
frequently until the toxicity resolves, but specific management is guided by the degree of toxicity and
ARV regimen. Tables 17a–17k in Management of Medication Toxicity or Intolerance provide
information about specific toxicities associated with ARV drugs.

Table 6 below provides one proposed general monitoring schedule, which should be adjusted based
on the specific ARV regimen that a child is receiving.

A patient’s baseline CD4 count affects how rapidly CD4 count improves after ART initiation;
children with very low CD4 counts may take longer than 1 year to achieve their highest values after
viral load suppression.11 Studies that have critically evaluated the frequency of laboratory monitoring
in both adults and children, particularly CD4 count and plasma viral load, support less frequent
monitoring in stable patients who have been consistently virologically suppressed for ≥1 year.12-18

The Adult and Adolescent Antiretroviral Guidelines—Laboratory Testing currently support

performing plasma viral load testing every 6 months for individuals who have both—
• Consistent virologic suppression ≥2 years; and
• CD4 counts that are consistently >300 cells/mm3.

The Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV finds
value in continuing to perform viral load testing every 3 to 4 months to provide enhanced monitoring
of adherence or disease progression among children and adolescents. Some experts monitor
CD4 count less frequently (e.g., every 6–12 months) in children and adolescents who are adherent to
therapy, who have CD4 count values well above the threshold for OI risk, and who have had
sustained virologic suppression and stable clinical status for more than 2 years.19 Furthermore, some
experts monitor viral load more often (with each injection) in adolescents receiving injectable
cabotegravir and rilpivirine.20

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-5
Testing at the Time of Switching Antiretroviral Regimens
When a patient switches regimens to simplify ART, clinicians should obtain the appropriate
laboratory test results at baseline for the toxicity profile of the new regimen. Follow-up should
include a measurement of plasma viral load at 4 weeks (and not >8 weeks) after the switch to ensure
that the new regimen is effective. If the regimen is switched because the regimen is failing (see
Recognizing and Managing Antiretroviral Treatment Failure), resistance testing should be performed
while a patient is still receiving the failing regimen. This optimizes the chance of identifying
resistance mutations, because resistant strains may revert to wild type within a few weeks of stopping
ARV drugs (see Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines).
Clinicians should consider performing phenotypic resistance testing, including co-receptor tropism
testing, in addition to genotypic viral resistance testing in children who have experienced prolonged
or repeated periods of viral nonsuppression on multiple ARV regimens.21

Immunologic Monitoring in Children: General Considerations

When interpreting CD4 counts and percentages in children, clinicians must consider age as a factor.
CD4 count and percentage values in healthy infants without HIV are considerably higher than values
observed in adults without HIV; these infant values slowly decline to adult values by age 5 years
(see Table 5 below).22

Table 5. CD4 Cell Counts and Percentages in Healthy Children: Distribution by Age

Age

0–3 3–6 6–12 1–2 2–6 6–12 12–18

months months months years years years years
2,160
CD4 cell 2,600 2,850 2,670 1,380 980 840
(1,300–
counta,b (1,600–4,000) (1,800–4,000) (1,400–4,300) (700–2,200) (650–1,500) (530–1,300)
3,400)

CD4 52 (35–64) 46 (35–56) 46 (31–56) 41 (32–51) 38 (28–47) 37 (31–47) 41 (31–52)

percentagea,c
a Values presented as median (10th to 90th percentile)
b n = 699;
c
n = 709
Source: Shearer WT, Rosenblatt HM, Gelman RS, et al. Lymphocyte subsets in healthy children from birth through 18 years of
age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol. 2003;112(5):973-980.

The current pediatric HIV disease classification is based on absolute CD4 count, which is
the preferred assay for monitoring and estimating the risk for disease progression and OIs23
(see Table A. HIV Infection Stage Based on Age-Specific CD4 Count or Percentage in Appendix C:
CDC Pediatric HIV CD4 Cell Count/Percentage and HIV-Related Diseases Categorization).
However, some clinicians find it useful to monitor CD4 percentages because they remain relatively
consistent, whereas absolute CD4 counts vary with age and changes in total leukocyte counts. CD4
counts and percentages are best measured when patients are clinically stable, as several factors,
including mild intercurrent illness and exercise, can transiently decrease levels.(Raszka, Meyer et al.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-6
1994)24 Low CD4 values should be confirmed by a repeat test at least 1 week after the first test to
inform clinical decisions.

CD4 count and percentage decline as HIV infection progresses; patients with lower CD4 counts or
percentage values have a poorer prognosis than patients with higher values (see Tables A–C in
Appendix D: Supplemental Information). Children with higher baseline CD4 percentages and of
younger ages (<4 years) can potentially recover normal CD4 counts, whereas children with severe
baseline immune suppression may not achieve normal CD4 levels with ART.25-27 Guidelines
recommend that all people with HIV receive ART, regardless of their CD4 count and clinical stage.
However, CD4 counts are used to determine HIV stage, potential for immunologic recovery, and
when to initiate or stop OI prophylaxis (see When to Initiate Therapy in Antiretroviral-Naive
Children).

HIV RNA Monitoring in Children: General Considerations

Quantitative HIV RNA assays measure the plasma concentration of HIV RNA as copies/mL.
Without therapy, plasma viral load initially rises to peak level during the period of primary infection
in adults and adolescents, and then declines by as much as 2 to 3 log 10 copies to reach a stable lower
level (the virologic set point) approximately 6 to 12 months after acute infection.28,29 In adults with
HIV, the virologic set point correlates with the subsequent risk of disease progression or death in the
absence of therapy.30

The pattern of change in plasma viral load in untreated infants with perinatal HIV differs from that
in adults and adolescents with HIV. In the absence of treatment, plasma viral load peaks by age
2 months and remains high until 12 months, then slowly declines until age 4 to 5 years.31-32,33 This
pattern probably reflects the lower efficiency of a developing immune system in containing viral
replication and, possibly, the rapid expansion of HIV-susceptible cells that occurs with somatic
growth.34

Despite the established association between high plasma viral load and disease progression, a
specific HIV RNA concentration has only moderate predictive value for disease progression and
death in an individual child.35 In both children and adults with HIV, CD4 count or percentage and
plasma viral load are independent predictors of disease progression and mortality risk, and using the
two markers together more accurately defines prognosis.35-38

Methodological Considerations When Interpreting and Comparing HIV RNA

Assays
Based on accumulated experience with currently available assays, the current definition of virologic
suppression is a plasma viral load that is below the quantification limit of the assay used (generally
<20 copies/mL to 75 copies/mL) (see Table 8 below). This definition of suppression has been much
more thoroughly investigated in adults with HIV than in children with HIV (see the Adult and
Adolescent Antiretroviral Guidelines). Temporary viral load elevations (“blips”) are often detected in
adults on ART39 (Grennan, Loutfy et al. 2012) and generally defined as up to 200 copies/mL, but
may be as high as 500 copies/mL in children on ART40; these temporary elevations do not represent
virologic failure as long as the values have returned to below the level of detection when testing is
repeated. For definitions and management of virologic treatment failure, see Recognizing and
Managing Antiretroviral Treatment Failure. These definitions of virologic suppression and virologic
failure are recommended for clinical use. Research protocols or surveillance programs may use
different definitions.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-7
Several different methods can be used for quantitating HIV RNA, each of which has a different level
of sensitivity (see Table 7 below). Because different assays use different methods to measure HIV
RNA, and because the tests have different levels of sensitivity, clinicians should consistently use a
single HIV RNA assay method to monitor an individual patient when possible.41-43 Moreover,
because of biologic variability, only differences >0.7 log 10 copies/mL (a fivefold difference) in
infants aged <2 years and differences >0.5 log 10 copies/mL (a threefold difference) in children aged
≥2 years should be considered as clinically significant plasma viral load changes.

The predominant HIV-1 subtype in the United States is subtype B, and early assays were designed to
detect this subtype. Current kit configurations for all companies have been designed to detect and
quantitate essentially all viral subtypes (see Diagnosis of HIV Infection in Infants and Children). This
ability is important in many regions of the world where non-B subtypes are predominant, as well as
in the United States for international adoptees and a small subset of individuals who contract non-B
viral subtypes.41,44-48 It is particularly relevant for immigrant and adopted children who are born
outside the United States or to non–U.S.-born parents.

Genetic Testing for Management of HIV

Modern disease intervention strategies often employ genetic testing to evaluate the genes of humans
and pathogens. This approach to treatment is an important component in the rise of precision medicine.
Clinicians who manage HIV have routinely probed HIV genetic sequences for mutations that are
associated with HIV drug resistance. Some ARV drugs are metabolized differently based on specific
human genotypes. For example, studies have shown that certain genotypes can affect efavirenz
exposure in young children.49-51 In addition, some human genetic polymorphisms are associated with
drug toxicity or AEs (e.g., using HLA-B*5701 testing to predict ABC hypersensitivity)52; for more
information, see the Abacavir section in Appendix A: Pediatric Antiretroviral Drug Information.
Future clinical practice will likely feature broader applications of multiple forms of genetic testing to
guide management of health and disease.

Table 6. Sample Schedule for Clinical and Laboratory Monitoring of Children Before and
After Initiation of Antiretroviral Therapya

Virologic
Weeks Weeks Every Every Failure (Prior
Laboratory Entry Into ART
1–2 on 2–4 on 3–4 6–12 to Switching
Testing Carea,b Initiationc
Therapy Therapy Monthsd Monthse ARV
Regimens)

Medical History
and Physical      
Examinationf,g

Adherence
    
Evaluationg

CD4 Count    

Plasma Viral
    
Loadh

Resistance
 
Testing

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-8
Table 6. Sample Schedule for Clinical and Laboratory Monitoring of Children Before and
After Initiation of Antiretroviral Therapy

Virologic
Weeks Weeks Every Every Failure (Prior
Laboratory Entry Into ART
1–2 on 2–4 on 3–4 6–12 to Switching
Testing Carea,b Initiationc
Therapy Therapy Monthsd Monthse ARV
Regimens)

CBC with
    
Differentiald

Chemistriesd,i     

Lipid Panele   

Random Plasma
 
Glucosej

Urinalysis   

HBV Screeningk  

Pregnancy Test
for Girls and
Young Women of   
Childbearing
Potentiall

HLA-B*5701m 
a See the texts on immunologic, virologic, general laboratory, and clinical monitoring of children with HIV for details on
recommended laboratory tests to perform.
bIf a child does not initiate ART after receiving an HIV diagnosis, the child’s CD4 count and plasma viral load should be
monitored at least every 3 to 4 months.
c If ART is initiated within 30 to 90 days of a pre-therapy laboratory result, repeat testing may not be necessary.
dCD4 count, CBC, and chemistries can be monitored less frequently (every 6–12 months) in children and youth who are
adherent to therapy, who have CD4 count values that are well above the threshold for opportunistic infection risk, and who have
had sustained virologic suppression and stable clinical status for more than 2 to 3 years. Viral load testing every 3 to 4 months is
generally recommended to monitor ARV adherence.
e If lipid levels have been abnormal in the past, more frequent monitoring may be needed. For patients treated with TDF, more
frequent urinalysis should be considered.
fPay special attention to changes in weight that might occur after altering an ARV regimen. Weight gain or weight loss may
occur when using some ARV drugs (see Table 17h. Lipodystrophies and Weight Gain).
gVirtual visits may be appropriate at some time points, particularly for adherence assessments and for visits for established
patients, see Table 4 above.
hSome experts monitor viral load more often (with each injection) in adolescents initiating injectable CAB and RPV. Viral load
monitoring should be performed 4 to 8 weeks after a switch to long-acting CAB and RPV. HIV-RNA also should be checked in
patients with unplanned missed visits and delayed dosing of long-acting CAB and RPV. When viremia develops during long-
acting therapy, resistance testing, including integrase resistance testing, should be performed. Follow-up dosing in patients with
missed doses should not be delayed while waiting for viral load and resistance test results. However, regimen changes should
be prompted if resistance to CAB and/or RPV is discovered (see Optimizing Antiretroviral Therapy in the Setting of Viral
Suppression in the Adult and Adolescent Antiretroviral Guidelines).
iChemistries refer to a comprehensive metabolic panel. Some experts perform a comprehensive panel at entry and routinely
test Cr, ALT, AST, with additional tests tailored to the history of the individual patient.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-9
Table 6. Sample Schedule for Clinical and Laboratory Monitoring of Children Before and
After Initiation of Antiretroviral Therapy
jRandom plasma glucose is collected in a gray-top blood collection tube or other designated tube. Some experts would consider
monitoring HgbA1C, rather than routine blood glucose, in children at risk for prediabetes/diabetes.
k This screening is only recommended for individuals who have previously demonstrated no immunity to HBV and who are
initiating a regimen that contains ARV drugs with activity against HBV, specifically 3TC, FTC, TAF, or TDF.
l See the Prepregnancy Counseling and Care for Persons of Childbearing Age with HIV in the Perinatal Guidelines.
mConduct HLA-B*5701 on entry or prior to initiating ABC if not done previously. Choose an alternative ARV drug if the patient is
HLA-B*5701 positive (see the Abacavir section in Appendix A: Pediatric Antiretroviral Drug Information).
Key: 3TC = lamivudine; ABC = abacavir; ALT = alanine aminotransferase; ART = antiretroviral therapy; ARV = antiretroviral;
AST = aspartate aminotransferase; CBC = complete blood count; CD4 = CD4 T lymphocyte; Cr = creatinine;
FTC = emtricitabine; HBV = hepatitis B virus; HgbA1C = glycosylated hemoglobin; OI = opportunistic infection;
TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

Table 7. Primary Food and Drug Administration–Approved Assays for Monitoring Viral
Load

COBAS
Abbott NucliSens Aptima HIV-1
Assay AmpliPrep/ Versant v1.0
Real Time EasyQ v2.0 Quant Assay
TaqMan v2.0
Method Real-time RT-PCR Real-time NASBA Real-time RT-PCR Real-time RT-PCR Real-time TMA

Dynamic 40–107 copies/mL 25–107 copies/mL 20–107 copies/mL 37–11×107 copies/mL 30–107 copies/mL
Range
Specimen 0.2–1 mL 0.1–1 mL 1 mL 0.5 mL ≥0.4 mL
Volumea
Manufacturer Abbott Laboratories bioMerieux Roche Siemens Hologic, Inc.
aLaboratories often request large blood volumes for standard viral load testing. Consider contacting the local laboratory to
determine minimum blood volume required to run the assay. Smaller volumes for children can be accommodated.
Key: NASBA = nucleic acid sequence-based amplification; RT-PCR = reverse transcription-polymerase chain reaction;
TMA = transcription-mediated amplification

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-10
References
1. Eckerle JK, Bresnahan MM, Kroupina M, Johnson DE, Howard CR. International
adoption: a review and update. Pediatr Rev. 2021;42(5):245-257. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33931509.

2. Jesson J, Dahourou DL, Renaud F, Penazzato M, Leroy V. Adverse events associated

with abacavir use in HIV-infected children and adolescents: a systematic review and meta-
analysis. Lancet HIV. 2016;3(2):e64-75. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26847228.

3. Hightow-Weidman LB, Muessig KE, Bauermeister J, Zhang C, LeGrand S. Youth,

technology, and HIV: recent advances and future directions. Curr HIV/AIDS Rep.
2015;12(4):500-515. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26385582.

4. Curfman A, McSwain SD, Chuo J, et al. Pediatric telehealth in the COVID-19 pandemic
era and beyond. Pediatrics. 2021;148(3). Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34215677.

5. Shah AC, Badawy SM. Telemedicine in pediatrics: systematic review of randomized

controlled trials. JMIR Pediatr Parent. 2021;4(1):e22696. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33556030.

6. Koay WLA, Prabhakar S, Neilan A, Meyers J, Lee N, Rakhmanina N. Brief report:

supporting access to HIV care for children and youth during the COVID-19 pandemic with
telemedicine and rideshare. J Acquir Immune Defic Syndr. 2021;88(4):384-388. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34710072.

7. Dandachi D, Lee C, Morgan RO, Tavakoli-Tabasi S, Giordano TP, Rodriguez-Barradas

MC. Integration of telehealth services in the healthcare system: with emphasis on the experience
of patients living with HIV. J Investig Med. 2019;67(5):815-820. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30826803.

8. Ohl ME, Richardson K, Rodriguez-Barradas MC, et al. Impact of availability of

telehealth programs on documented HIV viral suppression: a cluster-randomized program
evaluation in the veterans health administration. Open Forum Infect Dis. 2019;6(6):ofz206.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31211155.

9. Health Resources and Services Administration (HRSA). Telehealth programs. 2019.

Available at: www.hrsa.gov/rural-health/telehealth/index.html.

10. Regelmann MO, Conroy R, Gourgari E, et al. Pediatric endocrinology in the time of
COVID-19: considerations for the rapid implementation of telemedicine and management of
pediatric endocrine conditions. Horm Res Paediatr. 2020;93(6):343-350. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33486483.

11. Krogstad P, Patel K, Karalius B, et al. Incomplete immune reconstitution despite

virologic suppression in HIV-1 infected children and adolescents. AIDS. 2015;29(6):683-693.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25849832.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-11
12. Arrow Trial team, Kekitiinwa A, Cook A, et al. Routine versus clinically driven
laboratory monitoring and first-line antiretroviral therapy strategies in African children with HIV
(ARROW): a 5-year open-label randomised factorial trial. Lancet. 2013;381(9875):1391-1403.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/23473847.

13. Buscher A, Mugavero M, Westfall AO, et al. The association of clinical follow-up
intervals in HIV-infected persons with viral suppression on subsequent viral suppression. AIDS
Patient Care STDS. 2013;27(8):459-466. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23886048.

14. Hyle EP, Sax PE, Walensky RP. Potential savings by reduced CD4 monitoring in stable
patients with HIV receiving antiretroviral therapy. JAMA Intern Med. 2013;173(18):1746-1748.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/23978894.

15. Buclin T, Telenti A, Perera R, et al. Development and validation of decision rules to
guide frequency of monitoring CD4 cell count in HIV-1 infection before starting antiretroviral
therapy. PLoS One. 2011;6(4):e18578. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21494630.

16. Gaur AH, Flynn PM, Bitar W, Liang H. Optimizing frequency of CD4 assays in the era
of highly active antiretroviral therapy. AIDS Res Hum Retroviruses. 2013;29(3):418-422.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/23016543.

17. Gale HB, Gitterman SR, Hoffman HJ, et al. Is frequent CD4+ T-lymphocyte count
monitoring necessary for persons with counts >=300 cells/muL and HIV-1 suppression? Clin
Infect Dis. 2013;56(9):1340-1343. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23315315.

18. Davies MA, Ford N, Rabie H, et al. Reducing CD4 monitoring in children on
antiretroviral therapy with virologic suppression. Pediatr Infect Dis J. 2015;34(12):1361-1364.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26379169.

19. Kosalaraksa P, Boettiger DC, Bunupuradah T, et al. Low risk of CD4 decline after
immune recovery in human immunodeficiency virus-infected children with viral suppression. J
Pediatric Infect Dis Soc. 2017;6(2):173-177. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27295973.

20. Rakhmanina N, Richards K, Adeline Koay WL. Transient viremia in young adults with
HIV after the switch to long-acting cabotegravir and rilpivirine: considerations for dosing
schedule and monitoring. J Acquir Immune Defic Syndr. 2023;92(3):e14-e17. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/36480701.

21. Agwu AL, Yao TJ, Eshleman SH, et al. Phenotypic co-receptor tropism in perinatally
HIV-infected youth failing antiretroviral therapy. Pediatr Infect Dis J. 2016;35(7):777-781.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27078121.

22. Shearer WT, Rosenblatt HM, Gelman RS, et al. Lymphocyte subsets in healthy children
from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J
Allergy Clin Immunol. 2003;112(5):973-980. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/14610491.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-12
23. Centers for Disease Control and Prevention. Revised surveillance case definition for HIV
infection-United States. MMWR Recomm Rep. 2014;63(RR-03):1-10. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24717910.

24. Raszka WV, Jr., Meyer GA, Waecker NJ, et al. Variability of serial absolute and percent
CD4+ lymphocyte counts in healthy children born to human immunodeficiency virus 1-infected
parents. Military pediatric HIV consortium. Pediatr Infect Dis J. 1994;13(1):70-72. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/7909598.

25. Puthanakit T, Kerr S, Ananworanich J, Bunupuradah T, Boonrak P, Sirisanthana V.

Pattern and predictors of immunologic recovery in human immunodeficiency virus-infected
children receiving non-nucleoside reverse transcriptase inhibitor-based highly active
antiretroviral therapy. Pediatr Infect Dis J. 2009;28(6):488-492. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19504731.

26. Patel K, Hernan MA, Williams PL, et al. Long-term effects of highly active antiretroviral
therapy on CD4+ cell evolution among children and adolescents infected with HIV: 5 years and
counting. Clin Infect Dis. 2008;46(11):1751-1760. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18426371.

27. Yin DE, Warshaw MG, Miller WC, et al. Using CD4 percentage and age to optimize
pediatric antiretroviral therapy initiation. Pediatrics. 2014;134(4):e1104-1116. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25266426.

28. Henrard DR, Phillips JF, Muenz LR, et al. Natural history of HIV-1 cell-free viremia.
JAMA. 1995;274(7):554-558. Available at: https://www.ncbi.nlm.nih.gov/pubmed/7629984.

29. Katzenstein TL, Pedersen C, Nielsen C, Lundgren JD, Jakobsen PH, Gerstoft J.
Longitudinal serum HIV RNA quantification: correlation to viral phenotype at seroconversion
and clinical outcome. AIDS. 1996;10(2):167-173. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/8838704.

30. Mellors JW, Kingsley LA, Rinaldo CR, Jr., et al. Quantitation of HIV-1 RNA in plasma
predicts outcome after seroconversion. Ann Intern Med. 1995;122(8):573-579. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/7887550.

31. Shearer WT, Quinn TC, LaRussa P, et al. Viral load and disease progression in infants
infected with human immunodeficiency virus type 1. Women and Infants Transmission Study
Group. N Engl J Med. 1997;336(19):1337-1342. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/9134873.

32. Abrams EJ, Weedon J, Steketee RW, et al. Association of human immunodeficiency
virus (HIV) load early in life with disease progression among HIV-infected infants. New York
City Perinatal HIV Transmission Collaborative Study Group. J Infect Dis. 1998;178(1):101-108.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/9652428.

33. Palumbo PE, Kwok S, Waters S, et al. Viral measurement by polymerase chain reaction-
based assays in human immunodeficiency virus-infected infants. J Pediatr. 1995;126(4):592-
595. Available at: https://www.ncbi.nlm.nih.gov/pubmed/7699539.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-13
34. Grennan JT, Loutfy MR, Su D, et al. Magnitude of virologic blips is associated with a
higher risk for virologic rebound in HIV-infected individuals: a recurrent events analysis. J Infect
Dis. 2012;205(8):1230-1238. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22438396.

35. Krogstad P, Uittenbogaart CH, Dickover R, Bryson YJ, Plaeger S, Garfinkel A. Primary
HIV infection of infants: the effects of somatic growth on lymphocyte and virus dynamics. Clin
Immunol. 1999;92(1):25-33. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10413650.

36. Mofenson LM, Korelitz J, Meyer WA, 3rd, et al. The relationship between serum human
immunodeficiency virus type 1 (HIV-1) RNA level, CD4 lymphocyte percent, and long-term
mortality risk in HIV-1-infected children. National Institute of child health and human
development intravenous immunoglobulin clinical trial study group. J Infect Dis.
1997;175(5):1029-1038. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9129063.

37. Hughes MD, Johnson VA, Hirsch MS, et al. Monitoring plasma HIV-1 RNA levels in
addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response.
ACTG 241 Protocol Virology Substudy Team. Ann Intern Med. 1997;126(12):929-938.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/9182469.

38. Mellors JW, Munoz A, Giorgi JV, et al. Plasma viral load and CD4+ lymphocytes as
prognostic markers of HIV-1 infection. Ann Intern Med. 1997;126(12):946-954. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/9182471.

39. Palumbo PE, Raskino C, Fiscus S, et al. Predictive value of quantitative plasma HIV
RNA and CD4+ lymphocyte count in HIV-infected infants and children. JAMA.
1998;279(10):756-761. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9508151.

40. Coovadia A, Abrams EJ, Strehlau R, et al. Efavirenz-based antiretroviral therapy among
nevirapine-exposed HIV-infected children in South Africa: a randomized clinical trial. JAMA.
2015;314(17):1808-1817. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26529159.

41. Bourlet T, Signori-Schmuck A, Roche L, et al. HIV-1 load comparison using four
commercial real-time assays. J Clin Microbiol. 2011;49(1):292-297. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21068276.

42. Yan CS, Hanafi I, Kelleher AD, et al. Lack of correlation between three commercial
platforms for the evaluation of human immunodeficiency virus type 1 (HIV-1) viral load at the
clinically critical lower limit of quantification. J Clin Virol. 2010;49(4):249-253. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20884287.

43. Jennings C, Harty B, Granger S, et al. Cross-platform analysis of HIV-1 RNA data
generated by a multicenter assay validation study with wide geographic representation. J Clin
Microbiol. 2012;50(8):2737-2747. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22692747.

44. Haas J, Geiss M, Bohler T. False-negative polymerase chain reaction-based diagnosis of

human immunodeficiency virus (HIV) type 1 in children infected with HIV strains of African
origin. J Infect Dis. 1996;174(1):244-245. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/8656008.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-14
45. Kline NE, Schwarzwald H, Kline MW. False negative DNA polymerase chain reaction in
an infant with subtype C human immunodeficiency virus 1 infection. Pediatr Infect Dis J.
2002;21(9):885-886. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12380591.

46. Zaman MM, Recco RA, Haag R. Infection with non-B subtype HIV type 1 complicates
management of established infection in adult patients and diagnosis of infection in newborn
infants. Clin Infect Dis. 2002;34(3):417-418. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11774090.

47. Luft LM, Gill MJ, Church DL. HIV-1 viral diversity and its implications for viral load
testing: review of current platforms. Int J Infect Dis. 2011;15(10):e661-670. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21767972.

48. Sire JM, Vray M, Merzouk M, et al. Comparative RNA quantification of HIV-1 group M
and non-M with the Roche Cobas AmpliPrep/Cobas TaqMan HIV-1 v2.0 and Abbott real-time
HIV-1 PCR assays. J Acquir Immune Defic Syndr. 2011;56(3):239-243. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21164353.

49. Bienczak A, Cook A, Wiesner L, et al. The impact of genetic polymorphisms on the
pharmacokinetics of efavirenz in African children. Br J Clin Pharmacol. 2016;82(1):185-198.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26991336.

50. Bolton Moore C, Capparelli EV, Samson P, et al. CYP2B6 genotype-directed dosing is
required for optimal efavirenz exposure in children 3-36 months with HIV infection. AIDS.
2017;31(8):1129-1136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28323755.

51. Nikanjam M, Tran L, Chadwick EG, et al. Impact of CYP2B6 genotype, tuberculosis
therapy, and formulation on efavirenz pharmacokinetics in infants and children under 40 months
of age. AIDS. 2022;36(4):525-532. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34873089.

52. Small CB, Margolis DA, Shaefer MS, Ross LL. HLA-B*57:01 allele prevalence in HIV-
infected North American subjects and the impact of allele testing on the incidence of abacavir-
associated hypersensitivity reaction in HLA-B*57:01-negative subjects. BMC Infect Dis.
2017;17(1):256. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28399804.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-15
When to Initiate Therapy in Antiretroviral-Naive
Children
Updated: April 11, 2023
Reviewed: April 11, 2023

Panel’s Recommendations
• Antiretroviral therapy (ART) should be initiated in all infants and children with HIV infection (AI for children aged <3 months,
AI* for older children).
o Rapid ART initiation (defined as initiating ART immediately or within days of HIV diagnosis), accompanied by a
discussion of the importance of adherence and provision of subsequent adherence support, is recommended for all
children with HIV.
• If a child with HIV has not initiated ART, health care providers should closely monitor the virologic, immunologic, and
clinical status at least every 3 to 4 months (AIII).

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints;
I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying
data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical
outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term
outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical
outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical
outcome data; III = Expert opinion
†Studies that include children or children/adolescents, but not studies limited to postpubertal adolescents

Overview
The Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV (the
Panel) recommends initiating treatment for all children with HIV as soon as is feasible after
diagnosis. Multiple studies have shown a benefit to early antiretroviral therapy (ART) initiation,1-3
and that ART initiation within the first year of life is associated with reduced size of viral reservoirs.4
Treatment initiation in young infants with HIV during the early stages of infection may control viral
replication before HIV can evolve into diverse and potentially more pathogenic quasi-species.5
Initiation of therapy at higher CD4 T lymphocyte (CD4) counts has been associated with the
presence of fewer drug-resistant mutations at virologic failure in adults.6 Early therapy has also been
shown to preserve immune function and prevent clinical disease progression in perinatal infection7-9
and may prevent or reduce persistent inflammation, a precipitant of cardiovascular, kidney, and liver
disease and malignancy.10,11

Rapid treatment initiation, defined as therapy initiated immediately or within days of HIV diagnosis,
is recommended except in children with cryptococcal meningitis, disseminated Mycobacterium
avium complex disease, or Mycobacterium tuberculosis. Due to concerns regarding the risk of
immune reconstitution inflammatory syndrome, ART initiation may be deferred until the optimal
timing relative to treatment of the opportunistic infection (see Guidelines for the Prevention and
Treatment of Opportunistic Infections in Children With and Exposed to HIV and WHO Updated
Recommendations on HIV Prevention, Infant Diagnosis, Antiretroviral Initiation and Monitoring,
March 2021). Timing of ART initiation in these cases should be discussed with a pediatric HIV
specialist.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-1
Although rapid initiation of ART is recommended in all children with HIV, individual clinical and/or
psychosocial factors may lead patients, caregivers, and providers to make a collaborative decision to
defer ART initiation. When making the decision to defer ART, medical factors—such as the
opportunity to limit seeding of the viral reservoir in newborns, the child’s HIV disease stage,12 and
the presence of HIV-related signs and symptoms13—need to be balanced against any potential
barriers to rapid ART initiation. If ART is deferred, the health care provider should continue to
educate and work with the family to overcome barriers to treatment, as well as closely monitor the
child’s virologic, immunologic, and clinical status at least every 3 to 4 months (AIII) (see Clinical
and Laboratory Monitoring of Pediatric HIV Infection). Clinicians should initiate ART in children
with HIV for whom treatment has been deferred when at least one of the following conditions occur:

• HIV RNA levels increase,

• CD4 count or percentage values decline (e.g., approaching Centers for Disease Control and
Prevention Stage 2 or 3),12
• The child develops new HIV-related clinical symptoms,13
• The ability of a caregiver and child to adhere to the prescribed regimen improves.

Survival and Health Benefits Associated With Early Initiation of Antiretroviral

Therapy
The Children with HIV Early Antiretroviral Therapy (CHER) trial was a randomized clinical trial in
South Africa that initiated ART in infants with HIV who were aged 6 to 12 weeks and were
asymptomatic with normal CD4 percentages (>25%). Immediate initiation of ART resulted in a 75%
reduction in early mortality among these infants, compared with delayed treatment until the infants
met clinical or immune criteria according to standard of care at the time of the study.2 Consistent
with the CHER trial, data from a number of observational studies in the United States, Europe, and
South Africa demonstrated that infants who received early treatment were less likely to progress to
AIDS or death, and they also had improved growth compared with those who started treatment
later.14-17

In general, studies that evaluate later initiation of ART in children have a selection bias, because
children with perinatal infection and rapidly progressing disease may have died prior to receiving an
HIV diagnosis or ART, and children who present later for ART initiation may be slower progressors
with a better prognosis. However, in the multicenter, open-label Pediatric Randomised Early versus
Deferred Initiation in Cambodia and Thailand (PREDICT) trial, which randomized 300 children with
HIV aged 1 year to 12 years at enrollment (median age 6.4 years) to immediately initiate ART or to
defer treatment until their CD4 percentage was <15%, better height gain among children who started
ART immediately was reported.18 Similarly, other studies have reported an association between
younger age at initiation of ART and more rapid growth reconstitution.15,19-21 Studies conducted in
and outside the United States have reported an association between delayed ART initiation and delay
of pubertal development and menarche.22 Finally, among 32 youths with perinatally acquired HIV
from the Pediatric HIV/AIDS Cohort Study (PHACS), DNA methylation evaluating epigenetic aging
was compared to chronologic aging over time. Higher viral load and lower CD4 count were
associated with epigenetic aging that exceeded chronologic aging, highlighting the value of achieving
early viral suppression and maintaining or reconstituting immune function as close to an HIV
diagnosis as possible.23

A proteomics study of children who initiated ART early (within 12 weeks of birth) versus later (12 to
50 weeks after birth) identified a protein signature among later initiators associated with a

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-2
proinflammatory state, which was associated with elevated lipid levels and other metabolites and
clinical parameters, suggestive of a higher risk of premature onset of atherosclerotic disease and
metabolic disorders in adulthood.10 Furthermore, a recent cross-sectional study from Mozambique
found that earlier age at ART initiation was independently associated with improved large artery
stiffness in childhood, as measured by pulse wave velocity, independent of the effect of elevated
visceral fat, lipids, and insulin resistance.11

Neurodevelopmental Benefits Associated With Early Initiation of Antiretroviral

Therapy
A CHER trial substudy found that infants who initiated ART early had significantly better gross
motor and neurodevelopmental profiles than those whose therapy was deferred.24 In a cohort from
Thailand, the prevalence of global developmental impairment was 22% (95% confidence
interval [CI], 11% to 27%) among children with HIV who initiated ART within 3 months of birth,
compared with 44% (95% CI, 23% to 66%) among children who initiated ART from 3 to
12 months.25 A study of South African infants with perinatal HIV infection who initiated ART within
21 days of life (median 6 days) found that neurodevelopmental scores at 11 months of age for these
infants were within the normal range.26

Immune Benefits Associated With Early Initiation of Antiretroviral Therapy

In the CHER study, infants who were treated early had decreased immune activation, greater
recovery of CD4 cells, expanded CD4-naive T cells, and retention of innate effector frequencies,
resulting in greater immune reconstitution than that achieved in infants who received deferred ART.9
In a small study in Botswana, infants who initiated ART within the first 7 days of life were found to
have decreased immune activation, a more polyfunctional HIV-1-specific CD8 cell response, and a
markedly reduced HIV latent reservoir, compared with infants who initiated ART later in the first
year of life.27 Available data suggest that both children and adults who initiate treatment with a
higher CD4 percentage or CD4 count have better immune recovery than patients who initiate
treatment with lower CD4 percentages or CD4 counts.20,28-30 Among 1,236 children with perinatally
acquired HIV in the United States, only 36% of those who started ART with CD4 percentages <15%
achieved CD4 percentages >25% after 5 years of therapy, compared with 59% of children who
started with CD4 percentages of 15% to 24%.31 Finally, earlier age at ART initiation results in higher
rates of CD4:CD8 ratio normalization and improved immunogenicity of childhood vaccines.32-34

Early initiation of suppressive ART (i.e., in infants aged <6 months) results in a significant
proportion of infants with HIV who fail to produce their own HIV-specific antibodies. These infants
appear to be HIV-seronegative when tested; however, viral reservoirs remain, and viral rebound
occurs if ART is stopped.35-40

Viral Suppression and Viral Reservoirs With Early Initiation of Antiretroviral

Therapy
Early initiation of ART within the first 7 days of life, compared with initiation between 8 and 28 days
of life, resulted in a fourfold faster time to viral suppression among infants in a multinational study.41
Studies that compared the size of viral reservoirs in children who initiated ART before age 12 weeks
with those in children who initiated ART at ≥12 weeks to ≤2 years of age found that viral reservoir
size after 1 year and 4 years of ART significantly correlated with younger age at ART initiation and
younger age at viral control.42-44 Among 27 children in the Early-treated Perinatally HIV-infected
Individuals: Improving Children’s Actual Life with Novel Immunotherapeutic Strategies (EPIICAL)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-3
Consortium who initiated ART before 2 years of age and maintained a viral load <50 copies/mL for
more than 5 years, total HIV-1 DNA levels measured at a median of 12 years after treatment
initiation were reduced (interquartile range 7.3–15.4), with younger age and viral load at the time of
ART initiation each associated with lower reservoir levels.45 Finally, in the CHER study, early ART
initiation and longer duration of ART was associated with lower proviral DNA levels at age 5
years.46

These findings suggest that initiating ART soon after an infant acquires HIV can limit the size of the
HIV viral reservoir, and smaller reservoirs may provide some level of protection against viral
rebound in the setting of treatment nonadherence—a frequent event for infants with HIV who are
destined for lifelong treatment. Furthermore, very low levels of markers of HIV persistence have
been reported in infants who initiated ART early and who had sustained control of plasma
viremia.35,47

The report of a prolonged remission in a child with perinatally acquired HIV in Mississippi generated
discussion about early initiation of ART as presumptive treatment in newborns at high risk of HIV
acquisition.48,49 Two other children have experienced prolonged remission following early ART
initiation. A child from the CHER study received ART between 2 and 10 months of age, and in 2019,
at the age of 9.5 years, had HIV-1 detectable only at very low levels (plasma RNA 6.6 copies/mL)
and no detectable replication competent virus.50 A French child was treated with ART from 3 months
of age through approximately 6 years of age, and in 2016, at 18.6 years of age and still off ART, HIV
RNA had remained below 50 copies/mL with stable CD4 cell counts.51

These experiences have prompted increasing support for initiating treatment as soon as the diagnosis
is made, and if possible, during the first weeks of life to limit reservoir formation and possibly
facilitate ART-free remission. Although a limited number of case reports describe lengthy remissions
in children with perinatally acquired HIV who have undergone treatment interruption, current ART
regimens have not been shown to eradicate HIV infection, because HIV persists in CD4 cells and
other long-lived cells.50-53 For these reasons, the Panel does not recommend empiric treatment
interruption outside of a clinical trial setting.

Managing treatment in neonates with HIV is complex from a medical and social perspective.
Because of limited safety and pharmacokinetic (PK) data for ARV drugs in full-term infants aged
<2 weeks and preterm infants aged ≤4 weeks, drug and dose selection in this age group is
challenging54,55 (see What to Start and Antiretroviral Management of Newborns With Perinatal HIV
Exposure or HIV Infection). Hepatic and renal function are immature in newborns who are
undergoing rapid maturational changes during the first few months of life, which can result in
substantial differences in ARV dose requirements between young infants and older children.56,57
When drug concentrations are subtherapeutic—either because of inadequate dosing, poor absorption,
or incomplete adherence—ARV drug resistance can develop rapidly, particularly in young infants
who experience high levels of viral replication. Frequent follow-up for dose optimization during
periods of rapid growth is especially important when treating young infants. Furthermore, clinicians
should continually assess a patient’s adherence and address potential barriers to adherence during this
time (see Adherence to Antiretroviral Therapy in Children and Adolescents With HIV).

Summary
The Panel recommends rapid initiation of ART (defined as initiating ART immediately or within
days of HIV diagnosis) for all children who receive an HIV diagnosis, regardless of clinical,
immunologic, or virologic status. The urgency of rapid ART initiation is especially critical for
children aged <1 year who carry the highest risk of rapid disease progression and mortality.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-4
However, in ART-naive children and adolescents with cryptococcal meningitis, disseminated
Mycobacterium avium complex disease, and Mycobacterium tuberculosis disease, the Panel
recommends initiation of treatment for the opportunistic infection first, ahead of ART initiation (See
Guidelines for the Prevention and Treatment of Opportunistic Infections in Children With and
Exposed to HIV). Timing of ART initiation in these cases should be discussed with a pediatric HIV
specialist.

In preparation for ART initiation, it is important to assess and discuss issues associated with
adherence with caregivers and, when developmentally appropriate, with children. Intensive follow-up
during the first few weeks to months after ART initiation is also recommended to support the child
and caregiver. Medication adherence is the core requirement for successful virologic control. The
Panel recognizes that achieving consistent adherence in children is often challenging.58,59 Incomplete
adherence leads to loss of viral control and the selection of drug-resistant mutations, but forcibly
administrating ARV drugs to younger children may result in treatment aversion, which often persists
into adulthood.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-5
References

1. Schomaker M, Leroy V, Wolfs T, et al. Optimal timing of antiretroviral treatment

initiation in HIV-positive children and adolescents: a multiregional analysis from
Southern Africa, West Africa and Europe. Int J Epidemiol. 2017;46(2):453-465.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27342220.

2. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among
HIV-infected infants. N Engl J Med. 2008;359(21):2233-2244. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19020325.

3. Shiau S, Strehlau R, Technau KG, et al. Early age at start of antiretroviral therapy
associated with better virologic control after initial suppression in HIV-infected infants.
AIDS. 2017;31(3):355-364. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27828785.

4. Massanella M, Puthanakit T, Leyre L, et al. Continuous prophylactic

antiretrovirals/antiretroviral therapy since birth reduces seeding and persistence of the
viral reservoir in children vertically infected with human immunodeficiency virus. Clin
Infect Dis. 2021;73(3):427-438. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32504081.

5. Persaud D, Ray SC, Kajdas J, et al. Slow human immunodeficiency virus type 1
evolution in viral reservoirs in infants treated with effective antiretroviral therapy. AIDS
Res Hum Retroviruses. 2007;23(3):381-390. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17411371.

6. Palumbo PJ, Fogel JM, Hudelson SE, et al. HIV drug resistance in adults receiving early
vs. delayed antiretroviral therapy: HPTN 052. J Acquir Immune Defic Syndr.
2018;77(5):484-491. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29293156.

7. Rinaldi S, Pallikkuth S, Cameron M, et al. Impact of early antiretroviral therapy initiation

on HIV-specific CD4 and CD8 T cell function in perinatally infected children. J
Immunol. 2020;204(3):540-549. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31889024.

8. Planchais C, Hocqueloux L, Ibanez C, et al. Early antiretroviral therapy preserves

functional follicular helper T and HIV-specific B cells in the gut mucosa of HIV-1-
infected individuals. J Immunol. 2018;200(10):3519-3529. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29632141.

9. Azzoni L, Barbour R, Papasavvas E, et al. Early ART results in greater immune

reconstitution benefits in HIV-infected infants: working with data missingness in a
longitudinal dataset. PLoS One. 2015;10(12):e0145320. Available at:
https://pubmed.ncbi.nlm.nih.gov/26671450.

10. Tarancon-Diez L, Rull A, Herrero P, et al. Early antiretroviral therapy initiation effect on
metabolic profile in vertically HIV-1-infected children. J Antimicrob Chemother.
2021;76(11):2993-3001. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34463735.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-6
11. Dobe IS, Mocumbi AO, Majid N, Ayele B, Browne SH, Innes S. Earlier antiretroviral
initiation is independently associated with better arterial stiffness in children living with
perinatally acquired HIV with sustained viral suppression in Mozambique. South Afr J
HIV Med. 2021;22(1):1282. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34858652.

12. Centers for Disease Control and Prevention. Revised surveillance case definition for HIV
infection—United States, 2014. MMWR Recomm Rep. 2014;63(RR-03):1-10. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/24717910.

13. Centers for Disease Control and Prevention. 1994 revised classification system for human
immunodeficiency virus infection in children less than 13 years of age. MMWR.
1994;43(RR-12):1-10. Available at:
https://www.cdc.gov/mmwr/preview/mmwrhtml/00032890.htm.

14. Goetghebuer T, Le Chenadec J, Haelterman E, et al. Short- and long-term immunological

and virological outcome in HIV-infected infants according to the age at antiretroviral
treatment initiation. Clin Infect Dis. 2012;54(6):878-881. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22198788.

15. Shiau S, Arpadi S, Strehlau R, et al. Initiation of antiretroviral therapy before 6 months of
age is associated with faster growth recovery in South African children perinatally
infected with human immunodeficiency virus. J Pediatr. 2013;162(6):1138-1145 e1132.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/23312691.

16. Iyun V, Technau KG, Eley B, et al. Earlier antiretroviral therapy initiation and decreasing
mortality among HIV-infected infants initiating antiretroviral therapy within 3 months of
age in South Africa, 2006–2017. Pediatr Infect Dis J. 2020;39(2):127-133. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31725119.

17. Tagarro A, Dominguez Rodriguez S, Violari A, et al. Poor outcome in early treated HIV
perinatally infected infants in Africa. Abstract 806. Presented at: Conference on
Retroviruses and Opportunistic Infections 2020. Boston, Massachusetts. Available at:
https://www.croiconference.org/abstract/poor-outcome-in-early-treated-hiv-perinatally-
infected-infants-in-africa.

18. Puthanakit T, Saphonn V, Ananworanich J, et al. Early versus deferred antiretroviral

therapy for children older than 1 year infected with HIV (PREDICT): a multicentre,
randomised, open-label trial. Lancet Infect Dis. 2012;12(12):933-941. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23059199.

19. McGrath CJ, Chung MH, Richardson BA, Benki-Nugent S, Warui D, John-Stewart GC.
Younger age at HAART initiation is associated with more rapid growth reconstitution.
AIDS. 2011;25(3):345-355. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21102302.

20. Simms V, Rylance S, Bandason T, et al. CD4+ cell count recovery following initiation of
HIV antiretroviral therapy in older childhood and adolescence. AIDS. 2018;32(14):1977-
1982. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29927784.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-7
21. Traisathit P, Urien S, Le Coeur S, et al. Impact of antiretroviral treatment on height
evolution of HIV infected children. BMC Pediatr. 2019;19(1):287. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31421667.

22. Mwambenu B, Ramoloko V, Laubscher R, Feucht U. Growth and the pubertal growth
spurt in South African adolescents living with perinatally-acquired HIV infection. PLoS
One. 2022;17(1):e0262816. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35077489.

23. Shiau S, Brummel SS, Kennedy EM, et al. Longitudinal changes in epigenetic age in
youth with perinatally acquired HIV and youth who are perinatally HIV-exposed
uninfected. AIDS. 2021;35(5):811-819. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33587437.

24. Tarancon-Diez L, Rull A, Herrero P, et al. Early antiretroviral therapy initiation effect on
metabolic profile in vertically HIV-1-infected children. J Antimicrob Chemother.
2021;76(11):2993-3001. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34463735.

25. Dobe IS, Mocumbi AO, Majid N, Ayele B, Browne SH, Innes S. Earlier antiretroviral
initiation is independently associated with better arterial stiffness in children living with
perinatally acquired HIV with sustained viral suppression in Mozambique. South Afr J
HIV Med. 2021;22(1):1282. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34858652.

26. Laughton B, Cornell M, Grove D, et al. Early antiretroviral therapy improves

neurodevelopmental outcomes in infants. AIDS. 2012;26(13):1685-1690. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22614886.

27. Jantarabenjakul W, Chonchaiya W, Puthanakit T, et al. Low risk of neurodevelopmental

impairment among perinatally acquired HIV-infected preschool children who received
early antiretroviral treatment in Thailand. J Int AIDS Soc. 2019;22(4):e25278. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/30990969.

28. Laughton B, Naidoo S, Dobbels E, et al. Neurodevelopment at 11 months after starting

antiretroviral therapy within 3 weeks of life. South Afr J HIV Med. 2019;20(1):1008.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31745434.

29. Garcia-Broncano P, Maddali S, Einkauf KB, et al. Early antiretroviral therapy in neonates
with HIV-1 infection restricts viral reservoir size and induces a distinct innate immune
profile. Sci Transl Med. 2019;11(520). Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31776292.

30. Picat MQ, Lewis J, Musiime V, et al. Predicting patterns of long-term CD4 reconstitution
in HIV-infected children starting antiretroviral therapy in sub-Saharan Africa: a cohort-
based modelling study. PLoS Med. 2013;10(10):e1001542. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24204216.

31. Le T, Wright EJ, Smith DM, et al. Enhanced CD4+ T-cell recovery with earlier HIV-1
antiretroviral therapy. N Engl J Med. 2013;368(3):218-230. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23323898.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-8
32. Desmonde S, Dicko F, Koueta F, et al. Association between age at antiretroviral therapy
initiation and 24-month immune response in West-African HIV-infected children. AIDS.
2014;28(11):1645-1655. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24804858.

33. Patel K, Hernan MA, Williams PL, et al. Long-term effectiveness of highly active
antiretroviral therapy on the survival of children and adolescents with HIV infection: a
10-year follow-up study. Clin Infect Dis. 2008;46(4):507-515. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18199042.

34. Seers T, Vassallo P, Pollock K, Thornhill JP, Fidler S, Foster C. CD4:CD8 ratio in
children with perinatally acquired HIV-1 infection. HIV Med. 2018;19(9):668-672.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30084150.

35. Moonsamy S, Suchard M, Madhi SA. Effect of HIV-exposure and timing of anti-
retroviral treatment on immunogenicity of trivalent live-attenuated polio vaccine in
infants. PLoS One. 2019;14(4):e0215079. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31002702.

36. Pensieroso S, Cagigi A, Palma P, et al. Timing of HAART defines the integrity of
memory B cells and the longevity of humoral responses in HIV-1 vertically-infected
children. Proc Natl Acad Sci U S A. 2009;106(19):7939-7944. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19416836.

37. Ananworanich J, Puthanakit T, Suntarattiwong P, et al. Reduced markers of HIV

persistence and restricted HIV-specific immune responses after early antiretroviral
therapy in children. AIDS. 2014;28(7):1015-1020. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24384692.

38. Payne H, Mkhize N, Otwombe K, et al. Reactivity of routine HIV antibody tests in
children who initiated antiretroviral therapy in early infancy as part of the children with
HIV early antiretroviral therapy (CHER) trial: a retrospective analysis. Lancet Infect Dis.
2015;15(7):803-809. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26043884.

39. Kuhn L, Schramm DB, Shiau S, et al. Young age at start of antiretroviral therapy and
negative HIV antibody results in HIV-infected children when suppressed. AIDS.
2015;29(9):1053-1060. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25870988.

40. Butler KM, Gavin P, Coughlan S, et al. Rapid viral rebound after 4 years of suppressive
therapy in a seronegative HIV-1 infected infant treated from birth. Pediatr Infect Dis J.
2015;34(3):e48-51. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25742088.

41. Wamalwa D, Benki-Nugent S, Langat A, et al. Treatment interruption after 2-year

antiretroviral treatment initiated during acute/early HIV in infancy. AIDS.
2016;30(15):2303-2313. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27177316.

42. Veldsman KA, Laughton B, Janse van Rensburg A, et al. Viral suppression is associated
with HIV-antibody level and HIV-1 DNA detectability in early treated children at 2 years
of age. AIDS. 2021;35(8):1247-1252. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34076614.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-9
43. Dominguez-Rodriguez S, Tagarro A, Palma P, et al. Reduced time to suppression among
neonates with HIV initiating antiretroviral therapy within 7 days after birth. J Acquir
Immune Defic Syndr. 2019;82(5):483-490. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31714427.

44. McManus M, Mick E, Hudson R, et al. Early combination antiretroviral therapy limits
exposure to HIV-1 replication and cell-associated HIV-1 DNA levels in infants. PLoS
One. 2016;11(4):e0154391. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27104621.

45. Martinez-Bonet M, Puertas MC, Fortuny C, et al. Establishment and replenishment of the
viral reservoir in perinatally HIV-1-infected children initiating very early antiretroviral
therapy. Clin Infect Dis. 2015;61(7):1169-1178. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26063721.

46. van Zyl GU, Bedison MA, van Rensburg AJ, Laughton B, Cotton MF, Mellors JW. Early
antiretroviral therapy in South African children reduces HIV-1-infected cells and cell-
associated HIV-1 RNA in blood mononuclear cells. J Infect Dis. 2015;212(1):39-43.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25538273.

47. Foster C, Dominguez-Rodriguez S, Tagarro A, et al. The CARMA study: early infant
antiretroviral therapy-timing impacts on total HIV-1 DNA quantitation 12 years later. J
Pediatric Infect Dis Soc. 2021;10(3):295-301. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32678875.

48. Payne H, Chan MK, Watters SA, et al. Early ART-initiation and longer ART duration
reduces HIV-1 proviral DNA levels in children from the CHER trial. AIDS Res Ther.
2021;18(1):63. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34587974.

49. Bitnun A, Samson L, Chun TW, et al. Early initiation of combination antiretroviral
therapy in HIV-1-infected newborns can achieve sustained virologic suppression with
low frequency of CD4+ T cells carrying HIV in peripheral blood. Clin Infect Dis.
2014;59(7):1012-1019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24917662.

50. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after
treatment cessation in an infant. N Engl J Med. 2013;369(19):1828-1835. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24152233.

51. Luzuriaga K, Gay H, Ziemniak C, et al. Viremic relapse after HIV-1 remission in a
perinatally infected child. N Engl J Med. 2015;372(8):786-788. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25693029.

52. Violari A, Cotton MF, Kuhn L, et al. A child with perinatal HIV infection and long-term
sustained virological control following antiretroviral treatment cessation. Nat Commun.
2019;10(1):412. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30679439.

53. Frange P, Faye A, Avettand-Fenoel V, et al. HIV-1 virological remission lasting more
than 12 years after interruption of early antiretroviral therapy in a perinatally infected
teenager enrolled in the French ANRS EPF-CO10 paediatric cohort: a case report. Lancet
HIV. 2016;3(1):e49-54. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26762993.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-10
54. Shiau S, Abrams EJ, Arpadi SM, Kuhn L. Early antiretroviral therapy in HIV-infected
infants: can it lead to HIV remission? Lancet HIV. 2018;5(5):e250-e258. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29739699.

55. Koofhethile CK, Moyo S, Kotokwe KP, et al. Undetectable proviral deoxyribonucleic
acid in an adolescent perinatally infected with human immunodeficiency virus-1C and on
long-term antiretroviral therapy resulted in viral rebound following antiretroviral therapy
termination: a case report with implications for clinical care. Medicine (Baltimore).
2019;98(47):e18014. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31764816.

56. Cotton MF, Holgate S, Nelson A, Rabie H, Wedderburn C, Mirochnick M. The last and
first frontier—emerging challenges for HIV treatment and prevention in the first week of
life with emphasis on premature and low birth weight infants. J Int AIDS Soc.
2015;18(Suppl 6):20271. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26639118.

57. Clarke DF, Penazzato M, Capparelli E, et al. Prevention and treatment of HIV infection
in neonates: evidence base for existing WHO dosing recommendations and
implementation considerations. Expert Rev Clin Pharmacol. 2018;11(1):83-93. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/29039686.

58. Bekker A, Capparelli EV, Violari A, et al. Abacavir dosing in neonates from birth to 3
months of life: a population pharmacokinetic modelling and simulation study. Lancet
HIV. 2022;9(1):e24-e31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34883066.

59. Chadwick EG, Yogev R, Alvero CG, et al. Long-term outcomes for HIV-infected infants
less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral
therapy. AIDS. 2011;25(5):643-649. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21297419.

60. Hazra R, Siberry GK, Mofenson LM. Growing up with HIV: children, adolescents, and
young adults with perinatally acquired HIV infection. Annu Rev Med. 2010;61:169-185.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19622036.

61. Simoni JM, Montgomery A, Martin E, New M, Demas PA, Rana S. Adherence to
antiretroviral therapy for pediatric HIV infection: a qualitative systematic review with
recommendations for research and clinical management. Pediatrics. 2007;119(6):e1371-
1383. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17533177.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-11
What to Start: Regimens Recommended for Initial
Therapy of Antiretroviral-Naive Children
Updated: April 11, 2023
Reviewed: April 11, 2023

Panel’s Recommendations
• The selection of an initial antiretroviral (ARV) regimen should be individualized based on several factors, including the
characteristics of the proposed regimen, the patient’s characteristics, drug efficacy, potential adverse effects, patient and
family preferences, and the results of viral resistance testing (AIII).
• For treatment-naive children, the Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV
(the Panel) recommends initiating antiretroviral therapy with three drugs: a dual-nucleoside/nucleotide reverse
transcriptase inhibitor backbone plus an integrase strand transfer inhibitor, a non-nucleoside reverse transcriptase inhibitor,
or a boosted protease inhibitor (AI*).
• Table 8 below provides a list of Panel-recommended ARV regimens that are designated as Preferred or Alternative;
recommendations vary by a patient’s age, weight, and sexual maturity rating.
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints;
I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying
data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical
outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term
outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical
outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical
outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to postpubertal adolescents

Criteria Used for Recommendations

In general, the recommendations of the Panel on Antiretroviral Therapy and Medical Management of
Children Living With HIV (the Panel) are based on reviews of pediatric and adult clinical trial data
published in peer-reviewed journals, data prepared by manufacturers for U.S. Food and Drug
Administration (FDA) review, and data presented in abstract format at major scientific meetings.
Few randomized, Phase 3 clinical trials of antiretroviral therapy (ART) in pediatric patients have
directly compared different treatment regimens. Most pediatric drug data come from Phase 1/2 safety
and pharmacokinetic (PK) trials and nonrandomized, open-label studies. In general, even in studies
of adults, assessment of drug efficacy and potency is primarily based on surrogate marker endpoints,
such as CD4 T lymphocyte (CD4) cell count and viral load. The Panel continually modifies
recommendations on optimal initial therapy for children as new data become available, as new
therapies or drug formulations are developed, and as additional toxicities are recognized.

When developing recommendations for specific drugs or regimens, the Panel considers the following
information:

• Data demonstrating durable viral suppression, immunologic improvement, and clinical

improvement (when available) with the drug or regimen, preferably in children, as well as adults;
• The extent of pediatric experience with a specific drug or regimen;

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-1
• The incidence and types of short-term and long-term drug toxicity in people who are taking the
drug or regimen, focusing on toxicities that are reported in children;
• The availability and acceptability of formulations that are appropriate for pediatric use, including
palatability, ease of preparation (e.g., syrups vs. powders), pill size, and the number of pills or
volume of oral solution needed for an appropriate dose;
• Dosing frequency, and food and fluid requirements; and
• The potential for drug interactions with other medications.

The Panel classifies recommended drugs or drug combinations into one of two categories:

• Preferred: Drugs or drug combinations are designated as Preferred for use in treatment-naive
children when clinical trial data in children or, more often, in adults have demonstrated optimal
and durable efficacy with acceptable toxicity and ease of use, and when pediatric studies using
surrogate markers have demonstrated safety and appropriate drug exposure. Additional
considerations are listed above.
• Alternative: Drugs or drug combinations are designated as Alternative for initial therapy when
clinical trial data in children or adults show efficacy, but the drugs or drug combinations have
disadvantages when compared with Preferred regimens. Drugs or drug combinations may be
classified as Alternative for use in treatment-naive children if they are less effective or durable
than a Preferred regimen in adults or children; if specific concerns exist about toxicity, dosing,
formulation, administration, or interaction; or if experience with the use of these drugs or drug
combinations in children is limited.

Factors to Consider When Selecting an Initial Regimen

An antiretroviral (ARV) regimen for children should generally consist of two nucleoside reverse
transcriptase inhibitors (NRTIs) plus an active drug from one of the following classes: an integrase
strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase inhibitor (NNRTI), or a
boosted protease inhibitor (PI). Choice of a regimen should be individualized based on several
factors, including the characteristics of the proposed regimen; the patient’s age, weight, sexual
maturity rating (SMR), and other characteristics; and the results of drug-resistance testing.

Drug recommendations often include both age and weight limitations. Although age can be used as a
rough guide, body weight (when available) is the preferred determinant for selecting a specific drug.
An exception to this is infants aged <14 days. Many drugs that are recommended for use in very
young infants do not have dosing recommendations for premature infants. Additional information
regarding dosing recommendations in this population can be found in Antiretroviral Management of
Newborns With Perinatal HIV Exposure or HIV Infection.

The advantages and disadvantages of each regimen are described in detail in the sections that follow
and in Table 8 below. Additional information regarding the advantages and disadvantages of specific
drug combinations can be found in the What to Start: Initial Combination Antiretroviral Regimens
for People With HIV section of the Adult and Adolescent Antiretroviral Guidelines. Specific
information about the clinical efficacy, adverse events (AEs), and dosing recommendations for each
drug can be found in Appendix A: Pediatric Antiretroviral Drug Information. In addition, clinicians
should consider potential barriers to adherence. These barriers may include complex dosing
schedules, food requirements, palatability problems, and the need to use multiple formulations to
achieve an appropriate dose. Counseling patients and caregivers about adherence to therapy is

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-2
essential for successful ART. The Panel recommends rapid initiation of ART (defined as initiating
ART immediately or within days of diagnosis).

Emtricitabine (FTC), lamivudine (3TC), tenofovir disoproxil fumarate (TDF), and tenofovir
alafenamide (TAF) have antiviral activity and efficacy against hepatitis B virus (HBV) and should be
considered for use in children with HBV/HIV coinfection. For a comprehensive review, see the
Hepatitis B Virus, Hepatitis C Virus, and Mycobacterium tuberculosis (TB) sections of the Pediatric
Opportunistic Infection Guidelines.

Choosing an Initial Antiretroviral Regimen for Children With HIV

Preferred regimens for initial ARV therapy include INSTI-based, NNRTI-based, or boosted PI-based
regimens. A regimen should be chosen after considering the patient’s individual characteristics
(especially age), the results of drug-resistance testing, potential AEs, pill size, and dosing frequency.
Adherence to a prescribed regimen is necessary; therefore, the preferences of the patient and
caregivers also should be considered when choosing a regimen.

Clinical trial data in children provide some guidance for choosing between an NNRTI-based regimen
and a PI-based regimen for initial therapy. Three pediatric studies have compared an NNRTI-based
regimen to a PI-based regimen, and results varied based on the age of the population studied and the
specific drug used within the class.

• The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1060 study
demonstrated the superiority of a lopinavir/ritonavir (LPV/r)-based regimen over a nevirapine
(NVP)-based regimen in infants and children aged 2 months to 35 months, regardless of maternal
or infant exposure to peripartum, single-dose NVP prophylaxis. In children with prior NVP
exposure, 21.7% of children receiving the LPV/r-based regimen experienced death, virologic
failure, or toxicity by Week 24 compared with 39.6% of children receiving the NVP-based
regimen. For children with no prior NVP exposure, death, virologic failure, and toxicity occurred
in 18.4% of children receiving the LPV/r-based regimen and in 40.1% of children receiving the
NVP-based regimen.1
• Those in the NVP group demonstrated greater, but not statistically significant, improvements in
CD4 counts and growth parameters. However, improvements in CD4 counts were maintained
only up to 1 year after initiation of ART.2 Similar improved immune and growth parameters were
reported in the Nevirapine Resistance (NEVEREST) study, where these parameters were
compared in children who were switched to an NVP-containing regimen and those who were
continued on an LPV/r-containing regimen after achieving virologic suppression.3 Improvements
in metabolic parameters also have been seen in children who were switched from LPV/r to
efavirenz (EFV) at or after 3 years of age.4
• PENPACT-1 (PENTA 9/PACTG 390) compared a PI-based regimen and an NNRTI-based
regimen in treatment-naive children aged 30 days to <18 years (the study did not dictate the use
of specific NNRTIs or PIs). In the PI-based regimen group, 49% of children received LPV/r and
48% received nelfinavir; in the NNRTI-based regimen group, 61% of children received EFV and
38% received NVP. After 4 years of follow-up, 73% of children who were randomized to receive
PI-based therapy and 70% who were randomized to receive NNRTI-based therapy remained on
their initial ARV regimen. In both groups,5 82% of children had viral loads <400 copies/mL.
• The PROMOTE pediatrics trial demonstrated comparable virologic efficacy among children who
were randomized to receive either an NNRTI-based or an LPV/r-based ARV regimen.6 Children
were aged 2 months to <6 years and had no perinatal exposure to NVP. Selection of the NNRTI
was based on age (children aged <3 years received NVP, and those aged >3 years primarily

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-3
 received EFV). The proportion of children with viral loads <400 copies/mL at 48 weeks was 80%
in the LPV/r arm versus 76% in the NNRTI arm, a difference of 4% that was not statistically
significant (95% confidence interval [CI], –9% to +17%).

Clinical investigation of INSTI-based regimens in children has been limited to noncomparative

studies that have evaluated the safety, tolerability, and PKs of these drugs. The recommendation for
using an INSTI as part of an initial regimen is based largely on extrapolation from adult comparative
trials—which showed that INSTI-containing regimens have superior efficacy when compared to PI-
containing and NNRTI-containing regimens7,8—and small studies in ART-naive adolescents.9

When combined with two NRTIs, the following drugs and drug combinations are considered
Preferred initial regimens for children:

• Newborns aged <14 days: NVP

• Newborns aged <4 weeks and weighing ≥2 kg: raltegravir (RAL)
• Newborns aged ≥14 days to <4 weeks: LPV/r
• Infants and children aged ≥4 weeks and weighing ≥3 kg: dolutegravir (DTG)
• Children aged ≥2 years and weighing ≥14 kg: DTG or bictegravir (BIC). BIC is available only as
a component of the fixed-dose combination (FDC) tablet BIC/emtricitabine/tenofovir
alafenamide (BIC/FTC/TAF).

Preferred initial regimens by age, weight, and drug class are shown in Figure 1 below. Additional
information about Preferred initial regimens, Preferred NRTI backbones, Alternative initial
regimens, and Alternative NRTI backbones are shown in detail in Table 8 below.

Integrase Strand Transfer Inhibitor–Based Regimens

Four INSTIs—BIC, DTG, elvitegravir (EVG), and RAL—are approved by the FDA for treating
ARV-naive adults and children with HIV. INSTI-based regimens have quickly become the
recommended regimens in adults due to their virologic efficacy, lack of drug interactions, and
favorable toxicity profile. RAL is approved for the treatment of infants and children from birth
onward with a weight of ≥2 kg. DTG is approved by the FDA for use in infants and children aged ≥4
weeks and weighing ≥3 kg. The FDC tablet BIC/FTC/TAF (Biktarvy) is approved by the FDA for
use in children weighing ≥14 kg. EVG has been studied in adolescents in two FDC regimens and in
combination with two NRTIs and ritonavir (RTV, r) boosting. BIC and DTG, the second-generation
INSTIs, have higher barriers to resistance than the first-generation INSTIs RAL and EVG10,11 and
may have more activity against non-B subtypes of HIV.12,13

Table 8 below lists the advantages and disadvantages of using INSTIs. See Appendix A: Pediatric
Antiretroviral Drug Information for detailed pediatric information on each drug.

Preferred and Alternative INSTIs are presented in alphabetical order below.

Bictegravir
BIC/FTC/TAF was approved by the FDA in 2018 for use in adults and in 2019 for use in children or
adolescents weighing ≥25 kg. In October 2021, a lower strength formulation of BIC/FTC/TAF
received FDA approval for use in children weighing ≥14 kg to <25 kg. BIC/FTC/TAF is approved
for use in patients who are ART naive, and it also can be used to replace the current ARV regimen in

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-4
patients who have been virologically suppressed (viral load <50 copies/mL) on a stable ARV
regimen, with no history of treatment failure, and no known substitutions associated with resistance
to the individual components of the FDC tablet.

BIC/FTC/TAF has been studied in adolescents (Cohort 1) aged 12 years to <18 years and weighing
≥35 kg and in two younger cohorts of children: Cohort 2, aged 6 years to <12 years and weighing
≥25 kg, and Cohort 3, aged ≥2 years and weighing ≥14 kg to <25 kg. All participants had maintained
viral loads <50 copies/mL for ≥6 months. Cohorts 1 and 2 received the adult formulation of
BIC/FTC/TAF. Children in Cohort 3 received BIC 30 mg/FTC 120 mg/TAF 15 mg. Overall, the
drug was well tolerated in all participants in all cohorts. Drug exposure in all cohorts was similar to
the exposure observed in adults. At 24 weeks, all 50 adolescents (Cohort 1) and 50 children
(Cohort 2) maintained viral suppression, and at Week 48, 49 of 50 participants in each cohort
maintained suppression.14-15,16 Among children in Cohort 3, after 24 weeks, all 12 participants
maintained viral suppression.15,16

Recommendation

• BIC/FTC/TAF is recommended as a Preferred INSTI-based regimen for children aged ≥2 years

and weighing ≥14 kg (AI*). The Panel bases this recommendation on the virologic potency and
safety profile observed for this combination in adult and pediatric studies.

Dolutegravir
DTG is approved by the FDA for use in infants and children ≥4 weeks and weighing ≥3 kg. This
recommendation is based on PK and safety data from two ongoing clinical trials (IMPAACT P1093
and ODYSSEY),17,18 as well as a study of treatment-experienced (but INSTI-naive) older
children.9,19-21

Recommendation

• DTG plus a two-NRTI backbone is recommended as a Preferred INSTI-based regimen for

infants, children, and adolescents aged ≥4 weeks and weighing ≥3 kg (AI*). The Panel bases this
recommendation on the virologic potency and safety profile observed for this combination in
adult and pediatric studies.7,9,17,18,21-23
• Early concerns about the potential increased risk of NTDs with the use of DTG in women who
were receiving DTG at the time of conception have decreased substantially. The Panel for
Antiretroviral Guidelines for Adults and Adolescents and the Panel on Treatment of HIV During
Pregnancy and Prevention of Perinatal Transmission include DTG among the preferred ARV
agents for use in people of childbearing potential and for use by people who are pregnant or are
trying to conceive. Pediatric and adolescent care providers should discuss risks and benefits with
patients (and their caregivers) who are receiving or initiating DTG so that they can make
informed decisions about the use of DTG (see Appendix C: Antiretroviral Counseling Guide for
Health Care Providers in the Perinatal Guidelines).

Elvitegravir
EVG is an INSTI that is available as a single-drug tablet, an FDC tablet that contains
EVG/cobicistat (COBI, c)/FTC/TDF, and an FDC tablet that contains EVG/c/FTC/TAF. Both FDC
tablets are approved by the FDA for use in ART-naive adults with HIV. EVG/c/FTC/TAF is
approved for use in ART-naive children and adolescents weighing ≥25 kg. COBI, c is a specific,

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-5
potent cytochrome P450 (CYP) 3A inhibitor that has no activity against HIV. It is used as a PK
enhancer, which allows once-daily dosing of EVG.

Recommendation

• EVG/c/FTC/TAF is recommended as an Alternative INSTI-based regimen for children and

adolescents weighing ≥25 kg who have creatinine clearance (CrCl) ≥30 mL/min (AI*). The
Panel bases this recommendation on the virologic potency and safety profile observed for this
combination in adult and adolescent studies. The Panel does not recommend EVG/c/FTC/TAF as
a Preferred INSTI-based regimen because EVG has a lower barrier to resistance compared with
BIC or DTG and the potential for multiple drug–drug interactions from COBI.24-28

Raltegravir
RAL is approved by the FDA for treatment of infants and children weighing ≥2 kg, and it can be
used starting at birth. It is available in film-coated tablets, chewable tablets, and single-use packets of
granules for oral suspension. Clinicians should consult with an expert in pediatric HIV infection
when initiating RAL-based treatment regimens in neonates, infants, and very young children.
Additional information can be found in Antiretroviral Management of Newborns With Perinatal HIV
Exposure or HIV Infection.

Recommendation

• RAL plus a two-NRTI backbone is recommended as a Preferred INSTI-based regimen for

infants and children from birth to age 4 weeks who weigh ≥2 kg (AI*). It is an Alternative
INSTI-based regimen for children aged ≥4 weeks due to its twice-daily dosing requirement and
lower barrier to resistance compared with other INSTIs (AI*). The Panel bases this
recommendation on data from randomized clinical trials in adults and pediatric studies that were
performed largely in ARV-experienced children and adolescents.7,29-37
• Currently, the Panel does not recommend once-daily dosing of RAL for initial therapy in
children and infants.

Non-Nucleoside Reverse Transcriptase Inhibitor–Based Regimens

Doravirine (DOR; for children weighing ≥35 kg), EFV (for children aged ≥3 months),
etravirine (ETR; for children aged ≥6 years), NVP (for children aged ≥15 days), and rilpivirine
(RPV; for children aged ≥12 years) have been approved by the FDA for treatment of HIV infection
in pediatric patients. NNRTIs have a long half-life that allows less frequent drug administration; a
lower risk of dyslipidemia and fat maldistribution than some agents in the PI class; and, generally, a
lower pill burden than PIs. However, a single viral mutation can confer high-level drug resistance to
all NNRTIs except ETR, and cross-resistance to other NNRTIs is common. Rare, but serious and
potentially life-threatening, skin and hepatic toxicity can occur with the use of all NNRTI drugs, but
these AEs are most frequently observed in patients taking NVP, at least among adults with HIV.
NNRTIs have the potential to interact with other drugs that are also metabolized via hepatic
enzymes; however, these drug interactions are less frequent with NNRTIs than with boosted-PI
regimens. Table 8 below lists the advantages and disadvantages of using NNRTIs. See Appendix A:
Pediatric Antiretroviral Drug Information for detailed pediatric information for each drug.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-6
Preferred and Alternative NNRTIs are presented in alphabetical order below.

Doravirine
DOR is available both as a single-drug tablet and an FDC tablet that contains DOR 100 mg/3TC
300 mg/TDF 300 mg, marketed as Delstrigo. Efficacy studies in adults have demonstrated that
DOR/3TC/TDF is noninferior to EFV-based regimens and darunavir (DRV)-based regimens.
Virologic efficacy of DOR was similar in patients with higher viral loads >100,000 copies/mL as to
those with viral loads ≤100,000 copies/mL. DOR, more so than EFV, compared favorably to the
other drugs in these trials in terms of AEs (including better central nervous system tolerability) and is
recommended as initial ART in adults with certain clinical situations. The FDC tablet has been
studied in 45 adolescents aged 12 to 17 years and weighing ≥45 kg. Of these adolescents, 43 were
virologically suppressed and two were ART naive. After 24 weeks of treatment, the regimen was
well tolerated, with a low incidence of drug-related AEs (2.2%; 95% CI, 0.1–11.8). None of the AEs
were serious or led to regimen discontinuation. HIV-1 RNA <50 copies/mL was demonstrated in all
participants except for one ART-naive participant who met the criteria for virologic failure based on
poor adherence to the study regimen.38

Recommendation

• DOR plus a two-NRTI backbone is recommended as an Alternative NNRTI-based regimen for

initial treatment of HIV in children and adolescents weighing ≥35 kg (BI*). The Panel bases this
recommendation on data from studies that evaluated the efficacy and tolerability of this drug in
adults,39-41 as well as early findings from pediatric PK studies.38

Efavirenz
Although EFV dosing recommendations are available for patients aged ≥3 months and weighing
≥3.5 kg, the Panel does not endorse the use of this drug in infants and children aged 3 months to
3 years because the PKs of EFV in very young patients can be highly variable. There may be a role
for use of EFV in children aged <3 years who have HIV and TB coinfection, because EFV is one of
the few ARVs with minimal drug–drug interaction.42

Recommendation

• EFV plus a two-NRTI backbone is recommended as an Alternative NNRTI-based regimen for

initial treatment of HIV in children aged ≥3 years (AI*). The Panel bases this recommendation
on data from studies that evaluated the efficacy and tolerability of this drug in adults and
children.22,29,43-60
Nevirapine
Extensive clinical and safety data exist for the use of NVP in children with HIV, and NVP has shown
ARV efficacy when used as a component in a variety of combination regimens.1,5,6,61-65 NVP also has
been used extensively as prophylaxis for the prevention of HIV transmission in young infants during
the peripartum period and during breastfeeding.66 The safety and PKs of NVP have been studied at
low doses used for prophylaxis. Less information is currently available from studies in very young
infants about the safety and PKs of NVP at the higher doses required for treatment.

Early testing of infants allows HIV infection to be confirmed before 14 days of age. The Panel
recommends the use of NVP as a Preferred NNRTI when a clinician plans to initiate treatment
before age 14 days. Although early treatment initiation may limit the size of the viral reservoir,67,68

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-7
no clinical trial data currently suggest that initiating treatment within the first 14 days of life
improves outcomes compared to starting treatment after age 14 days (see When to Initiate Therapy in
Antiretroviral-Naive Children). Clinicians should consult an expert in pediatric HIV infection when
considering the use of NVP in infants aged <14 days. Additional considerations regarding the use of
NVP in infants aged <14 days can be found in Antiretroviral Management of Newborns With
Perinatal HIV Exposure or HIV Infection.

Recommendation

• NVP plus a two-NRTI backbone is recommended as a Preferred NNRTI-based regimen in

infants aged <14 days and as an Alternative NNRTI-based regimen for children aged ≥14 days to
<3 years (AI). Clinicians should consider switching from NVP to LPV/r or RAL in children aged
≥14 days to <4 weeks because these drugs are the Preferred ARV agents for this age bracket.
LPV/r has better clinical outcomes than NVP in children aged <3 years. The Panel recommends
switching from NVP to LPV/r in these patients because NVP is associated with rare occurrences
of significant hypersensitivity reactions, including Stevens-Johnson syndrome, and rare (but
potentially life-threatening) instances of hepatitis. NVP also has a low barrier to resistance, and
conflicting data exist about the virologic efficacy of NVP-based regimens compared to the
efficacy of Preferred regimens.1,5,6,63-65,69-76

Rilpivirine
RPV is currently available both as a single-drug tablet and in once-daily FDC tablets. Three-drug
FDC tablets containing FTC/RPV/TDF or FTC/RPV/TAF are approved for use in children and
adolescents weighing ≥35 kg and aged ≥12 years.

RPV also is available as an extended-release injectable suspension in a kit that contains an extended-
release injectable cabotegravir (CAB) suspension. The two-drug regimen of injectable CAB and RPV
is not approved for initial ARV therapy but is FDA approved for use in adults and in children and
adolescents aged ≥12 years and weighing ≥35 kg after they have obtained viral suppression on
another regimen.

Recommendation

• RPV plus a two-NRTI backbone is recommended as an Alternative NNRTI-based regimen for

children and adolescents aged ≥12 years and weighing ≥35 kg who have HIV viral loads
≤100,000 copies/mL (AI*). The Panel bases this recommendation on the limited experience with
RPV in adolescents and the larger body of evidence in adults.50,77-80

Protease Inhibitor–Based Regimens

Advantages of PI-based regimens include excellent virologic potency and a high barrier to drug
resistance (because multiple mutations are required for a patient to develop resistance). However,
because PIs are metabolized via hepatic enzymes, these drugs have the potential for multiple drug
interactions. They also may be associated with metabolic complications, such as dyslipidemia, fat
maldistribution, and insulin resistance. Factors to consider when selecting a PI-based regimen for
treatment-naive children include virologic potency, dosing frequency, pill burden, food or fluid
requirements, the availability of palatable pediatric formulations, the drug interaction profile, the
toxicity profile (particularly toxicities related to metabolic complications), the age of the child, and
the availability of data regarding the use of the drug in children. Table 8 below lists the advantages

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-8
and disadvantages of using PIs. See Appendix A: Pediatric Antiretroviral Drug Information for
detailed pediatric information on each drug.

RTV is a potent inhibitor of the CYP3A4 isoenzyme and can be used in low doses as a PK booster
when coadministered with some PIs, increasing drug exposure by prolonging the half-life of the
boosted PI. Currently, only LPV/r is available as a coformulated product. In addition, the use of RTV
boosting increases the risk of hyperlipidemia81 and drug interactions. COBI is an alternative
CYP3A4 inhibitor that also can be used as a booster. It is available in a single-drug tablet and in
coformulations with atazanavir (ATV) and with DRV. Currently, the single-drug tablet is approved
by the FDA for administration with ATV in children weighing ≥35 kg and for administration with
DRV in children weighing ≥40 kg.

Preferred and Alternative PIs are presented in alphabetical order below.

Atazanavir Boosted With Ritonavir or Cobicistat

ATV is a once-daily PI that was approved by the FDA in March 2008 for use in combination with a
two-NRTI backbone in children aged ≥6 years. ATV is most often boosted with RTV. Approval was
extended in 2014 for use in infants and children aged ≥3 months and weighing ≥5 kg.82,83 ATV
administered in combination with COBI has been approved by the FDA for use in adults (using the
single-agent COBI tablet) and in children weighing ≥35 kg.

Recommendation

• ATV/r plus a two-NRTI backbone is recommended as an Alternative PI-based regimen for

children aged ≥3 months (AI*). ATV/c plus a two-NRTI backbone is an Alternative PI-based
regimen for children weighing ≥35 kg. These regimens have been shown to be virologically
potent in adult and pediatric studies and have been well tolerated in pediatric studies. However,
the oral powder formulations of ATV and RTV and the oral solution formulation of RTV can be
cumbersome to administer.32,46,79,81,84-89
• The Panel does not recommend the use of unboosted ATV.

Darunavir Boosted With Ritonavir or Cobicistat

DRV/r is approved by the FDA for use in ARV-naive and ARV-experienced children aged ≥3 years
and weighing ≥10 kg. In addition, once-daily dosing of DRV/r is approved for ARV-naive children
aged ≥3 years and weighing ≥10 kg, and for ARV-experienced patients who do not have DRV
resistance-associated mutations. Once-daily dosing of DRV/r was investigated during a substudy of a
twice-daily dosing trial in children aged 3 years to <12 years. This PK evaluation lasted only
2 weeks, after which the participants were switched back to the twice-daily regimen.90 FDA dosing
recommendations are based on PK models from this study, but this dose has never undergone trials
for clinical efficacy in this age group. A more recent study also suggested that once-daily DRV/r
dosing is acceptable for children and adolescents. In this study, the plasma concentration-time curve
for DRV/r was substantially lower than the mean value observed in adults; however, trough levels
were similar. Due to these findings, and because of the lack of more information about the efficacy of
once-daily DRV/r dosing in ARV-naive and ARV-experienced children aged <12 years, the Panel
recommends a twice-daily dose of DRV/r in children aged >3 years to <12 years.91 DRV
administered in combination with COBI has been approved by the FDA for use in adults (using the
single-agent COBI tablet) and in children weighing ≥40 kg.92

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-9
Recommendation

• DRV/r plus a two-NRTI backbone is recommended as an Alternative PI-based regimen for

children aged ≥3 years and weighing ≥10 kg (AI*). The Panel bases these recommendations on
the virologic potency shown by DRV/r in adult and pediatric studies, and this combination’s high
barrier to the development of drug resistance and excellent toxicity profile in adults and
children.32,93-100
• Based on findings from the DIONE study, once-daily dosing of DRV/r can be used as part of an
Alternative PI-based regimen in ARV-naive children and adolescents weighing ≥40 kg (AI*).
• Twice-daily dosing of DRV/r should be used for children aged ≥3 years to <12 years.
• Twice-daily dosing of DRV/r should be used when the following DRV resistance-associated
substitutions are present in the HIV protease: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P,
L76V, I84V, and L89V.
• DRV/c plus a two-NRTI backbone is recommended as an Alternative PI-based regimen for
adolescents aged ≥12 years and weighing ≥40 kg who are not sexually mature.

Lopinavir/Ritonavir
LPV/r is approved to treat HIV infection in infants and children with a postmenstrual age ≥42 weeks
and postnatal age ≥14 days. Once-daily LPV/r dosing is approved by the FDA for initial therapy in
adults,101 but PK data in children do not support a recommendation for once-daily dosing.102,103

Recommendation

LPV/r plus a two-NRTI backbone is recommended as a Preferred PI-based regimen for infants with
a postmenstrual age ≥42 weeks and postnatal age ≥14 days to <4 weeks (AI) and as an Alternative
PI-based regimen in children aged ≥4 weeks (AI*). This regimen has been shown to be virologically
potent in adult and pediatric studies and has been well tolerated in pediatric studies. Although it is
recommended only as a Preferred PI-based regimen for a narrow age range, use of LPV/r is
supported by many Panel members as a Preferred PI-based regimen in children up to 3 years of age
due to extensive experience with this drug and ease of administering a liquid formulation in infants
and very young children.22,48,84,85,93,101-108

Selection of Dual-Nucleoside Reverse Transcriptase Inhibitor Backbone as Part of

Initial Combination Therapy
Dual-NRTI combinations form the backbone of combination regimens for both adults and children.
The advantages and disadvantages of the different dual-NRTI backbone options that are
recommended for initial therapy in children are listed in Table 8 below.14,28,56,86,109-113

See What Not to Start: Regimens Not Recommended for Use in Antiretroviral-Naive Children for
more information. Also, see Appendix A: Pediatric Antiretroviral Drug Information for detailed
pediatric information on each drug.

In the dual-NRTI backbones listed below, 3TC and FTC are interchangeable. Both 3TC and FTC are
well tolerated and have few AEs. FTC is similar to 3TC and can be substituted for 3TC as one
component of a Preferred dual-NRTI backbone (i.e., FTC used in combination with ABC, TDF, or
zidovudine [ZDV]). The main advantage of FTC over 3TC is that it can be administered once daily
as part of an initial regimen. Both 3TC and FTC select for the M184V resistance mutation, which is

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-10
associated with high-level resistance to both drugs, a modest decrease in susceptibility to ABC, and
improved susceptibility to ZDV and TDF as a result of decreased viral fitness.114,115

The Panel no longer recommends using didanosine or stavudine as part of ARV regimens for
children due to the significant toxicities observed when using these drugs and the availability of safer
agents. These drugs are no longer commercially available for use in general.

Dual-NRTI combinations are presented in alphabetical order below.

Abacavir in Combination With Lamivudine or Emtricitabine

ABC is approved by the FDA for use in children aged ≥3 months when administered as part of an
ARV regimen. ABC also has been reported to be safe in infants and children aged ≥1 month. More
recently, an ABC dosing recommendation using PK simulation models has been endorsed by the
World Health Organization using weight-band dosing for full-term infants from birth to 1 month of
age. Based on this endorsement, the Panel recommends ABC from birth in full-term infants testing
negative for the HLA-B5701 allele.116,117

Recommendation

• ABC plus 3TC or FTC is recommended as the Preferred dual-NRTI combination for children
aged ≥3 months (AI) and for full-term infants from birth (BIII). A negative test for the HLA-
B5701 allele should be obtained prior to starting ABC regardless of age.
• Studies of adults and children have reported virologic efficacy and favorable toxicity profiles for
these combinations.30,118-125 Recent data provide reassuring from the IMPAACT P1106 trial and
two observational cohorts provide reassuring support for the safety of ABC use in infants when
initiated at age <3 months.126-128 Additional information about the use of ABC between birth and
1 month of age can be found in the Appendix A: Pediatric Antiretroviral Drug Information. Due
to ABC-associated hypersensitivity, negative testing for HLA-B5701 allele should be confirmed
before administration of ABC.
• Once-daily dosing is recommended when using the pill formulation of ABC. Twice-daily
dosing of liquid ABC is recommended for initial therapy; a change to once-daily dosing can
be considered for clinically stable patients with undetectable viral loads and stable CD4
counts.129-132

Tenofovir Alafenamide in Combination With Emtricitabine

TAF is an oral prodrug of tenofovir. It is approved by the FDA as a component of an FDC tablet that
also contains EVG, COBI, and FTC for the treatment of HIV in ARV-naive individuals weighing
≥25 kg who have an estimated CrCl ≥30 mL/min. Additional safety and PK data are available for
children aged 6 years to <12 years who are receiving this FDC tablet.27 TAF formulated as an FDC
tablet with FTC and BIC is FDA approved for use in children weighing ≥14 kg (see Bictegravir).14,133
An FDC tablet that contains FTC/TAF (Descovy) is available for use in children weighing ≥14 kg,
with dosage determined by a child’s weight. In January 2022, the FDA approved a lower strength
formulation of the FTC/TAF FDC tablet for use in children weighing ≥14 kg to <25 kg.134

Coadministration of TAF with boosted ATV, DRV, or LPV increases TAF exposure to
concentrations that are higher than those seen with use of EVG/c/FTC/TAF. Because no data exist on
the use of this combination in children weighing <35 kg, the safety of FTC/TAF combined with

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-11
COBI-boosted or RTV-boosted PIs in children weighing <35 kg cannot be assured and is not
recommended.

Recommendation

• FTC/TAF is recommended as a Preferred dual-NRTI combination in children and adolescents

weighing ≥14 kg with estimated CrCl ≥30 mL/min when used with an INSTI or NNRTI.
FTC/TAF is a Preferred dual-NRTI combination when used with a PI in children and adolescents
weighing ≥35 kg who have estimated CrCl ≥30 mL/min (AI*). FTC/TAF also is recommended
as a Preferred drug combination when used in the regimen BIC/FTC/TAF for children and
adolescents weighing ≥14 kg (AI*). EVG/c/FTC/TAF is recommended as an Alternative drug
regimen for children and adolescents weighing ≥25 kg (AI*). The Panel makes these
recommendations because TAF has a lower risk of renal and bone AEs than TDF.
• FTC/TAF is neither approved by the FDA nor recommended for use in combination with a
boosted PI in children weighing <35 kg, because this combination has not been adequately
studied in this age and weight group.

Tenofovir Disoproxil Fumarate in Combination With Lamivudine or

Emtricitabine
TDF is approved by the FDA for use in children and adolescents aged ≥2 years when administered as
part of an ARV regimen. Decreases in bone mineral density (BMD) have been observed in adults and
children receiving TDF, but the clinical significance of these decreases is unknown.110-113,135,136
Before starting treatment, clinicians should consider whether the benefits of using TDF outweigh the
potential risk of decreased BMD.137

Recommendation

• TDF plus 3TC or FTC is recommended as an Alternative dual-NRTI combination for children
aged ≥2 years to 12 years (AI*). The Panel bases this recommendation on the virologic efficacy
and ease of dosing of these combinations.110-113,119-122,138-143

Zidovudine in Combination With Abacavir

In a European pediatric study, patients who received ZDV plus ABC had lower rates of viral
suppression and a greater number of toxicities that led to regimen modification than in patients who
received ABC plus 3TC.109,118 Recent data from the IMPAACT P1106 trial and two observational
cohorts provide reassuring data on the safety of ABC in infants when initiated at age <3 months.126-
128

Recommendation

• ZDV plus ABC is recommended as an Alternative dual-NRTI combination for children aged
≥1 month (BII).

Zidovudine in Combination With Lamivudine or Emtricitabine

ZDV is available as a syrup, a capsule, and a tablet, and it is also available in injectable/intravenous
preparations. It is approved by the FDA for treatment of HIV in infants aged ≥4 weeks and for
prophylaxis in newborns.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-12
Recommendation

• ZDV plus 3TC or FTC is recommended as a Preferred dual-NRTI combination for infants and
children from birth to age ≤1 month, and as an Alternative combination in children aged ≥1
month and adolescents (AI*). Twice-daily dosing is required for all ages with ZDV. Other
NRTIs that require only once-daily dosing in children aged ≥6 years are available.123,144-146
• In children aged ≥6 years and adolescents who are not sexually mature (i.e., those with SMRs of
1–3), the Panel recommends ZDV plus 3TC or FTC as an Alternative dual-NRTI combination
(BII).

Figure 1. Preferred Regimen by Age, Weight, and Drug Class

Patient Age and Weight Class

Birth to Aged ≥ 14 Days Aged ≥4 Weeks Aged ≥2 Years Aged ≥6 Years

<14 Days of and ≥2 kg to and ≥3 kg to and ≥14 kg and ≥25 kg
Agea,b,c <4 Weeks <2 Years
INSTI-Based
Regimens Two NRTIs plus RALc

Two NRTIs plus BICd

Two NRTIs plus DTGe

NNRTI-
Two NRTIs plus
Based
NVPa,f
Regimens
PI-Based Two NRTIs plus
Regimens LPV/rb
a Preferred NRTIs are listed in Table 8 below.
If treatment is scheduled to begin before a patient is aged 14 days, NVP or RAL are Preferred agents because they are the only
options with dosing information available for this age group. Although many pediatric experts favor initiating antiretroviral therapy
as soon as possible after birth to limit the establishment of viral reservoirs, available clinical trial data do not suggest that
initiating treatment within the first 14 days of life leads to better clinical outcomes than initiating treatment after 14 days of age.
Clinicians should consult an expert in pediatric HIV infection before initiating treatment in infants aged <14 days. Additional
considerations regarding the use of NVP or RAL in infants aged <14 days can be found in Antiretroviral Management of
Newborns With Perinatal HIV Exposure or HIV Infection. Switching from NVP to LPV/r should be considered when the infant is
aged ≥14 days with a postmenstrual age of 42 weeks (the span of time between the first day of the mother’s last menstrual
period and birth, plus the time elapsed after birth); LPV/r has produced better clinical outcomes than NVP in studies of children
aged <3 years. Data are limited on the clinical outcomes of using RAL in infants and children aged <2 years.
bIn general, LPV/r should not be administered to neonates before a postmenstrual age of 42 weeks and a postnatal age of
≥14 days (see the Lopinavir/Ritonavir section in Appendix A: Pediatric Antiretroviral Drug Information).
c RAL granules can be administered to infants and children weighing ≥2 kg from birth to age 2 years. Oral RAL granules can be
used up to a dose of 100 mg in the 14 kg to <20 kg weight band. RAL pills or chewable tablets can be used in children aged
≥2 years. Chewable RAL tablets can be crushed and dispersed in liquid to infants as young as 4 weeks of age who weigh at
least 3 kg.
d BIC is available only as part of a fixed-dose combination (FDC) tablet that contains BIC/FTC/TAF; this FDC tablet is
recommended as a Preferred regimen for children aged ≥ 2 years and weighing ≥14 kg. Two strengths of BIC/FTC/TAF are
available, with dosing according to a child’s weight (see Bictegravir).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-13
Figure 1. Preferred Regimen by Age, Weight, and Drug Class
eDTG is recommended as a Preferred agent for infants, children, and adolescents aged ≥4 weeks and weighing ≥3 kg. DTG
dispersible tablets can be administered in infants and children aged ≥4 weeks and weighing ≥3 kg. DTG film-coated tablets can
be used in children weighing ≥14 kg. An FDC that contains ABC/DTG/3TC is available in dispersible tablets (Triumeq PD) for
children weighing ≥10 kg to <25 kg and in a single tablet to be swallowed (Triumeq) for children weighing ≥25 kg. See
Dolutegravir for information about dosing and administration.
fNVP should not be used in post-pubertal girls with CD4 T lymphocyte cell counts >250/mm3, unless the benefit clearly
outweighs the risk. NVP is approved by the U.S. Food and Drug Administration for the treatment of infants aged ≥15 days.
Key: BIC = bictegravir; DTG = dolutegravir; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor;
LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase
inhibitor; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; TAF = tenofovir alafenamide

Table 8. Antiretroviral Regimens Recommended for Initial Therapy for HIV Infection in
Children

An antiretroviral (ARV) regimen for treatment-naive children is generally made up of a two–

nucleoside reverse transcriptase inhibitor (NRTI) backbone and either one non-nucleoside reverse
transcriptase inhibitor (NNRTI) or one integrase strand transfer inhibitor (INSTI) or one protease
inhibitor (PI) boosted with ritonavir or cobicistat (COBI). Regimens are designated Preferred based
on efficacy, ease of administration, and acceptable toxicity. Alternative regimens also have
demonstrated efficacy, but clinical experience with these regimens is limited, or these regimens are
more difficult to administer than Preferred regimens. Regimens should be tailored to the individual
patient by weighing the advantages and disadvantages of each combination. Many agents have
multiple formulations and age and weight recommendations. Refer to Appendix A: Pediatric
Antiretroviral Drug Information for additional information and recommended doses and formulations
(also see Table 8 below). In addition, many drugs that are recommended for use in newborns do not
have dosing recommendations for premature infants. Additional information regarding dosing
recommendations in this population can be found in Antiretroviral Management of Newborns With
Perinatal HIV Exposure or HIV Infection.

Children who are receiving effective and tolerable ARV regimens can continue using those
regimens as they age, even if the combinations they are receiving are no longer Preferred
regimens. Refer to the Management of Children Receiving Antiretroviral Therapy sections for
decisions about transitioning children to other regimens as they grow.

Preferred Initial Regimens Based on Age and Weight at Time of Treatment Initiation
FDC Available
Age Weight Restriction Regimens (see Appendix A,
Table 1)
Newborns, Birth to Age <14 Daysa,b None Two NRTIs plus NVP No

≥2 kg Two NRTIs plus RALc No

Neonates ≥14 Days to Age None Two NRTIs plus LPV/rb No

<4 Weeks
≥2 kg Two NRTIs plus RALc No

Infants and Children Aged ≥3 kg Two NRTIs plus DTGd No

≥4 Weeks
Two NRTIs plus DTGd Yes (≥10 kg)

Children Aged ≥2 Years ≥14 kg Two NRTIs plus BICe Yes

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-14
Table 8. Antiretroviral Regimens Recommended for Initial Therapy for HIV Infection in
Children

Adolescents Aged ≥12 Years With Refer to the Adult and Adolescent Antiretroviral Yes
SMRs of 4 or 5 Guidelines.

Preferred Dual-NRTI Backbone Options for Use in Combination with Other Drugs
Age Dual-NRTI Backbone Options FDC Available
Neonates Aged Birth to 1 Month ABC plus (3TC or FTC)f Nog

ZDV plus (3TC or FTC)h Nog

Infants and Children Aged >1 ABC plus (3TC or FTC)f Yes
Month to <2 Years
Children and Adolescents Aged ABC plus (3TC or FTC)f Yes
≥2 Years With SMRs of 1–3
FTC/TAFi in children and adolescents weighing ≥14 kg Yes
and receiving a regimen that contains an INSTI or an
NNRTI

FTC/TAFi in children and adolescents weighing ≥35 kg

and receiving a regimen that contains a boosted PI

Adolescents Aged ≥12 Years With Refer to the Adult and Adolescent Antiretroviral Yes
SMRs of 4 or 5 Guidelines.

Alternative Regimens Based on Age and Weight at Time of Treatment Initiation

Weight
Age Regimens FDC Available
Restriction
Neonates, Infants, and Children None Two NRTIs plus NVPj No
Aged ≥14 Days to <3 Years
Infants and Children Aged None Two NRTIs plus LPV/rb No
≥4 Weeks to <3 Months
≥2 kg Two NRTIs plus RALc No

Infants and Children Aged None Two NRTIs plus ATV/r No

≥3 Months to <3 Years
None Two NRTIs plus LPV/rb No

None Two NRTIs plus RALc No

Children Aged ≥3 Years None Two NRTIs plus ATV/r No

None Two NRTIs plus DRV/rk No

None Two NRTIs plus EFVl Nog

None Two NRTIs plus LPV/rb No

≥25 kg Two NRTIs plus EVG/cm Yes

≥35 kg Two NRTIs plus DORn Yes

Adolescents Aged ≥12 Years With None Two NRTIs plus ATV/r No
SMRs of 1–3
None Two NRTIs plus DRV/rk No

None Two NRTIs plus EFVl Yes

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-15
Table 8. Antiretroviral Regimens Recommended for Initial Therapy for HIV Infection in
Children

None Two NRTIs plus LPV/rb No

None Two NRTIs plus RALc No

≥25 kg Two NRTIs plus EVG/cm Yes

≥35 kg Two NRTIs plus ATV/co No

Two NRTIs plus DORn Yes

Two NRTIs plus RPVp Yes

≥40 kg Two NRTIs plus DRV/cq Yes

Adolescents Aged ≥12 Years With Refer to the Adult and Adolescent Antiretroviral Yes
SMRs of 4 or 5 Guidelines.

Alternative Dual-NRTI Backbone Options for Use in Combination With Other Drugs
Age Dual-NRTI Backbone Options FDC Available
Infants and Children Aged ≥1 ZDV plus (3TC or FTC)h Nog
Month to <6 Years
ZDV plus ABCf No

Children Aged ≥2 Years to 12 Years TDF plus (3TC or FTC)r Yes

Children and Adolescents Aged ZDV plus (3TC or FTC)h Yes

≥6 Years and SMRs of 1–3
ZDV plus ABCf No

a If treatment is scheduled to begin before a patient is aged 14 days, NVP or RAL are Preferred agents because they are the
only options with dosing information available for this age group. Although many pediatric experts favor initiating antiretroviral
therapy as soon as possible after birth to limit the establishment of viral reservoirs, available clinical trial data do not suggest that
initiating treatment within the first 14 days of life leads to better clinical outcomes than initiating treatment after 14 days of age.
Clinicians should consult an expert in pediatric HIV infection before initiating treatment in infants aged <14 days. Additional
considerations regarding the use of NVP or RAL in infants aged <14 days can be found in Antiretroviral Management of
Newborns With Perinatal HIV Exposure or HIV Infection. Switching from NVP to LPV/r should be considered when the infant is
aged ≥14 days with a postmenstrual age of 42 weeks (the span of time between the first day of the mother’s last menstrual
period and birth, plus the time elapsed after birth); LPV/r has produced better clinical outcomes than NVP in studies of children
aged <3 years. Data are limited on the clinical outcomes of using RAL in infants and children aged <2 years.
bIn general, LPV/r should not be administered to neonates before a postmenstrual age of 42 weeks and a postnatal age of
≥14 days (see the Lopinavir/Ritonavir section in Appendix A: Pediatric Antiretroviral Drug Information). Some experts would
choose not to start with LPV/r as a Preferred initial regimen in neonates aged ≥14 days to <4 weeks but would choose to start
with NVP instead.
cRAL granules can be administered to infants and children weighing ≥2 kg from birth to age 2 years. Oral RAL granules can be
used up to a dose of 100 mg in the 14 kg to <20 kg weight band. RAL pills or chewable tablets can be used in children aged
≥2 years. Chewable RAL tablets can be crushed and dispersed in liquid and administered to infants as young as 4 weeks of age
who weigh at least 3 kg.
dDTG is recommended as a Preferred agent for infants, children, and adolescents aged ≥4 weeks and weighing ≥3 kg. DTG
dispersible tablets can be administered in infants and children aged ≥4 weeks and weighing ≥3 kg. DTG film-coated tablets can
be used in children weighing ≥14 kg. An FDC that contains ABC/DTG/3TC is available in dispersible tablets (Triumeq PD) for
children weighing ≥10 kg to <25 kg and in a single tablet to be swallowed (Triumeq) for children weighing ≥25 kg. See
Dolutegravir for information about dosing and administration.
e BIC is available only as part of an FDC tablet that contains BIC/FTC/TAF; this FDC tablet is recommended as a Preferred
regimen for children weighing ≥14 kg. Two strengths of BIC/FTC/TAF are available, with dosing according to a child’s weight
(see Bictegravir).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-16
Table 8. Antiretroviral Regimens Recommended for Initial Therapy for HIV Infection in
Children
fABC is not approved by the U.S. Food and Drug Administration (FDA) for use in full-term neonates and infants aged <3
months. Recent data from the IMPAACT P1106 trial and two observational cohorts provide reassuring data on the safety of ABC
in infants when initiated at the age of <3 months (see Abacavir). Before ABC administration, a negative HLA-B 5701 allele test
should be available. An FDC tablet that contains ABC/3TC (Epzicom and generic) is available for use in children weighing ≥25
kg.
gFDA-approved FDC tablets are not included in this table when they are not approved for use in the specific patient populations
being discussed.
hAn FDC tablet that contains 3TC/ZDV (Combivir and generic) is available for use in children weighing ≥30 kg. Some members
of the Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV (the Panel) prefer ABC over ZDV
because ABC can be dosed once daily.
iFTC plus TAF is recommended as a Preferred NRTI combination for children and adolescents weighing ≥14 kg when used with
an INSTI or NNRTI; an FDC tablet that contains FTC/TAF (Descovy) is available in two strengths, with dosage determined by a
child’s weight (see Tenofovir Alafenamide). FTC/TAF is approved by the FDA for children weighing ≥14 kg when used in the
regimen BIC/FTC/TAF, which is also available in two strengths, with dosage determined by a child’s weight. EVG/c/FTC/TAF is
approved for use in children weighing ≥25 kg. FTC/TAF is a Preferred NRTI combination for children and adolescents weighing
≥35 kg when used with a boosted PI; FTC/TAF is not approved or recommended for use with a boosted PI in children weighing
<35 kg.
j NVP should not be used in post-pubertal girls with T lymphocyte cell counts >250/mm3, unless the benefit clearly outweighs the

risk. NVP is approved by the FDA for the treatment of infants aged ≥15 days.
kDRV should only be used in children weighing ≥10 kg. Once-daily DRV should not be used in children aged <12 years or
weighing <40 kg. Once-daily DRV should also not be used when any one of the following resistance-associated substitutions are
present: V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, and L89V. DRV/r is recommended as an Alternative drug
combination for children aged ≥6 years to <12 years and weighing >25 kg because there are other drugs that can be
administered once daily and that are better tolerated. Note that DRV/r can be administered once daily in adolescents aged
≥12 years and weighing ≥40 kg who are not sexually mature (SMR 1–3).
lEFV is approved by the FDA for use in children aged ≥3 months and weighing ≥3.5 kg, but it is not recommended by the
Panel for initial therapy in children aged ≥3 months to 3 years. FDC tablets that contain EFV/FTC/TDF (Atripla) and
EFV 600 mg/3TC/TDF (Symfi) are available. See the Efavirenz section in Appendix A: Pediatric Antiretroviral Drug Information
for information about use of the FDC EFV 400 mg/3TC/TDF (Symfi Lo).
m EVG is currently recommended only as a component of FDC tablets. Tablets that contain EVG/c/FTC/TAF (Genvoya) are
recommended as an Alternative regimen for children and adolescents weighing ≥25 kg due to multiple drug–drug interactions
from COBI and a lower barrier to the development of resistance to EVG.
nDOR is not FDA approved for pediatric use. Based on data from studies that evaluated the efficacy and tolerability of DOR in
adults, as well as early findings from pediatric PK studies, the Panel recommends DOR as an Alternative ARV for children and
adolescents weighing ≥35 kg. An FDC tablet containing DOR/3TC/TDF is available.
oATV/c is available as an FDC tablet containing ATV/c (Evotaz) that has been approved by the FDA for use in children and
adolescents weighing ≥35 kg.
pRPV should be administered to adolescents aged ≥12 years and weighing ≥35 kg who have initial viral loads
≤100,000 copies/mL. FDC tablets that contain FTC/RPV/TAF (Odefsey) and FTC/RPV/TDF (Complera) are available.
q DRV/c is available as part of an FDC tablet containing DRV/c/FTC/TAF (Symtuza) that has been approved by the FDA for use
in children and adolescents weighing ≥40 kg.
r An FDC tablet that contains FTC/TDF (Truvada) is available.
Key: 3TC = lamivudine; ABC = abacavir; ATV/c = atazanavir/cobicistat; ATV/r = atazanavir/ritonavir; BIC = bictegravir;
DOR = doravirine; DRV = darunavir; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; DTG = dolutegravir;
EFV = efavirenz; EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FDC = fixed-dose combination; FTC = emtricitabine;
INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor;
NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; PK = pharmacokinetic;
RAL = raltegravir; RPV = rilpivirine; SMR = sexual maturity rating; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil
fumarate; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-17
Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended for
Initial Therapy in Children

See Appendix A: Pediatric Antiretroviral Drug Information and Table 8. Antiretroviral Regimen
Considerations for Initial Therapy Based on Specific Clinical Scenarios in the Adult and Adolescent
Antiretroviral Guidelines for more information.

ARV Class/
Advantages Disadvantages
Agent(s)
All INSTIs INSTI Class Advantages INSTI Class Disadvantages
• Few drug–drug interactions • Limited data on pediatric dosing or safety
• Well tolerated • Possible weight gain in adults, especially
Black/African American women
BIC Once-daily administration The FDC tablet is not recommended for patients with
hepatic impairment or an estimated CrCl <30 mL/min.
Can give with or without food
The FDC tablet should not be coadministered with
Available in FDC tablets (see Appendix A, rifampin or dofetilide.
Table 1. Antiretrovirals Available in Fixed-Dose
Combination Tablets)
DTG Once-daily administration Drug interactions with EFV, FPV/r, TPV/r, and
rifampin, necessitating twice-daily dosing of DTG
Can give with food
CNS side effects, particularly sleep disturbances
Available in FDC tablets (see Appendix A,
Table 1. Antiretrovirals Available in Fixed-Dose Early concerns about a possible increased risk of
Combination Tablets) NTDs in infants born to women who were receiving
DTG at the time of conception have decreased
Single-agent DTG pills are available in several substantially. The Panel for Antiretroviral Guidelines
doses and are small in size. for Adults and Adolescents and the Panel on
Treatment of HIV During Pregnancy and Prevention of
DTG and the FDC ABC/DTG/3TC are available Perinatal Transmission include DTG among the
as dispersible tablets for suspension. preferred ARV agents for use in people of childbearing
potential and for use in people who are pregnant or
are trying to conceive. Risks and benefits should be
discussed to support informed decision-making (see
Dolutegravir, Appendix C: Antiretroviral Counseling
Guide for Health Care Providers).
EVG Once-daily administration Among INSTIs, EVG has the lowest barrier to the
development of resistance.
Available in FDC tablets (see Appendix A,
Table 1. Antiretrovirals Available in Fixed-Dose If EVG is coadministered with COBI, the potential
Combination Tablets) exists for multiple drug interactions because COBI is
metabolized by hepatic enzymes (e.g., CYP3A4).

COBI inhibits tubular secretion of creatinine, and this

may result in increased serum creatinine but normal
glomerular clearance.

RAL Can give with food Potential for rare systemic allergic reaction or hepatitis

Available in tablet, chewable tablet, and powder Granule formulation requires a multistep preparation
formulations before administration; caregiver must be taught how to
properly prepare this formulation.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-18
Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended for
Initial Therapy in Children

ARV Class/
Advantages Disadvantages
Agent(s)
Chewable tablets can be crushed and mixed
with various liquids for infants ≥4 weeks of age
who weigh ≥3 kg.

Once-daily administration (with RAL HD) can be

used for treatment-naive or virologically
suppressed children weighing ≥40 kg.

All NNRTIs NNRTI Class Advantages NNRTI Class Disadvantages

• Long half-life • A single mutation can confer resistance, with cross-
resistance between EFV and NVP.
• Lower risk of dyslipidemia and fat
maldistribution than PIs • Rare, but serious and potentially life-threatening,
cases of skin rash (including SJS) and hepatic
• PI-sparing toxicity. All NNRTIs pose this risk, but the risk is
• Lower pill burden than PIs for children taking greatest with NVP; these toxic effects have not been
the solid formulation; easier to use and reported in neonates.
adhere to than PI-based regimens • Potential for multiple drug interactions due to
metabolism via hepatic enzymes (e.g., CYP3A4).
Information about drug interactions is available in
the Adult and Adolescent Antiretroviral Guidelines
and the HIV Drug Interaction Checker.

DOR Once-daily administration Neuropsychiatric AEs, but fewer than reported for EFV

Available in FDC tablets (see Appendix A, DOR is contraindicated when co-administered with
Table 1. Antiretrovirals Available in Fixed-Dose drugs that are strong cytochrome P450 (CYP)3A
Combination Tablets) enzyme inducers (see Doravirine).

Can be taken with or without food Drug interactions between DOR and rifabutin induce
the metabolism of DOR and require an additional dose
Has continued antiviral activity in the setting of of DOR 100 mg to be administered 12 hours after a
some NNRTI mutations fixed-dose combination of DOR/3TC/TDF or an
increase of the DOR dose to 100 mg twice daily (see
Doravirine).

EFV Once-daily administration Neuropsychiatric AEs (bedtime dosing is

recommended to reduce CNS effects)
Available in FDC tablets (see Appendix A,
Table 1. Antiretrovirals Available in Fixed-Dose Rash (generally mild)
Combination Tablets)
No commercially available liquid formulation
Potent ARV activity
Limited data on dosing for children aged <3 years
Can give with food (but avoid high-fat meals)
No data on dosing for children aged <3 months
Capsules can be opened and added to food.

NVP Liquid formulation is available. Reduced virologic efficacy in young infants, regardless
of exposure to NVP as part of a peripartum preventive
Dosing information for young infants is regimen
available.
Higher incidence of rash/HSR than other NNRTIs
Can give with food

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-19
Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended for
Initial Therapy in Children

ARV Class/
Advantages Disadvantages
Agent(s)
Extended-release formulation that allows once- Higher rates of serious hepatic toxicity than EFV
daily dosing in older children is available.
Decreased virologic response compared with EFV

Twice-daily dosing necessary in children with BSA

<0.58 m2

Low barrier to resistance

RPV Once-daily dosing Should not use in patients with viral loads
>100,000 copies/mL
Available in FDC tablets (see Appendix A,
Table 1. Antiretrovirals Available in Fixed-Dose Must be taken with a ≥500 kcal meal at a consistent
Combination Tablets) time each day; this may affect adherence.

Low barrier to resistance

All PIs PI Class Advantages PI Class Disadvantages

• NNRTI-sparing • Metabolic complications, including dyslipidemia, fat
maldistribution, and insulin resistance
• Clinical, virologic, and immunologic efficacy
are well-documented. • Potential for multiple drug interactions because of
metabolism via hepatic enzymes (e.g., CYP3A4)
• Resistance to PIs requires multiple
mutations. • Higher pill burden than NRTI-based or NNRTI-
based regimens for patients taking solid
• When combined with a dual-NRTI backbone, formulations
a regimen that contains a PI targets HIV at
two steps of viral replication by inhibiting the • Poor palatability of liquid preparations, which may
activity of viral reverse transcriptase and affect adherence
protease enzymes.
• Most PIs require RTV boosting, resulting in drug
interactions that are associated with RTV.

Boosted ATV Once-daily dosing No liquid formulation

Powder formulation is available. Should be administered with food

ATV has less effect on TG and total cholesterol Indirect hyperbilirubinemia is common, but
levels than other PIs (but RTV boosting may be asymptomatic. Scleral icterus may be distressing to
associated with elevations in these the patient, which may affect adherence.
parameters).
Must be used with caution in patients with preexisting
conduction system defects (can prolong the PR
interval of an ECG)

RTV is associated with a large number of drug

interactions.

Boosted DRV Can be used once daily in children aged ≥12 Pediatric pill burden high with current tablet dose
years formulations

Liquid formulation is available. Should be administered with food

DRV requires a boosting agent. Must be boosted to achieve adequate plasma

concentrations

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-20
Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended for
Initial Therapy in Children

ARV Class/
Advantages Disadvantages
Agent(s)
Available in FDC tablets (see Appendix A, Contains sulfa moiety. The potential for cross-
Table 1. Antiretrovirals Available in Fixed-Dose sensitivity between DRV and other drugs in
Combination Tablets) sulfonamide class is unknown.

RTV is associated with a large number of drug

interactions.

Can be used only once daily in the absence of certain

PI-associated resistance mutations.

LPV/r LPV is only available coformulated with RTV in Poor palatability of liquid formulation (bitter taste)
liquid and tablet formulations.
Liquid formulation should be administered with food.
Tablets can be given without food, but they may
be better tolerated when taken with a meal or RTV is associated with a large number of drug
snack. interactions.

Should not be administered to neonates before a

postmenstrual age of 42 weeks (the span of time
between the first day of the mother’s last menstrual
period and birth, plus the time elapsed after birth) and
a postnatal age ≥14 days

Must be used with caution in patients with pre-existing

conduction system defects (can prolong PR and QT
interval of an ECG)

ABC plus (3TC Palatable liquid formulations Risk of ABC HSR; perform HLA-B*5701 screening
or FTC) before initiating ABC.
Can give with food

Available in FDC tablets (see Appendix A,

Table 1. Antiretrovirals Available in Fixed-Dose
Combination Tablets)

FTC/TAF for Once-daily dosing Limited data on the safety and efficacy of this
children aged combination in children
≥6 years Small tablet size
Increased lipid levels
Lower risk of TFV-associated renal and bone
toxicity with TAF than with TDF in adults

Available in FDC tablets (see Appendix A,

Table 1. Antiretrovirals Available in Fixed-Dose
Combination Tablets)

TDF plus (3TC Once-daily dosing for TDF Limited pediatric experience
or FTC) for
adolescents Resistance is slow to develop. Potential bone and renal toxicity
with SMRs of 4
or 5 Lower risk of mitochondrial toxicity than other Appropriate dosing is complicated by numerous drug–
NRTIs drug interactions with other ARV agents, including ddI,
LPV/r, ATV, and TPV.
Can give with food

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-21
Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended for
Initial Therapy in Children

ARV Class/
Advantages Disadvantages
Agent(s)
Available as reduced-strength tablets and oral
powder for use in younger children

Available in FDC tablets (see Appendix A,

Table 1. Antiretrovirals Available in Fixed-Dose
Combination Tablets)

ZDV plus (3TC Extensive pediatric experience Bone marrow suppression and lipoatrophy with ZDV
or FTC)
Coformulations of ZDV and 3TC are available ZDV requires twice-daily dosing.
(Combivir and generic) for children weighing
≥30 kg.

Palatable liquid formulations

Can give with food

FTC is available as a palatable liquid

formulation that can be administered once daily.

ZDV plus ABC Palatable liquid formulations Risk of ABC HSR; perform HLA-B*5701 screening
before initiating ABC.
Can give with food
Bone marrow suppression and lipoatrophy with ZDV

ZDV requires twice-daily dosing.

Key: 3TC = lamivudine; ABC = abacavir; AE = adverse event; ARV = antiretroviral; ATV = atazanavir; BIC = bictegravir;
BSA = body surface area; CNS = central nervous system; COBI = cobicistat; CrCl = creatinine clearance; CYP = cytochrome
P450; ddI = didanosine; DOR = doravirine; DRV = darunavir; DTG = dolutegravir; ECG = electrocardiogram; EFV = efavirenz;
EVG = elvitegravir; FDC = fixed-dose combination; FPV/r = fosamprenavir/ritonavir; FTC = emtricitabine; HD = high dose;
HSR = hypersensitivity reaction; INSTI = integrase strand transfer inhibitor; LPV = lopinavir; LPV/r = lopinavir/ritonavir;
NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NTD = neural tube
defect; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SJS = Stevens-Johnson
Syndrome; SMR = sexual maturity rating; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir;
TG = triglyceride; TPV = tipranavir; TPV/r = tipranavir/ritonavir; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-22
References

1. Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavir-boosted lopinavir
for HIV-infected children. N Engl J Med. 2012;366(25):2380-2389. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22716976.

2. Barlow-Mosha L, Angelidou K, Lindsey J, et al. Nevirapine- versus lopinavir/ritonavir-

based antiretroviral therapy in HIV-infected infants and young children: long-term
follow-up of the IMPAACT P1060 randomized trial. Clin Infect Dis. 2016;63(8):1113-
1121. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27439527.

3. Coovadia A, Abrams EJ, Stehlau R, et al. Reuse of nevirapine in exposed HIV-infected

children after protease inhibitor-based viral suppression: a randomized controlled trial.
JAMA. 2010;304(10):1082-1090. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20823434.

4. Murnane PM, Strehlau R, Shiau S, et al. Switching to efavirenz versus remaining on

ritonavir-boosted lopinavir in HIV-infected children exposed to nevirapine: long-term
outcomes of a randomized trial. Clin Infect Dis. 2017;65(3):477-485. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28419200.

5. Babiker A, Castro nee Green H, Compagnucci A, et al. First-line antiretroviral therapy

with a protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch
at higher versus low viral load in HIV-infected children: an open-label, randomised phase
2/3 trial. Lancet Infect Dis. 2011;11(4):273-283. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21288774.

6. Ruel TD, Kakuru A, Ikilezi G, et al. Virologic and immunologic outcomes of HIV-
infected Ugandan children randomized to lopinavir/ritonavir or nonnucleoside reverse
transcriptase inhibitor therapy. J Acquir Immune Defic Syndr. 2014;65(5):535-541.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/24326597.

7. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily

raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96
week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis.
2013;13(11):927-935. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24074642.

8. Molina JM, Clotet B, van Lunzen J, et al. Once-daily dolutegravir is superior to once-
daily darunavir/ritonavir in treatment-naive HIV-1-positive individuals: 96 week results
from FLAMINGO. J Int AIDS Soc. 2014;17(4 Suppl 3):19490. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25393999.

9. Viani RM, Alvero C, Fenton T, et al. Safety, pharmacokinetics and efficacy of

dolutegravir in treatment-experienced HIV-1 infected adolescents: 48-week results from
IMPAACT P1093. Pediatr Infect Dis J. 2015;34(11):1207-1213. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26244832.

10. Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a
novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-23
 profile. Antimicrob Agents Chemother. 2016;60(12):7086-7097. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27645238.

11. Hassounah SA, Alikhani A, Oliveira M, et al. Antiviral activity of bictegravir and
cabotegravir against integrase inhibitor-resistant SIVmac239 and HIV-1. Antimicrob
Agents Chemother. 2017;61(12):e01695-01617. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28923862.

12. Neogi U, Singh K, Aralaguppe SG, et al. Ex-vivo antiretroviral potency of newer
integrase strand transfer inhibitors cabotegravir and bictegravir in HIV type 1 non-B
subtypes. AIDS. 2018;32(4):469-476. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29239896.

13. Oliveira M, Ibanescu RI, Anstett K, et al. Selective resistance profiles emerging in
patient-derived clinical isolates with cabotegravir, bictegravir, dolutegravir, and
elvitegravir. Retrovirology. 2018;15(1):56. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30119633.

14. Gaur AH, Cotton MF, Rodriguez CA, et al. Fixed-dose combination bictegravir,
emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48
results of a single-arm, open-label, multicentre, phase 2/3 trial. Lancet Child Adolesc
Health. 2021;5(9):642-651. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34302760.

15. Zash R, L. Holmes, M. Diseko, et al. Update on neural tube defects with antiretroviral
exposure in the Tsepamo study, Botswana. Presented at: 23rd International AIDS
Conference 2020; 2020. Virtual, July 6-10, 2020. Available at:
https://www.natap.org/2020/IAC/IAC_112.htm.

16. Rodriguez. C, Chokephaibulkit. K, Liberty. A, et al. Safety, PK, and Efficacy of low dose
B/F/TAF in children ≥2 years old living with HIV. Presented at: Conference of
Retroviruses and Opportunistic Infections 2020. Boston, Massachusetts Available at:
https://www.croiconference.org/abstract/safety-pk-and-efficacy-of-low-dose-b-f-taf-in-
children-%e2%89%a52-years-old-living-with-hiv/.

17. Amuge P, Lugemwa A, Wynne B, et al. Once-daily dolutegravir-based antiretroviral

therapy in infants and children living with HIV from age 4 weeks: results from the below
14 kg cohort in the randomised ODYSSEY trial. Lancet HIV. 2022;9(9):e638-e648.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/36055295.

18. Ruel TD, Acosta EP, Liu JP, et al. Pharmacokinetics, safety, tolerability, and antiviral
activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT
P1093): results of an open-label, phase 1-2 trial. Lancet HIV. 2022;9(5):e332-e340.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/35489377.

19. R Ruel T, Farhad M, Alvero C, et al. Twenty-four week safety, tolerability and efficacy
of dolutegravir dispersible tablets in children 4 weeks to <6 years old with HIV: results
from IMPAACT P1093. Presented at: International AIDS Conference (AIDS 2020);
2020. San Francisco, California. Available at:

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-24
 https://www.impaactnetwork.org/sites/default/files/2020-
12/PEB0293_DTG_DT_24wkOutcomesFINAL_6.26.20.pdf

20. Wiznia A, Alvero C, Fenton T, et al. IMPAACT 1093: dolutegravir in 6- to 12-year-old

HIV-infected children: 48-week results. Presented at: Conference on Retroviruses and
Opporotunistic Infections 2016. Boston, MA. Available at:
https://www.natap.org/2016/CROI/croi_86.htm

21. Turkova A, White E, Mujuru HA, et al. Dolutegravir as first- or second-line treatment for
HIV-1 infection in children. N Engl J Med. 2021;385(27):2531-2543. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34965338.

22. Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine

for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and
week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic
Syndr. 2015;70(5):515-519. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26262777.

23. Viani RM, Ruel T, Alvero C, et al. Long-term safety and efficacy of dolutegravir in
treatment-experienced adolescents with human immunodeficiency virus infection: results
of the IMPAACT P1093 study. J Pediatric Infect Dis Soc. 2019;9(2):159-165. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/30951600.

24. Wohl DA, Cohen C, Gallant JE, et al. A randomized, double-blind comparison of single-
tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet
regimen efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection:
analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65(3):e118-120.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/24256630.

25. Clumeck N, Molina JM, Henry K, et al. A randomized, double-blind comparison of

single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-
boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1
infection: analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65(3):e121-
124. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24346640.

26. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil
fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial
treatment of HIV-1 infection: two randomised, double-blind, Phase 3, non-inferiority
trials. Lancet. 2015;385(9987):2606-2615. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25890673.

27. Natukunda E, Gaur A, Kosalaraksa P, et al. Safety, efficacy, and pharmacokinetics of

single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in
virologically suppressed, HIV-infected children: a single-arm, open-label trial. Lancet
Child Adolescent Health. 2017;1(1):27-34. Available at:
https://www.sciencedirect.com/science/article/pii/S2352464217300093?via%3Dihub.

28. Gaur AH, Kizito H, Prasitsueubsai W, et al. Safety, efficacy, and pharmacokinetics of a
single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir
alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-25
 Lancet HIV. 2016;3(12):e561-e568. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27765666.

29. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus
efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a
multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796-806.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19647866.

30. DeJesus E, Rockstroh JK, Lennox JL, et al. Efficacy of raltegravir versus efavirenz when
combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: week-
192 overall and subgroup analyses from STARTMRK. HIV Clin Trials. 2012;13(4):228-
232. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22849964.

31. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir
versus efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-
infected patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr.
2013;63(1):77-85. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23412015.

32. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside
reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive
volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern
Med. 2014;161(7):461-471. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25285539.

33. Briz V, Leon-Leal JA, Palladino C, et al. Potent and sustained antiviral response of
raltegravir-based highly active antiretroviral therapy in HIV type 1-infected children and
adolescents. Pediatr Infect Dis J. 2012;31(3):273-277. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22330165.

34. Nachman S, Zheng N, Acosta EP, et al. Pharmacokinetics, safety, and 48-week efficacy
of oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin Infect Dis.
2014;58(3):413-422. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24145879.

35. Nachman S, Alvero C, Acosta EP, et al. Pharmacokinetics and 48-week safety and
efficacy of raltegravir for oral suspension in human immunodeficiency virus type-1-
infected children 4 weeks to 2 years of age. J Pediatric Infect Dis Soc. 2015;4(4):e76-83.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26582887.

36. Nachman S, Alvero C, Teppler H, et al. Safety and efficacy at 240 weeks of different
raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-randomised,
multicentre trial. Lancet HIV. 2018;5(12):e715-e722. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30527329.

37. Clarke DF, Acosta EP, Cababasay M, et al. Raltegravir (RAL) in neonates: dosing,
pharmacokinetics (PK), and safety in HIV-1-exposed neonates at risk of infection
(IMPAACT P1110). J Acquir Immune Defic Syndr. 2020;84(1):70-77. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31913995.

38. Melvin AJ, Best B, Muresan P, et al. IMPAACT 2014 24-week pk and safety of
doravirine/3TC/TDF in adolescents with HIV-1. Presented at: Conference on

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-26
 Retroviruses and Opportnistic Infections; 2021. Virtual. Available at:
https://www.croiconference.org/abstract/impaact-2014-24-week-pk-and-safety-of-
doravirine-3tc-tdf-in-adolescents-with-hiv-1.

39. Orkin C, Elion R, Thompson M, et al. Changes in weight and BMI with first-line
doravirine-based therapy. AIDS. 2021;35(1):91-99. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33048879.

40. Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in
antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a
randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5(5):e211-
e220. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29592840.

41. Orkin C, Squires KE, Molina JM, et al. Doravirine/lamivudine/tenofovir disoproxil

fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in
treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results
of the DRIVE-AHEAD trial. Clin Infect Dis. 2019;68(4):535-544. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30184165.

42. Bwakura Dangarembizi M, Samson P, Capparelli EV, et al. Establishing dosing

recommendations for efavirenz in HIV/TB-coinfected children younger than 3 years. J
Acquir Immune Defic Syndr. 2019;81(4):473-480. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31241542.

43. Starr SE, Fletcher CV, Spector SA, et al. Combination therapy with efavirenz, nelfinavir,
and nucleoside reverse-transcriptase inhibitors in children infected with human
immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team. N Engl
J Med. 1999;341(25):1874-1881. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/10601506.

44. Teglas JP, Quartier P, Treluyer JM, Burgard M, Gregoire V, Blanche S. Tolerance of
efavirenz in children. AIDS. 2001;15(2):241-243. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11216933.

45. Nunez M, Soriano V, Martin-Carbonero L, et al. SENC (Spanish efavirenz vs. nevirapine
comparison) trial: a randomized, open-label study in HIV-infected naive individuals. HIV
Clin Trials. 2002;3(3):186-194. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12032877.

46. Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with
efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial
therapy for patients infected with HIV. J Acquir Immune Defic Syndr. 2004;36(5):1011-
1019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15247553.

47. Torti C, Maggiolo F, Patroni A, et al. Exploratory analysis for the evaluation of
lopinavir/ritonavir-versus efavirenz-based HAART regimens in antiretroviral-naive HIV-
positive patients: results from the Italian MASTER cohort. J Antimicrob Chemother.
2005;56(1):190-195. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15917286.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-27
48. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment
of HIV-1 infection. N Engl J Med. 2008;358(20):2095-2106. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18480202.

49. Cooper DA, Heera J, Goodrich J, et al. Maraviroc versus efavirenz, both in combination
with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with
CCR5-tropic HIV-1 infection. J Infect Dis. 2010;201(6):803-813. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20151839.

50. Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus
efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the
phase 3 double-blind randomized ECHO and THRIVE trials. J Acquir Immune Defic
Syndr. 2012;60(1):33-42. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22343174.

51. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine,
and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial
treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of
results after 48 weeks. Lancet. 2012;379(9835):2439-2448. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22748591.

52. Spector SA, Hsia K, Yong FH, et al. Patterns of plasma human immunodeficiency virus
type 1 RNA response to highly active antiretroviral therapy in infected children. J Infect
Dis. 2000;182(6):1769-1773. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11069252.

53. Starr SE, Fletcher CV, Spector SA, et al. Efavirenz liquid formulation in human
immunodeficiency virus-infected children. Pediatr Infect Dis J. 2002;21(7):659-663.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/12237599.

54. Fraaij PL, Neubert J, Bergshoeff AS, et al. Safety and efficacy of a NRTI-sparing
HAART regimen of efavirenz and lopinavir/ritonavir in HIV-1-infected children. Antivir
Ther. 2004;9(2):297-299. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15134193.

55. Funk MB, Notheis G, Schuster T, et al. Effect of first line therapy including efavirenz
and two nucleoside reverse transcriptase inhibitors in HIV-infected children. Eur J Med
Res. 2005;10(12):503-508. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16356864.

56. McKinney RE, Jr., Rodman J, Hu C, et al. Long-term safety and efficacy of a once-daily
regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive
children and adolescents: Pediatric AIDS Clinical Trials Group protocol P1021.
Pediatrics. 2007;120(2):e416-423. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17646352.

57. Gutierrez F, Navarro A, Padilla S, et al. Prediction of neuropsychiatric adverse events

associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin
Infect Dis. 2005;41(11):1648-1653. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16267739.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-28
58. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma
levels can predict treatment failure and central nervous system side effects in HIV-1-
infected patients. AIDS. 2001;15(1):71-75. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11192870.

59. Treisman GJ, Kaplin AI. Neurologic and psychiatric complications of antiretroviral
agents. AIDS. 2002;16(9):1201-1215. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12045485.

60. Kaul S, Ji P, Lu M, Nguyen KL, Shangguan T, Grasela D. Bioavailability in healthy

adults of efavirenz capsule contents mixed with a small amount of food. Am J Health Syst
Pharm. 2010;67(3):217-222. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20101064.

61. Bardsley-Elliot A, Perry CM. Nevirapine: a review of its use in the prevention and
treatment of paediatric HIV infection. Paediatr Drugs. 2000;2(5):373-407. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11022799.

62. Luzuriaga K, Bryson Y, Krogstad P, et al. Combination treatment with zidovudine,

didanosine, and nevirapine in infants with human immunodeficiency virus type 1
infection. N Engl J Med. 1997;336(19):1343-1349. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/9134874.

63. Luzuriaga K, McManus M, Mofenson L, et al. A trial of three antiretroviral regimens in

HIV-1-infected children. N Engl J Med. 2004;350(24):2471-2480. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15190139.

64. Verweel G, Sharland M, Lyall H, et al. Nevirapine use in HIV-1-infected children. AIDS.
2003;17(11):1639-1647. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12853746.

65. Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with
peripartum nevirapine exposure. N Engl J Med. 2010;363(16):1510-1520. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20942667.

66. Maswabi K, Ajibola G, Bennett K, et al. Safety and efficacy of starting antiretroviral
therapy in the first week of life. Clin Infect Dis. 2021;72(3):388-393. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31927562.

67. Dhummakupt A, Persaud D. Capitalizing on postexposure antiretroviral prophylaxis to

restrict seeding of the human immunodeficiency virus reservoir. Clin Infect Dis.
2021;73(3):439-440. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32503043.

68. Massanella M, Puthanakit T, Leyre L, et al. Continuous prophylactic

antiretrovirals/antiretroviral therapy since birth reduces seeding and persistence of the
viral reservoir in children vertically infected with human immunodeficiency virus. Clin
Infect Dis. 2021;73(3):427-438. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32504081.

69. van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of first-line antiretroviral

therapy with regimens including nevirapine, efavirenz, or both drugs, plus stavudine and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-29
 lamivudine: a randomised open-label trial, the 2NN Study. Lancet. 2004;363(9417):1253-
1263. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15094269.

70. Soriano V, Arasteh K, Migrone H, et al. Nevirapine versus atazanavir/ritonavir, each

combined with tenofovir disoproxil fumarate/emtricitabine, in antiretroviral-naive HIV-1
patients: the ARTEN Trial. Antivir Ther. 2011;16(3):339-348. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21555816.

71. Kamya MR, Mayanja-Kizza H, Kambugu A, et al. Predictors of long-term viral failure
among ugandan children and adults treated with antiretroviral therapy. J Acquir Immune
Defic Syndr. 2007;46(2):187-193. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17693883.

72. Lowenthal ED, Ellenberg JH, Machine E, et al. Association between efavirenz-based
compared with nevirapine-based antiretroviral regimens and virological failure in HIV-
infected children. JAMA. 2013;309(17):1803-1809. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23632724.

73. Buck WC, Kabue MM, Kazembe PN, Kline MW. Discontinuation of standard first-line
antiretroviral therapy in a cohort of 1434 Malawian children. J Int AIDS Soc. 2010;13:31.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20691049.

74. Mehta U, Maartens G. Is it safe to switch between efavirenz and nevirapine in the event
of toxicity? Lancet Infect Dis. 2007;7(11):733-738. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17961859.

75. Mbuagbaw L, Mursleen S, Irlam JH, Spaulding AB, Rutherford GW, Siegfried N.
Efavirenz or nevirapine in three-drug combination therapy with two nucleoside or
nucleotide-reverse transcriptase inhibitors for initial treatment of HIV infection in
antiretroviral-naive individuals. Cochrane Database Syst Rev. 2016;12:CD004246.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27943261.

76. Kekitiinwa A, Szubert AJ, Spyer M, et al. Virologic response to first-line efavirenz- or
nevirapine-based antiretroviral therapy in HIV-infected African children. Pediatr Infect
Dis J. 2017;36(6):588-594. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28505015.

77. Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two
background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive
adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial.
Lancet. 2011;378(9787):229-237. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21763935.

78. Cohen CJ, Molina JM, Cassetti I, et al. Week 96 efficacy and safety of rilpivirine in
treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS.
2013;27(6):939-950. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23211772.

79. Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and
emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-30
 randomised double-blind active-controlled trial. Lancet. 2011;378(9787):238-246.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/21763936.

80. Lombaard J, Bunupuradah T, Flynn PM, et al. Rilpivirine as a treatment for HIV-infected
antiretroviral-naive adolescents: week 48 safety, efficacy, virology and pharmacokinetics.
Pediatr Infect Dis J. 2016;35(11):1215-1221. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27294305.

81. Gatell J, Salmon-Ceron D, Lazzarin A, et al. Efficacy and safety of atazanavir-based

highly active antiretroviral therapy in patients with virologic suppression switched from a
stable, boosted or unboosted protease inhibitor treatment regimen: the SWAN Study
(AI424-097) 48-week results. Clin Infect Dis. 2007;44(11):1484-1492. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17479947.

82. Cotton MF, Liberty A, Torres-Escobar I, et al. Safety and efficacy of atazanavir powder
and ritonavir in HIV-1-infected infants and children from 3 months to <11 years of age:
the PRINCE-2 study. Pediatr Infect Dis J. 2018;37(6):e149-e156. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29206747.

83. Sevinsky H, Zaru L, Wang R, et al. Pharmacokinetics and pharmacodynamics of

atazanavir in HIV-1-infected children treated with atazanavir powder and ritonavir:
combined analysis of the PRINCE-1 and -2 studies. Pediatr Infect Dis J.
2018;37(6):e157-e165. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29206748.

84. Malan DR, Krantz E, David N, et al. Efficacy and safety of atazanavir, with or without
ritonavir, as part of once-daily highly active antiretroviral therapy regimens in
antiretroviral-naive patients. J Acquir Immune Defic Syndr. 2008;47(2):161-167.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/17971713.

85. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir

compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and
emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week
efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr.
2010;53(3):323-332. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20032785.

86. Kiser JJ, Fletcher CV, Flynn PM, et al. Pharmacokinetics of antiretroviral regimens
containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and
young adults with human immunodeficiency virus infection. Antimicrob Agents
Chemother. 2008;52(2):631-637. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18025112.

87. Kiser JJ, Rutstein RM, Samson P, et al. Atazanavir and atazanavir/ritonavir
pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS.
2011;25(12):1489-1496. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21610486.

88. Rutstein RM, Samson P, Fenton T, et al. Long-term safety and efficacy of atazanavir-
based therapy in HIV-infected infants, children and adolescents: the pediatric AIDS
clinical trials group protocol 1020A. Pediatr Infect Dis J. 2015;34:162-167. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25232777.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-31
89. Strehlau R, Donati AP, Arce PM, et al. PRINCE-1: safety and efficacy of atazanavir
powder and ritonavir liquid in HIV-1-infected antiretroviral-naive and -experienced
infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26066346.

90. Kakuda TN, Brochot A, van de Casteele T, Opsomer M, Tomaka F. Establishing

darunavir dosing recommendations in treatment-naive and treatment-experienced
pediatric patients. Presented at: 14th Clinical Pharmacology Workshop on HIV; 2013.
Amsterdam, Netherlands. Available at:
https://www.natap.org/2013/Pharm/Pharm_19.htm.

91. Larson KB, Cressey TR, Yogev R, et al. Pharmacokinetics of once-daily

darunavir/ritonavir with and without etravirine in human immunodeficiency virus-
infected children, adolescents, and young adults. J Pediatric Infect Dis Soc.
2016;5(2):131-137. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27199469.

92. Food and Drug Administration. Tybost supplemental approval. 2019. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2019/203094Orig1s013ltr.pdf.

93. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily

darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients
at week 48. AIDS. 2008;22(12):1389-1397. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18614861.

94. Mills AM, Nelson M, Jayaweera D, et al. Once-daily darunavir/ritonavir vs.

lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS.
2009;23(13):1679-1688. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19487905.

95. King J, Hazra R, et al. Pharmacokinetics of darunavir 800 mg with ritonavir 100 mg once
daily in HIV+ adolescents and young adults. Presented at: Conference on Retroviruses
and Opportunistic Infections 2013. Atlanta, GA.

96. Clotet B, Feinberg J, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus
ritonavir in antiretroviral-naive adults with HIV-1 infection (FLAMINGO): 48 week
results from the randomised open-label phase 3b study. Lancet. 2014;383(9936):2222-
2231. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24698485.

97. Flynn P, Komar S, Blanche S, et al. Efficacy and safety of darunavir/ritonavir at 48

weeks in treatment-naive, HIV-1-infected adolescents: results from a Phase 2 open-label
trial (DIONE). Pediatr Infect Dis J. 2014;33(9):940-945. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25361024.

98. Blanche S, Bologna R, Cahn P, et al. Pharmacokinetics, safety and efficacy of

darunavir/ritonavir in treatment-experienced children and adolescents. AIDS.
2009;23(15):2005-2013. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19724191.

99. Violari A, Bologna R, Kumarasamy N, et al. Safety and efficacy of darunavir/ritonavir in

treatment-experienced pediatric patients: week 48 results of the ARIEL trial. Pediatr
Infect Dis J. 2015;34(5):e132-137. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25719453.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-32
100. Violari A, Masenya M, Blanche S, et al. The DIANA study: continued access to
darunavir/ritonavir (DRV/r) and long-term safety follow-up in HIV-1-infected pediatric
patients aged 3 to < 18 years. Drug Saf. 2021;44(4):439-446. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33367975.

101. Gathe J, da Silva BA, Cohen DE, et al. A once-daily lopinavir/ritonavir-based regimen is
noninferior to twice-daily dosing and results in similar safety and tolerability in
antiretroviral-naive subjects through 48 weeks. J Acquir Immune Defic Syndr.
2009;50(5):474-481. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19225400.

102. van der Flier M, Verweel G, van der Knaap LC, et al. Pharmacokinetics of lopinavir in
HIV type-1-infected children taking the new tablet formulation once daily. Antivir Ther.
2008;13(8):1087-1090. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19195335.

103. la Porte C, van Heeswijk R, Mitchell CD, Zhang G, Parker J, Rongkavilit C.

Pharmacokinetics and tolerability of once- versus twice-daily lopinavir/ritonavir
treatment in HIV-1-infected children. Antivir Ther. 2009;14(4):603-606. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19578247.

104. Eron J, Jr., Yeni P, Gathe J, Jr., et al. The KLEAN study of fosamprenavir-ritonavir
versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial
treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet.
2006;368(9534):476-482. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16890834.

105. Pulido F, Estrada V, Baril JG, et al. Long-term efficacy and safety of fosamprenavir plus
ritonavir versus lopinavir/ritonavir in combination with abacavir/lamivudine over 144
weeks. HIV Clin Trials. 2009;10(2):76-87. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19487177.

106. Walmsley S, Avihingsanon A, Slim J, et al. Gemini: a noninferiority study of

saquinavir/ritonavir versus lopinavir/ritonavir as initial HIV-1 therapy in adults. J Acquir
Immune Defic Syndr. 2009;50(4):367-374. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19214123.

107. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily
darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naive
patients in the ARTEMIS trial. HIV Med. 2013;14(1):49-59. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23088336.

108. Paediatric European Network for Treatment of AIDS. Once vs. twice-daily
lopinavir/ritonavir in HIV-1-infected children. AIDS. 2015;29(18):2447-2457. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/26558544.

109. Paediatric European Network for Treatment of AIDS. Comparison of dual nucleoside-
analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children
with HIV-1 who have not previously been treated: the PENTA 5 randomised trial.
Lancet. 2002;359(9308):733-740. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11888583.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-33
110. Gafni RI, Hazra R, Reynolds JC, et al. Tenofovir disoproxil fumarate and an optimized
background regimen of antiretroviral agents as salvage therapy: impact on bone mineral
density in HIV-infected children. Pediatrics. 2006;118(3):e711-718. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16923923.

111. Giacomet V, Mora S, Martelli L, Merlo M, Sciannamblo M, Vigano A. A 12-month

treatment with tenofovir does not impair bone mineral accrual in HIV-infected children. J
Acquir Immune Defic Syndr. 2005;40(4):448-450. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16280700.

112. Hazra R, Balis FM, Tullio AN, et al. Single-dose and steady-state pharmacokinetics of
tenofovir disoproxil fumarate in human immunodeficiency virus-infected children.
Antimicrob Agents Chemother. 2004;48(1):124-129. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/14693529.

113. Hazra R, Gafni RI, Maldarelli F, et al. Tenofovir disoproxil fumarate and an optimized
background regimen of antiretroviral agents as salvage therapy for pediatric HIV
infection. Pediatrics. 2005;116(6):e846-854. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16291735.

114. Borroto-Esoda K, Vela JE, Myrick F, Ray AS, Miller MD. In vitro evaluation of the anti-
HIV activity and metabolic interactions of tenofovir and emtricitabine. Antivir Ther.
2006;11(3):377-384. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16759055.

115. Ross L, Parkin N, Chappey C, et al. Phenotypic impact of HIV reverse transcriptase
M184I/V mutations in combination with single thymidine analog mutations on
nucleoside reverse transcriptase inhibitor resistance. AIDS. 2004;18(12):1691-1696.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15280780.

116. Bekker A, Decloedt EH, Slade G, Cotton MF, Rabie H, Cressey TR. Single dose abacavir
pharmacokinetics and safety in neonates exposed to human immunodeficiency virus
(HIV). Clin Infect Dis. 2021;72(11):2032-2034. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32697327.

117. Bekker A, Capparelli EV, Violari A, et al. Abacavir dosing in neonates from birth to 3
months of life: a population pharmacokinetic modelling and simulation study. Lancet
HIV. 2022;9(1):e24-e31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34883066.

118. Green H, Gibb DM, Walker AS, et al. Lamivudine/abacavir maintains virological
superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in
children. AIDS. 2007;21(8):947-955. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17457088.

119. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine
for initial HIV-1 therapy. N Engl J Med. 2009;361(23):2230-2240. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19952143.

120. Smith KY, Patel P, Fine D, et al. Randomized, double-blind, placebo-matched,

multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-34
 lopinavir/ritonavir for initial HIV treatment. AIDS. 2009;23(12):1547-1556. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19542866.

121. Spaulding A, Rutherford GW, Siegfried N. Tenofovir or zidovudine in three-drug

combination therapy with one nucleoside reverse transcriptase inhibitor and one non-
nucleoside reverse transcriptase inhibitor for initial treatment of HIV infection in
antiretroviral-naive individuals. Cochrane Database Syst Rev. 2010(10):CD008740.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20927777.

122. Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects,
efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine,
administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week
results from the ASSERT study. J Acquir Immune Defic Syndr. 2010;55(1):49-57.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20431394.

123. Mulenga V, Musiime V, Kekitiinwa A, et al. Abacavir, zidovudine, or stavudine as

paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label,
parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169-179.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26481928.

124. Technau KG, Lazarus E, Kuhn L, et al. Poor early virologic performance and durability
of abacavir-based first-line regimens for HIV-infected children. Pediatr Infect Dis J.
2013;32(8):851-855. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23860481.

125. Technau KG, Schomaker M, Kuhn L, et al. Virologic response in children treated with
abacavir-compared with stavudine-based antiretroviral treatment: a South African multi-
cohort analysis. Pediatr Infect Dis J. 2014;33(6):617-622. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24378944.

126. Cressey TR, Bekker A, Cababasay M, et al. Abacavir safety and pharmacokinetics in
normal and low birth weight infants with HIV. Abstract #843. Presented at: Conference
on Retroviruses and Opportunistic Infections; 2020. Boston, MA. Available at:
https://www.croiconference.org/abstract/abacavir-safety-and-pharmacokinetics-in-
normal-and-low-birth-weight-infants-with-hiv/.

127. Crichton S, Collins IJ, Turkova A, et al. Abacavir dosing, effectivness, and safety in
young infants living with HIV in Europe. Abstract #844. Presented at: Conference on
Retroviruses and Opportunistic Infections 2020. Boston, MA. Available at:
https://www.croiconference.org/abstract/abacavir-dosing-effectiveness-and-safety-in-
young-infants-living-with-hiv-in-europe/.

128. De Waal R, Rabie H, Technau K, et al. Abacavir safety and efficacy in young infants in
South African observational cohort. Abstract #845. Presented at: Conference on
Retroviruses and Opportunistic Infections 2020. Boston, MA. Available at:
https://www.croiconference.org/abstract/abacavir-safety-and-efficacy-in-young-infants-
in-south-african-observational-cohorts/.

129. Bergshoeff A, Burger D, Verweij C, et al. Plasma pharmacokinetics of once- versus

twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-35
 infected children (PENTA-13). Antivir Ther. 2005;10(2):239-246. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15865218.

130. LePrevost M, Green H, Flynn J, et al. Adherence and acceptability of once daily
lamivudine and abacavir in human immunodeficiency virus type-1 infected children.
Pediatr Infect Dis J. 2006;25(6):533-537. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16732152.

131. Paediatric European Network for Treatment of AIDS. Pharmacokinetic study of once-
daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3–
<36 months. Antivir Ther. 2010;15(3):297-305. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20516550.

132. Musiime V, Kendall L, Bakeera-Kitaka S, et al. Pharmacokinetics and acceptability of

once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan
children in the ARROW Trial. Antivir Ther. 2010;15(8):1115-1124. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21149918.

133. Natukunda E, Rodriguez C, McGrath E, et al. B/F/TAF in virologically suppressed

adolescents and children: two-year outcomes in 6 to <18 year olds and six-month
outcomes in toddlers. Presented at: 13th International Workshop on HIV Pediatrics 2021.
Virtual Meeting. Available at: https://www.natap.org/2021/IAS/IAS_80.htm.

134. Descovy [package insert] [package insert]. Food and Drug Administration. 2021.
Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208215s020lbl.pdf.

135. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs
stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized
trial. JAMA. 2004;292(2):191-201. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15249568.

136. Vigano A, Bedogni G, Manfredini V, et al. Long-term renal safety of tenofovir disoproxil
fumarate in vertically HIV-infected children, adolescents and young adults: a 60-month
follow-up study. Clin Drug Investig. 2011;31(6):407-415. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21528939.

137. Giacomet V, Maruca K, Ambrosi A, Zuccotti GV, Mora S. A 10-year follow-up of bone
mineral density in HIV-infected youths receiving tenofovir disoproxil fumarate. Int J
Antimicrob Agents. 2017;50(3):365-370. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28689877.

138. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs.
zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006;354(3):251-260.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/16421366.

139. Arribas JR, Pozniak AL, Gallant JE, et al. Tenofovir disoproxil fumarate, emtricitabine,
and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive
patients: 144-week analysis. J Acquir Immune Defic Syndr. 2008;47(1):74-78. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/17971715.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-36
140. Papaleo A, Warszawski J, Salomon R, et al. Increased beta-2 microglobulinuria in human
immunodeficiency virus-1-infected children and adolescents treated with tenofovir.
Pediatr Infect Dis J. 2007;26(10):949-951. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17901802.

141. Riordan A, Judd A, Boyd K, et al. Tenofovir use in human immunodeficiency virus-1-
infected children in the United Kingdom and Ireland. Pediatr Infect Dis J.
2009;28(3):204-209. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19209091.

142. Andiman WA, Chernoff MC, Mitchell C, et al. Incidence of persistent renal dysfunction
in human immunodeficiency virus-infected children: associations with the use of
antiretrovirals, and other nephrotoxic medications and risk factors. Pediatr Infect Dis J.
2009;28(7):619-625. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19561425.

143. Pontrelli G, Cotugno N, Amodio D, et al. Renal function in HIV-infected children and
adolescents treated with tenofovir disoproxil fumarate and protease inhibitors. BMC
Infect Dis. 2012;12:18. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22269183.

144. Van Dyke RB, Wang L, Williams PL, Pediatric AIDS Clinical Trials Group C Team.
Toxicities associated with dual nucleoside reverse-transcriptase inhibitor regimens in
HIV-infected children. J Infect Dis. 2008;198(11):1599-1608. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19000014.

145. Moyle GJ, Sabin CA, Cartledge J, et al. A randomized comparative trial of tenofovir DF
or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS.
2006;20(16):2043-2050. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17053350.

146. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in
patients with HIV lipoatrophy: a randomized trial. JAMA. 2002;288(2):207-215.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/12095385.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-37
What Not to Start: Regimens Not Recommended for
Use in Antiretroviral-Naive Children
Updated: April 11, 2023
Reviewed: April 11, 2023

This section describes antiretroviral (ARV) drugs and drug combinations that either are not
recommended for use in ARV-naive children or lack sufficient data to recommend their use in
ARV-naive children. Although many ARV agents and combinations are available, some are not
recommended for use as part of an initial regimen in ARV-naive children, but they may be used in
ARV-experienced children (see Recognizing and Managing Antiretroviral Treatment Failure).
Several ARV drugs that are no longer available or recommended for use in children for several years
have been removed from this chapter, including the nucleoside reverse transcriptase
inhibitors (NRTIs) stavudine and didanosine; the protease inhibitors (PIs) indinavir, nelfinavir,
saquinavir, tipranavir (TPV), and fosamprenavir; and the fusion inhibitor enfuvirtide (see Archived
Drugs in Appendix A: Pediatric Antiretroviral Drug Information). The PI ritonavir is no longer
recommended for use as the sole PI in an ARV regimen but is used at a reduced dose as a
pharmacokinetic (PK) enhancer (boosting agent) with other ARV drugs (e.g., atazanavir, darunavir).

The Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV (the
Panel) classifies ARV drugs and drug combinations that are not recommended for use in ARV-naive
children into one of three categories:

• Not Recommended for Initial Therapy: These include ARV drugs and drug combinations that are
not recommended for initial therapy in ARV-naive children because they produce an inferior
virologic response, they pose potential serious safety concerns (including potentially overlapping
toxicities), they are associated with pharmacologic antagonism, or better options are available
within a drug class. These drugs and drug combinations are listed in Table 10, and selected drugs
or drug combinations are discussed below.
• Insufficient Data to Recommend for Initial Therapy: ARV drugs and drug combinations that are
approved for use in adults but have insufficient, limited, or no PK and/or safety data for children
cannot be recommended for initial therapy in children. However, these drugs and drug
combinations may be appropriate to consider when managing treatment-experienced children
(see Management of Children Receiving Antiretroviral Therapy). These drugs also are listed in
Table 10, and selected drugs or drug combinations are discussed below.
• Antiretroviral Drug Regimens That Are Never Recommended: Several ARV drug and drug
combinations should never be used in children or adults. They are summarized in Table 11.
Clinicians also should be aware of the components of fixed-dose combination (FDC) tablets so
that patients do not inadvertently receive a double dose of a drug contained in such a
combination.

Antiretroviral Drugs and Drug Combinations Not Recommended for Initial Therapy in
Children
Atazanavir Without Ritonavir or Cobicistat Boosting
Although unboosted atazanavir (ATV) is approved by the U.S. Food and Drug Administration (FDA)
for use in treatment-naive adolescents—aged ≥13 years and weighing ≥40 kg—who are unable to

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-38
tolerate ritonavir (RTV), data from the International Maternal Pediatric Adolescent AIDS Clinical
Trials Group (IMPAACT)/Pediatric AIDS Clinical Trials Group (PACTG) 1020A study indicate that
adolescents require higher doses of unboosted ATV (as measured by milligram per meter squared of
body surface area) than adults to achieve adequate drug concentrations.1 Because of these findings,
the Panel does not recommend using ATV without RTV boosting.

Efavirenz-Based Regimens for Children Aged ≥3 Months to 3 Years

Efavirenz (EFV) is approved by the FDA for use in children aged >3 months and weighing ≥3.5 kg.
An EFV-based regimen was shown to have variable PKs in studies of young children; therefore, at
this time the Panel does not recommend using EFV in children aged <3 years (see the Efavirenz
section in Appendix A: Pediatric Antiretroviral Drug Information). When the use of EFV is being
considered for children aged <3 years, cytochrome P450 (CYP) 2B6 genotyping should be
performed, if available, to predict a patient’s metabolic rate for EFV. Therapeutic drug monitoring
also can be considered. Additionally, EFV in children <3 years may be considered in the setting of
HIV/tuberculosis coinfection, because EFV is one of the few ARVs with minimal drug–drug
interactions seen with other ARVs and rifampin.2

Etravirine-Based Regimens
Etravirine (ETR) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) that has been studied in
treatment-experienced children aged ≥1 years and now is approved by the FDA for use in children
aged ≥2 years and weighing ≥10 kg.3-5 ETR is associated with multiple interactions with other ARV
drugs, including TPV/ritonavir, ATV/ritonavir, and unboosted PIs, and must be administered twice
daily. The use of ETR likely will not be studied in treatment-naive children.

Maraviroc-Based Regimens
Maraviroc (MVC) is an entry inhibitor approved by the FDA for use in children weighing ≥2 kg who
have CCR5-tropic HIV-1. It has been used infrequently in children. A recent dose-finding study
administered both the liquid and tablet formulations of MVC to treatment-experienced children aged
2 to 18 years who were grouped into four age cohorts.6 The initial dose was based on body surface
area and scaled from the recommended adult dose. Dose adjustments were required in patients who
were not receiving a potent CYP3A4 inhibitor or inducer.6 A recent study of MVC in newborns at
risk of HIV acquisition and weighing at least 2 kg established a dosing protocol that achieved target
exposures and was deemed safe. No apparent differences in PK parameters were observed among
infants of mothers with exposure to EFV and those without. None of the infants had HIV infection,
nor were they receiving potent CYP3A inhibitors.7 As an entry inhibitor, MVC is under study in
intensive treatment trials because of its hypothetical potential to limit the establishment of cell-
associated viral reservoirs. However, MVC has several features that limit its role for routine uses,
including multiple drug interactions, the need to be administered twice daily, and the fact that
tropism assays must be performed prior to its use to ensure the presence of only CCR5-tropic virus.
For those reasons, MVC is not recommended by the Panel for first-line treatment in neonates or
older children.

Cabotegravir With or Without Rilpivirine for Oral or Intramuscular Injections

In 2021, the FDA approved long-acting injectable formulations of cabotegravir (CAB), a novel
INSTI, and the NNRTI rilpivirine (RPV) for the treatment of HIV infection in adults to replace a
current, stable ARV regimen in patients with no prior history of treatment failure and no known
or suspected resistance to CAB or RPV who have demonstrated sustained viral suppression

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-39
(e.g., 3–6 months). These two long-acting injectable ARVs are co-packaged and marketed as
Cabenuva. In March 2022, the FDA approved Cabenuva for use in children and adolescents aged ≥12
years and weighing ≥35 kg. An oral lead-in with the oral formulations of the ARVs for at least 28
days is recommended to assess tolerability. The long-acting injectable formulations can then be
administered on a monthly or an every 2-month schedule. Clinical trials in adolescents are ongoing
and planned for younger children. The regimen of LAI CAB and RPV is not approved or
recommended for initial ARV therapy.

Regimens That Contain Only Nucleoside Reverse Transcriptase Inhibitors

In adult trials, regimens that contain only NRTIs have shown less potent virologic activity than
NNRTI–based or PI-based regimens.8,9 Data on the efficacy of triple-NRTI regimens for treatment of
ARV-naive children are limited to small observational studies.10,11 In a study on the use of the triple-
NRTI regimen abacavir plus lamivudine (3TC) plus zidovudine in ARV-experienced children, this
combination showed evidence of only modest viral suppression; only 10 of the 102 children had viral
loads of <400 copies/mL at Week 48 of treatment.12 Therefore, regimens that contain only NRTIs
are not recommended for treatment-naive or treatment-experienced children.

Regimens That Contain Three Drug Classes

The Panel does not recommend using regimens that contain agents from three drug classes as initial
regimens (e.g., an NRTI plus an NNRTI plus a PI or an integrase strand transfer inhibitor plus an
NRTI plus a PI or NNRTI). Although studies of regimens that contain three classes of drugs have
demonstrated that these regimens are safe and effective in ARV-experienced children and
adolescents, these regimens have not been studied as initial regimens in treatment-naive children and
adolescents. These regimens also have the potential to induce resistance to three drug classes, which
could severely limit future treatment options.13-17 Ongoing studies are investigating the use of drugs
from three drug classes to treat neonates.

Regimens That Contain Three Nucleoside Reverse Transcriptase Inhibitors and

a Non-Nucleoside Reverse Transcriptase Inhibitor
Current data are insufficient to recommend using a regimen that contains three NRTIs plus an
NNRTI in young infants. A review of nine cohorts from 13 European countries suggested that this
four-drug regimen produced responses that were superior to the responses observed in patients
receiving boosted-PI regimens or three-drug NRTI regimens.18 There has been speculation that poor
tolerance and poor adherence to a PI-based regimen may account for some of the differences. The
AntiRetroviral Research for Watoto (ARROW) trial, conducted in Uganda and Zimbabwe,
randomized 1,206 children (with a median age of 6 years) to receive either a standard NNRTI-based,
three-drug regimen (two NRTIs and one NNRTI) or a four-drug regimen (three NRTIs and one
NNRTI). After a 36-week induction period, the children on the four-drug regimen continued
treatment on a regimen that contained two NRTIs plus one NNRTI or a three-NRTI regimen.
Although improvements in CD4 T lymphocyte (CD4) cell counts were observed at Week 36 (with a
percentage change of approximately 14.4% in the four-drug arm compared with 12.6% in the three-
drug arm), these benefits were not sustained after patients switched to the three-drug regimens for the
duration of the study. Furthermore, no differences in viral suppression rates were observed between
the two arms at Week 36.19 Because three-drug regimens have been shown to be effective and well
tolerated and because efficacy data are lacking for the four-drug regimen, the Panel currently does
not recommend the four-drug regimen.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-40
Antiretroviral Drugs and Combinations With Insufficient Data to Recommend for
Initial Therapy in Children
Several ARV drugs and drug regimens are not recommended for use as initial therapy in ARV-naive
children or for specific age groups because of insufficient pediatric data. In some cases, new agents
have shown promise in adult clinical trials but do not have sufficient pediatric PK and safety data to
recommend their use as components of an initial therapeutic regimen in children. In addition, some
dosing schedules may not be recommended in certain age groups because of insufficient data. As
new data become available, these agents may become recommended agents or regimens, as
summarized below and listed in Table 10.

Darunavir With Low-Dose Ritonavir-Based Regimens Administered Once Daily

for Children Aged ≥3 Years to <12 Years
Whereas modeling studies identified a once-daily dosing schedule for darunavir/ritonavir (DRV/r)
that is now approved by the FDA, the Panel is concerned about the lack of direct PK studies for this
approach in individuals aged ≥3 years to <12 years. Therefore, the data are not sufficient to
recommend once-daily dosing for initial therapy in this age group. For children aged ≥3 years to
<12 years, twice-daily DRV/r is a Preferred drug combination. For older children who have
undetectable viral loads while receiving a twice-daily DRV/r-based regimen, practitioners can
consider switching to once-daily DRV/r dosing if no DRV-associated resistance mutations are
present. Once-daily dosing helps support adherence by making this drug combination easier to use.

Fostemsavir-Containing Regimens
Fostemsavir (FTR) is an HIV-1 glycoprotein (gp120)-directed attachment inhibitor that is not
approved for use in pediatric patients. FTR was approved by the FDA in 2020 for use in adults in
combination with other ARV drugs, with approval limited to heavily treatment-experienced adults
with multidrug-resistant HIV who are failing their current ART regimen due to resistance,
intolerance, or safety considerations. A PK and safety study of FTR in children and adolescents
≥20 kg (PENTA Foundation: NCT04648280) will soon be open to enrollment. At this time, the Panel
does not recommend FTR as part of an initial treatment regimen for HIV-1 infection in children.

Ibalizumab-Containing Regimens
Ibalizumab (IBA) is a humanized IgG4 monoclonal antibody that binds to CD4 extracellular
domain 2 and prevents conformational changes in the CD4-HIV envelope gp120 essential for viral
entry, thereby blocking HIV entry into CD4 cells.20 It was approved for use in adults with HIV-1
infection who are heavily pretreated, have multidrug-resistant virus, and are experiencing treatment
failure. IBA has an orphan drug designation exempting the requirement for pediatric studies under
the Pediatric Research Equity Act. At this time, because there is no experience with IBA in children,
the Panel does not recommend its use as initial treatment for HIV-1 infection.

Two-Drug Regimens
In adults, oral two-drug/two-class ARV regimens can be used in patients who have achieved and
sustained viral suppression on a three-drug ART regimen and may be used for initial therapy in some
individuals. In general, adults who have had viral suppression for at least 3 to 6 months and with

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-41
known susceptibility to the ARVs in the two-drug regimen have success after switching to these
regimens. Regimens that demonstrated efficacy in adult clinical trials include dolutegravir (DTG)
plus RPV, DTG plus 3TC or emtricitabine (FTC), and boosted DRV plus DTG. At this time, no data
support this strategy in children, and it is not recommended by the Panel. Although the Panel does
not recommend oral two-drug regimens for initial treatment in children, some two-drug regimens
might be considered for adolescents receiving ART when simplification or avoidance of NRTIs is
desired based on data from adults, see Modifying Antiretroviral Regimens in Children With
Sustained Virologic Suppression on Antiretroviral Therapy.

A two-drug/two-class regimen of LAI CAB and RPV has been approved by the FDA for use in
adults and in children and adolescents aged ≥12 years and weighing ≥35 kg who have achieved and
sustained viral suppression on another combination ARV regimen. However, this LAI regimen is not
recommended for initial therapy.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-42
Table 10. Antiretroviral Regimens or Components That Are Not Recommended for Initial
Treatment of HIV Infection in Children and Adolescents

ARV Regimen Rationale

Regimens containing only NRTIs Inferior virologic efficacy

Regimens containing three drug classes Potential to induce multiclass resistance

Use as an initial regimen in children has not been
studied

Regimens containing three NRTIs and one NNRTI Added cost and complexity outweighs any benefit

Full-dose, dual-PI regimens Insufficient data to recommend; potential for added

toxicities

Oral regimens containing only two ARVs Not FDA approved for pediatric use

ARV Component Rationale

Unboosted ATV-containing regimens in children Inadequate drug exposure

CAB Not FDA approved for use in ARV-naive individuals or

in children aged <12 years and weighing <35 kg

DRV/r in children <3 years Potential for seizures

Once-daily DRV-based regimens in children aged ≥3 years to Insufficient data to recommend

<12 years

EFV-based regimens for children aged <3 years CYP2B6 genotyping required to determine appropriate
dosing

ETR-based regimens Insufficient data to recommend; unlikely to be used as

initial therapy

FTR Not FDA approved for use in ARV-naive adults or for

pediatric use

IBA Not FDA approved for use in ARV-naive adults or for

pediatric use

LPV/r dosed once daily Inadequate drug exposure

MVC-based regimens Only effective for CCR5-tropic virus

TDF-containing regimens in children aged <2 years Potential bone toxicity

Appropriate dose has yet to be determined

Key: ARV = antiretroviral; ATV = atazanavir; CAB = cabotegravir; DRV = darunavir; DRV/r = darunavir/ritonavir;
FDA = U.S. Food and Drug Administration; EFV = efavirenz; ETR = etravirine; FTR = fostemsavir; GI = gastrointestinal;
IBA = ibalizumab; LPV/r = lopinavir/ritonavir; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor;
NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; TDF = tenofovir disoproxil fumarate

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-43
Table 11. Antiretroviral Regimens or Components That Are Never Recommended for
Treating HIV in Children and Adolescentsa

ARV Regimen or Component Rationale Exceptions

One ARV Drug Alone Rapid development of resistance Infants with perinatal HIV exposure and
(Monotherapy) negative virologic tests who are receiving
Inferior antiviral activity compared with 4–6 weeks of ZDV prophylaxis to prevent
regimens that include ≥3 ARV drugs perinatal transmission of HIV
Monotherapy “holding” regimens are
associated with more rapid CD4 count
declines than nonsuppressive ART.

Two NRTIs Alone Rapid development of resistance Not recommended for initial therapy

Inferior antiviral activity compared with Some clinicians may opt to continue using
regimens that include ≥3 ARV drugs two NRTIs alone in patients who achieve
virologic goals with this regimen.

Any Regimen Containing Both Similar resistance profile and no No exceptions

3TC Plus FTC additive benefit

Any Regimen Containing Both No data to support potential additive No exceptions

TDF and TAF efficacy or toxicity

Dual-NNRTI Combinations Enhanced toxicity No exceptions

TDF Plus ABC Plus (3TC or FTC) High rate of early viral failure when this No exceptions
as a Triple-NRTI Regimen triple-NRTI regimen was used as initial
therapy in treatment-naive adults

NVP as Component of Initial ARV Increased incidence of symptomatic Only if benefit clearly outweighs risk
Therapy Regimen in Adolescent (including serious and potentially fatal)
Girls With CD4 Counts hepatic events in these patient groups
>250 cells/mm3 or Adolescent
Boys With CD4 Counts
>400 cells/mm3
a Several ARV drugs that are no longer available or that have not been recommended for use in children for several years have

been removed from this chapter, including the NRTIs stavudine and didanosine; the protease inhibitors fosamprenavir indinavir,
nelfinavir, saquinavir, and tipranavir; and the fusion inhibitor enfuvirtide (see Archived Drugs).
Key: 3TC = lamivudine; ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; CD4 = CD4 T lymphocyte;
FTC = emtricitabine; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor;
NVP = nevirapine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-44
References

1. Kiser JJ, Rutstein RM, Samson P, et al. Atazanavir and atazanavir/ritonavir

pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS.
2011;25(12):1489-1496. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21610486.

2. Bwakura Dangarembizi M, Samson P, Capparelli EV, et al. Establishing dosing

recommendations for efavirenz in HIV/TB-coinfected children younger than 3 years. J
Acquir Immune Defic Syndr. 2019;81(4):473-480. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31241542.

3. Konigs C, Feiterna-Sperling C, Esposito S, et al. Pharmacokinetics and short-term safety

and tolerability of etravirine in treatment-experienced HIV-1-infected children and
adolescents. AIDS. 2012;26(4):447-455. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22156961.

4. Tudor-Williams G, Cahn P, Chokephaibulkit K, et al. Etravirine in treatment-

experienced, HIV-1-infected children and adolescents: 48-week safety, efficacy and
resistance analysis of the phase II PIANO study. HIV Med. 2014;15(9):513-524.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/24589294.

5. MacBrayne CE, Rutstein RM, Wiznia AA, et al. Etravirine in treatment-experienced

HIV-1-infected children 1 year to less than 6 years of age. AIDS. 2021;35(9):1413-1421.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/33831904.

6. Giaquinto C, Mawela MP, Chokephaibulkit K, et al. Pharmacokinetics, safety and

efficacy of maraviroc in treatment-experienced pediatric patients infected with CCR5-
tropic HIV-1. Pediatr Infect Dis J. 2018;37(5):459-465. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29023357.

7. Rosebush JC, Best BM, Chadwick EG, et al. Pharmacokinetics and safety of maraviroc in
neonates. AIDS. 2021;35(3):419-427. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33252481.

8. Gerstoft J, Kirk O, Obel N, et al. Low efficacy and high frequency of adverse events in a
randomized trial of the triple nucleoside regimen abacavir, stavudine and didanosine.
AIDS. 2003;17(14):2045-2052. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/14502007.

9. van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line
combination therapy with or without a protease inhibitor in HIV-1-infected patients.
AIDS. 2003;17(7):987-999. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12700448.

10. Saavedra J, Mccoig C, Mallory M, et al. Clinical experience with triple nucleoside
(NRTI) combination ZDV/3TC/abacavir (ABC) as initial therapy in HIV-infected
children. Presented at: 41st Interscience Conference on Antimicrobial Agents and
Chemotherapy; 2001. Chicago, IL.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-45
11. Handforth J, Sharland M. Triple nucleoside reverse transcriptase inhibitor therapy in
children. Paediatr Drugs. 2004;6(3):147-159. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15170362.

12. Saez-Llorens X, Nelson RP, Jr., Emmanuel P, et al. A randomized, double-blind study of
triple nucleoside therapy of abacavir, lamivudine, and zidovudine versus lamivudine and
zidovudine in previously treated human immunodeficiency virus type 1-infected children.
The CNAA3006 Study Team. Pediatrics. 2001;107(1):E4. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11134468.

13. Spector SA, Hsia K, Yong FH, et al. Patterns of plasma human immunodeficiency virus
type 1 RNA response to highly active antiretroviral therapy in infected children. J Infect
Dis. 2000;182(6):1769-1773. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11069252.

14. Starr SE, Fletcher CV, Spector SA, et al. Combination therapy with efavirenz, nelfinavir,
and nucleoside reverse-transcriptase inhibitors in children infected with human
immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team. N Engl
J Med. 1999;341(25):1874-1881. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/10601506.

15. Starr SE, Fletcher CV, Spector SA, et al. Efavirenz liquid formulation in human
immunodeficiency virus-infected children. Pediatr Infect Dis J. 2002;21(7):659-663.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/12237599.

16. Wiznia A, Stanley K, Krogstad P, et al. Combination nucleoside analog reverse

transcriptase inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral
therapy-experienced HIV-infected children: week 24 results of a randomized controlled
trial--PACTG 377. Pediatric AIDS Clinical Trials Group 377 Study Team. AIDS Res
Hum Retroviruses. 2000;16(12):1113-1121. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/10954886.

17. Krogstad P, Lee S, Johnson G, et al. Nucleoside-analogue reverse-transcriptase inhibitors

plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human
immunodeficiency virus type 1. Clin Infect Dis. 2002;34(7):991-1001. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11880966.

18. Judd A, and EP, Paediatric HIV Cohort Collaboration study group in EuroCoord. Early
antiretroviral therapy in HIV-1-infected infants, 1996–2008: treatment response and
duration of first-line regimens. AIDS. 2011;25(18):2279-2287. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21971357.

19. Arrow Trial team, Kekitiinwa A, Cook A, et al. Routine versus clinically driven
laboratory monitoring and first-line antiretroviral therapy strategies in African children
with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet.
2013;381(9875):1391-1403. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23473847.

20. Moore JP, Sattentau QJ, Klasse PJ, Burkly LC. A monoclonal antibody to CD4 domain 2
blocks soluble CD4-induced conformational changes in the envelope glycoproteins of

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-46
 human immunodeficiency virus type 1 (HIV-1) and HIV-1 infection of CD4+ cells. J
Virol. 1992;66(8):4784-4793. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/1378510.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-47
Antiretroviral Management of Newborns With
Perinatal HIV Exposure or HIV Infection
Updated: April 11, 2023
Reviewed: January 31, 2023

Panel’s Recommendations
• All newborns who were exposed perinatally to HIV should receive postpartum antiretroviral (ARV) drugs to reduce the risk
of perinatal transmission of HIV (AI).
• Newborn ARV regimens administered at doses that are appropriate for the infant’s gestational age should be initiated as
close to the time of birth as possible, preferably within 6 hours of delivery (AII).
• A newborn’s ARV regimen should be determined based on maternal and infant factors that influence the risk of perinatal
transmission of HIV (AII). The uses of ARV regimens in newborns include the following:
o ARV Prophylaxis: The administration of one or more ARV drugs to a newborn without documented HIV infection to
reduce the risk of perinatal acquisition of HIV.
o Presumptive HIV Therapy: The administration of a three-drug ARV regimen to newborns who are at highest risk of
perinatal acquisition of HIV. Presumptive HIV therapy is intended to be preliminary treatment for a newborn who is later
documented to have HIV, but it also serves as prophylaxis against HIV acquisition.
o HIV Therapy: The administration of a three-drug ARV regimen at treatment doses (called antiretroviral therapy [ART])
to newborns with documented HIV infection (see Diagnosis of HIV Infection in Infants and Children).
• For newborns at low-risk of perinatal HIV acquisition, a 2-week zidovudine (ZDV) ARV regimen is recommended for ARV
prophylaxis if the newborn is ≥37 weeks gestation and is born to a person with HIV who—
o Is currently receiving and has received at least 10 consecutive weeks of ART during pregnancy (BII); and
o Has achieved and maintained or maintained viral suppression (defined as at least two consecutive tests with HIV RNA
<50 copies/mL obtained at least 4 weeks apart) for the remainder of the pregnancy (AII); and
o Has a viral load <50 copies/mL at or after 36 weeks (AII); and
o Did not have acute HIV infection during pregnancy (BII); and
o Has reported good ART adherence, and adherence concerns have not been identified (BII).
• Infants born to individuals who do not meet the criteria above but who have a viral load <50 copies/mL at or after 36 weeks
gestation should receive ZDV for 4 to 6 weeks (BII).
• Newborns at high risk of perinatal acquisition of HIV should receive presumptive HIV therapy with 3-drug regimens
administered from birth for 2 to 6 weeks (see Tables 10 and 11); if the duration of the 3-drug regimen is shorter than 6
weeks, ZDV should be continued alone, to complete total of 6 weeks of prophylaxis. Newborns at high risk of HIV
acquisition include those born to people with HIV who—
o Have not received antepartum ARV drugs (AI), or
o Have received only intrapartum ARV drugs (AI), or
o Have received antepartum ARV drugs but who did not achieve viral suppression (defined as at least two consecutive
tests with HIV RNA level <50 copies/mL obtained at least 4 weeks apart) within 4 weeks of delivery (AIII), or
o Have primary or acute HIV infection during pregnancy (AI).
• All premature infants <37 weeks gestation who are not at high risk of perinatal acquisition of HIV should receive ZDV for 4
to 6 weeks (BII).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-1
 • Infants of people who have primary or acute HIV infection while breastfeeding should be managed like infants at high risk
of perinatal transmission with presumptive HIV therapy (see Table 12) (AII).
• The use of ARV drugs other than ZDV, lamivudine, and nevirapine cannot be recommended for any indication in
premature newborns (<37 weeks gestational age) because of the lack of dosing and safety data (BII).
• If an individual presents with unknown HIV status and has a positive expedited HIV test during labor or shortly after
delivery, the infant should begin presumptive HIV therapy (AII). If supplemental maternal testing is negative, the infant’s
ARV regimen should be discontinued (AII).
• For newborns with HIV infection, ART should be initiated (AI) (see What to Start in the Pediatric Antiretroviral Guidelines).
• People with HIV should receive patient-centered, evidence-based counseling to support shared decision-making about
infant feeding. See Infant Feeding for Individuals With HIV in the United States.
• Providers with questions about ARV management of perinatal HIV exposure should consult an expert in pediatric HIV
infection or the National Perinatal HIV hotline (1-888-448-8765), which provides free clinical consultation on all aspects of
perinatal HIV, including newborn care (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials with clinical outcomes and/or validated laboratory endpoints; II = One
or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; III = Expert
opinion

General Considerations for Antiretroviral Management of Newborns Exposed to HIV

or Born With HIV
All newborns with perinatal exposure to HIV should receive antiretroviral (ARV) drugs during the
neonatal period to reduce the risk of perinatal HIV transmission, with selection of the appropriate
ARV regimen guided by the level of transmission risk. HIV transmission can occur in utero,
intrapartum, or during breastfeeding.

Maternal viral load is the most important risk factor for HIV transmission to a newborn. Newborns
are at an increased risk for HIV acquisition when their mothers do not receive antiretroviral
therapy (ART) during pregnancy, when mothers start antepartum treatment late in pregnancy, or
when antepartum treatment does not result in viral suppression (defined as at least two consecutive
tests with HIV RNA level <50 copies/mL obtained at least 4 weeks apart). Higher maternal viral
load, especially in late pregnancy, correlates with higher risk of transmission. A spectrum of
transmission risk depends on these and other maternal and infant factors, including mode of delivery,
gestational age at delivery, and maternal health status.

Historically, the use of ARV drugs in the newborn period was referred to as ARV prophylaxis
because it primarily focused on protection against newborn perinatal acquisition of HIV. More
recently, clinicians have begun to identify newborns at highest risk for HIV acquisition and initiate
three-drug ARV regimens as presumptive treatment of HIV. In this section, the following terms will
be used:

• ARV Prophylaxis: The administration of ARV drugs to a newborn without documented HIV
infection to reduce the risk of HIV acquisition. Most ARV prophylaxis includes administration of
a single agent—usually zidovudine (ZDV). In some situations, combinations of two or three
ARV drugs may also be administered as ARV prophylaxis.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-2
• Presumptive HIV Therapy: The administration of a three-drug ARV regimen to newborns at
highest risk of HIV acquisition. Presumptive HIV therapy is intended to be early treatment for a
newborn who is later documented to have acquired HIV, but it also serves as ARV prophylaxis
against HIV acquisition.
• HIV Therapy: The administration of a three-drug ARV regimen to newborns with documented
HIV infection (see Diagnosis of HIV Infection in Infants and Children).

The terms ARV prophylaxis and presumptive HIV therapy describe the clinician’s intent when
prescribing ARV drugs, which may lead to an overlap between these two terms. For example, a
presumptive HIV therapy regimen also provides ARV prophylaxis for a newborn. However, two-
drug (or sometimes three-drug) ARV prophylaxis regimens, notably those that use prophylactic doses
rather than therapeutic doses of nevirapine (NVP), are not considered presumptive HIV therapy.

The interval during which newborn ARV prophylaxis or presumptive HIV therapy can be initiated
and still be beneficial is undefined; however, most studies support providing ARV drugs as early as
possible after delivery.1-6

Table 12 provides an overview of neonatal ARV management recommendations according to the risk
of perinatal HIV transmission to the newborn, and Table 13 summarizes the recommendations for
ARV drug dosing in newborns. Additional information about dose selection for newborns, including
premature infants (<37 weeks gestational age), can be found in the Pediatric Antiretroviral
Guidelines. Information about infants born to people with HIV-2 infection is available in HIV-2
Infection and Pregnancy and Table 12. In addition, the National Perinatal HIV hotline
(1­888­448­8765) is a federally funded service that provides free clinical consultation on difficult
cases to providers who are caring for pregnant people with HIV and their newborns, and consultants
can provide referrals to local or regional pediatric HIV specialists.

Table 12. Neonatal Antiretroviral Management According to Risk of HIV Infection in the
Newborn

Drug selection and dosing considerations are related to the age and gestational age of the newborn.
Consultation is available through the National Perinatal HIV hotline (1-888-448-8765) or from an
expert in pediatric HIV infection.

Level of Perinatal HIV

Description Neonatal ARV Management
Transmission Risk
Low Risk of Perinatal Infants ≥37 weeks gestation when the ZDV for 2 weeksa
HIV Transmission mother—
• Is currently receiving and has received at
least 10 consecutive weeks of ART during
pregnancy, and
• Has achieved and maintained or maintained
viral suppression (defined as at least two
consecutive tests with HIV RNA levels <50
copies/mL obtained at least 4 weeks apart)
for the remainder of the pregnancy, and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-3
Table 12. Neonatal Antiretroviral Management According to Risk of HIV Infection in the
Newborn

Level of Perinatal HIV

Description Neonatal ARV Management
Transmission Risk
• Has HIV RNA <50 copies/mL at or after
36 weeks and within 4 weeks of delivery, and
• Did not have acute HIV infection during
pregnancy, and
• Has reported good ART adherence, and
adherence concerns have not been identified.
Infants born to mothers who do not meet the ZDV for 4 to 6 weeksa
criteria above but who have a HIV RNA
<50 copies/mL at or after 36 weeks gestation
Premature infants (<37 weeks gestation) who ZDV for 4 to 6 weeksa
are not at high risk of perinatal acquisition of
HIV
High Risk of Perinatal Mothers who did not receive antepartum ARV Presumptive HIV therapy using either ZDV,
HIV Transmissiona,b drugs, or 3TC, and NVP (treatment dose) or ZDV,
3TC, and RAL administered together from
Mothers who received only intrapartum ARV birth for 2 to 6 weeks; if the duration of the
drugs, or 3-drug regimen is shorter than 6 weeks,
ZDV should be continued alone, to
Mothers who received antepartum ARV drugs complete a total of 6 weeks of prophylaxisd
but did not have viral suppression (defined as at
least two consecutive tests with HIV RNA level
<50 copies/mL obtained at least 4 weeks apart)
within 4 weeks prior to delivery, or

Mothers with acute or primary HIV infection

during pregnancy or breastfeeding (in which
case, breastfeeding should be immediately
discontinued)c

Presumed Newborn HIV Mothers with unconfirmed HIV status who have ARV management as described above for
Exposure at least one positive HIV test at delivery or newborns with a high risk of perinatal HIV
postpartum, or acquisition

Mothers whose newborn has a positive HIV Infant ARV drugs should be discontinued
antibody test immediately if supplemental testing
confirms that the mother does not have
HIV.
Newborn with HIVe Positive newborn HIV virologic test/NAT Three-drug ARV regimen using treatment
doses. Refer to the What to Start:
Regimens Recommended for Initial
Therapy of Antiretroviral-Naive Children in
the Pediatric Antiretroviral Guidelines for
specific treatment recommendations.
a ZDV prophylaxis is recommended for infants born to mothers with HIV-2 mono-infection; see HIV-2 Infection and Pregnancy. If
the mother has HIV-1 and HIV-2 infection, the infant ARV regimen should be based on the determination of low or high risk of
HIV-1 transmission as described in the above table. Because HIV-2 is not susceptible to NVP, RAL should be considered for

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-4
Table 12. Neonatal Antiretroviral Management According to Risk of HIV Infection in the
Newborn
infants at high risk of perinatal HIV-2 acquisition. See text for evidence that supports the use of presumptive HIV therapy and a
two-drug ARV prophylaxis regimen.
b See Intrapartum Care for People With HIV for guidance on indications for scheduled cesarean delivery and intrapartum
intravenous ZDV to reduce the risk of perinatal HIV transmission for mothers with an elevated viral load at delivery.
c Most Panel members would opt to administer presumptive HIV therapy to infants born to mothers with acute HIV infection
during pregnancy because of the higher risk for in utero transmission. If acute HIV is diagnosed during breastfeeding, the
mother should immediately discontinue breastfeeding.
d The optimal duration of presumptive HIV therapy in newborns who are at a high risk for HIV acquisition is unknown. Newborns
who are at a high risk for HIV acquisition should receive the ZDV component of the three-drug presumptive HIV therapy regimen
for 6 weeks. The other two ARVs (3TC and NVP or 3TC plus RAL) may be administered for 2 to 6 weeks; the recommended
duration for treatment with three ARVs varies depends on infant HIV NAT results, maternal viral load at the time of delivery, and
additional risk factors for HIV transmission including breastfeeding (see sections below). Consultation with an expert in pediatric
HIV is recommended when selecting a therapy duration because this decision should be based on case-specific risk factors and
interim infant HIV NAT results.
e InfantART should be initiated without waiting for the results of confirmatory HIV NAT testing, given the low likelihood of a false-
positive HIV NAT. However, the specimen for confirmatory HIV testing should be obtained prior to ART initiation.
Note: ARV drugs should be initiated as close to the time of birth as possible, preferably within 6 hours of delivery. See Table 13
for dosing specifics.
Key: 3TC = lamivudine; ART = antiretroviral therapy; ARV =antiretroviral; NAT = nucleic acid test; NVP = nevirapine;
Panel = Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission and Panel on Antiretroviral
Therapy and Medical Management of Children Living with HIV; RAL = raltegravir; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-5
Table 13. Antiretroviral Drug Dosing Recommendations for Newbornsa

Drug Drug Doses by Gestational Age at Birth

ZDV ≥35 Weeks Gestation at Birth

Note: For newborns who are Birth to Age 4 Weeks

unable to tolerate oral agents, • ZDV 4 mg/kg per dose orally twice daily or alternative simplified weight-band dosing
the IV dose is 75% of the oral (see below)
dose while maintaining the
same dosing interval. Age >4 Weeks
• ZDV 12 mg/kg per dose orally twice daily; only make this dose increase for infants with
confirmed HIV infection.

Simplified Weight-Band Dosing for Newborns Aged ≥35 Weeks Gestation From
Birth to 4 Weeks
Weight Band Volume of ZDV 10 mg/mL Oral Syrup Twice Daily
2 to <3 kg 1 mL
3 to <4 kg 1.5 mL
4 to <5 kg 2 mL

≥30 to <35 Weeks’ Gestation at Birth

Birth to Age 2 Weeks
• ZDV 2 mg/kg per dose orally twice daily

Age 2 Weeks to 6 to 8 Weeks

• ZDV 3 mg/kg per dose orally twice daily

Age >6 to 8 Weeks

• ZDV 12 mg/kg per dose orally twice daily; make this dose increase only for infants with
confirmed HIV infection.
<30 Weeks’ Gestation at Birth
Birth to Age 4 Weeks
• ZDV 2 mg/kg per dose orally twice daily

Age 4 to 8 to 10 Weeks
• ZDV 3 mg/kg per dose orally twice daily

Age >8 to 10 Weeks

• ZDV 12 mg/kg per dose orally twice daily; only make this dose increase for infants with
confirmed HIV infection.
ABCc ≥37 Weeks’ Gestation at Birth

Note: ABC is not approved by Birth to 1 Month

the FDA for use in neonates • ABC 2 mg/kg per dose orally twice daily
and infants aged <1 month.
However, dosing Age 1 Month to <3 Months

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-6
Table 13. Antiretroviral Drug Dosing Recommendations for Newborns

Drug Drug Doses by Gestational Age at Birth

recommendations have been • ABC 4 mg/kg per dose orally twice daily
modeled using PK simulation.
Because of ABC-associated
hypersensitivity, negative
testing for HLA-B5701 allele
should be confirmed prior to
administration of ABC.
3TC ≥32 Weeks’ Gestation at Birth
Birth to Age 4 Weeks
• 3TC 2 mg/kg per dose orally twice daily

Age >4 Weeks

• 3TC 4 mg/kg per dose orally twice daily
NVPd ≥37 Weeks’ Gestation at Birth
Birth to Age 4 Weeks
• NVP 6 mg/kg per dose orally twice daily

Age >4 Weeks

• NVP 200 mg/m2 BSA per dose orally twice daily; only make this dose increase for
infants with confirmed HIV infection.
≥34 to <37 Weeks’ Gestation at Birth
Birth to Age 1 Week
• NVP 4 mg/kg per dose orally twice daily
Age 1 to 4 Weeks
• NVP 6 mg/kg per dose orally twice daily
Age >4 Weeks
• NVP 200 mg/m2 BSA per dose orally twice daily; only make this dose increase for
infants with confirmed HIV infection.
≥32 to <34 Weeks’ Gestation at Birth
Birth to Age 2 Weeks
• NVP 2 mg/kg per dose orally twice daily
Age 2 to 4 Weeks
• NVP 4 mg/kg per dose orally twice daily

Age 4 to 6 Weeks
• NVP 6 mg/kg per dose orally twice daily

Age >6 Weeks

• NVP 200 mg/m2 BSA per dose orally twice daily; only make this dose increase for
infants with confirmed HIV infection.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-7
Table 13. Antiretroviral Drug Dosing Recommendations for Newborns

Drug Drug Doses by Gestational Age at Birth

RAL ≥37 Weeks’ Gestation at Birth and Weighing ≥2 kge

Note: If the mother has taken Birth to Age 6 Weeks

RAL 2 to 24 hours prior to
delivery, the neonate’s first Volume (Dose) of RAL
Body Weight
dose of RAL should be 10 mg/mL Suspension
delayed until 24 to 48 hours
after birth; additional ARV
Approximately 1.5 mg/kg
drugs should be started as Birth to 1 Week: Once-Daily Dosing
soon as possible.7 per dose
2 to <3 kg 0.4 mL (4 mg) once daily

3 to <4 kg 0.5 mL (5 mg) once daily

4 to <5 kg 0.7 mL (7 mg) once daily

Approximately 3 mg/kg
1 to 4 Weeks: Twice-Daily Dosing
per dose
2 to <3 kg 0.8 mL (8 mg) twice daily

3 to <4 kg 1 mL (10 mg) twice daily

4 to <5 kg 1.5 mL (15 mg) twice daily

Approximately 6 mg/kg
4 to 6 Weeks: Twice-Daily Dosing
per dose
3 to <4 kg 2.5 mL (25 mg) twice daily

4 to <6 kg 3 mL (30 mg) twice daily

6 to <8 kg 4 mL (40 mg) twice daily

a Theoptimal duration of presumptive HIV therapy in newborns who are at a high risk for perinatal HIV acquisition is unknown.
Newborns who are at a high risk for HIV acquisition should receive the ZDV component of the three-drug presumptive HIV
therapy regimen for 6 weeks. The other two ARVs (3TC and NVP or 3TC plus RAL) may be administered for 2 to 6 weeks; the
recommended duration for these ARVs varies depending on infant HIV NAT results, maternal viral load at the time of delivery,
and additional risk factors for HIV transmission. Consultation with an expert in pediatric HIV is recommended when selecting a
therapy duration because this decision should be based on case-specific risk factors and interim infant HIV NAT results.
b ForARV management of infants with HIV infection, see the What to Start: Regimens Recommended for Initial Therapy of
Antiretroviral-Naive Children section in the Pediatric Antiretroviral Guidelines.
c ABC is approved by the FDA for use in children aged ≥3 months when administered as part of an ARV regimen. ABC also has
been reported to be safe in infants and children ≥1 month of age. More recently, an ABC dosing recommendation using PK
simulation models has been endorsed by the WHO using weight-band dosing for full-term infants from birth to 1 month of age.
See Abacavir in Appendix A: Pediatric Antiretroviral Drug Information in the Pediatric Antiretroviral Guidelines for additional
information about the use of ABC between birth and 1 month of age. At this time, the Panels do not recommend ABC as part of
a presumptive HIV therapy regimen. However, in situations where ZDV is not available or the infant has ZDV-associated toxicity,
ABC could be considered an alternative to ZDV. This substitution should be considered in circumstances where increased risk
of ZDV toxicity may exist, such as in infants with anemia or neutropenia. Because of ABC-associated hypersensitivity, negative
testing for HLA-B5701 allele should be confirmed prior to administration of ABC.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-8
Table 13. Antiretroviral Drug Dosing Recommendations for Newborns

d The NVP doses for infants ≥32 to <37 weeks gestation at birth and infants ≥37 weeks gestation at birth are not yet approved
by the FDA. The FDA also has not approved a dose of NVP for infants aged <1 month. The doses for infants ≥32 to <34 weeks
gestation at birth are based on modeling and might underestimate potential toxicity in infants of 32 to <34 weeks gestational age
because the doses used to develop the model were lower than the doses now recommended. See Nevirapine in Appendix A:
Pediatric Antiretroviral Drug Information in the Pediatric Antiretroviral Guidelines for additional information about dosing.
e RAL dosing is increased at 1 week and 4 weeks of age because metabolism by UGT1A1 is low at birth and increases rapidly
during the next 4 to 6 weeks of life. No dosing information is available for preterm infants or infants weighing <2 kg at birth. In
infants with HIV infection, twice-daily RAL can be replaced with once-daily DTG at ≥ 4 weeks of age (see Dolutegravir and What
to Start: Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children in the Pediatric Antiretroviral Guidelines).
The current dosing regimen with two dose changes in the first month of life may be challenging for some families. To minimize
dosing changes, some experts increase to the 3 mg/kg twice daily dose upon discharge on day 4 or 5 of life.
Key: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; BSA = body surface area; DTG = dolutegravir; FDA = U.S. Food
and Drug Administration; IV = intravenous; NVP = nevirapine; the Panels = the Panel on Treatment of HIV During Pregnancy
and Prevention of Perinatal Transmission and the Panel on Antiretroviral Therapy and Medical Management of Children Living
with HIV; PK = pharmacokinetic; RAL = raltegravir; UGT = uridine diphosphate glucotransferase; WHO = World Health
Organization; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-9
Recommendations for Antiretroviral Drugs in Specific Clinical Situations
In this section and Table 12. Neonatal Antiretroviral Management According to Risk of HIV
Infection in the Newborn, the Panel on Treatment of HIV During Pregnancy and Prevention of
Perinatal Transmission and the Panel on Antiretroviral Therapy and Medical Management of
Children Living with HIV (the Panels) presents available data and recommendations for management
of newborns with documented HIV and newborns born to mothers who—

• Are at low risk for transmitting HIV to their newborns born at ≥37 weeks gestation, including
mothers who –
o Received at least 10 consecutive weeks of antepartum ARV drugs, and
o Achieved and maintained or maintained effective viral suppression (defined as at least two
HIV RNA level <50 copies/mL obtained at least 4 weeks apart) for the remainder of the
pregnancy, and
o Had a HIV RNA <50 copies/mL at or after 36 weeks, and
o Did not have acute HIV infection during pregnancy, and
o Have reported good ART adherence and adherence concerns have not been identified.
• Are at high risk for transmitting HIV to their newborns, including mothers who—
o Did not receive antepartum ARV drugs, or
o Received only intrapartum ARV drugs, or
o Received antepartum ARV drugs but do not have effective viral suppression (defined as at
least two consecutive tests with HIV RNA level <50 copies/mL obtained at least 4 weeks
apart) within 4 weeks prior to delivery
• Had acute or primary HIV infection during pregnancy or breastfeeding
• Have unknown HIV status
• Have known ARV drug-resistant virus

Newborns Born to Mothers Who Achieved and Maintained or Maintained Viral

Suppression on Antepartum Antiretroviral Drugs
The risk of HIV acquisition in newborns born to people who received ART during pregnancy and
labor and who had undetectable viral load near or at the time of delivery is <1%. In the Pediatric
AIDS Clinical Trials Group (PACTG) 076 study, ZDV alone reduced the incidence of perinatal HIV
transmission by 66%, and ZDV is recommended as prophylaxis for neonates whose mothers received
ART that resulted in consistent viral suppression during pregnancy.8 The optimal minimum duration
of neonatal ZDV prophylaxis has not been established in clinical trials. A 6-week ZDV regimen was
studied in newborns in PACTG 076. However, evidence supporting a reduced duration of ZDV
prophylaxis in infants born to people who were suppressed virologically during pregnancy and at the
time of delivery is mounting.9-11

In the United Kingdom and many other European countries, a 2­week neonatal ZDV prophylaxis
regimen is recommended for infants born to people who have a very low risk of HIV transmission.
These people have been on ART for longer than 10 weeks and have had at least two documented

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-10
HIV viral loads <50 copies/mL at least 4 weeks apart and have viral loads <50 copies/mL at or after
36 weeks’ gestation. A 4-week course of ZDV is recommended12 if any of these criteria are not
fulfilled but the maternal viral load is <50 copies/mL at or after 36 weeks gestation or the infant is
born prematurely (< 34 weeks gestation) but most recent maternal viral load is <50 copies/mL.
Compared with the 6-week ZDV regimen, 2 to 4 weeks on this regimen has been reported to allow
earlier recovery from anemia in otherwise healthy newborns.13,14 The Swiss Federal Office of Public
Health does not recommend infant ARV prophylaxis for infants of people with regular follow-up,
ART use during pregnancy, and where maternal viral load is <50 copies/mL, ideally sustained
throughout pregnancy, but at least at the last two consecutive measurements before delivery where
viral load testing is performed at least 4 weeks apart and the last viral load is measured after week
36 of pregnancy.15 Among 87 infants born to women with HIV RNA levels <50 copies/mL in the last
trimester, none acquired HIV infection.16

The Panels recommend 2 weeks of ZDV prophylaxis for newborns born at ≥37 weeks gestation if the
mother is receiving ART and has received at least 10 consecutive weeks of ART during pregnancy
and achieved and maintained or maintained viral suppression (defined as at least two consecutive
tests with HIV RNA levels <50 copies/mL obtained at least 4 weeks apart) for the remainder of the
pregnancy and has HIV RNA <50 copies/mL at or after 36 weeks and within 4 weeks of delivery,
and did not have acute HIV infection during pregnancy, and maternal ART adherence is not of
concern (see Table 12). Infants born to individuals who do not meet the criteria above, but who have
a viral load <50 copies/mL at or after 36 weeks, should receive ZDV for 4 to 6 weeks. In addition, all
premature infants (<37 weeks gestation) should receive 4 to 6 weeks of ZDV unless they are at high
risk of HIV acquisition. Dosing recommendations for ZDV are available for premature newborns,
and an intravenous preparation of ZDV is available. Table 13. Antiretroviral Drug Dosing
Recommendations for Newborns shows recommended neonatal ZDV dosing based on gestational
age and birthweight.

ARV Prophylaxis for Newborns at Low Risk of Perinatal HIV Transmission

Who Are Breastfed
Increasingly, individuals who have achieved and maintained or maintained viral suppression on ART
are considering breastfeeding their infants. Individuals with HIV on ART with a consistently
suppressed viral load during pregnancy (at a minimum during the third trimester) and at the time of
delivery should be counseled on the options of formula feeding, banked donor human milk, or
breastfeeding. The Panels recommend patient-centered, evidence-based counseling to support shared
decision-making about infant feeding. See Infant Feeding for Individuals With HIV in the United
States for more information on counseling, management, and monitoring.

There is no consensus on appropriate management of ARV prophylaxis for infants of individuals

with sustained viral suppression who are breastfed. Available data to guide decisions are from studies
in sub-Saharan Africa, where breastfeeding is recommended for all birthing parents with HIV
infection. It is important to note that the World Health Organization (WHO) recommends six weeks
of NVP for all infants who are breastfed by a parent who is receiving ART in resource-limited
countries.49 In the PROMISE study, among 1,219 infants of mothers on ART, there were 7 HIV
transmissions reported. Among these, five mothers had documented detectable viral loads
immediately prior to first report of the infant’s positive HIV nucleic acid test (NAT); the remaining
two mothers had elevated viral loads in subsequent testing.17 Note that these two infants had their
first detectable HIV NAT at weeks 13 and 38 of life, beyond 6 weeks of age where infant NVP was
administered according to WHO guidelines. In the Breastfeeding, Antiretrovirals, and Nutrition

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-11
study, a sub-study of 31 infected infants and 232 uninfected infants and their mothers18 demonstrated
that there were no HIV transmissions when the mother consistently maintained a viral load less than
100 copies/mL. Bispo et al. have reported a meta-analysis of 11 studies of breastfeeding mothers
with HIV who started ART before or during pregnancy and continued until at least 6 months
postnatally.19 The included studies were very heterogeneous and did not include viral load
measurements or information about adherence. In addition, some studies included infants receiving
NVP prophylaxis. Six of these studies provided estimates of postnatal transmission rates, excluding
peripartum infections. In these six studies, the postnatal transmission rate was 1.08% (95%
confidence interval: 0.32–1.85) at 6 months in infants who tested HIV negative at 4 to 6 weeks of
age. In a post-hoc analysis of the HIV Prevention Trials Network (HPTN) 046 study, which showed
<1% risk of postnatal HIV transmission in both the extended NVP and placebo arms, the addition of
infant prophylaxis did not further reduce breastfeeding transmission in mothers who were receiving
ART.20 Taken together, these data support the efficacy of ART with documented sustained viral
suppression to prevent postnatal transmission of HIV, suggesting that the recommended management
consisting of 2 weeks of infant ZDV prophylaxis is appropriate for breastfed infants when their
mothers have sustained viral suppression. This approach is currently recommended by the British
HIV Association (BHIVA).12

The Panels could not reach a consensus on recommendations for infant prophylaxis while
breastfeeding. Most Panel members agree on adopting the BHIVA recommendation of only 2 weeks
of infant ZDV in this scenario. However, several Panel members prefer to extend the duration of
ZDV prophylaxis to 4 to 6 weeks. Alternatively, some Panel members recommend 6 weeks of NVP,
as currently recommended by WHO for breastfeeding infants at low risk of HIV transmission in
resource limited countries. Some others opt to continue NVP dosing throughout breastfeeding. In
infants who cannot tolerate ZDV or NVP, alternative regimens include daily lamivudine (3TC) or
daily lopinavir/ritonavir (LPV/r).21,22 If one of these alternative regimens is used, dosing
recommendations for 3TC are included in Table 13. Weight band dosing for 3TC and dosing for
LPV/r is available in Lamivudine and Lopinavir/Ritonavir. LPV/r should not be used in infants
before a postmenstrual age of 42 weeks and a postnatal age of 14 days.

Table 14. Infant Antiretroviral Prophylaxis for Newborns of Mothers With Sustained Viral
Suppression Who Breastfeed

Newborns at Low Risk of HIV Acquisition During Breastfeeding

Recommended Regimen Recommended Duration

ZDV ZDV administered for 2 weeks (see Table 13 for dosing)

Optional Extended Postnatal Prophylaxis for Newborns at Low Risk of HIV Transmission During
Breastfeeding

Optional Regimen Optional Recommended Duration

ZDV ZDV administered for 4 to 6 weeks (see Table11 for dosing)
NVP Simplified Age-Based Dosing for Newborns ≥32 Weeks Gestation
Receiving Extended NVP Prophylaxis During Breastfeedinga
Volume of NVP 10 mg/mL Oral
Age
Syrup Daily

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-12
Table 14. Infant Antiretroviral Prophylaxis for Newborns of Mothers With Sustained Viral
Suppression Who Breastfed

Birth to 6 weeks 1.5 mL

6 weeks to 6 months 2.0 mL
6 months to 9 3.0 mL
months
9 months to 1 to 4 4.0 mL
weeks post-weaning
a Extended NVP prophylaxis during breastfeeding recommendations are adapted from the Consolidated Guidelines on HIV
Prevention, Testing, Treatment, Service Delivery and Monitoring: Recommendations for a Public Health Approach. If prescribed,
these simplified doses should start following confirmation of a negative infant NAT test and completion of a presumptive HIV
therapy regimen in infants at high risk of HIV acquisition. For infants at low risk of transmission, these doses can be given from
birth. Geneva: World Health Organization; 2021 Jul. Simplified Age-Based Dosing for Newborns ≥32 Weeks Gestation
Receiving Extended NVP Prophylaxis During Breastfeeding in Consolidated Guidelines on HIV Prevention, Testing, Treatment,
Service delivery and Monitoring: Recommendations for a Public Health Approach
bFor breastfeeding parents with viral resistance to NVP, alternative regimens for infant prophylaxis after completion of the 4 to
6 weeks of presumptive HIV therapy include daily 3TC or LPV/r; see Table 13. Antiretroviral Drug Dosing Recommendations for
Newborns for dosing information.

Newborns Born to Mothers Who Received No Antepartum Antiretroviral Drugs,

Who Received Intrapartum Antiretroviral Drugs Only, Who Received
Antiretroviral Drugs and Were Not Virally Suppressed Near Delivery, or Who
Acquired HIV During Pregnancy or Breastfeeding
The Panels recommend that all newborns born to mothers who do not have viral suppression (defined
as at least two consecutive tests with HIV RNA level <50 copies/mL obtained at least 4 weeks apart
and a HIV RNA <50 copies/mL at or after 36 weeks and within 4 weeks prior to delivery), who
received only intrapartum ARV drugs, or who received no ARV drugs during pregnancy are at high
risk for HIV acquisition and should receive presumptive HIV therapy.5,23-28 These infants should
also have a HIV NAT test performed as soon as possible to determine HIV infection status. Primary
or acute HIV infection during pregnancy also is associated with an increased risk of perinatal
transmission of HIV. Infants born to people who acquired HIV during pregnancy should receive
presumptive HIV therapy (see Early (Acute and Recent) HIV Infection).

Presumptive HIV Therapy

Early, effective treatment of HIV infection in infants restricts the viral reservoir size, reduces HIV
genetic variability, and modifies the immune response.29-37 Because of these potential benefits of
early ART, the Panels recommend a three-drug ARV presumptive HIV therapy regimen consisting of
ZDV, 3TC, and either NVP (at treatment dose) or raltegravir (RAL) for newborns at high risk of
perinatal acquisition of HIV.

Although no clinical trials have compared the safety and efficacy of presumptive ART with single-
drug or two-drug regimens, emerging data suggest that early presumptive HIV therapy has not been
associated with serious adverse events. In the International Maternal, Pediatric, Adolescent AIDS
Clinical Trials (IMPAACT) P1115, 438 neonates who were at least 34 weeks gestational age at birth
and enrolled within 48 hours of birth received a presumptive HIV therapy regimen containing two
nucleoside reverse transcriptase inhibitors (NRTIs) (97% received ZDV and 3TC) and NVP dosed at
6 mg/kg twice daily for term neonates (≥37 weeks gestational age) or 4 mg/kg twice daily for 1 week
and 6 mg/kg twice daily therapy for preterm neonates (34 to <37 weeks gestational age). Among the

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-13
study participants, 7% reported Division of AIDS Grade 3 or 4 adverse events at least possibly
related to ART. These Grade 3 or 4 events included 6% with neutropenia and 1% with anemia.28 The
Early Infant Treatment Study in Botswana initiated ART consisting of NVP 6 mg/kg twice daily,
ZDV, and 3TC at <7 days gestational age in 40 infants who were ≥35 weeks gestational age and
≥2 kg at birth with HIV infection. Eighteen percent of these infants had Grade 3 or 4 hematologic
toxicity, mostly neutropenia.38 Similar findings have been reported from other studies of presumed
HIV therapy or early treatment of confirmed HIV infection.38-40 In a prospective cohort in Thailand,
infants who received a presumptive HIV therapy regimen that contained ZDV, 3TC, and NVP were
more likely to have Grade 2 or higher anemia at 1 and 2 months of life than infants who received
ZDV alone (48.5% vs. 32.3%; P = 0.02). However, no difference was found in the incidence of
severe anemia (Grade 3) between the two groups.41 In a Madrid, Spain, cohort, 227 infants received
prophylaxis containing two or more drugs (64% who received ZDV, 3TC, and NVP) and
1,002 infants received ZDV alone. Although there were more frequent reports of anemia and
neutropenia among infants receiving prophylaxis with 2 or more drugs, there were no significant
differences in grade 3 or 4 anemia or neutropenia between the two groups.42 Additionally, in a
Canadian study, nonspecific signs and symptoms (e.g., vomiting, diarrhea, rash, jitteriness,
irritability) that were potentially attributable to medication-related adverse effects were reported
among the newborns who received presumptive HIV therapy but not among those who received
ZDV only (10.2% vs. 0%; P < 0.001). Infants were more likely to discontinue presumptive HIV
therapy prematurely than a regimen of ZDV alone (9.5% vs. 2.1%; P = 0.01).40

The pharmacokinetic (PK) and safety data of presumptive HIV therapy have provided reassuring
evidence for its use in the neonatal period. Although the use of NVP to prevent perinatal HIV
transmission has been found to be safe in neonates and newborns of low birthweight, these
prophylaxis-dose regimens target trough drug levels that are at least 10-fold lower than targeted
therapeutic levels. However, recent studies of therapeutic doses of NVP and RAL have established
safe doses that achieve targeted PK parameters.43-48

At this time, if a presumptive HIV therapy regimen is required, the Panels recommend using a
combination of ZDV, 3TC, and NVP (treatment dose) or ZDV, 3TC, and RAL (see Table 12.
Neonatal Antiretroviral Management According to Risk of HIV Infection in the Newborn, and
Table 13. Antiretroviral Drug Dosing Recommendations for Newborns). The optimal duration of
presumptive HIV therapy in newborns at high risk of perinatal HIV acquisition is unknown. Some
Panel members opt to discontinue additional medications if infant birth NAT results are negative,
whereas others would continue presumptive HIV therapy for 2 to 6 weeks depending on the risk of
HIV transmission. In all cases, ZDV should be continued for 6 weeks. If HIV infection is confirmed
and the infant is receiving NVP, NVP should be replaced with an integrase strand transfer inhibitor
or a boosted protease inhibitor at the appropriate infant age. Information about selecting an agent and
recommended dosing can be found in What to Start: Regimens Recommended for Initial Therapy of
Antiretroviral-Naive Children and Appendix A: Pediatric Antiretroviral Drug Information in the
Pediatric Antiretroviral Guidelines.

New dosing recommendations for abacavir (ABC) in neonates based on the IMPAACT P1106 trial
and two observational European and African cohorts are now available from WHO.49 ABC is not
approved by the U.S. Food and Drug Administration (FDA) for use in neonates and infants aged
<3 months. However, a 2-mg/kg-per-dose twice-daily dose has been modeled using PK simulation
and is endorsed by WHO using weight-band dosing for full-term infants from birth through 1 month
of age. Limited observational data suggested safety of ABC when initiated in neonates <1 month of
age (see Abacavir in the Pediatric Antiretroviral Guidelines).50,51 At this time, the Panels do not

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-14
recommend ABC as part of a presumptive HIV therapy regimen. However, in situations where ZDV
is not available or the infant has ZDV-associated toxicity, ABC could be considered an alternative to
ZDV. This substitution should be considered in circumstances where increased risk of ZDV toxicity
may exist, such as in infants with anemia or neutropenia. It also is suggested that negative testing for
HLA-B5701 allele be confirmed prior to administration of ABC. Consulting an expert in pediatric
HIV is recommended when selecting a therapy duration based on case-specific risk factors and
interim HIV NAT results.

Two-Drug Antiretroviral Prophylaxis

The Eunice Kennedy Shriver National Institute of Child Health and Human Development–HIV
Prevention Trials Network 040/Pediatric AIDS Clinical Trials Group 1043 (NICHD-HPTN
040/PACTG 1043) trial is the only randomized clinical trial of multi-ARV prophylaxis in newborns
at high risk of HIV acquisition.5 In this study, 1,746 formula-fed infants born to women with HIV
who did not receive any ARV drugs during pregnancy were randomized to receive one of three
newborn prophylaxis regimens: the standard 6-week ZDV regimen; 6 weeks of ZDV plus three doses
of NVP given during the first week of life (first dose given at birth or within 48 hours of birth,
second dose 48 hours after the first dose, and third dose 96 hours after the second dose); and 6 weeks
of ZDV plus 2 weeks of 3TC plus nelfinavir (NFV).

Forty-one percent of the mothers received ZDV during labor. The risk of intrapartum transmission
was significantly lower in the two-drug and three-drug arms (2.2% and 2.5%, respectively, vs. 4.9%
for 6 weeks of ZDV alone; P = 0.046 for each experimental arm vs. ZDV alone).5 The NICHD-
HPTN 040/PACTG 1043 regimen was associated with NRTI resistance in 3 of 53 participants (5.7%)
with in utero infection who were treated with ZDV alone and in 6 of 33 participants (18.2%) who
were treated with ZDV plus NVP (P > 0.05). In addition, the third drug in the three-arm regimen was
NFV, which has highly variable PKs in this age group and did not reach the NFV target plasma
concentration in 46% of study participants.52

Although transmission rates with the two regimens were similar, neutropenia was significantly more
common with the three-drug regimen than with the two-drug or ZDV-alone regimens (27.5% vs.
14.9% vs. 16.4%; P < 0.001 for both comparisons). For newborns who are at a high risk for HIV
acquisition, the two-drug regimen used in NICHD-HPTN 040/PACTG 1043 is an option for
preventing HIV transmission in infants aged ≥32 weeks gestation with a birthweight of ≥1.5 kg. This
two-drug regimen consists of 6 weeks of ZDV plus three doses of the prophylactic dose of NVP,
with the NVP doses given within 48 hours of birth, 48 hours after the first dose, and 96 hours after
the second dose. The prophylactic doses are NVP 12 mg per dose orally for infants weighing >2 kg
and NVP 8 mg per dose orally for infants weighing 1.5 kg to 2 kg. These are the actual doses, not
the milligram per kilogram doses. ZDV dosing is shown in Table 13.

Choosing Between Presumptive HIV Therapy and Two-Drug Antiretroviral Prophylaxis

Because a spectrum of transmission risk depends on maternal viral load and other maternal and infant
factors and no randomized trials have compared the safety and efficacy of presumptive HIV therapy
and two-drug ARV prophylaxis, experts have differing opinions about when to initiate presumptive
HIV therapy and when to initiate two-drug prophylaxis. For instance, among people who received
ARV drugs during pregnancy but who have a detectable viral load within 4 weeks prior to delivery,
the level of maternal viremia that would prompt the use of a two-drug ARV prophylaxis regimen or
presumptive HIV therapy is not definitively known.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-15
In two large observational studies of women on combination antenatal ARV drugs, perinatal
transmission rates were 0.05% and 0.3% when the mother had a viral load <50 copies/mL at delivery.
Rates of transmission in these studies increased to 1.1% and 1.5 percent when viral load was 50 to
399 copies/mL and 2.8% and 4.1% when viral load was >400 copies/mL.53,54 Although most Panel
members would recommend initiating presumptive HIV therapy with any detectable level of viremia
within 4 weeks prior to delivery, others may opt for a two-drug prophylaxis regimen if maternal viral
load was less than 200 copies/mL. Emerging data about the lack of serious safety issues associated
with presumptive HIV therapy in newborns is reassuring, even though mild-to-moderate adverse
events may occur more frequently.

In summary, in scenarios where the infant is at high risk for HIV acquisition, most Panel members
recommend presumptive HIV therapy. In some situations, a two-drug ARV prophylaxis regimen may
be considered (see “Two-Drug Antiretroviral Prophylaxis” in this section). Choosing between these
regimens will depend on the clinician’s assessment of the likelihood of HIV transmission, and a
decision should be made after weighing the risks and benefits of the proposed regimen and
discussing these transmission prevention strategies with the parents.

Consulting an expert in pediatric HIV or the Perinatal HIV/AIDS hotline (1-888-448-8765) is

recommended when selecting a regimen based on case-specific risk factors.

Breastfeeding in Newborns at High Risk of Perinatal HIV Acquisition

For people with HIV who are not on ART and/or have not achieved sustained viral suppression at the
time of delivery, the Panels strongly advise against breastfeeding. Replacement feeding with formula
or banked pasteurized donor human milk is recommended given the high risk of postnatal HIV
transmission associated with viremia during breastfeeding (see Infant Feeding for Individuals With
HIV in the United States).

If after counseling, the breastfeeding parent without a suppressed viral load chooses to continue to
breastfeed, the parent and provider should remain engaged; the provider should offer guidance on
ARV prophylaxis (see below) and testing for the infant and assist the parent to work with their
primary provider to most rapidly regain and maintain virologic suppression. Diagnosis of HIV
Infection in Infants and Children provides guidance about HIV diagnostic testing for infants who are
being breastfed.

Several studies of newborns who were breastfed by women with chronic HIV infection in low-
resource settings have shown that a newborn’s daily regimen of NVP, 3TC, LPV/r, or NVP plus
ZDV can reduce the risk of postnatal infection during breastfeeding.22,55-58 Many of these studies
were in mothers who were not receiving ART or, if receiving ART, did not have viral load routinely
measured. If, despite the recommendation not to breastfeed, the infant is breastfed by a parent with
unsuppressed viral load, the Panels recommend 6 weeks of presumptive HIV therapy followed by
daily NVP throughout breastfeeding and for 1 to 4 weeks after weaning to minimize the risk of
vertical transmission. Dosing recommendations are shown in Table 13. For breastfeeding parents
with viral resistance to NVP, alternative regimens for infant prophylaxis after completion of the 6
weeks of presumptive HIV therapy include daily 3TC or LPV/r. Consultation with an expert in
pediatric HIV infection is strongly recommended. Coordination with adult care providers (such as
obstetric or infectious disease clinicians) can provide appropriate services to support adherence.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-16
Newborns Born to Mothers With Unknown HIV Status Who Present in Labor
HIV testing is recommended during labor for people with unknown HIV status; if testing is not
performed during labor, it should be performed as soon as possible after birth for the mothers and/or
their newborns (see Maternal HIV Testing and Identification of Perinatal HIV Exposure). HIV test
results should be available within 60 minutes. If maternal or infant testing is positive, the newborn
should begin presumptive HIV therapy immediately without waiting for the results of
supplemental tests. HIV testing with quick turnaround times should be available on a 24-hour basis at
all facilities with a maternity service and/or neonatal intensive care unit or special care or newborn
nursery.

A positive initial test result in mothers or newborns should be presumed to indicate maternal HIV
infection until supplemental testing clarifies maternal and newborn HIV status. If appropriate test
results for a mother (or newborn) are negative, newborn ARV drugs can be discontinued. Clinicians
should be aware of their state laws because not all states allow HIV testing in infants without parental
consent.

A breastfeeding parent who is suspected of having HIV based on an initial positive antibody or
antibody/antigen test result should discontinue breastfeeding immediately until HIV is confirmed or
ruled out. Pumping and temporarily discarding or freezing breastmilk can be recommended. If HIV is
ruled out, breastfeeding can resume. If HIV is confirmed, breastfeeding should be discontinued
permanently.59

Newborns Born to Mothers With Antiretroviral Drug-Resistant Virus

The optimal ARV regimen for newborns born to mothers with ARV drug-resistant virus is unknown.
Although some studies have suggested that ARV drug-resistant virus may have decreased replicative
capacity (reduced viral fitness) and transmissibility,60 perinatal transmission of multidrug-resistant
virus does occur.61-66 Whether resistant virus in the mother increases the antepartum/intrapartum risk
of HIV acquisition by the infant also is unknown. A recently reported secondary analysis of data
from the NICHD-HPTN 040/PACTG 1043 study demonstrated that the risk of perinatal transmission
was not related to the presence of drug resistance mutations in mothers who had not received ARV
drugs before the start of the study (adjusted odds ratio 0.8; 95% confidence interval, 0.4–1.5).66
Maraviroc (MVC) was approved recently for infants ≥2 kg and may provide an additional treatment
option for newborns of mothers carrying multidrug-resistant HIV-1 that remains CCR5-trophic.67
However, the lack of data about MVC as prophylaxis or treatment in infants and the risk of drug
interactions will limit its role for routine use in neonates. The ARV regimen for newborns born to
mothers with known or suspected drug resistance should be determined in consultation with a
pediatric HIV specialist before delivery or through consultation via the National Perinatal HIV
hotline (1-888-448-8765). Additionally, no evidence exists that shows that neonatal prophylaxis
regimens customized based on presence of maternal drug resistance are more effective than standard
neonatal prophylaxis regimens.

Newborns With HIV Infection

Until recently, neonatal ARV regimens were designed for prophylaxis against perinatal HIV
transmission and were intended to be as simple as possible for practical use. There was little reason
to develop ARV regimens for the treatment of neonates because the long turnaround times to receive
HIV NAT results meant that neonatal infections, in general, were not diagnosed during the first

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-17
weeks of life. HIV NAT results are now available within a few days, and HIV in newborns is being
diagnosed as early as the first days of life in many centers. A positive HIV NAT must be repeated to
confirm HIV. However, ART initiation should not be delayed while waiting for the results of the
confirmatory HIV NAT, given the low likelihood of a false-positive HIV NAT. A confirmatory
specimen should be obtained prior to ART initiation. To date, evidence that early treatment (before
age 2 weeks) will lead conclusively to prolonged remission or better outcomes in newborns with HIV
is lacking.

Information regarding the safety of early treatment of HIV in newborns has been reported from two
studies. In the IMPAACT P1115 study, 54 infants with HIV began presumptive HIV therapy
between 0.4 and 40 hours of life. Grade 3 or 4 related events—most of which were hematologic—
occurred in 22 of 54 infants (41%) through 52 weeks of the study.68 Forty infants with HIV in
Botswana began treatment with NVP plus ZDV plus 3TC at a median age of 2 days (range 1–5 days)
and transitioned to LPV/r plus ZDV plus 3TC at approximately 2 weeks of age. These infants had
minimal toxicity during the first 12 weeks of treatment. Only one instance of Grade 3 neutropenia
was reported, and no instances of Grade 3 or 4 anemia were reported.38

Earlier diagnosis of HIV in newborns and the increasing use of presumptive HIV therapy in
newborns at high risk for HIV acquisition have necessitated the investigation of dosing and the safety
of ARV drugs in term and preterm newborns. Although data are still incomplete, especially for
preterm newborns, PK and safety profiles of ARV drugs are increasingly available. As already noted,
the recommended neonatal ARV doses for prophylaxis and for treatment are the same, with the
important exception of NVP (see the Pediatric Antiretroviral Guidelines).

For information about recommended ART regimens for newborns, please see What to Start:
Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children in the Pediatric
Antiretroviral Guidelines.

Newborns of Mothers Who Receive an HIV Diagnosis While Breastfeeding

People with suspected HIV (e.g., a positive initial screening test) should discontinue breastfeeding
immediately until HIV is ruled out. Pumping and temporarily discarding or freezing breast milk can
be recommended to breastfeeding parents who are suspected of having HIV but whose HIV
serostatus is not yet confirmed and who want to continue to breastfeed. If HIV is ruled out,
breastfeeding can resume. Given the high risk of HIV transmission when HIV is acquired or
diagnosed during breastfeeding, the Panels advise against breastfeeding and recommend replacement
feeding with formula or banked pasteurized donor human milk if HIV infection is confirmed in the
breastfeeding parent.69

Other than discontinuing breastfeeding, optimal strategies for managing a newborn who was
breastfed by a parent with HIV (often because the parent just learned of her own HIV diagnosis) have
yet to be defined. Some Panel members would consider the use of post-exposure prophylaxis in
newborns for 4 to 6 weeks after cessation of breastfeeding. Post-exposure prophylaxis, however, is
less likely to be effective in this circumstance than with other nonoccupational exposures because the
exposure to breast milk is likely to have occurred over a prolonged period rather than a single
exposure to the virus.70 No trials have evaluated the use of multidrug regimens to prevent
transmission after cessation of breastfeeding in mothers with acute HIV infection.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-18
Given the higher risk of postnatal transmission from a person with acute HIV infection who is
breastfeeding, an alternative approach favored by some Panel members is to offer presumptive HIV
therapy until the infant’s HIV status can be determined. If the infant’s initial HIV NAT is negative,
the optimal duration of presumptive HIV therapy is unknown. A 28-day course may be reasonable
based on current recommendations for nonoccupational HIV exposure.70 When making decisions
about ARV management, clinicians should consult a pediatric HIV specialist and counsel the parents
on the potential risks and benefits of a particular treatment strategy. The Perinatal HIV/AIDS hotline
(1-888-448-8765) can provide referrals to local or regional pediatric HIV specialists.

In the event that the parent does not stop breastfeeding, interventions similar to individuals with
chronic HIV infection and detectable viral load who breastfeed should be followed. In these
scenarios, 6 weeks of a presumptive HIV regimen followed by daily NVP throughout breastfeeding
and for 1 to 4 weeks after weaning should be considered to minimize the risk of vertical
transmission. See Breastfeeding in Newborns at High Risk of Perinatal HIV Acquisition, above, and
Infant Feeding for Individuals with HIV in the United States. Again, consultation with a pediatric
HIV specialist or the National Perinatal HIV hotline (1-888-448-8765) is recommended.

Newborns exposed to HIV during breastfeeding should be tested for HIV infection prior to initiating
presumptive HIV therapy, as well as at specified time points after diagnosis of HIV infection in the
breastfeeding person and cessation of breastfeeding. An additional virologic test should be performed
2 to 4 weeks after discontinuing presumptive HIV therapy (see Diagnosis of HIV Infection in Infants
and Children and Table 13. Recommended Virologic Testing Schedule for Infants Who Were
Exposed to HIV According to Risk of Perinatal HIV Acquisition At and After Birth). If an HIV-
exposed newborn is already receiving an ARV prophylaxis regimen other than presumptive HIV
therapy and is found to have HIV, prophylaxis should be discontinued and treatment for HIV should
be initiated. Resistance testing should be performed, and the ART should be modified if needed (see
the Pediatric Antiretroviral Guidelines).

Short-Term Antiretroviral Drug Safety

Newborn prophylaxis with ZDV has been associated with only minimal toxicity, primarily transient
hematologic toxicity (mainly anemia), which generally resolves by age 12 weeks (see Initial
Postnatal Management of the Neonate Exposed to HIV). Data on toxicities in newborns who were
exposed to multiple ARV drugs are limited.

Other than ZDV, 3TC is the NRTI with the most clinical experience for neonatal prophylaxis. In
early studies, neonatal exposure to combination ZDV/3TC therapy was limited, in general, to
1 week26,71,72 or 2 weeks.5 Six weeks of ZDV/3TC exposure in newborns also has been reported.
These studies suggest that hematologic toxicity may be greater with ZDV/3TC than with ZDV alone,
although the newborns in these studies also had in utero exposure to maternal HIV therapy that may
have contributed to the toxicity.

In a French study, more cases of severe anemia and neutropenia were observed in newborns who
were exposed to 6 weeks of ZDV/3TC prophylaxis plus maternal antepartum ZDV/3TC than in a
historical cohort of newborns who were exposed only to maternal and newborn ZDV. Anemia was
reported in 15% of newborns, and neutropenia was reported in 18% of newborns who were exposed
to ZDV/3TC, with 2% of newborns requiring blood transfusion and 4% requiring treatment
discontinuation for toxicity.73 Similarly, in a Brazilian study of maternal antepartum ZDV/3TC and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-19
6-week newborn ZDV/3TC prophylaxis, neonatal hematologic toxicity was common, with anemia
seen in 69% and neutropenia seen in 13% of newborns.74

Recent data from the IMPAACT P1106 trial and two observational European and African cohorts
provided reassuring data on the safety of ABC in infants when initiated at <3 months of age,
including in infants with weight <3 kg.75-77 See the Abacavir section of the Pediatric Antiretroviral
Guidelines for additional information. At this time, the Panels suggest using ABC as an alternative to
ZDV in certain situations and after negative HLA-B5701 allele testing.

Experience with other NRTI drugs for neonatal prophylaxis is more limited.78,79 Hematologic and
mitochondrial toxicity may be more common with exposure to multiple NRTI drugs than with
exposure to a single NRTI.73,80-83

In rare cases, chronic multiple-dose NVP prophylaxis in pregnant women has been associated with
severe and potentially life-threatening rash and hepatic toxicity.84 These toxicities have not been
observed in newborns receiving prophylactic dosing with single-dose NVP or the two-drug ZDV
regimen plus three doses of NVP in the first week of life used in NICHD-HPTN 040/PACTG 1043
or in breastfeeding newborns receiving NVP prophylaxis daily for 6 weeks to 18 months to prevent
transmission of HIV via breast milk.5,55-58,85

The FDA approved infant dosing of RAL for term neonates aged ≥37 weeks’ gestation at birth and
weighing ≥2 kg. Dosing information for RAL is not available for preterm or low-birthweight infants.
PK modeling studies in infants with birthweight <2.5 kg with gestational age at birth ranging from
32.7 to 40 weeks suggests that prematurity reduces RAL clearance, and a modified dosing regimen
may be needed to avoid elevated plasma RAL concentrations.86 Infant RAL dosing needs to be
increased at 1 week and 4 weeks of age. RAL is metabolized by uridine diphosphate
glucuronosyltransferase (UGT) 1A1, the same enzyme responsible for the elimination of bilirubin.
UGT enzyme activity is low at birth, and RAL elimination is prolonged in neonates. In addition,
bilirubin and RAL may compete for albumin binding sites, and extremely elevated neonatal plasma
RAL concentrations could pose a risk of kernicterus.46 IMPAACT P1110 is a Phase 1, multicenter
trial that enrolled full-term neonates who were exposed to HIV and who were at risk for acquiring
perinatal HIV-1 infection, with or without in utero RAL exposure. Daily RAL was safe and well
tolerated during the first 6 weeks of life. Infants were treated for ≤6 weeks from birth and followed
for 24 weeks. Only one episode of Grade 4 neutropenia, possibly related to RAL, was reported.
Among infants with RAL exposure (infants whose mothers received RAL within 2 to 24 hours before
delivery), the first dose of RAL should be delayed for 24 to 48 hours after birth.87 See the Raltegravir
section of the Pediatric Antiretroviral Guidelines for additional information.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-20
References
1. Wade NA, Birkhead GS, Warren BL, et al. Abbreviated regimens of zidovudine
prophylaxis and perinatal transmission of the human immunodeficiency virus. N Engl J
Med. 1998;339(20):1409-1414. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/9811915.

2. Van Rompay KK, Otsyula MG, Marthas ML, Miller CJ, McChesney MB, Pedersen NC.
Immediate zidovudine treatment protects simian immunodeficiency virus-infected
newborn macaques against rapid onset of AIDS. Antimicrob Agents Chemother.
1995;39(1):125-131. Available at: http://www.ncbi.nlm.nih.gov/pubmed/7695293.

3. Tsai CC, Follis KE, Sabo A, et al. Prevention of SIV infection in macaques by (R)-9-(2-
phosphonylmethoxypropyl)adenine. Science. 1995;270(5239):1197-1199. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/7502044.

4. Bottiger D, Johansson NG, Samuelsson B, et al. Prevention of simian immunodeficiency

virus, SIVsm, or HIV-2 infection in cynomolgus monkeys by pre- and postexposure
administration of BEA-005. AIDS. 1997;11(2):157-162. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/9030361.

5. Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens
to prevent intrapartum HIV infection. N Engl J Med. 2012;366(25):2368-2379. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/22716975.

6. Dunn DT, Brandt CD, Krivine A, et al. The sensitivity of HIV-1 DNA polymerase chain
reaction in the neonatal period and the relative contributions of intra-uterine and intra-
partum transmission. AIDS. 1995;9(9):F7-11. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/8527070.

7. Lommerse J, Clarke D, Kerbusch T, et al. Maternal-neonatal raltegravir population

pharmacokinetics modeling: implications for initial neonatal dosing. CPT
Pharmacometrics Syst Pharmacol. 2019;8(9):643-653. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31215170.

8. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of

human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS
Clinical Trials Group Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173-
1180. Available at: https://www.ncbi.nlm.nih.gov/pubmed/7935654.

9. de Ruiter A, Mercey D, Anderson J, et al. British HIV association and children’s HIV
association guidelines for the management of HIV infection in pregnant women 2008.
HIV Med. 2008;9(7):452-502. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18840151.

10. Ferguson W, Goode M, Walsh A, Gavin P, Butler K. Evaluation of 4 weeks’ neonatal

antiretroviral prophylaxis as a component of a prevention of mother-to-child transmission

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-21
 program in a resource-rich setting. Pediatr Infect Dis J. 2011;30(5):408-412. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/21266939.

11. Neubert J, Pfeffer M, Borkhardt A, et al. Risk adapted transmission prophylaxis to

prevent vertical HIV-1 transmission: effectiveness and safety of an abbreviated regimen
of postnatal oral zidovudine. BMC Pregnancy Childbirth. 2013;13:22. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23347580.

12. British HIV Association. British HIV association guidelines for the management of HIV
in pregnancy and postpartum 2018 (2020 third interim update). 2020. Available at:
https://www.bhiva.org/file/5f1aab1ab9aba/BHIVA-Pregnancy-guidelines-2020-3rd-
interim-update.pdf.

13. Lahoz R, Noguera A, Rovira N, et al. Antiretroviral-related hematologic short-term

toxicity in healthy infants: implications of the new neonatal 4-week zidovudine regimen.
Pediatr Infect Dis J. 2010;29(4):376-379. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19949355.

14. Nguyen TTT, Kobbe R, Schulze-Sturm U, et al. Reducing hematologic toxicity with
short course postexposure prophylaxis with zidovudine for HIV-1 exposed infants with
low transmission risk. Pediatr Infect Dis J. 2019;38(7):727-730. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31033907.

15. Swiss Federal Office of Public Health. Recommendations of the Swiss Federal
Commission for Sexual Health (FCHS) for medical care of HIV-infected women and
their offspring. 2018. Available at:
https://www.bag.admin.ch/dam/bag/en/dokumente/mt/p-und-p/richtlinien-
empfehlungen/fcsh-mtct-hiv.pdf.download.pdf/fcsh-mtct-hiv.pdf.

16. Traytel A SA, Aebi-Popp K., Crisinel PA., et al. Discontinuation of neonatal
postexposure prophylaxis in infants born to HIV-infected mothers with suppressed
plasma viral load: safety and implementation of the new Swiss recommendations.
Presented at: 17th European AIDS Conference. 2019. Basal, Switerzland. Available at:
https://onlinelibrary.wiley.com/doi/10.1111/hiv.12814.

17. Flynn PM, Taha TE, Cababasay M, et al. Association of maternal viral load and CD4
count with perinatal HIV-1 transmission risk during breastfeeding in the PROMISE
postpartum component. J Acquir Immune Defic Syndr. 2021;88(2):206-213. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34108383.

18. Davis NL, Miller WC, Hudgens MG, et al. Maternal and breastmilk viral load: impacts of
adherence on peripartum HIV infections averted-the breastfeeding, antiretrovirals, and
nutrition study. J Acquir Immune Defic Syndr. 2016;73(5):572-580. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27846071.

19. Bispo S, Chikhungu L, Rollins N, Siegfried N, Newell ML. Postnatal HIV transmission
in breastfed infants of HIV-infected women on ART: a systematic review and meta-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-22
 analysis. J Int AIDS Soc. 2017;20(1):21251. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28362072.

20. Coovadia H, Brown E, Maldonado Y, et al. Efficacy of extended daily infant nevirapine
(NVP) through age 6 months compared to 6 weeks for prevention of postnatal mother-to-
child transmission (MTCT) of HIV through breastfeeding (BF). Presented at: 18th
Conference on Retroviruses and Opportunistic Infections. 2011. Boston, MA.

21. Nagot N, Kankasa C, Tumwine JK, et al. Extended pre-exposure prophylaxis with
lopinavir-ritonavir versus lamivudine to prevent HIV-1 transmission through
breastfeeding up to 50 weeks in infants in Africa (ANRS 12174): a randomised
controlled trial. Lancet. 2016;387(10018):566-573. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26603917.

22. Kilewo C, Karlsson K, Massawe A, et al. Prevention of mother-to-child transmission of

HIV-1 through breast-feeding by treating infants prophylactically with lamivudine in Dar
es Salaam, Tanzania: the Mitra study. J Acquir Immune Defic Syndr. 2008;48(3):315-
323. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18344879.

23. Mofenson LM, Lambert JS, Stiehm ER, et al. Risk factors for perinatal transmission of
human immunodeficiency virus type 1 in women treated with zidovudine. Pediatric AIDS
Clinical Trials Group Study 185 Team. N Engl J Med. 1999;341(6):385-393. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/10432323.

24. Garcia PM, Kalish LA, Pitt J, et al. Maternal levels of plasma human immunodeficiency
virus type 1 RNA and the risk of perinatal transmission. Women and infants transmission
study group. N Engl J Med. 1999;341(6):394-402. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/10432324.

25. Cooper ER, Charurat M, Mofenson L, et al. Combination antiretroviral strategies for the
treatment of pregnant HIV-1-infected women and prevention of perinatal HIV-1
transmission. J Acquir Immune Defic Syndr. 2002;29(5):484-494. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11981365.

26. PETRA Study Team. Efficacy of three short-course regimens of zidovudine and
lamivudine in preventing early and late transmission of HIV-1 from mother to child in
Tanzania, South Africa, and Uganda (PETRA study): a randomised, double-blind,
placebo-controlled trial. Lancet. 2002;359(9313):1178-1186. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11955535.

27. Lallemant M, Jourdain G, Le Coeur S, et al. A trial of shortened zidovudine regimens to

prevent mother-to-child transmission of human immunodeficiency virus type 1. Perinatal
HIV prevention trial (Thailand) investigators. N Engl J Med. 2000;343(14):982-991.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/11018164.

28. Ruel TD, Capparelli EV, Tierney C, et al. Pharmacokinetics and safety of early
nevirapine-based antiretroviral therapy for neonates at high risk for perinatal HIV

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-23
 infection: a phase 1/2 proof of concept study. Lancet HIV. 2021;8(3):e149-e157.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/33242457.

29. Persaud D, Ray SC, Kajdas J, et al. Slow human immunodeficiency virus type 1
evolution in viral reservoirs in infants treated with effective antiretroviral therapy. AIDS
Res Hum Retroviruses. 2007;23(3):381-390. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17411371.

30. Luzuriaga K, Tabak B, Garber M, et al. HIV type 1 (HIV-1) proviral reservoirs decay
continuously under sustained virologic control in HIV-1-infected children who received
early treatment. J Infect Dis. 2014;210(10):1529-1538. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24850788.

31. Persaud D, Patel K, Karalius B, et al. Influence of age at virologic control on peripheral
blood human immunodeficiency virus reservoir size and serostatus in perinatally infected
adolescents. JAMA Pediatr. 2014;168(12):1138-1146. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25286283.

32. Rainwater-Lovett K, Ziemniak C, Watson D, et al. Paucity of intact non-induced provirus

with early, long-term antiretroviral therapy of perinatal HIV infection. PLoS One.
2017;12(2):e0170548. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28178277.

33. Rocca S, Zangari P, Cotugno N, et al. Human immunodeficiency virus (HIV)-antibody

repertoire estimates reservoir size and time of antiretroviral therapy initiation in virally
suppressed perinatally HIV-infected children. J Pediatric Infect Dis Soc. 2018;8(5):433-
438. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30169837.

34. Shiau S, Abrams EJ, Arpadi SM, Kuhn L. Early antiretroviral therapy in HIV-infected
infants: can it lead to HIV remission? Lancet HIV. 2018;5(5):e250-e258. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29739699.

35. Persaud D, Gaye H, al e. Absence of detectable HIV-1 viremia following treatment

cessation in an infant. N Engl J Med. 2013;369(19):1828-1835. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24152233.

36. Butler KM, Gavin P, Coughlan S, et al. Rapid viral rebound after 4 years of suppressive
therapy in a seronegative HIV-1 infected infant treated from birth. Pediatr Infect Dis J.
2014;34(3):e48-51. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25251719.

37. Violari A, Cotton MF, Kuhn L, et al. A child with perinatal HIV infection and long-term
sustained virological control following antiretroviral treatment cessation. Nat Commun.
2019;10(1):412. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30679439.

38. Maswabi K, Ajibola G, Bennett K, et al. Safety and efficacy of starting antiretroviral
therapy in the first week of life. Clin Infect Dis. 2021;72(3):388-393. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31927562.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-24
39. Bitnun A, Samson L, Chun TW, et al. Early initiation of combination antiretroviral
therapy in HIV-1-infected newborns can achieve sustained virologic suppression with
low frequency of CD4+ T cells carrying HIV in peripheral blood. Clin Infect Dis.
2014;59(7):1012-1019. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24917662.

40. Kakkar FW, Samson L, Vaudry W, et al. Safety of combination antiretroviral prophylaxis
in high-risk HIV-exposed newborns: a retrospective review of the Canadian experience. J
Int AIDS Soc. 2016;19(1):20520. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26880241.

41. Anugulruengkitt S, Suntarattiwong P, Ounchanum P, et al. Safety of 6-week neonatal

triple-combination antiretroviral postexposure prophylaxis in high-risk HIV-exposed
infants. Pediatr Infect Dis J. 2019;38(10):1045-1050. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31365477.

42. Illan Ramos M, Soto Sanchez B, Mazariegos Orellana D, et al. Safety and experience
with combined antiretroviral prophylaxis in newborn at high-risk of perinatal HIV
infection, in a cohort of mother living with HIV-infant pairs. Pediatr Infect Dis J.
2021;40(12):1096-1100. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34870390.

43. Lau E, Brophy J, Samson L, et al. Nevirapine pharmacokinetics and safety in neonates
receiving combination antiretroviral therapy for prevention of vertical HIV transmission.
J Acquir Immune Defic Syndr. 2017;74(5):493-498. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28114187.

44. Cressey TR, Punyawudho B, Le Coeur S, et al. Assessment of nevirapine prophylactic

and therapeutic dosing regimens for neonates. J Acquir Immune Defic Syndr.
2017;75(5):554-560. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28489732.

45. Clarke DF, Acosta EP, Rizk ML, et al. Raltegravir pharmacokinetics in neonates
following maternal dosing. J Acquir Immune Defic Syndr. 2014;67(3):310-315. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/25162819.

46. Clarke DF, Wong RJ, Wenning L, Stevenson DK, Mirochnick M. Raltegravir in vitro
effect on bilirubin binding. Pediatr Infect Dis J. 2013;32(9):978-980. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23470680.

47. Clarke DF, Penazzato M, Capparelli E, et al. Prevention and treatment of HIV infection
in neonates: evidence base for existing WHO dosing recommendations and
implementation considerations. Expert Rev Clin Pharmacol. 2018;11(1):83-93. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/29039686.

48. Clarke DF, Acosta EP, Cababasay M, et al. Raltegravir pharmacokinetics and safety in
HIV-1 exposed neonates at risk of infection: IMPAACT P1110. JAIDS 2020;84(1):70-77.
Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7144886/.

49. World Health Organization. Consolidated guidelines on HIV prevention, testing,

treatment, service delivery and monitoring: recommendations for a public health

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-25
 approach. Geneva: World Health Organization; 2021. Available at
https://www.who.int/publications/i/item/9789240031593.

50. Bekker A, Capparelli EV, Violari A, et al. Abacavir dosing in neonates from birth: a
pharmcokinetic analysis. Presented at: Conference on Retroviruses and Opportunistic
Infections. 2021. Virtual Conference. Available at:
https://www.croiconference.org/abstract/abacavir-dosing-in-neonates-from-birth-a-
pharmacokinetic-analysis.

51. Bekker A, Decloedt EH, Slade G, Cotton MF, Rabie H, Cressey TR. Single dose abacavir
pharmacokinetics and safety in neonates exposed to human immunodeficiency virus
(HIV). Clin Infect Dis. 2021;72(11):2032-2034. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32697327.

52. Mirochnick M, Nielsen-Saines K, Pilotto JH, et al. Nelfinavir and lamivudine

pharmacokinetics during the first two weeks of life. Pediatr Infect Dis J. 2011;30(9):769-
772. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21666540.

53. Mandelbrot L, Tubiana R, Le Chenadec J, et al. No perinatal HIV-1 transmission from

women with effective antiretroviral therapy starting before conception. Clin Infect Dis.
2015;61(11):1715-1725. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26197844.

54. Townsend CL, Byrne L, Cortina-Borja M, et al. Earlier initiation of ART and further
decline in mother-to-child HIV transmission rates, 2000–2011. AIDS. 2014;28(7):1049-
1057. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24566097.

55. Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to
reduce breast-milk HIV-1 transmission. N Engl J Med. 2008;359(2):119-129. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/18525035.

56. Six Week Extended-Dose Nevirapine Study Team, Bedri A, Gudetta B, et al. Extended-
dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via
breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled
trials. Lancet. 2008;372(9635):300-313. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18657709.

57. Chasela CS, Hudgens MG, Jamieson DJ, et al. Maternal or infant antiretroviral drugs to
reduce HIV-1 transmission. N Engl J Med. 2010;362(24):2271-2281. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20554982.

58. Flynn PM, Taha TE, Cababasay M, et al. Prevention of HIV-1 transmission through
breastfeeding: efficacy and safety of maternal antiretroviral therapy versus infant
nevirapine prophylaxis for duration of breastfeeding in HIV-1-infected women with high
CD4 cell count (IMPAACT PROMISE): a randomized, open-label, clinical trial. J Acquir
Immune Defic Syndr. 2018;77(4):383-392. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29239901.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-26
59. American Academy of Pediatrics. Breastfeeding and the use of human milk. 2012.
Available at: https://pediatrics.aappublications.org/content/129/3/e827.

60. Bauer GR, Colgrove RC, Larussa PS, Pitt J, Welles SL. Antiretroviral resistance in viral
isolates from HIV-1-transmitting mothers and their infants. AIDS. 2006;20(13):1707-
1712. Available at: http://www.ncbi.nlm.nih.gov/pubmed/16931934.

61. De Jose MI, Ramos JT, Alvarez S, Jimenez JL, Munoz-Fernandez MA. Vertical
transmission of HIV-1 variants resistant to reverse transcriptase and protease inhibitors.
Arch Intern Med. 2001;161(22):2738-2739. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11732941.

62. Desai N, Mathur M. Selective transmission of multidrug resistant HIV to a newborn

related to poor maternal adherence. Sex Transm Infect. 2003;79(5):419-421. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14573842.

63. Cohan D, Feakins C, Wara D, et al. Perinatal transmission of multidrug-resistant HIV-1

despite viral suppression on an enfuvirtide-based treatment regimen. AIDS.
2005;19(9):989-990. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15905684.

64. Fogel J, Li Q, Taha TE, et al. Initiation of antiretroviral treatment in women after
delivery can induce multiclass drug resistance in breastfeeding HIV-infected infants. Clin
Infect Dis. 2011;52(8):1069-1076. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21460326.

65. Zeh C, Weidle PJ, Nafisa L, et al. HIV-1 drug resistance emergence among breastfeeding
infants born to HIV-infected mothers during a single-arm trial of triple-antiretroviral
prophylaxis for prevention of mother-to-child transmission: a secondary analysis. PLoS
Med. 2011;8(3):e1000430. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21468304.

66. Yeganeh N, Kerin T, Ank B, et al. Human immunodeficiency virus antiretroviral

resistance and transmission in mother-infant pairs enrolled in a large perinatal study. Clin
Infect Dis. 2018;66(11):1770-1777. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29272365.

67. Rosebush JC, Best BM, Chadwick EG, et al. Pharmacokinetics and safety of maraviroc in
neonates. AIDS. 2021;35(3):419-427. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33252481.

68. Persaud D, Chadwick E, Tierney C, et al. Virologic response to very early ART in
neonates with in utero HIV: IMPAACT P115. Abstract 799. Presented at: Conference on
Retroviruses and Opportunistic Infections. 2019. Seattle, Washington. Available at:
http://www.croiconference.org/sessions/virologic-response-very-early-art-neonates-utero-
hiv-impaact-p1115.

69. Van de Perre P, Lepage P, Homsy J, Dabis F. Mother-to-infant transmission of human

immunodeficiency virus by breast milk: presumed innocent or presumed guilty? Clin

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-27
 Infect Dis. 1992;15(3):502-507. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/1445596.

70. Smith DK, Grohskopf LA, Black RJ, et al. Antiretroviral postexposure prophylaxis after
sexual, injection-drug use, or other nonoccupational exposure to HIV in the United
States: recommendations from the U.S. Department of Health and Human Services.
MMWR Recomm Rep. 2005;54(RR-2):1-20. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15660015.

71. Moodley J, Moodley D, Pillay K, et al. Pharmacokinetics and antiretroviral activity of

lamivudine alone or when coadministered with zidovudine in human immunodeficiency
virus type 1-infected pregnant women and their offspring. J Infect Dis.
1998;178(5):1327-1333. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9780252.

72. Moodley D, Moodley J, Coovadia H, et al. A multicenter randomized controlled trial of

nevirapine versus a combination of zidovudine and lamivudine to reduce intrapartum and
early postpartum mother-to-child transmission of human immunodeficiency virus type 1.
J Infect Dis. 2003;187(5):725-735. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12599045.

73. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine

combination for prevention of maternal-infant transmission of HIV-1. JAMA.
2001;285(16):2083-2093. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11311097.

74. Lambert JS, Nogueira SA, Abreu T, et al. A pilot study to evaluate the safety and
feasibility of the administration of AZT/3TC fixed dose combination to HIV infected
pregnant women and their infants in Rio de Janeiro, Brazil. Sex Transm Infect.
2003;79(6):448-452. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14663118.

75. Cressey TR, Bekker A, Cababasay M, et al. Abacavir safety and pharmacokinetics in
normal and low birth weight infants with HIV. Abstract #843. Presented at: Conference
on Retroviruses and Opportunistic Infections. 2020. Boston, MA

76. Crichton S, Collins IJ, Turkova A, et al. Abacavir dosing, effectivness, and safety in
young infants living with HIV in Europe. Abstract #844. Presented at: Conference on
Retroviruses and Opportunistic Infections. 2020. Boston, MA

77. De Waal R, Rabie H, Technau K, et al. Abacavir safety and efficacy in young infants in
South African observational cohort. Abstract #845. Presented at: Conference on
Retroviruses and Opportunistic Infections. 2020. Boston, MA

78. Gray G, Violari A, McIntyre J, et al. Antiviral activity of nucleoside analogues during
short-course monotherapy or dual therapy: its role in preventing HIV infection in infants.
J Acquir Immune Defic Syndr. 2006;42(2):169-176. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16639342.

79. Rongkavilit C, van Heeswijk RP, Limpongsanurak S, et al. Dose-escalating study of the
safety and pharmacokinetics of nelfinavir in HIV-exposed neonates. J Acquir Immune

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-28
 Defic Syndr. 2002;29(5):455-463. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11981361.

80. Torres SM, Walker DM, Carter MM, et al. Mutagenicity of zidovudine, lamivudine, and
abacavir following in vitro exposure of human lymphoblastoid cells or in utero exposure
of CD-1 mice to single agents or drug combinations. Environ Mol Mutagen. 2007;48(3-
4):224-238. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17358033.

81. Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, Blanche S, Enquete Perinatale

Francaise Study G. Perinatal antiretroviral treatment and hematopoiesis in HIV-
uninfected infants. AIDS. 2003;17(14):2053-2061. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14502008.

82. Pacheco SE, McIntosh K, Lu M, et al. Effect of perinatal antiretroviral drug exposure on
hematologic values in HIV-uninfected children: an analysis of the women and infants
transmission study. J Infect Dis. 2006;194(8):1089-1097. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16991083.

83. Feiterna-Sperling C, Weizsaecker K, Buhrer C, et al. Hematologic effects of maternal

antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected
newborn infants. J Acquir Immune Defic Syndr. 2007;45(1):43-51. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17356471.

84. Hitti J, Frenkel LM, Stek AM, et al. Maternal toxicity with continuous nevirapine in
pregnancy: results from PACTG 1022. J Acquir Immune Defic Syndr. 2004;36(3):772-
776. Available at: http://www.ncbi.nlm.nih.gov/pubmed/15213559.

85. Coovadia HM, Brown ER, Fowler MG, et al. Efficacy and safety of an extended
nevirapine regimen in infant children of breastfeeding mothers with HIV-1 infection for
prevention of postnatal HIV-1 transmission (HPTN 046): a randomised, double-blind,
placebo-controlled trial. Lancet. 2012;379(9812):221-228. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22196945.

86. Clarke DF, Lommerse J, Acosta EP, et al. Impact of low birth weight and prematurity on
neonatal raltegravir pharmacokinetics: IMPAACT P1097. J Acquir Immune Defic Syndr.
2020;85:626-634. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32925360.

87. Clarke DF, Acosta EP, Cababasay M, et al. Raltegravir (RAL) in neonates: dosing,
pharmacokinetics (PK), and safety in HIV-1-exposed neonates at risk of infection
(IMPAACT P1110). J Acquir Immune Defic Syndr. 2020;84(1):70-77. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31913995.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection G-29
Special Considerations for Antiretroviral Therapy
Use in Adolescents With HIV
Updated: April 11, 2023
Reviewed: April 11, 2023

Panel’s Recommendations
• All adolescents with HIV should receive maximally suppressive antiretroviral (ARV) therapy; this is urgent for those who
are sexually active, considering pregnancy, or pregnant (AII).
• ARV regimen selection should include consideration of the adolescent’s individual needs and preferences (AIII). See What
to Start: Regimens Recommended for Initial Therapy of Antiretroviral-Naive Children and Management of Children
Receiving Antiretroviral Therapy for more information.
• All adolescents with HIV should be screened for mental health disorders and substance use disorders (AII).
• Reproductive and sexual health issues—including pregnancy intentions, contraceptive methods, safer sex techniques to
prevent transmission of HIV and other sexually transmitted infections (STIs), regular STI screening, pre-exposure
prophylaxis for partners, pregnancy planning, and preconception care—should be discussed regularly (AII).
• Adolescents with HIV can use all available hormonal contraceptive methods (e.g., pill, patch, ring, injection, implant);
however, providers should consider potential drug–drug interactions between hormonal contraceptives and ARV
medications that could affect contraceptive efficacy (AII*). See Table 3. Drug Interactions Between Antiretroviral Agents
and Hormonal Contraceptives in the Perinatal Guidelines.
• Pediatric and adolescent care providers should prepare adolescents for the transition into adult care settings (AIII).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints;
I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying
data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical
outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term
outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical
outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical
outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to postpubertal adolescents.

Background
Most individuals in the United States who acquired HIV through perinatal transmission are now
adolescents or young adults. Most have had a long clinical course with an extensive
antiretroviral (ARV) treatment history.1,2 Older youth and adults may have initially received
nonsuppressive monotherapy or dual therapy prior to the availability of combination ARV regimens,
including fixed-dose combination (FDC) formulations. Challenges that affect the treatment of
adolescents with perinatally acquired HIV include extensive drug resistance, complex regimens, the
long-term consequences of HIV and antiretroviral therapy (ART) exposure,3 the developmental
transition to adulthood, and psychosocial factors.4-7

In the United States, most adolescents aged ≥14 years who recently received HIV diagnoses acquired
their infection through non-perinatal transmission.8 They generally follow a clinical course similar to
that of adults, and the Adult and Adolescent Antiretroviral Guidelines should be consulted for
treatment recommendations for these patients. Additional information that is specific to the care of
post-pubertal adolescents can be found in Adolescents and Young Adults With HIV.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-1
Timing and Selection of Antiretroviral Therapy
All adolescents with HIV (like all people with HIV) should initiate ART as soon as possible after
HIV diagnosis. Recommendations for ART selection in adolescents with sexual maturity
ratings (SMRs) between 1 and 3 can be found in What to Start: Regimens Recommended for Initial
Therapy of Antiretroviral-Naive Children and Appendix A: Pediatric Antiretroviral Drug
Information. ART recommendations for adolescents and young adults with SMRs between 4 and 5
are available in the What to Start: Initial Combination Antiretroviral Regimens for People With HIV
section of the Adult and Adolescent Antiretroviral Guidelines. Optimizing and simplifying treatment
may be especially important when treating adolescents, because this can help improve adherence (see
Modifying Antiretroviral Regimens in Children With Sustained Virologic Suppression on
Antiretroviral Therapy). Clinicians who are treating adolescents of childbearing potential should
consider additional factors before initiating ART, including potential drug interactions with
contraception and the safety of using certain ARV drugs before conception or during pregnancy (see
the Contraception, Pregnancy, and Antiretroviral Therapy section below).

Dosing of Antiretroviral Therapy for Adolescents With HIV

Clinical providers need to pay attention to the transition of adolescents from pediatric to adult ART
dosing. Many ARV drugs (e.g., abacavir, emtricitabine, lamivudine, tenofovir disoproxil
fumarate [TDF], and some protease inhibitors [PIs]) are administered to children at higher body
weight–based doses or body surface area–based doses than would be predicted by direct
extrapolation of adult doses. These doses are based on reported pharmacokinetic data that indicate
more rapid drug clearance in children than in adults. Therefore, failure to ensure weight-appropriate
dosing in adolescents can result in an increased risk of drug toxicity if higher pediatric dosing is not
transitioned to lower adult dosing (often between 25 kg and 40 kg, depending on the particular
drug).9

Adherence Concerns in Adolescents

Low adherence to ART is a common problem among adolescents with HIV. Both psychosocial and
cognitive developmental factors may contribute to adherence challenges, and these factors should be
assessed regularly. Assessment of antiretroviral adherence in adolescents with HIV can be
challenging, and discordance between self-report and other adherence measures—such as viral load
and therapeutic or cumulative drug levels—should prompt open discussions with the adolescent and
their caregiver. In one study conducted in Botswana, adolescents whose self-reported adherence and
electronic adherence monitoring were discordant reported reasons for not disclosing non-adherence
that included fear of disappointing caregivers and providers and a desire to avoid negative feedback
or punitive adherence counseling.10 Providers should encourage open discussions that normalize the
difficulties of taking life-long medications and provide positive reinforcement of disclosing
adherence challenges. The adolescent’s individual needs and preferences also should be considered
when making decisions about initiating or changing ART. Comprehensive systems of care are
required to serve both the medical and psychosocial needs of adolescents with HIV, because they are
frequently inexperienced with managing their health care and may also lack health insurance.
Adolescents with perinatally acquired HIV infection are at risk for neurocognitive impairment, which
also can interfere with medication adherence.11,12 Many also are at risk for mental health
comorbidities, including psychiatric, behavioral, and substance use disorders that may interfere with
adherence to ART.7,13 Compared with adults, youth have lower rates of viral suppression and higher
rates of virologic rebound and loss to follow-up.14,15 For further discussion of interventions to
promote adherence in adolescents, see the Adolescents and Young Adults With HIV section of the
Adult and Adolescent Antiretroviral Guidelines and a 2013 review by Agwu and Fairlie.3

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-2
A specific challenge is presented by youth who, despite interventions, remain unable to adhere to
therapy. In these cases, simplifying treatment to a once-daily regimen, an FDC tablet, or a long-
acting injectable ARV regimen may improve adherence. The first long-acting injectable ARV
regimen (cabotegravir and rilpivirine) was recently approved for use in adolescents aged ≥12 years
and weighing ≥35 kg who are virally suppressed; however, data on use in adolescents are limited to
safety, pharmacokinetics, and acceptability (see Cabotegravir and Rilpivirine).16,17 Data are not yet
available on the use of this combination ARV in adolescents and its potential use in those with
adherence concerns. Alternatives to changing the ARV regimen can include, but are not limited to,
using cellphone alerts and other mHealth approaches to remind patients to take their medication and
attend clinic visits18; initiating a short-term deferral of treatment until adherence improves or while
adherence-related problems (including mental health and substance use disorders) are aggressively
addressed; initiating an adherence testing and training period during which a placebo (e.g., vitamin
pill) is administered; scheduling appointments more frequently; employing directly observed therapy;
and avoiding regimens with a low genetic resistance threshold. Such decisions should be
individualized, and the patient’s clinical and laboratory status monitored carefully, integrating
transportation support and telemedicine options for flexible care engagement. Of note, even small
and short-term improvements in virologic suppression may have longer-term clinical value for
adolescents with HIV.19

Mental Health and Substance Use Concerns in Adolescents

Adolescent mental distress is a growing concern that has been exacerbated by the COVID-19
pandemic (see Background: The COVID-19 Pandemic’s Impact on the Mental Health of Children
and Youth in Protecting Youth Mental Health: The U.S. Surgeon General’s Advisory). Many factors
can increase the risk of adverse mental health outcomes among adolescents with perinatally acquired
HIV, including long-term medical treatment for a chronic disease, hospitalizations, stigma, the
neurocognitive impacts of HIV, parental psychiatric and substance use disorders, and family and
caregiver stress and loss. The prevalence of mental health disorders in youth with perinatally
acquired HIV is high, with nearly 70% of these adolescents meeting the criteria for a psychiatric
disorder at some point in their lives.7,20-22 The most common conditions include anxiety and
behavioral disorders, mood disorders (including depression), and attention deficit hyperactivity
disorder. Additionally, although data are sparse, the prevalence of attempted suicide has been notably
higher in adolescents with HIV compared to those that have been exposed to HIV but are
uninfected.23 In at least one cohort, the risk of psychosis and severe chronic mental health disorders
was higher in adolescents with perinatally acquired HIV than expected in the general young adult
population.24 Effectively managing psychiatric comorbidities can improve a patient’s adherence to
medical care, including ART, and can lead to better academic performance and interpersonal
relationships (see Substance Use Disorders and HIV in the Adult and Adolescent Antiretroviral
Guidelines).13,25-27

Interventions that address mental health in youth with perinatally acquired HIV include
pharmacologic interventions; behavioral modification; and individual, family, and group counseling.
The use of telehealth or counseling via videoconferencing may be feasible and acceptable and may
improve access to mental health treatment for adolescents with HIV.28 Current evidence suggests that
a combination of tailored psychotherapy—such as cognitive behavioral therapy—and
pharmacotherapy can reduce depressive symptoms in adolescents with HIV; however, clinicians who
prescribe pharmacotherapy for depression must take potential interactions with ARV drugs into
account.29,30 One recent study randomized 13 U.S. sites to either a cognitive behavioral therapy and
medication management algorithm (COMB-R) tailored for adolescents with HIV or enhanced
standard of care, including standard psychotherapy and medication management, for adolescents with
HIV who have depressive symptoms. After 6 months, sites using the COMB-R intervention showed

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-3
decreased depressive symptoms and higher remission from depression than the enhanced standard of
care; however, mean HIV viral load and CD4 cell count were not significantly different between
arms.31

There is evidence that adolescents with perinatally acquired HIV are more likely to have substance
use disorders compared to the general population.32 However, available studies on substance use
among adolescents with perinatally acquired HIV show age of initiation and rates of substance use
similar to age-matched peers without HIV.33 In a comparison of 390 youth with perinatal exposure to
HIV versus 211 youth living with perinatally acquired HIV, investigators from the Pediatric
HIV/AIDS Cohort Study (PHACS) found that nearly half of both groups had ever used alcohol or
marijuana, with a majority having used either substance in the last 3 months, and one out of five
marijuana users reporting at least daily use.34 In another study, there was no difference in substance
use between adolescents exposed to HIV and adolescents living with HIV. While rates of substance
use may not be higher in adolescents with perinatally acquired HIV, the impact on health
outcomes—including interference with medication adherence and increased risk taking and
decreased safe sex practices—and the potential for comorbid mental health concerns make
addressing substance use in adolescents with HIV an important consideration for HIV care
providers.35,36

Providers who are caring for adolescents with HIV should incorporate screening for psychiatric
(including suicidality) and substance use disorders into routine care and refer patients to age-
appropriate services as needed. The American Academy of Pediatrics Guidelines for Adolescent
Depression in Primary Care policy statement provides some guidance and screening tools,
particularly for depression. Screening tools for substance use—such as Screening, Brief Intervention,
and Referral to Treatment (SBIRT) or Car, Relax, Alone, Forget, Friends, and Trouble (CRAFFT)—
may be used.37 Providers also should consider emerging substance use trends when screening
adolescents with HIV. Further guidance on screening tools for substance use and mental health is
provided by the National Institute on Drug Abuse’s Screening and Assessment Tools Chart.

Sexually Transmitted Infections in Adolescents

At least half of new sexually transmitted infections (STIs) in the United States occur in youth aged
15 to 24. An analysis of three Adolescent Medicine Trials Network for HIV/AIDS Interventions
studies conducted between 2009 and 2015 identified rates of STIs in adolescents with HIV that were
higher than national averages for those without HIV.38 Although adolescents with either non-
perinatally or perinatally acquired HIV had elevated rates of STIs, those with non-perinatally
acquired HIV had higher rates than those with perinatally-acquired HIV. In addition, STIs were more
frequent during times when viral load was > 400 copies/mL. Clinicians should discuss the risk of
STIs with their patients. All adolescents with HIV should be screened for STIs and treated
appropriately. Clinicians should regularly obtain a detailed sexual history for adolescents to
determine which STI screening tests are appropriate. Screening for STIs in sexually active
adolescents with HIV often requires sampling from several body sites—including the oropharynx,
rectum, and urethra—because multiple sites of infection are common.39 Furthermore, a negative
assay at a single site does not preclude the possibility of infection at another site.40 For a more
detailed discussion of STIs, see the Centers for Disease Control and Prevention STI Treatment
Guidelines,41 Human Papillomavirus Disease in the Adult and Adolescent Opportunistic Infection
Guidelines, and Human Papillomavirus in the Pediatric Opportunistic Infection Guidelines. All
female adolescents with HIV who are sexually active should receive gynecologic services. All
adolescents with HIV should receive three doses of the 9-valent human papillomavirus vaccination.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-4
Contraception, Pregnancy, and Antiretroviral Therapy
Adolescents with HIV may initiate sexual activity before or after puberty. Sexually active
adolescents are at risk for unintended pregnancy. Approximately half of pregnancies in the
United States, including those among women with HIV, are unintended or unplanned.42,43 Providers
should regularly assess adolescents’ desires to become pregnant or avoid pregnancy (also known as
their pregnancy intentions). Family planning counseling—including a discussion of the risks of
sexual HIV transmission, perinatal HIV transmission, and methods for reducing these risks—should
be provided to all youth. Reproductive health options—such as pregnancy planning, preconception
care, contraceptive methods, pre-exposure prophylaxis for partners, the concept of
Undetectable = Untransmittable (U=U),44,45 and safer sex techniques (including instruction on the
correct and consistent use of condoms) for prevention of sexual HIV transmission—should be
discussed regularly (see U.S. Medical Eligibility Criteria for Contraceptive Use). Access to sexual
health care, including contraception and abortion care, varies by state. To provide complete guidance,
providers must be familiar with local laws and regulations. For additional information, refer to the
following sections of the Perinatal Guidelines: Prepregnancy Counseling and Care for Persons of
Childbearing Age With HIV and Reproductive Options When One or Both Partners Have HIV. The
American Academy of Pediatrics Committee on Adolescence offers guidance about the integration of
sexual and reproductive health care in pediatric clinical settings.46

The possibility of planned and unplanned pregnancy should be considered when selecting an ARV
regimen for a female adolescent. The most vulnerable period in fetal organogenesis is the first
trimester, often before pregnancy is recognized. When treating adolescents of childbearing potential,
clinicians should carefully review the potential toxicities of ARV drugs and consider making any
necessary changes to a regimen as promptly as possible (e.g., before conception, when possible). For
information about the selection and management of ARV drugs before and during pregnancy for
people with HIV who are of childbearing age, see Table 7 in the Recommendations for Use of
Antiretroviral Drugs During Pregnancy section of the Perinatal Guidelines. When discussing ART
options with female adolescents and their caregivers, it is important to consider the benefits and risks
of all ARV drugs and to provide the information and counseling needed to support informed
decision-making (see Appendix C: Antiretroviral Counseling Guide for Health Care Providers).

Interactions Between Contraceptives and Antiretroviral Drugs

People living with HIV can use all available contraceptive methods, including hormonal
contraceptives, implantable devices, intrauterine devices, the transdermal patch, and a vaginal ring.47

Several PIs and non-nucleoside reverse transcriptase inhibitors alter the metabolism of oral
contraceptives, which theoretically may reduce the efficacy of oral contraceptive agents or increase
the risk of estrogen-related or progestin-related adverse effects48-50 (see Drug–Drug Interactions in
the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug Interaction Checker). Integrase
strand transfer inhibitors appear to have no interaction with estrogen-based contraceptives.51,52 For
more information about potential interactions between ARV drugs and hormonal contraceptives, see
Table 3. Drug Interactions Between Antiretroviral Agents and Hormonal Contraceptives in the
Perinatal Guidelines.

Concerns about loss of bone mineral density with long-term use of depot medroxyprogesterone
acetate (DMPA), with or without coadministration of ART (specifically TDF), should not preclude
the use of DMPA as an effective contraceptive, unless clinical evidence indicates bone fragility.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-5
Pregnant Adolescents With HIV
Adolescents who want to become pregnant should receive preconception counseling and care,
including a discussion of pregnancy planning and special considerations when using ARV drugs
during pregnancy (see Prepregnancy Counseling and Care for Persons of Childbearing Age With
HIV in the Perinatal Guidelines). Pregnancy should not preclude the use of optimal therapeutic ARV
regimens. Clinicians need to consider maternal and fetal safety, as well as the need to prevent
perinatal transmission of HIV, when selecting regimens for pregnant people or adolescents who are
planning to become pregnant. See the Prepregnancy Counseling and Care for Persons of
Childbearing Age With HIV for more details about choosing an ARV regimen for pregnant people
with HIV, including adolescents. Pregnancies occur as adolescents with perinatally acquired HIV
enter adolescence and young adulthood.53,54 Some studies suggest higher rates of adverse pregnancy
outcomes—such as small-for-gestational-age infants—among pregnant people with perinatally
acquired HIV than among those who acquired HIV by non-perinatal transmission. Unplanned
pregnancy is not uncommon in youth living with perinatally acquired HIV.54-56 One site serving
pregnant women with HIV in Baltimore reported higher rates of unintended pregnancy (83.6% vs.
68.8%, p = 0.016), lower viral suppression, and higher marijuana use during pregnancy in
adolescents with HIV compared to adults with HIV.57 Pregnant adolescents with perinatally acquired
HIV also may be more likely to have complex ARV histories, virologic failure, and drug resistance at
the time of pregnancy.57-59 However, the rate of perinatal transmission among pregnant people with
perinatally acquired HIV who are receiving ART appears to be similar to the rate among people on
ART who acquired HIV by non-perinatal transmission.60-64

Special Considerations for Adolescents With HIV Who Are Sexual Minorities
Adolescence is a period of emerging recognition of sexual identity. Adolescents with HIV who are
lesbian, gay, bisexual, transgender, or nonbinary require both culturally competent providers and
tailored medical care. Health care providers should ask patients nonjudgmental questions about their
sexual and gender identity to determine whether they require specific medical and support services. It
is important to consider the possibility of drug–drug interactions in adolescents who are receiving
both ART and gender-affirming hormone therapy. Additional resources for the care of these
adolescents can be found in the Adolescents and Young Adults With HIV section and the
Transgender People With HIV section of the Adult and Adolescent Antiretroviral Guidelines.

Transitioning Adolescents Into Adult HIV Care Settings

Transition to adult care is defined by Reiss et. al. as “a multifaceted, active process that attends to the
medical, psychosocial, cognitive and educational, or vocational needs of adolescents as they move
from the child- to the adult-focused health care system.”65 Facilitating a successful transition for
adolescents with HIV from their pediatric/adolescent care clinic to adult care is important, but
challenging.66-69 Many adolescents disengage from care during the transition to adult care, putting
them at risk for HIV progression and transmission to partners.70-72 Pediatric and adolescent care
providers and their multidisciplinary teams should have a formal written plan in place to transition
adolescents to adult care. Although transition generally occurs when individuals are in their late teens
or early 20s, discussion of and planning for the transition process should be initiated early in the teen
years, with involvement from both the adolescent and their parents and/or caregivers. Care models
for children and adolescents with perinatally acquired HIV tend to be family centered, consisting of a
multidisciplinary team that often includes physicians, nurses, social workers, and mental health
professionals. These providers generally have long-standing relationships with patients and their
families, and care is rendered in discreet, intimate settings. A recent qualitative metasynthesis of
adolescent transition studies demonstrated that established patient–provider relationships among

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-6
adolescents with HIV and their providers are integral to HIV care engagement and that collaborative
approaches to build trusted, new patient–provider relationships is necessary to support successful
transition.73 Although expert care also is provided under the adult HIV care medical model,
adolescents and their caregivers may be unfamiliar with the busier, more individual-centered clinics
that are typical of adult medical care providers. These providers often expect patients to assume a
greater level of responsibility for their care, and adolescents may be uncomfortable with providers
with whom they do not have a long-standing relationship.

One multisite study in the United States found that adolescents who transitioned to adult care at an
older age reported greater satisfaction with their care than those who transitioned at a younger age.
Additionally, adolescents who reported being able to perform certain tasks that were related to their
care (e.g., making appointments, requesting prescriptions, arranging transportation to appointments)
were more likely to be engaged in adult care.74 Assessments of transition readiness using
standardized tools are emerging as a potentially helpful part of the transition process and may be
predictive of HIV outcomes, including virologic failure post-transition.75,76 It may be beneficial to
provide adolescents, caregivers, and their new adult medical care providers with support and
guidance regarding the expectations for each person involved in the patient–provider relationship. In
this situation, it may be helpful for a pediatric care provider and an adult care provider to share joint
care of a patient for a period.

Adolescent care providers should have a candid discussion with the transitioning adolescent and their
caregivers to understand what qualities the adolescent considers most important when choosing an
adult care setting (e.g., confidentiality, small clinic size, low patient-to-provider ratio, availability of
after-school or evening appointments). Social determinants—such as the patient’s developmental
status, behavioral/mental health comorbidities, housing, family support, employment status, recent
discharge from foster care, peer pressure, illicit drug use, and incarceration—should be considered
during transition.

No definitive model of transition to adult HIV care currently exists, and only a limited number of
studies have reported on outcomes following transition, although research in this area is ongoing.
However, emerging qualitative research has revealed the importance of the patient–provider
relationship, including trust, the need for developmentally appropriate preparation for transition, and
opportunities for growth and independence.69,77 Recent studies have shown potential for successful
transition and ongoing retention using models that include a multidisciplinary approach, which
utilizes providers co-trained in both internal medicine and pediatrics, peer navigators, social workers,
mental health support, and a youth-focused care model for adolescents who were already attending
adult HIV clinics.78,79

Several studies have shown that youth with HIV who transitioned into adult care settings had higher
rates of attrition from care than those who remained in pediatric/adolescent care; U.S. studies show
that less than half of youth who transitioned care to an adult clinic remained in care after 9 to
12 months.70,71,80 In addition to poor retention in care, several studies have identified poor viral
suppression rates in transitioned youth and young adults with HIV.2 Pre-transition virologic failure
and longer linkage times have been associated with worse outcomes post-transition.69,72 Furthermore,
some reports from the United Kingdom suggest that the mortality rate of adolescents with HIV
increases after transition,26,72,81 underscoring the need to critically examine transition and determine
the best mechanisms to optimize the long-term outcomes for youth with perinatally acquired HIV.70

Some general guidelines, mostly based on anecdotal evidence and consensus expert opinion, are
available about transition plans and who might benefit most from them.67,82-89 To maximize the
likelihood of success, providers should prepare adolescents for transition long before it occurs.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-7
Attention to the following key areas could improve retention in care and minimize the risk of ART
interruptions:

• Educating HIV care teams and staff about transitioning;

• Beginning discussions about transition early, before the actual transition process;
• Developing a written, individualized transition plan to address comprehensive care needs,
including medical, psychosocial, and financial aspects of transitioning;
• Optimizing communication between providers at pediatric/adolescent clinics and providers at
adult clinics;
• Identifying adult care providers who are experts in providing care to adolescents and young
adults;
• Fostering a trusting patient–provider relationship with new adult care providers;
• Addressing barriers caused by a lack of information, stigma, or disclosure concerns;
• Discussing the differences between the practice styles of adult clinics and pediatric/adolescent
clinics;
• Helping youth develop the skills needed to manage their care, including counseling them on
appointment management, the appropriate use of a primary care provider, the importance of
prompt symptom recognition and reporting, and the importance of managing medications,
insurance, and state and federal benefits;
• Identifying an optimal clinic model for a given setting (e.g., simultaneous transition of mental
health and/or case management services versus a gradual phase-in);
• Clearly defining the desired outcomes for the transition, such as retention in care, ongoing access
to other services (e.g., case management, mental health), clinical outcomes (e.g., viral
suppression), and patient satisfaction;
• Implementing ongoing evaluations to measure the success of a transition model;
• Engaging in regular multidisciplinary case conferences between adult and adolescent care
providers;
• Implementing interventions that may be associated with improved outcomes, such as support
groups and mental health consultation; and
• Identifying a care navigator who can provide support during the transition.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-8
References

1. Van Dyke RB, Patel K, Siberry GK, et al. Antiretroviral treatment of U.S. children with
perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009
and predictors of immunologic and virologic outcomes. J Acquir Immune Defic Syndr.
2011;57(2):165-173. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21407086.

2. Xia Q, Shah D, Gill B, Torian LV, Braunstein SL. Continuum of care among people
living with perinatally acquired HIV infection in New York City, 2014. Public Health
Rep. 2016;131(4):566-573. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27453601.

3. Agwu AL, Fairlie L. Antiretroviral treatment, management challenges and outcomes in

perinatally HIV-infected adolescents. J Int AIDS Soc. 2013;16:18579. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23782477.

4. Judd A, Lodwick R, Noguera-Julian A, et al. Higher rates of triple-class virological

failure in perinatally HIV-infected teenagers compared with heterosexually infected
young adults in Europe. HIV Med. 2017;18(3):171-180. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27625109.

5. Hermetet-Lindsay KD, Correia KF, Williams PL, et al. Contributions of disease severity,
psychosocial factors, and cognition to behavioral functioning in U.S. youth perinatally
exposed to HIV. AIDS Behav. 2017;21(9):2703-2715. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27475941.

6. Tarantino N, Brown LK, Whiteley L, et al. Correlates of missed clinic visits among youth
living with HIV. AIDS Care. 2018;30(8):982-989. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29455553.

7. Bucek A, Leu CS, Benson S, et al. Psychiatric disorders, antiretroviral medication

adherence and viremia in a cohort of perinatally HIV-infected adolescents and young
adults. Pediatr Infect Dis J. 2018;37(7):673-677. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29227462.

8. Centers for Disease Control and Prevention. HIV surveillance supplemental report, 2018
(updated). 2020. Available at: https://www.cdc.gov/hiv/library/reports/hiv-
surveillance.html.

9. Rakhmanina N, Phelps BR. Pharmacotherapy of pediatric HIV infection. Pediatr Clin

North Am. 2012;59(5):1093-1115. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23036246.

10. Lowenthal ED, Ohrenshall R, Moshashane N, et al. Reasons for discordance between
antiretroviral adherence measures in adolescents. AIDS Care. 2021:1-9. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34424796.

11. Harris LL, Chernoff MC, Nichols SL, et al. Prospective memory in youth with
perinatally-acquired HIV infection. Child Neuropsychol. 2018;24(7):938-958. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/28782457.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-9
12. Rowe K, Buivydaite R, Heinsohn T, et al. Executive function in HIV-affected children
and adolescents: a systematic review and meta-analyses. AIDS Care. 2021;33(7):833-
857. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33764813.

13. Mellins CA, Tassiopoulos K, Malee K, et al. Behavioral health risks in perinatally HIV-
exposed youth: co-occurrence of sexual and drug use behavior, mental health problems,
and nonadherence to antiretroviral treatment. AIDS Patient Care STDS. 2011;25(7):413-
422. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21992620.

14. Gray KM, Ocfemia MCB, Wang X, Li J, Nesheim SR. Characteristics and care outcomes
among persons living with perinatally acquired HIV infection in the United States, 2015.
J Acquir Immune Defic Syndr. 2019;82(1):17-23. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31169773.

15. Kacanek D, Huo Y, Malee K, et al. Nonadherence and unsuppressed viral load across
adolescence among U.S. youth with perinatally acquired HIV. AIDS. 2019;33(12):1923-
1934. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31274538.

16. Lowenthal ED CJ, Calabrese K, et al. Adolescent and parent experiences with long-
acting injectables in the MOCHA study. Presented at CROI; February 11, 2022. Virtual.
Available at: https://www.natap.org/2022/CROI/croi_154.htm.

17. Moore C, Calabrese K, Brookie M, et al. Safety and PK of long-acting Cabotegravir and
Rilpivirine adolescents. Type Presented at CROI; February 11,2022, Year; Virtual.
Available at: https://www.croiconference.org/wp-
content/uploads/sites/2/resources/2022/croi2022-program-guide.pdf.

18. Mehra N, Tunje A, Hallstrom IK, Jerene D. Effectiveness of mobile phone text message
reminder interventions to improve adherence to antiretroviral therapy among adolescents
living with HIV: a systematic review and meta-analysis. PLoS One.
2021;16(7):e0254890. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34293033.

19. Neilan AM, Bangs AC, Hudgens M, et al. Modeling adherence interventions among
youth with HIV in the United States: clinical and economic projections. AIDS Behav.
2021;25(9):2973-2984. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33547993.

20. Mellins CA, Malee KM. Understanding the mental health of youth living with perinatal
HIV infection: lessons learned and current challenges. J Int AIDS Soc. 2013;16:18593.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/23782478.

21. Mellins CA, Brackis-Cott E, Leu CS, et al. Rates and types of psychiatric disorders in
perinatally human immunodeficiency virus-infected youth and seroreverters. J Child
Psychol Psychiatry. 2009;50(9):1131-1138. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19298479.

22. Gadow KD, Chernoff M, Williams PL, et al. Co-occuring psychiatric symptoms in
children perinatally infected with HIV and peer comparison sample. J Dev Behav
Pediatr. 2010;31(2):116-128. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20110828.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-10
23. Kreniske P, Mellins CA, Dolezal C, et al. Predictors of attempted suicide among youth
living with perinatal HIV infection and perinatal HIV-exposed uninfected counterparts. J
Acquir Immune Defic Syndr. 2021;88(4):348-355. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34406984.

24. Mallik I, Pasvol T, Frize G, et al. Psychotic disorders in young adults with perinatally
acquired HIV: a UK case series. Psychol Med. 2020:1-7. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33183361.

25. Kapetanovic S, Wiegand RE, Dominguez K, et al. Associations of medically documented

psychiatric diagnoses and risky health behaviors in highly active antiretroviral therapy-
experienced perinatally HIV-infected youth. AIDS Patient Care STDS. 2011;25(8):493-
501. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21745118.

26. Fish R, Judd A, Jungmann E, O’Leary C, Foster C, HIV Young Persons Network.
Mortality in perinatally HIV-infected young people in England following transition to
adult care: an HIV young persons network (HYPNet) audit. HIV Med. 2013;15(4):239-
244. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24112550.

27. Kim SH, Gerver SM, Fidler S, Ward H. Adherence to antiretroviral therapy in
adolescents living with HIV: systematic review and meta-analysis. AIDS.
2014;28(13):1945-1956. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24845154.

28. Saberi P, McCuistian C, Agnew E, et al. Video-counseling intervention to address HIV

care engagement, mental health, and substance use challenges: a pilot randomized
clinical trial for youth and young adults living with HIV. Telemed Rep. 2021;2(1):14-25.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/33575683.

29. Brown LK, Kennard BD, Emslie GJ, et al. Effective treatment of depressive disorders in
medical clinics for adolescents and young adults living with HIV: a controlled trial. J
Acquir Immune Defic Syndr. 2016;71(1):38-46. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26761270.

30. Benton TD, Kee Ng WY, Leung D, Canetti A, Karnik N. Depression among youth living
with HIV/AIDS. Child Adolesc Psychiatr Clin N Am. 2019;28(3):447-459. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31076119.

31. Brown LK, Chernoff M, Kennard BD, et al. Site-randomized controlled trial of a
combined cognitive behavioral therapy and a medication management algorithm for
treatment of depression among youth living with HIV in the United States. J Acquir
Immune Defic Syndr. 2021;88(5):497-505. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34483297.

32. Abrams EJ, Mellins CA, Bucek A, et al. Behavioral health and adult milestones in young
adults with perinatal HIV infection or exposure. Pediatrics. 2018;142(3). Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30097528.

33. Alperen J, Brummel S, Tassiopoulos K, et al. Prevalence of and risk factors for substance
use among perinatally human immunodeficiency virus-infected and perinatally exposed

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-11
 but uninfected youth. J Adolesc Health. 2014;54(3):341-349. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24239286.

34. Nichols SL, Brummel S, Malee KM, et al. The role of behavioral and neurocognitive
functioning in substance use among youth with perinatally acquired HIV infection and
perinatal HIV exposure without infection. AIDS Behav. 2021;25(9):2827-2840. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/33616833.

35. Williams PL, Leister E, Chernoff M, et al. Substance use and its association with
psychiatric symptoms in perinatally HIV-infected and HIV-affected adolescents. AIDS
Behav. 2010;14(5):1072-1082. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20725774.

36. Elkington KS, Cruz JE, Warne P, Santamaria EK, Dolezal C, Mellins CA. Marijuana use
and psychiatric disorders in perinatally HIV-exposed youth: does HIV matter? J Pediatr
Psychol. 2016;41(3):277-286. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26698841.

37. Knight JR, Shrier LA, Bravender TD, Farrell M, Vander Bilt J, Shaffer HJ. A new brief
screen for adolescent substance abuse. Arch Pediatr Adolesc Med. 1999;153(6):591-596.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/10357299.

38. Neilan AM, DeMonte JB, Foote JHA, et al. Rates of sexually transmitted infection
diagnoses among U.S. youth with perinatally and nonperinatally acquired HIV. Sex
Transm Dis. 2022;49(3):223-230. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34711773.

39. Loerinc L, Scheel A, Jordan-Thompson S, Gillespie S, Camacho-Gonzalez A. Incidence,

reinfection, and discrepancy between sexual practice and anatomic site positivity of
sexually transmitted infections in youth with HIV. Pediatr Infect Dis J. 2022;41(4):306-
311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34773398.

40. Sultan B, White JA, Fish R, et al. The “3 in 1” study: pooling self-taken pharyngeal,
urethral and rectal samples into a single sample for analysis, for diagnosis of Neisseria
gonorrhoeae and Chlamydia trachomatis in men who have sex with men (MSM). J Clin
Microbiol. 2015;54(3):650-656. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26719439.

41. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually
transmitted diseases treatment guidelines, 2015. MMWR Recomm Rep. 2015;64(RR-
03):1-137. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26042815.

42. Finer LB, Zolna MR. Declines in unintended pregnancy in the United States, 2008–2011.
N Engl J Med. 2016;374(9):843-852. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26962904.

43. Sutton MY, Patel R, Frazier EL. Unplanned pregnancies among HIV-infected women in
care-United States. J Acquir Immune Defic Syndr. 2014;65(3):350-358. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24189153.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-12
44. Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of
HIV-1 transmission. N Engl J Med. 2016;375(9):830-839. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27424812.

45. Centers for Disease Control and Prevention. Evidence of HIV treatment and viral
suppression in preventing the sexual transmission of HIV. 2018. Available at:
https://www.cdc.gov/hiv/risk/art/evidence-of-hiv-treatment.html

46. Marcell AV, Burstein GR, Committee On A. Sexual and reproductive health care
services in the pediatric setting. Pediatrics. 2017;140(5). Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29061870.

47. Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission.
Recommendations for the use of antiretroviral drugs during pregnancy and interventions
to reduce perinatal HIV transmission in the United States. 2021. Available at:
https://clinicalinfo.hiv.gov/en/guidelines/perinatal/guidelines-panel-members?view=full.

48. Sevinsky H, Eley T, Persson A, et al. The effect of efavirenz on the pharmacokinetics of
an oral contraceptive containing ethinyl estradiol and norgestimate in healthy HIV-
negative women. Antivir Ther. 2011;16(2):149-156. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21447863.

49. Zhang J, Chung E, Yones C, et al. The effect of atazanavir/ritonavir on the

pharmacokinetics of an oral contraceptive containing ethinyl estradiol and norgestimate
in healthy women. Antivir Ther. 2011;16(2):157-164. Available at:
https://ncbi.nlm.nih.gov/pubmed/21447864.

50. El-Ibiary SY, Cocohoba JM. Effects of HIV antiretrovirals on the pharmacokinetics of
hormonal contraceptives. Eur J Contracept Reprod Health Care. 2008;13(2):123-132.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/18465473.

51. Song IH, Borland J, Chen S, Wajima T, Peppercorn AF, Piscitelli SC. Dolutegravir has
no effect on the pharmacokinetics of oral contraceptives with norgestimate and ethinyl
estradiol. Ann Pharmacother. 2015;49(7):784-789. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25862012.

52. Patel R, Stalter R, Onono M, et al. Dolutegravir-containing ART does not reduce
etonogestrel implant concentrations. Abstract 129. Presented at: Conference on
Retroviruses and Opportunistic Infections 2020. Boston, MA. Available at:
https://www.croiconference.org/abstract/dolutegravir-containing-art-does-not-reduce-
etonogestrel-implant-concentrations.

53. Kenny J, Williams B, Prime K, Tookey P, Foster C. Pregnancy outcomes in adolescents

in the UK and Ireland growing up with HIV. HIV Med. 2012;13(5):304-308. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22136754.

54. Byrne L, Thorne C, Foster C, Tookey P. Pregnancy outcomes in women growing up with
perinatally acquired HIV in the United Kingdom and Ireland. J Int AIDS Soc. 2014;17(4
Suppl 3):19693. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25397443.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-13
55. Jao J, Agwu A, Mhango G, et al. Growth patterns in the first year of life differ in infants
born to perinatally vs. nonperinatally HIV-infected women. AIDS. 2015;29(1):111-116.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25562495.

56. Jao J, Sigel KM, Chen KT, et al. Small for gestational age birth outcomes in pregnant
women with perinatally acquired HIV. AIDS. 2012;26(7):855-859. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22313958.

57. Murphy E, Keller J, Argani C, et al. Pregnancy in an urban cohort of adolescents living
with human immunodeficiency virus: characteristics and outcomes in comparison to
adults. AIDS Patient Care STDS. 2021;35(4):103-109. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33835849.

58. Lazenby GB, Mmeje O, Fisher BM, et al. Antiretroviral resistance and pregnancy
characteristics of women with perinatal and nonperinatal HIV infection. Infect Dis Obstet
Gynecol. 2016;2016:4897501. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27413359.

59. Cruz ML, Santos E, Benamor Teixeira Mde L, et al. Viral suppression and resistance in a
cohort of perinatally-HIV infected (PHIV+) pregnant women. Int J Environ Res Public
Health. 2016;13(6). Available at: https://www.ncbi.nlm.nih.gov/pubmed/27338425.

60. Meloni A, Tuveri M, Floridia M, et al. Pregnancy care in two adolescents perinatally
infected with HIV. AIDS Care. 2009;21(6):796-798. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19806493.

61. Williams SF, Keane-Tarchichi MH, Bettica L, Dieudonne A, Bardeguez AD. Pregnancy
outcomes in young women with perinatally acquired human immunodeficiency virus-1.
Am J Obstet Gynecol. 2009;200(2):149 e141-145. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18973871.

62. Cruz ML, Cardoso CA, Joao EC, et al. Pregnancy in HIV vertically infected adolescents
and young women: a new generation of HIV-exposed infants. AIDS. 2010;24(17):2727-
2731. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20827164.

63. Elgalib A, Hegazi A, Samarawickrama A, et al. Pregnancy in HIV-infected teenagers in

London. HIV Med. 2011;12(2):118-123. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20807252.

64. Calitri C, Gabiano C, Galli L, et al. The second generation of HIV-1 vertically exposed
infants: a case series from the Italian register for paediatric HIV infection. BMC Infect
Dis. 2014;14:277. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24885649.

65. Reiss JG, Gibson RW, Walker LR. Health care transition: youth, family, and provider
perspectives. Pediatrics. 2005;115(1):112-120. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15629990.

66. Tepper V, Zaner S, Ryscavage P. HIV healthcare transition outcomes among youth in
North America and Europe: a review. J Int AIDS Soc. 2017;20(Suppl 3):60-70. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/28530041.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-14
67. Judd A, Davies MA. Adolescent transition among young people with perinatal HIV in
high-income and low-income settings. Curr Opin HIV AIDS. 2018;13(3):236-248.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29528851.

68. Foster C, Fidler S. Optimizing HIV transition services for young adults. Curr Opin Infect
Dis. 2018;31(1):33-38. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29210712.

69. Ritchwood TD, Malo V, Jones C, et al. Healthcare retention and clinical outcomes among
adolescents living with HIV after transition from pediatric to adult care: a systematic
review. BMC Public Health. 2020;20(1):1195. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32746881.

70. Ryscavage P, Macharia T, Patel D, Palmeiro R, Tepper V. Linkage to and retention in

care following healthcare transition from pediatric to adult HIV care. AIDS Care.
2016;28(5):561-565. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26766017.

71. Tanner AE, Philbin MM, Chambers BD, et al. Healthcare transition for youth living with
HIV: outcomes from a prospective multi-site study. J Adolesc Health. 2018;63(2):157-
165. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29887488.

72. Hussen SA, Chakraborty R, Knezevic A, et al. Transitioning young adults from paediatric
to adult care and the HIV care continuum in Atlanta, Georgia, USA: a retrospective
cohort study. J Int AIDS Soc. 2017;20(1):1-9. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28872281.

73. Barr EA, Raybin JL, Dunlevy H, Abuogi L, Jones J. Transition from pediatric and
adolescent HIV care to adult HIV care and the patient-provider relationship: a qualitative
metasynthesis. J Assoc Nurses AIDS Care. 2022;33(2):132-154. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33654006.

74. Tassiopoulos K, Huo Y, Patel K, et al. Healthcare transition outcomes among young
adults with perinatally acquired human immunodeficiency virus infection in the United
States. Clin Infect Dis. 2020;71(1):133-141. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31584617.

75. Zanoni BC, Archary M, Sibaya T, et al. Development and validation of the HIV
adolescent readiness for transition scale (HARTS) in South Africa. J Int AIDS Soc.
2021;24(7):e25767. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34235876.

76. Harris LR, Hoffman HJ, Griffith CJ, Lee N, Koay WLA, Rakhmanina NY. Factors
associated with transition of HIV care readiness among adolescents and youth from a
specialty pediatric HIV clinic in the United States. AIDS Patient Care STDS.
2021;35(12):495-502. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34851725.

77. Barr EA, Raybin JL, Dunlevy H, Abuogi L, Jones J. Transition from pediatric and
adolescent HIV care to adult HIV care and the patient-provider relationship: a qualitative
metasynthesis. J Assoc Nurses AIDS Care. 2021. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33654006.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-15
78. Griffith D, Jin L, Childs J, Posada R, Jao J, Agwu A. Outcomes of a comprehensive
retention strategy for youth with HIV after transfer to adult care in the United States.
Pediatr Infect Dis J. 2019;38(7):722-726. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30985513.

79. Griffith D, Snyder J, Dell S, Nolan K, Keruly J, Agwu A. Impact of a youth-focused care
model on retention and virologic suppression among young adults with HIV cared for in
an adult HIV clinic. J Acquir Immune Defic Syndr. 2019;80(2):e41-e47. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30422910.

80. Farmer C, Yehia BR, Fleishman JA, et al. Factors associated with retention among non-
perinatally HIV-infected youth in the HIV research network. J Pediatric Infect Dis Soc.
2016;5(1):39-46. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26908490.

81. Foster C, Ayers S, McDonald S, et al. Clinical outcomes post transition to adult services
in young adults with perinatally acquired HIV infection: mortality, retention in care and
viral suppression. AIDS. 2020;34(2):261-266. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31651427.

82. Rosen DS, Blum RW, Britto M, Sawyer SM, Siegel DM, Society for Adolescent
Medicine. Transition to adult health care for adolescents and young adults with chronic
conditions: position paper of the Society for Adolescent Medicine. J Adolesc Health.
2003;33(4):309-311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14519573.

83. Gilliam PP, Ellen JM, Leonard L, Kinsman S, Jevitt CM, Straub DM. Transition of
adolescents with HIV to adult care: characteristics and current practices of the adolescent
trials network for HIV/AIDS interventions. J Assoc Nurses AIDS Care. 2011;22(4):283-
294. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20541443.

84. New York State Department of Health AIDS Institute. Transitioning HIV-infected
adolescents into adult care. 2011. Available at:
https://www.medscape.com/viewarticle/748356_2.

85. Andiman WA. Transition from pediatric to adult healthcare services for young adults
with chronic illnesses: the special case of human immunodeficiency virus infection. J
Pediatr. 2011;159(5):714-719. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21868035.

86. Dowshen N, D’Angelo L. Health care transition for youth living with HIV/AIDS.
Pediatrics. 2011;128(4):762-771. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21930548.

87. Committee On Pediatric AIDS. Transitioning HIV-infected youth into adult health care.
Pediatrics. 2013;132(1):192-197. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23796739.

88. Sharer M, Fullem A. Transitioning of care and other services for adolescents living with
HIV in Sub-Saharan Africa. Arlington, VA: USAID’s AIDS Support and Technical
Assistance Resources, AIDSTAR-One, Task Order 1. 2012.Available at:

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-16
 https://www.socialserviceworkforce.org/resources/transitioning-care-and-other-services-
adolescents-living-hiv-sub-saharan-africa.

89. Hussen SA, Chahroudi A, Boylan A, Camacho-Gonzalez AF, Hackett S, Chakraborty R.

Transition of youth living with HIV from pediatric to adult-oriented healthcare: a review
of the literature. Future Virol. 2015;9(10):921-929. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25983853.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-17
Adherence to Antiretroviral Therapy in Children and
Adolescents With HIV
Updated: April 11, 2023
Reviewed: April 11, 2023

Panel’s Recommendations
• Strategies to maximize adherence should be discussed before and/or at initiation of antiretroviral therapy (ART) and before
changing regimens (AIII).
• Adherence to therapy must be assessed and promoted at each visit, and strategies to maintain and/or improve adherence
must be continually explored (AIII).
• In addition to viral load monitoring, at least one other method of measuring adherence to ART should be used (AIII).
• Once-daily antiretroviral regimens and regimens with a low pill burden should be prescribed whenever feasible (AII*).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints;
I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying
data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical
outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term
outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical
outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical
outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to postpubertal adolescents

Background
Adherence to antiretroviral therapy (ART) is a principal determinant of virologic suppression.
Suboptimal adherence may include missed or late doses, treatment interruptions and
discontinuations, and subtherapeutic or partial dosing.1,2 Poor adherence will result in subtherapeutic
plasma antiretroviral (ARV) drug concentrations, facilitating the development of resistance to one or
more drugs in a given ARV regimen and possible cross-resistance to other drugs in the same class.
Multiple factors—including regimen potency, pharmacokinetics, drug interactions, viral fitness, and
the genetic barrier to ARV resistance—influence the adherence–resistance relationship.3-5 In addition
to compromising the efficacy of the current regimen, suboptimal adherence can limit the options for
future effective ARV drug regimens in patients who develop multidrug-resistant HIV; it also can
increase the risk of secondary transmission of drug-resistant virus.

Poor adherence to ARV drugs is commonly encountered in the treatment of children and adolescents
with HIV. Medication formulation and palatability, frequency of dosing, side effects, drug toxicities
and a child’s age and developmental stage can affect adherence. In addition, many psychosocial,
behavioral, and structural barriers for children and caregivers have also been associated with
inadequate adherence. No consistent predictors of either good or poor adherence in children have
been identified.6-8 However, findings from the U.S. Pediatric HIV/AIDS Cohort Study (PHACS)
demonstrated that the prevalence of nonadherence increased with age. Among 381 children and
adolescents with perinatally acquired HIV, the prevalence of nonadherence increased from 31% to
50% (P < 0.001), and the prevalence of unsuppressed viral loads increased from 16% to 40%
(P < 0.001) between pre-adolescence and late adolescence/young adulthood.9 Similarly, in a report
from the Early Pediatric Initiation Canada Cure Cohort, only 73% of the children with perinatal HIV

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-1
initiated on ART maintained viral suppression 3 years after it was first achieved.10 Furthermore,
several studies have demonstrated that adherence is not static and can vary with time on treatment.11
Adolescents struggle with sustained adherence over time. In a study of 933 adolescents in South
Africa aged 10 to 19 years followed for a 3- to 4-year period, adherence was assessed at baseline and
two subsequent times via self-report of previous week ART adherence. Thirty-seven percent of
participants reported continued adherence at all three assessments. Both older age (P = 0.007)
participants and those with horizontally acquired HIV (P = 0.002) were more likely to report
inconsistent adherence across the three assessments12. These findings illustrate the difficulty of
maintaining high levels of adherence and underscore the need to support patients and their caregivers
in developing strategies for long-term adherence to ART.

Specific Adherence Issues in Children

Adherence is a complex health behavior that is influenced by drug regimen, patient and family
factors, and the patient–provider relationship.13,14 Despite improvements over the last several years,
the availability of once-daily and single-tablet ARV regimens and palatable formulations for infants
and young children are still limited. Furthermore, infants and children are dependent on others for
medication administration; adult caregivers may face barriers that undermine adherence in children,
including forgetting doses, changes in routine, being too busy, and child refusal.15,16 Caregivers also
may be inadequately prepared to support their child’s adherence. In a study of communication
strategies among caretakers of children with perinatally acquired HIV in rural South Africa, many
caregivers used coercion and threats of grave consequences of nonadherence as a communication
strategy to enforce adherence.17 Furthermore, some caregivers may place too much responsibility for
managing medications on older children and adolescents before they are developmentally able to
undertake such tasks.18

Adherence also may be jeopardized by social and health issues within a family (e.g., substance use,
poor physical or mental health, unstable housing, poverty, violence, involvement with the criminal
justice system, limited social support).19-22 Furthermore, children with perinatally acquired HIV and
adolescents with non-perinatally acquired HIV typically enter care at different developmental stages
with potentially different levels of caregiver support, which can affect adherence to ART in different
ways. For adolescents transitioning from pediatric to adult care, the transition can be a vulnerable
time for adherence. Such factors as changing providers, navigating the health care system as the
primary medical decision-maker, and changes in insurance status and prescription access can
precipitate interruptions in ART and barriers to optimal adherence. Immigrant children and
families—particularly, those who have recently immigrated—may face social and cultural issues and
language barriers, which can affect adherence.

Adherence Assessment and Monitoring

Providers should begin assessing potential barriers to adherence and discussing the importance of
adherence with patients at initiation of ART and when changing an ARV regimen. Evaluations
should assess psychosocial and behavioral factors that may influence adherence, and interventions to
help decrease these barriers should be supported. Providers should ask patients about their
experiences with taking medications, as well as concerns and expectations about treatment. Before
beginning treatment, it is important that the patient and/or caregiver explicitly agree to the treatment
plan, which should include strategies to support adherence. It is also important to alert patients and
caregivers to potential adverse effects (AEs) of ARV drugs (e.g., nausea, headaches, abdominal
discomfort, sleep disturbances), explain how they can be managed, and emphasize the importance of
informing the clinical team if they occur.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-2
A routine adherence assessment should be incorporated into every clinical visit. Adherence is
difficult to assess accurately; different methods of assessment have yielded different results, and each
approach has limitations.23-25 Viral load monitoring is the most useful indicator of adherence and is a
routine component of monitoring individuals who are on ART (see Plasma HIV-1 RNA [Viral Load]
and CD4 Count Monitoring in the Adult and Adolescent Antiretroviral Guidelines). It also can be
used as positive reinforcement to encourage continued adherence.26 In addition to viral load
monitoring, providers should use at least one other method to assess adherence, such as self-report of
missed doses.24 Table 15 below includes common approaches to monitoring medication adherence.
When assessing adherence, a nonjudgmental approach and positive rather than negative feedback can
be more successful in encouraging accurate reporting related to ART adherence.27

Strategies to Improve and Support Adherence

When concerns about adherence emerge, a patient should be seen and/or contacted frequently to
assess adherence. Strategies to improve and support adherence should be individualized to the child
and/or caregivers based on the barriers identified, developmental stage, and unique circumstances.
Strategies should include simplifying the ARV drug regimen, developing treatment plans that
integrate medication administration into daily routines (e.g., associating medication administration
with daily activities, such as brushing teeth), and optimizing the use of social and community support
services. Multifaceted approaches that include regimen-related strategies; educational, behavioral,
and supportive strategies focused on children and families; and strategies that focus on health care
providers may be more effective than one specific intervention. Table 16 below summarizes some of
the strategies that can be used to support and improve adherence to ARV medications. The Centers
for Disease Control and Prevention (CDC) offer the evidence-based Partnership for Health –
Medication Adherence to HIV care providers.28 A recent analysis using the Cost-Effectiveness of
Preventing AIDS Complications (CEPAC)–Adolescent model of HIV disease and treatment modeled
the impact of a 12-month hypothetical adherence intervention (based on an interactive smartphone-
based reminder system) among youth with HIV in the United States. Compared with the standard of
care, the analysis showed that youth-targeted adherence interventions, even with modest efficacy to
improve virologic suppression, could improve life expectancy, prevent onward HIV transmissions,
and be cost-effective.29

Regimen-Related Strategies
ARV regimens should be simplified with respect to the number of daily doses and number of pills or
volume of liquid prescribed. Efforts should be made to prescribe once-daily ARV regimens and
single-tablet regimens whenever feasible (see Table 18 in Management of Children Receiving
Antiretroviral Therapy). Several studies in adults have demonstrated better adherence with once-
daily ARV regimens than with twice-daily regimens, as well as with single-tablet formulations than
with multiple-tablet regimens.30-34 See Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose
Combination Tablets or as a Co-packaged Formulation, by Drug Class and Appendix A, Table 2.
Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body
Weights and Considerations for Use in Children and Adolescents for information about using FDC
tablets in children. The long-acting injectable formulation of cabotegravir and rilpivirine may be an
additional formulation option for patients (see Cabotegravir and Rilpivirine for eligibility criteria).

Drugs in the regimen should be chosen to minimize drug interactions and AEs (see Management of
Medication Toxicity or Intolerance).35 If drug-specific toxicities are thought to be contributing to
nonadherence, efforts should be made to alleviate the AEs by changing the particular drug (or, if
necessary, the drug regimen) when feasible . When nonadherence is related to the poor palatability of
a liquid formulation or crushed pills, the offending taste can sometimes be masked with a small

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-3
amount of flavoring syrup or food if simultaneous administration of food is not contraindicated
(see Appendix A: Pediatric Antiretroviral Drug Information).36 Unfortunately, the taste of
lopinavir/ritonavir cannot be masked with flavoring syrup. A small study of children and youth aged
4 years to 21 years found that training children to swallow pills was associated with improved
adherence at 6 months post-training.37

Patient/Family-Related Strategies
Patient and caregiver education is an essential component of establishing good medication adherence
in children. Educating families about adherence should begin before initiating or changing ARV
medications and should include a discussion of the goals of therapy, the importance of optimizing
adherence, and the specific plans for supporting and maintaining a child’s medication adherence.
Caregiver adherence education strategies should include written and visual materials; a daily
schedule illustrating times and doses of medications; and demonstration of the use of syringes,
medication cups, and pill boxes. Additionally, it may be helpful to assess the medication adherence
of the caregiver or other household members who currently take ARV drugs or other chronic
medications. Several behavioral tools can be used to integrate taking medications into a child’s daily
routine. The use of behavior modification techniques, especially the application of positive
reinforcements and the use of small incentives (including financial incentives) for taking
medications, can be effective tools to promote adherence.38

Because psychological issues and mental health disorders (e.g., depression, substance use) can affect
ART adherence, recognition and treatment of these conditions is an essential part of preventing and
treating nonadherence.39,40 The ability to talk with children about their medications is also important.
If the child has not been informed of their HIV status, HIV disclosure should be discussed with the
caregivers. In a recent review that explored the relationship between ART adherence and disclosure,
five studies linked disclosure to improved adherence, four studies found that disclosure led to worse
adherence among study participants, and five studies found no association.41 In interviews with
caregivers of children with HIV in South Africa, investigators found that caregivers who had
disclosed to their child that they (i.e., the child) were living with HIV were truthful in their
communications and named the disease as HIV, but communication about HIV was infrequent and
focused on pill taking. By comparison, those who had not disclosed used deception, deflection, and
coercion in response to health-related questions and to enforce adherence.17 The decision to disclose
HIV status should not necessarily be expected to improve adherence but should be based on a
comprehensive assessment of psychosocial and developmental factors and the needs of the child and
family.

In poorly adherent children who are at risk of disease progression and who have severe and persistent
aversion to taking medications, the use of a gastrostomy tube may be considered.42 The growing use
of telemedicine visits, which allow remote and often face-to-face interaction, provides new
opportunities to support families and visualize ART handling/swallowing, as well as to conduct
directly observed therapy (DOT) in the home setting. The evidence is mixed as to the efficacy of
programs that are designed to improve adherence through DOT, but DOT may still be a useful
strategy for some patients.43-45 Among 50 adolescents on atazanavir-based second-line therapy
participating in a study of modified directly administered ART (mDAART), there was a significant
increase in self-reported adherence (relative risk [RR] = 0.1; 95% confidence interval [CI], 0.02–0.8;
P = 0.023) but a nonsignificant increase in virological suppression to <1,000 copies/mL (P = 0.105)
among those randomized to the intervention arm compared to the standard of care arm.46 A recent
randomized controlled trial (RCT) of a 12-week multicomponent intervention—including remote
coaching, electronic dose monitoring, and tailored outreach (Triggered Escalating Real-Time

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-4
Adherence)—for viremic youth in the United States demonstrated improved adherence but not viral
suppression compared with the standard of care.21

Other strategies to support adherence include using mobile applications (apps) that remind patients to
take medications; setting cellphone alarms to go off at medication times; sending text-message
reminders; conducting motivational interviews; providing pill boxes, blister packaging, and other
adherence support tools; and delivering medications to the home. The CDC has an adherence toolkit,
that includes a free mobile app (Every Dose, Every Day (E2D2) Toolkit and App).

Several systematic reviews evaluating the use of mobile phone technologies to improve ART
adherence (mHealth) have been published. In a recent review, the authors found what they described
as “ambiguous results with high variability” about the effectiveness of mHealth interventions to
improve adherence in low- and middle-income countries.47 Of 17 studies, 56% reported a statistically
significant positive impact of mHealth on adherence; 44% reported insignificant results. Another
systematic review reported that the efficacy of mobile short message service (SMS) interventions
varied depending on the specific SMS intervention tested.48 A third systematic review of the
effectiveness of using mobile phone interventions to improve adherence to ART also reported mixed
results; effectiveness varied depending on the measured outcomes and the specific intervention
(e.g., whether the study evaluated the use of texts or the use of phone calls).49 It should be noted,
however, that the evidence base for effective adherence interventions in adolescents and young adults
who are taking daily ART is limited.50-56

Lowenthal et al. examined the association between medication-specific reactance—an aversive

response to perceived threats against personal agency—and treatment failure in a cohort of
adolescents with HIV in Botswana. Reactant individuals may hear health messaging as a threat to
their perceived freedom and respond by engaging in the opposed behavior. Adolescents, scoring >4
on a 5-point scale had 2.05-fold (95% CI, 1.23–3.41) greater odds of treatment failure than non-
reactant youth (P = 0.043). Psychological reactance needs further study and may provide some
insight into adherence behaviors among youth; it also may be important to consider in adherence
counseling and in designing interventions.57

Two recently published studies provided evidence of the efficacy of peer-based interventions to
improve ART adherence and viral suppression among adolescents and young people living with HIV
in Africa. In Project YES! in Ndola, Zambia, 273 youth aged 15 to 24 years receiving HIV care in
four health facilities, including a pediatric clinic, were randomly assigned to monthly meetings with
youth peer mentors. At 6 months, viral suppression improved in both study arms, but among
participants in care at the pediatric clinic, the rate of viral suppression increased from 37.5% to
70.5% in the intervention arm versus the comparison arm, 60.3% to 59.4% (interaction term odds
ratio, 4.66; 95% CI, 1.84–11.78).58 Mavhu et al. tested the efficacy of a peer-led differentiated
service delivery intervention on HIV clinical outcomes among adolescents with HIV aged 13 to
19 years in rural Zimbabwe. Sixteen clinics were randomized to standard of care or the enhanced
intervention in which adolescents were assigned a community adolescent treatment supporter;
attended monthly support group; and received text messages, calls, home visits, and clinic-based
counseling. Overall, 212 adolescents were recruited at intervention sites and 284 at control sites, with
a median age of 15 years. At 96 weeks, among 479 adolescents with data, 52 (25%) adolescents in
the intervention arm versus 97 (36%) in the control arm had viral load >1,000 copies/mL or had died
(adjusted prevalence ratio 0.58; 95% CI, 0.36–0.94; P = 0.03). The study reported 28 deaths (17 in
the intervention arm, 11 in the control arm) and 57 hospital admissions (20 in the intervention arm,
37 in the control arm). These studies demonstrate that peer-based interventions have the potential to
improve adherence and health outcomes among youth with HIV.59

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-5
In addition to clinic- and community-based programs, camp experiences can offer a source of peer
support for children and youth with HIV and other chronic illnesses. Although data are limited,60-62
many children and youth living with HIV report attendance to camp programs to be empowering and
helpful to learn about adherence to daily ART regimens.

Further evidence of the efficacy of peer-support interventions for people living with HIV comes from
a recent systematic review and meta-analysis, including 20 RCTs comprising 7,605 participants from
nine countries. The authors found superior retention in care (RR 1.07; 95% CI, 1.02–1.12 at
12 months follow-up) and better ART adherence (RR 1.06; 95% CI, 1.01–1.10 at 3 months follow-
up) but no statistically significant difference in viral suppression (RR = 1.02; 95% CI, 0.94–1.11 at
6 months follow-up) among peer-support participants.63

Health Care Provider–Related Strategies

To improve and support ART adherence, providers should maintain a nonjudgmental attitude,
establish trust with patients and caregivers, and identify mutually acceptable goals for care. Providers
can improve adherence through their relationships with patients and families, starting at the first visit
together when they obtain explicit agreement on the medication and treatment plan, as well as
strategies to support adherence. Fostering a trusting relationship and engaging in open
communication are particularly important. Focus groups and semi-structured interviews were
conducted with adolescents and their caregivers participating in a longitudinal adherence study.
Participants who self-reported high adherence but for whom electronically monitored data reflected
low adherence were selected. Adolescents described hiding and discarding pills and lying about their
adherence. Adolescents and parents considered negative feedback for prior poor adherence as
motivation for efforts to hide current poor adherence. The authors suggest that positive feedback for
truth-telling may help develop family and staff alliances in support of adherence.27

Provider characteristics that have been associated with improved patient adherence in adults include
consistency, willingness to give information and ask questions, technical expertise, and commitment
to follow-up. Creating an environment in the health care setting that is child-centered and includes
caregivers in adherence support also has been shown to improve treatment outcomes. Providing
comprehensive multidisciplinary care (e.g., with nurses, case managers, pharmacists, social workers,
psychiatric care providers) also may better serve more complex patient and family needs, including
adherence. Provider-initiated education about viral load and counseling targeted at understanding
viral load results, the health benefits of undetectable viral load, and the
undetectable = untransmittable (U=U) concept are other strategies providers can use.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-6
Table 15. Approaches for Monitoring Medication Adherence

Routine Assessment of Medication Adherence in

Description
Clinical Carea
Monitor viral load. Viral load monitoring should be done more frequently after
initiating or changing medications.a
Assess a quantitative self-report of missed doses. Ask the patient and/or caregiver about the number of missed
doses over a defined period (1, 3, or 7 days).
Request a description of the medication regimen. Ask the patient and/or caregiver about the name,
appearance, and number of medications and how often the
medications are taken.
Assess barriers to medication administration. Engage the patient and caregiver in a dialogue about
potential barriers to adherence and strategies to overcome
them.
Monitor pharmacy refills. Approaches include a pharmacy-based or clinic-based
assessment of on-time medication refills.
Employ telemedicine to monitor and support medication Telemedicine visits allow remote and often face-to-face
administration. contact and provide new opportunities to support families; to
visualize ART preparation, handling, and swallowing; and to
conduct DOT in the home setting.
Conduct announced and unannounced pill counts. Approaches include asking patients to bring medications to
the clinic, conducting home visits, or providing referral to
community health nursing.

Targeted Approaches to Monitoring Adherence in

Description
Special Circumstances
Implement DOT in person and via telemedicine. Include a brief period of hospitalization if indicated.
Measure drug concentration in plasma or DBS. Measuring drug concentrations can be considered for
particular drugs.

Approaches to Monitoring Medication Adherence

Description
in Research Settings
Measure drug concentrations in hair. Measuring hair drug concentrations can be considered for
particular drugs; it provides a good measure of adherence
over time.23,64,65
Use electronic monitoring devices. Approaches include MEMS caps and Wisepill.
Use mobile phone-based technologies. Approaches include interactive voice response, text
messaging, and mobile apps.
a.See Clinical and Laboratory Monitoring of Pediatric HIV Infection regarding the frequency of adherence assessment after
initiating or changing therapy.
Key: apps = applications; ART = antiretroviral therapy; DBS = dried blood spots; DOT = directly observed therapy;
MEMS = Medication Event Monitoring System

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-7
Table 16. Strategies to Improve Adherence to Antiretroviral Medications

Initial Intervention Strategies

• Establish trust and identify mutually acceptable goals for care.
• Obtain explicit agreement on the need for treatment and adherence.
• Determine whether the child is aware of their HIV status. Consider talking to the child’s caregivers about disclosing this
information to the child in a developmentally appropriate way.
• Identify psychosocial, behavioral, or structural barriers that may affect adherence and help child and/or family access
resources to help eliminate these barriers.
• Identify family, friends, health team members, and others who can support adherence.
• Educate the patient and family about the critical role of adherence in therapy outcome, including the relationship between
partial adherence and resistance and the potential impact on future drug regimen choices.
• With the patient and family together, develop a treatment plan that they believe is achievable.
• Work with the patient and family to make specific plans for taking medications as prescribed and for supporting adherence.
Assist them in arranging administration during day care, school, and in other settings, when needed. Consider home
delivery of medications.
• Identify barriers—such as co-pays and insurance access—related to medication access to help prevent interruptions in
ART.
• Schedule a home visit or telemedicine visit to review medications and determine how they will be administered in the home
setting.
• In certain circumstances, consider a brief period of hospitalization at the start of therapy for patient education and to
assess the tolerability of the chosen medications.

Medication Strategies
• Choose the simplest regimen possible; reduce dosing frequency, pill size, and number of pills (see Appendix A, Table 1.
Antiretrovirals Available in Fixed-Dose Combination Tablets or as a Co-packaged Formulation, by Drug Class and
Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body
Weights and Considerations for Use in Children and Adolescents).
• When choosing a regimen, consider the patient’s routines and potential variations in patient and family activities.
• Choose the most palatable medicine possible (pharmacists may be able to add syrups or flavoring agents to improve
palatability).
• Choose drugs with the fewest AEs; provide anticipatory guidance for managing AEs.
• Simplify food requirements for medication administration.
• Prescribe drugs carefully to avoid adverse drug–drug interactions.
• Assess pill-swallowing capacity and offer pill-swallowing training and aids (e.g., pill-swallowing cup, pill glide). Adjust pill
size as needed.
• Choose ARV regimens with high genetic barriers to resistance, when available, if there are concerns about adherence.

Follow-Up Intervention Strategies

• Members of the multidisciplinary team should monitor adherence at each visit. In between visits, adherence can be
monitored and supported by telephone, email, text, and other secure applications; confidentiality of any communication
approach must be ensured.
• Provide ongoing support, encouragement, and understanding of the difficulties associated with maintaining adherence to
daily medication regimens.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-8
 • Provide education and counseling that explain the meaning and significance of viral load results.
• Use patient education aids, including pictures, calendars, and stickers.
• Encourage the use of pill boxes, reminders, mobile apps, alarms, and resources such as the CDC’s Every Dose, Every
Day (E2D2) Toolkit and App.
• Provide follow-up clinic visits, telephone calls, text messages, and telemedicine visits to support and assess adherence.
• Provide access to support groups, peer groups, summer camp programs, or one-on-one counseling for caregivers and
patients.
• Provide referrals and support access to counseling and treatment services for individuals with identified mental health
problems, including depression and substance abuse.
• Provide pharmacist-based adherence support, such as medication education and counseling, blister packs, refill
reminders, automatic refills, and home delivery of medications.
• Consider DOT at home, in the clinic, or, in certain circumstances, during a brief period of inpatient hospitalization.
• Consider gastrostomy tube use in certain circumstances.
• Information on other interventions to consider can be found at the Complete Listing of Medication Adherence Evidence-
Based Behavioral Interventions on the CDC’s website.
Key: apps = applications; AE = adverse effect; ARV = antiretroviral; CDC = Centers for Disease Control and Prevention;
DOT = directly observed therapy

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-9
References

1. Vreeman RC, Nyandiko WM, Liu H, et al. Measuring adherence to antiretroviral therapy
in children and adolescents in western Kenya. J Int AIDS Soc. 2014;17:19227. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/25427633.

2. Hawkins A, Evangeli M, Sturgeon K, Le Prevost M, Judd A, Aalphi Steering Committee.

Episodic medication adherence in adolescents and young adults with perinatally acquired
HIV: a within-participants approach. AIDS Care. 2016;28 Suppl 1:68-75. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26886514.

3. Gardner EM, Burman WJ, Steiner JF, Anderson PL, Bangsberg DR. Antiretroviral
medication adherence and the development of class-specific antiretroviral resistance.
AIDS. 2009;23(9):1035-1046. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19381075.

4. Judd A, Melvin D, Thompson LC, et al. Factors associated with nonadherence to

antiretroviral therapy among young people living with perinatally acquired HIV in
England. J Assoc Nurses AIDS Care. 2020;31(5):574-586. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32467489.

5. Parienti JJ, Fournier AL, Cotte L, et al. Forgiveness of dolutegravir-based triple therapy
compared with older antiretroviral regimens: a prospective multicenter cohort of
adherence patterns and HIV-RNA replication. Open Forum Infect Dis.
2021;8(7):ofab316. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34307726.

6. MacDonell KK, Jacques-Tiura AJ, Naar S, Fernandez MI, Team ATNP. Predictors of
self-reported adherence to antiretroviral medication in a multisite study of ethnic and
racial minority HIV-positive youth. J Pediatr Psychol. 2016;41(4):419-428. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26498724.

7. Gray ME, Nieburg P, Dillingham R. Pediatric human immunodeficiency virus continuum

of care: a concise review of evidence-based practice. Pediatr Clin North Am.
2017;64(4):879-891. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28734516.

8. Schlatter AF, Deathe AR, Vreeman RC. The need for pediatric formulations to treat
children with HIV. AIDS Res Treat. 2016;2016:1654938. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27413548.

9. Kacanek D, Huo Y, Malee K, et al. Nonadherence and unsuppressed viral load across
adolescence among U.S. youth with perinatally acquired HIV. AIDS. 2019;33(12):1923-
1934. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31274538.

10. Kakkar F, Lee T, Hawkes MT, et al. Challenges to achieving and maintaining viral
suppression among children living with HIV. AIDS. 2020;34(5):687-697. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31794519.

11. Giannattasio A, Albano F, Giacomet V, Guarino A. The changing pattern of adherence to

antiretroviral therapy assessed at two time points, 12 months apart, in a cohort of HIV-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-10
 infected children. Expert Opin Pharmacother. 2009;10(17):2773-2778. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19929700.

12. Zhou S, Cluver L, Shenderovich Y, Toska E. Uncovering ART adherence

inconsistencies: An assessment of sustained adherence among adolescents in South
Africa. J Int AIDS Soc. 2021;24(10):e25832. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34708912.

13. Haberer J, Mellins C. Pediatric adherence to HIV antiretroviral therapy. Curr HIV/AIDS
Rep. 2009;6(4):194-200. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19849962.

14. Shubber Z, Mills EJ, Nachega JB, et al. Patient-reported barriers to adherence to
antiretroviral therapy: a systematic review and meta-analysis. PLoS Med.
2016;13(11):e1002183. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27898679.

15. Marhefka SL, Koenig LJ, Allison S, et al. Family experiences with pediatric antiretroviral
therapy: responsibilities, barriers, and strategies for remembering medications. AIDS
Patient Care STDS. 2008;22(8):637-647. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18627275.

16. Skovdal M, Campbell C, Madanhire C, Nyamukapa C, Gregson S. Challenges faced by

elderly guardians in sustaining the adherence to antiretroviral therapy in HIV-infected
children in Zimbabwe. AIDS Care. 2011;23(8):957-964. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21400306.

17. Molokwane M, Madiba S. Truth, deception, and coercion; communication strategies used
by caregivers of children with perinatally acquired HIV during the pre-disclosure and
post-disclosure period in rural communities in South Africa. Glob Pediatr Health.
2021;8:2333794X211022269. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34104705.

18. Naar-King S, Montepiedra G, Nichols S, et al. Allocation of family responsibility for

illness management in pediatric HIV. J Pediatr Psychol. 2009;34(2):187-194. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/18586756.

19. Cluver LD, Hodes RJ, Toska E, et al. ‘HIV is like a tsotsi. ARVs are your guns’:
associations between HIV-disclosure and adherence to antiretroviral treatment among
adolescents in South Africa. AIDS. 2015;29 Suppl 1:S57-65. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26049539.

20. Cluver L, Meinck F, Toska E, Orkin FM, Hodes R, Sherr L. Multitype violence
exposures and adolescent antiretroviral nonadherence in South Africa. AIDS.
2018;32(8):975-983. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29547438.

21. Amico KR, Crawford J, Ubong I, et al. Correlates of high HIV viral load and
antiretroviral therapy adherence among viremic youth in the United States enrolled in an
adherence improvement intervention. AIDS Patient Care STDS. 2021;35(5):145-157.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/33960843.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-11
22. Haas AD, Technau KG, Pahad S, et al. Mental health, substance use and viral
suppression in adolescents receiving ART at a paediatric HIV clinic in South Africa. J Int
AIDS Soc. 2020;23(12):e25644. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33283916.

23. Pintye J, Bacchetti P, Teeraananchai S, et al. Brief report: lopinavir hair concentrations
are the strongest predictor of viremia in HIV-infected Asian children and adolescents on
second-line antiretroviral therapy. J Acquir Immune Defic Syndr. 2017;76(4):367-371.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28825944.

24. Al-Hassany L, Kloosterboer SM, Dierckx B, Koch BC. Assessing methods of measuring
medication adherence in chronically ill children-a narrative review. Patient Prefer
Adherence. 2019;13:1175-1189. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31413546.

25. Craker L, Tarantino N, Whiteley L, Brown L. Measuring antiretroviral adherence among

young people living with HIV: observations from a real-time monitoring device versus
self-report. AIDS Behav. 2019;23(8):2138-2145. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30888573.

26. Bonner K, Mezochow A, Roberts T, Ford N, Cohn J. Viral load monitoring as a tool to
reinforce adherence: a systematic review. J Acquir Immune Defic Syndr. 2013;64(1):74-
78. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23774877.

27. Lowenthal ED, Ohrenshall R, Moshashane N, et al. Reasons for discordance between
antiretroviral adherence measures in adolescents. AIDS Care. 2021:1-9. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34424796.

28. Centers for Disease Control and Prevention. Medication adherence. 2014. Available at:
https://www.cdc.gov/hiv/effective-interventions/treat/pfh-ma/index.html.

29. Neilan AM, Bangs AC, Hudgens M, et al. Modeling adherence interventions among
youth with HIV in the United States: clinical and economic projections. AIDS Behav.
2021;25(9):2973-2984. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33547993.

30. Nachega JB, Parienti JJ, Uthman OA, et al. Lower pill burden and once-daily
antiretroviral treatment regimens for HIV infection: a meta-analysis of randomized
controlled trials. Clin Infect Dis. 2014;58(9):1297-1307. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24457345.

31. Clay PG, Nag S, Graham CM, Narayanan S. Meta-analysis of studies comparing single
and multi-tablet fixed dose combination HIV treatment regimens. Medicine (Baltimore).
2015;94(42):e1677. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26496277.

32. Pantuzza LL, Ceccato M, Silveira MR, Junqueira LMR, Reis AMM. Association between
medication regimen complexity and pharmacotherapy adherence: a systematic review.
Eur J Clin Pharmacol. 2017;73(11):1475-1489. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28779460.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-12
33. Griffith DC, Farmer C, Gebo KA, et al. Uptake and virological outcomes of single-
versus multi-tablet antiretroviral regimens among treatment-naive youth in the HIV
Research Network. HIV Med. 2019;20(2):169-174. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30561888.

34. Altice F, Evuarherhe O, Shina S, Carter G, Beaubrun AC. Adherence to HIV treatment
regimens: systematic literature review and meta-analysis. Patient Prefer Adherence.
2019;13:475-490. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31040651.

35. Pham PA. Antiretroviral adherence and pharmacokinetics: review of their roles in
sustained virologic suppression. AIDS Patient Care STDS. 2009;23(10):803-807.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19795999.

36. Czyzewski D, Runyan D, Lopez M, et al. Teaching and maintaining pill swallowing in
HIV-infected children. The AIDS Reader. 2000;10(2):88-94. Available at:
https://www.scinapse.io/papers/2972005888.

37. Garvie PA, Lensing S, Rai SN. Efficacy of a pill-swallowing training intervention to
improve antiretroviral medication adherence in pediatric patients with HIV/AIDS.
Pediatrics. 2007;119(4):e893-899. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17353298.

38. Foster C, McDonald S, Frize G, Ayers S, Fidler S. "Payment by results"--financial

incentives and motivational interviewing, adherence interventions in young adults with
perinatally acquired HIV-1 infection: a pilot program. AIDS Patient Care STDS.
2014;28(1):28-32. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24428797.

39. Sin NL, DiMatteo MR. Depression treatment enhances adherence to antiretroviral
therapy: a meta-analysis. Ann Behav Med. 2014;47(3):259-269. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24234601.

40. Bucek A, Leu CS, Benson S, et al. Psychiatric disorders, antiretroviral medication
adherence and viremia in a cohort of perinatally HIV-infected adolescents and young
adults. Pediatr Infect Dis J. 2018;37(7):673-677. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29227462.

41. Nichols J, Steinmetz A, Paintsil E. Impact of HIV-status disclosure on adherence to

antiretroviral therapy among HIV-infected children in resource-limited settings: a
systematic review. AIDS Behav. 2017;21(1):59-69. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27395433.

42. Shingadia D, Viani RM, Yogev R, et al. Gastrostomy tube insertion for improvement of
adherence to highly active antiretroviral therapy in pediatric patients with human
immunodeficiency virus. Pediatrics. 2000;105(6):E80. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/10835093.

43. Bain-Brickley D, Butler LM, Kennedy GE, Rutherford GW. Interventions to improve
adherence to antiretroviral therapy in children with HIV infection. Cochrane Database
Syst Rev. 2011;12(12):CD009513. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22161452.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-13
44. Gaur AH, Belzer M, Britto P, et al. Directly observed therapy (DOT) for nonadherent
HIV-infected youth: lessons learned, challenges ahead. AIDS Res Hum Retroviruses.
2010;26(9):947-953. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20707731.

45. Hart JE, Jeon CY, Ivers LC, et al. Effect of directly observed therapy for highly active
antiretroviral therapy on virologic, immunologic, and adherence outcomes: a meta-
analysis and systematic review. J Acquir Immune Defic Syndr. 2010;54(2):167-179.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20375848.

46. Chawana TD, Katzenstein D, Nathoo K, Ngara B, Nhachi CFB. Evaluating an enhanced
adherence intervention among HIV positive adolescents failing atazanavir/ritonavir-based
second line antiretroviral treatment at a public health clinic. J AIDS HIV Res.
2017;9(1):17-30. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31649827.

47. Demena BA, Artavia-Mora L, Ouedraogo D, Thiombiano BA, Wagner N. A systematic

review of mobile phone interventions (SMS/IVR/calls) to improve adherence and
retention to antiretroviral treatment in low-and middle-income countries. AIDS Patient
Care STDS. 2020;34(2):59-71. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32049555.

48. Amankwaa I, Boateng D, Quansah DY, Akuoko CP, Evans C. Effectiveness of short
message services and voice call interventions for antiretroviral therapy adherence and
other outcomes: A systematic review and meta-analysis. PLoS One.
2018;13(9):e0204091. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30240417.

49. Shah R, Watson J, Free C. A systematic review and meta-analysis in the effectiveness of
mobile phone interventions used to improve adherence to antiretroviral therapy in HIV
infection. BMC Public Health. 2019;19(1):915. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31288772.

50. Shaw S, Amico KR. Antiretroviral therapy adherence enhancing interventions for
adolescents and young adults 13–24 years of age: a review of the evidence base. J Acquir
Immune Defic Syndr. 2016;72(4):387-399. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26959190.

51. Judd A, Sohn AH, Collins IJ. Interventions to improve treatment, retention and survival
outcomes for adolescents with perinatal HIV-1 transitioning to adult care: moving on up.
Curr Opin HIV AIDS. 2016;11(5):477-486. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27272537.

52. MacPherson P, Munthali C, Ferguson J, et al. Service delivery interventions to improve

adolescents’ linkage, retention and adherence to antiretroviral therapy and HIV care.
Trop Med Int Health. 2015;20(8):1015-1032. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25877007.

53. Kanters S, Park JJ, Chan K, et al. Interventions to improve adherence to antiretroviral
therapy: a systematic review and network meta-analysis. Lancet HIV. 2017;4(1):e31-e40.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27863996.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-14
54. Camacho-Gonzalez AF, Gillespie SE, Thomas-Seaton L, et al. The Metropolitan Atlanta
community adolescent rapid testing initiative study: closing the gaps in HIV care among
youth in Atlanta, Georgia, USA. AIDS. 2017;31 Suppl 3:S267-S275. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28665885.

55. Casale M, Carlqvist A, Cluver L. Recent interventions to improve retention in HIV care
and adherence to antiretroviral treatment among adolescents and youth: a systematic
review. AIDS Patient Care STDS. 2019;33(6):237-252. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31166783.

56. Abiodun O, Ladi-Akinyemi B, Olu-Abiodun O, et al. A single-blind, parallel design RCT

to assess the effectiveness of SMS reminders in improving ART adherence among
adolescents living with HIV (STARTA trial). J Adolesc Health. 2021;68(4):728-736.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/33342719.

57. Lowenthal E, Matesva M, Marukutira T, et al. Psychological reactance is a novel risk

factor for adolescent antiretroviral treatment failure. AIDS Behav. 2021;25(5):1474-1479.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/32754779.

58. Denison JA, Burke VM, Miti S, et al. Correction: project YES! youth engaging for
success: a randomized controlled trial assessing the impact of a clinic-based peer
mentoring program on viral suppression, adherence and internalized stigma among HIV-
positive youth (15–24 years) in Ndola, Zambia. PLoS One. 2020;15(4):e0232488.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/32324830.

59. Mavhu W, Willis N, Mufuka J, et al. Effect of a differentiated service delivery model on
virological failure in adolescents with HIV in Zimbabwe (Zvandiri): a cluster-randomised
controlled trial. Lancet Glob Health. 2020;8(2):e264-e275. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31924539.

60. Ness TE, Agrawal V, Guffey D, et al. Impact of using creative arts programming to
support HIV treatment in adolescents and young adults in Eswatini. AIDS Res Ther.
2021;18(1):100. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34930371.

61. Gillard A, Witt PA, Watts CE. Outcomes and processes at a camp for youth with
HIV/AIDS. Qual Health Res. 2011;21(11):1508-1526. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21709127.

62. Evangeli M, Lut I, Ely A. A longitudinal evaluation of an intensive residential

intervention (camp) for 12–16 year olds living with HIV in the UK: evidence of
psychological change maintained at six month follow-up. AIDS Care. 2019;31(1):85-89.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30045639.

63. Berg RC, Page S, Ogard-Repal A. The effectiveness of peer-support for people living
with HIV: a systematic review and meta-analysis. PLoS One. 2021;16(6):e0252623.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/34138897.

64. Olds PK, Kiwanuka JP, Nansera D, et al. Assessment of HIV antiretroviral therapy
adherence by measuring drug concentrations in hair among children in rural Uganda.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-15
 AIDS Care. 2015;27(3):327-332. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25483955.

65. Chawana TD, Gandhi M, Nathoo K, et al. Defining a cutoff for atazanavir in hair samples
associated with virological failure among adolescents failing second-line antiretroviral
treatment. J Acquir Immune Defic Syndr. 2017;76(1):55-59. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28520618.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-16
Management of Medication Toxicity or Intolerance
Updated: April 11, 2023
Reviewed: April 11, 2023

Panel’s Recommendations
• In children with HIV who have severe or life-threatening toxicity (e.g., a hypersensitivity reaction), all antiretroviral (ARV) drugs
should be stopped immediately (AIII). Once symptoms of toxicity have resolved, ARV therapy should be resumed with
substitution of a different ARV drug or drugs for the offending agent(s) (AII*).
• When modifying ARV therapy because of toxicity or intolerance to a specific drug in children with virologic suppression,
changing one drug in a multidrug regimen is permissible; if possible, an agent with a different toxicity and adverse effect profile
should be chosen (AI*).
• The toxicity and the medication presumed responsible should be documented in the medical record of the patient, and the
caregiver and patient should be advised of the drug-related toxicity (AIII).
• In general, dose reduction is not a recommended option for management of ARV toxicity (AII*).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints; I* = One or
more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying data in children†
from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical outcomes; II = One or
more well-designed, nonrandomized trials or observational cohort studies in children† with long-term outcomes; II* = One or more
well-designed, nonrandomized trials or observational studies in adults with long-term clinical outcomes with accompanying data in
children† from one or more similar nonrandomized trials or cohort studies with clinical outcome data; III = Expert opinion
† Studies that include children or children/adolescents but not studies limited to postpubertal adolescents

Medication Toxicity or Intolerance

The overall benefits of viral suppression and improved immune function because of effective
antiretroviral therapy (ART) far outweigh the risks associated with the adverse effects (AEs) of some
antiretroviral (ARV) drugs. AEs have been reported, however, with the use of all ARV drugs. Currently
recommended ARV regimens are associated with fewer serious and intolerable AEs than regimens used
in the past. In the mid-1990s when combination ART was introduced, AEs were among the most
common reasons for switching or discontinuing therapy and for medication nonadherence1-3 (see Adverse
Effects of Antiretroviral Agents in the Adult and Adolescent Antiretroviral Guidelines). In recent clinical
trials, however, <10% of ARV-treated patients had treatment-limiting AEs.4-14

The incidence of some longer-term complications of ART (e.g., bone or renal toxicity, dyslipidemia,
accelerated cardiovascular disease) might be underestimated, because most clinical trials enroll a select
group of patients based on highly specific inclusion criteria and the duration of participant follow-up is
relatively short.6,7,15-17 To achieve sustained viral suppression during a child’s lifetime, both short- and
long-term ART toxicities must be anticipated. The clinician must consider potential AEs and issues with
medication palatability when selecting an ARV regimen, as well as the individual child’s comorbidities,
concomitant medications, and history of drug intolerance or viral resistance.

The AEs caused by ARV drugs can vary from mild, more common symptoms (e.g., gastrointestinal
intolerance, fatigue) to infrequent but severe and life-threatening, illness. Drug-related toxicity can be
acute (i.e., occurring soon after a drug has been administered), subacute (i.e., occurring within 1 day to
2 days after administration), or late (i.e., occurring after prolonged drug administration). For a few ARV
medications, pharmacogenetic markers associated with the risk of early toxicity have been identified;

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-1
however, the only marker that is routinely screened for is HLA-B*5701, a marker for abacavir (ABC)
hypersensitivity.18 For selected children aged <3 years who require treatment with efavirenz (EFV), an
additional pharmacogenetic marker, cytochrome P450 (CYP) 2B6 genotype, should be assessed in an
attempt to prevent toxicity18-22 (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information).
For agents such as EFV, therapeutic ranges for plasma concentrations, as determined by therapeutic drug
monitoring (TDM), may indicate the need for dose reduction or modification of ART in patients who
experience central nervous system (CNS) AEs.

The most common acute and chronic AEs that are associated with currently recommended ARV drugs or
drug classes are presented in Tables 17a–17k, which are listed below. These tables include information
on common causative drugs, estimated frequency of occurrence, timing of symptoms, risk factors,
potential preventive measures, and suggested clinical management strategies. The tables also include
selected references that provide further information about these toxicities in pediatric patients.

• Table 17a. Central Nervous System Toxicity

• Table 17b. Dyslipidemia
• Table 17c. Gastrointestinal Effects
• Table 17d. Hematologic Effects
• Table 17e. Hepatic Events
• Table 17f. Insulin Resistance, Asymptomatic Hyperglycemia, and Diabetes Mellitus
• Table 17g. Lactic Acidosis
• Table 17h. Lipodystrophies and Weight Gain
• Table 17i. Nephrotoxic Effects
• Table 17j. Osteopenia and Osteoporosis
• Table 17k. Rash and Hypersensitivity Reactions

Information on toxicities associated with older ARV drugs that are no longer recommended can be found
in the Archived Drugs section and archived toxicity tables.

Management
ART-associated AEs can range from acute and potentially life threatening, to chronic and insidious.
Serious life-threatening events (e.g., hypersensitivity reaction [HSR] due to ABC, symptomatic
hepatotoxicity, severe cutaneous reactions) require the immediate discontinuation of all ARV drugs and
re-initiation of an alternative regimen without overlapping toxicity. Toxicities that are not life threatening
(e.g., urolithiasis caused by atazanavir, renal tubulopathy caused by tenofovir disoproxil fumarate)
usually can be managed by substituting another ARV agent for the presumed causative agent without
interrupting ART. Other chronic, non–life-threatening AEs (e.g., dyslipidemia, weight gain) can be
addressed either by switching the potentially causative agent for another agent or by managing the AE
with additional pharmacological or nonpharmacological interventions, such as lifestyle modification.

Management strategies must be individualized for each child, taking into account the severity of the
toxicity, the child’s viral suppression status, and the available ARV options. Clinicians should anticipate
the appearance of common, self-limited AEs and reassure patients that many AEs will resolve after the
first few weeks of ART. For example, when initiating therapy with boosted protease inhibitors (PIs),
many patients experience gastrointestinal AEs, such as nausea, vomiting, diarrhea, and abdominal pain.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-2
Instructing patients to take PIs with food may help minimize these AEs. Some patients may require
antiemetic and antidiarrheal agents for symptom management. CNS AEs are encountered commonly
when initiating therapy with EFV. Symptoms can include dizziness, drowsiness, vivid dreams, or
insomnia. Patients should be instructed to take EFV-containing regimens at bedtime and on an empty
stomach to help minimize these AEs. Patients should be advised that these AEs usually diminish within
2 to 4 weeks of initiating therapy in most people; however, they may persist for months in some patients
and may require a medication change.23 In addition, mild rash can be ameliorated with drugs, such as
antihistamines. Addressing AEs is essential, because continued use of an ARV agent that a patient finds
intolerable may lead the patient to stop their treatment, risking viral rebound and the development of
drug resistance.

In patients who experience intolerable AEs from ART, every attempt should be made to identify the
offending agent and to replace the drug with another effective agent as soon as possible.9,24 For mild-to-
moderate toxicities, changing to a drug with a different toxicity profile might be sufficient, and
discontinuation of all therapy might not be required. When interrupting a non-nucleoside reverse
transcriptase inhibitor (NNRTI)-based regimen, many experts will stop the NNRTI for 7 to 14 days
before stopping the dual nucleoside analogue reverse transcriptase backbone, because of the long half-
life of NNRTI drugs. However, patients who have a severe or life-threatening toxicity (e.g., HSR—see
Table 17k. Rash and Hypersensitivity Reactions) should stop all components of the drug regimen
simultaneously, regardless of drug half-life. Once the offending drug or alternative cause for the AE has
been determined, planning can begin for—

• Resuming therapy with a new ARV regimen that does not contain the offending drug, or
• Resuming therapy with the original regimen if the event is attributable to another cause.

All drugs in the ARV regimen should then be started simultaneously, rather than one at a time, while
observing the patient for AEs.

When therapy is changed because of toxicity or intolerance in a patient with virologic suppression,
agents with different toxicity and AE profiles should be chosen, when possible.25-28 Clinicians should
have comprehensive knowledge of the toxicity profile of each agent before selecting a new regimen. In
the event of drug intolerance, changing a single drug in a multidrug regimen is permissible only for
patients whose viral loads are undetectable.

In general, dose reduction is not a recommended strategy for toxicity management, because inadequate
ARV drug levels may lead to decreased virologic efficacy and, for most agents, there is not a clear
relationship between drug levels and the AE. Therefore, TDM is rarely recommended; however, it may
be considered to assist in the management for a child with mild or moderate toxicity if the toxicity is
thought to be the result of a drug concentration exceeding the normal therapeutic range and other ARV
options are limited.29-31 An expert in the management of pediatric HIV should be consulted when
considering dose reduction based on the results of TDM. Dose reduction after TDM has been studied
most extensively with EFV, because increased CNS toxicity has clearly been associated with higher
levels of EFV (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information).

To summarize, management strategies for drug intolerance include the following:

• Symptomatic treatment of mild-to-moderate, transient AEs.

• Switching one drug for another drug that is active against a patient’s virus (e.g., changing to ABC for
zidovudine-related anemia or to a PI or integrase strand transfer inhibitor for EFV-related CNS

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-3
 symptoms) (see Modifying Antiretroviral Regimens in Children With Sustained Virologic
Suppression on Antiretroviral Therapy).
• Using dose reduction, guided by TDM, after consulting with an expert in pediatric HIV.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-4
References

1. Desta Z, Gammal RS, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium

(CPIC) guideline for CYP2B6 and efavirenz-containing antiretroviral therapy. Clin
Pharmacol Ther. 2019;106(4):726-733. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31006110.

2. Szpak R, Lombardi NF, Dias FA, Borba HHL, Pontarolo R, Wiens A. Safety of antiretroviral
therapy in the treatment of HIV/AIDS in children: systematic review and meta-analysis.
AIDS Rev. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34082441.

3. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents adults and adolescents with HIV. 2022. Available at:
https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-
arv/whats-new-guidelines

4. Tukei VJ, Asiimwe A, Maganda A, et al. Safety and tolerability of antiretroviral therapy
among HIV-infected children and adolescents in Uganda. J Acquir Immune Defic Syndr.
2012;59(3):274-280. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22126740.

5. Arrow Trial team, Kekitiinwa A, Cook A, et al. Routine versus clinically driven laboratory
monitoring and first-line antiretroviral therapy strategies in African children with HIV
(ARROW): a 5-year open-label randomised factorial trial. Lancet. 2013;381(9875):1391-
1403. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23473847.

6. Barlow-Mosha L, Eckard AR, McComsey GA, Musoke PM. Metabolic complications and
treatment of perinatally HIV-infected children and adolescents. J Int AIDS Soc.
2013;16(1):18600. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23782481.

7. Purswani M, Patel K, Kopp JB, et al. Tenofovir treatment duration predicts proteinuria in a
multiethnic United States cohort of children and adolescents with perinatal HIV-1 infection.
Pediatr Infect Dis J. 2013;32(5):495-500. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23249917.

8. Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine

and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis.
AIDS. 2013;27(9):1403-1412. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23343913.

9. Fortuin-de Smidt M, de Waal R, Cohen K, et al. First-line antiretroviral drug

discontinuations in children. PLoS One. 2017;12(2):e0169762. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28192529.

10. Nachman S, Alvero C, Acosta EP, et al. Pharmacokinetics and 48-week safety and efficacy
of raltegravir for oral suspension in human immunodeficiency virus type-1-infected children
4 weeks to 2 years of age. J Pediatric Infect Dis Soc. 2015;4(4):e76-83. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26582887.

11. Viani RM, Alvero C, Fenton T, et al. Safety, pharmacokinetics and efficacy of dolutegravir
in treatment-experienced HIV-1 infected adolescents: 48-week results from IMPAACT

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-5
 P1093. Pediatr Infect Dis J. 2015;34(11):1207-1213. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26244832.

12. Levy ME, Griffith C, Ellenberger N, et al. Outcomes of integrase inhibitor-based

antiretroviral therapy in a clinical cohort of treatment-experienced children, adolescents and
young adults with HIV infection. Pediatr Infect Dis J. 2020;39(5):421-428. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32176183.

13. Abo YN, Refsum E, Mackie N, Lyall H, Tudor-Williams G, Foster C. Paediatric integrase
inhibitor use in a real-life setting: a single-centre cohort experience 2009–2018. Clin Drug
Investig. 2019;39(6):585-590. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30976998.

14. Ciccullo A, Baldin G, Putaggio C, Di Giambenedetto S, Borghetti A. Comparative safety

review of recommended, first-line single-tablet regimens in patients with HIV. Expert Opin
Drug Saf. 2021;20(11):1317-1332. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34018892.

15. Hill A, Hughes SL, Gotham D, Pozniak AL. Tenofovir alafenamide versus tenofovir
disoproxil fumarate: is there a true difference in efficacy and safety? J Virus Erad.
2018;4(2):72-79. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29682298.

16. Ryom L, Lundgren JD, El-Sadr W, et al. Cardiovascular disease and use of contemporary
protease inhibitors: the D:A:D international prospective multicohort study. Lancet HIV.
2018;5(6):e291-e300. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29731407.

17. Aurpibul L, Namwongprom S, Sudjaritruk T, Ounjaijean S. Metabolic syndrome,

biochemical markers, and body composition in youth living with perinatal HIV infection on
antiretroviral treatment. PLoS One. 2020;15(3):e0230707. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32226033.

18. Asensi V, Collazos J, Valle-Garay E. Can antiretroviral therapy be tailored to each human
immunodeficiency virus-infected individual? Role of pharmacogenomics. World J Virol.
2015;4(3):169-177. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26279978.

19. Sinxadi PZ, Leger PD, McIlleron HM, et al. Pharmacogenetics of plasma efavirenz exposure
in HIV-infected adults and children in South Africa. Br J Clin Pharmacol. 2015;80(1):146-
156. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25611810.

20. Bolton Moore C, Capparelli EV, Samson P, et al. CYP2B6 genotype-directed dosing is
required for optimal efavirenz exposure in children 3–36 months with HIV infection. AIDS.
2017;31(8):1129-1136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28323755.

21. Gallien S, Journot V, Loriot MA, et al. Cytochrome 2B6 polymorphism and efavirenz-
induced central nervous system symptoms : a substudy of the ANRS ALIZE trial. HIV Med.
2017;18(8):537-545. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28145050.

22. Soeria-Atmadja S, Osterberg E, Gustafsson LL, et al. Genetic variants in CYP2B6 and
CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-6
 infected children with diverse ethnic origin. PLoS One. 2017;12(9):e0181316. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28886044.

23. Wynberg E, Williams E, Tudor-Williams G, Lyall H, Foster C. Discontinuation of efavirenz

in paediatric patients: why do children switch? Clin Drug Investig. 2018;38(3):231-238.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29181714.

24. Strehlau R, Shiau S, Arpadi S, et al. Substituting abacavir for stavudine in children who are
virally suppressed without lipodystrophy: randomized clinical trial in Johannesburg, South
Africa. J Pediatric Infect Dis Soc. 2018;7(3):e70-e77. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29373687.

25. Valantin MA, Bittar R, de Truchis P, et al. Switching the nucleoside reverse transcriptase
inhibitor backbone to tenofovir disoproxil fumarate + emtricitabine promptly improves
triglycerides and low-density lipoprotein cholesterol in dyslipidaemic patients. J Antimicrob
Chemother. 2010;65(3):556-561. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20053692.

26. Murnane PM, Strehlau R, Shiau S, et al. Switching to efavirenz versus remaining on
ritonavir-boosted lopinavir in HIV-infected children exposed to nevirapine: long-term
outcomes of a randomized trial. Clin Infect Dis. 2017;65(3):477-485. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28419200.

27. Raffi F, Esser S, Nunnari G, Perez-Valero I, Waters L. Switching regimens in virologically

suppressed HIV-1-infected patients: evidence base and rationale for integrase strand transfer
inhibitor (INSTI)-containing regimens. HIV Med. 2016;17 Suppl 5:3-16. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27714978.

28. Jao J, Yu W, Patel K, et al. Improvement in lipids after switch to boosted atazanavir or
darunavir in children/adolescents with perinatally acquired HIV on older protease inhibitors:
results from the Pediatric HIV/AIDS Cohort Study. HIV Med. 2018;19(3):175-183. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/29159965.

29. Vo TT, Varghese Gupta S. Role of cytochrome P450 2B6 pharmacogenomics in determining
efavirenz-mediated central nervous system toxicity, Treatment outcomes, and dosage
adjustments in patients with human immunodeficiency virus infection. Pharmacotherapy.
2016;36(12):1245-1254. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27779789.

30. Engelbrecht AE, Wiesner L, Norman J, Rabie H, Decloedt EH. Pediatric antiretroviral
therapeutic drug monitoring: a five and a half year experience from a South African tertiary
hospital. J Trop Pediatr. 2020;66(4):385-394. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31754710.

31. Senneker T, Tseng A. An update on neuropsychiatric adverse effects with second-generation

integrase inhibitors and nonnucleoside reverse transcriptase inhibitors. Curr Opin HIV AIDS.
2021;16(6):309-320. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34475342.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-7
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous
System Toxicity
Updated: April 11, 2023
Reviewed: April 11, 2023

Adverse Associated Onset/ Prevention/

Estimated Frequency Risk Factors Management
Effects ARVs Clinical Manifestations Monitoring
Global CNS LPV/r oral Onset Unknown; rare case Prematurity Avoid use of LPV/r Discontinue LPV/r;
Depression solution which reports have been until a symptoms should resolve
contains both • 1–6 days after starting LPV/r published. Low birth weight postmenstrual age in 1–5 days.
ethanol (42.4% v/v) of 42 weeks and a
Presentation Aged <14 days If needed, reintroduction of
and propylene postnatal age of
glycol (15.3% w/v) Neonates/Premature Infants (whether birth was ≥14 days unless no LPV/r can be considered
as excipients premature or term) other alternatives when the patient is outside
• Global CNS depression the vulnerable period
are available. See
(e.g., abnormal EEG, altered (i.e., postmenstrual age of
Lopinavir/Ritonavir.
state of consciousness, 42 weeks and a postnatal
somnolence) age ≥14 days).
Neuropsychiatric EFV Onset Variable, depending on Insomnia is Avoid use of EFV If symptoms are excessive
Symptoms and age, symptoms, and associated with for initial ARV or persistent, obtain EFV
Other CNS • For many symptoms, onset assessment method elevated EFV treatment in trough concentration. If
Manifestations is 1–2 days after starting trough children and EFV trough concentration
EFV. Children concentration adolescents to is >4 mcg/mL and/or
• Many symptoms subside or (≥4 mcg/mL). prevent EFV- symptoms are severe,
• 24% of patients
diminish by 2–4 weeks, but associated CNS strongly consider drug
experienced any EFV- CYP2B6
symptoms may persist in a side effects. See substitution if a suitable
related CNS polymorphisms that
significant proportion of What to Start: alternative exists.
manifestation in one decrease EFV
patients. Regimens
case series, with 18% metabolism and Alternatively, consider
Recommended for
of participants requiring cause increased dose reduction with repeat
Presentation (May Include Initial Therapy of
drug discontinuation. EFV serum TDM and dose adjustment
One or More of the Antiretroviral-Naive
Following) • Five of 45 participants concentrations Children. (with input from an expert
(11%) experienced (CYP2B6 516 T/T pharmacologist).
Neuropsychiatric Symptoms genotype or co- In situations where
new-onset seizures in
• Abnormal dreams one study of children carriage of EFV treatment may
aged <36 months; two CYP2B6 516 G/T be indicated,

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-8
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous
System Toxicity

Adverse Associated Onset/ Prevention/

Estimated Frequency Risk Factors Management
Effects ARVs Clinical Manifestations Monitoring
• Psychosis of these participants and 983 T/C consider the
had alternative causes variants) following:
• Suicidal ideation or for seizures.
attempted/ completed History of • Administer EFV
suicide • Cases of cerebellar psychiatric illness on an empty
dysfunction have been or use of stomach,
Other CNS Manifestations reported in children psychoactive drugs preferably at
with very high EFV bedtime.
• Dizziness
plasma levels.
• Prescreen for
• Somnolence
Adults psychiatric
• Insomnia or poor sleep illness; avoid use
quality • 30% incidence for any in the presence
CNS manifestations of of psychiatric
• Impaired concentration any severity. illness, including
• Seizures (including absence depression or
• 6% incidence for EFV-
seizures) suicidal thoughts.
related, severe CNS
Avoid
• Cerebellar dysfunction manifestations,
concomitant use
(e.g., tremor, dysmetria, including suicidality.
of psychoactive
ataxia) However, evidence is
drugs.
conflicting about
Note: CNS side effects whether EFV use • Consider using
(e.g., impaired concentration, increases the incidence TDM in children
abnormal dreams, sleep of suicidality. with mild or
disturbances) may be more moderate EFV-
• One case series
difficult to assess in children. associated
reported 20 women
toxicities.
with ataxia
that resolved upon EFV
discontinuation, but
frequency was not
reported.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-7
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous
System Toxicity

Adverse Associated Onset/ Prevention/

Estimated Frequency Risk Factors Management
Effects ARVs Clinical Manifestations Monitoring
RPV Onset Children History of • Monitor carefully Consider drug substitution
neuropsychiatric for depressive in cases of severe
• Most symptoms occur in the • Depressive disorders of illness symptoms.
disorders and
first 4–8 weeks of treatment. all severity grades were
other CNS
reported in 19.4% of
Presentation symptoms.
pediatric patients aged
Neuropsychiatric Symptoms 12–17 years. Severe
depressive disorders
• Depressive disorders were reported in 5.6%
of patients, including
• Suicidal ideation
one suicide attempt.
• Abnormal
• Somnolence was
dreams/nightmares
reported in 5 of 36
Other CNS Manifestations children (14%).

• Headache Adults
• Dizziness • CNS/neuropsychiatric
adverse events of all
• Insomnia severity grades were
• Somnolence reported in 43% of
patients at 96 weeks
(most were Grade 1).
Depressive disorders of
all severity grades were
reported in 9% of
patients; 1% of patients
discontinued RPV
because of severe
depressive disorders.
Higher frequency of
depression and
dizziness reported
when coadministered
with DTG.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-8
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous
System Toxicity

Adverse Associated Onset/ Prevention/

Estimated Frequency Risk Factors Management
Effects ARVs Clinical Manifestations Monitoring
RAL Onset Children Elevated RAL Prescreen for Consider drug substitution
concentrations psychiatric (RAL or coadministered
• As early as 3–4 days after • Increased psychomotor symptoms. drug) in cases of severe
starting RAL activity was reported in Co-treatment with insomnia or other
one child. TDF, a PPI, or Monitor carefully for neuropsychiatric
Presentation inhibitors of CNS symptoms. symptoms.
Adults UGT1A1
• Increased psychomotor
activity • Headache Use with caution in
Prior history of the presence of
• Headaches • Insomnia (<5% in adult insomnia or drugs that increase
trials) depression RAL concentration.
• Insomnia
• Rare case reports of
• Depression cerebellar dysfunction
• Cerebellar dysfunction in adults
(e.g., tremor, dysarthria,
ataxia)
DTG Onset Children Preexisting Use with caution in For persistent or severe
depression or other the presence of neuropsychiatric
• 7–30 days after starting • In a retrospective psychiatric illness psychiatric illness, symptoms, consider
DTG cohort analysis, especially in discontinuing DTG if a
neuropsychiatric events History of ARV- patients with suitable alternative exists.
Presentation that resulted in related depression or a
Neuropsychiatric Symptoms discontinuation neuropsychiatric history of ARV- For mild symptoms,
occurred in 2 of 29 symptoms related continue DTG and counsel
• Depression or exacerbation (6.8%) children who patient that symptoms
neuropsychiatric
of preexisting depression initiated DTG. Higher frequency of likely will resolve with time.
symptoms.
• Anxiety • Significantly higher overall
frequency of self-harm neuropsychiatric Consider morning
• Self-harm thoughts, suicidal symptoms reported dosing of DTG.
or suicidal thoughts
ideation or attempted/ when DTG is
reported in children in
completed suicide coadministered
the ODYSSEY trial
receiving DTG (23%) with ABC, and of
• Drowsiness
compared to SOC depression and
ARVs (5%). They were dizziness when
transient, self-resolved, DTG is
coadministered

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-9
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous
System Toxicity

Adverse Associated Onset/ Prevention/

Estimated Frequency Risk Factors Management
Effects ARVs Clinical Manifestations Monitoring
• Neurocognitive deficits and did not lead to with RPV.
(lower total competence and treatment changes. However, evidence
school performance) is conflicting for
Adults ABC association.
Other CNS Manifestations
• 2.7% of the
(Generally Mild)
neuropsychiatric AEs
• Sleep disturbances reported in a large
prospective cohort
• Dizziness resulted in treatment
• Headache discontinuation.
• Higher frequency of
neuropsychiatric
symptoms reported
with DTG than with
other INSTIs. A class
effect has been
suggested.
BIC Onset Children Preexisting Use with caution in For persistent or severe
depression or other the presence of neuropsychiatric
• 1–63 days after starting BIC • One child (1%) had psychiatric psychiatric symptoms, consider
(as late as 233 days for Grade 2 insomnia and conditions conditions or in discontinuing BIC if a
schizoaffective disorders) anxiety that led to drug patients with a suitable alternative exists.
discontinuation in History of history of ARV-
Presentation clinical trials. ARV-related For mild symptoms,
related
Neuropsychiatric Symptoms neuropsychiatric neuropsychiatric continue BIC and counsel
Adults symptoms patient that symptoms
symptoms.
• Depression or exacerbation likely will resolve with time.
• Overall, the frequency
of preexisting depression
of neuropsychiatric
• Suicidal ideation or events in BIC and DTG
attempted suicide comparator arms
appeared similar in
• Schizoaffective disorders adult clinical trials.
• Anxiety • Abnormal dreams,
dizziness, and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-10
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous
System Toxicity

Adverse Associated Onset/ Prevention/

Estimated Frequency Risk Factors Management
Effects ARVs Clinical Manifestations Monitoring
Other CNS Manifestations insomnia occurred in
(Generally Mild) 1% to 5% of adults.
• Sleep disturbances • Suicidal ideation,
suicide attempts,
• Dizziness schizoaffective
• Insomnia disorders, and
depression occurred in
<1% of adults.
• A recent study reported
a 3.3% short-term BIC-
related discontinuation
rate due to
neuropsychiatric AEs
after ART switch in a
large cohort of adults
with HIV in routine
clinical practice setting.
CAB Presentation Children Preexisting Monitor individuals Promptly evaluate severe
depression or other for depressive depressive symptoms,
Neuropsychiatric Symptoms • Insomnia was psychiatric symptoms or self- self-injurious behavior, or
(Generally Mild or Moderate, reported in 1 of 8 conditions could be injurious thoughts other CNS symptoms for a
Occasionally Serious) adolescents in the contributing factors, or behavior, possible relationship with
ongoing MOCHA but causal links especially if prior CAB, and assess risks
• Mood disorders, including
trial. have not clearly history of such. and benefits of continued
depression and suicidal
ideation or attempt been identified. CAB treatment.
Adults
• Anxiety disorders • 2–4% pooled incidence CAB exposure did If CAB is discontinued—
reported in Phase 3 not differ between
Other CNS Manifestations subjects with or • Counsel the individual
trials for CNS AEs, about prolonged
(Generally Mild or Moderate) without CNS or
including sleep residual CAB levels in
• Sleep disorders disorders, dizziness, neuropsychiatric
manifestations. the blood for 52 weeks
and headache. or longer, and monitor
• Dizziness
• Less than 2% frequently for symptom
• Headache incidence reported for resolution.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-11
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous
System Toxicity

Adverse Associated Onset/ Prevention/

Estimated Frequency Risk Factors Management
Effects ARVs Clinical Manifestations Monitoring
• Somnolence depressive disorders, • Ensure that a new
including suicidal suppressive regimen is
ideation, in Phase 3 started within 30 days of
trials, with comparable last injection.
incidence in CAB and
control groups.
Key: ABC = abacavir; AE = adverse event; ARV = antiretroviral; BIC = bictegravir; CAB = cabotegravir; CNS = central nervous system; CYP2B6 = cytochrome P450 2B6;
DTG = dolutegravir; EEG = electroencephalogram; EFV = efavirenz; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; MOCHA = More Options for Children and
Adolescents; PPI = proton pump inhibitor; RAL = raltegravir; RPV = rilpivirine; SOC = standard of care; TDF = tenofovir disoproxil fumarate; TDM = therapeutic drug monitoring;
UGT1A = uridine diphosphate(UDP)-glucuronosyltransferase Family 1 Member A Complex; % v = volume; w = weight

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-12
References
1. Allen Reeves A, Fuentes AV, Caballero J, Thomas JE, Mosley Ii JF, Harrington C. Neurotoxicities in the treatment of HIV between
dolutegravir, rilpivirine and dolutegravir/rilpivirine: a meta-analysis. Sex Transm Infect. 2021;97(4):261-267. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33782144.

2. Arenas-Pinto A, Grund B, Sharma S, et al. Risk of suicidal behavior with use of efavirenz: results from the strategic timing of antiretroviral
treatment trial. Clin Infect Dis. 2018;67(3):420-429. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29538636.

3. Apretude (cabotegravir extended-release injectable suspension), for intramuscular use [package insert]. Food and Drug Administration.
2021. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215499s000lbl.pdf.

4. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release injectable suspension), co-packaged for
intramuscular use [package insert]. Food and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212888s002lbl.pdf.

5. Capetti AF, Di Giambenedetto S, Latini A, et al. Morning dosing for dolutegravir-related insomnia and sleep disorders. HIV Med.
2018;19(5):e62-e63. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28762661.

6. Cohen CJ, Molina JM, Cassetti I, et al. Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III
randomized trials. AIDS. 2013;27(6):939-950. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23211772.

7. Cuzin L, Pugliese P, Katlama C, et al. Integrase strand transfer inhibitors and neuropsychiatric adverse events in a large prospective cohort.
J Antimicrob Chemother. 2019;74(3):754-760. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30534993.

8. de Boer MG, van den Berk GE, van Holten N, et al. Intolerance of dolutegravir-containing combination antiretroviral therapy regimens in
real-life clinical practice. AIDS. 2016;30(18):2831-2834. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27824625.

9. Fernandez C, Michie K, et al. Adverse events and discontinuation of dolutegravir-based therapy in naive and experienced HIV patients:
tertiary HIV centre experience. Abstract #P212. Presented at: HIV Drug Therapy; 2016. Glasgow, Scotland. Available at:
https://hivglasgow.org/2016-abstracts.

10. Fettiplace A, Stainsby C, Winston A, et al. Psychiatric symptoms in patients receiving dolutegravir. J Acquir Immune Defic Syndr.
2017;74(4):423-431. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27984559.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-6
11. Food and Drug Administration. FDA drug safety communication: serious health problems seen in premature babies given Kaletra
(lopinavir/ritonavir) oral solution. 2011. Available at: https://www.fda.gov/Drugs/DrugSafety/ucm246002.htm.

12. FDA Application Review Files, Vocabria and Cabenuva, Integrated Review. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2021/212887Orig1s000,212888Orig1s000IntegratedR.pdf.

13. FDA Application Review Files, Apretude, Integrated Review. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2022/215499Orig1s000IntegratedR.pdf.

14. Ford N, Shubber Z, Pozniak A, et al. Comparative safety and neuropsychiatric adverse events associated with efavirenz use in first-line
antiretroviral therapy: a systematic review and meta-analysis of randomized trials. J Acquir Immune Defic Syndr. 2015;69(4):422-429.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25850607.

15. Gaur AH, Cotton MF, Rodriguez CA, et al. Fixed-dose combination bictegravir, emtricitabine, and tenofovir alafenamide in adolescents and
children with HIV: week 48 results of a single-arm, open-label, multicentre, phase 2/3 trial. Lancet Child Adolesc Health. 2021;5(9):642-
651. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34302760.

16. Haas DW, Ribaudo HJ, Kim RB, et al. Pharmacogenetics of efavirenz and central nervous system side effects: an adult AIDS clinical trials
group study. AIDS. 2004;18(18):2391-2400. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15622315.

17. Hammond CK, Eley B, Ing N, Wilmshurst JM. Neuropsychiatric and neurocognitive manifestations in HIV-infected children treated with
efavirenz in South Africa–a retrospective case series. Front Neurol. 2019;10:742. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31338063.

18. Hauptfleisch MP, Moore DP, Rodda JL. Efavirenz as a cause of ataxia in children. S Afr Med J. 2015;105(11):897-898. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26632310.

19. Hoffmann C, Llibre JM. Neuropsychiatric adverse events with dolutegravir and other integrase strand transfer inhibitors. AIDS Rev.
2019;21(1):4-10. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30899113.

20. Hoffmann C, Schewe K, Fenske S, et al. Short-term neuropsychiatric tolerability of bictegravir combined with emtricitabine/tenofovir
alafenamide in clinical practice. Antivir Ther. 2020;25(2):83-90. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32235038.

21. Hoffmann C, Welz T, Sabranski M, et al. Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women
and older patients. HIV Med. 2017;18(1):56-63. https://www.ncbi.nlm.nih.gov/pubmed/27860104.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-7
22. Kheloufi F, Allemand J, Mokhtari S, Default A. Psychiatric disorders after starting dolutegravir: report of four cases. AIDS.
2015;29(13):1723-1725. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26372287.

23. Leutscher PD, Stecher C, Storgaard M, Larsen CS. Discontinuation of efavirenz therapy in HIV patients due to neuropsychiatric adverse
effects. Scand J Infect Dis. 2013;45(8):645-651. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23427878.

24. Lombaard J, Bunupuradah T. Week 48 safety and efficacy of a rilpivirine (TMC278)-based regimen in HIV-infected treatment-naïve
adolescents: PAINT Phase II trial. Presented at: 7th International Workshop on HIV Pediatrics; 2015. Vancouver, Canada.

25. Madeddu G, Menzaghi B, Ricci E, et al. Raltegravir central nervous system tolerability in clinical practice: results from a multicenter
observational study. AIDS. 2012;26(18):2412-2415. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23032413.

26. Mills A, Garner W, Pozniak A, et al. Patient-reported symptoms over 48 weeks in a randomized, open-label, phase IIIb non-inferiority trial
of adults with HIV switching to co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir DF versus continuation of non-
nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir DF. Patient. 2015;8(4):359-371. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26045359.

27. Mollan KR, Smurzynski M, Eron JJ, et al. Association between efavirenz as initial therapy for HIV-1 infection and increased risk for
suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med. 2014;161(1):1-10. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24979445.

28. Mollan KR, Tierney C, Hellwege JN, et al. Race/ethnicity and the pharmacogenetics of reported suicidality with efavirenz among clinical
trials participants. J Infect Dis. 2017;216(5):554-564. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28931220.

29. Nachman S, Alvero C, Teppler H, et al. Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-1: a
phase 1/2 open label, non-randomised, multicentre trial. Lancet HIV. 2018;5(12):e715-e722. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30527329.

30. Napoli AA, Wood JJ, Coumbis JJ, Soitkar AM, Seekins DW, Tilson HH. No evident association between efavirenz use and suicidality was
identified from a disproportionality analysis using the FAERS database. J Int AIDS Soc. 2014;17:19214. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25192857.

31. Nkhoma ET, Coumbis J, Farr AM, et al. No evidence of an association between efavirenz exposure and suicidality among HIV patients
initiating antiretroviral therapy in a retrospective cohort study of real world data. Medicine (Baltimore). 2016;95(3):e2480. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26817882.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-8
32. Perez Valero I, Cabello A, Ryan P, et al. Randomized trial evaluating the neurotoxicity of dolutegravir/abacavir/lamivudine and its
reversibility after switching to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide: GESIDA 9016. Open Forum Infect Dis.
2020;7(12):ofaa482. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33335931.

33. Pinillos F, Dandara C, Swart M, et al. Case report: severe central nervous system manifestations associated with aberrant efavirenz
metabolism in children: the role of CYP2B6 genetic variation. BMC Infect Dis. 2016;16:56. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26831894.

34. Puthanakit T, Tanpaiboon P, Aurpibul L, Cressey TR, Sirisanthana V. Plasma efavirenz concentrations and the association with CYP2B6-
516G >T polymorphism in HIV-infected Thai children. Antivir Ther. 2009;14(3):315-320. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19474465.

35. Reiss KA, Bailey JR, Pham PA, Gallant JE. Raltegravir-induced cerebellar ataxia. AIDS. 2010;24(17):2757. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20980871.

36. Rizzardini G, Overton ET, Okrin C, et al. Long-acting cabotegravir+rilpiviring for HIV maintenance therapy:week 48 pooled analysis of
phase 3 ATLAS and FLAIR trials. J Acquir Immune Defic Syndr. 2020;85:498-506. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33136751.

37. Rubin, LH, O'Halloran, JA, Williams, DW, et al. Integrase inhibitors are associated with neuropsychiatric symptoms in women with HIV. J
Neuroimmune Pharmacol. 2022 Feb 17:10.1007/s11481-021-10042-3. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35178611.

38. Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral
therapy: a systematic review and meta-analysis. AIDS. 2013;27(9):1403-1412. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23343913.

39. Smith C, Ryom L, Monforte A, et al. Lack of association between use of efavirenz and death from suicide: evidence from the D:A:D study.
J Int AIDS Soc. 2014;17(4 Suppl 3):19512. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25394021.

40. Strehlau R, Martens L, Coovadia A, et al. Absence seizures associated with efavirenz initiation. Pediatr Infect Dis J. 2011;30(11):1001-
1003. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21633320.

41. Teppler H, Brown DD, Leavitt RY, et al. Long-term safety from the raltegravir clinical development program. Curr HIV Res. 2011;9(1):40-
53. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21198432.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-9
42. Turkova A, Kekitiinwa A, White E, et al. Neuropsychiatric manifestations and sleep disturbances in children and adolescents randomised to
dolutegravir-based ART vs standard-of-care in the ODYSSEY trial. Abstract OAB0404. Presented at: 11th IAS Conference on HIV Science
2021. Virtual Conference.

43. Van de Wijer L, McHaile DN, de Mast Q, et al. Neuropsychiatric symptoms in Tanzanian HIV-infected children receiving long-term
efavirenz treatment: a multicentre, cross-sectional, observational study. Lancet HIV. 2019;6(4):e250-e258. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30770324.

44. van Dijk JH, Sutcliffe CG, Hamangaba F, Bositis C, Watson DC, Moss WJ. Effectiveness of efavirenz-based regimens in young HIV-
infected children treated for tuberculosis: a treatment option for resource-limited settings. PLoS One. 2013;8(1):e55111. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23372824.

45. Variava E, Sigauke FR, Norman J, et al. Brief report: late efavirenz-induced ataxia and encephalopathy: a case series. J Acquir Immune
Defic Syndr. 2017;75(5):577-579. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28520619.

46. Vocabria (cabotegravir) tablets,for oral use [package insert]. Food and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212887s005s006lbl.pdf.

47. Waalewijn H, Turkova A, Rakhmanina N, et al. Optimizing pediatric dosing recommendations and treatment management of antiretroviral
drugs using therapeutic drug monitoring data in children living with HIV. Ther Drug Monit. 2019;41(4):431-443. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31008997.

48. Walmsley S, Baumgarten A, Berenguer J, et al. Brief report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in
antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic
Syndr. 2015;70(5):515-519. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26262777.

49. Waters L, Fisher M, Winston A, et al. A Phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the
feasibility of switching individuals receiving efavirenz with continuing central nervous system adverse events to etravirine. AIDS.
2011;25(1):65-71. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21099666.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-10
Table 17b. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Dyslipidemia
Updated: April 11, 2022
Reviewed: April 11, 2023

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
Dyslipidemia PIs Onset Reported Advanced-stage Prevention Assess all patients for additional
frequency varies HIV disease ASCVD risk factors. Patients with
• All PIs, • As early as with specific ARV • Low-fat diet HIV are considered to be at
especially 2 weeks to regimen, duration High-fat, moderate risk for ASCVD.b
RTV-boosted months after • Exercise
of ART, and the high-cholesterol
PIs; lower beginning specific laboratory diet • Smoking-prevention ARV regimen changes should be
incidence therapy parameters used counseling considered, especially when the
reported with to diagnose lipid Sedentary lifestyle patient is receiving older PIs
DRV/r and Presentation • Use of ARVs is associated
abnormalities. (e.g., LPV/r) and/or RTV
ATV, with or Obesity with a lower prevalence of
PIs boosting. Switching to a PI-
without RTV dyslipidemia, such as
10% to 20% of sparing regimen, a PI-based
• ↑ LDL-C, TC, and Hypertension INSTIs, and to a lesser
young children regimen with a more favorable
NRTIs TG extent, newer PIs (e.g.,
receiving LPV/r will lipid profile, or COBI boosting
Smoking ATV, DRV).
• Lower have lipid causes a decline in LDL-C or TG
NRTIs
incidence abnormalities. Family history of • When considering a TDF- values. The lipid-lowering effect
reported with • ↑ LDL-C, TC, and dyslipidemia or based or TAF-based of an ARV regimen switch on
TDF than with TG. Significant 40% to 75% of regimen, the lipid-lowering LDL-C is less pronounced than
premature ASCVD
TAF increase in older children and beneficial effect of TDF with statin therapy but may be
plasma lipid adolescents with Metabolic should be weighed against enough to re-establish a healthy
NNRTIs values was prolonged ART syndrome its potential for increased lipid profile.
observed in history will have renal and bone toxicities.
• Lower lipid abnormalities. Refer patients to a lipid specialist
adults switching Fat maldistribution
incidence Monitoringa early if LDL-C is ≥250 mg/dL or
from TDF to TAF,
reported with Pooled TG is ≥500 mg/dL.
regardless of • Obtain fasting (or
NVP, RPV, dyslipidemia
third agent or non-fasting) lipid profile (TC,
and ETR than prevalence of If LDL-C is ≥130 mg/dL but
presence of a HDL-C, non-HDL-C, LDL-C,
with EFV 39.5% and an <250 mg or TG is ≥150 mg/dL
boosting agent. and TG) twice (>2 weeks
incidence of 32% but <500 mg/dL, the following
INSTIs (191 per 1,000 but ≤3 months apart) and staged treatment approach is
person-years) average these results. recommended by the NHLBI
• EVG/c Monitor every 6 months (for
reported in a guidelinesb:
abnormal results) or every

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-11
Table 17b. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Dyslipidemia

NNRTIs recent meta- 12 months (for normal • Implement diet, nutrition, and
analysis and a results). lifestyle management for
• ↑ LDL-C, TC, and recent review of a 6–9 months. Consult with a
HDL-C large consortium • If TG or LDL-C is elevated dietician if one is available.
of prospective or if a patient has additional • If a 6- to 9-month trial of
observational risk factors, obtain FLP. lifestyle modification fails and
cohorts, the patient is aged ≥10 years,
respectively. Children With Lipid consider implementing lipid-
Abnormalities and/or Additional lowering therapy after
Risk Factors consulting a lipid specialist.
• Obtain 12-hour fasting lipid • Statin therapy should be
profile (FLP) before initiating considered for patients with
or changing therapy and elevated LDL-C levels. NHLBI
every 6 months thereafter guidelines provide
(more often if indicated). recommendations for statin
therapy in patients with specific
Children Receiving Lipid-
LDL-C levels and risk factors.b
Lowering Therapy With Statins
Concurrent substitution—
or Fibrates
preferably to ARVs with no
• Obtain 12-hour FLP, LFT, inhibitory or inducing effect on
and CK at 4 weeks, CYP3A4 or OATP1B1
8 weeks, and 3 months after (e.g., INSTI)—also should be
starting lipid therapy. considered as appropriate to
limit drug–drug interaction
• If minimal alterations in AST, potential.
ALT, and CK are indicated,
monitor every 3–4 months • Drug therapy can be
during the first year and considered in cases of
every 6 months thereafter severe hypertriglyceridemia
(or as clinically indicated). (TG ≥500 mg/dL). Fibrates
(gemfibrozil and fenofibrate)
• Repeat FLP 4 weeks after may be used.
increasing doses of
antihyperlipidemic agents. The long-term risks of lipid
abnormalities in children who are
receiving ART are unclear.
However, persistent dyslipidemia
in children may lead to premature
ASCVD.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-12
Table 17b. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Dyslipidemia

aBecause of the burden of collecting fasting blood samples, some practitioners routinely measure cholesterol and TG from nonfasting blood samples and follow-up abnormal
values with a test done in the fasted state.
b Refer to the NHLBI guidelines: Expert Panel on Integrated Guidelines for Cardiovascular Health and Risk Reduction in Children and Adolescents.
Key to Symbol:
↑ = increase
Key: ALT = alanine aminotransferase; ART = antiretroviral therapy; ARV = antiretroviral; ASCVD = atherosclerotic cardiovascular disease; AST = aspartate aminotransferase;
ATV = atazanavir; CK = creatine kinase; COBI = cobicistat; CYP3A4 = cytochrome P450 3A4; DRV = darunavir; DRV/r = darunavir/ritonavir; EFV = efavirenz; ETR = etravirine;
EVG/c = elvitegravir/cobicistat; FLP = fasting lipid profile; HDL-C = high-density lipoprotein cholesterol; INSTI = integrase strand transfer inhibitor; LDL­C = low-density lipoprotein
cholesterol; LFT = liver function test; LPV/r = lopinavir/ritonavir; NHLBI = National Heart, Lung, and Blood Institute; NNRTI = non-nucleoside reverse transcriptase inhibitor;
NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; OATP1B1 = organic anion transporter polypeptide 1B1; PI = protease inhibitor; PUFA = polyunsaturated
fatty acid; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TC = total cholesterol; TDF = tenofovir disoproxil fumarate; TG = triglycerides

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-13
References
1. Aldrovandi GM, Lindsey JC, Jacobson DL, et al. Morphologic and metabolic abnormalities in vertically HIV-infected children and
youth. AIDS. 2009;23(6):661-672. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19279441.

2. Arpadi S, Shiau S, Strehlau R, et al. Metabolic abnormalities and body composition of HIV-infected children on lopinavir or
nevirapine-based antiretroviral therapy. Arch Dis Child. 2013;98(4):258-264. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23220209.

3. Barlow-Mosha L, Eckard AR, McComsey GA, Musoke PM. Metabolic complications and treatment of perinatally HIV-infected
children and adolescents. J Int AIDS Soc. 2013;16:18600. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23782481.

4. Blazquez D, Ramos-Amador JT, Sainz T, et al. Lipid and glucose alterations in perinatally-acquired HIV-infected adolescents and
young adults. BMC Infect Dis. 2015;15:119. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25880777.

5. Bwakura-Dangarembizi M, Musiime V, Szubert AJ, et al. Prevalence of lipodystrophy and metabolic abnormalities in HIV-infected
African children after 3 years on first-line antiretroviral therapy. Pediatr Infect Dis J. 2015;34(2):e23-31. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25068287.

6. Casado JL, de Los Santos I, Del Palacio M, et al. Lipid-lowering effect and efficacy after switching to etravirine in HIV-infected
patients with intolerance to suppressive HAART. HIV Clin Trials. 2013;14(1):1-9. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23372109.

7. Cid-Silva P, Fernandez-Bargiela N, Margusino-Framinan L, et al. Treatment with tenofovir alafenamide fumarate worsens the lipid
profile of HIV-infected patients versus treatment with tenofovir disoproxil fumarate, each coformulated with elvitegravir, cobicistat,
and emtricitabine. Basic Clin Pharmacol Toxicol. 2019;124(4):479-490. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30388308.

8. Courlet P, Livio F, Alves Saldanha S, et al. Real-life management of drug-drug interactions between antiretrovirals and statins.
J Antimicrob Chemother. 2020;75(7):1972-1980. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32240298.

9. Dejkhamron P, Unachak K, Aurpibul L, Sirisanthana V. Insulin resistance and lipid profiles in HIV-infected Thai children receiving
lopinavir/ritonavir-based highly active antiretroviral therapy. J Pediatr Endocrinol Metab. 2014;27(5-6):403-412. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24259240.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-14
10. Echecopar-Sabogal J, D’Angelo-Piaggio L, Chaname-Baca DM, Ugarte-Gil C. Association between the use of protease inhibitors in
highly active antiretroviral therapy and incidence of diabetes mellitus and/or metabolic syndrome in HIV-infected patients: a
systematic review and meta-analysis. Int J STD AIDS. 2018;29(5):443-452. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28956700.

11. Echeverria P, Bonjoch A, Puig J, Ornella A, Clotet B, Negredo E. Significant improvement in triglyceride levels after switching
from ritonavir to cobicistat in suppressed HIV-1-infected subjects with dyslipidaemia. HIV Med. 2017;18(10):782-786. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28671337.

12. Expert Panel on Integrated Guidelines for Cardiovascular H, Risk Reduction in C, Adolescents, National Heart L, Blood I. Expert
panel on integrated guidelines for cardiovascular health and risk reduction in children and adolescents: summary report. Pediatrics.
2011;128 Suppl 5(Suppl 5):S213-256. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22084329.

13. Food and Drug Administration. FDA drug safety communication: interactions between certain HIV or hepatitis C drugs and
cholesterol-lowering statin drugs can increase the risk of muscle injury. 2012. Available at: https://www.fda.gov/drugs/drug-safety-
and-availability/fda-drug-safety-communication-interactions-between-certain-hiv-or-hepatitis-c-drugs-and-cholesterol

14. Grand M, Bia D, Diaz A. Cardiovascular risk assessment in people living with HIV: a systematic review and meta-analysis of real-
life data. Curr HIV Res. 2020;18(1):5-18. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31830884.

15. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA
guideline on the management of blood cholesterol: executive summary: a report of the American College of Cardiology/American
Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1046-e1081. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30565953.

16. Hazra R, Cohen RA, Gonin R, et al. Lipid levels in the second year of life among HIV-infected and HIV-exposed uninfected Latin
American children. AIDS. 2012;26(2):235-240. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22008654.

17. Innes S, Abdullah KL, Haubrich R, Cotton MF, Browne SH. High prevalence of dyslipidemia and insulin resistance in HIV-infected
pre-pubertal African children on antiretroviral therapy. Pediatr Infect Dis J. 2015;35(1):e1-7. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26421804.

18. Irira ME, Philemon RN, Mmbaga JY, et al. Dyslipidemia in HIV-infected children and adolescents on antiretroviral therapy
receiving care at Kilimanjaro Christian Medical Centre in Tanzania: a cross-sectional study. Infect Dis (Auckl).
2020;13:1178633720948860. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32922028.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-15
19. Jacobson DL, Williams P, Tassiopoulos K, Melvin A, Hazra R, Farley J. Clinical management and follow-up of
hypercholesterolemia among perinatally HIV-infected children enrolled in the PACTG 219C study. J Acquir Immune Defic Syndr.
2011;57(5):413-420. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21602698.

20. Jao J, Yu W, Patel K, et al. Improvement in lipids after switch to boosted atazanavir or darunavir in children/adolescents with
perinatally acquired HIV on older protease inhibitors: results from the Pediatric HIV/AIDS Cohort Study. HIV Med.
2018;19(3):175-183. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29159965.

21. Kauppinen KJ, Kivela P, Sutinen J. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide significantly worsens the
lipid profile in a real-world setting. AIDS Patient Care STDS. 2019;33(12):500-506. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31742421.

22. Lagoutte-Renosi J, Flammang M, Chirouze C, et al. Real-life impact on lipid profile of a switch from tenofovir disoproxil fumarate
to tenofovir alafenamide in HIV-infected patients. Curr HIV Res. 2021;19(1):84-89. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32838719.

23. Langat A, Benki-Nugent S, Wamalwa D, et al. Lipid changes in Kenyan HIV-1-infected infants initiating highly active antiretroviral
therapy by 1 year of age. Pediatr Infect Dis J. 2013;32(7):e298-304. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23385950.

24. Lazzaretti RK, Kuhmmer R, Sprinz E, Polanczyk CA, Ribeiro JP. Dietary intervention prevents dyslipidemia associated with highly
active antiretroviral therapy in human immunodeficiency virus type 1-infected individuals: a randomized trial. J Am Coll Cardiol.
2012;59(11):979-988. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22402068.

25. Lee FJ, Monteiro P, Baker D, et al. Rosuvastatin vs. protease inhibitor switching for hypercholesterolaemia: a randomized trial. HIV
Med. 2016;17(8):605-614. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26987376.

26. Melvin AJ, Montepiedra G, Aaron L, et al. Safety and efficacy of atorvastatin in human immunodeficiency virus-infected children,
adolescents and young adults with hyperlipidemia. Pediatr Infect Dis J. 2017;36(1):53-60. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27749649.

27. O’Gorman CS, O’Neill MB, Conwell LS. Considering statins for cholesterol-reduction in children if lifestyle and diet changes do
not improve their health: a review of the risks and benefits. Vasc Health Risk Manag. 2011;7:1-14. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21339908.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-16
28. Patel K, Lindsey J, Angelidou K, Aldrovandi G, Palumbo P, IMPAACT P1060 Study Team. Metabolic effects of initiating
lopinavir/ritonavir-based regimens among young children. AIDS. 2018;32(16):2327-2336. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30102656.

29. Ramteke SM, Shiau S, Foca M, et al. Patterns of growth, body composition, and lipid profiles in a South African cohort of human
immunodeficiency virus-infected and uninfected children: a cross-sectional study. J Pediatric Infect Dis Soc. 2017;7(2):143-150.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28481997.

30. Rhoads MP, Lanigan J, Smith CJ, Lyall EG. Effect of specific ART drugs on lipid changes and the need for lipid management in
children with HIV. J Acquir Immune Defic Syndr. 2011;57(5):404-412. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21499114.

31. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with elvitegravir,
cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two randomised, double-blind, phase 3, non-inferiority trials.
Lancet. 2015;385(9987):2606-2615. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25890673.

32. Singh S, Willig JH, Mugavero MJ, et al. Comparative effectiveness and toxicity of statins among HIV-infected patients. Clin Infect
Dis. 2011;52(3):387-395. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21189273.

33. Strehlau R, Coovadia A, Abrams EJ, et al. Lipid profiles in young HIV-infected children initiating and changing antiretroviral
therapy. J Acquir Immune Defic Syndr. 2012;60(4):369-376. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22134152.

34. Taramasso L, Tatarelli P, Ricci E, et al. Improvement of lipid profile after switching from efavirenz or ritonavir-boosted protease
inhibitors to rilpivirine or once-daily integrase inhibitors: results from a large observational cohort study (SCOLTA). BMC Infect
Dis. 2018;18(1):357. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30064371.

35. Tassiopoulos K, Williams PL, Seage GR, 3rd, et al. Association of hypercholesterolemia incidence with antiretroviral treatment,
including protease inhibitors, among perinatally HIV-infected children. J Acquir Immune Defic Syndr. 2008;47(5):607-614.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/18209684.

36. Vieira ADS, Silveira G. Effectiveness of n-3 fatty acids in the treatment of hypertriglyceridemia in HIV/AIDS patients: a meta-
analysis. Cien Saude Colet. 2017;22(8):2659-2669. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28793080.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-17
Table 17c. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—
Gastrointestinal Effects
Updated: April 11, 2022
Reviewed: April 11, 2023

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
Nausea/ All ARV drugs, but Onset Varies by ARV Unknown Instruct patient to take PIs Reassure the patient that
Vomiting most notably RTV- agent; generally with food. these adverse effects
boosted PIs • Early <15% generally improve over time
Monitor for weight loss and (usually in 6–8 weeks).
Presentation ARV adherence.
• Nausea and Consider switching to ARV
emesis, both of drugs with smaller tablet sizes
which may be (see Appendix A,Table 2.
associated with Antiretroviral Fixed-Dose
anorexia and/or Combination Tablets:
abdominal pain Minimum Body Weights and
Considerations for Use in
Children and Adolescents).

Provide supportive care.

In extreme or persistent
cases, use antiemetics or
switch to another ARV
regimen.
Diarrhea All ARV drugs, but Onset Varies by ARV Unknown Monitor for weight loss and In prolonged or severe cases,
most notably RTV- agent; generally dehydration. exclude infectious or
boosted PIs • Early <15% noninfectious (e.g., lactose
intolerance) causes of
Presentation
diarrhea.
• More frequent
bowel movements Reassure patient that this
and stools that are adverse effect generally
generally soft improves over time (usually in
6–8 weeks). Consider

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-18
Table 17c. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Gastrointestinal Effects

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
switching to another ARV
regimen in persistent and
severe cases.

Treatment data in children are

lacking; however, the
following strategies may be
useful when the ARV regimen
cannot be changed:
• Modifying the diet
• Using bulk-forming agents
(e.g., psyllium)
• Using antimotility agents
(e.g., loperamide)
• Using crofelemer, which is
approved by the FDA to
treat ART-associated
diarrhea in adults aged
≥18 years; no pediatric data
are available.
Pancreatitis Rare, but may Onset <2% Use of concomitant Measure serum amylase and Discontinue offending agent
occur with NRTIs medications that are lipase concentrations if and avoid reintroduction.
or RTV-boosted • Any time, usually associated with persistent abdominal pain
PIs after months of pancreatitis develops. Manage symptoms of acute
therapy (e.g., TMP-SMX, episodes.
pentamidine,
Presentation If pancreatitis is associated
ribavirin)
• Emesis, abdominal with hypertriglyceridemia,
pain, elevated Hypertriglyceridemia consider using interventions
amylase and lipase to lower TG levels.
levels Advanced HIV
(asymptomatic infection
hyperamylasemia
or elevated lipase

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-19
Table 17c. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Gastrointestinal Effects

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
do not in and of Previous episode of
themselves indicate pancreatitis
pancreatitis)
Alcohol use
Key: ART = antiretroviral therapy; ARV = antiretroviral; FDA = U.S. Food and Drug Administration; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor;
RTV = ritonavir; TG = triglyceride; TMP-SMX = trimethoprim sulfamethoxazole

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-20
References
1. Basile FW, Fedele MC, Lo Vecchio A. Gastrointestinal diseases in children living with HIV. Microorganisms. 2021;9(8). Available
at: https://www.ncbi.nlm.nih.gov/pubmed/34442651.

2. Buck WC, Kabue MM, Kazembe PN, Kline MW. Discontinuation of standard first-line antiretroviral therapy in a cohort of 1,434
Malawian children. J Int AIDS Soc. 2010;13:31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20691049.

3. Castro JG, Chin-Beckford N. Crofelemer for the symptomatic relief of non-infectious diarrhea in adult patients with HIV/AIDS on
anti-retroviral therapy. Expert Rev Clin Pharmacol. 2015;8(6):683-690. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26517110.

4. Clay PG, Crutchley RD. Noninfectious diarrhea in HIV seropositive individuals: a review of prevalence rates, etiology, and
management in the era of combination antiretroviral therapy. Infect Dis Ther. 2014;3(2):103-122. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25388760.

5. Dikman AE, Schonfeld E, Srisarajivakul NC, Poles MA. Human immunodeficiency virus-associated diarrhea: still an issue in the
era of antiretroviral therapy. Dig Dis Sci. 2015;60(8):2236-2245. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25772777.

6. Logan C, Beadsworth MB, Beeching NJ. HIV and diarrhoea: what is new? Curr Opin Infect Dis. 2016;29(5):486-494. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27472290.

7. Malan N, Su J, Mancini M, et al. Gastrointestinal tolerability and quality of life in antiretroviral-naive HIV-1-infected patients: data
from the CASTLE study. AIDS Care. 2010;22(6):677-686. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20467943.

8. Nachman SA, Chernoff M, Gona P, et al. Incidence of noninfectious conditions in perinatally HIV-infected children and adolescents
in the HAART era. Arch Pediatr Adolesc Med. 2009;163(2):164-171. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19188649.

9. Oumar AA, Diallo K, Dembele JP, et al. Adverse drug reactions to antiretroviral therapy: prospective study in children in Sikasso
(Mali). J Pediatr Pharmacol Ther. 2012;17(4):382-388. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23411444.

10. Szoke D, Ridolfo A, Valente C, Galli M, Panteghini M. Frequency of pancreatic hyperamylasemia in human immunodeficiency
virus–positive patients in the highly active antiretroviral therapy era. Am J Clin Pathol. 2016;145(1):128-133. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26712880.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-21
11. Tian X, Yao Y, He G, Jia Y, Wang K, Chen L. Systematic analysis of safety profile for darunavir and its boosted agents using data
mining in the FDA Adverse Event Reporting System database. Sci Rep. 2021;11(1):12438. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34127681.

12. Tukei VJ, Asiimwe A, Maganda A, et al. Safety and tolerability of antiretroviral therapy among HIV-infected children and
adolescents in Uganda. J Acquir Immune Defic Syndr. 2012;59(3):274-280. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22126740.

13. Wattanutchariya N, Sirisanthana V, Oberdorfer P. Effectiveness and safety of protease inhibitor-based regimens in HIV-infected
Thai children failing first-line treatment. HIV Med. 2013;14(4):226-232. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23094820.

14. Wegzyn CM, Fredrick LM, Stubbs RO, Woodward WC, Norton M. Diarrhea associated with lopinavir/ritonavir-based therapy:
results of a meta-analysis of 1,469 HIV-1-infected participants. J Int Assoc Physicians AIDS Care (Chic). 2012;11(4):252-259.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22544446.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-22
Table 17d. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—
Hematologic Effects
Updated: April 11, 2022
Reviewed: April 11, 2023

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
Anemiaa ZDV Onset Newborns Exposed Newborns Exposed Newborns Exposed Newborns Exposed to HIV
to HIV to HIV to HIV
• Variable; weeks • Anemia rarely requires intervention
to months after • Severe anemia is • Premature birth is the • Obtain CBC at birth. unless it is symptomatic or
starting therapy uncommon but most common risk Hgb <7.0 g/dL.
might be factor. • Consider repeating
Presentation coincident with CBC at 4 weeks for • ZDV administration can be limited to 4
physiologic Hgb • In utero exposure to neonates who are at weeks in low-risk neonates
More Common ZDV-containing higher risk (e.g., those (see Antiretroviral Management of
nadir.
• Asymptomatic regimens born prematurely or Newborns With Perinatal HIV Exposure
Children With HIV who are known to or HIV Infection).
• Mild fatigue • Advanced maternal HIV have low birth Hgb)
Who Are Taking
ARV Drugs • Neonatal blood loss and for neonates who Children With HIV Who Are Taking ARV
• Pallor Drugs
receive ZDV beyond
• Tachypnea • Anemia is two to • Combination ARV 4 weeks.
three times more prophylaxis or • Discontinue non-ARV, marrow-toxic
common with presumptive HIV Children With HIV Who drugs, if feasible.
Rare
ZDV-containing therapy, although no Are Taking ARV Drugs • Treat coexisting iron deficiency, OIs, and
• Congestive heart regimens than particular regimen has
• Avoid using ZDV in malignancies.
failure with all other been identified as being
regimens. worse than others. children with severe • For persistent, severe anemia that is
anemia when thought to be associated with ARV drugs
Children With HIV Who alternative agents are (typically macrocytic anemia), switch to a
Are Taking ARV Drugs available. regimen that does not contain ZDV.
• Underlying • Obtain CBC as part of
hemoglobinopathy routine care (see
(e.g., sickle cell disease, Clinical and
G6PD deficiency) Laboratory Monitoring
of Pediatric HIV
Infection).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-23
Table 17d. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Hematologic Effects

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
• Myelosuppressive drugs
(e.g., TMP-SMX,
rifabutin)
• Iron deficiency
• Advanced or poorly
controlled HIV disease
• OIs of the bone marrow
• Malnutrition
Macrocytosis ZDV Onset >90% to 95% for all None No monitoring required— No management required.
ages macrocytosis can be
• Within days or detected if CBC is
weeks of starting obtained as part of
therapy routine care (see Clinical
and Laboratory
Presentation
Monitoring of Pediatric
• Asymptomatic, HIV Infection).
but MCV often is
>100 fL
• Sometimes
associated with
anemia
Neutropeniaa ZDV Onset Newborns Exposed Newborns Exposed Children With HIV Who Newborns Exposed to HIV
to HIV to HIV Are Taking ARV Drugs
• Variable • No established threshold for intervention;
• Rare • In utero exposure to • Obtain CBC as part of some experts would consider using an
Presentation ARV drugs routine care. alternative NRTI for prophylaxis if ANC
Children With HIV reaches <500 cells/mm3. ZDV
• Asymptomatic Who Are Taking • Combination ARV administration can be limited to 4 weeks
ARV Drugs prophylaxis, particularly in low-risk neonates (see Antiretroviral
ZDV plus 3TC and NVP Management of Newborns With
• 2% to 4% of
Perinatal HIV Exposure or HIV Infection).
children on ARV
drugs

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-24
Table 17d. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Hematologic Effects

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
• Highest rates Children With HIV Who Children With HIV Who Are Taking ARV
occur in children Are Taking ARV Drugs Drugs
on ZDV-containing
• Advanced or poorly • Discontinue non-ARV, marrow-toxic
regimens
controlled HIV infection drugs, if feasible.
• Myelosuppressive drugs • Treat coexisting OIs and malignancies.
(e.g., TMP-SMX,
ganciclovir, hydroxyurea, • In cases of persistent, severe
rifabutin) neutropenia that is thought to be
associated with ARV drugs, switch to a
regimen that does not contain ZDV.
aHIV infection itself, OIs, and medications that are used to prevent OIs (e.g., TMP-SMX) can all contribute to anemia and neutropenia. Prolonged use of NVP with ZDV in three
drug regimens for the prevention of perinatal HIV transmission has been associated with increased rates of anemia and neutropenia in some, but not all, studies. The effects are
of uncertain clinical significance and appear to be transient.
Key: 3TC = lamivudine; ANC = absolute neutrophil count; ARV = antiretroviral; CBC = complete blood count; fL = femtoliter; G6PD = glucose-6-phosphate dehydrogenase;
g/dL = grams per deciliter; Hgb = hemoglobin; MCV = mean cell volume; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine; OI = opportunistic infection;
TMP­SMX = trimethoprim-sulfamethoxazole; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-25
References
1. Arrow Trial team, Kekitiinwa A, Cook A, et al. Routine versus clinically driven laboratory monitoring and first-line antiretroviral
therapy strategies in African children with HIV (ARROW): a 5-year open-label randomised factorial trial. Lancet.
2013;381(9875):1391-1403. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23473847.

2. Bunupuradah T, Kariminia A, Chan KC, et al. Incidence and predictors of severe anemia in Asian HIV-infected children using first-
line antiretroviral therapy. Int J Infect Dis. 2013;17(10):e806-e810. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23764352.

3. Dollfus C, Le Chenadec J, Mandelbrot L, et al. Improved hematologic outcomes in HIV1-exposed infants receiving nevirapine
compared with zidovudine for postnatal prophylaxis in a high resource setting. Pediatr Infect Dis J. 2022;41(5):420-423. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/35135997.

4. Dryden-Peterson S, Shapiro RL, Hughes MD, et al. Increased risk of severe infant anemia after exposure to maternal HAART,
Botswana. J Acquir Immune Defic Syndr. 2011;56(5):428-436. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21266910.

5. Esan MO, Jonker FA, Hensbroek MB, Calis JC, Phiri KS. Iron deficiency in children with HIV-associated anaemia: a systematic
review and meta-analysis. Trans R Soc Trop Med Hyg. 2012;106(10):579-587. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22846115.

6. European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord. Severe haematologic toxicity is
rare in high risk HIV-exposed infants receiving combination neonatal prophylaxis. HIV Med. 2019;20(5):291-307. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30844150.

7. Greiter BM, Kahlert CR, Eberhard N, Sultan-Beyer L, Berger C, Paioni P. Lymphocyte subsets in HIV-exposed uninfected infants:
the impact of neonatal postexposure prophylaxis with zidovudine. Open Forum Infect Dis. 2020;7(4):ofaa108. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32368562.

8. Illan Ramos M, Soto Sanchez B, Mazariegos Orellana D, et al. Safety and experience with combined antiretroviral prophylaxis in
newborn at high-risk of perinatal infection, in a cohort of mother living with HIV-infant pairs. Pediatr Infect Dis J.
2021;40(12):1096-1100. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34870390.

9. Kibaru EG, Nduati R, Wamalwa D, Kariuki N. Impact of highly active antiretroviral therapy on hematological indices among HIV-1
infected children at Kenyatta National Hospital-Kenya: retrospective study. AIDS Res Ther. 2015;12:26. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26279668.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-26
10. Lahoz R, Noguera A, Rovira N, et al. Antiretroviral-related hematologic short-term toxicity in healthy infants: implications of the
new neonatal 4-week zidovudine regimen. Pediatr Infect Dis J. 2010;29(4):376-379. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19949355.

11. Lau E, Brophy J, Samson L, et al. Nevirapine pharmacokinetics and safety in neonates receiving combination antiretroviral therapy
for prevention of vertical HIV transmission. J Acquir Immune Defic Syndr. 2017;74(5):493-498. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28114187.

12. Melvin AJ, Warshaw M, Compagnucci A, et al. Hepatic, renal, hematologic, and inflammatory markers in HIV-infected children on
long-term suppressive antiretroviral therapy. J Pediatric Infect Dis Soc. 2017;6(3):e109-e115. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28903520.

13. Mocroft A, Lifson AR, Touloumi G, et al. Haemoglobin and anaemia in the SMART study. Antivir Ther. 2011;16(3):329-337.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/21555815.

14. Mulenga V, Musiime V, Kekitiinwa A, et al. Abacavir, zidovudine, or stavudine as paediatric tablets for African HIV-infected
children (CHAPAS-3): an open-label, parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169-179. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/26481928.

15. Nguyen TTT, Kobbe R, Schulze-Sturm U, et al. Reducing hematologic toxicity with short course postexposure prophylaxis with
zidovudine for HIV-1 exposed infants with low transmission risk. Pediatr Infect Dis J. 2019;38(7):727-730. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31033907.

16. Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens to prevent intrapartum HIV infection.
N Engl J Med. 2012;366(25):2368-2379. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22716975.

17. Nyesigire Ruhinda E, Bajunirwe F, Kiwanuka J. Anaemia in HIV-infected children: severity, types and effect on response to
HAART. BMC Pediatr. 2012;12:170. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23114115.

18. Renner LA, Dicko F, Koueta F, et al. Anaemia and zidovudine-containing antiretroviral therapy in paediatric antiretroviral
programmes in the IeDEA Paediatric West African Database to evaluate AIDS. J Int AIDS Soc. 2013;16(1):18024. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24047928.

19. Shet A, Bhavani PK, Kumarasamy N, et al. Anemia, diet and therapeutic iron among children living with HIV: a prospective cohort
study. BMC Pediatr. 2015;15:164. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26482352.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-27
20. Smith C, Forster JE, Levin MJ, et al. Serious adverse events are uncommon with combination neonatal antiretroviral prophylaxis: a
retrospective case review. PLoS One. 2015;10(5):e0127062. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26000984.

21. Smith C, Weinberg A, Forster JE, et al. Maternal lopinavir/ritonavir is associated with fewer adverse events in infants than
nelfinavir or atazanavir. Infect Dis Obstet Gynecol. 2016;2016:9848041. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27127401.

22. Szpak R, Lombardi NF, Dias FA, Borba HHL, Pontarolo R, Wiens A. Safety of antiretroviral therapy in the treatment of HIV/AIDS
in children: systematic review and meta-analysis. AIDS Rev.2021;23(4):196-203. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34082441.

23. The European Pregnancy and Paediatric HIV Cohort Collaboration (EPPICC) study group in EuroCoord. Safety of
zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand. Eur J Clin Pharmacol.
2017;73(4):463-468. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5350228.

24. Van Dyke RB, Wang L, Williams PL, Pediatric AIDS Clinical Trials Group C. Team. Toxicities associated with dual nucleoside
reverse-transcriptase inhibitor regimens in HIV-infected children. J Infect Dis. 2008;198(11):1599-1608. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19000014.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-28
Table 17e. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Hepatic Events
Updated: April 11, 2022
Reviewed: April 11, 2023

Associated Onset/Clinical Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Manifestations Frequency Monitoring
Hepatitis Most ARV drugs Onset Uncommon HBV or HCV coinfection Prevention Evaluate the patient
have been for other infectious
associated with • Acute toxic hepatitis Underlying liver disease • Avoid concomitant and noninfectious
hepatitis, but a occurs most use of hepatotoxic causes of hepatitis
strong association commonly within the Use of other hepatotoxic medications. and monitor the
exists between first few months of medications and patient closely.
therapy, but it can • In patients with
hepatitis and the use supplements elevated levels of
occur later. (e.g., St. John’s wort
of NVP and EFV. hepatic enzymes (>5 Asymptomatic
• Steatosis presents [Hypericum perforatum], times to 10 times Hepatitis
NVP, EFV, ABC, after months or years chaparral [Larrea ULN) or chronic liver • Potentially offending
RAL, DTG, and of therapy. tridentata], germander disease, most
MVC have been [Teucrium chamaedrys]) ARV drugs should
clinicians would be discontinued if
associated with • Patients with HBV avoid NVP.
hepatitis in the coinfection can Alcohol use ALT or AST level is
context of HSRs. experience a hepatitis >5 times ULN.
Monitoring
flare with the initiation Pregnancy
NRTIs, especially or withdrawal of 3TC, For ARV Drugs Other Symptomatic
ZDV, have been FTC, TDF, or TAF. A Obesity than NVP Hepatitis
associated with flare also can occur
Higher drug concentrations • Obtain AST and ALT • Discontinue all ARV
lactic acidosis and with the emergence of levels at baseline drugs and other
of PIs
hepatic steatosis. resistance to 3TC or and at least every potentially
FTC (especially if the For NVP-Associated 3–4 months hepatotoxic drugs.
patient is receiving Hepatic Events in Adults thereafterb; monitor
only one anti-HBV • If a patient
at-risk patients more experiences
agent). Note that TDF • Female sex with pre-
frequently hepatitis that is
and TAF have high NVP CD4 count
(e.g., those with HBV attributed to NVP,
barriers to resistance >250 cells/mm3
or HCV coinfection NVP should be
when used to treat or elevated baseline
• Male sex with pre-NVP discontinued
HBV. AST and ALT
CD4 count permanently.
>400 cells/mm3 levels).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-29
Table 17e. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Hepatic Events

Associated Onset/Clinical Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Manifestations Frequency Monitoring
• Hepatitis can be a • Population-specific HLA For NVP • Consider viral
manifestation of IRIS typesa causes of hepatitis:
• Obtain AST and ALT
if it occurs early in HAV, HBV, HCV,
levels at baseline, at
therapy, especially in EBV, and CMV.
2 weeks, 4 weeks,
patients with HBV or
and then every
HCV coinfection.
3 months.
Presentation
• Asymptomatic
elevation of AST and
ALT levels
• Symptomatic hepatitis
with nausea, fatigue,
and jaundice
• Hepatitis may present
in the context of HSR
with rash, lactic
acidosis, and hepatic
steatosis.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-30
Table 17e. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Hepatic Events

Associated Onset/Clinical Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Manifestations Frequency Monitoring
Indirect ATV Onset In long-term follow- None established Monitoring Isolated indirect
Hyperbilirubinemia up, 9% of children hyperbilirubinemia is
• Within the first months who were • No ongoing not an indication to
of therapy receiving ATV had monitoring needed. stop ATV.
at least one total • After an initial rise
Presentation Psychological impact
bilirubin level >5 over the first few
• Can be asymptomatic times ULN, and months of therapy, of jaundice should be
or associated with 1.4% of children unconjugated evaluated, and
jaundice. experienced bilirubin levels alternative agents
jaundice. generally stabilize; should be considered.
• Levels of direct
levels can improve
bilirubin can be Jaundice can result in
over time.
normal or slightly nonadherence,
elevated when levels particularly in
of indirect bilirubin are adolescents; this side
very high. effect should be
discussed with
• Normal AST and ALT
patients.
a For example, HLA-DRB1*0101 in White people, HLA-DRB1*0102 in South African people, and HLA-B35 in Thai people and White people.
b Less frequent monitoring can be considered in children whose clinical status has been stable for >2 years to 3 years (see Clinical and Laboratory Monitoring of Pediatric
HIV Infection).
Key: 3TC = lamivudine; ABC = abacavir; ALT = alanine transaminase; ARV = antiretroviral; AST = aspartate aminotransferase; ATV = atazanavir; CD4 = CD4 T lymphocyte;
CMV = cytomegalovirus; DTG = dolutegravir; EBV = Epstein-Barr virus; EFV = efavirenz; FTC = emtricitabine; HAV = hepatitis A virus; HBV = hepatitis B virus; HCV = hepatitis C
virus; HLA = human leukocyte antigen; HSR = hypersensitivity reaction; IRIS = immune reconstitution inflammatory syndrome; MVC = maraviroc; NRTI = nucleoside reverse
transcriptase inhibitor; NVP = nevirapine; PI = protease inhibitor; RAL = raltegravir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ULN = upper limit of normal;
ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-31
References
1. Anadol E, Lust K, Boesecke C, et al. Exposure to previous cART is associated with significant liver fibrosis and cirrhosis in human
immunodeficiency virus-infected patients. PLoS One. 2018;13(1):e0191118. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29346443.

2. Aurpibul L, Bunupuradah T, Sophan S, et al. Prevalence and incidence of liver dysfunction and assessment of biomarkers of liver
disease in HIV-infected Asian children. Pediatr Infect Dis J. 2015;34(6):e153-158. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25970117.

3. Bienczak A, Denti P, Cook A, et al. Determinants of virological outcome and adverse events in African children treated with
paediatric nevirapine fixed-dose-combination tablets. AIDS. 2017;31(7):905-915. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28060017.

4. Cai J, Osikowicz M, Sebastiani G. Clinical significance of elevated liver transaminases in HIV-infected patients. AIDS.
2019;33(8):1267-1282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31008799.

5. Cotton MF, Liberty A, Torres-Escobar I, et al. Safety and efficacy of atazanavir powder and ritonavir in HIV-1-infected infants and
children from 3 months to <11 years of age: the PRINCE-2 study. Pediatr Infect Dis J. 2018;37(6):e149-e156. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29206747.

6. Crutchley RD, Guduru RC, Cheng AM. Evaluating the role of atazanavir/cobicistat and darunavir/cobicistat fixed-dose
combinations for the treatment of HIV-1 infection. HIV AIDS (Auckl). 2016;8:47-65. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27022304.

7. European P, Paediatric HIVCCSGiE. Safety of darunavir and atazanavir in HIV-infected children in Europe and Thailand. Antivir
Ther. 2016;21(4):353-358. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26561496.

8. European Paediatric HC-iSGitEP, Paediatric HIVCCiE. Coinfection with HIV and hepatitis C virus in 229 children and young
adults living in Europe. AIDS. 2017;31(1):127-135. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27898593.

9. Gervasoni C, Cattaneo D, Filice C, Galli M, Gruppo Italiano Studio Nimi. Drug-induced liver steatosis in patients with HIV
infection. Pharmacol Res. 2019;145:104267. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31077811.

10. Gowda C, Newcomb CW, Liu Q, et al. Risk of acute liver injury with antiretroviral therapy by viral hepatitis status. Open Forum
Infect Dis. 2017;4(2):ofx012. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28470014.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-32
11. Huntington S, Thorne C, Newell ML, et al. Pregnancy is associated with elevation of liver enzymes in HIV-positive women on
antiretroviral therapy. AIDS. 2015;29(7):801-809. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25710412.

12. Kaspar MB, Sterling RK. Mechanisms of liver disease in patients infected with HIV. BMJ Open Gastroenterol. 2017;4(1):e000166.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29119002.

13. Kovari H, Sabin CA, Ledergerber B, et al. Antiretroviral drugs and risk of chronic alanine aminotransferase elevation in human
immunodeficiency virus (HIV)-monoinfected persons: the Data Collection on Adverse Events of Anti-HIV Drugs Study. Open
Forum Infect Dis. 2016;3(1):ofw009. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26925429.

14. Leger P, Chirwa S, Nwogu JN, et al. Race/ethnicity difference in the pharmacogenetics of bilirubin-related atazanavir
discontinuation. Pharmacogenet Genomics. 2018;28(1):1-6. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29117017.

15. Melvin AJ, Warshaw M, Compagnucci A, et al. Hepatic, renal, hematologic, and inflammatory markers in HIV-infected children on
long-term suppressive antiretroviral therapy. J Pediatric Infect Dis Soc. 2017;6(3):e109-e115. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28903520.

16. Naidoo K, Hassan-Moosa R, Mlotshwa P, et al. High rates of drug-induced liver injury in people living with HIV Coinfected with
tuberculosis (TB) irrespective of antiretroviral therapy timing during antituberculosis treatment: results from the starting
antiretroviral therapy at three points in TB trial. Clin Infect Dis. 2020;70(12):2675-2682. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31622456.

17. Navarro VJ, Khan I, Bjornsson E, Seeff LB, Serrano J, Hoofnagle JH. Liver injury from herbal and dietary supplements.
Hepatology. 2017;65(1):363-373. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27677775.

18. Neukam K, Mira JA, Collado A, et al. Liver toxicity of current antiretroviral regimens in HIV-infected patients with chronic viral
hepatitis in a real-life setting: the HEPAVIR SEG-HEP cohort. PLoS One. 2016;11(2):e0148104. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26848975.

19. Otto AO, Rivera CG, Zeuli JD, Temesgen Z. Hepatotoxicity of contemporary antiretroviral drugs: a review and evaluation of
published clinical data. Cells. 2021;10(5). Available at: https://www.ncbi.nlm.nih.gov/pubmed/34065305.

20. Phillips E, Bartlett JA, Sanne I, et al. Associations between HLA-DRB1*0102, HLA-B*5801, and hepatotoxicity during initiation of
nevirapine-containing regimens in South Africa. J Acquir Immune Defic Syndr. 2013;62(2):e55-57. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23328091.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-33
21. Phung BC, Sogni P, Launay O. Hepatitis B and human immunodeficiency virus co-infection. World J Gastroenterol.
2014;20(46):17360-17367. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25516647.

22. Pillaye JN, Marakalala MJ, Khumalo N, Spearman W, Ndlovu H. Mechanistic insights into antiretroviral drug-induced liver injury.
Pharmacol Res Perspect. 2020;8(4):e00598. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32643320.

23. Pokorska-Spiewak M, Stanska-Perka A, Popielska J, et al. Prevalence and predictors of liver disease in HIV-infected children and
adolescents. Sci Rep. 2017;7(1):12309. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28951598.

24. Rutstein RM, Samson P, Fenton T, et al. Long-term safety and efficacy of atazanavir-based therapy in HIV-infected infants, children
and adolescents: the Pediatric AIDS Clinical Trials Group protocol 1020A. Pediatr Infect Dis J. 2015;34:162-167. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25232777.

25. Scott JA, Chew KW. Treatment optimization for HIV/HCV co-infected patients. Ther Adv Infect Dis. 2017;4(1):18-36. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28357062.

26. Sevinsky H, Zaru L, Wang R, et al. Pharmacokinetics and pharmacodynamics of atazanavir in HIV-1-infected children treated with
atazanavir powder and ritonavir: combined analysis of the PRINCE-1 and -2 studies. Pediatr Infect Dis J. 2018;37(6):e157-e165.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29206748.

27. Sohrab SS, Suhail M, Ali A, Qadri I, Harakeh S, Azhar EI. Consequence of HIV and HCV co-infection on host immune response,
persistence and current treatment options. Virusdisease. 2018;29(1):19-26. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29607354.

28. Sonderup MW, Maughan D, Gogela N, et al. Identification of a novel and severe pattern of efavirenz drug-induced liver injury in
South Africa. AIDS. 2016;30(9):1483-1485. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26959511.

29. Sonderup MW, Wainwright HC. Human Immunodeficiency virus infection, antiretroviral therapy, and liver pathology.
Gastroenterol Clin North Am. 2017;46(2):327-343. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28506368.

30. Strehlau R, Donati AP, Arce PM, et al. PRINCE-1: safety and efficacy of atazanavir powder and ritonavir liquid in HIV-1-infected
antiretroviral-naive and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26066346.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-34
31. Sudjaritruk T, Bunupuradah T, Aurpibul L, et al. Nonalcoholic fatty liver disease and hepatic fibrosis among perinatally HIV-
monoinfected Asian adolescents receiving antiretroviral therapy. PLoS One. 2019;14(12):e0226375. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31856189.

32. Tadesse BT, Foster BA, Kabeta A, et al. Hepatic and renal toxicity and associated factors among HIV-infected children on
antiretroviral therapy: a prospective cohort study. HIV Med. 2019;20(2):147-156. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30474906.

33. The European Pregnancy and Paediatric HIV Cohort Collaboration, (EPPICC) Study Group in EuroCoord. Safety of
zidovudine/lamivudine scored tablets in children with HIV infection in Europe and Thailand. Eur J Clin Pharmacol.
2017;73(4):463-468. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28028587.

34. The National Institute of Diabetes and Digestive and Kidney Diseases. Clinical and research information on drug-induced liver
Injury. 2019.

35. Wu PY, Cheng CY, Liu CE, et al. Multicenter study of skin rashes and hepatotoxicity in antiretroviral-naive HIV-positive patients
receiving non-nucleoside reverse-transcriptase inhibitor plus nucleoside reverse-transcriptase inhibitors in Taiwan. PLoS One.
2017;12(2):e0171596. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28222098.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-35
Table 17f. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Insulin Resistance,
Asymptomatic Hyperglycemia, and Diabetes Mellitus
Updated: April 11, 2022
Reviewed: April 11, 2023

Associated Onset/Clinical Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Manifestations Frequency Monitoring
Insulin ZDV, LPV/r and, Onset Children Risk Factors for Type Prevention Counsel patient on lifestyle
Resistance, possibly, other 2 DM modification
Asymptomatic PIs and INSTIs • Weeks to months after • IR, 6% to 12% • Lifestyle modification (e.g., implementing a diet low
Hyperglycemia, beginning therapy (incidence is • Lipodystrophy in saturated fat, cholesterol,
higher during Monitoring
and Diabetes • Metabolic syndrome trans fat, and refined sugars;
Presentation puberty, 20% to
Mellitusa • Monitor for signs of increasing physical activity;
30%) • Family history of DM ceasing smoking).
• Asymptomatic fasting DM, change in body
hyperglycemia (which • IFPG, 0% to 7% • High BMI (obesity) habitus, and
sometimes occurs in acanthosis nigricans. Recommend that the patient
the setting of • IGT, 3% to 4% consult with a dietician.
lipodystrophy), • Obtain RPG levels at
• DM, 0.2 per initiation of ART, If the patient is receiving
metabolic syndrome, 100 child-years
or growth delay 3–6 months after ZDV, switch to TAF, TDF, or
ART initiation, and ABC.
• Symptomatic DM yearly thereafter.
(rare) For Patients With Either an
• In patients with an RPG ≥200 mg/dL Plus
RPG ≥140 mg/dL, Symptoms of DM or an
obtain FPG after an FPG ≥126 mg/dL
8-hour fast and
consider referring the • These patients meet
patient to an diagnostic criteria for DM;
endocrinologist. consult an endocrinologist.

For Patients With an FPG

of 100–125 mg/dL
• Impaired FPG suggests
insulin resistance; consult
an endocrinologist.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-36
Table 17f. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Insulin Resistance,
Asymptomatic Hyperglycemia, and Diabetes Mellitus

Associated Onset/Clinical Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Manifestations Frequency Monitoring
For Patients With an FPG
<100 mg/dL
• This FPG is normal, but a
normal FPG does not
exclude IR. Recheck FPG
in 6–12 months.
a IR, asymptomatic hyperglycemia, IFPG, IGT, and DM form a spectrum of increasing severity.
IR: Often defined as elevated insulin levels for the level of glucose observed.
IFPG: Often defined as an FPG of 100–125 mg/dL.
IGT: Often defined as an elevated 2-hour plasma glucose (PG) of 140–199 mg/dL in a 75-g oral glucose tolerance test (OGTT) (or, if the patient weighs <43 kg, 1.75 g per kg of
glucose up to a maximum of 75 g).
DM: Often defined as either an FPG ≥126 mg/dL, an RPG ≥200 mg/dL in a patient with hyperglycemia symptoms, a glycosylated hemoglobin (HgbA1c) of ≥6.5%, or a 2-hour PG
≥200 mg/dL in an OGTT.
However, the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV does not recommend performing routine measurements of insulin levels,
HgbA1c, or glucose tolerance without consulting an endocrinologist. These guidelines are instead based on the readily available RPG and FPG levels. The HgbA1c test may
underestimate glycemia in people with HIV; it is not recommended for diagnosis and may present challenges for monitoring.
Key: ABC = abacavir; ART = antiretroviral therapy; ARV = antiretroviral; BMI = body mass index; DM = diabetes mellitus; FPG = fasting plasma glucose; IFPG = impaired fasting
plasma glucose; IGT = impaired glucose tolerance; INSTI = integrase strand transfer inhibitor; IR = insulin resistance; LPV/r = lopinavir/ritonavir; mg/dL = milligrams per deciliter;
PI = protease inhibitor; RPG = random plasma glucose; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-37
References1-24

1. Aldrovandi GM, Lindsey JC, Jacobson DL, et al. Morphologic and metabolic abnormalities in vertically HIV-infected children
and youth. AIDS. 2009;23(6):661-672. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19279441.

2. American Diabetes Association. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes-2022. Diabetes
Care. 2022;45(Suppl 1):S17-S38. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34964875.

3. Chantry CJ, Hughes MD, Alvero C, et al. Lipid and glucose alterations in HIV-infected children beginning or changing
antiretroviral therapy. Pediatrics. 2008;122(1):e129-138. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18519448.

4. Dirajlal-Fargo S, Musiime V, Cook A, et al. Insulin resistance and markers of inflammation in HIV-infected Ugandan children
in the CHAPAS-3 Trial. Pediatr Infect Dis J. 2017;36(8):761-767. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28067719.

5. Espiau M, Yeste D, Noguera-Julian A, et al. Metabolic syndrome in children and adolescents living with HIV. Pediatr Infect Dis
J. 2016;35(6):e171-176. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26910591.

6. Fitch KV. Contemporary lifestyle modification interventions to improve metabolic comorbidities in HIV. Curr HIV/AIDS Rep.
2019;16(6):482-491. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31776973.

7. Fortuny C, Deya-Martinez A, Chiappini E, Galli L, de Martino M, Noguera-Julian A. Metabolic and renal adverse effects of
antiretroviral therapy in HIV-infected children and adolescents. Pediatr Infect Dis J. 2015;34(5 Suppl 1):S36-43. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25629891.

8. Geffner ME, Patel K, Jacobson DL, et al. Changes in insulin sensitivity over time and associated factors in HIV-infected
adolescents. AIDS. 2018;32(5):613-622. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29280758.

9. Geffner ME, Patel K, Miller TL, et al. Factors associated with insulin resistance among children and adolescents perinatally
infected with HIV-1 in the Pediatric HIV/AIDS Cohort Study. Horm Res Paediatr. 2011;76(6):386-391. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22042056.

10. Gojanovich GS, Jacobson DL, Jao J, et al. Mitochondrial dysfunction and insulin resistance in pubertal youth living with
perinatally acquired HIV. AIDS Res Hum Retroviruses. 2020;36(9):703-711. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32586116.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-38
11. Hadigan C, Kattakuzhy S. Diabetes mellitus type 2 and abnormal glucose metabolism in the setting of human immunodeficiency
virus. Endocrinol Metab Clin North Am. 2014;43(3):685-696. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25169561.

12. Hazra R, Hance LF, Monteiro JP, et al. Insulin resistance and glucose and lipid concentrations in a cohort of perinatally HIV-
infected Latin American children. Pediatr Infect Dis J. 2013;32(7):757-759. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23360832.

13. Innes S, Abdullah KL, Haubrich R, Cotton MF, Browne SH. High prevalence of dyslipidemia and insulin resistance in HIV-
infected pre-pubertal African children on antiretroviral therapy. Pediatr Infect Dis J. 2015;35(1):e1-7. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26421804.

14. Loomba-Albrecht LA, Bregman T, Chantry CJ. Endocrinopathies in children infected with human immunodeficiency virus.
Endocrinol Metab Clin North Am. 2014;43(3):807-828. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25169569.

15. Mirani G, Williams PL, Chernoff M, et al. Changing trends in complications and mortality rates among U.S. youth and young
adults with HIV infection in the era of combination antiretroviral therapy. Clin Infect Dis. 2015;61(12):1850-1861. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26270680.

16. Non LR, Escota GV, Powderly WG. HIV and its relationship to insulin resistance and lipid abnormalities. Transl Res.
2017;183:41-56. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28068521.

17. Paengsai N, Jourdain G, Salvadori N, et al. Recommended first-line antiretroviral therapy regimens and risk of diabetes mellitus
in HIV-infected adults in resource-limited settings. Open Forum Infect Dis. 2019;6(10):ofz298. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31660327.

18. Paganella MP, Cohen RA, Harris DR, et al. Association of dyslipidemia and glucose abnormalities with antiretroviral treatment
in a cohort of HIV-infected Latin American children. J Acquir Immune Defic Syndr. 2017;74(1):e1-e8. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27570910.

19. Patel K, Wang J, Jacobson DL, et al. Aggregate risk of cardiovascular disease among adolescents perinatally infected with the
human immunodeficiency virus. Circulation. 2014;129(11):1204-1212. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24366631.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-39
20. Rebeiro PF, Jenkins CA, Bian A, et al. Risk of incident diabetes mellitus, weight gain, and their relationships with integrase
inhibitor-based initial antiretroviral therapy among persons with human immunodeficiency virus in the United States and
Canada. Clin Infect Dis. 2021;73(7):e2234-e2242. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32936919.

21. Samaras K. Prevalence and pathogenesis of diabetes mellitus in HIV-1 infection treated with combined antiretroviral therapy. J
Acquir Immune Defic Syndr. 2009;50(5):499-505. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19223782.

22. Shah S, Hill A. Risks of metabolic syndrome and diabetes with integrase inhibitor-based therapy: Republication. Curr Opin HIV
AIDS. 2021;16(2):106-114. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33625041.

23. Summers NA, Lahiri CD, Angert CD, et al. Metabolic changes associated with the use of integrase strand transfer inhibitors
among virally controlled women. J Acquir Immune Defic Syndr. 2020;85(3):355-362. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33060420.

24. Takemoto JK, Miller TL, Wang J, et al. Insulin resistance in HIV-infected youth is associated with decreased mitochondrial
respiration. AIDS. 2017;31(1):15-23. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27755108.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-40
Table 17g. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lactic Acidosis
Updated: April 11, 2022
Reviewed: April 11, 2023

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
Lactic NRTIs Onset 3TC, FTC, ABC, Adults Prevention For Patients With Lactate
Acidosis TAF, and TDF 2.1–5.0 mmol/L (Confirmed
• ZDV • Generally after years of are less likely to • Female sex • Due to the presence of With a Second Test)
exposure induce clinically propylene glycol as a
• Less likely with • High BMI diluent, LPV/r oral solution • Consider discontinuing all
3TC, FTC, significant
Presentation • Chronic HCV infection should not be used in ARV drugs temporarily while
ABC, TAF, and mitochondrial
dysfunction than preterm neonates or any conducting additional
TDF • Lactic acidosis may be • African American race
ZDV. neonate who has not diagnostic work-up.
clinically asymptomatic.
• Coadministration of attained a postmenstrual
Other Drugs For Patients With Lactate
Lactic Acidosis May Also TDF with metformin age of 42 weeks and a
• See the Risk postnatal age of ≥14 days. >5.0 mmol/L (Confirmed With
Present With Insidious
Factors and • Overdose of propylene a Second Test)b or
Onset of a Combination of • Monitor for clinical
Prevention/ glycol >10.0 mmol/L (Any One Test)
Signs and Symptoms manifestations of lactic
Monitoring • Discontinue all ARV drugs.
• Generalized fatigue, • CD4 count acidosis and promptly
columns for
weakness, and myalgias <350 cells/mm3 adjust therapy.
information • Provide supportive therapy
regarding the • Acquired riboflavin or Monitoring (e.g., IV fluids; some
• Vague abdominal pain,
toxicity of thiamine deficiency patients may require
weight loss, unexplained
propylene glycol Asymptomatic Patients sedation and respiratory
nausea, or vomiting • Possible pregnancy
when LPV/r oral support to reduce oxygen
• Routine measurement of
solution is used • Dyspnea demand and ensure
• Overdose in setting of serum lactate is not
in neonates. adequate oxygenation of
• Peripheral neuropathy renal insufficiency (e.g., recommended.
tissues).
3TC)
Note: Patients may present Patients With Clinical Signs
Anecdotal (Unproven)
with acute multiorgan failure Preterm Infants or Any or Symptoms Consistent
Supportive Therapies
(e.g., fulminant hepatic Neonates Who Have Not With Lactic Acidosis
failure, pancreatic failure, Attained a Postmenstrual • Administer bicarbonate
• Obtain blood lactate
respiratory failure). Age of 42 Weeks and a infusions, THAM, high doses
level.a
Postnatal Age of of thiamine and riboflavin,
≥14 Days • Additional diagnostic and oral antioxidants
evaluations should include (e.g., L-carnitine, co-enzyme
• Exposure to propylene
serum bicarbonate, anion Q10, vitamin C).
glycol, which is used as
gap, and/or arterial blood
a diluent in LPV/r oral
gas; amylase and lipase;

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-41
Table 17g. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lactic Acidosis

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
solution, because these serum albumin; and Following the resolution of
newborns have a hepatic transaminases. clinical and laboratory
diminished ability to abnormalities, resume therapy
metabolize propylene either with an NRTI-sparing
glycol may lead to regimen or a revised NRTI-
accumulation, containing regimen. Institute a
increasing the risk of revised NRTI-containing
adverse events. regimen with caution, using
NRTIs that are less likely to
induce mitochondrial
dysfunction (ABC, TAF, TDF,
FTC, or 3TC). Lactate should
be monitored monthly for
≥3 months.
a Blood for lactate determination should be collected, without prolonged tourniquet application or fist clenching, into a pre-chilled, gray-top, fluoride-oxalate-containing tube and transported
on ice to the laboratory to be processed within 4 hours of collection.
b Management can be initiated before receiving the results of the confirmatory test.
Key: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; BMI = body mass index; CD4 = CD4 T lymphocyte; FTC = emtricitabine; HCV = hepatitis C virus; IV = intravenous;
LPV/r = lopinavir/ritonavir; NRTI = nucleoside reverse transcriptase inhibitor; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; THAM = tris (hydroxymethyl)
aminomethane; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-42
References1-21
General Reviews

1. Fortuny C, Deya-Martinez A, Chiappini E, Galli L, de Martino M, Noguera-Julian A. Metabolic and renal adverse effects of antiretroviral
therapy in HIV-infected children and adolescents. Pediatr Infect Dis J. 2015;34(5 Suppl 1):S36-43. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25629891.

2. Margolis AM, Heverling H, Pham PA, Stolbach A. A review of the toxicity of HIV medications. J Med Toxicol. 2014;10(1):26-39.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/23963694.

3. Tukei VJ, Asiimwe A, Maganda A, et al. Safety and tolerability of antiretroviral therapy among HIV-infected children and adolescents in
Uganda. J Acquir Immune Defic Syndr. 2012;59(3):274-280. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22126740.

4. Bartlett AW, Mohamed TJ, Sudjaritruk T, et al. Disease- and treatment-related morbidity in adolescents with perinatal HIV infection in
Asia. Pediatr Infect Dis J. 2019;38(3):287-292. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30281549.

5. Tshamala HK, Aketi L, Tshibassu PM, et al. The lipodystrophy syndrome in HIV-infected children under antiretroviral therapy: a first
report from the Central Africa. Int J Pediatr. 2019;2019:7013758. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30941184.

6. Smith ZR, Horng M, Rech MA. Medication-induced hyperlactatemia and lactic acidosis: a systematic review of the literature.
Pharmacotherapy. 2019;39(9):946-963. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31361914.

Risk Factors

7. Aperis G, Paliouras C, Zervos A, Arvanitis A, Alivanis P. Lactic acidosis after concomitant treatment with metformin and tenofovir in a
patient with HIV infection. J Ren Care. 2011;37(1):25-29. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21288314.

8. Konala VM, Adapa KP, Dinesh KP. et al. Lamivudine-associated lactic acidosis. Am J Ther. 2022;29(4):449-451. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35622009.

9. Kaletra (lopinavir/ritonavir) [package insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021251s059,021906s054lbl.pdf.

10. Firnhaber C, Smeaton LM, Grinsztejn B, et al. Differences in antiretroviral safety and efficacy by sex in a multinational randomized clinical
trial. HIV Clin Trials. 2015;16(3):89-99. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25979186.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-43
11. Fortuin-de Smidt M, de Waal R, Cohen K, et al. First-line antiretroviral drug discontinuations in children. PLoS One. 2017;12(2):e0169762.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28192529.

12. Lim TY, Poole RL, Pageler NM. Propylene glycol toxicity in children. J Pediatr Pharmacol Ther. 2014;19(4):277-282. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25762872.

13. Kirmse B, Hobbs L, Aaron L, et al. Acylcarnitines and genetic variation in fat oxidation genes in HIV-infected, antiretroviral-treated
children with and without myopathy. Pediatr Infect Dis J. 2022;41(8):e306-e311. Available at
https://www.ncbi.nlm.nih.gov/pubmed/35622436.

14. Mamiafo CT, Moor VJ, Nansseu JR, Pieme CA, Tayou C, Yonkeu JN. Hyperlactatemia in a group of HIV patients living in Yaounde-
Cameroon. AIDS Res Ther. 2014;11(1):2. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24428886.

15. Matthews LT, Giddy J, Ghebremichael M, et al. A risk-factor guided approach to reducing lactic acidosis and hyperlactatemia in patients on
antiretroviral therapy. PLoS One. 2011;6(4):e18736. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21494566.

16. Moren C, Noguera-Julian A, Garrabou G, et al. Mitochondrial evolution in HIV-infected children receiving first- or second-generation
nucleoside analogues. J Acquir Immune Defic Syndr. 2012;60(2):111-116. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22362155.

17. Tetteh RA, Nartey ET, Lartey M, et al. Association between the occurrence of adverse drug events and modification of first-line highly
active antiretroviral therapy in Ghanaian HIV patients. Drug Saf. 2016;39(11):1139-1149. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27638659.

18. Wester CW, Eden SK, Shepherd BE, et al. Risk factors for symptomatic hyperlactatemia and lactic acidosis among combination
antiretroviral therapy-treated adults in Botswana: results from a clinical trial. AIDS Res Hum Retroviruses. 2012;28(8):759-765. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/22540188.

Monitoring and Management

19. Arnouk S, Whitsett M, Papadopoulos Z, et al. Successful treatment of tenofovir alafenamide-induced lactic acidosis: a case report. J Pharm
Pract. 2022;8971900221105042. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35635046.

20. Barlow-Mosha L, Eckard AR, McComsey GA, Musoke PM. Metabolic complications and treatment of perinatally HIV-infected children
and adolescents. J Int AIDS Soc. 2013;16(1):18600. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23782481.

21. Claessens YE, Cariou A, Monchi M, et al. Detecting life-threatening lactic acidosis related to nucleoside-analog treatment of human
immunodeficiency virus-infected patients, and treatment with L-carnitine. Crit Care Med. 2003;31(4):1042-1047. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12682470.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-44
22. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309-2319. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25494270.

23. Marfo K, Garala M, Kvetan V, Gasperino J. Use of Tris-hydroxymethyl aminomethane in severe lactic acidosis due to highly active
antiretroviral therapy: a case report. J Clin Pharm Ther. 2009;34(1):119-123. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19125910.

24. Jung B, Martinez M, Claessens YE, et al. Diagnosis and management of metabolic acidosis: guidelines from a French expert panel. Ann
Intensive Care. 2019;9(1):92. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31418093.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-45
Table 17h. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lipodystrophies
and Weight Gain
Updated: April 11, 2022
Reviewed: April 11, 2023

Onset/Clinical Estimated Prevention/

Adverse Effects Associated ARVs Risk Factors Management
Manifestations Frequency Monitoring
Lipodystrophy (Fat See below for specific Onset Frequency is low • Genetic Prevention • Physicians should
Maldistribution) associations. • Increase in trunk (<5%) with current predisposition • Initiate a calorically perform a regimen
General Information and limb fat is the regimens. appropriate low-fat review and consider
• Puberty changing the regimen
first sign; peripheral diet and an exercise
fat wasting may not • HIV-associated regimen. when lipodystrophy
appear for 12–24 inflammation occurs.
months after ART Monitoring • Improvement in fat
• Older age
initiation. • BMI measurement maldistribution can
• Longer duration vary following a
of ART • Waist circumference
regimen change.
and waist-hip ratio
• Body habitus Improvement may
occur after several
months or years, or it
may not occur at all.
Central Can occur in the Presentation Frequency is low • Obesity before Prevention • Counsel patient on
Lipohypertrophy absence of ART, but • Central fat (<5%) with current initiation of • Initiate a calorically lifestyle modification
or Lipo- these conditions most accumulation with regimens. therapy appropriate low-fat and dietary
Accumulation often are associated increased diet and an exercise interventions
with the use of PIs • Sedentary (e.g., maintaining a
abdominal girth, lifestyle regimen.
and EFV. which may include calorically appropriate
a dorsocervical fat Monitoring diet that is low in
pad (buffalo hump). saturated fats and
• BMI measurement
Gynecomastia may simple carbohydrates
occur in males, or • Waist circumference and starting an
breast hypertrophy and waist-hip ratio exercise regimen,
may occur in measurements especially strength
females, training).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-46
Table 17h. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lipodystrophies and
Weight Gain

Onset/Clinical Estimated Prevention/

Adverse Effects Associated ARVs Risk Factors Management
Manifestations Frequency Monitoring
particularly with the • Recommend smoking
use of EFV. cessation (if
applicable) to
decrease future CVD
risk.
• Consider using an
INSTI instead of a PI
or EFV, although
some INSTIs may be
associated with
generalized weight
gain (see below).
Data Are Insufficient to
Allow the Panel to
Safely Recommend
Use of Any of the
Following Modalities in
Children
• Recombinant human
growth hormone
• Growth hormone–
releasing hormone
• Metformin
• Thiazolidinediones
• Recombinant human
leptin
• Anabolic steroids
• Liposuction
Facial/Peripheral Most cases are Presentation Frequency is low Underweight Prevention • Replace ZDV with
Lipoatrophy associated with the • Thinning of (<5%) with current before ART • Limit the use of ZDV. another NRTI when
use of ZDV, a subcutaneous fat in regimens. initiation. possible.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-47
Table 17h. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lipodystrophies and
Weight Gain

Onset/Clinical Estimated Prevention/

Adverse Effects Associated ARVs Risk Factors Management
Manifestations Frequency Monitoring
thymidine analogue the face, buttocks, Monitoring Data Are Insufficient to
NRTI. and extremities, • Patient self-report Allow the Panel to
measured as a and physical Safely Recommend
decrease in examination are the Use of Any of the
trunk/limb fat by most sensitive Following Modalities in
DXA or triceps methods of Children
skinfold thickness. monitoring • Injections of
Preservation of lipoatrophy. poly-L-lactic acid
lean body mass
distinguishes • Recombinant human
lipoatrophy from leptin
HIV-associated
• Autologous fat
wasting.
transplantation
• Thiazolidinediones
Weight Gain Significant weight Onset Rate of In Infants and Prevention Counsel patient on
gain may occur with development of Children • Initiate a calorically lifestyle modification and
all ARV regimens, but • Gradual weight obesity is unclear. dietary interventions
gain after initiating • Have not been appropriate low-fat
it appears to be more evaluated yet diet and an exercise (e.g., maintaining a
pronounced with ARV drugs is calorically appropriate
common with all regimen.
DTG, BIC, and TAF. In Adolescents healthy diet that is low in
currently used saturated fats and
regimens. The • Female sex Monitoring
simple carbohydrates
mechanism for • BMI measurement
• Pre-treatment and starting an exercise
weight gain is regimen, especially
obesity • Waist circumference
unclear and under strength training).
and waist-hip ratio
investigation. In Adults measurements
• Low pre-
treatment BMI
• Older age
• Female sex
• Black race

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-48
Table 17h. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lipodystrophies and
Weight Gain
Key: ART = antiretroviral therapy; ARV = antiretroviral; BIC = bictegravir; BMI = body mass index; CVD = cardiovascular disease; DTG = dolutegravir; DXA = dual energy X-ray
absorptiometry; EFV = efavirenz; INSTI = integrase strand transfer inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; TAF = tenofovir
alafenamide; ZDV = zidovudine
See the archived version of Supplement III, February 23, 2009, Pediatric Guidelines on the Clinicalinfo website for a more complete discussion and reference list.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-49
References1-36
1. Alves Junior CAS, de Lima LRA, de Souza MC, Silva DAS. Anthropometric measures associated with fat mass estimation in children and
adolescents with HIV. Appl Physiol Nutr Metab. 2019;44(5):493-498. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30286302.

2. Arbeitman LE, O'Brien RC, Somarriba G, et al. Body mass index and waist circumference of HIV-infected youth in a Miami cohort:
comparison to local and national cohorts. J Pediatr Gastroenterol Nutr. 2014;59(4):449-454. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24709829.

3. Arrive E, Viard JP, Salanave B, et al. Metabolic risk factors in young adults infected with HIV since childhood compared with the general
population. PLoS One. 2018;13(11):e0206745. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30408056.

4. Bares SH. Is Modern Antiretroviral Therapy Causing Weight Gain? Clin Infect Dis. 2020;71(6):1390-1392. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31608360.

5. Bhagwat P, Ofotokun I, McComsey GA, et al. Changes in waist circumference in HIV-infected individuals initiating a raltegravir or
protease inhibitor regimen: effects of sex and race. Open Forum Infect Dis. 2018;5(11):ofy201. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30465010.

6. Bourgi K, Rebeiro PF, Turner M, et al. Greater weight gain in treatment naive persons starting dolutegravir-based antiretroviral therapy.
Clin Infect Dis. 2019;70(7):1267-1274. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31100116.

7. Cohen S, Innes S, Geelen SP, et al. Long-term changes of subcutaneous fat mass in HIV-infected children on antiretroviral therapy: a
retrospective analysis of longitudinal data from two pediatric HIV-cohorts. PLoS One. 2015;10(7):e0120927. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26148119.

8. de Castro JAC, de Lima LRA, Silva DAS. Accuracy of octa-polar bioelectrical impedance analysis for the assessment of total and
appendicular body composition in children and adolescents with HIV: comparison with dual energy X-ray absorptiometry and air displacement
plethysmography. J Hum Nutr Diet. 2018;31(2):276-285. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28799180.

9. de Medeiros R, da Silva TAL, de Oliveira ALV, et al. Influence of Healthy Habits Counseling on Biochemical and Metabolic Parameters
in Children and Adolescents with HIV: Longitudinal Study. Nutrients. 2021;13(9). Available at: https://www.ncbi.nlm.nih.gov/pubmed/34579114.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-50
10. Dos Reis LC, de Carvalho Rondo PH, de Sousa Marques HH, Jose Segri N. Anthropometry and body composition of vertically HIV-
infected children and adolescents under therapy with and without protease inhibitors. Public Health Nutr. 2015;18(7):1255-1261. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25115797.

11. Falutz J, Mamputu JC, Potvin D, et al. Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human
immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase
3 trials with safety extension data. J Clin Endocrinol Metab. 2010;95(9):4291-4304. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20554713.

12. Giacomet V, Lazzarin S, Manzo A, et al. Body Fat Distribution and Metabolic Changes in a Cohort of Adolescents Living With HIV
Switched to an Antiretroviral Regimen Containing Dolutegravir. Pediatr Infect Dis J. 2021;40(5):457-459. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33847293.

13. Innes S, Harvey J, Collins IJ, Cotton MF, Judd A. Lipoatrophy/lipohypertrophy outcomes after antiretroviral therapy switch in children in
the UK/Ireland. PLoS One. 2018;13(4):e0194132. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29617438.

14. Kenny J, Doerholt K, Gibb DM, Judd A, Collaborative HIV Paediatric Study Steering Committee. Who gets severe gynecomastia among
HIV-infected children in the United Kingdom and Ireland? Pediatr Infect Dis J. 2017;36(3):307-310. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27879556.

15. Koay WLA, Dirajlal-Fargo S, Levy ME, et al. Integrase Strand Transfer Inhibitors and Weight Gain in Children and Youth With Perinatal
Human Immunodeficiency Virus in the DC Cohort. Open Forum Infect Dis. 2021;8(7):ofab308. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34295943.

16. Kumar S, Samaras K. The impact of weight gain during HIV treatment on risk of pre-diabetes, diabetes mellitus, cardiovascular disease,
and mortality. Front Endocrinol (Lausanne). 2018;9:705. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30542325.

17. Li J, Yusuf EH, Agwu AL. Excessive Weight Gain Associated With Dolutegravir Initiation in a 10-Year-Old Female With Perinatally
Acquired Human Immunodeficiency Virus: A Case Report and Review of the Literature. J Pediatric Infect Dis Soc. 2021;10(3):373-375.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/32448908.

18. Lindegaard B, Hansen T, Hvid T, et al. The effect of strength and endurance training on insulin sensitivity and fat distribution in human
immunodeficiency virus-infected patients with lipodystrophy. J Clin Endocrinol Metab. 2008;93(10):3860-3869. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/18628529.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-51
19. Lo J, You SM, Canavan B, et al. Low-dose physiological growth hormone in patients with HIV and abdominal fat accumulation: a
randomized controlled trial. JAMA. 2008;300(5):509-519. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18677023.

20. McComsey GA, Moser C, Currier J, et al. Body composition changes after initiation of raltegravir or protease inhibitors: ACTG A5260s.
Clin Infect Dis. 2016;62(7):853-862. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26797215.

21. Moure R, Domingo P, Gallego-Escuredo JM, et al. Impact of elvitegravir on human adipocytes: alterations in differentiation, gene
expression and release of adipokines and cytokines. Antiviral Res. 2016;132:59-65. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27216995.

22. Negredo E, Miro O, Rodriguez-Santiago B, et al. Improvement of mitochondrial toxicity in patients receiving a nucleoside reverse-
transcriptase inhibitor-sparing strategy: results from the Multicenter Study with Nevirapine and Kaletra (MULTINEKA). Clin Infect Dis.
2009;49(6):892-900. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19663689.

23. Prendergast AJ. Complications of long-term antiretroviral therapy in HIV-infected children. Arch Dis Child. 2013;98(4):245-246.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/23413313.

24. Raboud JM, Diong C, Carr A, et al. A meta-analysis of six placebo-controlled trials of thiazolidinedione therapy for HIV lipoatrophy. HIV
Clin Trials. 2010;11(1):39-50. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20400410.

25. Ramteke SM, Shiau S, Foca M, et al. Patterns of growth, body composition, and lipid profiles in a South African cohort of human
immunodeficiency virus-infected and uninfected children: a cross-sectional study. J Pediatric Infect Dis Soc. 2017;7(2):143-150. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28481997.

26. Santiprabhob J, Chokephaibulkit K, Khantee P, et al. Adipocytokine dysregulation, abnormal glucose metabolism, and lipodystrophy in
HIV-infected adolescents receiving protease inhibitors. Cytokine. 2020;136:155145. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32920318.

27. Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative
clinical trials. Clin Infect Dis. 2020;71(6):1379-1389. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31606734.

28. Sharma TS, Somarriba G, Arheart KL, et al. Longitudinal changes in body composition by dual-energy radiograph absorptiometry among
perinatally HIV-infected and HIV-uninfected youth: increased risk of adiposity among HIV-infected female youth. Pediatr Infect Dis J.
2018;37(10):1002-1007. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29474262.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-52
29. Sheth SH, Larson RJ. The efficacy and safety of insulin-sensitizing drugs in HIV-associated lipodystrophy syndrome: a meta-analysis of
randomized trials. BMC Infect Dis. 2010;10:183. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20573187.

30. Spoulou V, Kanaka-Gantenbein C, Bathrellou I, et al. Monitoring of lipodystrophic and metabolic abnormalities in HIV-1 infected
children on antiretroviral therapy. Hormones (Athens). 2011;10(2):149-155. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21724540.

31. Su J, Shiau S, Arpadi SM, et al. Switch to Efavirenz Attenuates Lipoatrophy in Girls With Perinatal HIV. J Pediatr Gastroenterol Nutr.
2021;72(1):e15-e20. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32804904.

32. Taramasso L, Di Biagio A, Bovis F, et al. Switching to integrase inhibitors unlinked to weight increase in perinatally HIV-infected young
adults and adolescents: a 10-year observational study. Microorganisms. 2020;8(6). Available at: https://www.ncbi.nlm.nih.gov/pubmed/32521616.

33. Thivalapill N, Simelane T, Mthethwa N, et al. Transition to Dolutegravir Is Associated With an Increase in the Rate of Body Mass Index
Change in a Cohort of Virally Suppressed Adolescents. Clin Infect Dis. 2021;73(3):e580-e586. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33119739.

34. Tungsiripat M, Bejjani DE, Rizk N, et al. Rosiglitazone improves lipoatrophy in patients receiving thymidine-sparing regimens. AIDS.
2010;24(9):1291-1298. Available at: http://www.ncbi.nlm.nih.gov/pubmed/20453626.

35. Violari A, Masenya M, Blanche S, et al. The DIANA Study: Continued Access to Darunavir/Ritonavir (DRV/r) and Long-Term Safety
Follow-Up in HIV-1-Infected Pediatric Patients Aged 3 to < 18 Years. Drug Saf. 2021;44(4):439-446. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33367975.

36. Young L, Wohl DA, Hyslop WB, Lee YZ, Napravnik S, Wilkin A. Effects of raltegravir combined with tenofovir/emtricitabine on body
shape, bone density, and lipids in African-Americans initiating HIV therapy. HIV Clin Trials. 2015;16(5):163-169. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26249671.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-53
Table 17i. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—
Nephrotoxic Effects
Updated: April 11, 2022
Reviewed: April 11, 2023

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
Urolithiasis/ ATV Onset ATV-related In adults, elevated Prevention Provide adequate
Nephrolithiasis nephrolithiasis occurs in urine pH (>5.7) hydration and pain
DRV causes • Weeks to months after <10% of patients and • Maintain adequate control. Consider
crystalluria, but it is starting therapy The risk factors in hydration.
has been reported after using another ARV
not associated with children are
stopping ATV. drug in place of ATV.
nephrolithiasis. Clinical Findings unknown. Monitoring
• Crystalluria • Obtain urinalysis
at least every
• Hematuria 6–12 months.
• Pyuria
• Flank pain
• Increased creatinine levels
in some cases
Renal TDF Onset Adults Risk May Increase Monitor urine protein, If TDF is the likely
Dysfunction in Children With the urine glucose, and cause, consider using
• Variable; in adults, renal • Approximately 2% of Following serum creatinine at an alternative ARV
dysfunction may occur adults experience Characteristics 3- to 6-month drug. TAF has
weeks to months after increased serum intervals. Some significantly less
initiating therapy. creatinine levels. • Aged >6 years Panel members toxicity than TDF.
• Hypophosphatemia appears • Approximately 0.5% • Black race, routinely monitor Changing from TDF to
at a median of 18 months. of adults experience Hispanic/Latino serum phosphate TAF may improve
severe renal ethnicity levels in patients who renal function.
• Glucosuria may occur after complications. are taking TDF.
1 year of therapy. • Advanced HIV
Children infection Measure serum
• Abnormal urine
phosphate if the
protein/osmolality ratio may • Approximately 4% of • Hypertension
patient experiences
be an early indicator. children experience persistent proteinuria

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-54
Table 17i. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Nephrotoxic Effects

Presentation hypophosphatemia or • Diabetes or glucosuria or has

proximal tubulopathy; symptoms of bone
More Common • Concurrent use of
frequency increases pain, muscle pain, or
with prolonged TDF PIs (especially weakness.
• Increased serum creatinine
therapy and advanced LPV/r) and
levels, proteinuria,
HIV infection. preexisting renal Because toxicity risk
normoglycemic glucosuria
dysfunction increases with the
• Increased urinary duration of TDF
• Longer duration of
protein/creatinine ratio and treatment, do not
TDF treatment
albumin/creatinine ratio decrease the
• The presence of frequency of
• Hypophosphatemia, usually
the apolipoprotein monitoring over time.
asymptomatic; may present
L1 variants G1
with bone and muscle pain
and G2 appears to
or muscle weakness
increase the risk
Less Common of renal
abnormality in
• Renal failure, acute tubular children with HIV.
necrosis, Fanconi These alleles are
syndrome, proximal renal more common in
tubulopathy, interstitial persons of Black
nephritis, nephrogenic descent.
diabetes insipidus with
polyuria
Elevation in DTG, COBI, RPV, Onset Common laboratory The risk factors in Monitor serum No need to change
Serum BIC finding. children are creatinine. Assess for therapy.
Creatinine • Within 1 month of starting unknown. renal dysfunction if
treatment serum creatinine Reassure the patient
increases by about the benign
Presentation nature of the
>0.4 mg/dL or if
• Asymptomatic. These drugs increases continue laboratory
decrease renal tubular over time. abnormality.
secretion of creatinine,
leading to an increase in
serum creatinine levels
without a true change in
eGFR.
• Clinicians need to
distinguish between a true

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-55
Table 17i. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Nephrotoxic Effects

change in eGFR and other

causes. A true change may
be associated with other
medical conditions, the
continuing rise of serum
creatinine levels over time,
and albuminuria.

Key: ARV = antiretroviral; ATV = atazanavir; BIC = bictegravir; COBI = cobicistat; DRV = darunavir; DTG = dolutegravir; eGFR = estimated glomerular filtration rate;
LPV/r = lopinavir/ritonavir; mg/dL = milligrams per deciliter; Panel = The Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV;
PI = protease inhibitor; RPV = rilpivirine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-56
References
1. Aliyannissa A, Kuswiyanto RB, Setiabudi D, Nataprawira HM, Alam A, Sekarwana N. Correlation between CD4 count and
glomerular filtration rate or urine protein:creatinine ratio in human immunodeficiency virus–infected children. Kidney Res Clin
Pract. 2020;39(1):40-46. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32146732.

2. Andiman WA, Chernoff MC, Mitchell C, et al. Incidence of persistent renal dysfunction in human immunodeficiency virus–infected
children: associations with the use of antiretrovirals, and other nephrotoxic medications and risk factors. Pediatr Infect Dis J.
2009;28(7):619-625. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19561425.

3. Beng H, Rakhmanina N, Moudgil A, et al. HIV-Associated CKDs in children and adolescents. Kidney Int Rep. 2020;5(12):2292-
2300. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33305123.

4. Bk K, Tiwari S, Chhapola V, Debnath E, Seth A, Jain A. Brief report: subclinical kidney dysfunction in HIV-infected children: a
cross-sectional study. J Acquir Immune Defic Syndr. 2020;85(4):470-474. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33136747.

5. Brunel V, Massy N, Malval B. Atazanavir urolithiasis without recent intake of atazanavir. Ann Biol Clin (Paris). 2019;77(4):459-
460. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31418708.

6. Bunupuradah T, Phupitakphol T, Sophonphan J, et al. Prevalence of persistent renal dysfunction in perinatally HIV-infected Thai
adolescents. Pediatr Infect Dis J. 2017. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28719505.

7. Campbell L, Barbini B, Burling B, et al. Safety of tenofovir alafenamide in people with HIV who experienced proximal renal
tubulopathy on tenofovir disproxil fumarate. J Acquir Immune Defic Syndr. 2021;88(2):214-219. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34506361.

8. de Lastours V, Ferrari Rafael De Silva E, Daudon M, et al. High levels of atazanavir and darunavir in urine and crystalluria in
asymptomatic patients. J Antimicrob Chemother. 2013;68(8):1850-1856. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23599359.

9. Ekulu PM, Nkoy AB, Betukumesu DK, et al. APOL1 risk genotypes are associated with early kidney damage in children in sub-
Saharan Africa. Kidney Int Rep. 2019;4(7):930-938. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31317115.

10. German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal
function. J Acquir Immune Defic Syndr. 2012;61(1):32-40. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22732469.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-57
11. Gupta SK, Post FA, Arribas JR, et al. Renal safety of tenofovir alafenamide vs tenofovir disoproxil fumarate: a pooled analysis of
26 clinical trials. AIDS. 2019;33(9):1455–1465. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30932951.

12. Judd A, Boyd KL, Stohr W, et al. Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on
antiretroviral therapy: a nested case-control study. AIDS. 2010;24(4):525-534. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20139752.

13. Lim Y, Lyall H, Foster C. Tenofovir-associated nephrotoxicity in children with perinatally-acquired HIV infection: a single-centre
cohort study. Clin Drug Investig. 2015;35(5):327-333. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25861908.

14. Lin KY, Liao SH, Liu WC, et al. Cholelithiasis and nephrolithiasis in HIV-positive patients in the era of combination antiretroviral
therapy. PLoS One. 2015;10(9):e0137660. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26360703.

15. Marcelin JR, Berg ML, Tan EM, Amer H, Cummins NW, Rizza SA. Is abnormal urine protein/osmolality ratio associated with
abnormal renal function in patients receiving tenofovir disoproxil fumarate? PLoS One. 2016;11(2):e0149562. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26872144.

16. Nachman SA, Chernoff M, Gona P, et al. Incidence of noninfectious conditions in perinatally HIV-infected children and adolescents
in the HAART era. Arch Pediatr Adolesc Med. 2009;163(2):164-171. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19188649.

17. Nishijima T, Hamada Y, Watanabe K, et al. Ritonavir-boosted darunavir is rarely associated with nephrolithiasis compared with
ritonavir-boosted atazanavir in HIV-infected patients. PLoS One. 2013;8(10):e77268. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24130871.

18. Purswani M, Patel K, Kopp JB, et al. Tenofovir treatment duration predicts proteinuria in a multiethnic United States cohort of
children and adolescents with perinatal HIV-1 infection. Pediatr Infect Dis J. 2013;32(5):495-500. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23249917.

19. Purswani MU, Patel K, Winkler CA, et al. Brief report: APOL1 renal risk variants are associated with chronic kidney disease in
children and youth with perinatal HIV infection. J Acquir Immune Defic Syndr. 2016;73(1):63-68. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27035887.

20. Riordan A, Judd A, Boyd K, et al. Tenofovir use in human immunodeficiency virus-1-infected children in the United Kingdom and
Ireland. Pediatr Infect Dis J. 2009;28(3):204-209. Available at: http://www.ncbi.nlm.nih.gov/pubmed/19209091.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-58
21. Samarawickrama A, Cai M, Smith ER, et al. Simultaneous measurement of urinary albumin and total protein may facilitate
decision-making in HIV-infected patients with proteinuria. HIV Med. 2012;13(9):526-532. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22413854.

22. Seo JW, Kim K, Jun KI, et al. Recovery of tenofovir-induced nephrotoxicity following switch from tenofovir disoproxil fumarate to
tenofovir alafenamide in human immunodeficiency virus–positive patients. Infect Chemother. 2020;52(3):381-388. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32757496.

23. Soares DS, Cavalcante MG, Ribeiro SM, et al. Acute kidney injury in HIV-infected children: comparison of patients according to
the use of highly active antiretroviral therapy. J Pediatr (Rio J). 2016;92(6):631-637. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27542916.

24. Soler-Palacin P, Melendo S, Noguera-Julian A, et al. Prospective study of renal function in HIV-infected pediatric patients receiving
tenofovir-containing HAART regimens. AIDS. 2011;25(2):171-176. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21076275.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-59
Table 17j. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Osteopenia and
Osteoporosis
Updated: April 11, 2023
Reviewed: April 11, 2023

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
Osteopenia Any ARV regimen Onset BMD z score Less • Longer duration and Prevention • Same options as for
and Than −2.0 greater severity of HIV prevention
Specific Agents • Any age; decrease • Ensure that the patient
Osteoporosis disease
of Concern in BMD is usually • <10% in U.S. has sufficient intake and • Consider changing the ARV
seen soon after cohorts • Detectable viral load levels of both calcium and regimen (e.g., switching from
• TDF,
initiating ART. vitamin D. TDF to TAF and/or from
especially • Approximately • Vitamin D LPV/r to RPV or an
when used in Presentation 10% to 20% in insufficiency/deficiency • Encourage weight-bearing
unboosted INSTI whenever
a regimen that international exercise.
• Usually • Delayed growth or possible).
includes a cohorts
boosting agent asymptomatic pubertal delay • Minimize modifiable risk
• Supplement with vitamin D3
(i.e., RTV, factors (e.g., smoking, low
• Rarely presents as • Low BMI to raise serum 25-OH-
COBI) BMI, use of steroids or
osteoporosis, a vitamin D concentrations to
• Lipodystrophy medroxyprogesterone).
clinical diagnosis >30 ng/mL. There is no clear
• PIs (LPV,
defined by • Smoking • Use TAF instead of TDF benefit to administering daily
ATV>DRV)
evidence of bone whenever possible. supplemental vitamin D3
• EFV • Prolonged systemic doses that are >4,000 IU. If
fragility (e.g., a • Use TDF with RPV or an
corticosteroid use patients are receiving a daily
fracture with unboosted INSTI.
minimal trauma). dose of vitamin D3 that is
• Medroxyprogesterone
• When using TDF or EFV >4,000 IU, consider
use
in a regimen, consider monitoring levels of 25-OH-
• Lack of weight-bearing measuring vitamin D vitamin D.
exercise levels and supplementing • An increase in BMD was
with vitamin D3 if seen in one trial that
deficiency is identified. evaluated the use of
alendronate in youth with
HIV and low BMD. However,
the role of bisphosphonates
in managing osteopenia and
osteoporosis in children with

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-60
Table 17j. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Osteopenia and
Osteoporosis

Monitoring HIV has not been

established.
• Assess nutritional intake
(calcium, vitamin D, and
total calories).
• Consider measuring
serum 25-OH-vitamin D
levels, particularly in
patients who are taking
ARV drugs of concern.a
• DXA is rarely indicated.b
a Drugsof greatest concern are TDF and EFV. Some experts measure 25-OH-vitamin D in children with HIV with additional risk factors, including living at high latitudes, sun
avoidance, low dietary intake, and obesity.
b DXA scanning is not routinely recommended for children and youth who are being treated with TDF. DXA scanning can be considered for children and youth who are receiving
additional medications that also affect bone density or have non-HIV related conditions for which DXA scans may be indicated (e.g., cerebral palsy).
Key: 25-OH-vitamin D = 25-hydroxy vitamin D; ART = antiretroviral therapy; ARV = antiretroviral; ATV = atazanavir; BMD = bone mineral density; BMI = body mass index;
COBI = cobicistat; DRV = darunavir; DXA = dual-energy X-ray absorptiometry; EFV = efavirenz; INSTI = integrase strand transfer inhibitor; IU = international unit; LPV = lopinavir;
LPV/r = lopinavir/ritonavir; PI = protease inhibitor; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-61
References1-40
1. Arpadi SM, Shiau S, Strehlau R, et al. Efavirenz is associated with higher bone mass in South African children with HIV. AIDS.
2016;30(16):2459-2467. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27427876.

2. Aurpibul L, Cressey TR, Sricharoenchai S, et al. Efficacy, safety and pharmacokinetics of tenofovir disoproxil fumarate in virologic-
suppressed HIV-infected children using weight-band dosing. Pediatr Infect Dis J. 2015;34(4):392-397. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25760566.

3. Bachrach LK, Gordon CM, Section On E. Bone densitometry in children and adolescents. Pediatrics. 2016;138(4). Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27669735.

4. Baranek B, Wang S, Cheung AM, Mishra S, Tan DH. The effect of tenofovir disoproxil fumarate on bone mineral density: a systematic
review and meta-analysis. Antivir Ther. 2020;25(1):21-32. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32077867.

5. Bi X, Liu F, Zhang X, et al. Vitamin D and Calcium Supplementation Reverses Tenofovir-Caused Bone Mineral Density Loss in People
Taking ART or PrEP: A Systematic Review and Meta-Analysis. Front Nutr. 2022;9:749948. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35433788.

6. Braithwaite K, McPherson TD, Shen Y, et al. Bone outcomes in virally suppressed youth with HIV switching to tenofovir disoproxil
fumarate. South Afr J HIV Med. 2021;22(1):1243. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34522425.

7. Burt LA, Billington EO, Rose MS, Raymond DA, Hanley DA, Boyd SK. Effect of high-dose vitamin D supplementation on volumetric
bone density and bone strength: a randomized clinical trial. JAMA. 2019;322(8):736-745. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31454046.

8. Dave JA, Cohen K, Micklesfield LK, Maartens G, Levitt NS. Antiretroviral therapy, especially efavirenz, is associated with low bone
mineral density in HIV-infected South Africans. PLoS One. 2015;10(12):e0144286. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26633015.

9. Eckard AR, Mora S. Bone health in HIV-infected children and adolescents. Curr Opin HIV AIDS. 2016;11(3):294-300. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26890208.

10. Eckard AR, O'Riordan MA, Rosebush JC, et al. Effects of vitamin D supplementation on bone mineral density and bone markers in HIV-
Infected Youth. J Acquir Immune Defic Syndr. 2017;76(5):539-546. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28902705.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-62
11. Golden NH, Abrams SA, Committee on N. Optimizing bone health in children and adolescents. Pediatrics. 2014;134(4):e1229-1243.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25266429.

12. Gregson CL, Hartley A, Majonga E, et al. Older age at initiation of antiretroviral therapy predicts low bone mineral density in children
with perinatally-infected HIV in Zimbabwe. Bone. 2019;125:96-102. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31082498.

13. Havens PL, Long D, Schuster GU, et al. Tenofovir disoproxil fumarate appears to disrupt the relationship of vitamin D and parathyroid
hormone. Antivir Ther. 2018;23(7):623-628. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30260797.

14. Havens PL, Stephensen CB, Van Loan MD, et al. Vitamin D3 supplementation increases spine bone mineral density in adolescents and
young adults with human immunodeficiency virus infection being treated with tenofovir disoproxil fumarate: a randomized, placebo-
controlled trial. Clin Infect Dis. 2018;66(2):220-228. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29020329.

15. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society
clinical practice guideline. J Clin Endocrinol Metab. 2011;96(7):1911-1930. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21646368.

16. Jacobson DL, Lindsey JC, Gordon C, et al. Alendronate improves bone mineral density in children and adolescents perinatally infected
with human immunodeficiency virus with low bone mineral density for age. Clin Infect Dis. 2020;71(5):1281-1288. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31573608.

17. Jacobson DL, Yu W, Hazra R, et al. Fractures in children and adolescents living with perinatally acquired HIV. Bone. 2020;139:115515.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/32619695.

18. LaFleur J, Bress AP, Myers J, et al. Tenofovir-associated bone adverse outcomes among a US national historical cohort of HIV-infected
veterans: risk modification by concomitant antiretrovirals. Infect Dis Ther. 2018;7(2):293-308. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29492905.

19. Lima LR, Silva RC, Giuliano Ide C, Sakuno T, Brincas SM, Carvalho AP. Bone mass in children and adolescents infected with human
immunodeficiency virus. J Pediatr (Rio J). 2013;89(1):91-99. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23544816.

20. Lindsey JC, Jacobson DL, Spiegel HM, Gordon CM, Hazra R, Siberry GK. Safety and efficacy of 48 and 96 weeks of alendronate in
children and adolescents with perinatal human immunodeficiency virus infection and low bone mineral density for age. Clin Infect Dis.
2021;72(6):1059-1063. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32584996.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-63
21. Mahtab S, Scott C, Asafu-Agyei NAA, et al. Prevalence and predictors of bone health among perinatally HIV-infected adolescents. AIDS.
2020;34(14):2061-2070. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32910060.

22. McComsey GA, Lupo S, Parks D, et al. Switch from tenofovir disoproxil fumarate combination to dolutegravir with rilpivirine improves
parameters of bone health. AIDS. 2018;32(4):477-485. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29239893.

23. Mills A, Arribas JR, Andrade-Villanueva J, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide in antiretroviral
regimens for virologically suppressed adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase 3, non-
inferiority study. Lancet Infect Dis. 2016;16(1):43-52. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26538525.

24. Negredo E, Langohr K, Bonjoch A, et al. High risk and probability of progression to osteoporosis at 10 years in HIV-infected individuals:
the role of PIs. J Antimicrob Chemother. 2018;73(9):2452-2459. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29860519.

25. Okonkwo RI, Weidmann AE, Effa EE. Renal and bone adverse effects of a tenofovir-based regimen in the treatment of HIV-infected
children: a systematic review. Drug Saf. 2016;39(3):209-218. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26692394.

26. Overton ET, Chan ES, Brown TT, et al. Vitamin D and calcium attenuate bone loss with antiretroviral therapy initiation: a randomized
trial. Ann Intern Med. 2015;162(12):815-824. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26075752.

27. Palchetti CZ, Szejnfeld VL, de Menezes Succi RC, et al. Impaired bone mineral accrual in prepubertal HIV-infected children: a cohort
study. Braz J Infect Dis. 2015;19(6):623-630. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26477385.

28. Penner J, Ferrand RA, Richards C, Ward KA, Burns JE, Gregson CL. The impact of vitamin D supplementation on musculoskeletal health
outcomes in children, adolescents, and young adults living with HIV: A systematic review. PLoS One. 2018;13(11):e0207022. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/30439968.

29. Pornpaisalsakul K, Songtaweesin WN, Tepmongkol S, et al. Effects of vitamin D and calcium supplementation on bone mineral density
among Thai youth using daily HIV pre-exposure prophylaxis. J Int AIDS Soc. 2020;23(10):e25624. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33040465.

30. Ross AC, Manson JE, Abrams SA, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of
Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53-58. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21118827.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-64
31. Rukuni R, Rehman AM, Mukwasi-Kahari C, et al. Effect of HIV infection on growth and bone density in peripubertal children in the era
of antiretroviral therapy: a cross-sectional study in Zimbabwe. Lancet Child Adolesc Health. 2021;5(8):569-581. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34139202.

32. Shen Y, Shiau S, Strehlau R, et al. Persistently lower bone mass and bone turnover among south african children living with well-
controlled HIV. AIDS. 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34127577.

33. Starup-Linde J, Rosendahl SB, Storgaard M, Langdahl B. Management of osteoporosis in patients living with HIV-a systematic review
and meta-analysis. J Acquir Immune Defic Syndr. 2020;83(1):1-8. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31809356.

34. Sudjaritruk T, Bunupuradah T, Aurpibul L, et al. Impact of Vitamin D and Calcium Supplementation on Bone Mineral Density and Bone
Metabolism Among Thai Adolescents With Perinatally Acquired Human Immunodeficiency Virus (HIV) Infection: A Randomized
Clinical Trial. Clin Infect Dis. 2021;73(9):1555-1564. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34125899.

35. Sudjaritruk T, Bunupuradah T, Aurpibul L, et al. Adverse bone health and abnormal bone turnover among perinatally HIV-infected Asian
adolescents with virological suppression. HIV Med. 2017;18(4):235-244. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27477214.

36. Tebas P, Kumar P, Hicks C, et al. Greater change in bone turnover markers for efavirenz/emtricitabine/tenofovir disoproxil fumarate
versus dolutegravir + abacavir/lamivudine in antiretroviral therapy-naive adults over 144 weeks. AIDS. 2015;29(18):2459-2464. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/26355674.

37. Torrejon C, Galaz MI, Vizueta E, et al. Evaluation of bone mineral density in children with vertical infection by HIV. Rev Chilena
Infectol. 2018;35(6):634-641. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31095183.

38. Van Welzen BJ, Thielen MAJ, Mudrikova T, Arends JE, Hoepelman AIM. Switching tenofovir disoproxil fumarate to tenofovir
alafenamide results in a significant decline in parathyroid hormone levels: uncovering the mechanism of tenofovir disoproxil fumarate-
related bone loss? AIDS. 2019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31021851.

39. Wohl DA, Orkin C, Doroana M, et al. Change in vitamin D levels and risk of severe vitamin D deficiency over 48 weeks among HIV-1-
infected, treatment-naive adults receiving rilpivirine or efavirenz in a Phase III trial (ECHO). Antivir Ther. 2014;19(2):191-200. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/24430534.

40. Zemel BS, Kalkwarf HJ, Gilsanz V, et al. Revised reference curves for bone mineral content and areal bone mineral density according to
age and sex for black and non-black children: results of the bone mineral density in childhood study. J Clin Endocrinol Metab.
2011;96(10):3160-3169. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21917867.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-65
Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-66
Table 17k. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Rash and
Hypersensitivity Reactions
Updated: April 11, 2023
Reviewed: April 11, 2023

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
Rash Any ARV drug Onset Common (>10%) • Sulfonamide allergy When Starting NVP or Mild-to-Moderate
can cause is a risk factor for Restarting NVP After Maculopapular Rash Without
rash. • First few days to • EFV Interruptions of >14 Days Systemic or Mucosal
rash in patients who
weeks after Involvement
• ETR are taking PIs that
starting new ARV • Utilize once-daily lead-in
contain a
drug(s) • FTC dosing.a This may not be • Most rashes will resolve
sulfonamide moiety
necessary in children ages without intervention; ARV
Presentation • NVP (i.e., DRV).
<2 years.b drugs can be continued while
• Polymorphisms in monitoring.a
• Most rashes mild Less Common • Avoid the use of systemic
to moderate CYP2B6 and multiple
(5% to 10%) corticosteroids during NVP • Antihistamines may provide
diffuse HLA loci are
dose escalation. some relief.
maculopapular • ABC associated with an
eruptions increased risk of rash • Assess the patient for rash Severe Rash and/or Rash
• ATV in patients who are severity, mucosal Accompanied by Systemic
Note: A rash can be • DRV taking NVP. involvement, and other Symptoms
the initial signs of systemic reaction.
manifestation of • TDF • Manage as SJS/TEN/EM
systemic major, DRESS, or HSR as
Unusual (2% to 4%) applicable (see below).
hypersensitivity (see
the SJS/TEN/EM • BIC
major and HSR Rash in Patients Receiving
sections below). • LPV/r NVP
• MVC • Given the elevated risk of
HSR, measure hepatic
• RAL transaminases.
• RPV • If hepatic transaminases are
elevated, NVP should be
discontinued and not

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-67
Table 17k. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Rash and
Hypersensitivity Reactions

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
restarted (see the HSR
section below).

SJS/TEN/EM Many ARV Onset Infrequent Adults When Starting NVP or • Discontinue all ARV drugs
Major drugs, Restarting NVP After and other possible causative
especially • First few days to • NVP (0.3%) • Female sex Interruptions of >14 Days agents (e.g., TMP- SMX).
NNRTIs (see weeks after
• EFV (0.1%) Patients who are Black,
the Estimated starting new ARV • Utilize once-daily lead-in • Provide intensive supportive
Asian, or Hispanic at
Frequency drug(s) • ETR (<0.1%) dosing.a This may not be care, including IV hydration,
higher risk
column) necessary in children aged aggressive wound care, eye
Presentation Case Reports <2 years.b care, labial adhesion
• Initial rash may be preventive care, pain
• ABC • Counsel families to report
mild, but it often management, and
symptoms as soon as they
becomes painful, • ATV antipyretics. Parenteral
appear.
evolving to nutrition and antibiotics may
• DRV also be necessary.
blister/bulla
formation with • LPV/r • Corticosteroids and/or IVIG
necrosis in severe are sometimes used, but the
• RAL
cases. Usually use of these interventions is
involves mucous • ZDV controversial.
membrane
ulceration and/or • Do not reintroduce the
conjunctivitis. offending medication.

• Systemic • In cases where a patient

symptoms may experiences SJS/TEN/EM
also include fever, major while taking an NNRTI,
tachycardia, many experts would avoid
malaise, myalgia, using other NNRTIs when
and arthralgia. restarting ART.

DRESS DRV, DTG, Onset Rare • Unknown Obtain a CBC and AST, ALT, • Discontinue all ARV drugs
EFV, ETR, and creatinine levels from and other possible causative
NVP, RAL, • 1–8 weeks after • Potential association patients who present with agents (e.g., TMP-SMX).
RPV starting new ARV with HLA-B*53:01 suggestive symptoms.
drug(s). • The role of systemic steroids
or IVIG in treatment is

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-68
Table 17k. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Rash and
Hypersensitivity Reactions

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
Presentation and RAL-induced unclear; consultation with a
DRESS specialist is recommended.
• Fever
• Provide supportive care for
• Lymphadenopathy end-organ disease.
• Facial swelling • Do not reintroduce the
• Morbilliform to offending medication.
polymorphous rash
• Peripheral
eosinophilia
• Atypical circulating
lymphocytes
• Internal organ
involvement
(particularly the
liver and/or
kidneys)

HSR ABC Onset <1% to 9% (varies • HLA-B*5701 (HSR is • Screen for HLA-B*5701. • Discontinue all ARV drugs
by ethnicity) very uncommon in ABC should not be and investigate other causes
With or With First Use
people who are HLA- prescribed if HLA-B*5701 of the symptoms (e.g., a
without skin
• Within first 6 B*5701 negative). is present. The medical concurrent viral illness).
involvement
weeks of initiating record should clearly
and excluding • The risk of HSR is • Provide symptomatic
ABC indicate that ABC is
SJS/TEN higher in patients treatment.
contraindicated in these
With Reintroduction who are white than in patients.
patients who are • Most symptoms resolve within
• Within hours of Black or East Asian. • When starting ABC, 48 hours after discontinuing
initiating ABC counsel patients and ABC.
families about the signs
Do not rechallenge with ABC
Presentation and symptoms of HSR to
even if the patient is HLA-
ensure prompt reporting of
• Symptoms include B*5701 negative.
reactions.
high fever, diffuse
skin rash, malaise,

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-69
Table 17k. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Rash and
Hypersensitivity Reactions

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
nausea, headache,
myalgia, arthralgia,
diarrhea, vomiting,
abdominal pain,
pharyngitis, and
respiratory
symptoms
(e.g., dyspnea).
• With continuation
of ABC, symptoms
may progress to
hypotension and
vascular collapse.
With rechallenge,
symptoms can
mimic anaphylaxis.

NVP Onset Occurs in 4% of Adults When Starting NVP or • Discontinue all ARV drugs.
patients on average, Restarting NVP After
• Occurs most with a range of 2.5% • ARV-naive with a Interruptions of >14 Days • Consider other causes of
frequently in the to 11%. higher CD4 count hepatitis and discontinue all
first few weeks of (>250 cells/mm3 in • A 2-week lead-in period hepatotoxic medications.
therapy but can women; >400 with once-daily dosing,
occur through cells/mm3 in men) followed by dose • Provide supportive care as
18 weeks. escalation to twice daily as indicated and monitor the
• Female sex (risk is recommended, may patient closely.
Presentation threefold higher in reduce the risk of
females than in • Do not reintroduce NVP. It is
reaction.a This may not be unclear whether it is safe to
• Flu-like symptoms males). necessary in children aged use other NNRTIs after a
(including nausea,
<2 years.b patient experiences
vomiting, myalgia, Children
fatigue, fever, • Counsel families about symptomatic hepatitis due to
abdominal pain, • NVP hepatotoxicity NVP, and many experts
signs and symptoms of
and jaundice) with and HSR are less would avoid the NNRTI drug
HSR to ensure prompt
or without skin common in class when restarting
reporting of reactions.
rash that may prepubertal children treatment.
progress to hepatic than in adults, and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-70
Table 17k. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Rash and
Hypersensitivity Reactions

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
failure with both are uncommon • Obtain AST and ALT
encephalopathy. in infants. levels in patients with rash.
Obtain AST and ALT
• High CD4
levels at baseline, before
percentage is
dose escalation, 2 weeks
associated with an
after dose escalation, and
increased risk of
thereafter at 3-month
NVP toxicity. In the
intervals.
PREDICT Study, the
risk of NVP toxicity • Avoid NVP use in women
(rash, hepatotoxicity, with CD4 counts
and hypersensitivity) >250 cells/mm3 and in
was 2.65 times men with CD4 counts
greater in children >400 cells/mm3, unless
who had CD4 benefits outweigh risks.
percentages ≥15%
than in children who • Do not use NVP as PEP
had CD4 outside of the neonatal
percentages <15%. period.

ETR Onset Rare Unknown Evaluate for hypersensitivity • Discontinue all ARV drugs.
if the patient is symptomatic.
• Any time during • Rechallenge with ETR is not
therapy recommended.

Presentation
• Symptoms may
include rash,
constitutional
findings, and
sometimes organ
dysfunction,
including hepatic
failure.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-71
Table 17k. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Rash and
Hypersensitivity Reactions

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
MVC Rash preceding Rare Unknown Obtain AST and ALT levels • Discontinue all ARV drugs.
hepatotoxicity from patients with rash or
other symptoms of • Rechallenge with MVC is not
hypersensitivity. recommended.

DTG Rash with hepatic • Rare Unknown Obtain AST and ALT levels • Discontinue all ARV drugs.
dysfunction from patients with rash or
other symptoms of • Rechallenge with DTG is
hypersensitivity. contraindicated.

a The prescribing information for NVP states that patients who experience rash during the 14-day lead-in period should not have the NVP dose increased until the rash has
resolved. However, prolonging the lead-in phase beyond 14 days may increase the risk of NVP resistance because of subtherapeutic drug levels. Children who have
persistent mild or moderate rash after the lead-in period should receive individualized care. Consult an expert in HIV care when managing these patients. NVP should be
stopped and not restarted if the rash is severe or progressing. See the Nevirapine section of the Drug Appendix.
b Lead-in dosing is not recommended when using NVP for either presumptive or definitive HIV therapy in newborns with perinatal HIV exposure or perinatal HIV infection.
See the Nevirapine section of the Drug Appendix and Table 13. Antiretroviral Drug Dosing Recommendations for Newborns in Antiretroviral Management of Newborns With
Perinatal HIV Exposure or HIV Infection.
Key: ABC = abacavir; ALT = alanine transaminase; ART = antiretroviral therapy; ARV = antiretroviral; AST = aspartate aminotransferase; ATV = atazanavir; BIC =
bictegravir; CBC = complete blood count; CD4 = CD4 T lymphocyte; CYP2B6 = Cytochrome P450 Family 2 Subfamily B Member 6; DRESS = drug reaction (or rash) with
eosinophilia and systemic symptoms; DRV = darunavir; DTG = dolutegravir; EFV = efavirenz; EM = erythema multiforme; ETR = etravirine; FTC = emtricitabine; HLA =
human leukocyte antigen; HLA-B*5701 = human leucocyte antigen gene variant; HSR = hypersensitivity reaction; IV = intravenous; IVIG = intravenous immune globulin;
LPV/r = lopinavir/ritonavir; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP = nevirapine; PEP = post-exposure prophylaxis; PI = protease
inhibitor; PREDICT Study = Personalised Responses to Dietary Composition Trial Study; RAL = raltegravir; RPV = rilpivirine; SJS = Stevens-Johnson syndrome; TDF =
tenofovir disoproxil fumarate; TEN = toxic epidermal necrolysis; TMP-SMX = trimethoprim-sulfamethoxazole; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-72
References
1. Pelchen-Matthews A, Larsen JF, Shepherd L, et al. Hypersensitivity reactions, hepatotoxicity, and other discontinuations in persons
receiving integrase strand transfer inhibitors: results from the EuroSIDA study. HIV Res Clin Pract. 2021;22(6):160-168. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/34779362.

2. Yuan J, Guo S, Hall D, et al. Toxicogenomics of nevirapine-associated cutaneous and hepatic adverse events among populations of
African, Asian, and European descent. AIDS. 2011;25(10):1271-1280. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21505298.

3. Vitezica ZG, Milpied B, Lonjou C, et al. HLA-DRB1*01 associated with cutaneous hypersensitivity induced by nevirapine and
efavirenz. AIDS. 2008;22(4):540-541. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18301070.

4. Tudor-Williams G, Cahn P, Chokephaibulkit K, et al. Etravirine in treatment-experienced, HIV-1-infected children and adolescents:
48-week safety, efficacy and resistance analysis of the phase II PIANO study. HIV Med. 2014;15(9):513-524. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24589294.

5. Thomas SJ, Kilgore JT, Becken BA, Cunningham CK, Thompson AB. Raltegravir-associated drug-reaction with eosinophilia and
systemic symptoms syndrome in a pediatric patient without characteristic human leukocyte antigen B*57:01 or B*53:01 alleles. J
Pediatric Infect Dis Soc. 2021;10(3):363-366. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32766769.

6. Thomas M, Hopkins C, Duffy E, et al. Association of the HLA-B*53:01 allele with drug reaction with eosinophilia and systemic
symptoms (DRESS) syndrome during treatment of HIV infection with raltegravir. Clin Infect Dis. 2017;64(9):1198-1203. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/28369189.

7. Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine and efavirenz-based first-line
antiretroviral therapy: a systematic review and meta-analysis. AIDS. 2013;27(9):1403-1412. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23343913.

8. Shah R, Nabiswa H, Okinda N, Revathi G, Hawken M, Nelson M. Prevalence of HLA-B*5701 in a Kenyan population with HIV
infection. J Infect. 2018;76(2):212-214. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28919349.

9. Rutstein RM, Samson P, Fenton T, et al. Long-term safety and efficacy of atazanavir-based therapy in HIV-infected infants, children
and adolescents: the pediatric AIDS clinical trials group protocol 1020A. Pediatr Infect Dis J. 2015;34(2):162-167. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25232777.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-73
10. Ripamonti D, Benatti SV, Di Filippo E, Ravasio V, Rizzi M. Drug reaction with eosinophilia and systemic symptoms associated
with raltegravir use: case report and review of the literature. AIDS. 2014;28(7):1077-1079. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24685746.

11. Puthanakit T, Bunupuradah T, Kosalaraksa P, et al. Prevalence of human leukocyte antigen-B*5701 among HIV-infected children in
Thailand and Cambodia: implications for abacavir use. Pediatr Infect Dis J. 2013;32(3):252-253. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22986704.

12. Prasertvit P, Chareonyingwattana A, Wattanakrai P. Nevirapine patch testing in Thai human immunodeficiency virus infected
patients with nevirapine drug hypersensitivity. Contact Dermatitis. 2017;77(6):379-384. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28782122.

13. Peter J, Choshi P, Lehloenya RJ. Drug hypersensitivity in HIV infection. Curr Opin Allergy Clin Immunol. 2019;19(4):272-282.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31145192.

14. Nishijima T, Gatanaga H, Teruya K, et al. Skin rash induced by ritonavir-boosted darunavir is common, but generally tolerable in an
observational setting. J Infect Chemother. 2014;20(4):285-287. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24507978.

15. Nachman S, Alvero C, Teppler H, et al. Safety and efficacy at 240 weeks of different raltegravir formulations in children with HIV-
1: a phase 1/2 open label, non-randomised, multicentre trial. Lancet HIV. 2018;5(12):e715-e722. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30527329.

16. Mounzer K, Hsu R, Fusco JS, et al. HLA-B*57:01 screening and hypersensitivity reaction to abacavir between 1999 and 2016 in the
OPERA((R)) observational database: a cohort study. AIDS Res Ther. 2019;16(1):1. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30651100.

17. Martin C, Payen MC, De Wit S. Dolutegravir as a trigger for DRESS syndrome? Int J STD AIDS. 2018;29(10):1036-1038.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29621952.

18. Mallal S, Phillips E, Carosi G, et al. HLA-B*5701 screening for hypersensitivity to abacavir. N Engl J Med. 2008;358(6):568-579.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/18256392.

19. Lefebvre M, Walencik A, Allavena C, et al. Rate of DRESS syndrome with raltegravir and role of the HLA-B*53: 01 allele. J
Acquir Immune Defic Syndr. 2020;85(4):e77-e80. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33136758.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-74
20. Kim GY, Anderson KR, Davis DMR, Hand JL, Tollefson MM. Drug reaction with eosinophilia and systemic symptoms (DRESS) in
the pediatric population: a systematic review of the literature. J Am Acad Dermatol. 2020;83(5):1323-1330. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32247873.

21. Hayes E, Derrick C, Smalls D, Smith H, Kremer N, Weissman S. Short-term adverse events with BIC/FTC/TAF: postmarketing
study. Open Forum Infect Dis. 2020;7(9):ofaa285. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32908943.

22. Hasan M, Yunihastuti E, Abdullah M. Incidence and predictors of nevirapine and efavirenz-associated rash among Indonesian HIV
patients. Asian Pac J Allergy Immunol. 2020;12932/AP-080719-0596. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32061245.

23. Fillekes Q, Mulenga V, Kabamba D, et al. Is nevirapine dose escalation appropriate in young, African, HIV-infected children?
AIDS. 2013;27(13):2111-2115. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23595153.

24. Dziuban EJ, Hughey AB, Stewart DA, et al. Stevens-Johnson syndrome and HIV in children in Swaziland. Pediatr Infect Dis J.
2013;32(12):1354-1358. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23743542.

25. du Toit JD, Kotze K, van der Westhuizen HM, Gaunt TL. Nevirapine-induced Stevens-Johnson syndrome in children living with
HIV in South Africa. South Afr J HIV Med. 2021;22(1):1182. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33824730.

26. Borras-Blasco J, Navarro-Ruiz A, Borras C, Castera E. Adverse cutaneous reactions associated with the newest antiretroviral drugs
in patients with human immunodeficiency virus infection. J Antimicrob Chemother. 2008;62(5):879-888. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18653488.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-75
Management of Children Receiving Antiretroviral
Therapy
Updated: April 11, 2023
Reviewed: April 11, 2023

In the United States, most children with HIV are receiving antiretroviral therapy (ART), making
treatment-experienced children the norm. Providers may consider antiretroviral (ARV) regimen
changes for the following reasons:

• Treatment simplification: Modifying ARV regimens in children who are currently receiving
effective ART to simplify the regimen.
• Treatment optimization: Increasing the treatment potency or barrier to resistance of an effective
but older or potentially fragile regimen or improving the adverse-event profile.
• Toxicity management: Recognizing and managing ARV drug toxicity or intolerance (see
Management of Medication Toxicity or Intolerance).
• Treatment failure: Recognizing and managing treatment failure (see Recognizing and Managing
Antiretroviral Treatment Failure).

Modifying Antiretroviral Regimens in Children With Sustained Virologic Suppression

on Antiretroviral Therapy

Panel’s Recommendations
• Children who have sustained virologic suppression on their current antiretroviral (ARV) regimen should be evaluated
regularly for opportunities to change to a new regimen that facilitates adherence, simplifies administration, increases ARV
potency or barrier to drug resistance, and decreases the risk of drug-associated toxicity (AII).
• Before changing a patient’s ARV regimen, clinicians must carefully consider the patient’s previous regimens, past episodes
of ARV therapy failure, prior drug-resistance test results, drug cost, and insurance coverage, as well as the patient’s ability
to tolerate the new drug regimen (AIII). Archived drug resistance can limit the antiviral activity of a new drug regimen.
• Children should be monitored carefully after a change in treatment. Viral load measurement is recommended 2 to 4 weeks
after a change in a child’s ARV regimen (BIII).

Rating of Recommendations: A = Strong; B = Moderate; C = Optional

Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints;
I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying
data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical
outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term
outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical
outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical
outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to postpubertal adolescents

Clinicians choose initial ARV regimens for children with HIV by evaluating the pharmacokinetic,
safety, and efficacy data for the drugs that are available in formulations suitable for the child’s age
and weight at the start of treatment. New ARV drug options may become available as children grow

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-1
and learn to swallow pills and as new drugs, drug formulations, and data become available. Even in
cases wherein patients have achieved sustained virologic suppression (i.e., suppression for
6–12 months) on their current regimen, clinicians should consider switching patients to new ARV
regimens to permit the use of pills instead of liquids, reduce pill burden, allow the use of once-daily
medications, reduce the risk of adverse events, minimize drug interactions, and align a child’s
regimen with widely used, efficacious adult regimens.1 These changes often enhance adherence and
improve quality of life.2

Treatment Simplification
Many infants and children with HIV initiated treatment with twice-daily dosing (especially prior to
the approval of integrase strand transfer inhibitor [INSTI] medications for pediatric use), and
regimens included a variety of drug formulations, depending on which formulations were available
for a child’s age and weight. Clinicians should regularly review treatment options as children grow,
because it may be possible to simplify dosing using coformulated drugs and/or once-daily regimens
(see Table 18 below). Clinicians also should consider a child’s ART history, drug-resistance test
results, and ability to swallow tablets. Small studies have shown that children who achieve virologic
suppression using twice-daily dosing for certain ARV drugs (e.g., abacavir [ABC]) maintain
virologic suppression when they are switched from twice-daily dosing to once-daily dosing of the
same drugs (see the Abacavir and Nevirapine sections and fixed-dose combinations [FDCs] in
Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets and Appendix A,
Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum Body Weights and Consideration
for Use in Children and Adolescents). However, these studies reported mixed results when switching
the dosing for lopinavir/ritonavir (LPV/r) from twice daily to once daily. Therefore, once-daily
dosing of LPV/r is not recommended.3-6

Long-acting injectable ARV medications may be considered a treatment simplification approach for
some virologically suppressed adolescents. The co-packaged, two-drug injectable ARV regimen of
cabotegravir and rilpivirine (CAB and RPV; Cabenuva) is approved by the U.S. Food and Drug
Administration (FDA) for use in children weighing ≥35 kilograms and ≥12 years of age, with viral
suppression (defined as <50 copies/mL), on a stable ARV regimen, without a history of treatment
failure, and without known or suspected drug resistance to either drug. Studies in adults—such as the
First Long-Acting Injectable Regimen (FLAIR) and Antiretroviral Therapy as Long-Acting
Suppression (ATLAS) trials—have demonstrated non-inferiority in those receiving monthly CAB
and RPV injections compared to adults who stayed on a daily three-drug oral regimen.7,8 Similarly, in
the ATLAS-2M trial, injections of CAB and RPV every 2 months were found to be non-inferior to
monthly injections.9 The International Maternal Pediatric Adolescent AIDS Clinical
Trials (IMPAACT) Study 2017 is currently evaluating CAB and RPV in children 12 to 18 years of
age. Participants received one injection of either CAB or RPV, and early findings showed acceptable
pharmacokinetics, lack of new safety concerns,7,8 and high acceptability from youth and their
caregivers. This ongoing study is now assessing the full two-drug injectable regimen. The Panel on
Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel) notes that
significant questions remain, including whether an oral lead-in is beneficial and acceptable in the
adolescent population, if there are additional adverse effects specific to the pediatric population, if a
two-drug nucleoside-sparing regimen for children with significant ARV treatment history10 will be
effective, and what potential implementation challenges will emerge. However, given the FDA
approval for those as young as 12 years of age, some providers may consider injectable CAB and
RPV in adolescents who meet the approved indications and may benefit from a long-acting injectable
regimen. See Cabotegravir and Rilpivirine for additional information about these drugs and the

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-2
dosing and administration of CAB and RPV, and see Management of the Treatment-Experienced
Patient: Optimizing Antiretroviral Therapy in the Setting of Viral Suppression in the Adult and
Adolescent ARV Guidelines for practical considerations.

Oral two-drug regimens, specifically nucleoside-sparing regimens, have some data supporting
efficacy in pediatric and adult populations. A two-drug FDC tablet containing
dolutegravir (DTG)/RPV—a nucleoside-sparing, dual-therapy regimen that is marketed as Juluca—is
approved by the FDA as a complete regimen to replace the current ARV regimen in adult patients
who have been virologically suppressed (HIV RNA <50 copies/mL) on a stable ARV regimen for at
least 6 months and who have no history of treatment failure. This approval was based on two Phase 3
clinical trials, SWORD-1 and SWORD-2, in which treatment-experienced adults who were
virologically suppressed on three- or four-drug regimens were randomized either to switch to
DTG/RPV (early-switch group) or stay on their original regimens through 48 weeks and then switch
to DTG/RPV (late-switch group). Results from these trials showed similar rates of virologic
suppression in both groups (non-inferiority) through 3 years of follow-up.11-13 No equivalent data
exist for this drug combination in pediatric patients, although a clinical trial to evaluate it is planned.
The Panel usually endorses the use of adult formulations in adolescents, and this product may be
appropriate for certain adolescents. DTG/RPV regimens could be useful in patients in whom there is
concern for toxicity from nucleoside reverse transcriptase inhibitors (NRTIs). Additionally, early
findings from the PENTA-17 SMILE study evaluating darunavir/ritonavir (DRV/r) combined with an
INSTI, including 318 children aged 6 to 18 years in 11 countries, found that DRV/r plus an INSTI
was non-inferior in maintaining virologic suppression at 48 weeks in participants without INSTI or
protease inhibitor (PI) resistance.14 Although the Panel does not recommend this combination for
initial treatment, it might be considered in situations in which simplification or avoidance of NRTIs
is desired. However, the Panel notes that adolescents may have difficulties adhering to therapy and
recommends close monitoring with viral load testing.

Treatment Optimization
The aims of treatment optimization may include improving the potency of the regimen, improving a
child’s growth or other health outcomes through reduced drug side effects and/or better treated HIV,
or maximizing palatability. More studies are directly evaluating treatment optimization in children,
and early results support the safety and efficacy of regimen switches for those with viral suppression.
Older studies have demonstrated sustained viral suppression and improved growth outcomes in
young children who have demonstrated good adherence and no baseline resistance and who were
switched from LPV/r-based regimens an efavirenz (EFV)-based regimen (NEVEREST 3).15-17
Replacing LPV/r with EFV may provide some benefits (e.g., once-daily dosing and a different side-
effect profile), but most pediatric HIV experts would prefer replacing LPV/r with an equally potent
PI (e.g., darunavir [DRV] or atazanavir [ATV]) or an INSTI (e.g., elvitegravir [EVG], raltegravir,
DTG, or bictegravir [BIC]), based on studies in adults and emerging evidence of non-inferiority or
superiority in children.18,19 Although not a switch trial, findings from the randomized controlled
Once-daily DTG-based ART in Young People vs. Standard Therapy (ODYSSEY) study of more than
700 children aged <18 years in eight countries initiating DTG as first- or second-line therapy showed
superior virologic and clinical outcomes in children randomized to optimization with DTG-based
ART compared with those in the standard of care (PI- or non-nucleoside reverse transcriptase
inhibitor [NNRTI]-based regimens), contributing to evidence supporting optimization with DTG-
based regimens.20 Results from the younger ODYSSEY cohort of children weighing between 3 and
14 kilograms also showed superiority of DTG-based ART compared to other regimens, more than
70% of which were PI-based regimens.21 Additionally, several observational studies in sub-Saharan

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-3
Africa that are evaluating efforts to optimize pediatric ARV regimens have shown improved viral
suppression rates in children that were switched to DTG-based regimens.22-25 Similarly, a
retrospective study from six African countries reporting on 2,655 children aged 0 to ≤19 years
demonstrated sustained high levels of viral suppression in children optimized from NNRTI- and PI-
based regimens to DTG-based regimens.26 The INSTI-based FDC regimen BIC/emtricitabine (FTC)/
tenofovir alafenamide (TAF) has also shown efficacy and high rates of long-term viral suppression in
adolescents and children >2 years weighing 14 to <25 kilograms.27,28 Similarly,
EVG/cobicistat/FTC/TAF has shown efficacy in adolescents. Early results from small, randomized
studies also show potential for switches to newer-generation NNRTI medications—such as
rilpivirine (RPV)29 and doravirine (DOR)30—in children and adolescents weighing ≥35 kg who have
been virologically suppressed on a stable ARV regimen.

Toxicity Management
Several studies of small cohorts of children have demonstrated sustained virologic suppression and
reassuring safety outcomes when drugs that have greater long-term toxicity risks are replaced with
drugs that are thought to have lower toxicity risks (e.g., replacing stavudine with tenofovir disoproxil
fumarate, TAF, zidovudine, or ABC; replacing PIs with NNRTIs), including improved lipid
profiles.31-35 Similarly, adolescents who were switched from EFV to RPV, a newer generation of
NNRTIs, showed similar rates of viral suppression with improved metabolic profiles and cognitive
outcomes.29 Additionally, studies in adults have shown improved tolerability, lipid profiles, and
insulin sensitivity in patients who were switched from PIs to INSTIs,36-40 and adults who were
switched from EFV to an INSTI have shown improvement in neuropsychiatric symptoms. However,
the use of INSTIs, as well as TAF, has been associated with weight gain in adults and adolescents,
with emerging data showing an association in children.41-45 Finally, NRTI-sparing regimens,
including the dual-drug oral regimens (DRV and an INSTI or DTG/RPV) and the approved long-
acting injectable regimen (CAB with RPV) described above, may be considered in patients with
NRTI toxicity who otherwise are eligible for these complete ARV regimens. In a small subgroup
analysis of the SWORD study, participants switched to DTG/RPV experienced small but statistically
significant improvement in bone mineral density and bone turnover markers compared to those who
continued on tenofovir disoproxil fumarate (TDF).46 Of note, however, is that, although small in
number, more participant adverse events that led to discontinuation were reported in the DTG/RPV
arm (3%) than in the arm in which participants stayed on their current regimen (<1%).11

Treatment Failure
Treatment failure is another common reason providers change ARV regimens in children with HIV.
This topic is covered in Recognizing and Managing Antiretroviral Treatment Failure.

Regimens That Are Not Recommended for Use in Children

Monotherapy PI regimens (DRV/r, LPV/r, ATV/r)47,48 and monotherapy regimens of DTG49,50 have
been used to simplify or reduce the toxicity of regimens in adult patients who have sustained
virologic suppression, but with varying success. These strategies are still being explored, but they are
not currently recommended as management strategies in children because of the lack of data.48,51-54

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-4
Potential Antiretroviral Drug Switches in Children With Virologic Suppression
Table 18 below contains examples of potential ARV drug changes in children with sustained
virologic suppression on their current regimen for the purpose of treatment simplification,
optimization, or reduced toxicity. When considering such a change, a clinician should first ensure
that a recent viral load test indicates that the child is not experiencing virologic failure and that the
child has a reliable history of good adherence (assessed by self and parental report, pharmacy refill,
prior viral loads, etc.). Among treatment-naive youth in the United States aged 13 to 24 years, some
evidence exists that single-tablet regimens (STRs) improve the odds of viral suppression55; emerging
evidence also supports the safety, efficacy, and tolerability of STRs in younger children.56-58
Although these data have not been replicated in treatment-experienced adolescents, clinicians should
consider using STRs in children and youth with sustained viral suppression because these regimens
reduce pill burden and dosing frequency. Clinicians also must consider ART history, tolerability,
ability to swallow tablets, and all prior drug-resistance test results to avoid choosing new ARV drugs
for which archived drug resistance would reemerge and limit the activity of the regimen.59-63 The
evidence that supports many of these ARV changes is indirect, that is, extrapolated from data about
drug performance during initial therapy or follow-up therapy after treatment failure. When such
changes are made, careful monitoring (e.g., taking a viral load measurement 2–4 weeks after making
the switch to the new regimen) is important to ensure that virologic suppression is maintained.

Table 18. Examples of Changes in Antiretroviral Regimen Components for Children With
Sustained Virologic Suppression

This list is not exhaustive and does not necessarily contain all potential treatment options. Instead, it
provides examples of changes that could be made. The table includes information only about
switching between ARV drugs; it does not include all the information that clinicians should
consider before prescribing these drugs, such as drug cost and the patient’s insurance
coverage. Refer to the individual drug sections, Appendix A, Table 1. Antiretrovirals Available in
Fixed-Dose Combination Tablets or as a Co-Packaged Formulation, by Drug Class, and Appendix A,
Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum
Body Weights and Considerations for Use in Children and Adolescents in Appendix A: Pediatric
Antiretroviral Drug Information for further information about the use and administration of specific
ARV drugs and FDC formulations.

For images of most of the ARV drugs listed in this table, see the Antiretroviral Medications section
of the National HIV Curriculum. In addition, a resource from the United Kingdom illustrates the
relative sizes of individual ARV drugs FDC tablets (see the ARV Chart in HIV i-Base). Although
most of the drugs listed in that chart are the same as those in the United States, not all formulations
available in the United States are included, and there are differences in a few of the brand names.

Age, Weight,
Current ARV and Sexual Potential ARV
Comment
Drug(s) Maturity Rating Drug Switcha
Requirements
NRTIs
ABC Twice Daily Aged ≥3 monthsb ABC once daily See the Abacavirb section.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-5
Table 18. Examples of Changes in Antiretroviral Regimen Components for Children With
Sustained Virologic Suppression

Age, Weight,
Current ARV and Sexual Potential ARV
Comment
Drug(s) Maturity Rating Drug Switcha
Requirements
3TC Twice Daily Aged ≥3 years 3TC once daily See the Lamivudine section.

Any age (starting FTC once daily See the Emtricitabine section.
at full-term birth)
Any weight

ZDV Aged ≥1 monthsb ABC Less long-term mitochondrial toxicity

Children aged ≥3 months can take ABC once daily.

Weighing 17 kg to TDF TDF is a reasonable, once-daily option for HLA-B*5701-

<25 kg positive children for whom ABC is not recommended and in
whom ZDV is not tolerated. TDF is available as an oral
powder and as low-strength tablets alone or in combination
with FTC.

Weighing ≥14 kg TAFc Less long-term mitochondrial toxicity. Once-daily dosing.

Only available in coformulation with other ARV drugs; can
further reduce pill burden. TAF is preferred over TDF
because of the lower risk of bone and renal toxicity, but it
may be associated with weight gain and lipid abnormalities.

Weighing ≥14 kg FTC/TAFc Once-daily dosing. This combination NRTI medication may
(Descovy) be more desirable because of smaller pill size and reduced
pill burden. Benefits as described for TAF.

Any NRTI Aged ≥12 years CAB and RPV NRTI-sparing regimen. Long-acting injectable, complete
co-packaged ARV regimen requiring two IM injections every 1 to
Weighing ≥35 kg
regimen as 2 months that together are an alternative to daily oral ARV
Cabenuva regimens. Must consider prior history of treatment failure
and known or suspected drug resistance to individual
drugs. Injection site reactions are common but do not often
result in discontinuation of the regimen. See Cabotegravir.

Aged ≥12 years DTG/RPV NRTI-sparing FDC that is a complete regimen. In addition
(Juluca) to age and weight criteria (based on RPV component since
Weighing ≥35 kg
DTG approved to younger age/lower weight), must be
virologically suppressed (HIV RNA <50 copies/mL) on a
stable ARV regimen for at least 6 months and without
history of treatment failure. Should be taken with food. No
pediatric data.

NNRTIs
NVP or EFV Any age (starting at RALd RAL is preferred over NVP in infants from birth to age
full-term birth) 4 weeks who weigh ≥2 kg. Both are dosed twice daily in
children. Note that DTG and BIC have a higher barrier to
Weighing ≥2 kg
resistance than RAL. In a child >1 month of age, DTG is
preferred. See DTG below.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-6
Table 18. Examples of Changes in Antiretroviral Regimen Components for Children With
Sustained Virologic Suppression

Age, Weight,
Current ARV and Sexual Potential ARV
Comment
Drug(s) Maturity Rating Drug Switcha
Requirements
Age ≥4 weeks DTG DTG is available as a single drug in dispersible and film-
coated tablet formulations, or as part of an FDC tablet, all of
Weighing ≥3 kg
which can be dosed once daily if no documented resistance
or history of failure with INSTI agents exists. DTG plus
FTC/TAF (Descovy) in patients weighing at least 14 kg or
the weight-appropriate dose of FTC/TDF (Truvada) can be
used in children weighing 20 kg to <25 kg. DTG is available
as a component of the FDC ABC/DTG/3TC, which is a
complete ARV regimen that can be given to children
weighing ≥10 to <25 kg in dispersible tablets (Triumeq PD)
and to children and adolescents weighing ≥25 kg in a single
tablet to be swallowed (Triumeq). Higher barrier to
resistance, which makes it a good choice for patients who
have poor adherence. May improve lipid levels. See the
Dolutegravir section for more information.

Aged ≥3 months ATV/r ATV/r has a potentially greater barrier to resistance;

however, taking ATV/r may be difficult for some patients, as
Weighing ≥5 kg
ATV oral powder must be mixed with food or a beverage
before administration, and the palatability of the RTV oral
solution is poor.

Aged ≥3 years DRV/r DRV/r has a potentially greater barrier to resistance. DRV/r
is administered twice daily to patients aged <12 years but
Weighing ≥10 kg
may be administered once daily in children aged ≥12 years
who do not have any DRV resistance mutations. Note that
the palatability of the RTV oral solution is poor when
considering administering to children not able to swallow
tablets.

Weighing ≥14 kg BIC as Biktarvy Once-daily dosing. BIC is available as a component of the
FDC tablet BIC/FTC/TAF (Biktarvy) in two weight-based
dose formulations—one formulation for those ≥14 to <25 kg
and another for those ≥25 kg. This is a complete ARV
regimen that can be taken with or without food.

Weighing ≥25 kg EVG as Genvoya EVG is available as a component of the FDC tablet
EVG/c/FTC/TAF (Genvoya), which is a complete ARV
regimen that must be taken with food.

Weighing ≥35 kg DOR DOR is available in a once-daily FDC tablet DOR/3TC/TDF

(Delstrigo). Fewer side effects than reported with EFV. It
has continued activity in the setting of some NNRTI
mutations.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-7
Table 18. Examples of Changes in Antiretroviral Regimen Components for Children With
Sustained Virologic Suppression

Age, Weight,
Current ARV and Sexual Potential ARV
Comment
Drug(s) Maturity Rating Drug Switcha
Requirements
Aged ≥12 years CAB and RPV Long-acting injectable, complete ARV regimen requiring two
co-packaged IM injections every 1 to 2 months that together are an
Weighing ≥35 kg
regimen as alternative to daily oral ARV regimens. Must consider prior
Cabenuva history of treatment failure and known or suspected drug
resistance to individual drugs. Injection site reactions are
common but do not often result in discontinuation of the
regimen. See Cabotegravir.

Aged ≥12 years RPV Lower incidence of adverse lipid effects. May have fewer
sleep disturbances and neuropsychiatric symptoms
Weighing ≥35 kg
compared to EFV. RPV has continued activity in the setting
of some NNRTI mutations.

PIs
LPV/r Twice Any age (starting at RALd Better palatability. RAL HD can only be given once daily in
Daily full-term birth) those weighing ≥40 kg. Unlike LPV/r, the use of RAL is not
restricted to infants with a corrected gestational age of
Weighing ≥2 kg
≥42 weeks and a postnatal age of ≥14 days. RAL granules
may be difficult to dose for some caregivers.

Age ≥4 weeks DTG Once-daily dosing if no documented resistance or history of

failure with INSTI agents exists. May be better tolerated, and
Weighing ≥3 kg
it can be given as a dispersible tablet in young children. DTG
is available as a component of the FDC ABC/DTG/3TC,
which is a complete ARV regimen that can be given to
children weighing ≥10 kg to <25 kg in dispersible tablets
(Triumeq PD) and to children and adolescents weighing
≥25 kg in a single tablet to be swallowed (Triumeq). DTG
plus FTC/TAF (Descovy) in those weighing at least 14 kg or
the weight-appropriate dose of FTC/TDF (Truvada) can be
used in children weighing 20 kg to <25 kg. May improve lipid
levels. See the Dolutegravir section for more information.

Aged ≥3 years EFV Once-daily dosing. Better palatability. Lower incidence of

adverse lipid effects. Review NNRTI mutations before use.
Weighing ≥10 kg
See the Efavirenz section for concerns about EFV dosing
for children aged <3 years.

Aged ≥3 months ATV/r Once-daily dosing. ATV/r may have a lower incidence of
adverse lipid effects; however, taking ATV/r may be difficult
Weighing ≥5 kg
for some patients, as ATV oral powder must be mixed with
food or a beverage before administration, and the
palatability of the RTV oral solution is poor.

Aged ≥3 years DRV/r DRV/r may have a lower incidence of adverse lipid effects.
DRV/r is administered twice daily to patients aged
Weighing ≥10 kg
<12 years, but it may be administered once daily in children
aged ≥12 years who do not have DRV resistance mutations.
Note that palatability of the RTV oral solution is poor when

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-8
Table 18. Examples of Changes in Antiretroviral Regimen Components for Children With
Sustained Virologic Suppression

Age, Weight,
Current ARV and Sexual Potential ARV
Comment
Drug(s) Maturity Rating Drug Switcha
Requirements
considering administering to children not able to swallow
tablets.

Weighing ≥14 kg BIC as Biktarvy Once-daily dosing. BIC is available as a component of the
FDC tablet BIC/FTC/TAF (Biktarvy) in two weight-based
dose formulations—one for those ≥14 to <25 kg and
another for those ≥25 kg. This is a complete ARV regimen
that can be taken with or without food.

Weighing ≥25 kg EVG as Genvoya EVG is available as a component of the FDC tablet
EVG/c/FTC/TAF (Genvoya), which is a complete ARV
regimen that must be taken with food.

Weighing ≥35 kg DOR DOR is available in a once-daily FDC tablet DOR/3TC/TDF

(Delstrigo). Fewer side effects than reported with EFV. It
has continued activity in the setting of some NNRTI
mutations.

Aged ≥12 years CAB and RPV Long-acting injectable, complete ARV regimen requiring two
co-packaged IM injections every 1 to 2 months that together are an
Weighing ≥35 kg
regimen as alternative to daily oral ARV regimens. Must consider prior
Cabenuva history of treatment failure and known or suspected drug
resistance to individual drugs. Injection site reactions are
common but do not often result in discontinuation of the
regimen. See Cabotegravir.

Aged ≥12 years RPV May be better tolerated. Lower incidence of adverse lipid
effects. It has continued activity in the setting of some
Weighing ≥35 kg
NNRTI mutations.

INSTIs
RAL Age >1 month and DTG Once-daily dosing. Higher barrier to resistance. DTG is
weighing <14 kg available as a single drug in a dispersible tablet for infants
DTG or BIC and children weighing ≥3 kg; in a single-drug film-coated
Weighing >14 kg
tablet for children weighing ≥14 kg; or as an FDC. All of
these can be dosed once daily if no documented resistance
or history of failure with INSTI agents exists. DTG plus
FTC/TAF (Descovy) in those weighing at least 14 kg or the
weight-appropriate dose of FTC/TDF (Truvada) can be used
in children weighing 20 kg to <25 kg. DTG is available as a
component of the FDC ABC/DTG/3TC, which is a complete
ARV regimen that can be given to children weighing ≥10 to
<25 kg in dispersible tablets (Triumeq PD) and to children
and adolescents weighing ≥25 kg in a single tablet to be
swallowed (Triumeq). See the Dolutegravir section for more
information.
BIC has once-daily dosing and a higher barrier to
resistance. BIC is available as a component of the FDC
tablet BIC/FTC/TAF (Biktarvy) in two weight-based dose

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-9
Table 18. Examples of Changes in Antiretroviral Regimen Components for Children With
Sustained Virologic Suppression

Age, Weight,
Current ARV and Sexual Potential ARV
Comment
Drug(s) Maturity Rating Drug Switcha
Requirements
formulations—one for those ≥14 to <25 kg and another for
those ≥25 kg. This is a complete ARV regimen that can be
taken with or without food.

Aged ≥12 years CAB and RPV Long-acting injectable, complete ARV regimen requiring two
co-packaged IM injections every 1 to 2 months that together are an
Weighing ≥35 kg
regimen as alternative to daily oral ARV regimens. Must consider prior
Cabenuva history of treatment failure and known or suspected drug
resistance to individual drugs. Injection site reactions are
common but do not often result in discontinuation of the
regimen. See Cabotegravir.

EVG/c Weighing ≥14 kg DTG or BIC Once-daily dosing. Higher barrier to resistance. DTG is
available as a single drug in a dispersible tablet for infants
and children weighing ≥3 kg; in a single-drug film-coated
tablet for children weighing 14 kg; or as an FDC. All of these
can be dosed once daily if no documented resistance or
history of failure with INSTI agents exists. DTG plus
FTC/TAF (Descovy) in those weighing at least 14 kg or the
weight-appropriate dose of FTC/TDF (Truvada) can be used
in children weighing 20 kg to <25 kg. DTG is available as a
component of the FDC ABC/DTG/3TC), which is a complete
ARV regimen that can be given to children weighing ≥10 to
<25 kg in dispersible tablets (Triumeq PD) and to children
and adolescents weighing ≥25 kg in a single tablet to be
swallowed (Triumeq), See the Dolutegravir section for more
information.
BIC has once-daily dosing and a higher barrier to
resistance. BIC is available as a component of the FDC
tablet BIC/FTC/TAF (Biktarvy) in two weight-based dose
formulations—one for those ≥14 to <25 kg and another for
those ≥25 kg. This is a complete ARV regimen that can be
taken with or without food.

Aged ≥12 years CAB and RPV Long-acting injectable, complete ARV regimen requiring two
co-packaged IM injections every 1 to 2 months that together are an
Weighing ≥35 kg
regimen as alternative to daily oral ARV regimens. Must consider prior
Cabenuva history of treatment failure and known or suspected drug
resistance to individual drugs. Injection site reactions are
common but do not often result in discontinuation of the
regimen. See Cabotegravir.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-10
Table 18. Examples of Changes in Antiretroviral Regimen Components for Children With
Sustained Virologic Suppression

Age, Weight,
Current ARV and Sexual Potential ARV
Comment
Drug(s) Maturity Rating Drug Switcha
Requirements
Other
Any Multi-Pill Weighing ≥14 kg to ABC/DTG/3TC Once-daily dosing. Dispersible tablets with dosage for use in
and/or Twice- <25 kg (Triumeq PD) children based on weight. Aligns a child’s regimen with an
Daily Regimen efficacious regimen that is used in adults. See the
Dolutegravir section for more information.

Weighing ≥14 kg FTC/TAFc Once-daily dosing. This regimen may be more desirable
(Descovy) plus because of smaller pill sizes, but it has a higher pill burden
DTG (two pills instead of one). Aligns a child’s regimen with an
efficacious regimen that is used in adults. See the
Dolutegravir section for more information.

Weighing ≥14 kg BIC/FTC/TAF Once-daily dosing. Single pill that can be taken with or
(Biktarvy) without food. Available in two weight-based dose
formulations—one for those ≥14 to <25 kg and another for
those ≥25 kg.

Weighing ≥25 kg ABC/DTG/3TC Once-daily dosing. Single pill to be swallowed. Aligns a

(Triumeq) child’s regimen with an efficacious regimen that is used in
adults. Large pill size may be a deterrent. See the
Dolutegravir section for more information.

Weighing ≥25 kg EVG/c/FTC/TAF Once-daily dosing. Single pill. Alignment with adult ARV
(Genvoya) regimens. Must be taken with food.

Weighing ≥35 kg DOR/3TC/TDF Once-daily dosing. Single pill. Aligns a child’s regimen with
(Delstrigo) an efficacious regimen that is used in adults. Must be taken
with food at a consistent time daily. Renal and bone toxicity
of TDF limit its use. Review NNRTI mutations and check for
drug–drug interactions before use.

Weighing ≥35 kg EVG/c/FTC/TDF Once-daily dosing. Single pill. Aligns a child’s regimen with
(Stribild) an efficacious regimen that is used in adults. Must be taken
SMR 4 or 5
with food. Renal and bone toxicity of TDF limit its use.

Aged ≥12 years CAB and RPV Long-acting injectable, complete ARV regimen requiring two
co-packaged IM injections every 1 to 2 months that together are an
Weighing ≥35 kg
regimen as alternative to daily oral ARV regimens. Must consider prior
Cabenuva history of treatment failure and known or suspected drug
resistance to individual drugs. Injection site reactions are
common but do not often result in discontinuation of the
regimen. See Cabotegravir.

Aged ≥12 years FTC/RPV/TAF Once-daily dosing. Single pill. Aligns a child’s regimen with
(Odefsey) an efficacious regimen that is used in adults. Review NNRTI
Weighing ≥35 kg
mutations and check for drug–drug interactions before use.
Must be taken with food at a consistent time daily.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-11
Table 18. Examples of Changes in Antiretroviral Regimen Components for Children With
Sustained Virologic Suppression

Age, Weight,
Current ARV and Sexual Potential ARV
Comment
Drug(s) Maturity Rating Drug Switcha
Requirements
Aged ≥12 years FTC/RPV/TDF Once-daily dosing. Single pill. Aligns a child’s regimen with
(Complera) an efficacious regimen that is used in adults. Review NNRTI
Weighing ≥35 kg
mutations and check for drug–drug interactions before use.
SMR 4 or 5 Must be taken with food at a consistent time daily. Renal
and bone toxicity of TDF limit its use.

Aged ≥12 years DTG/RPV NRTI-sparing FDC that is a complete regimen. In addition to
(Juluca) age and weight criteria (based on RPV component since
Weighing ≥35 kg
DTG approved to younger age/lower weight), must be
virologically suppressed (HIV RNA <50 copies/mL) on a
stable ARV regimen for at least 6 months and without
history of treatment failure. Should be taken with food. No
pediatric data.
a The possibility of planned and unplanned pregnancy should be considered when selecting an ART regimen for an adolescent.
When discussing ART options with adolescents of childbearing potential and their caregivers, it is important to consider the
benefits and risks of all ARV drugs and to provide the information and counseling needed to support informed decision-making;
refer to the Perinatal Guidelines (see Recommendations for Use of Antiretroviral Drugs During Pregnancy, Table 7. Situation-
Specific Recommendations for Use of Antiretroviral Drugs in Pregnant People and Nonpregnant People Who Are Trying to
Conceive, and Appendix C: Antiretroviral Counseling Guide for Health Care Providers).
b For infants and young children who are being treated with liquid formulations of ABC, initiation with once-daily ABC is not
generally recommended. In clinically stable patients with undetectable viral loads who have had stable CD4 T lymphocyte cell
counts on twice-daily ABC, the dose can be changed from twice daily to once daily. ABC is not approved by the U.S. Food and
Drug Administration for use in neonates and infants aged <3 months. Recent data from the IMPAACT P1106 trial and two
observational cohorts provide reassuring evidence of the safety of ABC in infants aged <3 months. Based on these data,
clinicians may consider the use of ABC in infants aged ≥1 month to <3 months, in consultation with a pediatric HIV specialist
(see Abacavir).
c For children and adolescents weighing ≥14 kg to <35 kg, TAF can be used in combination with an INSTI or an NNRTI, but not

a boosted PI. For children and adolescents weighing ≥35 kg, TAF can be used in combination with an INSTI, an NNRTI, or a
boosted PI.
dRAL is recommended for twice-daily use in children. Chewable tablets can be used as dispersible tablets starting at 4 weeks of
age. RAL HD once daily is only recommended for virologically suppressed children weighing ≥40 kg.
Key: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; ATV = atazanavir; ATV/r = atazanavir/ritonavir; BIC = bictegravir;
CAB = cabotegravir; DOR = doravirine; DRV = darunavir; DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz;
EVG = elvitegravir; EVG/c = elvitegravir/cobicistat; FDC = fixed-dose combination; FTC = emtricitabine; HD = high dose;
HLA = human leukocyte antigen; IM = intramuscular; INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir;
NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; NVP = nevirapine;
PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SMR = sexual maturity rating; TAF = tenofovir
alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-12
References
1. Hsu AJ, Neptune A, Adams C, Hutton N, Agwu AL. Antiretroviral stewardship in a pediatric HIV
clinic: development, implementation and improved clinical outcomes. Pediatr Infect Dis J.
2016;35(6):642-648. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26906161.

2. Maiese EM, Johnson PT, Bancroft T, Goolsby Hunter A, Wu AW. Quality of life of HIV-infected
patients who switch antiretroviral medication due to side effects or other reasons. Curr Med Res
Opin. 2016;32(12):2039-2046. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27552553.

3. Foissac F, Blanche S, Dollfus C, et al. Population pharmacokinetics of atazanavir/ritonavir in HIV-

1-infected children and adolescents. Br J Clin Pharmacol. 2011;72(6):940-947. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21649692.

4. Chokephaibulkit K, Prasitsuebsai W, Wittawatmongkol O, et al. Pharmacokinetics of

darunavir/ritonavir in Asian HIV-1-infected children aged ≥7 years. Antivir Ther.
2012;17(7):1263-1269. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22954687.

5. Paediatric European Network for Treatment of AIDS. Once vs. twice-daily lopinavir/ritonavir in
HIV-1-infected children. AIDS. 2015;29(18):2447-2457. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26558544.

6. Gondrie IPE, Bastiaans DET, Fraaij PLA, et al. Sustained viral suppression in HIV-infected children
on once-daily lopinavir/ritonavir in clinical practice. Pediatr Infect Dis J. 2017;36(10):976-980.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28475554.

7. Orkin C, Bernal Morell E, Tan DHS, et al. Initiation of long-acting cabotegravir plus rilpivirine as
direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week 124 results of the
open-label phase 3 FLAIR study. Lancet HIV. 2021;8(11):e668-e678. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34656207.

8. Lowenthal E, Chapman J, Calabrese K, et al. Adolescent and parent experiences with long-acting
injectables in the MOCHA study. Presented at: Conference on Retroviruses and Opportunistic
Infections; 2022. Virtual conference. Available at:
https://www.croiconference.org/abstract/adolescent-and-parent-experiences-with-long-acting-
injectables-in-the-mocha-study/.

9. Jaeger H, Overton ET, Richmond G, et al. Long-acting cabotegravir and rilpivirine dosed every 2
months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised, multicentre,
open-label, phase 3b, non-inferiority study. Lancet HIV. 2021;8(11):e679-e689. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34648734.

10. Waters L, Sparrowhawk A. Clinical implementation of long-acting antiretroviral treatment in

high-income countries: challenges and advantages. Curr Opin HIV AIDS. 2022;17(3):121-126.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/35439786.

11. Llibre JM, Hung CC, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-rilpivirine for
the maintenance of virological suppression in adults with HIV-1: phase 3, randomised, non-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-13
 inferiority SWORD-1 and SWORD-2 studies. Lancet. 2018;391(10123):839-849. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29310899.

12. Aboud M, Orkin C, Podzamczer D, et al. Efficacy and safety of dolutegravir-rilpivirine for
maintenance of virological suppression in adults with HIV-1: 100-week data from the
randomised, open-label, phase 3 SWORD-1 and SWORD-2 studies. Lancet HIV. 2019;6(9):e576-
e587. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31307948.

13. van Wyk J, Orkin C, Rubio R, et al. Durable suppression and low rate of virologic failure 3 years
after switch to dolutegravir + rilpivirine 2-drug regimen: 148-week results from the SWORD-1
and -2 randomized clinical trials. J Acquir Immune Defic Syndr. 2020;85(3):325-330. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32675772.

14. Compagnucci A, Chan M, Saïdi Y, et al. Once daily integrase inhibitor (INSTI) with boosted
darunavir is non-inferior to standard of care in virologically suppressed children - Week 48
results of the SMILE Penta-17 Trial. Presented at: The 11th IAS Conference on HIV Sciences;
2021. Available at: https://penta-id.org/publications/hiv-publications/hiv-trials/penta-17/once-
daily-integrase-inhibitor-insti-with-boosted-darunavir-is-non-inferior-to-standard-of-care-in-
virologically-suppressed-children-week-48-results-of-the-smile-penta-17-trial/.

15. Kuhn L, Coovadia A, Strehlau R, et al. Switching children previously exposed to nevirapine to
nevirapine-based treatment after initial suppression with a protease-inhibitor-based regimen:
long-term follow-up of a randomised, open-label trial. Lancet Infect Dis. 2012;12(7):521-530.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22424722.

16. Coovadia A, Abrams EJ, Strehlau R, et al. Efavirenz-based antiretroviral therapy among
nevirapine-exposed HIV-infected children in South Africa: a randomized clinical trial. JAMA.
2015;314(17):1808-1817. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26529159.

17. Murnane PM, Strehlau R, Shiau S, et al. Switching to efavirenz versus remaining on ritonavir-
boosted lopinavir in HIV-infected children exposed to nevirapine: long-term outcomes of a
randomized trial. Clin Infect Dis. 2017;65(3):477-485. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28419200.

18. Natukunda E, Rodriguez C, McGrath E, et al. B/F/TAF in virologically suppressed adolescents and
children: two-year outcomes in 6 to <18 year olds and six-month outcomes in toddlers.
Presented at: 13th International Workshop on HIV Pediatrics 2021. Virtual meeting. Available at:
https://www.natap.org/2021/IAS/IAS_80.htm.

19. Anugulruengkitt S, A. Gaur, P. Kosalaraksa, A. Liberty, Y. Shao, et al. . Long-term safety & efficacy
of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (E/C/F/TAF) single-
tablet regimen in children and adolescents living with HIV [Abstract 4] Presented at:
International Workshop on HIV Pediatrics 2021. Virtual meeting. Available at:
https://www.natap.org/2021/IAS/IAS_79.htm.

20. Turkova A, White E, Mujuru HA, et al. Dolutegravir as first- or second-line treatment for HIV-1
infection in children. N Engl J Med. 2021;385(27):2531-2543. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34965338.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-14
21. Amuge P, Lugemwa A, Wynne B, et al. Once-daily dolutegravir-based antiretroviral therapy in
infants and children living with HIV from age 4 weeks: results from the below 14 kg cohort in the
randomised ODYSSEY trial. Lancet HIV. 2022;9(9):e638-e648. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/36055295.

22. Gill M, Songane M, Herrera N, et al. Pediatric ARV optimization in a real-world setting:
dolutegravir transition in Mozambique. Presented at: International Workshop on HIV Pediatrics
2021. Virtual. Available at: https://academicmedicaleducation.com/meeting/international-
workshop-hiv-pediatrics-2021/abstract/pediatric-arv-optimization-real-world.

23. Kouamou V, Manasa J, Maposphere C, et al. Tenofovir, lamivudine and dolutegravir (TLD) among
rural adolescents in Zimbabwe, a cautionary tale. Presented at: International Workshop on HIV
Pediatrics 2021. Virtual. Available at:
https://academicmedicaleducation.com/meeting/international-workshop-hiv-pediatrics-
2021/abstract/tenofovir-lamivudine-and-dolutegravir.

24. Van de Ven R, Antelman G, Masenge T, Kimambo S. Impact of ARV optimization on HIV viral load
suppression among children in Tanzania. Presented at: International AIDS Society 2021. Virtual.
Available at: https://theprogramme.ias2021.org/Abstract/Abstract/1498.

25. Bacha J, Mayalla B, Chodota M, Jiwa N, Mwita L, Campbell L. There is no substitute for hard
work(ing dolutegravir): outcomes of single drug substitutions among CALHIV shifted to a
dolutegravir antiretroviral regimen in Mbeya and Mwanza, Tanzania. Presented at: International
Workshop on HIV Pediatrics 2021. Virtual. Available at:
https://academicmedicaleducation.com/meeting/international-workshop-hiv-pediatrics-
2021/abstract/there-no-substitute-hard-working.

26. Bacha Jea. The fast and the continuous: dolutegravir-based antiretroviral therapy achieves
impressive viral load suppression in CALHIV in the short- and long-term. Presented at: AIDS
2022; 2022. Available at: https://programme.aids2022.org/Abstract/Abstract/?abstractid=2849

27. Rodriguez C, Strehlau R, Chokephaibulkit K, et al. One year outcome of

bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in virologically suppressed children ≥
2 years weighing 14 to < 25kg. Presented at: Internataional Workshop on HIV & Pediatrics 2022.
Montreal, Canada. Available at: https://www.natap.org/2022/IAC/IAC_90.htm.

28. Gaur AH, Cotton MF, Rodriguez CA, et al. Fixed-dose combination bictegravir, emtricitabine, and
tenofovir alafenamide in adolescents and children with HIV: week 48 results of a single-arm,
open-label, multicentre, phase 2/3 trial. Lancet Child Adolesc Health. 2021;5(9):642-651.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/34302760.

29. Phongsamart W, Jantarabenjakul W, Chantaratin S, et al. Switching efavirenz to rilpivirine in

virologically suppressed adolescents with HIV: a multi-centre 48-week efficacy and safety study
in Thailand. J Int AIDS Soc. 2022;25(1):e25862. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35001501.

30. Melvin AJ, Yee KL, Gray KP, et al. Pharmacokinetics, tolerability, and safety of doravirine and
doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination tablets in

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-15
 adolescents living with HIV: week 24 results from IMPAACT 2014. J Acquir Immune Defic Syndr.
2023;92(2):153-161. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36215957.

31. Vigano A, Aldrovandi GM, Giacomet V, et al. Improvement in dyslipidaemia after switching
stavudine to tenofovir and replacing protease inhibitors with efavirenz in HIV-infected children.
Antivir Ther. 2005;10(8):917-924. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16430197.

32. Fabiano V, Giacomet V, Vigano A, et al. Long-term body composition and metabolic changes in
HIV-infected children switched from stavudine to tenofovir and from protease inhibitors to
efavirenz. Eur J Pediatr. 2013;172(8):1089-1096. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23636286.

33. Rosso R, Nasi M, Di Biagio A, et al. Effects of the change from stavudine to tenofovir in human
immunodeficiency virus-infected children treated with highly active antiretroviral therapy:
studies on mitochondrial toxicity and thymic function. Pediatr Infect Dis J. 2008;27(1):17-21.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/18162932.

34. Aurpibul L, Puthanakit T, Sirisanthana T, Sirisanthana V. Haematological changes after switching

from stavudine to zidovudine in HIV-infected children receiving highly active antiretroviral
therapy. HIV Med. 2008;9(5):317-321. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18331562.

35. Gonzalez-Tome MI, Amador JT, Pena MJ, Gomez ML, Conejo PR, Fontelos PM. Outcome of
protease inhibitor substitution with nevirapine in HIV-1 infected children. BMC Infect Dis.
2008;8:144. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18945352.

36. Arribas JR, Pialoux G, Gathe J, et al. Simplification to coformulated elvitegravir, cobicistat,
emtricitabine, and tenofovir versus continuation of ritonavir-boosted protease inhibitor with
emtricitabine and tenofovir in adults with virologically suppressed HIV (STRATEGY-PI): 48 week
results of a randomised, open-label, phase 3b, non-inferiority trial. Lancet Infect Dis.
2014;14(7):581-589. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24908551.

37. Martinez E, Larrousse M, Llibre JM, et al. Substitution of raltegravir for ritonavir-boosted
protease inhibitors in HIV-infected patients: the SPIRAL study. AIDS. 2010;24(11):1697-1707.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20467288.

38. Curran A, Martinez E, Saumoy M, et al. Body composition changes after switching from protease
inhibitors to raltegravir: SPIRAL-LIP substudy. AIDS. 2012;26(4):475-481. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22112606.

39. Bagella P, Squillace N, Ricci E, et al. Lipid profile improvement in virologically suppressed HIV-1-
infected patients switched to dolutegravir/abacavir/lamivudine: data from the SCOLTA project.
Infect Drug Resist. 2019;12:1385-1391. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31213857.

40. Calza L, Colangeli V, Borderi M, et al. Improvement in insulin sensitivity and serum leptin
concentration after the switch from a ritonavir-boosted PI to raltegravir or dolutegravir in non-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-16
 diabetic HIV-infected patients. J Antimicrob Chemother. 2019;74(3):731-738. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30541118.

41. Eckard AR, McComsey GA. Weight gain and integrase inhibitors. Curr Opin Infect Dis.
2020;33(1):10-19. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31789693.

42. Sokhela Sea. ADVANCE trial: DTG + TDF or TAF vs EFV 1st Line ART excess weight gain with DTG-
TAF. Presented at: International Workshop on HIV & Pediatrics 2020; 2020. Virtual conference.

43. Dirajlal-Fargo S, Koay WLA, Levy ME, Monroe AK, Castel AD, Rakhmanina N. Effect of integrase
inhibitors on weight gain in children and adolescents with HIV. Abstract 826. Presented at:
Conference on Retroviruses and Opportunistic Infections; 2020. Boston, MA. Available at:
https://www.croiconference.org/abstract/effect-of-integrase-inhibitors-on-weight-gain-in-
children-and-adolescents-with-hiv/.

44. Yeoh DK, Campbell AJ, Bowen AC. Increase in body mass index in children with HIV, switched to
tenofovir alafenamide fumarate or dolutegravir containing antiretroviral regimens. Pediatr
Infect Dis J. 2021;40(5):e215-e216. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33847305.

45. Mallon PW, Brunet L, Hsu RK, et al. Weight gain before and after switch from TDF to TAF in a
U.S. cohort study. J Int AIDS Soc. 2021;24(4):e25702. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33838004.

46. McComsey GA, Lupo S, Parks D, et al. Switch from tenofovir disoproxil fumarate combination to
dolutegravir with rilpivirine improves parameters of bone health. AIDS. 2018;32(4):477-485.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29239893.

47. Soriano V, Fernandez-Montero JV, Benitez-Gutierrez L, et al. Dual antiretroviral therapy for HIV
infection. Expert Opin Drug Saf. 2017;16(8):923-932. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28621159.

48. Arribas JR, Girard PM, Paton N, et al. Efficacy of protease inhibitor monotherapy vs. triple
therapy: meta-analysis of data from 2303 patients in 13 randomized trials. HIV Med.
2016;17(5):358-367. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26709605.

49. Brenner BG, Thomas R, Blanco JL, et al. Development of a G118R mutation in HIV-1 integrase
following a switch to dolutegravir monotherapy leading to cross-resistance to integrase
inhibitors. J Antimicrob Chemother. 2016;71(7):1948-1953. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27029845.

50. Wijting IEA, Wit F, Rokx C, et al. Immune reconstitution inflammatory syndrome in HIV infected
late presenters starting integrase inhibitor containing antiretroviral therapy. EClinicalMedicine.
2019;17:100210. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31891143.

51. Rokx C, Schurink CA, Boucher CA, Rijnders BJ. Dolutegravir as maintenance monotherapy: first
experiences in HIV-1 patients. J Antimicrob Chemother. 2016;71(6):1632-1636. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26888910.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-17
52. Pinnetti C, Lorenzini P, Cozzi-Lepri A, et al. Randomized trial of DRV/r or LPV/r QD monotherapy
vs maintaining a PI/r-based antiretroviral regimen in persons with suppressed HIV replication. J
Int AIDS Soc. 2014;17(4 Suppl 3):19809. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25397553.

53. Santos JR, Llibre JM, Bravo I, et al. Short communication: efficacy and safety of treatment
simplification to lopinavir/ritonavir or darunavir/ritonavir monotherapy: a randomized clinical
trial. AIDS Res Hum Retroviruses. 2016;32(5):452-455. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26781004.

54. Kosalaraksa P, Ananworanich J, Puthanakit T, et al. Long-term lopinavir/ritonavir monotherapy

in HIV-infected children. Pediatr Infect Dis J. 2013;32(4):350-353. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23190774.

55. Griffith DC, Farmer C, Gebo KA, et al. Uptake and virological outcomes of single- versus multi-
tablet antiretroviral regimens among treatment-naive youth in the HIV Research Network. HIV
Med. 2019;20(2):169-174. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30561888.

56. Natukunda E, Gaur A, Kosalaraksa P, et al. Safety, efficacy, and pharmacokinetics of single-tablet
elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically suppressed, HIV-
infected children: a single-arm, open-label trial. Lancet Child Adolescent Health. 2017;1(1):27-34.
Available at:
https://www.sciencedirect.com/science/article/pii/S2352464217300093?via%3Dihub.

57. Liberty A, Strehlau R, Rakhmanina N, et al. Acceptability & palatability of low dose B/F/TAF &
E/C/F/TAF in children (≥2y) with HIV. Presented at: International Workshop on HIV & Pediatrics
2020; 2020. Virtual. Available at:
https://academicmedicaleducation.com/meeting/international-workshop-hiv-pediatrics-
2020/abstract/acceptability-palatability-low-dose.

58. Rotsaert A, Nostlinger C, Collin O, et al. Acceptability of a new 4-in-1

abacavir/lamivudine/lopinavir/ritonavir paediatric fixed-dose combination: the caregiver-child
dyad's perspective. Presented at: International Workshop on HIV & Pediatrics 2020; 2020.
Virtual. Available at: https://academicmedicaleducation.com/meeting/international-workshop-
hiv-pediatrics-2020/abstract/acceptability-new-4-1.

59. Agwu AL, Fairlie L. Antiretroviral treatment, management challenges and outcomes in
perinatally HIV-infected adolescents. J Int AIDS Soc. 2013;16:18579. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23782477.

60. Wensing AM, Calvez V, Gunthard HF, et al. 2015. Update of the drug resistance mutations in
HIV-1. Top Antivir Med. 2015;23(4):132-141. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26713503.

61. Dehority W, Deville JG, Lujan-Zilbermann J, Spector SA, Viani RM. Effect of HIV genotypic drug
resistance testing on the management and clinical course of HIV-infected children and
adolescents. Int J STD AIDS. 2013;24(7):549-553. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23970770.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-18
62. Tobin NH, Learn GH, Holte SE, et al. Evidence that low-level viremias during effective highly
active antiretroviral therapy result from two processes: expression of archival virus and
replication of virus. J Virol. 2005;79(15):9625-9634. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16014925.

63. Kuritzkes DR. Preventing and managing antiretroviral drug resistance. AIDS Patient Care STDS.
2004;18(5):259-273. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15186710.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-19
Recognizing and Managing Antiretroviral Treatment
Failure
Updated: April 11, 2023
Reviewed: April 11, 2023

Panel’s Recommendations
• The causes of antiretroviral (ARV) treatment failure—which include poor adherence, drug resistance, poor absorption of
medications, inadequate dosing, and drug–drug interactions—should be assessed and addressed (AII).
• Perform ARV drug-resistance testing when virologic failure occurs, while the patient is still taking the failing regimen (AI*)
(see Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines for more information).
• ARV regimens should be chosen based on treatment history and drug-resistance testing, including both past and current
resistance test results (AI*).
• The new regimen should include at least two, but preferably three, fully active ARV medications; the assessment of
anticipated ARV activity should be based on treatment history and past resistance test results (AII*).
• The goal of therapy following treatment failure is to achieve and maintain virologic suppression, which is defined as a
plasma viral load that is below the limits of detection as measured by highly sensitive assays with lower limits of
quantification of 20 copies/mL to 75 copies/mL (AI*).
• When complete virologic suppression cannot be achieved, the goals of therapy are to preserve or restore immunologic
function (as measured by CD4 T lymphocyte values), prevent clinical disease progression, and prevent the development of
additional drug resistance that could further limit future ARV drug options (AII).
• Children who require evaluation and management of treatment failure should be managed by or in collaboration with a
pediatric HIV specialist (AI*).
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints;
I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying
data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical
outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term
outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical
outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical
outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to postpubertal adolescents

Categories of Treatment Failure

Treatment failure can be categorized as virologic failure, immunologic failure, clinical failure, or
some combination of the three. Immunologic failure refers to a suboptimal immunologic response to
therapy or an immunologic decline while on therapy, but no standardized definition exists. Clinical
failure is defined as the occurrence of new opportunistic infections (OIs) (excluding immune
reconstitution inflammatory syndrome [IRIS]) and/or other clinical evidence of HIV disease
progression during therapy. Almost all antiretroviral (ARV) management decisions for treatment
failure are based on addressing virologic failure.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-20
Virologic Failure
Virologic failure refers to either an incomplete initial response to therapy or a viral rebound after
virologic suppression is achieved. Virologic suppression is defined as having a plasma viral load
below the lower level of detection, as measured by highly sensitive assays with lower limits of
quantitation of 20 copies/mL to 75 copies/mL. Virologic failure is defined as the inability to achieve
or maintain plasma viral load <200 copies/mL after 6 months of therapy. Laboratory results must be
confirmed with repeat testing before a final assessment of virologic failure is made.

Infants with high plasma viral loads at the initiation of antiretroviral therapy (ART) occasionally take
longer than 6 months to achieve virologic suppression. Because of this, some experts continue the
treatment regimen for infants if their viral load is declining but is still ≥200 copies/mL at 6 months.
These infants should be monitored closely until they achieve virologic suppression.1 However,
ongoing nonsuppression—especially with non-nucleoside reverse transcriptase inhibitor (NNRTI)-
based regimens—increases the risk of drug resistance.2,3

The clinical implications of HIV RNA levels that are between the lower level of detection and
<200 copies/mL in patients on ART remain unclear. Adults with HIV who have detectable viral
loads and a quantified result <200 copies/mL after 6 months of ART generally achieve virologic
suppression without changing regimens.4,5 However, some studies in adults have found that multiple
viral load measurements of 50 copies/mL to <200 copies/mL (sometimes characterized as low-level
viremia) may be associated with an increased risk of later virologic failure.6-9 In contrast, a recent
study that followed a cohort of 57 adult patients with low-level viremia (21–200 copies/mL) reported
that none of the patients had resistance to their regimens, and all had adequate plasma ARV
concentrations. At 96 weeks of follow-up, 67% remained with low-level viremia, 26% had viral
loads <20 copies/mL, and only 7% had viral failure; none was attributed to viral resistance.10

“Blips”—defined as isolated episodes of a detectable but low level of plasma viral load
(i.e., <500 copies/mL) that are followed by a return to viral suppression—are common and not
generally reflective of short-term virologic failure, although they may indicate an increased risk of
virologic failure after 12 to 24 months.11-13 However, repeated or persistent plasma viral loads that
are ≥200 copies/mL (especially viral loads that are >500 copies/mL) in patients who have previously
achieved virologic suppression usually indicate virologic failure.5,13-15

In a cohort of children from Cambodia, Indonesia, Malaysia, Thailand, and Vietnam who were on
first-line combination therapy,16 among those who achieved viral suppression (<50 copies/mL on two
successive measurements), 17% had at least one viral load with low-level viremia over a median
follow-up of 6 years. More than a third of those had repeated episodes of low-level viremia. The rate
of viral failure was 8.9 per 100 patient-years in those with low-level viremia versus 3.3 per
100 patient-years in those without low-level viremia. Of note, 97% of the cohort were started on an
NNRTI-based regimen, which has a lower barrier to resistance than other regimens and, therefore,
may not be generalizable to patients on other regimens.

Poor Immunologic Response Despite Virologic Suppression

Poor immunologic response despite virologic suppression is uncommon in children.17 Patients with
baseline severe immunosuppression often take longer than 1 year to achieve immune recovery, even
if virologic suppression occurs more promptly (see Appendix C: CDC Pediatric HIV CD4 Cell
Count/Percentage and HIV-Related Diseases Categorization). Patients who have very low baseline

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-21
CD4 values before initiating ART are at higher risk of an impaired CD4 response to ART and, based
on data from adult studies, may be at higher risk of death and AIDS-defining illnesses despite
virologic suppression.18-20 During the early treatment period, before immune recovery or in cases of
persistent immunosuppression, clinical disease progression can occur. In an international study, 68%
of children and adolescents had advanced/severe immunosuppression for age at initiation of ART,
and 12% of pediatric and adolescent patients had a poor immunologic response (defined as
advanced/severe immunosuppression for age) 1 year after viral suppression (defined as
<400 copies/mL).21 Among those with a poor immunologic response at 1 year post viral suppression,
a fourfold increased risk of an AIDS diagnosis or death was observed compared with immune
responders (rate ratio 4.04; 95% confidence interval, 1.83–8.92). Poor immunologic response
dropped to 7% at 2 years and 3% at 3 years in those with continued viral suppression.21 Studies in
adults with HIV note that CD4 count recovery at 1 year and 2 years post-initiation of initial therapy
is independent of the drug class used (i.e., boosted protease inhibitor [PI], integrase strand transfer
inhibitor [INSTI], or NNRTI).22

In cases of poor immunologic response despite virologic suppression, clinicians should first exclude
laboratory error in CD4 values or viral load measurements and ensure that CD4 values have been
interpreted correctly in relation to the natural decline in CD4 count that occurs during the first 5 to
6 years of life. Another laboratory consideration is that some viral load assays may not amplify all
HIV groups and subtypes (e.g., HIV-1 non-M groups, HIV-2), resulting in falsely low or negative
viral load results (see Diagnosis of HIV Infection in Infants and Children and Clinical and
Laboratory Monitoring of Pediatric HIV Infection). Once laboratory results are confirmed, clinicians
should evaluate patients for adverse events, medical conditions, and other factors that can cause CD4
values to decrease (see Table 19 below). Several drugs (e.g., corticosteroids, chemotherapeutic
agents) and conditions (e.g., hepatitis C virus [HCV], tuberculosis [TB], malnutrition, Sjogren’s
syndrome, sarcoidosis, syphilis, cirrhosis, acute viral infections) are independently associated with
low CD4 values.23

In summary, poor immunologic response to treatment can occur. Management consists of confirming
that CD4 values and viral load measurements are accurate, avoiding the use of drugs that are
associated with low CD4 values, and treating other conditions that could impair CD4 recovery. The
Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV (the Panel)
does not recommend modifying an ARV regimen based on lack of immunologic response if
virologic suppression is confirmed.

Poor Clinical Response Despite Adequate Virologic and Immunologic Responses

Clinicians must carefully evaluate patients who experience clinical disease progression despite
favorable immunologic and virologic responses to ART; not all cases represent ART failure. At
times, after initiation of ART, patients will suffer a clinical deterioration due to paradoxical
worsening of a known OI or unmasking of a previously undiagnosed OI due to a profound immune
response (i.e., IRIS) related to successful viral suppression. This does not represent ART treatment
failure and does not generally require discontinuation of or a change in ART. IRIS does not mean
that ART has failed, and it does not generally require discontinuation of ART.24,25 Children who have
suffered irreversible damage to their lungs, brain, or other organs—especially during prolonged and
profound pre-treatment immunosuppression—may continue to have recurrent infections or symptoms
in the damaged organs, because the immunologic improvement may not reverse damage to the
organs.26 Such cases do not represent ART failure, and these children would not benefit from a
change in ARV regimen. Before a definitive conclusion of ART clinical failure is reached, a child

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-22
should be evaluated to rule out (and, when indicated, treat) other causes or conditions that can occur
with or without HIV-related immunosuppression, such as pulmonary TB, malnutrition, and
malignancy.

Occasionally, however, children will develop new HIV-related OIs (e.g., Pneumocystis jirovecii
pneumonia or esophageal candidiasis that occurs more than 6 months after achieving markedly
improved CD4 values and virologic suppression) that are not related to IRIS, pre-existing organ
damage, or another cause.17 Although such cases are rare, they may represent ART clinical failure,
and improvement in CD4 values may not necessarily normalize immunologic function. In children
who have signs of new or progressive abnormal neurodevelopment, some experts change the ARV
regimen, aiming to include agents that are known to achieve higher concentrations in the central
nervous system. However, the data regarding the effectiveness of this strategy are inconclusive.27,28

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-23
Table 19. Discordance Among Virologic, Immunologic, and Clinical Responses

Differential Diagnosis of Poor Immunologic Response Despite Virologic Suppression

Poor Immunologic Response Despite Virologic Suppression and Good Clinical Response
• Laboratory error (in CD4 value or viral load measurement)
• Misinterpretation of normal, age-related CD4 count decline (i.e., the immunologic response is not actually poor)
• Low pre-treatment CD4 count or percentage
• AEs that are associated with the use of certain drugs (e.g., ZDV, TMP-SMX, systemic corticosteroids)
• Use of systemic corticosteroids or chemotherapeutic agents
• Conditions that can cause low CD4 values (e.g., HCV, acute viral infections, TB, malnutrition, Sjogren’s syndrome,
sarcoidosis, syphilis)

Poor Immunologic and Clinical Responses Despite Virologic Suppression

• Laboratory error (in CD4 value or viral load measurement)
• Falsely low viral load result for an HIV strain/type that is not detected by viral load assay (i.e., HIV-1 non-M groups, HIV-1
non-B subtypes, HIV-2 [although this is unusual with newer viral load assays])
• Persistent immunodeficiency that occurs soon after initiating ART, but before ART-related reconstitution
• Primary protein-calorie malnutrition
• Untreated TB
• Malignancy

Differential Diagnosis of Poor Clinical Response Despite Adequate

Virologic and Immunologic Responses
• IRIS
• A previously unrecognized, pre-existing infection or condition (e.g., TB, malignancy)
• Malnutrition
• Clinical manifestations of previous organ damage: brain (e.g., strokes, vasculopathy, worsening neurodevelopmental
delay), lungs (e.g., bronchiectasis), cardiac (i.e., cardiomyopathy), renal (i.e., HIV-related kidney disease)
• A new clinical event due to a non-HIV illness or condition
• A new, or otherwise unexplained, HIV-related clinical event (e.g., treatment failure)
Key: AEs = adverse effects; ART = antiretroviral therapy; CD4 = CD4 T lymphocyte; HCV = hepatitis C virus;
IRIS = immune reconstitution inflammatory syndrome; TB = tuberculosis; TMP-SMX = trimethoprim-sulfamethoxazole;
ZDV = zidovudine

Management of Virologic Failure

The approach to managing and subsequently treating virologic failure will differ, depending on the
etiology of the problem. When assessing a child with suspected virologic failure, clinicians should
evaluate therapy adherence and medication intolerance, confirm that the prescribed dosing is correct
(and understood by the child and/or caregiver) for all medications in the regimen, consider possible
pharmacokinetic interactions that might lead to low drug levels, and test for possible drug resistance
(see Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines). Although many

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-24
factors can contribute to virologic failure, the main barrier to sustained virologic suppression in
adults and children is incomplete adherence to medication regimens, with the subsequent emergence
of viral mutations that confer partial or complete resistance to one or more components of the ARV
regimen. See Adherence to Antiretroviral Therapy in Children and Adolescents With HIV for
guidance on assessing adherence and strategies for improving adherence.

Virologic Failure With No Antiretroviral Drug Resistance Identified

Persistent viremia in the absence of detectable viral resistance to current medications is usually a
result of nonadherence, but it is important to consider other factors, such as poor drug absorption,
incorrect dosing, and drug interactions. If adequate drug exposure can be ensured, then adherence to
the current regimen should result in virologic suppression. Resistance testing should take place while
a child is on therapy. After discontinuing therapy, plasma viral strains may quickly revert to wild
type and reemerge as the predominant viral population, in which case, resistance testing can fail to
identify the drug-resistant virus (see Drug-Resistance Testing in the Adult and Adolescent
Antiretroviral Guidelines). In this situation, resistance can be identified by restarting the prior
medications while emphasizing adherence and repeating resistance testing in 4 weeks if plasma virus
remains detectable. If the HIV plasma viral load becomes undetectable, then nonadherence was likely
the original cause of virologic failure.

Virologic failure in children receiving boosted PI-based regimens is frequently associated with no
detected major PI-resistance mutations, as it is generally secondary to non-adherence.29 Virologic
suppression may be achieved by continuing the PI-based regimen, implementing adherence-
improvement measures, and addressing any PI-related side effects.30-32 However, continued virologic
failure on PI-based regimens—especially if PI drug levels are subtherapeutic or in the presence of
nucleoside reverse transcriptase inhibitor (NRTI)-resistance mutations—can lead to major PI
mutations.33

If a new, more convenient regimen could address the main barrier to adherence, it is reasonable for a
clinician to switch a patient to this new regimen (e.g., a single fixed-dose combination [FDC] tablet
taken once daily) while closely monitoring adherence and viral load. Similarly, if an ART side effect
or tolerability is found to be impacting adherence, switching to a new regimen with close monitoring
should be considered. INSTI-based, once-daily regimens in FDC address both convenience and
tolerability in most cases. However, in cases where clinicians determine that patients have poor
adherence to the current regimen and that adherence is unlikely to improve with a new regimen,
clinicians should focus on improving adherence before initiating a new regimen (see Adherence to
Antiretroviral Therapy in Children and Adolescents With HIV).

Virologic Treatment Failure With Antiretroviral Drug Resistance Identified

After deciding that a change in therapy is necessary, a clinician should attempt to identify at least
two, but preferably three, fully active ARV agents from at least two different drug classes to use in a
patient’s new regimen. The clinician should consider all of the patient’s past and recent drug-
resistance test results, the patient’s prior exposure to ARV drugs, whether the patient is likely to
adhere to the regimen, and whether the patient finds a particular regimen acceptable.34-38 This process
often requires using agents from one or more drug classes that are new to the patient. However,
clinicians should be aware that drug-resistance mutations can confer cross-resistance within a drug
class, so a drug that is new to the patient may still have diminished antiviral potency. Substituting or
adding a single drug to a failing regimen is not recommended, because this is unlikely to lead to

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-25
durable virologic suppression and will likely result in additional drug resistance. When reviewing
results of drug-resistance assays, clinicians should consult the Stanford University HIV Drug
Resistance Database to determine if a change in the ARV regimen is required and, if a change is
required, which ARV agents can be retained.

The process of switching a patient to a new regimen must include an extensive discussion of
treatment adherence and potential toxicity with the patient and the patient’s caregivers. This
discussion should be appropriate for the patient’s age and stage of development. Clinicians should be
aware that some medications have conflicting food requirements and concomitant medication
restrictions that may complicate the administration of a regimen. Timing of medication
administration is particularly important because it helps ensure adequate ARV drug exposures
throughout the day. Palatability, pill size, number of pills, and dosing frequency all need to be
considered when choosing a new regimen.39

Therapeutic Options to Achieve Complete Virologic Suppression After Virologic

Failure
A pediatric HIV specialist should be consulted when determining which new regimen will have the
best chance of achieving complete virologic suppression in children who have already experienced
treatment failure.

ARV regimens should be chosen based on a patient’s treatment history and drug-resistance test
results to optimize ARV drug potency in the new regimen (see Adherence to Antiretroviral Therapy
in Children and Adolescents With HIV). A general strategy for regimen changes is shown in Table
20 below; however, as additional agents are licensed and studied for use in children, newer regimens
that are better tailored to the needs of each patient may be constructed.

The availability of newer drugs within existing drug classes and the introduction of new classes of
drugs increase the likelihood of finding three active drugs, even for children with extensive drug
resistance (see Table 20 below). INSTI-based regimens are increasingly used for children who have
experienced treatment failure on NNRTI-based regimens or PI-based regimens.40,41
Raltegravir (RAL) is the INSTI that has been studied and used longest in children, but both
dolutegravir (DTG) and bictegravir (BIC) have the advantage of once-daily dosing, small pill size,
and higher barrier to the development of drug resistance; they also often retain ARV activity in
patients who have experienced treatment failure on RAL-based therapy (see Dolutegravir and
Bictegravir for the latest age and weight indications).42

Data from adult and pediatric studies support the efficacy of a regimen that contains a second-
generation INSTI (DTG or BIC) plus two NRTIs for those who experience treatment failure on an
initial NNRTI-based regimen. Both the Once-daily DTG based ART in Young People vs. Standard
Therapy(ODYSSEY)43 and Nucleosides And Darunavir/Dolutegravir in Africa(NADIA)44 trials
indicate that DTG is not inferior to a boosted PI regimen when transitioning from a failing NNRTI-
based regimen. In the NADIA trial, patients experiencing virologic failure on a NNRTI plus
lamivudine (3TC) or emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF) regimen were
randomized to DTG or boosted darunavir (DRV) plus 3TC and either TDF or zidovudine (ZDV). At
both 48 and 96 weeks, >85% of participants met the primary endpoint of viral suppression, defined
as <400 copies/mL in all arms of the study.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-26
However, caution should be exercised when considering the use of regimens that include first-
generation INSTIs with a lower barrier to resistance (e.g., RAL), because children who experience
treatment failure on NNRTI-based regimens often have substantial NRTI resistance.45

Resistance to the NNRTI nevirapine (NVP) results in cross-resistance to the NNRTI

efavirenz (EFV), and vice versa. The NNRTIs etravirine (ETR) and rilpivirine (RPV) can retain
activity against NVP-resistant virus or EFV-resistant virus in the absence of certain key NNRTI
mutations, but ETR has generally been tested only in regimens that also contain a boosted PI.34,46 For
this reason, the Panel recommends using ETR as part of a regimen that includes a ritonavir-boosted
PI (see the Etravirine section). Doravirine is a once-daily NNRTI that retains activity against
EFV/NVP-resistant virus and was recently approved by the U.S. Food and Drug
Administration (FDA) for use in children and adolescents weighing ≥35 kg. Studies are ongoing in
adolescents aged 12 to 18 years47 (see the Doravirine section).

If a child experiences virologic failure on an initial PI-based regimen, there are often limited
resistance mutations detected, indicating that poor adherence/tolerance of the regimen may be the
cause of poor viral control.45,48 In these cases, a more tolerable ARV regimen should be sought to
improve adherence and achieve virologic suppression. Switching to an INSTI-based regimen can be
effective in some PI-experienced children and are typically better tolerated than PI-based
regimens.40,41,49-51 If an INSTI-based regimen is not available, an alternative PI that might be potent
and better tolerated could also be used.

Maraviroc, a CCR5 antagonist, provides a new drug class; however, many ART-experienced children
and some ART-naive children already harbor a CXCR4-tropic virus, which precludes its use.52,53
Regimens that include an INSTI and a potent boosted PI with or without ETR have been effective
during small studies of extensively ART-experienced patients with multiclass drug resistance.54-57

It is important to review individual drug profiles for information about drug interactions and dose
adjustments when devising a regimen for children with multiclass drug resistance. Appendix A:
Pediatric Antiretroviral Drug Information provides detailed information on drug formulations,
pediatric and adult doses, and toxicity, as well as discussions of the available data on the use of ARV
drugs in children.

Previously prescribed drugs that were discontinued because of poor tolerance or poor adherence may
sometimes be reintroduced if drug resistance did not develop and if prior difficulties with tolerance
and adherence can be overcome (e.g., by switching to a new formulation, such as an FDC tablet).

Some studies in adults have suggested that 3TC can still contribute to suppression of HIV replication
in patients with 3TC resistance mutations. Continuation of 3TC also can maintain a 3TC mutation
(184V) that can partially reverse the effects of other mutations that confer resistance to ZDV and
TDF.58-60

Studies have compared the use of NRTI-sparing and NRTI-containing regimens in adults with
multidrug resistance who experienced virologic failure on a previous regimen. These studies have
demonstrated no clear benefit of including NRTIs in the new regimen.61,62 One of these studies
reported no difference in rate of virologic suppression but a trend toward a higher mortality in adults
who were randomized to receive a regimen that included NRTIs than in adults who were randomized
to receive an NRTI-sparing regimen.62 There are no studies of NRTI-sparing regimens in children

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-27
with virologic failure and multidrug resistance, but an NRTI-sparing regimen may be a reasonable
option for children with extensive NRTI resistance.

Enfuvirtide (T-20) is approved by the FDA for use in ART-experienced children aged ≥6 years, but it
must be administered by subcutaneous injection twice daily.63,64 Regimens that contain more than
three drugs (up to three PIs and/or two NNRTIs) have shown efficacy in a pediatric case series, but
they are complex, often poorly tolerated, and subject to unfavorable drug–drug interactions.65 The
availability of agents with an increased barrier to resistance—such as the second generation INSTIs
DTG and BIC, the PI DRV, and the second-generation NNRTIs ETR and RPV—have lessened the
need for T-20, dual-PI regimens, and regimens of four or more drugs.

Two agents that inhibit the attachment of the glycoprotein (gp) 120 region of the virus to the CD4
molecule are approved for adolescents >18 years with multidrug resistance. Oral fostemsavir (FTR)
is a gp120 attachment inhibitor, and ibalizumab (given by infusion twice monthly) is a humanized
monoclonal antibody that targets the gp120 attachment area on the CD4 molecule.66,67 Because these
represent drugs with new novel targets, they would be expected to be beneficial in patients with
multiclass drug resistance. In a Phase 3 study of adults with multi-drug resistant HIV-1 who are
heavily treatment-experienced, adding FTR to optimized background therapy resulted in improved
and sustained viral suppression at 96 weeks in 60% (163/272) of participants.68 It should be noted
that resistance can develop with incomplete adherence to these new agents, especially when added to
a failing regimen.

When searching for at least two fully active agents in cases of extensive drug resistance, clinicians
should consider the potential availability of new therapeutic agents that are not currently being
studied in children or that may be approved for use in children in the future. Information about
clinical trials can be found using the National Institute of Allergy and Infectious Diseases Clinical
Trials database and by consulting a pediatric HIV specialist. Children should be enrolled in clinical
trials of new drugs whenever possible. See ClinicalTrials.gov for more information.

Pediatric dosing for off-label use of ARV drugs is problematic, because absorption, hepatic
metabolism, and excretion change with age.69 In clinical trials of several ARV agents, direct
extrapolation of a pediatric dose from an adult dose, based on a child’s body weight or body surface
area, was shown to result in an underestimation of the appropriate pediatric dose.70

Off-label use of ARV agents, however, may be necessary for children with HIV who have limited
ARV drug options. In this circumstance, consulting a pediatric HIV specialist for advice about
potential regimens, assistance with access to unpublished data from clinical trials or other limited off-
label pediatric use, and referral to suitable clinical trials are recommended.

Management Options When Two Fully Active Agents Cannot Be Identified or

Administered
It may be impossible to provide an effective and sustainable therapeutic regimen when there is no
combination of currently available agents that are active against an extensively drug-resistant virus in
a patient or when a patient is unable to adhere to or tolerate ART.

The decision to continue a nonsuppressive regimen must be made on an individual basis after
weighing potential benefits and risks. Specifically, providers must balance the inherent tension
between the benefits of virologic suppression and the risks of continued viral replication with

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-28
potential evolution of viral drug resistance in the setting of inadequate ARV drug exposure
(e.g., nonadherence or a nonsuppressive, suboptimal regimen). Nonsuppressive regimens could
decrease viral fitness and, thus, slow clinical and immunologic deterioration while a patient is either
working on adherence or awaiting access to new agents that are expected to achieve sustained
virologic suppression.71 However, persistent viremia in the context of ARV drug pressure has the
potential to generate additional resistance mutations that could further compromise agents in the
same class that might otherwise have been active in subsequent regimens (e.g., continuing first-
generation INSTIs or NNRTIs). Patients who continue to use nonsuppressive regimens should be
followed more closely than those with stable virologic status, and the potential to successfully initiate
a fully suppressive ARV regimen should be reassessed at every opportunity.

The use of NRTI-only holding regimens or a complete interruption of therapy is not recommended.
One trial, the International Maternal Pediatric Adolescents AIDS Clinical Trials (IMPAACT P1094),
randomized children with the M184V resistance mutation and documented nonadherence to continue
their nonsuppressive, non-NNRTI-based regimen or to switch to a 3TC (or emtricitabine)
monotherapy-holding regimen. Children who switched to monotherapy were significantly more
likely to experience a 30% decline in absolute CD4 count (the primary outcome) over a 28-week
period.72

Complete treatment interruption also has been associated with immunologic declines and poor
clinical outcomes73,74; therefore, it is not recommended (see Antiretroviral Treatment Interruption in
Children With HIV).

Table 20. Options for Regimens With at Least Two Fully Active Agents to Achieve
Virologic Suppression in Patients With Virologic Failure and Evidence of Viral Resistance

To optimize antiretroviral (ARV) drug effectiveness, clinicians should evaluate a patient’s treatment
history and drug-resistance test results when choosing a new ARV regimen. Doing so is particularly
important when selecting the nucleoside reverse transcriptase inhibitor (NRTI) components of a non-
nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, where drug resistance to the
NNRTI can occur rapidly if the virus is not sufficiently sensitive to the NRTIs. Regimens should
contain at least two, but preferably three, fully active drugs for durable and potent virologic
suppression. If the M184V/I mutation associated with FTC and 3TC is present, these medications
should be continued if the new regimen contains TDF, tenofovir alafenamide, or ZDV. The presence
of this mutation may increase susceptibility to these NRTIs.

Please see individual drug profiles for information about weight and age limitations (e.g., do not use
darunavir in children aged <3 years), drug interactions, and dose adjustments when devising a
regimen for children with multiclass drug resistance (see Appendix A: Pediatric Antiretroviral Drug
Information). Collaboration with a pediatric HIV specialist is especially important when choosing
regimens for children with multiclass drug resistance. Regimens in this table are provided as
examples, but the list is not exhaustive.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-29
 Prior Regimen New Regimen Optionsa
Two NRTIs plus an NNRTI Two NRTIs plus an INSTIb

Two NRTIs plus a boosted PI

Two NRTIs plus a PI Two NRTIs plus a second-generation INSTIb

Two NRTIs plus a different boosted PI

INSTI plus a different boosted PI and with or without NRTI(s)

Two NRTIs plus an NNRTIc

Two NRTIs plus an INSTI Two NRTIs plus a boosted PI

DTGa,b or BICa,b (if not used in the prior regimen) with a

boosted PI with or without one or two NRTIs. DTG must be
given twice daily if a patient has certain documented INSTI
mutations, or if there is concern about certain mutations (see
the Dolutegravir section).

Two NRTIs plus an NNRTIc

Failed regimen(s) that included NRTI(s), NNRTI(s), and If NRTIs Are Fully Active
PI(s)
• INSTI plus two NRTIs

If NRTIs Are Not Fully Active

• INSTI plus two NRTIs with or without an RTV-boosted PI

If There Is Minimal NRTI Activity*

• INSTI with or without an RTV-boosted PI with or without
ETR, or RPV with or without NRTI(s)
• Consider adding T-20 and/or MVC if additional active
drug(s) are needed.
• Consider off-label use of approved agents or enrollment in
clinical trials for novel antiretroviral treatments.
• Hepatitis B co-infectiond
a The possibility of planned and unplanned pregnancy should be considered when selecting an ART regimen for an adolescent.
When discussing ART options with adolescents of childbearing potential and their caregivers, it is important to consider the
benefits and risks of all ARV drugs and to provide the information and counseling needed to support informed decision-making;
refer to the Perinatal Guidelines (see Recommendations for Use of Antiretroviral Drugs During Pregnancy, Table 7 Situation-
Specific Recommendations for Use of Antiretroviral Drugs in Pregnant People and Nonpregnant People Who Are Trying to
Conceive, and Appendix C: Antiretroviral Counseling Guide for Health Care Providers).
b Raltegravirhas a low barrier to resistance and requires twice-daily dosing in children and adolescents; BIC and DTG have a
higher barrier to resistance and only require once-daily dosing. Many Panel members would use
bictegravir/emtricitabine/tenofovir alafenamide (Biktarvy) in patients with prior treatment failure who have virus with the M184
mutation (see the Bictegravir section).
c NNRTIs could be an option in younger patients with no exposure to NNRTIs and with taste aversion to boosted PIs.
d When modifying ARV regimens in children with chronic Hepatitis B/HIV co-infection, the new regimen must contain agents
active against Hepatitis B.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-30
Key: BIC = bictegravir; DTG = dolutegravir; ETR = etravirine; INSTI = integrase strand transfer inhibitor; MVC = maraviroc;
NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor;
PI = protease inhibitor; RPV = rilpivirine; RTV = ritonavir; T-20 = enfuvirtide

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-31
References
1. Chadwick EG, Capparelli EV, Yogev R, et al. Pharmacokinetics, safety and efficacy of
lopinavir/ritonavir in infants less than 6 months of age: 24 week results. AIDS.
2008;22(2):249-255. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18097227.
2. Babiker A, Castro nee Green H, Compagnucci A, et al. First-line antiretroviral therapy with a
protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher
versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial.
Lancet Infect Dis. 2011;11(4):273-283. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21288774.
3. Eshleman SH, Krogstad P, Jackson JB, et al. Analysis of human immunodeficiency virus
type 1 drug resistance in children receiving nucleoside analogue reverse-transcriptase
inhibitors plus nevirapine, nelfinavir, or ritonavir (Pediatric AIDS Clinical Trials Group 377).
J Infect Dis. 2001;183(12):1732-1738. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11372025.
4. Antiretroviral Therapy Cohort Collaboration, Vandenhende MA, Ingle S, et al. Impact of
low-level viremia on clinical and virological outcomes in treated HIV-1-infected patients.
AIDS. 2015;29(3):373-383. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25686685.
5. Boillat-Blanco N, Darling KE, Schoni-Affolter F, et al. Virological outcome and
management of persistent low-level viraemia in HIV-1-infected patients: 11 years of the
Swiss HIV Cohort Study. Antivir Ther. 2014;20(2):165-175. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24964403.
6. Laprise C, de Pokomandy A, Baril JG, Dufresne S, Trottier H. Virologic failure following
persistent low-level viremia in a cohort of HIV-positive patients: results from 12 years of
observation. Clin Infect Dis. 2013;57(10):1489-1496. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23946221.
7. Vandenhende MA, Perrier A, Bonnet F, et al. Risk of virological failure in HIV-1-infected
patients experiencing low-level viraemia under active antiretroviral therapy (ANRS C03
cohort study). Antivir Ther. 2015;20(6):655-660. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25735799.
8. Pernas B, Grandal M, Pertega S, et al. Any impact of blips and low-level viraemia episodes
among HIV-infected patients with sustained virological suppression on ART? J Antimicrob
Chemother. 2016;71(4):1051-1055. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26702924.
9. Fleming J, Mathews WC, Rutstein RM, et al. Low-level viremia and virologic failure in
persons with HIV infection treated with antiretroviral therapy. AIDS. 2019;33(13):2005-
2012. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31306175.
10. Palich R, Wirden M, Peytavin G, et al. Persistent low-level viraemia in antiretroviral
treatment-experienced patients is not linked to viral resistance or inadequate drug
concentrations. J Antimicrob Chemother. 2020;75(10):2981-2985. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32642769.
11. Lee KJ, Shingadia D, Pillay D, et al. Transient viral load increases in HIV-infected children
in the U.K. and Ireland: what do they mean? Antivir Ther. 2007;12(6):949-956. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17926649.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-32
 12. Coovadia A, Abrams EJ, Stehlau R, et al. Reuse of nevirapine in exposed HIV-infected
children after protease inhibitor-based viral suppression: a randomized controlled trial.
JAMA. 2010;304(10):1082-1090. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20823434.
13. Grennan JT, Loutfy MR, Su D, et al. Magnitude of virologic blips is associated with a higher
risk for virologic rebound in HIV-infected individuals: a recurrent events analysis. J Infect
Dis. 2012;205(8):1230-1238. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22438396.
14. Karlsson AC, Younger SR, Martin JN, et al. Immunologic and virologic evolution during
periods of intermittent and persistent low-level viremia. AIDS. 2004;18(7):981-989.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15096800.
15. Aleman S, Soderbarg K, Visco-Comandini U, Sitbon G, Sonnerborg A. Drug resistance at
low viraemia in HIV-1-infected patients with antiretroviral combination therapy. AIDS.
2002;16(7):1039-1044. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11953470.
16. Sudjaritruk T, Teeraananchai S, Kariminia A, et al. Impact of low-level viraemia on
virological failure among Asian children with perinatally acquired HIV on first-line
combination antiretroviral treatment: a multicentre, retrospective cohort study. J Int AIDS
Soc. 2020;23(7):e25550. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32628816.
17. Krogstad P, Patel K, Karalius B, et al. Incomplete immune reconstitution despite virologic
suppression in HIV-1 infected children and adolescents. AIDS. 2015;29(6):683-693.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25849832.
18. Resino S, Alvaro-Meca A, de Jose MI, et al. Low immunologic response to highly active
antiretroviral therapy in naive vertically human immunodeficiency virus type 1-infected
children with severe immunodeficiency. Pediatr Infect Dis J. 2006;25(4):365-368. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/16567992.
19. Lewis J, Walker AS, Castro H, et al. Age and CD4 count at initiation of antiretroviral therapy
in HIV-infected children: effects on long-term T-cell reconstitution. J Infect Dis.
2012;205(4):548-556. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22205102.
20. van Lelyveld SF, Gras L, Kesselring A, et al. Long-term complications in patients with poor
immunological recovery despite virological successful HAART in Dutch ATHENA cohort.
AIDS. 2012;26(4):465-474. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22112603.
21. European Pregnancy and Paediatric HIV Cohort Collaboration Study Group in EuroCoord.
Prevalence and clinical outcomes of poor immune response despite virologically suppressive
antiretroviral therapy among children and adolescents with human immunodeficiency virus in
Europe and Thailand: cohort study. Clin Infect Dis. 2020;70(3):404-415. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30919882.
22. Milanes-Guisado Y, Gutierrez-Valencia A, Munoz-Pichardo JM, et al. Is immune recovery
different depending on the use of integrase strand transfer inhibitor-, non-nucleoside reverse
transcriptase- or boosted protease inhibitor-based regimens in antiretroviral-naive HIV-
infected patients? J Antimicrob Chemother. 2020;75(1):200-207. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31617904.
23. Claassen CW, Diener-West M, Mehta SH, Thomas DL, Kirk GD. Discordance between
CD4+ T-lymphocyte counts and percentages in HIV-infected persons with liver fibrosis. Clin
Infect Dis. 2012;54(12):1806-1813. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22460963.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-33
 24. Smith K, Kuhn L, Coovadia A, et al. Immune reconstitution inflammatory syndrome among
HIV-infected South African infants initiating antiretroviral therapy. AIDS. 2009;23(9):1097-
1107. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19417581.
25. Meintjes G, Lynen L. Prevention and treatment of the immune reconstitution inflammatory
syndrome. Curr Opin HIV AIDS. 2008;3(4):468-476. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19373007.
26. Graham SM. Non-tuberculosis opportunistic infections and other lung diseases in HIV-
infected infants and children. Int J Tuberc Lung Dis. 2005;9(6):592-602. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15971385.
27. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS penetration-
effectiveness rank for quantifying antiretroviral penetration into the central nervous system.
Arch Neurol. 2008;65(1):65-70. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18195140.
28. Patel K, Ming X, Williams PL, et al. Impact of HAART and CNS-penetrating antiretroviral
regimens on HIV encephalopathy among perinatally infected children and adolescents. AIDS.
2009;23(14):1893-1901. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19644348.
29. Teeraananchai S, Kerr SJ, Gandhi M, et al. Determinants of viral resuppression or persistent
virologic failure after initial failure with second-line antiretroviral treatment among asian
children and adolescents with HIV. J Pediatric Infect Dis Soc. 2020;9(2):253-256. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/31125411.
30. van Zyl GU, van der Merwe L, Claassen M, et al. Protease inhibitor resistance in South
African children with virologic failure. Pediatr Infect Dis J. 2009;28(12):1125-1127.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19779394.
31. Zheng Y, Hughes MD, Lockman S, et al. Antiretroviral therapy and efficacy after virologic
failure on first-line boosted protease inhibitor regimens. Clin Infect Dis. 2014;59(6):888-896.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/24842909.
32. Bircher RE, Ntamatungiro AJ, Glass TR, et al. High failure rates of protease inhibitor-based
antiretroviral treatment in rural Tanzania - a prospective cohort study. PLoS One.
2020;15(1):e0227600. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31929566.
33. Court R, Gordon M, Cohen K, et al. Random lopinavir concentrations predict resistance on
lopinavir-based antiretroviral therapy. Int J Antimicrob Agents. 2016;48(2):158-162.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27345268.
34. Katlama C, Haubrich R, Lalezari J, et al. Efficacy and safety of etravirine in treatment-
experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials.
AIDS. 2009;23(17):2289-2300. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19710593.
35. Steigbigel RT, Cooper DA, Teppler H, et al. Long-term efficacy and safety of raltegravir
combined with optimized background therapy in treatment-experienced patients with drug-
resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 Phase III trials. Clin
Infect Dis. 2010;50(4):605-612. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20085491.
36. De Luca A, Di Giambenedetto S, Cingolani A, Bacarelli A, Ammassari A, Cauda R. Three-
year clinical outcomes of resistance genotyping and expert advice: extended follow-up of the

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-34
 Argenta trial. Antivir Ther. 2006;11(3):321-327. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16759048.
37. Baxter JD, Mayers DL, Wentworth DN, et al. A randomized study of antiretroviral
management based on plasma genotypic antiretroviral resistance testing in patients failing
therapy. CPCRA 046 Study Team for the Terry Beirn Community Programs for Clinical
Research on AIDS. AIDS. 2000;14(9):F83-93. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/10894268.
38. Tural C, Ruiz L, Holtzer C, et al. Clinical utility of HIV-1 genotyping and expert advice: the
Havana trial. AIDS. 2002;16(2):209-218. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11807305.
39. Lin D, Seabrook JA, Matsui DM, King SM, Rieder MJ, Finkelstein Y. Palatability, adherence
and prescribing patterns of antiretroviral drugs for children with human immunodeficiency
virus infection in Canada. Pharmacoepidemiol Drug Saf. 2011;20(12):1246-1252. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/21936016.
40. Briand C, Dollfus C, Faye A, et al. Efficacy and tolerance of dolutegravir-based combined
ART in perinatally HIV-1-infected adolescents: a French multicentre retrospective study. J
Antimicrob Chemother. 2017;72(3):837-843. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27999017.
41. Viani RM, Ruel T, Alvero C, et al. Long-term safety and efficacy of dolutegravir in
treatment-experienced adolescents with human immunodeficiency virus infection: results of
the IMPAACT P1093 study. J Pediatric Infect Dis Soc. 2020;9(2):159-165. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30951600.
42. Santoro MM, Fornabaio C, Malena M, et al. Susceptibility to HIV-1 integrase strand transfer
inhibitors (INSTIs) in highly treatment-experienced patients who failed an INSTI-based
regimen. Int J Antimicrob Agents. 2020;56(1):106027. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32450199.
43. Turkova A, White E, Mujuru HA, et al. Dolutegravir as first- or second-line treatment for
HIV-1 infection in children. N Engl J Med. 2021;385(27):2531-2543. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34965338.
44. Paton NI, Musaazi J, Kityo C, et al. Efficacy and safety of dolutegravir or darunavir in
combination with lamivudine plus either zidovudine or tenofovir for second-line treatment of
HIV infection (NADIA): week 96 results from a prospective, multicentre, open-label,
factorial, randomised, non-inferiority trial. Lancet HIV. 2022;9(6):e381-e393. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35460601.
45. Harrison L, Melvin A, Fiscus S, et al. HIV-1 drug resistance and second-line treatment in
children randomized to switch at low versus higher RNA thresholds. J Acquir Immune Defic
Syndr. 2015;70(1):42-53. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26322666.
46. MacBrayne CE, Rutstein RM, Wiznia AA, et al. Etravirine in treatment-experienced HIV-1-
infected children 1 year to less than 6 years of age. AIDS. 2021;35(9):1413-1421. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/33831904.
47. Melvin AJ, Yee KL, Gray KP, et al. Pharmacokinetics, tolerability, and safety of doravirine
and doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination tablets in
adolescents living with HIV: week 24 results from IMPAACT 2014. J Acquir Immune Defic
Syndr. 2023;92(2):153-161. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36215957.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-35
 48. Meyers T, Sawry S, Wong JY, et al. Virologic failure among children taking
lopinavir/ritonavir-containing first-line antiretroviral therapy in South Africa. Pediatr Infect
Dis J. 2015;34(2):175-179. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25741970.
49. Viani RM, Alvero C, Fenton T, et al. Safety, pharmacokinetics and efficacy of dolutegravir
in treatment-experienced HIV-1 infected adolescents: 48-week results from IMPAACT
P1093. Pediatr Infect Dis J. 2015;34(11):1207-1213. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26244832.
50. Patten G, Puthanakit T, McGowan CC, et al. Raltegravir use and outcomes among children
and adolescents living with HIV in the IeDEA global consortium. J Int AIDS Soc.
2020;23(7):e25580. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32722897.
51. Levy ME, Griffith C, Ellenberger N, et al. Outcomes of integrase inhibitor-based
antiretroviral therapy in a clinical cohort of treatment-experienced children, adolescents and
young adults with HIV infection. Pediatr Infect Dis J. 2020;39(5):421-428. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32176183.
52. Agwu AL, Yao TJ, Eshleman SH, et al. Phenotypic co-receptor tropism in perinatally HIV-
infected youth failing antiretroviral therapy. Pediatr Infect Dis J. 2016;35(7):777-781.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27078121.
53. Arayapong N, Pasomsub E, Kanlayanadonkit R, et al. Viral tropism in human
immunodeficiency virus type 1-infected children and adolescents in Thailand. J Pediatric
Infect Dis Soc. 2021;10(1):1-6. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31981458.
54. Huerta-Garcia G, Vazquez-Rosales JG, Mata-Marin JA, Peregrino-Bejarano L, Flores-Ruiz
E, Solorzano-Santos F. Genotype-guided antiretroviral regimens in children with multidrug-
resistant HIV-1 infection. Pediatr Res. 2016;80(1):54-59. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26999770.
55. Kirk BL, Gomila A, Matshaba M, et al. Early outcomes of darunavir- and/or raltegravir-
based antiretroviral therapy in children with multidrug-resistant HIV at a pediatric center in
Botswana. J Int Assoc Provid AIDS Care. 2013;12(2):90-94. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23315674.
56. Thuret I, Chaix ML, Tamalet C, et al. Raltegravir, etravirine and r-darunavir combination in
adolescents with multidrug-resistant virus. AIDS. 2009;23(17):2364-2366. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19823069.
57. Capetti AF, Sterrantino G, Cossu MV, et al. Salvage therapy or simplification of salvage
regimens with dolutegravir plus ritonavir-boosted darunavir dual therapy in highly cART-
experienced subjects: an Italian cohort. Antivir Ther. 2017;22(3):257-262. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27661787.
58. Campbell TB, Shulman NS, Johnson SC, et al. Antiviral activity of lamivudine in salvage
therapy for multidrug-resistant HIV-1 infection. Clin Infect Dis. 2005;41(2):236-242.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15983922.
59. Nijhuis M, Schuurman R, de Jong D, et al. Lamivudine-resistant human immunodeficiency
virus type 1 variants (184V) require multiple amino acid changes to become co-resistant to
zidovudine in vivo. J Infect Dis. 1997;176(2):398-405. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/9237704.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-36
 60. Ross L, Parkin N, Chappey C, et al. Phenotypic impact of HIV reverse transcriptase M184I/V
mutations in combination with single thymidine analog mutations on nucleoside reverse
transcriptase inhibitor resistance. AIDS. 2004;18(12):1691-1696. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15280780.
61. Imaz A, Llibre JM, Mora M, et al. Efficacy and safety of nucleoside reverse transcriptase
inhibitor-sparing salvage therapy for multidrug-resistant HIV-1 infection based on new-class
and new-generation antiretrovirals. J Antimicrob Chemother. 2011;66(2):358-362. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/21172789.
62. Tashima KT, Smeaton LM, Fichtenbaum CJ, et al. HIV salvage therapy does not require
nucleoside reverse transcriptase inhibitors: a randomized, controlled trial. Ann Intern Med.
2015;163(12):908-917. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26595748.
63. Wiznia A, Church J, Emmanuel P, et al. Safety and efficacy of enfuvirtide for 48 weeks as
part of an optimized antiretroviral regimen in pediatric human immunodeficiency virus 1-
infected patients. Pediatr Infect Dis J. 2007;26(9):799-805. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17721374.
64. Zhang X, Lin T, Bertasso A, et al. Population pharmacokinetics of enfuvirtide in HIV-1-
infected pediatric patients over 48 weeks of treatment. J Clin Pharmacol. 2007;47(4):510-
517. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17389560.
65. King JR, Acosta EP, Chadwick E, et al. Evaluation of multiple drug therapy in human
immunodeficiency virus-infected pediatric patients. Pediatr Infect Dis J. 2003;22(3):239-
244. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12634585.
66. Emu B, Fessel J, Schrader S, et al. Phase 3 study of ibalizumab for multidrug-resistant HIV-
1. N Engl J Med. 2018;379(7):645-654. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30110589.
67. Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with multidrug-resistant HIV-1
infection. N Engl J Med. 2020;382(13):1232-1243. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32212519.
68. Lataillade M, Lalezari JP, Kozal M, et al. Safety and efficacy of the HIV-1 attachment
inhibitor prodrug fostemsavir in heavily treatment-experienced individuals: week 96 results
of the phase 3 BRIGHTE study. Lancet HIV. 2020;7(11):e740-e751. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33128903.
69. Kearns GL, Abdel-Rahman SM, Alander SW, Blowey DL, Leeder JS, Kauffman RE.
Developmental pharmacology-drug disposition, action, and therapy in infants and children. N
Engl J Med. 2003;349(12):1157-1167. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/13679531.
70. Fletcher CV, Brundage RC, Fenton T, et al. Pharmacokinetics and pharmacodynamics of
efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve
controlled trial. Clin Pharmacol Ther. 2008;83(2):300-306. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17609682.
71. Wong FL, Hsu AJ, Pham PA, Siberry GK, Hutton N, Agwu AL. Antiretroviral treatment
strategies in highly treatment experienced perinatally HIV-infected youth. Pediatr Infect Dis
J. 2012;31(12):1279-1283. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22926213.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-37
 72. Agwu AL, Warshaw MG, McFarland EJ, et al. Decline in CD4 T lymphocytes with
monotherapy bridging strategy for non-adherent adolescents living with HIV infection:
results of the IMPAACT P1094 randomized trial. PLoS One. 2017;12(6):e0178075.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28604824.
73. Saitoh A, Foca M, Viani RM, et al. Clinical outcomes after an unstructured treatment
interruption in children and adolescents with perinatally acquired HIV infection. Pediatrics.
2008;121(3):e513-521. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18310171.
74. Fairlie L, Karalius B, Patel K, et al. CD4+ and viral load outcomes of antiretroviral therapy
switch strategies after virologic failure of combination antiretroviral therapy in perinatally
HIV-infected youth in the United States. AIDS. 2015;29(16):2109-2119. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26182197.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-38
Antiretroviral Treatment Interruption in Children With
HIV
Updated: April 11, 2023
Reviewed: April 11, 2023

Panel’s Recommendations
• Outside the context of clinical trials, structured interruptions of antiretroviral therapy are not recommended for children
(AII).
• Families should receive education and counseling about common causes of temporary unplanned treatment interruptions
and ways to prevent them, e.g., automatic refills, mailed prescriptions, planning for the adequate supply of medications
when traveling, etc. (see Adherence to Antiretroviral Therapy in Children and Adolescents With HIV).
• At times, ARV therapy may need to be interrupted or changed due to drug-related side effects or toxicity. See
Management of Medication Toxicity for guidance.
Rating of Recommendations: A = Strong; B = Moderate; C = Optional
Rating of Evidence: I = One or more randomized trials in children† with clinical outcomes and/or validated endpoints;
I* = One or more randomized trials in adults with clinical outcomes and/or validated laboratory endpoints with accompanying
data in children† from one or more well-designed, nonrandomized trials or observational cohort studies with long-term clinical
outcomes; II = One or more well-designed, nonrandomized trials or observational cohort studies in children† with long-term
outcomes; II* = One or more well-designed, nonrandomized trials or observational studies in adults with long-term clinical
outcomes with accompanying data in children† from one or more similar nonrandomized trials or cohort studies with clinical
outcome data; III = Expert opinion
† Studies that include children or children/adolescents, but not studies limited to postpubertal adolescents

Unplanned Treatment Interruptions

Temporary discontinuation of antiretroviral therapy (ART) may be unavoidable in some situations—
such as in cases of serious treatment-related toxicity, acute illnesses, or planned surgeries—that
preclude oral intake. Lack of available medication also may result in temporary ART discontinuation.
In resource-limited settings, children might experience interruptions due to drugs being out of stock
locally. Children with HIV who are immigrating to the United States also may experience gaps in
medication availability. Prolonged interruptions of ART also can result from disengagement from
care or other social or psychological issues that affect adherence. Some patients, particularly
adolescents and young adults, might attempt to conceal long periods of treatment interruption by
restarting treatment in the few weeks ahead of clinic visits and viral load testing.

Observational studies of children and youth with unplanned or nonprescribed treatment interruptions
suggest that interruptions are common and that prolonged interruptions can lead to immunologic
decline.1-4 In a retrospective study of 483 children in a French pediatric cohort from the National
Agency for Research on AIDS and Viral Hepatitis (ANRS), 42% of participants had treatment
interruptions of ≥3 months (with a median of 12.1 months). Interruption was associated with lower
CD4+ T lymphocyte (CD4) cell percentages after 4 years, even in those who restarted therapy.5 A
similar retrospective study of 136 youth (median age 12.9 years) in the United States found that
38 participants (28%) with histories of treatment interruption had lower CD4 counts and higher HIV
RNA levels than participants who had continuous treatment.6 A study from the International

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-39
Epidemiology Databases to Evaluate AIDS Southern Africa, which includes 53,674 children
<16 years of age, found that lapses in clinical care of greater than 180 days within the first 6 months
of treatment were associated with increased mortality (adjusted hazard ratio [AHR] = 1.52,
95% CI 1.12-2.04); while lapses in care after the first 6 months were not (AHR = 1.05,
95% CI 0.77–1.44).7

Whether unplanned interruptions occur by accident or necessity (e.g., because of toxicity), all efforts
should be made to minimize their duration. If a child will be traveling for an extended period,
clinicians can help prevent treatment interruption by ensuring that the child will have access to the
necessary drugs during the trip. If the required drugs will not be available at the destination,
pharmacies can be asked to dispense extra medication. Additional guidance on supporting adherence
can be found in Adherence to Antiretroviral Therapy in Children and Adolescents With HIV.

Structured Treatment Interruptions

Structured treatment interruptions are scheduled periods of time during which ART is not prescribed
or administered. This strategy was once considered a method for providing patients with time off
ART to reduce the risk of toxicity and costs. Randomized clinical trials of adults with HIV have
demonstrated that structured treatment interruptions are associated with significantly higher
morbidity and mortality than continuous ART.8 Current U.S. Department of Health and Human
Services HIV treatment guidelines recommend against planned, long-term structured treatment
interruptions in adults (see Discontinuation or Interruption of Antiretroviral Therapy in the Adult and
Adolescent Antiretroviral Guidelines).

Few studies have evaluated structured treatment interruption in children. In one trial from Europe and
Thailand (PENTA 11), 109 children (median age 9 years) on ART and with virologic suppression
were randomized to receive continuous therapy (CT) or to undergo treatment interruption. Although
no significant differences in rates of adverse events (AEs) were observed between the two groups at
2 years, 19 of 56 children (34%) in the structured treatment interruption arm met CD4 criteria to
restart therapy between 6 and 42 weeks after interruption, suggesting that the time off ART provided
by this strategy was ultimately limited.9,10 The Children with HIV Early Antiretroviral
Therapy (CHER) trial in South Africa was designed to determine whether infants who initiated ART
early could safely discontinue therapy at either 40 weeks or 96 weeks; infants would reinitiate
treatment based on CD4 decline. The median time to the start of continuous ART after interruption
was 3 weeks (interquartile range [IQR] 26–45 weeks) among the infants who discontinued ART after
40 weeks, and 70 weeks (IQR 35–109 weeks) among the infants who discontinued ART after
96 weeks.11,12 A secondary analysis of neurodevelopmental outcomes at age 5 years did not show any
significant differences among the children in the different study arms.13 However, brain magnetic
resonance imaging studies in a subset of participants found that children with HIV on interrupted
ART (n = 21) had a thicker cortex than uninfected controls in the left frontal and right insular
regions, but children with HIV on CT (n = 25) showed no difference from controls; the clinical
significance of these differences is not known.14 In another randomized trial, 12 of 21 infants in the
treatment interruption arm met ART restart criteria within 3 months.15 In summary, although trials of
structured treatment interruptions in children have not shown significant short-term morbidity, the
gains in time off ART are limited, and the long-term outcomes remain unknown.

The case of an infant from Mississippi who initiated ART soon after birth and had a prolonged period
of time without viremia after an unplanned treatment interruption raised the hope that it may be
possible to stop or reduce the intensity of ART (e.g., use fewer agents) in some infants (see

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-40
Antiretroviral Management of Newborns With Perinatal HIV Exposure or HIV).16,17 However, the
“Mississippi infant” had documented viral rebound after 28 months off ART,18 and additional reports
have emerged of infants who experienced rebound viremia after stopping ART, despite having
undetectable HIV DNA and RNA while on ART.19-21 A South African child aged 9.5 years was
reported to have low levels of virus that was not replication competent after receiving ART from
approximately 2 to 24 months of age; the factors that led to this outcome remain unknown.22 Future
research might identify treatment strategies and diagnostic tests that enable ART to be safely
interrupted in some children. “Analytical” treatment interruptions are currently being incorporated
into studies of remission in adults and children, but the potential risks and benefits of strategies need
to be critically evaluated.23-25

Currently, the Panel on Antiretroviral Therapy and Medical Management of Children Living With
HIV (the Panel) does not recommend treatment interruption as a strategy in clinical settings to
confirm diagnosis or to assess remission or cure in infants who reverted to negative serology, tested
negative for HIV DNA, or received an initial diagnosis that was based on a single positive nucleic
acid test. The Panel encourages providers to consult an expert on pediatric HIV when they are
concerned about the validity of the test results that led to treatment initiation in children with HIV.

Short-Cycle Therapy Strategies

One approach, called short-cycle therapy (SCT), schedules 4-day treatment interruptions, rather than
waiting to restart ART after CD4 count declines or other AEs occur. In one proof-of-concept
study (ATN015), 32 participants (aged 12–24 years) underwent short cycles of 4 days on and 3 days
off ART.26 Participants received protease inhibitor–based ART and had at least 6 months of
documented viral suppression (defined as a viral load <400 copies/mL) and CD4 counts above
350 cells/mm3. Most participants demonstrated good adherence to the schedule, but 12 participants
(37.5%) developed confirmed viral load rebounds >400 copies/mL, and 18 participants (56%) left the
study. SCT had no impact on CD4 counts.

The BREATHER (PENTA 16) study sought to examine the safety and benefits of SCT with 5 days
on and 2 days off ART; PENTA 16 was a noninferiority trial that randomized 199 children and
young adults (aged 8–24 years) for SCT or CT.27,28 To enroll, participants had to be receiving
efavirenz (EFV) plus two nucleoside reverse transcriptase inhibitors, and they had to have been
virologically suppressed (defined as a viral load <50 copies/mL) for >12 months. By 48 weeks, six
participants (6%) in the SCT arm and seven participants (7%) in the CT arm experienced confirmed
virologic failure, which was defined as a viral load >50 copies/mL (difference −1.2%; 90%
confidence interval, −7.3% to 4.9%). Of the six participants in the SCT arm who experienced
virologic failure, five were able to regain virologic suppression. Two participants in the SCT arm and
five participants in the CT arm had major mutations related to resistance to non-nucleoside reverse
transcriptase inhibitors at the time of virologic failure. At 48 weeks, the SCT arm had higher D-dimer
levels but no other evidence of increased inflammation across a number of other biomarkers.
Participants generally reported appreciating the option of SCT.29

A long-term follow-up study of children from the BREATHER study (which included 194 of the
original 199 children) suggests comparable virologic failure rates between the SCT and CT arms
after a median of 3.6 years; both arms had a failure rate of approximately 16%.30 The participants in
the SCT arm experienced a greater number of serious AEs than participants in the CT arm
(20 serious AEs in the SCT arm versus 8 in the CT arm, with the primary difference being rate of
hospitalizations); however, the arms experienced comparable rates of the Centers for Disease Control

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-41
and Prevention Grade 3 or 4 AEs. The BREATHER trial suggests that SCT with EFV-based ART
may be safe in some adolescents and may yield increased patient satisfaction that could lead to better
long-term adherence. However, the Panel currently believes that additional data are needed to decide
whether the BREATHER strategy would be safe in different patient populations, with different
antiretroviral (ARV) regimens, outside of the context of a trial, and over longer periods.

Conclusion
Cumulative data have demonstrated that treatment interruptions long enough for viremia to recur are
generally harmful to children with HIV. Analytic treatment interruptions to assess for remission are
employed in research, but not recommended in the clinical context. SCT treatment may be safe and
increase satisfaction in some patients, but the Panel concludes that more data are needed before SCT
can be recommended for routine use in pediatric populations. Currently, the Panel does not
recommend structured treatment interruption in the clinical care of children with HIV; additional
studies of treatment-interruption strategies in specific situations are warranted.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-42
References
1. Gibb DM, Duong T, Leclezio VA, et al. Immunologic changes during unplanned treatment
interruptions of highly active antiretroviral therapy in children with human immunodeficiency
virus type 1 infection. Pediatr Infect Dis J. 2004;23(5):446-450. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15131469.

2. Saitoh A, Foca M, Viani RM, et al. Clinical outcomes after an unstructured treatment
interruption in children and adolescents with perinatally acquired HIV infection. Pediatrics.
2008;121(3):e513-521. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18310171.

3. Siberry GK, Patel K, Van Dyke RB, et al. CD4+ lymphocyte-based immunologic outcomes of
perinatally HIV-infected children during antiretroviral therapy interruption. J Acquir Immune
Defic Syndr. 2011;57(3):223-229. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21423022.

4. Bartlett AW, Lumbiganon P, Kurniati N, et al. Use and outcomes of antiretroviral monotherapy
and treatment interruption in adolescents with perinatal HIV infection in Asia. J Adolesc Health.
2019;65(5):651-659. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31395514.

5. Aupiais C, Faye A, Le Chenadec J, et al. Interruption of cART in clinical practice is associated with
an increase in the long-term risk of subsequent immunosuppression in HIV-1-infected children.
Pediatr Infect Dis J. 2014;33(12):1237-1245. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24945880.

6. Rakhmanina N, Lam KS, Hern J, Young HA, Walters A, Castel AD. Interruptions of antiretroviral
therapy in children and adolescents with HIV infection in clinical practice: a retrospective cohort
study in the USA. J Int AIDS Soc. 2016;19(1):20936. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27797320.

7. Davies C, Johnson L, Sawry S, et al. Effect of antiretroviral therapy care interruptions on

mortality in children living with HIV. AIDS. 2022;36(5):729-737. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35152225.

8. Strategies for Management of Antiretroviral Therapy Study Group, El-Sadr WM, Lundgren JD, et
al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med.
2006;355(22):2283-2296. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17135583.

9. Paediatric European Network for Treatment of AIDS. Response to planned treatment

interruptions in HIV infection varies across childhood. AIDS. 2010;24(2):231-241. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20010073.

10. Bunupuradah T, Duong T, Compagnucci A, et al. Outcomes after reinitiating antiretroviral

therapy in children randomized to planned treatment interruptions. AIDS. 2013;27(4):579-589.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/23135172.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-43
11. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among HIV-
infected infants. N Engl J Med. 2008;359(21):2233-2244. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19020325.

12. Cotton MF, Violari A, Otwombe K, et al. Early time-limited antiretroviral therapy versus deferred
therapy in South African infants infected with HIV: results from the children with HIV early
antiretroviral (CHER) randomised trial. Lancet. 2013;382(9904):1555-1563. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24209829.

13. Laughton B, Cornell M, Kidd M, et al. Five year neurodevelopment outcomes of perinatally HIV-
infected children on early limited or deferred continuous antiretroviral therapy. J Int AIDS Soc.
2018;21(5):e25106. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29722482.

14. Nwosu EC, Holmes MJ, Cotton MF, et al. Cortical structural changes related to early
antiretroviral therapy (ART) interruption in perinatally HIV-infected children at 5 years of age.
IBRO Neurosci Rep. 2021;10:161-170. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34179869.

15. Wamalwa D, Benki-Nugent S, Langat A, et al. Treatment interruption after 2-year antiretroviral
treatment initiated during acute/early HIV in infancy. AIDS. 2016;30(15):2303-2313. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/27177316.

16. Persaud D, Gay H, Ziemniak C, et al. Absence of detectable HIV-1 viremia after treatment
cessation in an infant. N Engl J Med. 2013;369(19):1828-1835. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24152233.

17. Persaud D, Luzuriaga K. Absence of HIV-1 after treatment cessation in an infant. N Engl J Med.
2014;370(7):678. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24521123.

18. Luzuriaga K, Gay H, Ziemniak C, et al. Viremic relapse after HIV-1 remission in a perinatally
infected child. N Engl J Med. 2015;372(8):786-788. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/25693029.

19. Mekonen T, Mulang R, Nghimbwasha H, et al. Structured antiretroviral treatment interruptions

in vertically HIV-1 infected children with complete pro-viral DNA PCR reversions in Namibia,
following durable viral suppression, led to rapid rebound viremias and significant immunologic
destruction. Presented at: AIDS Conference; 2016. Durban, South Africa. Available at.

20. Butler KM, Gavin P, Coughlan S, et al. Rapid viral rebound after 4 years of suppressive therapy in
a seronegative HIV-1 infected infant treated from birth. Pediatr Infect Dis J. 2014;34(3):e48-51.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/25251719.

21. Koofhethile CK, Moyo S, Kotokwe KP, et al. Undetectable proviral deoxyribonucleic acid in an
adolescent perinatally infected with human immunodeficiency virus-1C and on long-term
antiretroviral therapy resulted in viral rebound following antiretroviral therapy termination: A
case report with implications for clinical care. Medicine (Baltimore). 2019;98(47):e18014.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31764816.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-44
22. Violari A, Cotton MF, Kuhn L, et al. A child with perinatal HIV infection and long-term sustained
virological control following antiretroviral treatment cessation. Nat Commun. 2019;10(1):412.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30679439.

23. Clinicaltrials.gov. Very early intensive treatment of HIV-infected infants to achieve HIV
remission. 2019. Available at: https://clinicaltrials.gov/ct2/show/NCT02140255

24. Julg B, Dee L, Ananworanich J, et al. Recommendations for analytical antiretroviral treatment
interruptions in HIV research trials-report of a consensus meeting. Lancet HIV. 2019;6(4):e259-
e268. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30885693.

25. Stecher M, Classen A, Klein F, et al. Systematic review and meta-analysis of treatment
interruptions in human immunodeficiency virus (HIV) type 1-infected patients receiving
antiretroviral therapy: implications for future HIV cure trials. Clin Infect Dis. 2020;70(7):1406-
1417. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31102444.

26. Rudy BJ, Sleasman J, Kapogiannis B, et al. Short-cycle therapy in adolescents after continuous
therapy with established viral suppression: the impact on viral load suppression. AIDS Res Hum
Retroviruses. 2009;25(6):555-561. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/19534628.

27. Butler K, Inshaw J, Ford D, et al. BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2
days off) in young people with chronic human immunodeficiency virus infection: an open,
randomised, parallel-group Phase II/III trial. Health Technol Assess. 2016;20(49):1-108. Available
at: http://www.ncbi.nlm.nih.gov/pubmed/27377073.

28. Breather Trial Group. Weekends-off efavirenz-based antiretroviral therapy in HIV-infected

children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority,
phase 2/3 trial. Lancet HIV. 2016;3(9):e421-e430. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27562743.

29. Bernays S, Paparini S, Seeley J, Namukwaya Kihika S, Gibb D, Rhodes T. Qualitative study of the
BREATHER trial (Short Cycle antiretroviral therapy): is it acceptable to young people living with
HIV? BMJ Open. 2017;7(2):e012934. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28213595.

30. Turkova A, Moore CL, Butler K, et al. Weekends-off efavirenz-based antiretroviral therapy in HIV-
infected children, adolescents and young adults (BREATHER): Extended follow-up results of a
randomised, open-label, non-inferiority trial. PLoS One. 2018;13(4):e0196239. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29684092.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-45
Appendix A: Pediatric Antiretroviral Drug Information
Overview
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors (NRTIs)
Abacavir

Emtricitabine

Lamivudine

Tenofovir Alafenamide

Tenofovir Disoproxil Fumarate

Zidovudine

Non-Nucleoside Analogue Reverse Transcriptase Inhibitors (NNRTIs)

Doravirine

Efavirenz

Etravirine

Nevirapine

Rilpivirine

Protease Inhibitors (PIs)

Atazanavir

Darunavir

Lopinavir/Ritonavir

Entry and Fusion Inhibitors

Fostemsavir

Ibalizumab

Maraviroc

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-1
Integrase Inhibitors (INSTIs)
Bictegravir

Cabotegravir

Dolutegravir

Elvitegravir

Raltegravir

Pharmacokinetic Enhancers
Cobicistat

Ritonavir

Fixed-Dose Combinations
Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or as a
Co-packaged Formulation, by Drug Class

Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum Body Weights and
Considerations for Use in Children and Adolescents

Archived Drugs
Didanosine

Enfuvirtide

Fosamprenavir

Indinavir

Nelfinavir

Saquinavir

Stavudine

Tipranavir

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-2
Appendix A: Pediatric Antiretroviral Drug Information
Nucleoside and Nucleotide Analogue Reverse Transcriptase Inhibitors
Abacavir (ABC, Ziagen)

Emtricitabine (FTC, Emtriva)

Lamivudine (3TC, Epivir)

Tenofovir Alafenamide (TAF, Vemlidy)

Tenofovir Disoproxil Fumarate (TDF, Viread)

Zidovudine (ZDV, Retrovir)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-3
Abacavir (ABC, Ziagen)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Pediatric Oral Solution: 20 mg/mL

Tablet: 300 mg (scored)

Generic Formulations
• 300-mg tablet
• 20 mg/mL pediatric oral solution

Fixed-Dose Combination Tablets

• [Epzicom and generic] Abacavir 600 mg/lamivudine 300 mg
• [Triumeq] Abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg
• [Triumeq PD] Abacavir 60 mg/dolutegravir 5 mg/lamivudine 30 mg

When using fixed-dose combination (FDC) tablets, refer to other sections of Appendix A: Pediatric Antiretroviral Drug
Information for information about the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-
Dose Combination Tablets: Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Neonate (Aged Birth Through <1 Month) Dose • Hypersensitivity reactions (HSRs) can be fatal.
HSRs usually occur during the first few weeks of
Oral Solution
starting therapy. Symptoms may include fever,
• Abacavir (ABC) is not approved by the U.S. Food and Drug rash, nausea, vomiting, malaise or fatigue, loss of
Administration (FDA) for use in neonates aged <1 month. appetite, and respiratory symptoms (e.g., cough,
shortness of breath).
• The Panel on Antiretroviral Therapy and Medical Management of
Children Living with HIV (the Panel) recommends ABC 2 mg/kg
Special Instructions
twice daily for full-term infants from birth through <1 month of age.
This recommendation is based on data from pharmacokinetic (PK) • Test patients for the HLA-B*5701 allele before
modeling of neonatal ABC dosing to target adult plasma ABC starting therapy to predict the risk of HSRs.
exposures, and observational data supporting safety of ABC in Patients who test positive for the HLA-
neonates. The World Health Organization (WHO) Consolidated B*5701 allele should not be given ABC. Patients
Guidelines on HIV Prevention, Testing, Treatment, Service with no prior HLA-B*5701 testing who are
Delivery, and Monitoring Annex 1: Dosages for ARV Drugs tolerating ABC do not need to be tested.
provides weight-band dosing recommendations for full-term
neonates based on the same data. See Approval, • Warn patients and caregivers about the risk of
Pharmacokinetics in Neonates and Infants, and Safety in serious, potentially fatal HSRs. Occurrence of an
Neonates and Infants sections below. HSR requires immediate and permanent
discontinuation of ABC. Do not rechallenge.
• ABC can be given without food. The oral solution
does not require refrigeration.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-4
 Infant (Aged ≥1 Month to <3 Months) Dose • For ABC/DTG/3TC dispersible tablets, fully
disperse them in 20 mL of drinking water in the
Oral Solution
supplied cup and swirl the suspension so that no
• ABC is not approved by the FDA for use in infants aged lumps remain. After full dispersion and within 30
<3 months. minutes of mixing, administer the oral suspension.
Rinse the dosing cup with a small amount of
• The Panel recommends ABC 4 mg/kg twice daily in full-term water and give this additional water to the child to
infants aged ≥1 month to <3 months. This recommendation is ensure that the child takes the full dose and no
based on modeling data of the ABC 4 mg/kg twice-daily dose medication remains in the dosing cup.
using PK simulation for full-term infants aged ≥1 month to ABC/DTG/3TC dispersible tablets should not be
<3 months. The International Maternal Pediatric Adolescent AIDS swallowed whole, chewed, cut, or crushed.
Clinical Trials (IMPAACT) P1106 study and two observational
cohorts provide reassuring data on the safety of ABC in infants • Screen patients for hepatitis B virus (HBV)
with HIV aged <3 months. See Approval, Pharmacokinetics in infection before using ABC FDC tablets that
Neonates and Infants, and Safety in Neonates and Infants contain lamivudine (3TC). Severe acute
sections below. exacerbation of HBV infection can occur when
3TC is discontinued (see Lamivudine).
Infant and Child (Aged ≥3 Months) Dose
Oral Solution Metabolism/Elimination
• ABC 8 mg/kg twice daily (maximum 300 mg per dose) or ABC • ABC is systemically metabolized by alcohol
16 mg/kg once daily (maximum 600 mg per dose) dehydrogenase and glucuronyl transferase.
• In infants and young children who are being treated with liquid • The majority of ABC is excreted as metabolites in
formulations of ABC, initiation with once-daily ABC is not generally urine.
recommended. In older children who can be treated with tablet
formulations, therapy can be initiated with once-daily Abacavir Dosing in Patients With Hepatic
administration. In clinically stable patients who have undetectable Impairment
viral loads and stable CD4 T lymphocyte counts while receiving
the liquid formulation of ABC twice daily, the ABC dose can be • ABC requires a dose adjustment in patients with
changed from twice daily to once daily with the liquid or tablet mild hepatic insufficiency and is contraindicated
formulations (see text below). with moderate or severe hepatic insufficiency.
• Do not use Epzicom, Triumeq PD, or Triumeq (or
Weight-Band Dosing of ABC Tablets for Children and the generic equivalents of these FDC tablets) in
Adolescents Weighing ≥14 kg and <25 kg patients with impaired hepatic function, because
the dose of ABC cannot be adjusted.
Scored 300-mg ABC Tablet
Weight Abacavir Dosing in Patients With Renal
Twice-Daily Twice-Daily Once-Daily
Impairment
Dose, AM Dose, PM Dose
14 kg to ½ tablet ½ tablet 1 tablet • ABC does not require dose adjustment in patients
<20 kg (150 mg) (150 mg) (300 mg) with renal impairment.

≥20 kg to ½ tablet 1 tablet 1½ tablets • Do not use FDC tablets containing 3TC
<25 kg (150 mg) (300 mg) (450 mg) (Epzicom, Triumeq PD, Triumeq, or the generic
equivalents of these FDC tablets) in patients with
creatinine clearance <30 mL/min or patients on
Child and Adolescent (Weighing ≥25 kg) and Adult Dose
dialysis, because the doses of 3TC cannot be
• ABC 300 mg twice daily or ABC 600 mg once daily adjusted. Data from FDC DTG/3TC (Dovato)
suggest that patients with a sustained creatinine
[Epzicom] Abacavir/Lamivudine clearance 30–49 mL/min may experience a higher
3TC exposure and should be monitored for
Child and Adolescent (Weighing ≥25 kg) and Adult Dose hematologic toxicities and potential FDC
• One tablet once daily discontinuation and subsequent adjustment of the
treatment regimen. See package inserts for
additional information.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-5
 [Triumeq PD] Abacavir/Dolutegravir (DTG)/Lamivudine (3TC)
Child Weighing ≥10 kg to <25 kg
• Dispersible Triumeq PD tablets are FDA approved for children
weighing ≥10 to <25 kg. Triumeq PD is not recommended for
children weighing ≥25 kg who are eligible for adult Triumeq
dosing.
• Administer the appropriate number of tablets once daily dispersed
in 20 mL of water. See Special Instructions. Triumeq PD tablets
should not be swallowed whole, chewed, cut, or crushed.

Weight-Band Dosing of Triumeq PD Tablets for Children

Weighing ≥10 kg and <25 kg

Number of
Recommended
Weight Triumeq PD
Daily Dose
Tablets

10 kg to <14 kg ABC 240 mg, 4

DTG 20 mg,
3TC 120 mg

14 kg to <20 kg ABC 300 mg, 5

DTG 25 mg,
3TC 150 mg

20 kg to <25 kg ABC 360 mg, 6

DTG 30 mg,
3TC 180 mg

• For use in children who are antiretroviral (ARV) naive or ARV

experienced (but integrase strand transfer inhibitor-naive) and
who are not being treated with uridine diphosphate
glucuronosyltransferase 1A1 (UGT1A1) or cytochrome
P450 (CYP450) 3A inducers.

[Triumeq] Abacavir/Dolutegravir/Lamivudine
Child and Adolescent (Weighing ≥25 kg) and Adult Dose
• One tablet once daily
• This FDC tablet can be used in patients who are antiretroviral
(ARV)-naive or ARV-experienced (but integrase strand transfer
inhibitor–naive) and who are not being treated with other drugs
that act as UGT1A1 or CYP450 3A inducers.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Abacavir (ABC) neither inhibits nor is metabolized by hepatic cytochrome P450 enzymes.
Therefore, it does not cause significant changes in the clearance of agents that are metabolized

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-6
 through these pathways, such as protease inhibitors (PIs) and non-nucleoside reverse
transcriptase inhibitors.
• ABC plasma concentrations can decrease when ABC is used concurrently with the ritonavir-
boosted PIs atazanavir/ritonavir, lopinavir/ritonavir (LPV/r), and darunavir/ritonavir.1-3 The
mechanism and the clinical significance of the drug interactions with these PIs are unknown.
Currently, no recommendations exist for dose adjustments when ABC is coadministered with one
of these boosted PIs.
• In the pooled analysis of 230 African children with HIV with a median age of 2.1 years
(range 0.1–12.8) and a median weight of 9.8 kg (range 2.5–30.0), the population
pharmacokinetics of ABC showed that children on LPV/r or efavirenz had similar ABC
exposures, while concomitant tuberculosis treatment and use of super-boosting with lopinavir
significantly reduced ABC concentrations.4
• Alcohol exposure (0.7 g per kg ethanol, which is equivalent to five alcoholic drinks) interferes
with ABC metabolism; it affects the activity of alcohol dehydrogenase and glucuronyl
transferase. This interference increased ABC area under the curve (AUC) plasma exposure by
41% in adult men with HIV who received ABC 600 mg daily.5
• ABC oral solution contains sorbitol, which decreased the exposure of lamivudine (3TC) oral
solution in adults when the drugs were administered concurrently.6

Major Toxicities
• More common: Nausea, vomiting, fever, headache, diarrhea, rash, anorexia
• Less common (more severe): Serious and sometimes fatal hypersensitivity reactions (HSRs) have
been observed in approximately 5% of adults and children (the rate varies by race/ethnicity)
receiving ABC. HSRs generally occur during the first 6 weeks of therapy, but they have also
been reported after a single dose of ABC. The risk of an ABC HSR is associated with the
presence of the HLA-B*5701 allele; the risk is greatly reduced by not using ABC in those who
test positive for the HLA-B*5701 allele. The HSR to ABC is a multiorgan clinical syndrome
usually characterized by rash, or signs or symptoms in two or more of the following groups:
o Fever
o Constitutional symptoms, including malaise, fatigue, or achiness
o Gastrointestinal signs and symptoms, including nausea, vomiting, diarrhea, or abdominal
pain
o Respiratory signs and symptoms, including dyspnea, cough, or pharyngitis
o Laboratory and radiologic abnormalities, including elevated liver function tests, elevated
creatine phosphokinase, elevated creatinine, lymphopenia, and pulmonary infiltrates. Lactic
acidosis and severe hepatomegaly with steatosis—including fatal cases—also have been
reported. Pancreatitis with laboratory abnormalities can occur.
If an HSR is suspected, ABC should be stopped immediately and not restarted because
hypotension and death may occur upon rechallenge.
• Rare: Increased levels of liver enzymes, elevated blood glucose levels, elevated triglycerides (see
cardiovascular risk below). Pancreatitis, lactic acidosis, and severe hepatomegaly with
steatosis—including fatal cases—have been reported.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-7
• Rare: Drug reaction (or rash) with eosinophilia and systemic symptoms (DRESS) syndrome.
• Rare: Several observational cohort studies suggest that an increased risk of myocardial infarction
exists in adults who are currently using ABC or who have recently used ABC; however, other
studies have not substantiated this finding, and no prospective data are available on the
cardiovascular risks associated with ABC use in children. One cohort study of South African
adolescents (in which 385 participants had HIV and 63 participants were HIV-negative controls)
with a median age of 12 years reported an association between ABC exposure and insulin
resistance, which was evaluated using homeostatic model assessment. These findings suggest that
the use of ABC may be a cardiovascular risk factor for young people with perinatally acquired
HIV.7

Resistance
The International Antiviral Society–USA (IAS–USA) maintains a list of updated HIV drug resistance
mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each
mutation.

Pediatric Use
Approval
ABC is approved by the U.S. Food and Drug Administration (FDA) for use in children with HIV
aged ≥3 months as part of the nucleoside reverse transcriptase inhibitor (NRTI) component of
antiretroviral therapy (ART). The World Health Organization (WHO), however, provides dosing
guidance for ABC as a component of the NRTI backbone for full-term neonates starting at birth and
weighing ≥2 kg (see Annex 1: Dosages for ARV Drugs in the WHO Consolidated Guidelines on
HIV Prevention, Testing, Treatment, Service Delivery, and Monitoring). The WHO guidance for
ABC dosing in neonates increases the choices of antiretroviral (ARV) agents for the management of
newborns in special situations where stock outs of nevirapine or zidovudine (ZDV) may affect the
ability to effectively provide postnatal prophylaxis or treatment of neonatal HIV. The WHO
recommendation of ABC dosing for infants starting at 1 month of age is based on the inclusion of
ABC as a preferred NRTI component of the first- and second-line ARV regimens for children in the
WHO Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery, and
Monitoring. This recommendation also takes into account the availability of the President’s
Emergency Plan for AIDS Relief (PEPFAR) tentatively approved pediatric generic ABC
formulations—including coformulations that include 3TC—and the cost of ARV drugs in resource-
limited settings.

Efficacy
Both the once-daily and twice-daily doses of ABC have demonstrated durable antiviral efficacy in
pediatric clinical trials that is comparable to the efficacy observed for other NRTIs in children.8-12

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-8
Pharmacokinetics
Pharmacokinetics in Neonates and Infants
The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1106 trial
reported PK data in 25 infants with HIV aged <3 months, who were initiated on a median ABC dose
of 10 mg/kg (range, 6–13 mg/kg) twice daily in combination with lamivudine and LPV/r after
1 month of life. Median age was 6 weeks (range, 1.5–11 weeks); median weight was 2,250 g
(range 1,360–3,320 g); median gestational age was 36 weeks (range, 27–39 weeks). Sparse and pre-
dose PK ABC samples were repeatedly obtained throughout 24 weeks of study follow-up. ABC
plasma exposures were high compared to the published data in infants aged >3 months and decreased
rapidly between 2 and 8 months of age as the infants matured and ABC clearance increased.13 In the
Tygerberg cohort study from South Africa, 10 healthy term neonates at the median postnatal age of
10 days (range 6–15), who were administered a single ABC dose of 8 mg/kg/dose before 15 days of
life, had substantially higher exposures than those reported in infants and children and no reported
adverse events.14 ABC exposure also was higher in neonates compared to infants and children, likely
due to slower drug clearance through immature enzyme pathways in neonates.

PK modeling of ABC starting at birth has been conducted using pooled data from 308 ABC
concentration measurements obtained from three studies administering ABC liquid to 45 young
infants (including 21 full-term neonates <15 days of age with intensive PK).15 Two of these studies,
the Pediatric AIDS Clinical Trials Group (PACTG) 321 study and the Tygerberg cohort, performed
intensive PK sampling in full-term neonates receiving ABC for HIV prophylaxis. The third study,
IMPAACT P1106 described above, performed sparse PK sampling on full-term and low-birth
weight (LBW; <2,500 g) infants with HIV. LBW infants were older at the first PK assessment, with a
median postnatal age of 73 days (range 41–190) and weight of 3.8 kg (range 2.4–5.8). ABC PK
parameters in neonates were estimated using PK simulations to achieve plasma ABC exposures
(AUC 0–12 ) within the expected adult range (3.2–25.2 mcg•hr/mL). The PK model predicted a slow
ABC clearance of 2.51 mL/min per kg at birth, which doubled by 4 weeks of age. Simulations
predicted that an ABC dose of 2 mg/kg twice daily in full-term neonates from birth to <4 weeks and
an ABC dose of 4 mg/kg twice daily in infants aged 4 to 12 weeks would achieve target AUC 0–12 ;
however, data in LBW infants are lacking.15 Based on these data, the weight-band dosing of ABC for
neonates has been developed for neonates from birth to age <1 month and is included in the WHO
Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery, and Monitoring
Annex 1: Dosages for ARV Drugs.16 This weight-band dosing for neonates approximates the ABC
dosing per kg based on the postnatal age (see Table 1 below).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-9
Table 1. Simplified Weight-Band Dosing for Full-Term Neonates from Birth to <1 Month of
Age (WHO Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery,
and Monitoring Annex 1: Table A1.4)

Birth to <1 Month of Age

Weight Volume of ABC Oral Solution ABC Dose in mg Twice Daily

20 mg/mL Twice Dailya,b (ranges mg/kg, from lowest to highest weight
within the weight band)a,b
2 kg to <3 kg 0.4 mL 8 mg (4.0–2.8 mg/kg)

3 kg to <4 kg 0.5 mL 10 mg (3.3–2.6 mg/kg)

4 kg to < 5 kg 0.6 mL 12 mg (3.0–2.4 mg/kg)

a Simplified weight-band dosing exceeds recommended mg/kg ABC dosing in neonates and infants.
b Neonatal ABC dose is based on birth weight and does not require weight-based adjustment during the first month of life.
Key: ABC = Abacavir

For infants aged ≥1 month with weight 3 to <6 kg, the WHO Consolidated Guidelines on HIV
Prevention, Testing, Treatment, Service Delivery, and Monitoring currently recommend a twice-
daily dose of 3 mL (60 mg) of ABC 20 mg/mL solution (range 20.0–10.2 mg/kg). The weight-band
dosing for neonates and infants within the WHO HIV guidelines is higher than the modeled weight-
based dosing for practical considerations in resource-limited settings. As new, generic pediatric
formulations of ABC become available in resource-limited settings, there is potential for the revision
of the WHO guidelines for weight-band dosing of ABC for young infants.

Based on the PK modeling from three infant studies15 and the neonatal and infant safety data from
the IMPAACT 1106 study and two observational cohort studies (see Safety in Neonates and Infants
below), the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV
recommends an ABC dose of 2 mg/kg twice daily for neonates from birth to <1 month of age and an
ABC dose of 4 mg/kg twice daily for full-term infants aged ≥1 month and <3 months.

Pharmacokinetics in Children
PK studies of ABC in children aged <12 years have demonstrated that metabolic clearance of ABC
in adolescents and young adults (aged 13–25 years) is slower than that observed in younger children
and approximates clearance seen in older adults.17

The PKs of ABC administered once daily in children with HIV aged 3 months through 12 years were
evaluated in three crossover, open-label PK trials of twice-daily versus once-daily dosing of ABC
and 3TC (PENTA 13 [n = 14], PENTA 15 [n = 18], and ARROW [n = 36]).5,18-21 The data from these
three pediatric trials were used to develop a model for ABC PKs; this model predicted that systemic
plasma ABC exposure after once-daily dosing would be equivalent to the exposure seen after twice-
daily dosing in infants and children aged ≤12 years.18-22 Both these trials and PK modeling have
demonstrated that once-daily dosing with either the tablet or the liquid formulation of ABC produces
plasma exposures comparable to those seen with a twice-daily dosing schedule that uses the same
total daily dose of ABC.5

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-10
Dosing
Dosing and Formulations
Initially, the recommended dose for pediatric use was ABC 8 mg/kg twice daily for a total of 16
mg/kg per day. A 2015 FDA review suggested that a total daily dose of ABC 600 mg could be used
safely in a person weighing 25 kg (i.e., ABC 24 mg/kg per day, a 50% increase from the previously
recommended dose). The weight-band dosing table recommends total daily doses as high as ABC
21.5 mg/kg per day to ABC 22.5 mg/kg per day when treating patients with the tablet formulation.5
No difference is seen in the ABC peak plasma concentration (C max ) and AUC for the ABC liquid
formulation compared to the tablet formulation.23 Doses of the liquid ABC formulation are similar to
those used for weight-band dosing with tablet formulations and should be considered for use in
younger children who are unable to swallow a pill.

In the three ABC dosing pediatric trials described above,18-21 only children who had low viral loads
and who were clinically stable on the twice-daily dose of ABC were eligible to change to once-daily
ABC dosing. Efficacy data from a 48-week follow-up in the ARROW trial demonstrated clinical
non-inferiority of once-daily ABC (n = 336) versus twice-daily ABC (n = 333) in tablet form
combined with a once-daily or twice-daily 3TC-based ARV regimen.12 To date, no clinical trials
have been conducted involving children who initiated therapy with once-daily dosing of the ABC
liquid formulation. In children who can be treated with pill formulations, initiating therapy with
once-daily dosing of ABC at a dose of 16 mg/kg (with a maximum dose of ABC 600 mg) is
recommended. However, twice-daily dosing is recommended for infants and young children who
initiate therapy with the liquid formulation of ABC. Switching to once-daily dosing with the liquid or
pill formulation could be considered in clinically stable children with suppressed viral loads and
stable CD4 T lymphocyte counts.

Toxicity
Safety in Neonates and Infants
Data from the PACTG 321, the IMPAACT P1106 trial, and two observational European and African
cohorts provided reassuring data on the safety of ABC in infants when initiated at <3 months of age,
including infants with weight <3 kg.13,24,25 The IMPAACT P1106 trial reported 24 weeks of safety
data in 27 infants in whom repeated dosing of ABC was initiated at the median age of 60 days.
Fifteen infants (55.6%; 90% CI, 38.3–72.0) met the safety endpoint of death or a Grade 3 or higher
adverse event (AE). None of the AEs were related to ABC, and none led to interruptions or
adjustments of ABC dosing. No hypersensitivity reactions were reported with the multidose
treatment.13 In two cohorts of neonates (<1 months of age) who received a single ABC dose, ABC
was well tolerated; all reported AEs in the PACTG 321 study were unrelated to ABC, and no AEs
were reported in the Tygerberg cohort.14,26 The European Pregnancy and Paediatric Infections Cohort
Collaboration (EPPICC) reported safety outcomes among 139 children from 13 cohorts in
11 countries in Europe who initiated ABC at age <3 months. By 12 months on ABC, 3.6% (n = 4)
had discontinued ABC because of an ART safety concern and 11.8% (n = 15) discontinued ABC for
any reason.24 Another observational study of nine cohorts from the International Epidemiology
Databases to Evaluate AIDS (IeDEA) Southern Africa collaboration compared safety outcomes
between infants who started ABC aged <28 days (n = 96) and those aged ≥28 days (n = 835), and
between infants who started ABC with weight <3 kg (n = 246) and those with weight ≥3 kg

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-11
(n = 53).25 ABC discontinuations at 6 and 12 months were not significantly different in infants who
started ART aged <28 days and ≥28 days or in infants who weighed <3 kg and ≥3 kg.25

ABC has less of an effect on mitochondrial function than the NRTI ZDV8,9 and less bone and renal
toxicity than tenofovir disoproxil fumarate.27,28

Recent systemic review and meta-analysis of the 54 full-text articles on the observational and
experimental studies conducted in infants, children, and adolescents with HIV who are aged 10 to 19
years and that included data on safety, efficacy, or both, and were published in English or French
between 2009 and 2022 reported that toxic effects due to ABC use in infants, children, and
adolescents remain rare and manageable.29

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-12
References

1. Waters LJ, Moyle G, Bonora S, et al. Abacavir plasma pharmacokinetics in the absence
and presence of atazanavir/ritonavir or lopinavir/ritonavir and vice versa in HIV-infected
patients. Antivir Ther. 2007;12(5):825-830. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17713166.

2. Pruvost A, Negredo E, Theodoro F, et al. Pilot pharmacokinetic study of human

immunodeficiency virus-infected patients receiving tenofovir disoproxil fumarate (TDF):
investigation of systemic and intracellular interactions between TDF and abacavir,
lamivudine, or lopinavir-ritonavir. Antimicrob Agents Chemother. 2009;53(5):1937-1943.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19273671.

3. Jackson A, Moyle G, Dickinson L, et al. Pharmacokinetics of abacavir and its anabolite

carbovir triphosphate without and with darunavir/ritonavir or raltegravir in HIV-infected
subjects. Antivir Ther. 2012;17(1):19-24. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22267465.

4. Tikiso T, McIlleron H, Burger D, et al. Abacavir pharmacokinetics in African children

living with HIV: a pooled analysis describing the effects of age, malnutrition and
common concomitant medications. Br J Clin Pharmacol. 2022;88(2):403-415. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/34260082.

5. Abacavir (Ziagen) [package insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/020977s035,020978s038lbl.
pdf.

6. Adkison K, Wolstenholme A, Lou Y, et al. Effect of sorbitol on the pharmacokinetic

profile of lamivudine oral solution in adults: an open-label, randomized study. Clin
Pharmacol Ther. 2018;103(3):402-408. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29150845.

7. Frigati LJ, Jao J, Mahtab S, et al. Insulin resistance in South African youth living with
perinatally acquired HIV receiving antiretroviral therapy. AIDS Res Hum Retroviruses.
2019;35(1):56-62. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30156434.

8. Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual

nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir
in children with HIV-1 who have not previously been treated: the PENTA 5 randomised
trial. Lancet. 2002;359(9308):733-740. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11888583.

9. Green H, Gibb DM, Walker AS, et al. Lamivudine/abacavir maintains virological

superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in
children. AIDS. 2007;21(8):947-955. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17457088.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-13
10. Adetokunboh OO, Schoonees A, Balogun TA, Wiysonge CS. Efficacy and safety of
abacavir-containing combination antiretroviral therapy as first-line treatment of HIV
infected children and adolescents: a systematic review and meta-analysis. BMC Infect
Dis. 2015;15:469. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26502899.

11. Mulenga V, Musiime V, Kekitiinwa A, et al. Abacavir, zidovudine, or stavudine as

paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label,
parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169-179.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26481928.

12. Musiime V, Kasirye P, Naidoo-James B, et al. Once vs. twice-daily abacavir and
lamivudine in African children. AIDS. 2016;30(11):1761-1770. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27064996.

13. Cressey TR, Bekker A, Cababasay M, et al. Abacavir safety and pharmacokinetics in
normal and low birth weight infants with HIV. Abstract #843. Presented at: Conference
on Retroviruses and Opportunistic Infections; 2020. Boston, MA Available at:
https://www.croiconference.org/abstract/abacavir-safety-and-pharmacokinetics-in-
normal-and-low-birth-weight-infants-with-hiv/.

14. Bekker A, Decloedt EH, Slade G, Cotton MF, Rabie H, Cressey TR. Single dose abacavir
pharmacokinetics and safety in neonates exposed to human immunodeficiency virus
(HIV). Clin Infect Dis. 2021;72(11):2032-2034. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32697327.

15. Bekker A, Capparelli EV, Violari A, et al. Abacavir dosing in neonates from birth: a
phramcokinetic analysis. Presented at: Conference on Retroviruses and Opportunistic
Infections; 2021. Virtual Conference. Available at:
https://www.croiconference.org/abstract/abacavir-dosing-in-neonates-from-birth-a-
pharmacokinetic-analysis/.

16. World Health Organization. Consolidated guidelines on HIV prevention, testing,

treatment, service delivery and monitoring: recommendations for a public health
approach. 2021. Available at: https://www.who.int/publications/i/item/9789240031593.

17. Sleasman JW, Robbins BL, Cross SJ, et al. Abacavir pharmacokinetics during chronic
therapy in HIV-1-infected adolescents and young adults. Clin Pharmacol Ther.
2009;85(4):394-401. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19118380.

18. LePrevost M, Green H, Flynn J, et al. Adherence and acceptability of once daily
lamivudine and abacavir in human immunodeficiency virus type-1 infected children.
Pediatr Infect Dis J. 2006;25(6):533-537. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16732152.

19. Bergshoeff A, Burger D, Verweij C, et al. Plasma pharmacokinetics of once- versus

twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-
infected children (PENTA-13). Antivir Ther. 2005;10(2):239-246. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15865218.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-14
20. Paediatric European Network for Treatment of AIDS. Pharmacokinetic study of once-
daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-
<36 months. Antivir Ther. 2010;15(3):297-305. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20516550.

21. Musiime V, Kendall L, Bakeera-Kitaka S, et al. Pharmacokinetics and acceptability of

once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan
children in the ARROW Trial. Antivir Ther. 2010;15(8):1115-1124. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21149918.

22. Zhao W, Piana C, Danhof M, Burger D, Della Pasqua O, Jacqz-Aigrain E. Population

pharmacokinetics of abacavir in infants, toddlers and children. Br J Clin Pharmacol.
2013;75(6):1525-1535. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23126277.

23. Kasirye P, Kendall L, Adkison KK, et al. Pharmacokinetics of antiretroviral drug varies
with formulation in the target population of children with HIV-1. Clin Pharmacol Ther.
2012;91(2):272-280. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22190066.

24. Crichton S, Collins IJ, Turkova A, et al. Abacavir dosing, effectivness, and safety in
young infants living with HIV in Europe. Abstract #844. Presented at: Conference on
Retroviruses and Opportunistic Infections 2020. Boston, MA Available at:
https://www.croiconference.org/abstract/abacavir-dosing-effectiveness-and-safety-in-
young-infants-living-with-hiv-in-europe/.

25. De Waal R, Rabie H, Technau K, et al. Abacavir safety and efficacy in young infants in
South African observational cohort. Abstract #845. Presented at: Conference on
retroviruses and opportunistic infections 2020. Boston, MA Available at:
https://www.croiconference.org/abstract/abacavir-safety-and-efficacy-in-young-infants-
in-south-african-observational-cohorts/.

26. Bekker A, Capparelli EV, Violari A, et al. Abacavir dosing in neonates from birth to 3
months of life: a population pharmacokinetic modelling and simulation study. Lancet
HIV. 2022;9(1):e24-e31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34883066.

27. Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects,
efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine,
administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week
results from the ASSERT study. J Acquir Immune Defic Syndr. 2010;55(1):49-57.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20431394.

28. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in
antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir
disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS
clinical trials group A5224s, a substudy of ACTG A5202. J Infect Dis.
2011;203(12):1791-1801. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21606537.

29. Jesson J, Saint-Lary L, Revegue M, et al. Safety and efficacy of abacavir for treating
infants, children, and adolescents living with HIV: a systematic review and meta-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-15
 analysis. Lancet Child Adolesc Health. 2022;6(10):692-704. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/36058225.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-16
Emtricitabine (FTC, Emtriva)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Pediatric Oral Solution: 10 mg/mL

Capsule: 200 mg

Fixed-Dose Combination (FDC) Tablets

• [Atripla and generic] Efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg
• [Biktarvy]
o Bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg
o Bictegravir 30 mg/emtricitabine 120 mg/tenofovir alafenamide 15 mg
• [Complera] Emtricitabine 200 mg/rilpivirine 25 mg/tenofovir disoproxil fumarate 300 mg
• [Descovy]
o Emtricitabine 200 mg/tenofovir alafenamide 25 mg
o Emtricitabine 120 mg/tenofovir alafenamide 15 mg
• [Genvoya] Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg
• [Odefsey] Emtricitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 25 mg
• [Stribild] Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg
• [Symtuza] Darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg
• [Truvada]
o Emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg
o Emtricitabine 167 mg/tenofovir disoproxil fumarate 250 mg
o Emtricitabine 133 mg/tenofovir disoproxil fumarate 200 mg
o Emtricitabine 100 mg/tenofovir disoproxil fumarate 150 mg

When using FDC tablets, refer to other sections of the Drug Appendix for information about the individual components of the
FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum Body Weights and
Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Neonatal and Infant (Aged 0 to <3 Months) Dose • Hyperpigmentation/skin discoloration on palms
and/or soles
Oral Solution
• Emtricitabine (FTC) 3 mg/kg once daily

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-17
 Child (Aged ≥3 Months) and Adolescent Dose
Special Instructions
Oral Solution
• Although FTC can be administered without
• FTC 6 mg/kg once daily (maximum 240 mg per dose). The regard to food, some FDC tablet formulations
maximum dose of oral solution is higher than the capsule dose that contain FTC have food requirements.
because a pediatric pharmacokinetic analysis reported that the
plasma exposure for FTC was 20% lower in patients who received • FTC oral solution can be kept at room
the oral solution than in patients who received the capsule temperature, up to 77°F (25°C), if used within
formulation. 3 months; refrigerate oral solution for long-term
storage.
Capsules (For Patients Weighing >33 kg)
• Screen patients for hepatitis B virus (HBV)
• FTC 200 mg once daily infection before using FTC or FDC tablets that
contain FTC. Severe acute exacerbation of HBV
Adult Dose infection can occur when FTC is discontinued;
therefore, hepatic function and hepatitis B viral
Oral Solution for Patients Who Are Unable to Swallow Capsules
load should be monitored for several months
• FTC 240 mg (24 mL) once daily after patients with HBV infection stop taking
FTC.
Capsules
• FTC 200 mg once daily Metabolism/Elimination
• No cytochrome P450 interactions
[Atripla and Generic] Efavirenz/Emtricitabine/Tenofovir Disoproxil
Fumarate (TDF) • Eighty-six percent of FTC is excreted in urine.
FTC may compete with other compounds that
Child and Adolescent (Weighing ≥40 kg) and Adult Dose
undergo renal elimination.
• One tablet once daily
Emtricitabine Dosing in Patients With Hepatic
• Take on an empty stomach. Impairment
[Biktarvy] Bictegravir/Emtricitabine/Tenofovir Alafenamide (TAF) • Atripla should be used with caution in patients
with hepatic impairment.
Neonate or Child (Aged <2 Years and Weighing <14 kg) Dose
• Biktarvy, Genvoya, Stribild, and Symtuza are
• No data are available on the appropriate dose of Biktarvy in children not recommended for use in patients with
aged <2 years and weighing <14 kg. Studies are currently being severe hepatic impairment.
conducted to identify the appropriate dose for this age and weight
group. • Complera, Descovy, and Odefsey do not require
dose adjustment in mild or moderate hepatic
Child, Adolescent, and Adult Dose impairment, but should not be used in patients
with severe hepatic impairment, because they
• One tablet once daily, with or without food.
have not been studied in this group.
Body Weight Dose Emtricitabine Dosing in Patients With Renal
≥14 to <25 kg Bictegravir 30 mg/emtricitabine 120 mg/ Impairment
tenofovir alafenamide 15 mg • Decrease the dose of FTC in patients with
≥25 kg Bictegravir 50 mg/emtricitabine 200 mg/ impaired renal function. Consult the
tenofovir alafenamide 25 mg manufacturer’s prescribing information for
recommended dose adjustments.
• The U.S. Food and Drug Administration approved Biktarvy for use • Do not use the FDC tablets Atripla or Complera
only in antiretroviral therapy (ART)-naive patients or to replace the in patients with creatinine clearance (CrCl)
current antiretroviral (ARV) regimen in patients who have been <50 mL/min or in patients who require dialysis.
virologically suppressed (HIV RNA <50 copies/mL) on a stable ARV
regimen with no history of treatment failure and no known mutations • Do not use the FDC tablets Truvada or Biktarvy
associated with resistance to the individual components of Biktarvy. in patients with CrCl <30 mL/min. Do not use
Some members of the Panel on Antiretroviral Therapy and Medical Truvada in patients who require dialysis.
Management of Children Living With HIV (the Panel) recommend

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-18
 the use of Biktarvy in patients with prior treatment failure and who • Stribild should not be initiated in patients with
have virus containing the M184V mutation. estimated CrCl <70 mL/min and should be
discontinued in patients with estimated
• See the Bictegravir section for additional information.
CrCl <50 mL/min.
[Complera] Emtricitabine/Rilpivirine/TDF • TAF-containing formulations are not
Child and Adolescent (Aged ≥12 Years and Weighing ≥35 kg) and recommended for use in patients with estimated
Adult Dose CrCl <30 mL/min.

• One tablet once daily in ART-naive patients who have baseline

plasma HIV RNA ≤100,000 copies/mL. This dose of Complera also
can be used to replace a stable ARV regimen in patients who are
currently on their first or second regimen and who have been
virologically suppressed (HIV RNA <50 copies/mL) with no history of
treatment failure and no known mutations associated with
resistance to the individual components of Complera.
• Administer with a meal of at least 500 calories.

[Descovy] Emtricitabine/TAF
Child and Adolescent and Adult Dose

Body Weight Dose

≥14 kg to <25 kg FTC 120 mg/TAF 15 mg, in combination with
an integrase strand transfer inhibitor (INSTI)
or a non-nucleoside reverse transcriptase
inhibitor (NNRTI). In this weight band,
Descovy should not be used with protease
inhibitors (PIs) that require a cytochrome
P450 (CYP) 3A inhibitor (e.g., ritonavir [RTV]
or cobicistat [COBI]).
≥25 kg to <35 kg FTC 200 mg/TAF 25 mg, in combination with
an INSTI or an NNRTI. In this weight band,
Descovy should not be used with PIs that
require a CYP3A inhibitor (i.e., RTV or
COBI).
≥35 kg FTC 200 mg/TAF 25 mg, in combination with
an INSTI, NNRTI, or boosted PI.

[Genvoya] Elvitegravir/Cobicistat/Emtricitabine/TAF
Child and Adolescent (Weighing ≥25 kg) and Adult Dose
• One tablet once daily with food in ART-naive patients. This dose of
Genvoya also can be used to replace the current ARV regimen in
patients who have been virologically suppressed (HIV RNA
<50 copies/mL) on a stable ARV regimen with no history of
treatment failure and no known mutations associated with
resistance to the individual components of Genvoya.

[Odefsey] Emtricitabine/Rilpivirine/TAF
Child and Adolescent (Aged ≥12 Years and Weighing ≥35 kg) and
Adult Dose

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-19
 • One tablet once daily in ART-naive patients with HIV RNA
≤100,000 copies per mL. This dose of Odefsey also can be used to
replace the current ARV regimen in patients who have been
virologically suppressed (HIV RNA <50 copies/mL) with no history of
treatment failure and no known mutations associated with
resistance to the individual components of Odefsey.
• Administer with a meal of at least 500 calories.

[Stribild] Elvitegravir/Cobicistat/Emtricitabine/TDF
Child and Adolescent (Weighing ≥35 kg with a Sexual Maturity Rating
of 4 or 5) and Adult Dose
• One tablet once daily with food in ART-naive patients. This dose of
Stribild also can be used to replace the current ARV regimen in
patients who have been virologically suppressed (HIV RNA
<50 copies/mL) with no history of treatment failure and no known
mutations associated with resistance to the individual components
of Stribild.

[Symtuza] Darunavir/Cobicistat/Emtricitabine/TAF
Child and Adolescent (Weighing ≥40 kg) and Adult Dose
• One tablet once daily with food in ART-naive patients or in patients
who have been virologically suppressed (HIV RNA <50 copies/mL)
with no known mutations associated with resistance to darunavir or
tenofovir.

[Truvada] Emtricitabine/TDF (FTC/TDF)

Truvada Dosing Table
Child, Adolescent, and Adult Dose

FTC/TDF Tablet
Body Weight
Once Daily

17 kg to <22 kg One FTC 100 mg/TDF 150-mg tablet

22 kg to <28 kg One FTC 133 mg/TDF 200-mg tablet
28 kg to <35 kg One FTC 167 mg/TDF 250-mg tablet
≥35 kg and adults One FTC 200 mg/TDF 300-mg tablet

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Other nucleoside reverse transcriptase inhibitors (NRTIs): Do not use emtricitabine (FTC) in
combination with lamivudine (3TC), because these agents share similar resistance profiles and
lack additive benefit. Do not use FTC with fixed-dose combination (FDC) medications that
contain 3TC or FTC. See Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose
Combination Tablets and refer to other sections of the Drug Appendix for drug interaction
information for each individual component of an FDC tablet.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-20
• Renal elimination: FTC may compete with other compounds that undergo renal tubular secretion.
Drugs that decrease renal function could decrease clearance of FTC.

Major Toxicities
• More common: Headache, insomnia, diarrhea, nausea, rash. Hyperpigmentation/skin
discoloration, which may be more common in children than in adults.
• Less common (more severe): Neutropenia. Lactic acidosis and severe hepatomegaly with
steatosis, including fatal cases, have been reported. Exacerbations of hepatitis have occurred
in patients with hepatitis B virus (HBV)/HIV coinfection who switched from regimens that
included FTC to regimens that did not include FTC.

Resistance
The International Antiviral Society–USA maintains a list of HIV drug resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
FTC is approved by the U.S. Food and Drug Administration for once-daily administration in
children, starting at birth. FTC often is used as part of a dual-NRTI backbone in antiretroviral (ARV)
regimens for children and adolescents because of its once-daily dosing, minimal toxicity, and
favorable pediatric pharmacokinetic (PK) data.

Efficacy and Pharmacokinetics

Comparative Clinical Trials
Studies that assess the efficacy and/or potency of nucleoside/nucleotide analogues have been more
concerned with the dynamic components of the regimen—such as tenofovir disoproxil
fumarate (TDF), tenofovir alafenamide (TAF), or abacavir—than the more static components, such
as FTC or 3TC. FTC and 3TC have been considered interchangeable, but data to support this
conclusion are lacking. Investigators studying the AIDS Therapy Evaluation in the
Netherlands (ATHENA) cohort compared the efficacy of TDF plus FTC with TDF plus 3TC when
these drugs were administered with a ritonavir-boosted protease inhibitor (darunavir, atazanavir, or
lopinavir) in antiretroviral therapy (ART)-naive patients.1 The adjusted hazard ratio for the virologic
failure of 3TC-containing regimens compared with FTC-containing regimens within 240 weeks of
starting therapy was 1.15 (95% confidence interval, 0.58–2.27). No difference between these
regimens was observed in the time to virologic suppression during the first 48 weeks of therapy or
time to virologic failure after attaining suppression. In a Swiss cohort, Yang et al. found a potential
difference in efficacy between FTC and 3TC; however, the difference disappeared after adjusting for
pill burden.2 Current evidence suggests that FTC and 3TC have equivalent efficacy and toxicity in
ARV-naive patients.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-21
Efficacy
Following a dose-finding study by Wang et al. (described in the Pharmacokinetics: Liquid Versus
Capsule section below),3 a once-daily dose of FTC 6 mg/kg administered in combination with other
ARV drugs was studied in 116 patients aged 3 months to 16 years.4 The study used a maximum dose
of 240 mg of the FTC liquid formulation. PK results showed that the plasma exposures seen in these
children and adolescents were similar to those seen in adults who received FTC 200 mg once daily.
Follow-up data extending to Week 96 indicated that 89% of ART-naive children and 76% of ARV-
experienced children maintained plasma HIV RNA <400 copies/mL (75% of ARV-naive children
and 67% of ARV-experienced children had HIV RNA <50 copies/mL). Minimal toxicity was
observed during this trial. Pediatric AIDS Clinical Trials Group (PACTG) P10215 evaluated the use
of FTC 6 mg/kg (with a maximum dose of FTC 200 mg per day of the liquid formulation) as part of a
three-drug regimen dosed once daily to ARV-naive children aged 3 months to 21 years. In this trial,
85% of children achieved HIV RNA <400 copies/mL, and 72% of children maintained virologic
suppression (HIV RNA <50 copies/mL) through 96 weeks of therapy. The median CD4
T lymphocyte count rose by 329 cells/mm3 at Week 96.

Pharmacokinetics: Liquid Versus Capsule

A single-dose PK study of the FTC oral solution and FTC capsules enrolled 25 children with HIV
aged 2 years to 17 years.3 FTC was found to be well absorbed following oral administration, with a
mean elimination half-life of 11 hours (range, 9.7–11.6 hours). Plasma concentrations in children
who received the once-daily dose of FTC 6 mg/kg were approximately equivalent to those seen in
adults who received the standard dose of FTC 200 mg. However, plasma concentrations of FTC after
administration of the capsule formulation were approximately 20% higher than those observed after
administration of the oral solution in this small cohort of children.

Pharmacokinetics in Infants
A study in South Africa evaluated the PKs of FTC in 20 infants aged <3 months with perinatal HIV
exposure. The participants received a dose of FTC 3 mg/kg once daily for two 4-day courses,
separated by an interval of ≥2 weeks.6 FTC exposure (area under the curve [AUC]) in neonates
receiving FTC 3 mg/kg once daily was within the range of exposures seen in pediatric patients aged
>3 months who received the recommended dose of FTC 6 mg/kg once daily and adults who received
the recommended once-daily dose of FTC 200 mg. During the first 3 months of life, FTC AUC
decreased with increasing age, correlating with an increase in total body clearance of the drug. In a
small group of neonates (n = 6) who received a single dose of FTC 3 mg/kg and whose mothers
received a single dose of FTC 600 mg during delivery, the FTC AUC exceeded the AUC seen in
adults and older children. However, FTC had a half-life of 9.2 hours in these neonates, which is
similar to that observed in adults and older children.7 Extensive safety data are lacking for this age
range.

Considerations for Use

The FTC oral solution has an advantage over the liquid formulation of 3TC, because it can be given
once daily at ARV initiation, whereas the liquid formulation of 3TC needs to be given twice daily at
ARV initiation. When pill formulations of 3TC or FTC are used, they can be administered once
daily.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-22
Both FTC and 3TC have antiviral activity and efficacy against HBV. For a comprehensive review of
this topic, see the Hepatitis B Virus section in the Pediatric Opportunistic Infection Guidelines.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-23
References

1. Rokx C, Gras L, van de Vijver D, Verbon A, Rijnders B, Athena National Observational

Cohort Study. Virological responses to lamivudine or emtricitabine when combined with
tenofovir and a protease inhibitor in treatment-naive HIV-1-infected patients in the Dutch AIDS
Therapy Evaluation in the Netherlands (ATHENA) cohort. HIV Med. 2016;17(8):571-580
Available at: http://www.ncbi.nlm.nih.gov/pubmed/26842457.

2. Yang WL, Kouyos RD, Scherrer AU, et al. Assessing efficacy of different nucleos(t)ide
backbones in NNRTI-containing regimens in the Swiss HIV cohort study. J Antimicrob
Chemother. 2015;70(12):3323-3331. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26362944.

3. Wang LH, Wiznia AA, Rathore MH, et al. Pharmacokinetics and safety of single oral
doses of emtricitabine in human immunodeficiency virus-infected children. Antimicrob Agents
Chemother. 2004;48(1):183-191. Available at: http://www.ncbi.nlm.nih.gov/pubmed/14693538.

4. Saez-Llorens X, Violari A, Ndiweni D, et al. Long-term safety and efficacy results of

once-daily emtricitabine-based highly active antiretroviral therapy regimens in human
immunodeficiency virus-infected pediatric subjects. Pediatrics. 2008;121(4):e827-835.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18332076.

5. McKinney RE, Jr., Rodman J, Hu C, et al. Long-term safety and efficacy of a once-daily
regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive children and
adolescents: Pediatric AIDS clinical trials group protocol P1021. Pediatrics. 2007;120(2):e416-
423. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17646352.

6. Blum M, Ndiweni D, Chittick Gea. Steady state pharmacokinetic evaluation of

emtricitabine in neonates exposed to HIV in utero. Presented at: Conference on Retroviruses and
Opportunistic Infections; 2006. Denver, CO. Available at.

7. Flynn PM, Mirochnick M, Shapiro DE, et al. Pharmacokinetics and safety of single-dose
tenofovir disoproxil fumarate and emtricitabine in HIV-1-infected pregnant women and their
infants. Antimicrob Agents Chemother. 2011;55(12):5914-5922. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21896911.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-24
Lamivudine (3TC, Epivir)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Pediatric Oral Solution
• [Epivir] 10 mg/mL
• [Epivir HBV]a 5 mg/mL

Tablets
• [Epivir] 150 mg (scored) and 300 mg
• [Epivir HBV]a 100 mg

Generic Formulations
• 100-mg, 150-mg, and 300-mg tablets

Fixed-Dose Combination (FDC) Tablets

• [Cimduo] Lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Combivir and generic] Lamivudine 150 mg/zidovudine 300 mg
• [Delstrigo] Doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Dovato] Dolutegravir 50 mg/lamivudine 300 mg
• [Epzicom] Abacavir 600 mg/lamivudine 300 mg
• [Symfi] Efavirenz 600 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Symfi Lo] Efavirenz 400 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Temixys] Lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Triumeq] Abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg
• [Triumeq PD] Abacavir 60 mg/dolutegravir 5 mg/lamivudine 30 mg
• [Trizivir] Abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg

When using FDC tablets, refer to other sections of the Drug Appendix for information about the individual components of the
FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum Body Weights and
Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Note: See Antiretroviral Management of Newborns With Perinatal HIV • Headache
Exposure or HIV Infection and Table 12: Antiretroviral Dosing
Recommendations for Newborns for information about using
lamivudine (3TC) to prevent perinatal HIV transmission.
Special Instructions
• 3TC can be given without regard to food.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-25
 Neonate (≥32 Weeks Gestation at Birth) and Infant (Birth to • Store 3TC oral solution at room temperature.
<4 Weeks) Dose
• For ABC/DTG/3TC dispersible tablets, fully
Oral Solution disperse them in 20 mL of drinking water in the
supplied cup and swirl the suspension so that no
• 3TC 2 mg/kg twice daily
lumps remain. After full dispersion and within
Infant and Child Dose 30 minutes of mixing, administer the oral
suspension. Rinse the dosing cup with a small
• Once-daily dosing of the 3TC oral solution is not recommended amount of water and give this additional water to
when initiating 3TC oral solution in infants and young children. the child to ensure that the child takes the full
Patients can be transitioned to once-daily treatment with the oral dose and no medication remains in the dosing
solution when they have been stable on twice-daily treatment for cup. ABC/DTG/3TC dispersible tablets should
36 weeks and are aged ≥3 years. Please see the note below and not be swallowed whole, chewed, cut, or
refer to the text for more detail. crushed.

Aged ≥4 Weeks to <3 Months • Screen patients for hepatitis B virus (HBV)
infection before using 3TC or FDC tablets that
• 3TC 4 mg/kg twice daily of the oral solution contain 3TC. Severe acute exacerbations of
HBV can occur after discontinuation of
Aged ≥3 Months to <3 Years lamivudine. Hepatic function and HBV viral load
• 3TC 5 mg/kg twice daily of the oral solution (maximum 150 mg should be monitored for several months after
per dose) patients with HBV infection stop taking 3TC.
Patients with HBV/HIV coinfection who receive
Aged ≥3 Years Dovato will require additional treatment for
chronic HBV infection.
• 3TC 5 mg/kg twice daily of the oral solution (maximum 150 mg
per dose); or • For any FDC tablet containing abacavir (ABC),
test patients for the HLA-B*5701 allele before
• 3TC 10 mg/kg once daily of the oral solution (maximum 300 mg starting therapy to predict the risk of
per dose) hypersensitivity reactions. Patients who test
positive for the HLA-B*5701 allele should not be
Weight-Band Dosing for the 10-mg/mL Lamivudine Oral Solution given an ABC-containing FDC. Patients with no
in Children Weighing ≥3 kg
prior HLA-B*5701 testing who are tolerating an
ABC containing regimen do not need to be
Twice-Daily Dose, Twice-Daily Dose, tested. See Abacavir.
Weight
AM PM

3 kg to <6 kg 3 mL 3 mL Metabolism/Elimination
6 kg to <10 kg 4 mL 4 mL Lamivudine Dosing in Patients with Hepatic
Impairment
10 kg to <14 kg 6 mL 6 mL
• No change in 3TC dosing is required for patients
with hepatic impairment.
Weighing ≥14 kg and Able to Swallow Tablets
• FDC tablets containing ABC or zidovudine (ZDV)
• Weight-band dosing (see table below; dose is approximately 3TC
should not be used in patients who have
5 mg/kg per day twice daily or 3TC 10 mg/kg once daily)
impaired hepatic function.
• The scored tablet is the preferred formulation for pediatric patients
• Symfi and Symfi Lo should be used with caution
weighing ≥14 kg who can swallow a tablet.
in patients with hepatic impairment; Symfi and
Symfi Lo are not recommended for use in
moderate or severe hepatic impairment.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-26
 Weight-Band Dosing for the Scored, 150-mg Lamivudine Tablet in • Delstrigo and Dovato do not require dose
Children Weighing ≥14 kg adjustment in mild or moderate hepatic
impairment but have not been studied in patients
Twice-Daily Twice-Daily Once-Daily and so are not recommended with severe
Weight
Dose, AM Dose, PM Dose hepatic impairment.
14 kg to <20 kg ½ tablet ½ tablet 1 tablet Lamivudine Dosing in Patients With Renal
(75 mg) (75 mg) (150 mg) Impairment
≥20 kg to <25 kg ½ tablet 1 tablet 1½ tablets • Dose adjustment of 3TC is required for patients
(75 mg) (150 mg) (225 mg) with renal insufficiency.
≥25 kg 1 tablet 1 tablet 2 tablets • Do not use FDC tablets containing 3TC in
(150 mg) (150 mg) (300 mg) patients with creatinine clearance <30 mL/min or
patients on dialysis, because the doses of 3TC
Note: The Panel on Antiretroviral Therapy and Medical Management of cannot be adjusted. Data from the FDC
Children Living With HIV (the Panel) supports switching from twice- DTG/3TC (Dovato) suggest that patients with a
daily dosing to once-daily dosing of 3TC (using the oral solution or sustained creatinine clearance 30–49 mL/min
tablets) in children aged ≥3 years who have been clinically stable for may experience a higher 3TC exposure and
36 weeks with undetectable viral loads and stable CD4 T lymphocyte should be monitored for hematologic toxicities
cell counts. Clinicians should choose a once-daily regimen using the and potential FDC discontinuation and
once-daily dose of 3TC indicated above (approximately 3TC 10 mg/kg, subsequent adjustment of the treatment
with a maximum of 3TC 300 mg once daily). regimen. See package inserts for additional
information.
Child and Adolescent (Weighing ≥25 kg) and Adult Dose
• 3TC 150 mg twice daily; or
• 3TC 300 mg once daily

[Cimduo] Lamivudine/Tenofovir Disoproxil Fumarate (TDF)

Child and Adolescent (Weighing >35 kg) and Adult Dose
• One tablet once daily

[Combivir and Generic] Lamivudine/Zidovudine

Child and Adolescent (Weighing ≥30 kg) and Adult Dose
• One tablet twice daily

[Delstrigo] Doravirine/Lamivudine/TDF
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• One tablet once daily in antiretroviral (ARV)-naive patients and ARV-
experienced patients who have been virologically suppressed (HIV
RNA <50 copies/mL) on a stable ARV regimen with no history of
treatment failure and no known mutations associated with resistance
to the individual components of Delstrigo.

[Dovato] Dolutegravir/Lamivudine
Adult Dose
• One tablet once daily with or without food as a complete ARV
regimen in antiretroviral therapy (ART)–naive adults with no known
mutations associated with resistance to the individual components of
Dovato.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-27
 • Dovato is not approved by the U.S. Food and Drug Administration
(FDA) or recommended by the Panel for use in children or
adolescents as a complete ARV regimen. However, it could be used
as part of a three-drug regimen in patients who meet the minimum
body weight requirements for each component drug.

[Epzicom] Abacavir/Lamivudine
Child and Adolescent (Weighing ≥25 kg) and Adult Dose
• One tablet once daily

[Symfi] Efavirenz 600 mg/Lamivudine/TDF

Child and Adolescent (Weighing ≥40 kg) and Adult Dose
• One tablet once daily on an empty stomach

[Symfi Lo] Efavirenz 400 mg/Lamivudine/TDF

Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• One tablet once daily on an empty stomach
• Symfi Lo has not been studied in children (sexual maturity ratings
[SMRs] 1–3), and major interindividual variability in efavirenz (EFV)
plasma concentrations has been found in pediatric patients in a
multiethnic setting. The 400-mg dose of EFV may be too low in
children or adolescents with SMRs 1 to 3 who weigh ≥40 kg. The
use of therapeutic drug monitoring is suggested by some Panel
members when Symfi Lo is used in pediatric patients who weigh
≥40 kg (see the Efavirenz section for more information).

[Temixys] Lamivudine/TDF
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• One tablet once daily

[Triumeq PD] Abacavir/Dolutegravir (DTG)/Lamivudine (3TC)

Child Weighing ≥10 kg to <25 kg
• Dispersible Triumeq PD tablets are FDA approved for children
weighing ≥10 to <25 kg. Triumeq PD is not recommended for
children weighing ≥25 kg who are eligible for adult Triumeq dosing.
• Administer the appropriate number of tablets for a child’s weight
once daily, dispersed in 20 mL of water. See Special Instructions.
Triumeq PD tablets should not be swallowed whole, chewed, cut, or
crushed.

Weight-Band Dosing of Triumeq PD Tablets for Children Weighing

≥10 kg

Recommended Daily Number of Triumeq

Weight
Dose PD Tablets
10 kg to <14 kg ABC 240 mg, 4
DTG 20 mg,
3TC 120 mg

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-28
 14 kg to <20 kg ABC 300 mg, 5
DTG 25 mg,
3TC 150 mg
20 kg to <25 kg ABC 360 mg, 6
DTG 30 mg,
3TC 180 mg
≥25 kg Use Triumeq (see below)

• For use in children who are ARV naive or ARV experienced (but
integrase strand transfer inhibitor naive) and who are not being
treated with uridine diphosphate glucuronosyltransferase 1A1
(UGT1A1) or cytochrome P450 (CYP450) 3A inducers

[Triumeq] Abacavir/Dolutegravir/Lamivudine
Child and Adolescent (Weighing ≥25 kg) and Adult Dose
• One tablet once daily
• This FDC tablet can be used in patients who are ART naive or ART
experienced (but integrase strand transfer inhibitor naive) and who
are not being treated with UGT 1A1 or CYP450 3A inducers.

[Trizivir and Generic] Abacavir/Lamivudine/Zidovudine

Child and Adolescent (Weighing ≥30 kg) and Adult Dose
• One tablet twice daily
a Epivir HBV oral solution and tablets contain a lower amount of 3TC than Epivir oral solution and tablets. The amount of 3TC in
the Epivir HBV solution and tablet was based on dosing for treatment of HBV infection in people without HIV coinfection.
Patients with HIV who are taking Epivir HBV as part of their ARV regimen should receive the appropriate amount of oral solution
or the appropriate number of tablets to achieve the higher doses of 3TC that are used to treat HIV.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Drugs that decrease renal function could decrease clearance of lamivudine (3TC).
• Do not use 3TC in combination with emtricitabine (FTC), because these drugs have similar
resistance profiles and using them together offers no additional benefit.1 Do not use 3TC with
fixed-dose combination (FDC) medications that contain 3TC or FTC. Please see Appendix A,
Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets and refer to other sections
of the Drug Appendix for drug interaction information about each individual component of FDC
tablets.

Major Toxicities
• More common: Headache, nausea
• Less common (more severe): Peripheral neuropathy, lipodystrophy/lipoatrophy

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-29
• Rare: Increased levels of liver enzymes. Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported.

Resistance
The International Antiviral Society–USA maintains a list of HIV drug resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
Although 3TC is approved by the U.S. Food and Drug Administration (FDA) for the treatment of
children aged ≥3 months, both the Panel on Antiretroviral Therapy and Medical Management of
Children Living With HIV (the Panel) and the Panel on Treatment of HIV During Pregnancy and
Prevention of Perinatal Transmission recommend the use of 3TC from birth.

Considerations for Use

The efficacy and toxicity of 3TC are equivalent to the efficacy and toxicity of FTC. The oral
formulation of FTC has an advantage over the liquid formulation of 3TC because it can be given
once daily at antiretroviral (ARV) initiation, whereas the liquid formulation of 3TC needs to be given
twice daily at ARV initiation. When pill formulations of 3TC or FTC are used, they can be
administered once daily.

Comparative Clinical Trials

Investigators studying the AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort compared
the efficacy of tenofovir disoproxil fumarate (TDF) plus FTC to TDF plus 3TC when these drugs
were administered with a ritonavir-boosted protease inhibitor (darunavir, atazanavir, or lopinavir) in
ART-naive patients.2 The adjusted hazard ratio for the virologic failure of 3TC-containing regimens
compared to FTC-containing regimens within 240 weeks of starting therapy was 1.15
(95% confidence interval, 0.58–2.27). These regimens had no difference in time to virologic
suppression during the first 48 weeks of therapy or time to virologic failure after attaining
suppression. In a Swiss cohort, Yang et al. found a potential difference in efficacy between FTC and
3TC; however, the difference disappeared after adjusting for pill burden. Current evidence suggests
that FTC and 3TC have equivalent efficacy and toxicity in ARV-naive patients.3

Efficacy
3TC has been studied in children with HIV both alone and in combination with other ARV drugs.
Extensive data have demonstrated the safety of 3TC and have shown that this drug is associated with
clinical improvement and virologic response. It is commonly used in children with HIV as a
component of a dual nucleoside reverse transcriptase inhibitor (NRTI) backbone.4-12 In one study that
evaluated the efficacy of NRTI background components, the combination of 3TC plus
abacavir (ABC) was superior to zidovudine (ZDV) plus 3TC or ZDV plus ABC in achieving long-
term virologic efficacy.13

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-30
Pharmacokinetics in Infants
Because of its safety profile and availability in a liquid formulation, 3TC has been given to infants
during the first 6 weeks of life starting at a dose of 2 mg/kg every 12 hours before age 4 weeks.9 A
population pharmacokinetic (PK) analysis of infants who received 3TC affirms that adjusting the
dose from 3TC 2 mg/kg to 3TC 4 mg/kg every 12 hours at age 4 weeks provides optimal 3TC
exposure for infants with normal maturation of renal function.14 For infants, the World Health
Organization weight-band dosing (which is up to five times higher than the FDA-approved dose)
results in greater plasma concentrations than the 3TC 2 mg/kg dose.15 In HIV Prevention Trials
Network (HPTN) 040, 3TC was administered as a component of a three-drug regimen to prevent
perinatal transmission during the first 2 weeks of life. For 2 weeks, all infants weighing >2,000 g
received 3TC 6 mg twice daily, and infants weighing ≤2,000 g received 3TC 4 mg twice daily. These
doses resulted in 3TC exposure that was similar to the exposure seen in infants who received the
standard twice-daily dosing schedule of 3TC 2 mg/kg per dose for neonates.16

Pharmacokinetics of Liquid Versus Tablet Preparations

The PKs of 3TC have been studied after either single or repeat doses in 210 pediatric subjects.
Pediatric subjects who received 3TC oral solution according to the recommended dose regimen
achieved plasma concentrations of 3TC that were approximately 25% lower than those of adults with
HIV who received the oral solution. Pediatric subjects who received 3TC tablets achieved plasma
concentrations that were comparable to or slightly higher than those observed in adults who received
tablets. In pediatric subjects, the relative bioavailability of 3TC oral solution is approximately 40%
lower than the relative bioavailability of tablets that contain 3TC, despite no difference in the
bioavailability of these two formulations among adults. The mechanisms for the diminished relative
bioavailability of 3TC oral solution are unknown,17 but results from a study in adults that compared
the PKs of 3TC oral solution administered either alone or with increasing concentrations of sorbitol
indicate that sorbitol decreases the total exposure of 3TC oral solution.18 Sorbitol is a component of
several ARV solutions, including ABC, as well as common over-the-counter medications that may be
used in infants and young children; this may explain the PK discrepancy between the oral solution
and tablet formulations. Modeling of PK data in pediatric patients suggests that increasing the oral
solution dose to 3TC 5 mg/kg per dose twice daily or 3TC 10 mg/kg per dose once daily (with a
maximum of 3TC 300 mg administered daily) in children aged ≥3 months would provide exposures
similar to those seen in adult patients who received tablet formulations. However, modeling was
done with PK data derived from studies that did not use 3TC liquid formulation, and so modeling
may not predict exposures for 3TC oral solution, especially when used with liquid ABC. The Panel
does not recommend using a once-daily dose of 3TC until a child is aged ≥3 years. However, this
new dosing schedule is now included in the 3TC package insert, even though no clinical data are
available for patients who received both 3TC and sorbitol-containing medications.

Dosing Considerations—Once-Daily Versus Twice-Daily Administration

The standard adult dose for 3TC is 300 mg once daily, but data are lacking on once-daily
administration of 3TC in children. Population PK data indicate that once-daily dosing of 3TC
8 mg/kg leads to area under the curve over 24 hours (AUC 0–24h ) values that are similar to those seen
in patients taking 3TC 4 mg/kg twice daily, but minimum blood plasma concentration (C min ) values
are significantly lower and maximum blood plasma concentration (C max ) values are significantly
higher in children aged 1 year to 18 years.19 Intensive PKs of once-daily versus twice-daily dosing of
3TC were evaluated in children with HIV aged 2 to 13 years in the PENTA (Paediatric European

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-31
Network for Treatment of AIDS) 13 trial4 and in children aged 3 months to 36 months in the PENTA
15 trial.20 Both the PENTA 13 and PENTA 15 trials used a crossover design with doses of 3TC
8 mg/kg once daily or 3TC 4 mg/kg twice daily. AUC 0–24 and clearance values were similar between
these two dosing schedules, and most children maintained an undetectable HIV RNA value after the
switch. An ARROW (AntiRetroviral Research fOr Watoto) trial PK study of 41 children aged 3 to
12 years (median age 7.6 years) in Uganda who were stable on twice-daily 3TC also showed
equivalent AUC 0–24h and good clinical outcomes (defined by a low disease stage and a high CD4 T
lymphocyte [CD4] cell count) after switching to once-daily 3TC. Median follow-up time during this
study was 1.15 years.21 The larger ARROW trial was a randomized, noninferiority trial that
investigated once-daily versus twice-daily doses of 3TC in >600 pediatric patients who had initiated
therapy with twice-daily 3TC and who had been receiving therapy for ≥36 weeks. Median follow-up
time during the study was 114 weeks. Rates of plasma HIV RNA suppression and adverse event
profiles for once-daily 3TC were similar to (and statistically noninferior to) those of twice-daily
3TC.22

All four of the studies discussed above enrolled patients who had a low plasma HIV RNA or who
were clinically stable on twice-daily 3TC before switching to once-daily dosing. Therefore, the Panel
supports switching from twice-daily to once-daily dosing of 3TC in children aged ≥3 years who have
been clinically stable for 36 weeks with an undetectable viral load and stable CD4 count. Clinicians
should use a 10 mg/kg per dose of 3TC oral solution or a weight-based dose of 3TC tablets (neither
exceeding 3TC 300 mg) as part of a once-daily regimen.23 More long-term clinical trials with viral
efficacy endpoints are needed to confirm that once-daily dosing of 3TC can be used effectively as
part of an initial ARV regimen in children.

3TC undergoes intracellular metabolism to reach its active form, 3TC triphosphate. In adolescents,
the mean half-life of intracellular 3TC triphosphate (17.7 hours) is considerably longer than that of
unphosphorylated 3TC in plasma (1.5–2 hours). Intracellular concentrations of 3TC triphosphate are
equivalent whether 3TC is given once daily or twice daily in adults and adolescents. This supports a
recommendation for once-daily 3TC dosing based on FDA recommendations.24,25

Considerations for Use

Weight-band dosing recommendations for 3TC have been developed for children weighing ≥3 kg
and receiving either the 10-mg/mL oral solution or the 150-mg scored tablets.26-28

Both FTC and 3TC have antiviral activity and efficacy against hepatitis B virus. For a comprehensive
review of this topic, see the Hepatitis B Virus section in the Pediatric Opportunistic Infection
Guidelines.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-32
References

1. Anderson PL, Lamba J, Aquilante CL, Schuetz E, Fletcher CV. Pharmacogenetic

characteristics of indinavir, zidovudine, and lamivudine therapy in HIV-infected adults: a
pilot study. J Acquir Immune Defic Syndr. 2006;42(4):441-449. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16791115.

2. Rokx C, Gras L, van de Vijver D, Verbon A, Rijnders B, Athena National Observational

Cohort Study. Virological responses to lamivudine or emtricitabine when combined with
tenofovir and a protease inhibitor in treatment-naive HIV-1-infected patients in the Dutch
AIDS Therapy Evaluation in the Netherlands (ATHENA) cohort. HIV Med.
2016;17(8):571-580 Available at: http://www.ncbi.nlm.nih.gov/pubmed/26842457.

3. Yang WL, Kouyos RD, Scherrer AU, et al. Assessing efficacy of different nucleos(t)ide
backbones in NNRTI-containing regimens in the Swiss HIV Cohort Study. J Antimicrob
Chemother. 2015;70(12):3323-3331. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26362944.

4. Bergshoeff A, Burger D, Verweij C, et al. Plasma pharmacokinetics of once- versus

twice-daily lamivudine and abacavir: simplification of combination treatment in HIV-1-
infected children (PENTA-13). Antivir Ther. 2005;10(2):239-246. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15865218.

5. Chadwick EG, Rodman JH, Britto P, et al. Ritonavir-based highly active antiretroviral
therapy in human immunodeficiency virus type 1-infected infants younger than 24
months of age. Pediatr Infect Dis J. 2005;24(9):793-800. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16148846.

6. Chaix ML, Rouet F, Kouakoussui KA, et al. Genotypic human immunodeficiency virus
type 1 drug resistance in highly active antiretroviral therapy-treated children in Abidjan,
Cote d'Ivoire. Pediatr Infect Dis J. 2005;24(12):1072-1076. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16371868.

7. Krogstad P, Lee S, Johnson G, et al. Nucleoside-analogue reverse-transcriptase inhibitors

plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human
immunodeficiency virus type 1. Clin Infect Dis. 2002;34(7):991-1001. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/11880966.

8. LePrevost M, Green H, Flynn J, et al. Adherence and acceptability of once daily

lamivudine and abacavir in human immunodeficiency virus type-1 infected children.
Pediatr Infect Dis J. 2006;25(6):533-537. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16732152.

9. Mirochnick M, Stek A, Acevedo M, et al. Safety and pharmacokinetics of nelfinavir

coadministered with zidovudine and lamivudine in infants during the first 6 weeks of life.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-33
 J Acquir Immune Defic Syndr. 2005;39(2):189-194. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/15905735.

10. Mueller BU, Lewis LL, Yuen GJ, et al. Serum and cerebrospinal fluid pharmacokinetics
of intravenous and oral lamivudine in human immunodeficiency virus-infected children.
Antimicrob Agents Chemother. 1998;42(12):3187-3192. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/9835513.

11. Nachman SA, Stanley K, Yogev R, et al. Nucleoside analogs plus ritonavir in stable
antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial.
Pediatric AIDS clinical trials group 338 study team. JAMA. 2000;283(4):492-498.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/10659875.

12. Scherpbier HJ, Bekker V, van Leth F, Jurriaans S, Lange JM, Kuijpers TW. Long-term
experience with combination antiretroviral therapy that contains nelfinavir for up to 7
years in a pediatric cohort. Pediatrics. 2006;117(3):e528-536. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/16481448.

13. Green H, Gibb DM, Walker AS, et al. Lamivudine/abacavir maintains virological
superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in
children. AIDS. 2007;21(8):947-955. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17457088.

14. Tremoulet AH, Capparelli EV, Patel P, et al. Population pharmacokinetics of lamivudine
in human immunodeficiency virus-exposed and -infected infants. Antimicrob Agents
Chemother. 2007;51(12):4297-4302. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/17893155.

15. Tremoulet AH, Nikanjam M, Cressey TR, et al. Developmental pharmacokinetic changes
of lamivudine in infants and children. J Clin Pharmacol. 2012;52(12):1824-1832.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22180560.

16. Mirochnick M, Nielsen-Saines K, Pilotto JH, et al. Nelfinavir and Lamivudine

pharmacokinetics during the first two weeks of life. Pediatr Infect Dis J. 2011;30(9):769-
772. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21666540.

17. Choi SY, Li F, Florian J, Seo SK. Lamivudine and abacavir clinical summary review.
2014. Available at:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResou
rces/UCM446104.pdf

18. Adkison K, Wolstenholme A, Lou Y, et al. Effect of sorbitol on the pharmacokinetic

profile of lamivudine oral solution in adults: an open-label, randomized study. Clin
Pharmacol Ther. 2018;103(3):402-408. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29150845.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-34
19. Bouazza N, Hirt D, Blanche S, et al. Developmental pharmacokinetics of lamivudine in
580 pediatric patients ranging from neonates to adolescents. Antimicrob Agents
Chemother. 2011;55(7):3498-3504. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21576443.

20. Paediatric European Network for Treatment of AIDS. Pharmacokinetic study of once-
daily versus twice-daily abacavir and lamivudine in HIV type-1-infected children aged 3-
<36 months. Antivir Ther. 2010;15(3):297-305. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/20516550.

21. Musiime V, Kendall L, Bakeera-Kitaka S, et al. Pharmacokinetics and acceptability of

once- versus twice-daily lamivudine and abacavir in HIV type-1-infected Ugandan
children in the ARROW Trial. Antivir Ther. 2010;15(8):1115-1124. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21149918.

22. Musiime V, Kasirye P, Naidoo-James B, et al. Once vs. twice-daily abacavir and
lamivudine in African children. AIDS. 2016;30(11):1761-1770. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/27064996.

23. Janssen EJH, Bastiaans DET, Valitalo PAJ, et al. Dose evaluation of lamivudine in
human immunodeficiency virus-infected children aged 5 months to 18 years based on a
population pharmacokinetic analysis. Br J Clin Pharmacol. 2017;83(6):1287-1297.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28079918.

24. Yuen GJ, Lou Y, Bumgarner NF, et al. Equivalent steady-state pharmacokinetics of
lamivudine in plasma and lamivudine triphosphate within cells following administration
of lamivudine at 300 milligrams once daily and 150 milligrams twice daily. Antimicrob
Agents Chemother. 2004;48(1):176-182. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/14693537.

25. Flynn PM, Rodman J, Lindsey JC, et al. Intracellular pharmacokinetics of once versus
twice daily zidovudine and lamivudine in adolescents. Antimicrob Agents Chemother.
2007;51(10):3516-3522. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17664328.

26. World Health Organization. Preferred antiretroviral medicines for treating and preventing
HIV infection in younger children: Report of the WHO paediatric antiretroviral working
group. 2008. Available at:
http://apps.who.int/iris/bitstream/handle/10665/43882/9789241596619_eng.pdf;jsessioni
d=31285037F69DEBBDEE7C08D16ADD48F7?sequence=1

27. L'Homme R F, Kabamba D, Ewings FM, et al. Nevirapine, stavudine and lamivudine
pharmacokinetics in African children on paediatric fixed-dose combination tablets. AIDS.
2008;22(5):557-565. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18316996.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-35
28. World Health Organization. Annex 3. Dosages of ARV drugs for adults and adolescents.
2018. Available at: https://cdn.who.int/media/docs/default-source/hq-hiv-hepatitis-and-
stis-library/arv_guidelines-2018-annex3a.pdf?sfvrsn=1318b82d_3

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-36
Tenofovir Alafenamide (TAF, Vemlidy)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Tablets: 25 mga

Fixed-Dose (FDC) Combination Tablets

• [Biktarvy]
o Bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg
o Bictegravir 30 mg/emtricitabine 120 mg/tenofovir alafenamide 15 mg
• [Descovy]
o Emtricitabine 200 mg/tenofovir alafenamide 25 mg
o Emtricitabine 120 mg/tenofovir alafenamide 15 mg
• [Genvoya] Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg
• [Odefsey] Emtricitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 25 mg
• [Symtuza] Darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg

When using FDC tablets, refer to other sections of Appendix A: Pediatric Antiretroviral Drug Information for information about
the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-
packaged Formulations: Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

[Biktarvy] Bictegravir (BIC)/Emtricitabine (FTC)/Tenofovir • Asthenia, headache, diarrhea, nausea
Alafenamide (TAF)
• Increased serum lipids
Neonate or Child (Aged <2 Years and Weighing <14 kg) Dose
• No data are currently available on the appropriate dose of Special Instructions
Biktarvy in children aged <2 years and weighing <14 kg.
Studies are currently being conducted to identify the • Measure serum creatinine before starting a TAF-
appropriate dose for this age and weight group. containing regimen.

Child (aged ≥ 2 years), Adolescent, and Adult Dose • Screen patients for hepatitis B virus (HBV) infection
before initiating TAF. Severe acute exacerbation of
• One tablet once daily, with or without food. HBV infection can occur when TAF is discontinued;
therefore, hepatic function should be monitored for
Body Weight Dose several months after patients with HBV infection stop
taking TAF.
≥14 kg to <25 BIC 30 mg/FTC 120 mg/TAF 15 mg
kg • The FDA does not recommend using Genvoya with
other ARV drugs, but this FDC tablet has been safely
≥25 kg BIC 50 mg/FTC 200 mg/TAF 25 mg used with DRV.1 Descovy can be safely used2 with
DRV or atazanavir in patients weighing ≥35 kg.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-37
 • Do not use Genvoya with EVG, COBI, tenofovir
• The U.S. Food and Drug Administration (FDA) approved
disoproxil fumarate, FTC, lamivudine, or PIs that are
Biktarvy for use only in antiretroviral therapy (ART)-naive
coformulated with COBI.
patients or to replace the current antiretroviral (ARV) regimen
in patients who have been virologically suppressed (HIV RNA • When using Odefsey, patients must be able to take it
<50 copies/mL) on a stable ARV regimen, with no history of with a meal of at least 500 calories on a regular
treatment failure, and no known mutations associated with schedule (a protein drink alone does not constitute a
resistance to the individual components of Biktarvy. Some meal), because it contains RPV.
members of the Panel on Antiretroviral Therapy and Medical
Management of Children Living With HIV recommend the use Metabolism/Elimination
of Biktarvy in patients with prior treatment failure who have
virus with the M184V mutation. See the Bictegravir section for TAF Dosing in Patients With Hepatic Impairment
additional information.
• TAF-containing formulations do not require dose
[Descovy] FTC/TAF adjustment in patients with mild or moderate hepatic
impairment, but they should not be used in patients
Child, Adolescent, and Adult Dose with severe hepatic impairment because they have not
been studied in that group.
• One tablet once daily, with or without food.
TAF Dosing in Patients With Renal Impairment
Body Weight Dose
• The TAF metabolite tenofovir is renally excreted.
≥14 kg to <25 kg FTC 120 mg/TAF 15 mg, in
• No dose adjustment of the TAF 25-mg tablet
combination with an integrase strand
(Vemlidy)a is required in patients with estimated
transfer inhibitor (INSTI) or a non-
creatinine clearance (CrCl) ≥15 mL/min or in patients
nucleoside reverse transcriptase
with estimated CrCl <15 mL/min (i.e., end-stage renal
inhibitor (NNRTI). In this weight band,
disease) who are receiving chronic hemodialysis. See
Descovy should not be used with
the Vemlidy product label3 for information on the use
protease inhibitors (PIs) that require a
of the TAF 25-mg tablet in patients with estimated
cytochrome P450 (CYP) 3A inhibitor
CrCl ≤15 mL/min.
(i.e., ritonavir [RTV] or cobicistat
[COBI]). • TAF-containing coformulations are not
recommended for use in patients with estimated CrCl
≥25 kg to <35 kg FTC 200 mg/TAF 25 mg, in
<30 mL/min.
combination with an INSTI or an
NNRTI. In this weight band, Descovy
should not be used with PIs that
require a CYP3A inhibitor (i.e., RTV or
COBI).
≥35 kg FTC 200 mg/TAF 25 mg, in
combination with an INSTI, NNRTI, or
boosted PI.

[Genvoya] Elvitegravir (EVG)/COBI/FTC/TAF

Child (Aged >2 Years and Weighing 14 kg to <25 kg) Dose
• Data are currently limited on the appropriate dose of Genvoya
in children aged ≥2 years to <6 years and weighing 14 kg to
<25 kg. Studies are being conducted to identify the safety and
efficacy of a low-dose Genvoya tablet. See the Elvitegravir
section for details.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-38
 Child and Adolescent (Weighing ≥25 kg) and Adult Dose
• One tablet once daily with food in ART-naive patients. This
dose of Genvoya also can be used to replace the current ARV
regimen in patients who have been virologically suppressed
(HIV RNA <50 copies/mL) on a stable ARV regimen, with no
history of treatment failure, and no known mutations
associated with resistance to the individual components of
Genvoya.

[Odefsey] FTC/Rilpivirine (RPV)/TAF

Child and Adolescent (Aged ≥12 Years and Weighing ≥35 kg)
and Adult Dose
• One tablet once daily with a meal in ART-naive patients with
HIV RNA ≤100,000 copies/mL. This dose of Odefsey also can
be used to replace the current ARV regimen in patients who
have been virologically suppressed (HIV RNA <50 copies/mL)
on a stable ARV regimen, with no history of treatment failure,
and no known mutations associated with resistance to the
individual components of Odefsey.

[Symtuza] Darunavir (DRV)/COBI/FTC/TAF

Child and Adolescent (Weighing ≥40 kg) and Adult Dose
• One tablet once daily with food in ART-naive patients. This
dose of Symtuza also can be used to replace the current ARV
regimen in patients who have been virologically suppressed
(HIV RNA <50 copies/mL) on a stable ARV regimen, with no
history of treatment failure, and no known mutations
associated with resistance to the individual components of
Symtuza.
aTAF 25-mg tablets (Vemlidy) are approved by the FDA for treatment of HBV. In certain circumstances, TAF 25-mg tablets
(Vemlidy) might be used as one component of a combination ARV regimen, with dosing recommendations similar to those for
Descovy.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Tenofovir alafenamide (TAF) is a substrate of the adenosine triphosphate-dependent

transporters P-glycoprotein (P-gp) and the breast cancer resistance protein (BCRP). Drugs that
strongly affect P-gp and BCRP activity may lead to changes in TAF absorption. P-gp inducers
are expected to decrease TAF exposure, and P-gp inhibitors are expected to increase absorption
and plasma concentrations of TAF.2 A study of 98 healthy participants without HIV measured
plasma TAF and tenofovir (TFV) exposures when TAF was administered with other
antiretroviral (ARV) drugs. Coadministration of TAF with rilpivirine (RPV) and dolutegravir
(DTG) did not change either TAF or TFV exposure. Coadministration of TAF with the P-gp and
BCRP inhibitor cobicistat (COBI), or coadministration with atazanavir/ritonavir (ATV/r) or
lopinavir/ritonavir (LPV/r), increased both TAF and TFV exposures. Coadministration of TAF
with darunavir/ritonavir (DRV/r) resulted in unchanged TAF area under the curve (AUC) and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-39
 doubled TFV AUC. Coadministration of TAF with the P-gp and BCRP inducer efavirenz
decreased TAF and TFV exposures.4
• Coadministration of TAF with rifamycins (rifabutin, rifampin, or rifapentine) is not
recommended.3,5
• Genvoya contains elvitegravir (EVG) and COBI, in addition to TAF (see the Elvitegravir and
Cobicistat sections for details). EVG is metabolized predominantly by cytochrome P450 (CYP)
3A4, secondarily by uridine diphosphate glucuronosyltransferase 1A1/3, and by oxidative
metabolism pathways. EVG is a modest inducer of CYP2C9. COBI is an inhibitor of CYP3A4
and a weak inhibitor of CYP2D6; in addition, COBI inhibits the adenosine triphosphate-
dependent transporters BCRP and P-gp and the organic anion-transporting polypeptides OAT1B1
and OAT1B3. Potential exists for multiple drug interactions when using both EVG and COBI.
• Absorption: Administering EVG and bictegravir (BIC) concurrently with antacids or
supplements that contain iron, calcium, aluminum and/or magnesium lowers plasma
concentrations of these ARV drugs (see the Elvitegravir and Bictegravir sections for details).
• Odefsey contains RPV, which is a CYP3A substrate, and requires dose adjustments when
administered with CYP3A-modulating medications.
• Before Genvoya, Odefsey, Descovy, Biktarvy, or Symtuza is administered, a patient’s
medication profile should be carefully reviewed for potential drug interactions.
• Renal elimination: Drugs that decrease renal function or compete for active tubular secretion
(e.g., acyclovir, ganciclovir, high-dose nonsteroidal anti-inflammatory drugs) could reduce
clearance of the TAF metabolite TFV or emtricitabine (FTC). Concomitant use of nephrotoxic
drugs should be avoided when using Genvoya.
• Protease inhibitors: Genvoya should not be administered concurrently with products or regimens
that contain ritonavir (RTV), because COBI and RTV have similar effects on CYP3A
metabolism.

Major Toxicities
• More common: Nausea, diarrhea, headache. Greater weight gain has been reported with the use
of TAF than with tenofovir disoproxil fumarate (TDF) in adults and children6 (see Table 17h.
Lipodystrophies and Weight Gain for details).
• Less common (more severe): Cases of lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported with the use of nucleoside reverse transcriptase
inhibitors (NRTIs).

Resistance
The International Antiviral Society–USA maintains a list of updated HIV drug resistance mutations,
and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-40
Pediatric Use
Approval
TAF is available as a component of several fixed-dose combination (FDC) tablets. These FDC tablets
are listed in Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or as
a Co-packaged Formulation, by Drug Class and Appendix A, Table 2. Antiretroviral Fixed-Dose
Combination Tablets and Co-packaged Formulations: Minimum Body Weights and Considerations
for Use in Children and Adolescents.

Descovy, an FDC tablet that contains FTC and TAF (FTC/TAF), is approved by the U.S. Food and
Drug Administration (FDA) for use in children who weigh ≥14 kg to <25 kg at a dose of FTC
120 mg/TAF 15 mg and for children who weigh ≥25 kg to <35 kg at a dose of FTC 200 mg/TAF
25 mg when used as part of an ARV regimen that does not include a boosted protease inhibitor (PI).
Descovy is approved by the FDA for use in children who weigh ≥35 kg at a dose of FTC
200 mg/TAF 25 mg when used in combination with any ARV drugs, including RTV-boosted or
COBI-boosted PIs. Odefsey, an FDC tablet that contains FTC, RPV, and TAF (FTC/RPV/TAF), is
approved by the FDA7 for use in children who weigh ≥35 kg. Genvoya, an FDC tablet that contains
EVG, COBI, FTC, and TAF (EVG/c/FTC/TAF), is approved by the FDA for use in children who
weigh ≥25 kg when used without other ARV drugs8 (see Table A below). BIC is available only as
part of the FDC tablet Biktarvy, which contains BIC, FTC, and TAF (BIC/FTC/TAF). Biktarvy is
approved by the FDA9,10 for use in children or adolescents with body weight ≥14 kg to <25 kg at a
dose of BIC 30 mg/FTC 120 mg/TAF 15 mg and for children, adolescents, and adults with body
weight ≥25 kg at a dose of BIC 50 mg/FTC 200 mg/TAF 25 mg. 10,11 10,1110,11 Symtuza, an FDC tablet
that contains DRV, COBI, FTC, and TAF (DRV/c/FTC/TAF) is approved by the FDA12 for use in
children and adolescents who weigh ≥40 kg.

TAF has antiviral activity and efficacy against hepatitis B virus (HBV). Testing for HBV should be
performed prior to starting treatment with TAF. If HBV is found, rebound of clinical hepatitis could
occur when TAF is stopped. For more information about hepatitis rebound in patients with HBV/HIV
coinfection, see the Hepatitis B Virus section of the Pediatric Opportunistic Infection Guidelines.
TAF alone (as Vemlidy) is approved by the FDA for use in persons aged ≥8 years, but it is approved
only for treating HBV, not HIV.

Formulations
TAF-containing pills are smaller than their TDF-containing counterparts, a significant advantage for
some pediatric patients who may have trouble swallowing larger pills (see Appendix A, Table 2.
Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body
Weights and Considerations for Use in Children and Adolescents). EVG/c/FTC/TAF contains TAF
10 mg, whereas FTC/TAF and FTC/RPV/TAF contain TAF 25 mg. BIC/FTC/TAF is available in
two strengths: one containing TAF 15 mg for children aged ≥2 years and weighing <25 kg and the
other containing TAF 25 mg for persons weighing ≥25 kg. COBI boosts TAF blood concentrations
and tenofovir diphosphate (TFV-DP) intracellular exposure after TAF administration. Therefore, in
persons weighing ≥25 kg, administration of EVG/c/FTC/TAF, which contains TAF 10 mg and
COBI, achieves TFV-DP systemic exposure that is similar to the exposure achieved by
FTC/RPV/TAF or BIC/FTC/TAF containing TAF 25 mg but no COBI.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-41
Table A. U.S. Food and Drug Administration–Approved Tenofovir Alafenamide-
Containing Formulations

Minimum
Dose of Minimum Body Weight
Drug Contains Comment
TAF Age or Weight
Range
Vemlidy TAF 25 mg 18 years N/A Approved for HBV treatment only.

Descovy FTC/TAF 15 mg N/A ≥14 kg to <25 kg Use with an INSTI or NNRTI, but
not with a boosted PI.
FTC/TAF 25 mg N/A ≥25 kg

FTC/TAF 25 mg N/A 35 kg Use with any ARV drugs, including

a boosted PI.

Odefsey FTC/RPV/TAF 25 mg 12 years 35 kg Generally not to be used with

other ARV drugs.a

Genvoya EVG/c/FTC/TAF 10 mg N/A 25 kg TAF dose is lower due to the COBI

boosting. Generally not to be
used with other ARV drugs.a

Symtuza DRV/c/FTC/TAF 10 mg N/A 40 kg TAF dose is lower due to the COBI

boosting. Generally not to be
used with other ARV drugs.a

Biktarvy BIC/FTC/TAF 15 mg N/A ≥14 kg to <25 kg Generally not to be used with

other ARV drugs.a
BIC/FTC/TAF 25 mg N/A ≥25 kg
a Consult a specialist in HIV care before using these fixed-dose combination tablets with other ARV agents.
Key: ARV = antiretroviral; BIC = bictegravir; COBI = cobicistat; DRV/c = darunavir/cobicistat; EVG/c = elvitegravir/cobicistat;
FTC = emtricitabine; HBV = hepatitis B virus; INSTI = integrase strand transfer inhibitor; NNRTI = non-nucleoside reverse
transcriptase inhibitor; PI = protease inhibitor; RPV = rilpivirine; TAF = tenofovir alafenamide

Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate

Both TDF and TAF are prodrugs of the NRTI TFV. After oral administration, TDF is well
absorbed13,14 and is so rapidly metabolized to TFV that TDF itself cannot be measured in blood (even
when plasma is sampled within 5 minutes of administration).15 TFV is the main compound that is
measurable in plasma after TDF administration. From the bloodstream, TFV enters cells and is
phosphorylated to the active agent TFV-DP.

TAF also has good oral bioavailability.16,17 Within the enterocyte and liver, TAF is not metabolized
to TFV as quickly as TDF, so the plasma TFV concentration is much lower with administration of
TAF than with TDF, and the main component in plasma is the prodrug itself, TAF.18 Once inside the
cell, TAF is hydrolyzed to TFV,19,20 and then TFV-DP is produced by the same mechanism as for
TDF. Relative to TDF, TAF more effectively delivers TFV to cells throughout the body.16 Therefore,
a much lower dose of TAF results in intracellular concentrations of TFV-DP that are higher than the
concentrations seen after TDF administration (see Table B below). Additionally, the half-life of
TFV-DP in peripheral blood mononuclear cells is longer for TAF (2.9 days, 95% confidence
interval [CI], 1.5–5.5) than for TDF (2.1 days, 95% CI, 1.5–2.9).21

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-42
The key pharmacokinetic (PK) difference between TDF and TAF is that TDF results in higher
plasma TFV concentrations than TAF, but when administered at FDA-approved doses, both drugs
produce high, therapeutically effective intracellular TFV-DP concentrations.18,22 Because it is
intracellular TFV-DP that suppresses viral replication, TAF should have antiviral efficacy that is
equivalent to the antiviral efficacy of TDF. However, the toxicities that are specifically related to
high plasma TFV concentrations should not occur when using TAF. High plasma TFV concentration
has been linked to TDF-related endocrine disruption that is associated with low bone mineral
density (BMD).23 High plasma TFV concentration also has been closely associated with both
glomerular23-25 and proximal tubular26 renal toxicity.

Table B. Multiple-Dose Pharmacokinetics at Day 10 of Once-Daily Oral Administration in

Adults With HIV: Tenofovir Alafenamide vs. Tenofovir Disoproxil Fumarate

Parameter TAF 25 mg (n = 8) TDF 300 mg (n = 6)

Plasma TFV AUC tau (ng·h/mL) 267.7 (26.7) 1,918.0 (39.4)

Plasma TFV C max (ng/mL) 15.7 (22.1) 252.1 (36.6)

Plasma TFV C tau (ng/mL) 9.2 (26.1) 38.7 (44.7)

PBMC TFV-DP AUC tau (µM·h) 21.4 (76.9) 3.0 (119.6)

Note: The mean age of participants was 38 years, with a range of 20 to 57 years. Data presented are mean (% coefficient of
variation).
Source: Ruane PJ, DeJesus E, Berger D, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of tenofovir
alafenamide as 10-day monotherapy in HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013;63(4):449-455. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/23807155.
Key: AUC = area under the curve; AUC tau = AUC for dosing interval (i.e., 24 hours); C max = peak concentration;
C tau = concentration at the end of a dosing interval (i.e., at 24 hours, the trough concentration); PBMC = peripheral blood
mononuclear cell; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir; TFV-DP = tenofovir
diphosphate

Tenofovir Alafenamide Efficacy in Clinical Trials in Adults

In adults, TAF is noninferior to TDF in its ability to control viral load over 48 to 96 weeks when used
in combination with EVG, COBI, and FTC27-30; with FTC and RPV31; with DRV, COBI, and FTC32-
34
; and when TAF and FTC are administered in combination with other ARV drugs.35 In a switch
study of adults who were virologically suppressed on a three-drug regimen that included
abacavir (ABC), FTC/TAF was noninferior to a regimen of lamivudine plus ABC plus a third ARV
drug over 48 weeks. No differences occurred in BMD or the frequency of renal glomerular toxicities
or renal tubular toxicities between these groups, but the TAF group showed a decline in high-density
lipoprotein (HDL) cholesterol levels, whereas the ABC group had an increase in HDL cholesterol
levels36 (−2 mg/dL vs. +2 mg/dL, respectively; P = 0.0003). Viral load suppression was attained in
about 90% of study participants when TAF was given as part of the coformulated BIC/FTC/TAF.37-39

Tenofovir Alafenamide Efficacy in Clinical Trials in Adolescents and Children

The combination of EVG, COBI, FTC, and TAF has been shown to have similar efficacy when used
in adults and two groups of children: those weighing ≥35 kg and aged ≥12 years40 and those
weighing ≥25 kg and aged ≥6 years41 (see the Elvitegravir section for details). In a switch study,

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-43
treatment with BIC/FTC/TAF resulted in viral load suppression at 48 weeks in 49 of 50 (98%)
children aged 6 years to <12 years and in 50 of 50 (100%) children aged 12 years to <18 years9 (see
the Bictegravir section for details).

Pharmacokinetics
Drug Exposure and Virologic Response
Virologic suppression in people who are taking TAF or TDF is most closely related to intracellular
TFV-DP concentrations. In adults, TAF generates peripheral blood mononuclear cell TFV-DP
concentrations that are twofold22 to sevenfold higher than those generated with TDF at clinically
meaningful doses.18,21,27 Higher TFV-DP concentrations result in a stronger antiviral potency18 and a
higher barrier to resistance.42,43 Therefore, because TAF administration leads to higher intracellular
TFV-DP concentrations than TDF, TAF may be more effective against NRTI-resistant virus than
TDF. The mean TFV-DP concentration is higher in youth aged 12 to 18 years than in adults:
221.8 fmol/million cells (with a coefficient of variation [CV] of 94.4%) versus 120.8 fmol/million
cells (CV 91.4%), respectively.40

Drug Exposure and Safety: All Age Groups

FTC/TAF can be safely combined with DTG or raltegravir without concern for drug interactions.
FTC and TAF also have been safely combined with BIC in the FDC tablet Biktarvy.

When FTC/TAF, which contains TAF 25 mg, is combined with boosted ATV, DRV, or LPV, the
P-gp inhibitors COBI or RTV increase the TAF exposure to higher concentrations than those seen
with the use of EVG/c/FTC/TAF, which contains TAF 10 mg. However, the plasma TFV
concentrations seen with the use of EVG/c/FTC/TAF or TAF plus DRV/r or DRV/c are still much
lower than those seen with the use of Stribild, an FDC tablet that contains EVG, COBI, FTC, and
TDF (see Table C below).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-44
Table C. Plasma Tenofovir Alafenamide and Plasma Tenofovir Exposures When Tenofovir
Alafenamide and Tenofovir Disoproxil Fumarate Are Used With Boosted Antiretroviral
Drugs

TAF AUC Ratio TFV AUC Ratio

TAF TAF AUC of TAF-Containing TFV TFV AUC of TAF-Containing
Regimen
AUCa Regimen/TAF AUC of AUCa Regimen/TFV AUC of
Genvoya (Adult Exposure) Stribild (Adult Exposure)

Adult
Stribild (EVG/c/FTC/TDF 300 mg) N/A N/A 4,400 1.00
Genvoya (EVG/c/FTC/TAF 10 mg) 210 1.0 290 0.07
DRV/r plus TAF 25 mgb 196 0.93 259 0.06
DRV/c plus TAF 25 mg 239 1.1 935 0.21

Pediatric
Stribild (EVG/c/FTC/TDF 300 mg) N/A N/A 6,028 1.37
for ages 12–18 years
Genvoya (EVG/c/FTC/TAF 10 mg) 200 0.95 290 0.07
for ages 12–18 years
Genvoya (EVG/c/FTC/TAF 10 mg) 330 1.6 440 0.10
for ages 6–12 years
a AUC: ng·h/mL
bValues for this row do not come from observed data. These values were predicted based on data from studies that used TAF
10 mg. The AUC values predicted for TAF 25 mg were obtained by multiplying the TAF 10 mg AUC by 2.5 for both TAF and
TFV AUC.
Source: Table modified from U.S. Food and Drug Administration Summary Review of TAF and from the TAF clinical
pharmacology review using data from the Stribild product label and Genvoya product label.
Key: AUC = area under the curve; DRV/c = darunavir/cobicistat; DRV/r = darunavir/ritonavir; EVG/c = elvitegravir/cobicistat;
FTC = emtricitabine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; TFV = tenofovir

The clinical trials in adults that have shown the safety of FTC plus TAF administered with ATV/r or
DRV/r have used FTC 200 mg/TAF 10 mg, a formulation that is not available in the United States.44
The FDA states that when FTC 200 mg/TAF 25 mg is combined with boosted ATV, DRV, or LPV in
adults, “no clinically significant drug interactions have been observed or are expected.”2 The
combination of FTC 200 mg/TAF 25 mg is approved by the FDA for use in adults, independent of
the accompanying ARV drugs (which may include a boosted PI or an integrase strand transfer
inhibitor [INSTI]).2 Moreover, in Trial GS-US-299-0102 (NCT01565850) a Phase 2b trial in adults
that compared a regimen of DRV/c plus FTC/TAF 10 mg to a regimen of DRV/c plus FTC/TDF,
virologic outcomes at Week 48 were worse for participants in the TAF 10-mg arm than in the TDF
arm.45 Hence, FTC/TAF 25 mg was recommended for approval instead of FTC/TAF 10 mg.45 This is
not the case in Canada or Europe where FTC is combined with TAF 10 mg in an FDC for use in
combination with boosted PIs.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-45
Drug Exposure and Safety: Aged 12 to 18 Years and Weighing ≥35 kg
A study of FTC/TAF in 18 children and adolescents (aged 12 years to 18 years and weighing ≥35 kg)
was performed using FTC 200 mg/TAF 10 mg plus a boosted third ARV drug or FTC 200 mg/TAF
25 mg with an unboosted third ARV drug. The results of this study showed TAF exposures in
children and adolescents that were like those seen in adults. TAF was well tolerated and efficacious
during the 24 weeks of study. Asymptomatic Grade 3 or 4 elevations in amylase levels were noted in
5 of 28 participants (18%), and Grade 3 or 4 elevations in fasting low-density-lipoprotein (LDL)
levels were noted in 2 of 28 participants (7%).46

Studies of EVG/c/FTC/TAF in children aged 12 years to 18 years and weighing ≥35 kg showed that
TAF and TFV exposures were like those found in adults (see Table C above), and that the drug
combination was well tolerated and efficacious over 48 weeks of study.40 Because these TAF and
TFV exposures were similar to those seen in adults, FTC 200 mg/TAF 25 mg was also approved by
the FDA for use in this age and weight group, independent of the accompanying ARV drugs in the
regimen (which may include a boosted PI or an INSTI).2

The formulation of Biktarvy, which contains BIC 50 mg/FTC 200 mg/TAF 25 mg, was administered
to 50 children aged 6 years to <12 years and weighing ≥25 kg and 50 children and adolescents aged
12 years to <18 years and weighing ≥35 kg who had had viral loads <50 copies/mL for at least
6 months. The drug was well tolerated. All 50 participants in the study9 had viral loads
<50 copies/mL at Week 24, and 49 participants had viral loads <50 copies/mL at Week 48 (see the
Bictegravir section for details).

Drug Exposure and Safety: Aged 6 Years to <12 Years and Weighing 25 kg to
<35 kg
Studies of EVG/c/FTC/TAF in children aged 6 years to <12 years who weighed ≥25 kg showed that
TAF and TFV exposures were somewhat higher than those found in adults (see Table C above), but
the drug combination was well tolerated and efficacious over 24 weeks of study.41,47 This led to FDA
approval of EVG/c/FTC/TAF for use in children aged ≥6 years and weighing ≥25 kg.8 Follow-up to
96 weeks in a small number of participants showed no change from baseline in the median spine
BMD z-score, but there was a decline in the median total body BMD z-score, and a possible decline
in the median estimated glomerular filtration rate.48

Because INSTIs do not increase TAF concentrations, regimens that include FTC/TAF 25 mg plus an
INSTI are expected to result in safe drug exposures that are like those seen with coformulated
EVG/c/FTC/TAF 10 mg. This led the FDA to approve FTC/TAF 25 mg for use in children aged
≥6 years and weighing ≥25 kg when used in combination with other ARV drugs that do not include a
boosted PI.2

Because boosted ATV, DRV, or LPV increase TAF exposure to concentrations that are higher than
those seen with use of EVG/c/FTC/TAF, and because no data exist on the use of this combination in
children weighing <35 kg, the safety of FTC/TAF combined with COBI-boosted or RTV-boosted PIs
in children weighing between 25 kg and <35 kg cannot be assured. Therefore, FDA approval for
FTC/TAF used in combination with boosted PIs is limited to children weighing ≥35 kg (see
Table A above).2

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-46
Drug Exposure and Safety: Aged ≥2 Years and Weighing ≥14 kg to <25 kg
Biktarvy tablets consisting of BIC 30 mg/FTC 120 mg/TAF 15 mg were administered to children
aged ≥2 years weighing 14 kg to <25 kg and who had viral loads <50 copies/mL on stable ART. At
24 weeks, the median change in CD4 T lymphocyte (CD4) cell count was −100 cells/mm3, and the
change in CD4 percentage was +0.5%. HIV RNA at <50 copies/mL was maintained in 20 of the
22 participants at 24 weeks49 (see the Bictegravir section for details).

Dosing: Crushing Emtricitabine/Tenofovir Alafenamide Tablets

Viral load suppression was reported in one adult patient with HIV who received crushed FTC/TAF
tablets plus crushed DTG tablets. The crushed tablets were mixed with water and administered via a
gastrostomy tube. Each dose was followed by a can of a nutritional supplement. No PK parameters
were measured.50 In adults without HIV, the PKs of crushed DRV/c/FTC/TAF tablets showed
decreased TAF bioavailability compared to whole tablets. The clinical implications of these findings
are unclear.51 Case reports in adults with HIV who are receiving crushed BIC/FTC/TAF, a film-
coated FDC tablet, lacked PK measurements and described inconsistent virological outcomes.52
Based on an adult bioequivalence study, crushed BIC/FTC/TAF may lead to suboptimal FTC and
TAF exposures.53 Thus, crushed BIC/FTC/TAF is not recommended (see Bictegravir for details).

Toxicity
Bone
TAF causes bone toxicity less frequently than TDF.27-29,32-35,54,55 For example, in one study of
1,733 randomized adult participants with HIV, those treated with EVG/c/FTC/TAF had a smaller
decrease in BMD at the spine (mean change −1.30% vs. −2.86%; P < 0.0001) and hip (−0.66% vs.
−2.95%; P < 0.0001) at 48 weeks than those given EVG/c/FTC/TDF.27 These differences were
maintained until 96 weeks.30 The clinical importance of these changes in BMD is unclear.

Renal
Studies in adolescents aged 12 to 17 years40 and adults27-29,32,33,35 show that TAF is less frequently
associated with glomerular and renal tubular damage than TDF.56 For example, in one study of
1,733 randomized adult participants with HIV, those treated with EVG/c/FTC/TAF had a smaller
mean increase in serum creatinine (0.08 mg/dL vs. 0.12 mg/dL; P < 0.0001) than those given
EVC/c/FTC/TDF, and a smaller percent change from baseline in urine protein to creatinine ratio
(median % change −3% vs. +20%; P < 0.0001) at 48 weeks.27 These differences persisted until
96 weeks of follow-up.30 Safety of EVG/c/FTC/TAF has been demonstrated in adults with estimated
creatinine clearances between 30 mL/min and 69 mL/min.57 Postmarketing cases of renal
impairment—including acute renal failure, proximal renal tubulopathy, and Fanconi syndrome—
have been reported with TAF-containing products.2,3 TAF may require less intense renal safety
monitoring than TDF, but more experience with the drug in broad clinical practice will be needed
before a specific recommendation can be made.

Lipids
In treatment-naive adults who were evaluated after 48 weeks of therapy, initiation of
EVG/c/FTC/TAF was associated with increases in serum lipids that were greater than those observed

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-47
with the initiation of EVG/c/FTC/TDF, with a mean increase in total cholesterol levels of 31 mg/dL
versus 23 mg/dL, and a mean increase in LDL cholesterol levels of 16 mg/dL versus 4 mg/dL,
respectively. In 48 adolescents who were treated with EVG/c/FTC/TAF, the following median
changes from baseline occurred at Weeks 24 and 36: Fasting total cholesterol levels increased
26 mg/dL and 36 mg/dL, respectively; fasting direct LDL levels increased 10 mg/dL and 17 mg/dL,
respectively; and fasting triglycerides increased 14 mg/dL and 19 mg/dL, respectively.58 Similar
TAF-related increases in total cholesterol levels and LDL cholesterol levels have been found when
TAF is administered with other combinations of ARV drugs.33 Monitoring serum lipids while the
patient is taking TAF-containing FDC tablets is warranted, given these data (see Table 17b.
Dyslipidemia for details).

Weight Gain
Observational data are limited, and no randomized controlled trials have examined TAF-associated
weight gain in children. In adults, greater weight gain has been reported with the use of TAF than
with the use of TDF59-65 (see Table 17h. Lipodystrophies and Weight Gain for details). Although
weight gain at ART initiation might represent a “return to health,”63 patients initiating treatment with
TAF had larger increases in weight than those initiating treatment with TDF60,61; increases in weight
and BMI have been observed in ARV switch studies, as well.62,65,66 In adults, the effect may be
greatest in Black females,61,65 especially if administered in combination with INSTIs.61,63 A study in
adult women showed increased BMI with the switch to either an INSTI or TAF, but these BMI
increases were only seen in persons with BMI <30 kg/m2 at baseline.59

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-48
References

1. Huhn GD, Tebas P, Gallant J, et al. A randomized, open-label trial to evaluate switching to
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide plus darunavir in treatment-
experienced HIV-1-infected adults. J Acquir Immune Defic Syndr. 2017;74(2):193-200.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27753684.

2. Descovy (emtricitabine and tenofovir alafenamide) [package insert]. Food and Drug
Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208215s020lbl.pdf.

3. Vemlidy (tenofovir alafenamide) [package insert]. Food and Drug Administration. 2022.
Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/208464s014lbl.pdf

4. Begley R, Das M, Zhong L, Ling J, Kearney BP, Custodio JM. Pharmacokinetics of

tenofovir alafenamide when coadministered with other HIV antiretrovirals. J Acquir Immune
Defic Syndr. 2018;78(4):465-472. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29649076.

5. Cerrone M, Alfarisi O, Neary M, et al. Rifampicin effect on intracellular and plasma

pharmacokinetics of tenofovir alafenamide. J Antimicrob Chemother. 2019;74(6):1670-1678.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30815689.

6. Yeoh DK, Campbell AJ, Bowen AC. Increase in body mass index in children with HIV,
switched to tenofovir alafenamide fumarate or dolutegravir containing antiretroviral
regimens. Pediatr Infect Dis J. 2021;40(5):e215-e216. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33847305.

7. Odefsey (emtricitabine/rilpivirine/tenofovir alafenamide) [package insert]. Food and Drug

Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/208351s013lbl.pdf.

8. Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) [package insert]. Food

and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207561s029lbl.pdf.

9. Gaur AH, Cotton MF, Rodriguez CA, et al. Fixed-dose combination bictegravir,
emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48
results of a single-arm, open-label, multicentre, phase 2/3 trial. Lancet Child Adolesc Health.
2021;5(9):642-651. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34302760.

10. Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) [package insert]. Food and Drug

Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210251s008lbl.pdf.

11. Gaur A, Rodriguez C, McGrath EJ, et al. Bictegravir/FTC/TAF single-tablet regimen in

adolescents: week 24 results. Presented at: Conference on Retroviruses and Opportunistic
Infections; 2018. Boston, MA. Available at:

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-49
 https://www.croiconference.org/sessions/bictegravirftctaf-single-tablet-regimen-adolescents-
week-24-results.

12. Symtuza (Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) [package insert].
Food and Drug Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/210455s016lbl.pdf.

13. Barditch-Crovo P, Deeks SG, Collier A, et al. Phase i/ii trial of the pharmacokinetics, safety,
and antiretroviral activity of tenofovir disoproxil fumarate in human immunodeficiency
virus-infected adults. Antimicrob Agents Chemother. 2001;45(10):2733-2739. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11557462.

14. Tong L, Phan TK, Robinson KL, et al. Effects of human immunodeficiency virus protease
inhibitors on the intestinal absorption of tenofovir disoproxil fumarate in vitro. Antimicrob
Agents Chemother. 2007;51(10):3498-3504. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17664327.

15. Lee WA, Martin JC. Perspectives on the development of acyclic nucleotide analogs as
antiviral drugs. Antiviral Res. 2006;71(2-3):254-259. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16837073.

16. Lee WA, He GX, Eisenberg E, et al. Selective intracellular activation of a novel prodrug of
the human immunodeficiency virus reverse transcriptase inhibitor tenofovir leads to
preferential distribution and accumulation in lymphatic tissue. Antimicrob Agents
Chemother. 2005;49(5):1898-1906. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15855512.

17. Babusis D, Phan TK, Lee WA, Watkins WJ, Ray AS. Mechanism for effective lymphoid cell
and tissue loading following oral administration of nucleotide prodrug GS-7340. Mol Pharm.
2013;10(2):459-466. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22738467.

18. Ruane PJ, DeJesus E, Berger D, et al. Antiviral activity, safety, and
pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in
HIV-1-positive adults. J Acquir Immune Defic Syndr. 2013;63(4):449-455. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23807155.

19. Birkus G, Kutty N, He GX, et al. Activation of 9-[(R)-2-[[(S)-[[(S)-1-

(Isopropoxycarbonyl)ethyl]amino] phenoxyphosphinyl]-methoxy]propyl]adenine (GS-7340)
and other tenofovir phosphonoamidate prodrugs by human proteases. Mol Pharmacol.
2008;74(1):92-100. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18430788.

20. Birkus G, Wang R, Liu X, et al. Cathepsin A is the major hydrolase catalyzing the
intracellular hydrolysis of the antiretroviral nucleotide phosphonoamidate prodrugs GS-7340
and GS-9131. Antimicrob Agents Chemother. 2007;51(2):543-550. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17145787.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-50
21. Yager JL, Brooks KM, Castillo-Mancilla JR, et al. Tenofovir-diphosphate in peripheral blood
mononuclear cells during low, medium, and high adherence to F/TAF vs. F/TDF. AIDS.
2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34482350.

22. Podany AT, Bares SH, Havens J, et al. Plasma and intracellular pharmacokinetics of
tenofovir in patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide.
AIDS. 2018;32(6):761-765. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29334548.

23. Havens PL, Kiser JJ, Stephensen CB, et al. Association of higher plasma vitamin D binding
protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and
intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency?
Antimicrob Agents Chemother. 2013;57(11):5619-5628. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24002093.

24. Poizot-Martin I, Solas C, Allemand J, et al. Renal impairment in patients receiving a

tenofovir-cART regimen: impact of tenofovir trough concentration. J Acquir Immune Defic
Syndr. 2013;62(4):375-380. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23196828.

25. Baxi SM, Scherzer R, Greenblatt RM, et al. Higher tenofovir exposure is associated with
longitudinal declines in kidney function in women living with HIV. AIDS. 2016;30(4):609-
618. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26558723.

26. Rodriguez-Novoa S, Labarga P, D'Avolio A, et al. Impairment in kidney tubular function in

patients receiving tenofovir is associated with higher tenofovir plasma concentrations. AIDS.
2010;24(7):1064-1066. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20299966.

27. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate,
coformulated with elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1
infection: two randomised, double-blind, Phase 3, non-inferiority trials. Lancet.
2015;385(9987):2606-2615. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25890673.

28. Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in
single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir
Immune Defic Syndr. 2014;67(1):52-58. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24872136.

29. Mills A, Garner W, Pozniak A, et al. Patient-reported symptoms over 48 weeks in a

randomized, open-label, phase IIIb non-inferiority trial of adults with HIV switching to co-
formulated elvitegravir, cobicistat, emtricitabine, and tenofovir DF versus continuation of
non-nucleoside reverse transcriptase inhibitor with emtricitabine and tenofovir DF. Patient.
2015;8(4):359-371. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26045359.

30. Wohl D, Oka S, Clumeck N, et al. Brief report: a randomized, double-blind comparison of
tenofovir alafenamide versus tenofovir disoproxil fumarate, each coformulated with
elvitegravir, cobicistat, and emtricitabine for initial HIV-1 treatment: week 96 results. J
Acquir Immune Defic Syndr. 2016;72(1):58-64. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26829661.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-51
31. Orkin C, DeJesus E, Ramgopal M, et al. Switching from tenofovir disoproxil fumarate to
tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed
adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-
inferiority study. Lancet HIV. 2017;4(5):e195-e204. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28259777.

32. Mills A, Crofoot G, Jr., McDonald C, et al. Tenofovir alafenamide versus tenofovir
disoproxil fumarate in the first protease inhibitor-based single-tablet regimen for initial HIV-
1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2015;69(4):439-445.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25867913.

33. Eron JJ, Orkin C, Gallant J, et al. A week-48 randomized phase-3 trial of
darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.
AIDS. 2018;32(11):1431-1442. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29683855.

34. Orkin C, Molina JM, Negredo E, et al. Efficacy and safety of switching from boosted
protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-
tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults
with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority
trial. Lancet HIV. 2018;5(1):e23-e34. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28993180.

35. Gallant JE, Daar ES, Raffi F, et al. Efficacy and safety of tenofovir alafenamide versus
tenofovir disoproxil fumarate given as fixed-dose combinations containing emtricitabine as
backbones for treatment of HIV-1 infection in virologically suppressed adults: a randomised,
double-blind, active-controlled phase 3 trial. Lancet HIV. 2016;3(4):e158-165. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27036991.

36. Winston A, Post FA, DeJesus E, et al. Tenofovir alafenamide plus emtricitabine versus
abacavir plus lamivudine for treatment of virologically suppressed HIV-1-infected adults: a
randomised, double-blind, active-controlled, non-inferiority phase 3 trial. Lancet HIV.
2018;5(4):e162-e171. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29475804.

37. Sax PE, Pozniak A, Montes ML, et al. Coformulated bictegravir, emtricitabine, and tenofovir
alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for initial
treatment of HIV-1 infection (GS-US-380-1490): a randomised, double-blind, multicentre,
phase 3, non-inferiority trial. Lancet. 2017;390(10107):2073-2082. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28867499.

38. Sax PE, DeJesus E, Crofoot G, et al. Bictegravir versus dolutegravir, each with emtricitabine
and tenofovir alafenamide, for initial treatment of HIV-1 infection: a randomised, double-
blind, phase 2 trial. Lancet HIV. 2017;4(4):e154-e160. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28219610.

39. Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir alafenamide
versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-
US-380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-52
 trial. Lancet. 2017;390(10107):2063-2072. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28867497.

40. Gaur AH, Kizito H, Prasitsueubsai W, et al. Safety, efficacy, and pharmacokinetics of a
single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir
alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial.
Lancet HIV. 2016;3(12):e561-e568. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27765666.

41. Natukunda E, Gaur A, Kosalaraksa P, et al. Safety, efficacy, and pharmacokinetics of single-
tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in virologically
suppressed, HIV-infected children: a single-arm, open-label trial. Lancet Child Adolescent
Health. 2017;1(1):27-34. Available at:
https://www.sciencedirect.com/science/article/pii/S2352464217300093?via%3Dihub.

42. Margot NA, Liu Y, Miller MD, Callebaut C. High resistance barrier to tenofovir alafenamide
is driven by higher loading of tenofovir diphosphate into target cells compared to tenofovir
disoproxil fumarate. Antiviral Res. 2016;132:50-58. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27208653.

43. Margot NA, Wong P, Kulkarni R, et al. Commonly transmitted HIV-1 drug resistance
mutations in reverse-transcriptase and protease in antiretroviral treatment-naive patients and
response to regimens containing tenofovir disoproxil fumarate or tenofovir alafenamide. J
Infect Dis. 2017;215(6):920-927. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28453836.

44. Post FA, Yazdanpanah Y, Schembri G, et al. Efficacy and safety of emtricitabine/tenofovir
alafenamide (FTC/TAF) vs. emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) as a
backbone for treatment of HIV-1 infection in virologically suppressed adults: subgroup
analysis by third agent of a randomized, double-blind, active-controlled phase 3 trial. HIV
Clin Trials. 2017;18(3):135-140. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28303753.

45. Food and Drug Administration. Descovy medical review. 2015. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/208215Orig1s000MedR.pdf.

46. Chen J, Saez-Llorens X, Castano E, et al. Safety, pharmacokinetics, and efficacy of

FTC/TAF in HIV-infected adolescents (12‒18 years) abstract #843. Presented at: Conference
on Retroviruses and Opportunistic Infections 2018. Boston, MA. Available at:
https://www.croiconference.org/sessions/safety-pk-efficacy-ftctaf-hiv-infected-adolescents-
12-18-yrs.

47. Foca M. Fixed-dose combination therapy for paediatric HIV infection. The Lancet.
2017;1(1):3-4. Available at: https://www.thelancet.com/journals/lanchi/article/PIIS2352-
4642(17)30015-9/fulltext.

48. Rakhmanina N, Natukunda E, Kosalaraksa P, Batra J, Gaur A, et al. Safety and efficacy of
E/C/F/TAF in virologically suppressed, HIV-infected children through 96 weeks. Abstract

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-53
 22. Presented at: 11th International Workshop on HIV Pediatrics; 2019. Mexico City,
Mexico.

49. Natukunda E, Rodriguez C, McGrath CJ, et al. B/F/TAF in virologically suppressed

adolescents and children: two-year outcomes in 6 to <18 year olds and six-month outcomes
in toddlers. Presented at: 13th International Workshop on HIV Pediatrics 2021. Virtual
Conference.

50. Fulco PP, Higginson RT. Enhanced HIV viral load suppression with crushed combination
tablets containing tenofovir alafenamide and emtricitabine. Am J Health Syst Pharm.
2018;75(10):594-595. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29748295.

51. Brown K, Thomas D, McKenney K, et al. Impact of splitting or crushing on the relative
bioavailability of the darunavir/cobicistat/emtricitabine/tenofovir alafenamide single-tablet
regimen. Clin Pharmacol Drug Dev. 2019;8(4):541-548. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30508308.

52. Rowe SM, Clary JC, Drummond M, Derrick C, Sanasi K, Bookstaver PB. Increased viral
load in a hospitalized patient on treatment with crushed bictegravir/emtricitabine/tenofovir
alafenamide: A case report and review of the literature. Am J Health Syst Pharm.
2022;79(16):1330-1336. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35511892.

53. Hocqueloux L, Lefeuvre S, Bois J, et al. Bioavailability of dissolved and crushed single
tablets of bictegravir, emtricitabine, tenofovir alafenamide in healthy adults: the SOLUBIC
randomized crossover study. J Antimicrob Chemother. 2022;78(1):161-168. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/36322475.

54. Mills A, Arribas JR, Andrade-Villanueva J, et al. Switching from tenofovir disoproxil
fumarate to tenofovir alafenamide in antiretroviral regimens for virologically suppressed
adults with HIV-1 infection: a randomised, active-controlled, multicentre, open-label, phase
3, non-inferiority study. Lancet Infect Dis. 2016;16(1):43-52. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26538525.

55. DeJesus E, Haas B, Segal-Maurer S, et al. Superior efficacy and improved renal and bone
safety after switching from a tenofovir disoproxil fumarate- to a tenofovir alafenamide-based
regimen through 96 weeks of treatment. AIDS Res Hum Retroviruses. 2018;34(4):337-342.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29368537.

56. Gupta SK, Post FA, Arribas JR, et al. Renal safety of tenofovir alafenamide vs tenofovir
disoproxil fumarate: A pooled analysis of 26 clinical trials. AIDS. 2019;33(9):1455–1465.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30932951.

57. Pozniak A, Arribas JR, Gathe J, et al. Switching to tenofovir alafenamide, coformulated with
elvitegravir, cobicistat, and emtricitabine, in HIV-infected patients with renal impairment:
48-week results from a single-arm, multicenter, open-label phase 3 study. J Acquir Immune
Defic Syndr. 2016;71(5):530-537. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26627107.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-54
58. Tauber WB, Lewis LL. Clinical review of elvitegravir/cobicistat/emtricitabine/tenofovir
alafenamide (genvoya). 2015. Available at:
https://www.fda.gov/downloads/drugs/developmentapprovalprocess/developmentresources/u
cm478088.pdf.

59. Lahiri CD, Xu Y, Wang K, et al. Weight and body mass index change after switching to
integrase inhibitors or tenofovir alafenamide among women living with HIV. AIDS Res Hum
Retroviruses. 2021;37(6):461-467. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33231474.

60. Gomez M, Seybold U, Roider J, Harter G, Bogner JR. A retrospective analysis of weight
changes in HIV-positive patients switching from a tenofovir disoproxil fumarate (TDF)- to a
tenofovir alafenamide fumarate (TAF)-containing treatment regimen in one German
university hospital in 2015-2017. Infection. 2019;47(1):95-102. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30269210.

61. Venter WDF, Moorhouse M, Sokhela S, et al. Dolutegravir plus two different prodrugs of
tenofovir to treat HIV. N Engl J Med. 2019;381(9):803-815. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31339677.

62. Taramasso L, Berruti M, Briano F, Di Biagio A. The switch from tenofovir disoproxil
fumarate to tenofovir alafenamide determines weight gain in patients on rilpivirine-based
regimen. AIDS. 2020;34(6):877-881. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32271252.

63. Hill A, Waters L, Pozniak A. Are new antiretroviral treatments increasing the risks of clinical
obesity? J Virus Erad. 2019;5(1):41-43. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30800425.

64. Bares SH. Is modern antiretroviral therapy causing weight gain? Clin Infect Dis.
2019;71(6):1390-1392. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31608360.

65. Sax PE, Erlandson KM, Lake JE, et al. Weight gain following initiation of antiretroviral
therapy: risk factors in randomized comparative clinical trials. Clin Infect Dis. 2019.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31606734.

66. Surial B, Mugglin C, Calmy A, et al. Weight and metabolic changes after switching from
tenofovir disoproxil fumarate to tenofovir alafenamide in people living with HIV: a cohort
study. Ann Intern Med. 2021;174(6):758-767. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33721521.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-55
Tenofovir Disoproxil Fumarate (TDF, Viread)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Oral Powder: 40 mg per 1 g of oral powder (one level scoop, measured with supplied dosing scoop, equals 1 g oral powder)

Tablets: 150 mg, 200 mg, 250 mg, and 300 mg

Fixed-Dose Combination (FDC) Tablets

• [Atripla and generic] Efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg
• [Cimduo] Lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Complera] Emtricitabine 200 mg/rilpivirine 25 mg/tenofovir disoproxil fumarate 300 mg
• [Delstrigo] Doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Stribild] Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg
• [Symfi] Efavirenz 600 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Symfi Lo] Efavirenz 400 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Temixys] Lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Truvada tablet]
o Emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg
o Emtricitabine 167 mg/tenofovir disoproxil fumarate 250 mg
o Emtricitabine 133 mg/tenofovir disoproxil fumarate 200 mg
o Emtricitabine 100 mg/tenofovir disoproxil fumarate 150 mg

When using FDC tablets, refer to other sections of Appendix A: Pediatric Antiretroviral Drug Information for information about
the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and
Co-packaged Formulations: Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Neonate and Infant Dose • Asthenia, headache, diarrhea, nausea, vomiting, flatulence
• Tenofovir disoproxil fumarate (TDF) has not been • Glomerular and proximal renal tubular dysfunction
approved by the U.S. Food and Drug Administration
(FDA) or recommended for use in neonates or infants • Decreased bone mineral densitya
aged <2 years.

Child (Aged ≥2 Years to <12 Years) and Weighing

≥10 kg Dosea
• TDF 8 mg/kg per dose once daily

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-56
 TDF Oral Powder Dosing Table
Special Instructions
TDF Oral Powder • TDF oral powder formulation is available for patients who are
Body Weight
Once-Daily Scoops of Powder unable to swallow tablets.
10 kg to <12 kg 2 scoops (80 mg)
• TDF oral powder should be measured only with the supplied
12 kg to <14 kg 2.5 scoops (100 mg) dosing scoop: one level scoop = 1 g powder = TDF 40 mg.
14 kg to <17 kg 3 scoops (120 mg) • Mix TDF oral powder with 2–4 oz of soft food that does not
require chewing (e.g., applesauce, yogurt). Administer
17 kg to <19 kg 3.5 scoops (140 mg) immediately after mixing to avoid the bitter taste.
19 kg to <22 kg 4 scoops (160 mg) • Do not try to mix the TDF oral powder with liquid. The
22 kg to <24 kg 4.5 scoops (180 mg) powder may float on the top even after vigorous stirring.
24 kg to <27 kg 5 scoops (200 mg) • Although TDF can be administered without food, food
requirements vary depending on the other ARV drugs
27 kg to <29 kg 5.5 scoops (220 mg) contained in an FDC tablet. Food requirements are listed
29 kg to <32 kg 6 scoops (240 mg) with dosing recommendations and in Appendix A, Table 2.
Antiretroviral Fixed-Dose Combination Tablets and
32 kg to <34 kg 6.5 scoops (260 mg) Co-packaged Formulations: Minimum Body Weights and
34 kg to <35 kg 7 scoops (280 mg) Considerations for Use in Children and Adolescents.

≥35 kg 7.5 scoops (300 mg) • Measure serum creatinine and perform a urine dipstick test
for protein and glucose before starting a TDF-containing
regimen. Serum creatinine should be monitored, and urine
0

TDF Tablet Dosing Table should be tested for protein and glucose at intervals during
continued therapy (see Table 15i. Nephrotoxic Effects).
TDF Tablet Measure serum phosphate if there is clinical suspicion of
Body Weight hypophosphatemia.
Once Daily
17 kg to <22 kg 150 mg • Screen patients for hepatitis B virus (HBV) infection before
using TDF. Severe acute exacerbation of HBV infection can
22 kg to <28 kg 200 mg occur when TDF is discontinued; therefore, hepatic function
28 kg to <35 kg 250 mg should be monitored for several months after patients with
HBV infection stop taking TDF.
≥35 kg 300 mg
• Tenofovir alafenamide (TAF) is associated with less bone
Child and Adolescent (Weighing ≥35 kg)a and Adult and renal toxicity than TDF, but it has equal antiviral efficacy.
Dose Do not use TAF and TDF together. Consider switching
from TDF to TAF in appropriate clinical settings.
• TDF 300 mg once daily

[Atripla and Generic] Efavirenz/Emtricitabine/TDF

Child and Adolescent (Weighing ≥40 kg) and Adult Dose
• One tablet once daily
• Take on an empty stomach.

[Cimduo] Lamivudine/TDF
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• One tablet once daily

[Complera] Emtricitabine/Rilpivirine/TDF

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-57
 Child and Adolescent (Aged ≥12 Years and Weighing
≥35 kg) and Adult Dose Metabolism/Elimination
• One tablet once daily in antiretroviral therapy (ART)– TDF Dosing in Patients with Hepatic Impairment
naive adults with baseline HIV RNA • No change in TDF dosing is required for patients with hepatic
≤100,000 copies/mL. This dose of Complera also can impairment.
be used in virologically suppressed (HIV RNA
<50 copies/mL) adults who are currently on their first or • Stribild should not be used in patients with severe hepatic
second regimen and who have no history of virologic impairment.
failure or resistance to rilpivirine and other antiretroviral • Atripla, Symfi, and Symfi Lo should be used with caution in
(ARV) drugs. patients with hepatic impairment; Symfi and Symfi Lo are not
• Administer with a meal of ≥500 calories. recommended for use in moderate or severe hepatic
impairment.
[Delstrigo] Doravirine/Lamivudine/TDF
TDF Dosing in Patients with Renal Insufficiency
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• The tenofovir metabolite of TDF is renally excreted.
• One tablet once daily in ART-naive patients and
ARV-experienced patients who have been virologically • The dose of TDF should be decreased in patients with
suppressed (HIV RNA <50 copies/mL) on a stable ARV impaired renal function (creatinine clearance [CrCl]
regimen, with no history of treatment failure, and no <50 mL/min). Consult the manufacturer’s prescribing
known mutations associated with resistance to the information for directions on how to adjust the dose in
individual components of Delstrigo accordance with CrCl.

[Stribild] Elvitegravir/Cobicistat/Emtricitabine/TDF • The FDCs Atripla, Cimduo, Complera, Delstrigo, Symfi,

Symfi Lo, or Temixys should not be used in patients with
Adolescent (Weighing >35 kg with a Sexual Maturity CrCl <50 mL/min or in patients who require dialysis.
Rating [SMR] of 4 or 5) and Adult Dose
• The FDC Truvada should not be used in patients with CrCl
• One tablet once daily in ART-naive adults. This dose of <30 mL/min or in patients who require dialysis.
Stribild also can be used to replace the current ARV
regimen in patients who have been virologically • The FDC Stribild should not be initiated in patients with
suppressed (HIV RNA <50 copies/mL) on a stable ARV estimated CrCl <70 mL/min and should be discontinued in
regimen, with no history of treatment failure, and no patients with estimated CrCl <50 mL/min.
known mutations associated with resistance to the
individual components of Stribild.
• Administer with food.

[Symfi] Efavirenz 600 mg/Lamivudine/TDF

Child and Adolescent (Weighing ≥40 kg) and Adult Dose
• One tablet once daily
• Take on an empty stomach.

[Symfi Lo] Efavirenz 400 mg/Lamivudine/TDF

Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• One tablet once daily
• Take on an empty stomach.
• Symfi Lo has not been studied in children (SMR 1–3),
and major inter-individual variability in efavirenz (EFV)
plasma concentrations has been found in pediatric
patients in a multi-ethnic setting. The 400-mg dose of
EFV may be too low in children or adolescents with
SMRs of 1–3 who weigh ≥40 kg. Some members of the

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-58
 Panel on Antiretroviral Therapy and Medical
Management of Children Living With HIV suggest
therapeutic drug monitoring when Symfi Lo is used in
pediatric patients weighing ≥40 kg. See the Efavirenz
section for more information.

[Temixys] Lamivudine/TDF
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• One tablet once daily

[Truvada] Emtricitabine/TDF (FTC/TDF)

Child, Adolescent, and Adult Dose
Truvada Dosing Table

FTC/TDF Tablet
Body Weight
Once Daily
17 kg to <22 kg One FTC 100 mg/
TDF 150 mg tablet

22 kg to <28 kg One FTC 133 mg/

TDF 200 mg tablet

28 kg to <35 kg One FTC 167 mg/

TDF 250 mg tablet

≥35 kg and adults One FTC 200 mg/

TDF 300 mg tablet

aSee the text for a discussion of the concerns about decreased bone mineral density in patients who are receiving TDF,
especially in prepubertal patients and those in early puberty (SMR 1 or 2).

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Tenofovir disoproxil fumarate (TDF) is a substrate of the adenosine triphosphate–

dependent transporters P-glycoprotein and breast cancer resistance protein. When TDF is
coadministered with inhibitors of these transporters, an increase in TDF absorption may be
observed, with the potential for enhanced TDF toxicity.1
• Renal elimination: Drugs that decrease renal function or compete for active tubular secretion
could reduce clearance of plasma tenofovir (TFV). Avoid frequent or long-term use of
nonsteroidal anti-inflammatory drugs in patients who are taking TDF.
• Other nucleoside reverse transcriptase inhibitors: Didanosine (ddI) serum concentrations
increase when this drug is coadministered with TDF, and this combination should not be used
because of the increased risk of ddI toxicity.
• Protease inhibitors (PIs): Atazanavir (ATV) without ritonavir (RTV) should not be
coadministered with TDF, because TDF decreases ATV plasma concentrations. The

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-59
 combination of ATV/r, darunavir (DRV)/r, and lopinavir/r increases plasma TFV concentrations
and increases the risk of TDF-associated toxicity.1,2
• Absorption: Administering elvitegravir (EVG) concurrently with antacids and supplements that
contain iron, calcium, aluminum, and/or magnesium lowers plasma concentrations of EVG. If
using Stribild, see the Elvitegravir section of Appendix A: Pediatric Antiretroviral Drug
Information for additional information.

Major Toxicities
• More common: Nausea, diarrhea, vomiting, flatulence
• Less common (more severe): TDF caused bone toxicity (osteomalacia and reduced bone mineral
density [BMD]) in animals when given in high doses. Decreases in BMD have been reported in
both adults and children taking TDF. Renal toxicity—including increased serum creatinine,
glycosuria, proteinuria, phosphaturia, and/or calciuria and decreased serum phosphate—has been
observed. Patients at increased risk of renal glomerular or tubular dysfunction should be closely
monitored. Cases of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported.

Resistance
The International Antiviral Society–USA maintains a list of updated HIV drug resistance mutations,
and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
TDF has been approved by the U.S. Food and Drug Administration (FDA) for use in children aged
≥2 years and weighing ≥10 kg when used as a component of antiretroviral therapy (ART). TDF is
available as a component of fixed-dose combination tablets (see Appendix A, Table 2. Antiretroviral
Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and
Considerations for Use in Children and Adolescents).

TDF has antiviral activity and efficacy against hepatitis B virus (HBV) and is approved by the FDA
for HBV treatment in children aged ≥2 years and weighing ≥10 kg. For a comprehensive review of
this topic, see the Hepatitis B Virus section in the Pediatric Opportunistic Infection Guidelines.

Efficacy in Clinical Trials in Adults Compared With Children and Adolescents

The standard adult dose that was approved by the FDA for adults and children aged ≥12 years and
weighing ≥35 kg is TDF 300 mg once daily. For children aged 2 to 12 years, the FDA-approved dose
is TDF 8 mg/kg per dose administered once daily, which closely approximates the dose of TDF
208 mg/m2 per dose used in early studies in children.3

In adults, the recommended once-daily dose of TDF 300 mg is highly effective when used in
combination with other antiretroviral (ARV) drugs.4-11 The FDA approved Cimduo and Temixys
(both of which contain lamivudine [3TC] 300 mg/TDF 300 mg) and Symfi (efavirenz [EFV]
600 mg/3TC 300 mg/TDF 300 mg) based on results of prior clinical trials.5,12 FDA approval of

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-60
Symfi Lo (EFV 400 mg/3TC 300 mg/TDF 300 mg) was based on a study that compared the use of
EFV 400 mg with the use of EFV 600 mg, each administered with emtricitabine 200 mg and TDF
300 mg, in 630 ART-naive adults.13 See the Efavirenz section for a detailed discussion of this study.
In a large randomized controlled trial comparing second-line ART regimens, continuing TDF was
superior to switching to zidovudine, when given in combination with 3TC and either dolutegravir or
DRV/r.14,15

In children, the published efficacy data for TDF-containing ARV combinations are mixed, but
potency equal to that in adults has been seen in pediatric patients aged 3 to 18 years with susceptible
virus. In children aged 2 years to <12 years, TDF 8 mg/kg per dose once daily was noninferior to
twice-daily zidovudine-containing ART or stavudine-containing ART over 48 weeks of randomized
treatment.16,17 Virologic success is lower in treatment-experienced patients with extensive multiclass
drug resistance.18-20

Pharmacokinetics
Relationship of Drug Exposure to Virologic Response
Virologic suppression is most closely related to intracellular tenofovir diphosphate (TFV-DP)
concentrations and, for TDF, intracellular TFV-DP is linked to plasma TFV concentration.21 A
modeling study suggests that children and adolescents who are treated with TDF may have higher
intracellular TFV-DP concentrations than adults,22 even though plasma TFV concentrations are lower
in children and adolescents, because weight-adjusted renal clearance of TFV is higher in children
than in adults.3,23,24

Formulations
Special Considerations
The taste-masked granules that make up the TDF oral powder give the vehicle (e.g., applesauce,
yogurt) a gritty consistency. Once mixed with a vehicle, TDF should be administered promptly
because its taste becomes bitter when it is allowed to sit for too long.

Toxicity
Bone Toxicity
TDF administration is associated with decreased BMD in both adults25,26 and children.17,27-29
When treated with TDF, younger children with sexual maturity ratings (SMRs) of 1 and 2 may be
at a higher risk of decreased BMD than children with more advanced pubertal development
(i.e., SMRs ≥3).23 Discontinuation of TDF results in partial or complete recovery of BMD.27,30

In the study that led to FDA approval of TDF in adolescents aged ≥12 years and weighing ≥35 kg,
6 of 33 participants (18%) in the TDF arm experienced a >4% decline in absolute lumbar spine BMD
in 48 weeks, whereas only 1 of 33 participants (3%) in the placebo arm experienced this decline.18

TDF administration disrupts vitamin D metabolism,31,32 and the decrease in BMD associated with
TDF initiation was attenuated in adults with coadministration of high doses of vitamin D3
(4,000 International Units [IU] daily) and calcium carbonate (1,000 mg daily) for the first 48 weeks

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-61
of TDF treatment.33 During chronic TDF administration, youth with HIV who received vitamin D3
supplements (50,000 IU once monthly) had decreased serum parathyroid hormone levels and
increased lumbar spine BMD compared with study participants who were not treated with high doses
of vitamin D3.31,34 The serum 25-hydroxy vitamin D concentration was 37 ng/mL in the group with
improved BMD. Similar improvements in BMD were seen in youth with HIV who were treated with
an ARV regimen that included TDF and who received vitamin D3 2,000 IU or 4,000 IU daily.35
Measurement of plasma vitamin D concentration is recommended for patients who are being treated
with an ARV regimen that includes TDF, and vitamin D supplementation is recommended for those
with vitamin D deficiency (see Table 17j. Osteopenia and Osteoporosis).

High concentrations of the TDF metabolite plasma TFV have been associated with TDF-related
endocrine disruption and low BMD.36 Plasma TFV concentrations are higher when TDF is
coadministered with boosted PIs.1 Tenofovir alafenamide (TAF), which is associated with lower
plasma TFV concentrations than TDF, has less effect on parathyroid hormone levels37 and causes
less decline in BMD than TDF. See the Tenofovir Alafenamide section for more information.
Consider switching from TDF to TAF or avoiding coadministration of TDF with boosted PIs in
patients for whom loss of BMD is a concern.

Monitoring Potential Bone Toxicity

The Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV (the
Panel) does not recommend routine dual-energy X-ray absorptiometry (DXA) monitoring for
children or adolescents who are being treated with TDF (see Table 17j. Osteopenia and
Osteoporosis).

TDF has been shown to be effective, and it can be administered once daily; however, the use of
TDF has been associated with a risk of BMD loss. Because childhood and early adolescence are
important periods of rapid bone accrual, and because children with perinatally acquired HIV are at
risk for low peak bone mass,38,39 the Panel favors the use of abacavir or TAF over TDF in children
with SMRs 1 to 3.

Renal Toxicity
New-onset renal impairment and worsening renal impairment have been reported in adults40 and
children41,42 receiving TDF. In one study, renal toxicity led to discontinuation of TDF in 6 of
159 (3.7%) children with HIV who were treated with TDF.20 Although TDF is clearly associated
with a decline in glomerular filtration rate, the effect is generally small, and severe glomerular
toxicity is rare.40,41 Irreversible renal failure is quite rare, but cases have been reported.43

The main target of TDF nephrotoxicity is the renal proximal tubule.41 Case reports highlight the
infrequent but most severe manifestations of renal Fanconi syndrome, hypophosphatemia,
hypocalcemia, diabetes insipidus, myalgias, bone pain, and fractures.44,45

Subclinical renal tubular damage is more common than clinically apparent renal tubular injury.
Increased urinary beta-2 microglobulin was identified in 12 of 44 children (27%) who were treated
with TDF and in 2 of 48 children (4%) who were not treated with TDF.46 The risks of TDF-
associated proteinuria and chronic kidney disease increase with the duration of treatment.47,48 Of
89 participants aged 2 to 12 years who received TDF in Gilead Study 352 (where participants had a
median drug exposure of 104 weeks), four participants were discontinued from the study for renal

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-62
tubular dysfunction, with the discontinuations occurring between 84 and 156 weeks on TDF
therapy.16 In adults, renal dysfunction is more common when TDF is used in patients with older age
or a pre-existing renal disease49; in children, renal dysfunction may be more common when TDF is
used with boosted PIs than with non-nucleoside reverse transcriptase inhibitors.50

Plasma TFV is the TDF metabolite most closely associated with both glomerular36,51 and proximal
tubular52 toxicity. As previously noted, plasma TFV concentrations are higher when TDF is
coadministered with boosted PIs.1 TAF, which generates lower plasma TFV concentrations than
TDF, is associated with a lower risk of renal toxicity than TDF53 (see Tenofovir Alafenamide).

Monitoring Potential Renal Toxicity

Because TDF has the potential to decrease creatinine clearance and cause renal tubular dysfunction,
the Panel recommends measuring serum creatinine and using a urine dipstick to check protein and
glucose concentration before initiating TDF. It is unclear how often creatinine and renal tubular
function (urine protein and glucose) should be monitored in asymptomatic patients. Many Panel
members monitor creatinine with other blood tests every 3 to 4 months and perform urinalysis every
6 to 12 months. Serum phosphate should be measured if clinically indicated; renal phosphate loss can
occur in the presence of normal creatinine and in the absence of proteinuria. Because nephrotoxicity
increases with the duration of TDF treatment, monitoring should be continued during long-term
therapy with the drug.

Because renal glomerular damage primarily increases the concentration of albumin in urine, and
proximal renal tubular damage increases the concentration of low-molecular-weight proteins like
beta-2 microglobulin in urine, dipstick urinalysis (which primarily measures urine albumin) may be a
relatively insensitive marker for TDF-associated tubular damage. Measuring urine albumin and urine
protein and calculating the ratio of urine albumin to urine protein can be helpful in identifying the
non-albumin proteinuria that is seen in TDF-associated nephrotoxicity.54,55 Although these more
complex and expensive tests may be used in research settings, in clinical practice, using a renal
dipstick to identify normoglycemic glycosuria and proteinuria is the easiest way to detect renal
damage.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-63
References

1. Viread (tenofovir disoproxil fumarate) [package insert]. Food and Drug Administration.
2019. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/021356s058,022577s014lbl.
pdf.

2. Bedimo R, Rosenblatt L, Myers J. Systematic review of renal and bone safety of the
antiretroviral regimen efavirenz, emtricitabine, and tenofovir disoproxil fumarate in
patients with HIV infection. HIV Clin Trials. 2016;17(6):246-266. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27809711.

3. Hazra R, Balis FM, Tullio AN, et al. Single-dose and steady-state pharmacokinetics of
tenofovir disoproxil fumarate in human immunodeficiency virus-infected children.
Antimicrob Agents Chemother. 2004;48(1):124-129. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/14693529.

4. Arribas JR, Pozniak AL, Gallant JE, et al. Tenofovir disoproxil fumarate, emtricitabine,
and efavirenz compared with zidovudine/lamivudine and efavirenz in treatment-naive
patients: 144-week analysis. J Acquir Immune Defic Syndr. 2008;47(1):74-78. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/17971715.

5. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs
stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized
trial. JAMA. 2004;292(2):191-201. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15249568.

6. Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs.
zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006;354(3):251-260.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/16421366.

7. Sax PE, Tierney C, Collier AC, et al. Abacavir-lamivudine versus tenofovir-emtricitabine

for initial HIV-1 therapy. N Engl J Med. 2009;361(23):2230-2240. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19952143.

8. Sax PE, Tierney C, Collier AC, et al. Abacavir/lamivudine versus tenofovir

TDF/emtricitabine as part of combination regimens for initial treatment of HIV: final
results. J Infect Dis. 2011;204(8):1191-1201. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21917892.

9. Smith KY, Patel P, Fine D, et al. Randomized, double-blind, placebo-matched,

multicenter trial of abacavir/lamivudine or tenofovir/emtricitabine with
lopinavir/ritonavir for initial HIV treatment. AIDS. 2009;23(12):1547-1556. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19542866.

10. Post FA, Moyle GJ, Stellbrink HJ, et al. Randomized comparison of renal effects,
efficacy, and safety with once-daily abacavir/lamivudine versus tenofovir/emtricitabine,
administered with efavirenz, in antiretroviral-naive, HIV-1-infected adults: 48-week

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-64
 results from the ASSERT study. J Acquir Immune Defic Syndr. 2010;55(1):49-57.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20431394.

11. Spaulding A, Rutherford GW, Siegfried N. Tenofovir or zidovudine in three-drug

combination therapy with one nucleoside reverse transcriptase inhibitor and one non-
nucleoside reverse transcriptase inhibitor for initial treatment of HIV infection in
antiretroviral-naive individuals. Cochrane Database Syst Rev. 2010(10):CD008740.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20927777.

12. Margot NA, Lu B, Cheng A, Miller MD, Study 903 Team. Resistance development over
144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or
stavudine with lamivudine and efavirenz in Study 903. HIV Med. 2006;7(7):442-450.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/16925730.

13. ENCORE1 Study Group, Carey D, Puls R, et al. Efficacy and safety of efavirenz 400 mg
daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-
controlled, non-inferiority ENCORE1 study. Lancet Infect Dis. 2015;15(7):793-802.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25877963.

14. Paton NI, Musaazi J, Kityo C, et al. Efficacy and safety of dolutegravir or darunavir in
combination with lamivudine plus either zidovudine or tenofovir for second-line
treatment of HIV infection (NADIA): week 96 results from a prospective, multicentre,
open-label, factorial, randomised, non-inferiority trial. Lancet HIV. 2022;9(6):e381-e393.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/35460601.

15. Paton NI, Musaazi J, Kityo C, et al. Dolutegravir or darunavir in combination with
zidovudine or tenofovir to treat HIV. N Engl J Med. 2021;385(4):330-341. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34289276.

16. Saez-Llorens X, Castaño E, Rathore M, et al. A randomized, open-label study of the

safety and efficacy of switching stavudine or zidovudine to tenofovir disoproxil fumarate
in HIV-1-infected children with virologic suppression. Pediatr Infect Dis J.
2015;34(4):376-382. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25760565.

17. Aurpibul L, Cressey TR, Sricharoenchai S, et al. Efficacy, safety and pharmacokinetics
of tenofovir disoproxil fumarate in virologic-suppressed HIV-infected children using
weight-band dosing. Pediatr Infect Dis J. 2015;34(4):392-397. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25760566.

18. Della Negra M, de Carvalho AP, de Aquino MZ, et al. A randomized study of tenofovir
disoproxil fumarate in treatment-experienced HIV-1 infected adolescents. Pediatr Infect
Dis J. 2012;31(5):469-473. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22301477.

19. Della Negra M, De Carvalho AP, De Aquino MZ, et al. Long-term efficacy and safety of
tenofovir disoproxil fumarate in HIV-1-infected adolescents failing antiretroviral therapy:
the final results of study GS-US-104-0321. Pediatr Infect Dis J. 2015;34(4):398-405.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25599284.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-65
20. Riordan A, Judd A, Boyd K, et al. Tenofovir use in human immunodeficiency virus-1-
infected children in the United Kingdom and Ireland. Pediatr Infect Dis J.
2009;28(3):204-209. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19209091.

21. Baheti G, Kiser JJ, Havens PL, Fletcher CV. Plasma and intracellular population
pharmacokinetic analysis of tenofovir in HIV-1-infected patients. Antimicrob Agents
Chemother. 2011;55(11):5294-5299. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21896913.

22. Baheti G, King JR, Acosta EP, Fletcher CV. Age-related differences in plasma and
intracellular tenofovir concentrations in HIV-1-infected children, adolescents and adults.
AIDS. 2013;27(2):221-225. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23032419.

23. Hazra R, Gafni RI, Maldarelli F, et al. Tenofovir disoproxil fumarate and an optimized
background regimen of antiretroviral agents as salvage therapy for pediatric HIV
infection. Pediatrics. 2005;116(6):e846-854. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16291735.

24. Kiser JJ, Fletcher CV, Flynn PM, et al. Pharmacokinetics of antiretroviral regimens
containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and
young adults with human immunodeficiency virus infection. Antimicrob Agents
Chemother. 2008;52(2):631-637. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18025112.

25. Stellbrink HJ, Orkin C, Arribas JR, et al. Comparison of changes in bone density and
turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV-infected adults:
48-week results from the ASSERT study. Clin Infect Dis. 2010;51(8):963-972. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/20828304.

26. McComsey GA, Kitch D, Daar ES, et al. Bone mineral density and fractures in
antiretroviral-naive persons randomized to receive abacavir-lamivudine or tenofovir
disoproxil fumarate-emtricitabine along with efavirenz or atazanavir-ritonavir: AIDS
clinical trials group A5224s, a substudy of ACTG A5202. J Infect Dis.
2011;203(12):1791-1801. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21606537.

27. Gafni RI, Hazra R, Reynolds JC, et al. Tenofovir disoproxil fumarate and an optimized
background regimen of antiretroviral agents as salvage therapy: impact on bone mineral
density in HIV-infected children. Pediatrics. 2006;118(3):e711-e718. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16923923.

28. Purdy JB, Gafni RI, Reynolds JC, Zeichner S, Hazra R. Decreased bone mineral density
with off-label use of tenofovir in children and adolescents infected with human
immunodeficiency virus. J Pediatr. 2008;152(4):582-584. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18346519.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-66
29. Aurpibul L, Puthanakit T. Review of tenofovir use in HIV-infected children. Pediatr
Infect Dis J. 2015;34(4):383-391. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25247583.

30. Havens PL, Perumean-Chaney SE, Patki A, et al. Changes in bone mass after
discontinuation of pre-exposure prophylaxis (PrEP) with tenofovir disoproxil
fumarate/emtricitabine in young men who have sex with men: extension phase results of
adolescent trials network protocols 110 and 113. Clin Infect Dis. 2020;70(4):687–691.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31179503.

31. Havens PL, Stephensen CB, Van Loan MD, et al. Vitamin D3 supplementation increases
spine bone mineral density in adolescents and young adults with human
immunodeficiency virus infection being treated with tenofovir disoproxil fumarate: a
randomized, placebo-controlled trial. Clin Infect Dis. 2018;66(2):220-228. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29020329.

32. Havens PL, Long D, Schuster GU, et al. Tenofovir disoproxil fumarate appears to disrupt
the relationship of vitamin D and parathyroid hormone. Antivir Ther. 2018;23(7):623-
628. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30260797.

33. Overton ET, Chan ES, Brown TT, et al. Vitamin D and calcium attenuate bone loss with
antiretroviral therapy initiation: a randomized trial. Ann Intern Med. 2015;162(12):815-
824. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26075752.

34. Havens PL, Stephensen CB, Hazra R, et al. Vitamin D3 decreases parathyroid hormone
in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled
trial. Clin Infect Dis. 2012;54(7):1013-1025. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22267714.

35. Eckard AR, O’Riordan MA, Rosebush JC, et al. Effects of vitamin D supplementation on
bone mineral density and bone markers in HIV-infected youth. J Acquir Immune Defic
Syndr. 2017;76(5):539-546. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28902705.

36. Havens PL, Kiser JJ, Stephensen CB, et al. Association of higher plasma vitamin D
binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and
plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D
deficiency? Antimicrob Agents Chemother. 2013;57(11):5619-5628. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24002093.

37. Van Welzen BJ, Thielen MAJ, Mudrikova T, Arends JE, Hoepelman AIM. Switching
tenofovir disoproxil fumarate to tenofovir alafenamide results in a significant decline in
parathyroid hormone levels: uncovering the mechanism of tenofovir disoproxil fumarate-
related bone loss? AIDS. 2019;33(9):1531-1534. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31021851.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-67
38. DiMeglio LA, Wang J, Siberry GK, et al. Bone mineral density in children and
adolescents with perinatal HIV infection. AIDS. 2013;27(2):211-220. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23032412.

39. Yin MT, Lund E, Shah J, et al. Lower peak bone mass and abnormal trabecular and
cortical microarchitecture in young men infected with HIV early in life. AIDS.
2014;28(3):345-353. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24072196.

40. Cooper RD, Wiebe N, Smith N, Keiser P, Naicker S, Tonelli M. Systematic review and
meta-analysis: renal safety of tenofovir disoproxil fumarate in HIV-infected patients. Clin
Infect Dis. 2010;51(5):496-505. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20673002.

41. Hall AM. Update on tenofovir toxicity in the kidney. Pediatr Nephrol. 2013;28(7):1011-
1023. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22878694.

42. Andiman WA, Chernoff MC, Mitchell C, et al. Incidence of persistent renal dysfunction
in human immunodeficiency virus-infected children: associations with the use of
antiretrovirals, and other nephrotoxic medications and risk factors. Pediatr Infect Dis J.
2009;28(7):619-625. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19561425.

43. Wood SM, Shah SS, Steenhoff AP, Meyers KE, Kaplan BS, Rutstein RM. Tenofovir-
associated nephrotoxicity in two HIV-infected adolescent males. AIDS Patient Care
STDS. 2009;23(1):1-4. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19183077.

44. Hussain S, Khayat A, Tolaymat A, Rathore MH. Nephrotoxicity in a child with perinatal
HIV on tenofovir, didanosine and lopinavir/ritonavir. Pediatr Nephrol. 2006;21(7):1034-
1036. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16773419.

45. Lucey JM, Hsu P, Ziegler JB. Tenofovir-related Fanconi’s syndrome and osteomalacia in
a teenager with HIV. BMJ Case Rep. 2013;2013. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23843401.

46. Papaleo A, Warszawski J, Salomon R, et al. Increased beta-2 microglobulinuria in human

immunodeficiency virus-1-infected children and adolescents treated with tenofovir.
Pediatr Infect Dis J. 2007;26(10):949-951. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17901802.

47. Soler-Palacín P, Melendo S, Noguera-Julian A, et al. Prospective study of renal function

in HIV-infected pediatric patients receiving tenofovir-containing HAART regimens.
AIDS. 2011;25(2):171-176. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21076275.

48. Purswani M, Patel K, Kopp JB, et al. Tenofovir treatment duration predicts proteinuria in
a multiethnic United States cohort of children and adolescents with perinatal HIV-1
infection. Pediatr Infect Dis J. 2013;32(5):495-500. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23249917.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-68
49. Mocroft A, Lundgren JD, Ross M, et al. Development and validation of a risk score for
chronic kidney disease in HIV infection using prospective cohort data from the D:A:D
study. PLoS Med. 2015;12(3):e1001809. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25826420.

50. Mashingaidze-Mano R, Bwakura-Dangarembizi MF, Maponga CC, et al. Proximal renal

tubular function in HIV-infected children on tenofovir disoproxil fumarate for treatment
of HIV infection at two tertiary hospitals in Harare, Zimbabwe. PLoS One.
2020;15(7):e0235759. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32634168.

51. Poizot-Martin I, Solas C, Allemand J, et al. Renal impairment in patients receiving a

tenofovir-cART regimen: impact of tenofovir trough concentration. J Acquir Immune
Defic Syndr. 2013;62(4):375-380. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23196828.

52. Rodríguez-Nóvoa S, Labarga P, D’Avolio A, et al. Impairment in kidney tubular function

in patients receiving tenofovir is associated with higher tenofovir plasma concentrations.
AIDS. 2010;24(7):1064-1066. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20299966.

53. Gupta SK, Post FA, Arribas JR, et al. Renal safety of tenofovir alafenamide vs. tenofovir
disoproxil fumarate: a pooled analysis of 26 clinical trials. AIDS. 2019;33(9):1455–1465.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/30932951.

54. Sise ME, Hirsch JS, Canetta PA, Herlitz L, Mohan S. Nonalbumin proteinuria
predominates in biopsy-proven tenofovir nephrotoxicity. AIDS. 2015;29(8):941-946.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25784440.

55. Samarawickrama A, Cai M, Smith ER, et al. Simultaneous measurement of urinary

albumin and total protein may facilitate decision-making in HIV-infected patients with
proteinuria. HIV Med. 2012;13(9):526-532. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22413854.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-69
Zidovudine (ZDV, Retrovir)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Syrup: 10 mg/mL

Capsule: 100 mg

Concentrate for Injection or Intravenous Infusion: 10 mg/mL (Retrovir)

Generic Formulations
• 100-mg capsule
• 10-mg/mL syrup
• 300-mg tablet

Fixed-Dose Combination (FDC) Tablets

• [Combivir and generic] Lamivudine 150 mg/zidovudine 300 mg (scored)
• [Trizivir and generic] Abacavir 300 mg/lamivudine 150 mg/zidovudine 300 mg

When using FDC tablets, refer to other sections of the Drug Appendix for information about the individual components of
the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum Body Weights and
Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Note: Zidovudine (ZDV) is frequently used in neonates to prevent • Bone marrow suppression leading to anemia and
perinatal transmission of HIV. See Antiretroviral Management of neutropenia, macrocytosis with or without anemia
Newborns with Perinatal HIV Exposure or HIV Infection and Table 12
for information about using ZDV to prevent perinatal transmission. • Nausea, vomiting, headache, insomnia, asthenia
• Lactic acidosis/severe hepatomegaly with hepatic
Recommended Neonatal Dose for Treatment of HIV by steatosis
Gestational Age at Birtha
• Lipodystrophy and lipoatrophy
Gestational • Myopathy (associated with prolonged use of
Oral ZDV Dose
Age at Birth ZDV) and myositis
≥35 weeks Birth to Age 4 Weeks
Special Instructions
• ZDV 4 mg/kg twice daily; or
• Give ZDV without regard to food.
• Alternative simplified weight-band dosing
• If substantial granulocytopenia or anemia
Simplified Weight-Band Dosing for Infants develops in patients who are receiving ZDV, it
With a Gestational Age ≥35 Weeks at Birth may be necessary to discontinue therapy until
Note: The doses in this table provide bone marrow recovery is observed. In this
approximately ZDV 4 mg/kg twice daily from setting, some patients may require erythropoietin
birth to age 4 weeks. or filgrastim injections or transfusions of red
blood cells.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-70
 Twice-Daily Volume of • Screen patients for hepatitis B virus (HBV)
Weight Band ZDV 10 mg/mL Syrup infection before using FDC products that contain
lamivudine (3TC). Severe acute exacerbation of
HBV infection can occur when 3TC is
2 kg to <3 kg 1 mL discontinued; therefore, hepatic function should
3 kg to <4 kg 1.5 mL be monitored for several months after patients
with HBV infection stop taking 3TC.
4 kg to <5 kg 2 mL
Metabolism/Elimination
Aged >4 Weeks
• ZDV is eliminated primarily by hepatic
• ZDV 12 mg/kg twice daily metabolism. The major metabolite is ZDV
glucuronide, which is renally excreted.
≥30 weeks to Birth to Age 2 Weeks
<35 weeks • ZDV is phosphorylated intracellularly to active
• ZDV 2 mg/kg twice daily
ZDV-triphosphate.
Aged 2 Weeks to 6 Weeks
Zidovudine Dosing in Patients With Hepatic
• ZDV 3 mg/kg twice daily Impairment
• The dose of ZDV may need to be reduced in
• Aged >6 Weeks ZDV 12 mg/kg twice daily
patients with hepatic impairment.
<30 weeks Birth to Age 4 Weeks
• Do not use FDC products (e.g., Combivir, Trizivir)
• ZDV 2 mg/kg twice daily in patients who have impaired hepatic function.

Aged 4 Weeks to 8 Weeks Zidovudine Dosing in Patients With Renal

Impairment
• ZDV 3 mg/kg twice daily
• A dose adjustment is required for ZDV in patients
Aged >8 Weeks with renal insufficiency.

• ZDV 12 mg/kg twice daily • Do not use FDC products (e.g., Combivir, Trizivir)
in patients with creatinine clearance <50 mL/min
Note: For infants who are unable to tolerate oral agents, the and patients who are on hemodialysis.
intravenous dose should be 75% of the oral dose, but the dosing
interval should remain the same.

Infant (Aged ≥35 Weeks Post-Conception and ≥4 Weeks Post-

Delivery, Weighing ≥4 kg) and Child Dose
Weight-Based Dosing for Zidovudine

Weight Twice-Daily Dosing

4 kg to <9 kg 12 mg/kg
9 kg to <30 kg 9 mg/kg
≥30 kg 300 mg

Alternative Body Surface Area Dosing

Oral
• ZDV 180 mg to 240 mg per m2 of body surface area every 12 hours

Child and Adolescent (Weighing ≥30 kg) and Adult Dose

• ZDV 300 mg twice daily

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-71
 [Combivir and Generic] Lamivudine/Zidovudine
Child and Adolescent (Weighing ≥30 kg) and Adult Dose
• One tablet twice daily

[Trizivir and Generic] Abacavir/Lamivudine/Zidovudine

Child and Adolescent (Weighing ≥30 kg) and Adult Dose
• One tablet twice daily
a Forpremature infants who receive an HIV diagnosis, the time to change to the continuation dose varies with post-gestational
age and clinical status of the infant.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Bone marrow suppressive/cytotoxic agents, including ganciclovir, valganciclovir, interferon alfa,

and ribavirin: These agents may increase the hematologic toxicity of zidovudine (ZDV).
• Nucleoside analogues that affect DNA replication: Nucleoside analogues—such as ribavirin—
antagonize in vitro antiviral activity of ZDV.
• Doxorubicin: Simultaneous use of doxorubicin and ZDV should be avoided. Doxorubicin may
inhibit the phosphorylation of ZDV to its active form.

Major Toxicities
• More common: Hematologic toxicity, including neutropenia and anemia, particularly in patients
with advanced HIV disease. Headache, malaise, nausea, vomiting, and anorexia. Neutropenia
may occur more frequently in infants who are receiving both lamivudine (3TC) and ZDV than in
infants who are receiving only ZDV.1
• Less common (more severe): Myopathy (associated with prolonged use), myositis, and liver
toxicity. Cases of lactic acidosis and severe hepatomegaly with steatosis, including fatal cases,
have been reported. Fat maldistribution has been observed in patients receiving antiretroviral
medications.
• Rare: Possible increased risk of cardiomyopathy.2-4

Resistance
The International Antiviral Society–USA maintains a list of HIV drug resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
ZDV is frequently included as a component of the nucleoside reverse transcriptase inhibitor (NRTI)
backbone for antiretroviral therapy (ART), and it has been studied in children in combination with

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-72
other NRTIs, including abacavir (ABC) and 3TC.5-8 Pediatric experience with ZDV both for treating
HIV and for preventing perinatal transmission is extensive. However, the mitochondrial toxicity of
ZDV leads many experts to favor the use of ABC or tenofovir alafenamide in cases where the
patient’s age and the results of viral resistance testing do not restrict the use of these drugs.

Efficacy in Clinical Trials

The combination of ZDV and 3TC has been extensively studied in children and has been a part of
antiretroviral (ARV) regimens in many trials. The safety and efficacy of ZDV plus 3TC were
compared to the safety and efficacy of ABC plus 3TC and stavudine (d4T) plus 3TC in children aged
<5 years in the CHAPAS-3 (Children with HIV in Africa Pharmacokinetics and Adherence of
Simple antiretroviral regimens) study. All regimens also included either nevirapine or efavirenz. All
the NRTIs had low toxicity and produced good clinical, immunologic, and virologic responses.9 A
number of studies have evaluated the efficacy and toxicity of different dual-nucleoside reverse
transcriptase inhibitor backbones used as part of combination ART.10-12

Infants with Perinatal HIV Exposure

The Pediatric AIDS Clinical Trials Group (PACTG) 076 clinical trial13 demonstrated that
administering ZDV to pregnant women and their infants could reduce the risk of perinatal HIV
transmission by nearly 70%. See Antiretroviral Management of Newborns With Perinatal HIV
Exposure or HIV Infection for further discussion on using ZDV to prevent perinatal transmission of
HIV. A dose of approximately ZDV 4 mg/kg of body weight every 12 hours is recommended for
prevention of perinatal HIV transmission in neonates and infants with gestational ages ≥35 weeks.
Infants who have been exposed to HIV but who are uninfected should continue on the prophylactic
dose for 4 weeks to 6 weeks, depending on their gestational age at time of delivery and the risk
assessment for perinatal transmission.

Simplified, alternative weight-band dosing has also been developed, and the rationale for these doses
is based on the intracellular metabolism of ZDV (see Pharmacokinetics below). The rate-limiting
step in the phosphorylation of ZDV to active ZDV triphosphate is the limited amount of thymidylate
kinase. Increasing the dose of ZDV will lead to increased ZDV plasma concentrations and increased
intracellular concentrations of ZDV monophosphate, but not ZDV diphosphate or ZDV triphosphate.

In 31 infants who received ZDV to prevent perinatal transmission, levels of intracellular ZDV
metabolites were measured after delivery. Plasma ZDV and intracellular ZDV monophosphate
decreased by roughly 50% between post-delivery Day 1 and Day 28, whereas ZDV diphosphate and
ZDV triphosphate remained low throughout the sampling period.14 ZDV dose is poorly correlated
with the active form of ZDV that is found intracellularly. Because of this, a simplified weight-band
dosing approach can be used for the first 4 weeks of life in infants with gestational ages ≥35 weeks
(see the dosing table above). This approach should simplify the minor dose adjustments that are
commonly made based on changes in infant weight during ZDC use in the first 4 weeks of life and
will make it easier for caregivers to administer ZDV oral syrup to their infants. The changes in
weight and the small differences in ZDV dose will have minor effects on the intracellular
concentrations of ZDV triphosphate.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-73
Infants With HIV Infection
The Early Infant Treatment Study in Botswana evaluated the safety and efficacy of initiation of
antiretroviral therapy in the first week of life. Forty infants who tested positive for HIV within
96 hours of birth were started on ZDV, 3TC, and nevirapine (NVP) with successful transition to
lopinavir/ritonavir (LPV/r) at 2 to 5 weeks after delivery. Early treatment was found to be safe and
effective, with most infants achieving and maintaining viral suppression by 24 weeks of age.15

For full-term neonates who receive an HIV diagnosis during the first days to weeks of life, the ZDV
dose should be increased to the continuation dose at age 4 weeks (see the dosing table above). The
activity of the enzymes responsible for glucuronidation is low at birth and increases dramatically
during the first 4 to 6 weeks of life in full-term neonates. This increase in metabolizing enzyme
activity leads to an increased clearance of plasma ZDV, and the dose of ZDV should be adjusted
when ZDV is used to treat HIV after the first 4 weeks in full-term infants.

For premature infants who receive an HIV diagnosis, the time to increase the ZDV dose from the
initial dose varies with post-gestational age and the clinical status of the neonate. On the basis of
population pharmacokinetic (PK) modeling and simulations and data from studies that have
evaluated ZDV PKs in premature infants, the Panel on Antiretroviral Therapy and Medical
Management of Children Living With HIV recommends the following:

• For infants with HIV born at ≥30 weeks to <35 weeks, switch to a dose of ZDV 12 mg/kg twice
daily at a post-gestational age of 6 weeks to 8 weeks.
• For infants born at <30 weeks, switch to ZDV 12 mg/kg twice daily at a post-gestational age of
8 weeks to 10 weeks.16

Clinicians should perform a careful clinical assessment of the infant, evaluate hepatic and renal
function, and review concomitant medications before increasing the ZDV dose to the dose
recommended for full-term infants.

Pharmacokinetics
ZDV undergoes intracellular metabolism to achieve its active form, ZDV triphosphate.
Phosphorylation requires multiple steps: ZDV is phosphorylated by thymidine kinase to ZDV
monophosphate, ZDV monophosphate is phosphorylated by thymidylate kinase to ZDV diphosphate,
and ZDV diphosphate is phosphorylated by nucleoside diphosphate kinase to ZDV triphosphate.
Overall, ZDV PKs in pediatric patients aged >3 months are like those seen in adults. Although the
mean half-life of intracellular ZDV triphosphate (9.1 hours) is considerably longer than that of
unmetabolized ZDV in plasma (1.5 hours), once-daily ZDV dosing is not recommended because of
the low intracellular ZDV triphosphate concentrations seen with 600-mg, once-daily dosing in
adolescents.17 PK studies, such as PACTG 331, demonstrate that dose adjustments are necessary for
premature infants because they have reduced clearance of ZDV compared with the clearance
observed in term newborns of similar postnatal ages.6 ZDV has good central nervous system (CNS)
penetration (cerebrospinal fluid-to-plasma concentration ratio is 0.68), and ZDV has been used in
children with HIV-related CNS disease.8

PK and safety of ZDV, 3TC, and LPV/r in children living with HIV and severe acute
malnutrition (SAM) was studied in International Maternal, Pediatric, Adolescent AIDS Clinical
Trials (IMPAACT) P1092.18 Steady-state PK, safety, and tolerability was compared in children with

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-74
HIV with and without SAM. Overall safety and tolerability did not differ between the two cohorts
and similar area-under-the-curve values for ZDV, 3TC, and LPV/r were observed in these children
who were dosed according to World Health Organization weight-band dosing recommendations.18

Toxicity
Several studies suggest that the adverse hematologic effects of ZDV may be concentration-
dependent, with a higher risk of anemia and neutropenia in patients with higher mean plasma area-
under-the-curve values for ZDV.5,6,19 A significant reduction in the incidence of hematologic toxicity
was observed during a retrospective analysis of infants who received a short course of ZDV
(2 weeks) to prevent perinatal HIV transmission.20 In this study, 137 infants received ZDV for
2 weeks, and 184 infants received ZDV for >2 weeks; of these infants, 168 (91.3%) received 4 weeks
of ZDV prophylaxis. The risk of anemia (defined as a Division of AIDS [DAIDS] severity grade of
mild or higher) was significantly lower in the short-course group at both age 1 month (P < 0.001) and
age 3 months (P < 0.001).20 Some national guidelines, including those from Germany/Austria and
Great Britain, recommend a minimum of 2 weeks of post-exposure prophylaxis in infants at low risk
or very low risk of HIV transmission.20,21 Current U.S. guidelines recommend 4 weeks of
prophylaxis for infants at low risk of HIV transmission. For infants who develop significant anemia
while receiving ZDV for prevention of perinatal HIV transmission, early discontinuation may be
considered for infants who are determined to be at a low risk of transmission after expert
consultation. A recent study conducted in Thailand evaluated the safety of triple antiretroviral
neonatal presumptive therapy with ZDV/3TC/nevirapine for 6 weeks in infants at high risk of
acquisition of HIV compared with 4 weeks of monotherapy with ZDV in infants considered at low
risk. No significant differences were observed in the incidence of neutropenia, hepatoxicity, or severe
anemia between the triple antiretroviral and the ZDV monotherapy groups.22

Incidence of hematological toxicity was investigated in the ARROW study, which randomized ART-
naive Ugandan and Zimbabwean children to receive either ZDV-containing regimens or ABC-
containing regimens. The incidence of severe anemia was similar regardless of ZDV use, and this
finding suggests that advanced HIV disease contributed to low hemoglobin values. ZDV use was
associated with severe neutropenia in a small number of children.23 In a retrospective study
conducted in Ethiopia, an evaluation of predictors of anemia among children on ART24 was
conducted for the time period of 2007 to 2017. Study participants receiving ZDV-containing
regimens were four times more likely to develop anemia than those children receiving ABC-
containing regimens. Other predictors of anemia in addition to ZDV in this patient population
included tuberculosis, severe immunosuppression, and undernutrition.

ZDV is associated with greater mitochondrial toxicity than ABC and tenofovir disoproxil fumarate,
but it is associated with less mitochondrial toxicity than d4T.25,26

Although the incidence of cardiomyopathy associated with perinatal HIV infection has decreased
dramatically since the use of ART became routine, the use of a regimen that contains ZDV may
increase the risk.2,4 Analysis of data from a U.S.-based multicenter prospective cohort study (PACTG
219/219C) found that ongoing ZDV exposure was independently associated with a higher rate of
cardiomyopathy.2 As part of the Pediatric HIV/AIDS Cohort Study (PHACS)/Adolescent Master
Protocol (AMP) study, echocardiogram measurements were collected between 2008 and 2010 in 325
youth aged 7 to 16 years with perinatally acquired HIV infection. An association between ZDV use
and increased end-systolic wall stress was observed in this study. The investigators speculate that
alterations in cardiac structure in these children could progress to symptomatic cardiomyopathy later

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-75
in life.3 A large cohort study to evaluate the prevalence of cardiac dysfunction in children and young
adults <26 years of age was conducted in Kenya.4 Approximately 28% of participants were found to
have evidence of early cardiac dysfunction. Left ventricular ejection fraction negatively correlated
with prior ZDV exposure, detectable HIV RNA, and elevated interleukin-6 concentrations.4

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-76
References

1. Nielsen-Saines K, Watts DH, Veloso VG, et al. Three postpartum antiretroviral regimens
to prevent intrapartum HIV infection. N Engl J Med. 2012;366(25):2368-2379. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22716975.

2. Patel K, Van Dyke RB, Mittleman MA, et al. The impact of HAART on cardiomyopathy
among children and adolescents perinatally infected with HIV-1. AIDS. 2012;26(16):2027-2037.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/22781228.

3. Williams PL, Correia K, Karalius B, et al. Cardiac status of perinatally HIV-infected

children: assessing combination antiretroviral regimens in observational studies. AIDS.
2018;32(16):2337-2346. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30102660.

4. McCrary AW, Nyandiko WM, Ellis AM, et al. Early cardiac dysfunction in children and
young adults with perinatally acquired HIV. AIDS. 2020;34(4):539-548. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31794518.

5. Balis FM, Pizzo PA, Murphy RF, et al. The pharmacokinetics of zidovudine administered
by continuous infusion in children. Ann Intern Med. 1989;110(4):279-285. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/2643914.

6. Capparelli EV, Mirochnick M, Dankner WM, et al. Pharmacokinetics and tolerance of

zidovudine in preterm infants. J Pediatr. 2003;142(1):47-52. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12520254.

7. McKinney RE, Jr., Maha MA, Connor EM, et al. A multicenter trial of oral zidovudine in
children with advanced human immunodeficiency virus disease. The protocol 043 study group. N
Engl J Med. 1991;324(15):1018-1025. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/1672443.

8. Pizzo PA, Eddy J, Falloon J, et al. Effect of continuous intravenous infusion of

zidovudine (AZT) in children with symptomatic HIV infection. N Engl J Med.
1988;319(14):889-896. Available at: http://www.ncbi.nlm.nih.gov/pubmed/3166511.

9. Mulenga V, Musiime V, Kekitiinwa A, et al. Abacavir, zidovudine, or stavudine as

paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label, parallel-group,
randomised controlled trial. Lancet Infect Dis. 2016;16(2):169-179. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/26481928.

10. Paediatric European Network for Treatment of AIDS. Comparison of dual nucleoside-
analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with
HIV-1 who have not previously been treated: the PENTA 5 randomised trial. Lancet.
2002;359(9308):733-740. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11888583.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-77
11. Green H, Gibb DM, Walker AS, et al. Lamivudine/abacavir maintains virological
superiority over zidovudine/lamivudine and zidovudine/abacavir beyond 5 years in children.
AIDS. 2007;21(8):947-955. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17457088.

12. Mega TA, Usamo FB, Negera GZ. Immunologic Response of HIV-Infected Children to
Different Regimens of Antiretroviral Therapy: A Retrospective Observational Study. AIDS Res
Treat. 2020;2020:6415432. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32855823.

13. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of
human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials
Group Protocol 076 Study Group. N Engl J Med. 1994;331(18):1173-1180. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/7935654.

14. Kinai E, Kato S, Hosokawa S, et al. High plasma concentrations of zidovudine (AZT) do
not parallel intracellular concentrations of AZT-triphosphates in infants during prevention of
mother-to-child HIV-1 transmission. J Acquir Immune Defic Syndr. 2016;72(3):246-253.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26859826.

15. Maswabi K, Ajibola G, Bennett K, et al. Safety and Efficacy of Starting Antiretroviral
Therapy in the First Week of Life. Clin Infect Dis. 2021;72(3):388-393. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31927562.

16. Capparelli EV, Englund JA, Connor JD, et al. Population pharmacokinetics and
pharmacodynamics of zidovudine in HIV-infected infants and children. J Clin Pharmacol.
2003;43(2):133-140. Available at: http://www.ncbi.nlm.nih.gov/pubmed/12616665.

17. Flynn PM, Rodman J, Lindsey JC, et al. Intracellular pharmacokinetics of once versus
twice daily zidovudine and lamivudine in adolescents. Antimicrob Agents Chemother.
2007;51(10):3516-3522. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17664328.

18. Owor M, Tierney C, Ziemba L, et al. Pharmacokinetics and Safety of Zidovudine,

Lamivudine, and Lopinavir/Ritonavir in HIV-infected Children With Severe Acute Malnutrition
in Sub-Saharan Africa: IMPAACT Protocol P1092. Pediatr Infect Dis J. 2021;40(5):446-452.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/33464021.

19. Fillekes Q, Kendall L, Kitaka S, et al. Pharmacokinetics of zidovudine dosed twice daily
according to world health organization weight bands in Ugandan HIV-infected children. Pediatr
Infect Dis J. 2014;33(5):495-498. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24736440.

20. Nguyen TTT, Kobbe R, Schulze-Sturm U, et al. Reducing Hematologic Toxicity With
Short Course Postexposure Prophylaxis With Zidovudine for HIV-1 Exposed Infants With Low
Transmission Risk. Pediatr Infect Dis J. 2019;38(7):727-730. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31033907.

21. British HIV Association. British HIV association guidelines for the management of HIV
in pregnancy and postpartum 2018 (2020 third interim update). 2020. Available at:

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-78
https://www.bhiva.org/file/5f1aab1ab9aba/BHIVA-Pregnancy-guidelines-2020-3rd-interim-
update.pdf

22. Anugulruengkitt S, Suntarattiwong P, Ounchanum P, et al. Safety of 6-week neonatal

triple-combination antiretroviral postexposure prophylaxis in high-risk HIV-exposed infants.
Pediatr Infect Dis J. 2019;38(10):1045-1050. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31365477.

23. Musiime V, Cook A, Nahirya Ntege P, et al. The effect of long-term zidovudine on
hematological parameters in the ARROW randomized trial. Presented at: The 22nd Conference
on Retroviruses and Opportunistic Infections 2015. Seattle, WA. Available at.

24. Techane MA, Anlay DZ, Tesfaye E, Agegnehu CD. Incidence and Predictors of Anemia
Among Children on Antiretroviral Therapy at the University of Gondar Comprehensive
Specialized Hospital, Northwest Ethiopia, 2007-2017: A Retrospective Follow-Up Study. HIV
AIDS (Auckl). 2020;12:951-962. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33364852.

25. Moyle GJ, Sabin CA, Cartledge J, et al. A randomized comparative trial of tenofovir DF
or abacavir as replacement for a thymidine analogue in persons with lipoatrophy. AIDS.
2006;20(16):2043-2050. Available at: http://www.ncbi.nlm.nih.gov/pubmed/17053350.

26. Carr A, Workman C, Smith DE, et al. Abacavir substitution for nucleoside analogs in
patients with HIV lipoatrophy: a randomized trial. JAMA. 2002;288(2):207-215. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/12095385.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-79
Appendix A: Pediatric Antiretroviral Drug Information
Non-Nucleoside Analogue Reverse Transcriptase Inhibitors
Doravirine (DOR, Pifeltro)

Efavirenz (EFV, Sustiva)

Etravirine (ETR, Intelence)

Nevirapine (NVP, Viramune)

Rilpivirine (RPV, Edurant)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-80
Doravirine (DOR, Pifeltro)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Tablet: 100 mg

Fixed-Dose Combination (FDC) Tablet

• [Delstrigo] Doravirine 100 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg

When using FDC tablets, refer to other sections of the Appendix A: Pediatric Antiretroviral Drug Information for information
about the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets:
Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Child and Adolescent (Weighing ≥35 kg) and Adult Dose • Nausea
• DOR 100 mg once daily in antiretroviral (ARV)-naive • Abdominal pain
patients and ARV-experienced patients who have been
virologically suppressed (HIV RNA <50 copies/mL) on a • Diarrhea
stable ARV regimen with no history of treatment failure • Abnormal dreams
and no known mutations associated with resistance to
DOR • Insomnia, somnolence

[Delstrigo] Doravirine (DOR)/Lamivudine (3TC)/Tenofovir Special Instructions

Disoproxil Fumarate (TDF)
• DOR can be taken with or without food.
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• Screen patients for hepatitis B virus (HBV) infection before
• One tablet once daily in ARV-naive patients and ARV- using Delstrigo, which contains 3TC and TDF. Severe
experienced patients who have been virologically acute exacerbation of HBV can occur when 3TC or TDF
suppressed (HIV RNA <50 copies/mL) on a stable ARV are discontinued; therefore, hepatic function and HBV viral
regimen with no history of treatment failure and no known load should be monitored for several months after halting
mutations associated with resistance to the individual therapy with 3TC or TDF.
components of Delstrigo
Metabolism/Elimination
• DOR is metabolized by the enzyme cytochrome P450 3A.
• DOR has multiple interactions with several drugs (see
Drug Interactions section below).

• When DOR is coadministered with rifabutin, the dose

should be increased from DOR 100 mg once daily to DOR
100 mg twice daily. When DOR/3TC/TDF (Delstrigo) is
coadministered with rifabutin, an additional 100-mg dose
of freestanding DOR needs to be administered
approximately 12 hours later. (see Drug Interactions
below)
Doravirine Dosing in Patients With Hepatic Impairment

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-81
 • Dose adjustment is not required in patients with mild or
moderate hepatic impairment. DOR has not been studied
in patients with severe hepatic impairment.

Doravirine Dosing in Patients With Renal Impairment

• Dose adjustment is not required when using DOR in
patients with mild, moderate, or severe renal impairment.
DOR use has not been studied in patients with end-stage
renal disease or in patients on dialysis.
• DOR administered with 3TC and TDF as components of
Delstrigo is not recommended in patients with estimated
creatinine clearance <50 mL/min.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Doravirine (DOR) is a cytochrome P450 (CYP) 3A substrate that is associated with several
important drug interactions with drugs that are strong CYP3A enzyme inducers.
Coadministration with these drugs may cause significant decreases in DOR plasma
concentrations and potential decreases in efficacy, which can lead to the development of
resistance. Before DOR is administered, a patient’s medication profile should be reviewed
carefully for potential drug interactions with DOR.1,2
• In a Phase 1 trial (described below under Efficacy in Clinical Trials), DOR plasma exposure
transiently decreased by 62% when DOR was started immediately after stopping EFV. A post
hoc analysis of the Phase 3 DRIVE-SHIFT study (described below under Efficacy in Clinical
Trials), however, showed that at Week 4, DOR plasma levels in patients who had switched from
an EFV-based regimen to a DOR-based regimen were similar to DOR plasma levels in patients
who switched from a protease inhibitor (PI)–based regimen to a DOR-based regimen (all of the
regimens in the study used a backbone of lamivudine [3TC] plus tenofovir disoproxil fumarate
[TDF]).3 A similar effect of prior EFV-based ART on the pharmacokinetics (PK) of DOR was
demonstrated in IMPAACT 2014 (described below under Efficacy in Clinical Trials) among
adolescents weighing ≥45 kg who switched from EFV-based ART to DOR-based ART with
3TC/TDF.4,5
• DOR should not be coadministered with the following drugs: the anticonvulsants
carbamazepine, oxcarbazepine, phenobarbital, and phenytoin; the androgen receptor inhibitor
enzalutamide; the antimycobacterials rifampin and rifapentine; the cytotoxic agent mitotane; or
St. John’s wort.6,7
• Drug interactions between DOR and rifabutin induce the metabolism of DOR and require an
additional dose of DOR 100 mg to be administered 12 hours after a fixed-dose combination of
DOR/3TC/TDF or an increase of the DOR dose to 100 mg twice daily.2,6,7

Major Toxicities
• More common: Nausea, headache, fatigue, diarrhea, abdominal pain, abnormal dreams

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-82
• Less common (more severe): Neuropsychiatric adverse events (AEs), including insomnia,
somnolence, dizziness, and altered sensorium. Immune reconstitution inflammatory syndrome
may occur.

Resistance
The International Antiviral Society-USA maintains a list of updated drug resistance mutations, and
the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

DOR is expected to have activity against HIV with isolated NNRTI resistance that is associated with
mutations at positions 103, 181, or 190. Some single mutations and combinations of viral mutations,
however, have been shown to significantly decrease susceptibility to DOR. Specifically, clinical HIV
isolates containing the Y188L mutation alone or in combinations with K103N or V106I,
combinations of V106A with G190A and F227L, or combinations of E138K with Y181C and
M230L have shown ≥100-fold reduction in susceptibility to DOR.6,7 In patients with multiple NNRTI
mutations, consult an HIV expert and a resistance database to evaluate the potential efficacy of DOR.

Pediatric Use
Approval
DOR is approved by the U.S. Food and Drug Administration for use in children or adolescents
weighing ≥35 kg.6,7 IMPAACT 2014, a Phase 1/2 study (described below under Efficacy in Clinical
Trials), evaluated the PKs, safety, and tolerability of DOR and DOR/3TC/TDF in children and
adolescents with HIV.4,8

Efficacy in Clinical Trials

The efficacy of DOR was evaluated using data from four randomized adult clinical trials. The first
study was a Phase 2b dose-selection, double-blind trial that enrolled treatment-naive adults with
HIV.9 The efficacy trials included two randomized, multicenter, double-blind, active-controlled
Phase 3 trials (DRIVE-FORWARD and DRIVE-AHEAD) in treatment-naive adults10-13 and one
open-label, active-controlled, randomized, noninferiority trial that enrolled virologically suppressed
adults on antiretroviral therapy (DRIVE-SHIFT).14

The dose-selection trial enrolled treatment-naive adults stratified by HIV RNA level at screening
(≤100,000 copies/mL or >100,000 copies/mL) and randomized participants to receive one of four
different doses (25 mg, 50 mg, 100 mg, or 200 mg) of once-daily DOR or EFV 600 mg with open-
label emtricitabine (FTC) 200 mg/TDF 300 mg. After dose selection at Week 24, all participants
were switched to DOR 100 mg and, with additional enrollment, 216 participants were randomized to
receive once-daily DOR 100 mg (n = 108) or EFV 600 mg (n = 108) for 96 weeks with FTC/TDF. At
Week 24, 72.9% of participants on DOR 100 mg and 73.1% of participants on EFV 600 mg had HIV
RNA <40 copies/mL.9

In the DRIVE-FORWARD trial, adult subjects received either DOR 100 mg (n = 383) or darunavir
800 mg/ritonavir 100 mg (DRV/r) (n = 383) once daily, each in combination with FTC/TDF or
abacavir/3TC.10 In the DRIVE-AHEAD trial, adult subjects received either coformulated
DOR/3TC/TDF (n = 364) or EFV/FTC/TDF (n = 364) once daily.11 An integrated efficacy analysis
from both trials (DRIVE-FORWARD and DRIVE-AHEAD) at Week 48 demonstrated that 84.1% of

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-83
patients who were treated with the DOR-based regimen achieved HIV RNA <50 copies/mL,
compared with 79.9% of patients who were treated with the DRV/r-based regimen and 80.8% of
patients who were treated with EFV/FTC/TDF. Results were similar across different baseline viral
loads, genders, races, and HIV-1 subtypes.11 In a longer-term analysis, at Week 96 in the DRIVE-
AHEAD trial, among 728 randomized participants, 77.5% of those treated with DOR/3TC/TDF
achieved HIV RNA <50 copies/mL, compared with 73.6% in participants treated with
EFV/FTC/TDF. No additional resistance to DOR was observed between Weeks 48 and 96.13 At
Week 96 in the DRIVE-FORWARD trial, 277 (95%) of 292 participants who remained on DOR
maintained viral suppression (that is, 73% of the overall 383 participants), whereas 248 (91%) of 273
participants who remained on DRV/r maintained viral suppression (that is, 66% of the overall 383
participants).12

In the DRIVE-SHIFT study, adult subjects with HIV who were virologically suppressed for
≥6 months on two nucleoside reverse transcriptase inhibitors (NRTIs) plus a boosted PI, boosted
elvitegravir or an NNRTI were randomized to switch to a once-daily, single-tablet regimen of DOR
100 mg/3TC 300 mg/TDF 300 mg or to continue their current therapy (baseline regimen). At
Week 24, 93.7% on DOR/3TC/TDF versus 94.6% on baseline regimen had HIV-1 RNA
<50 copies/mL (difference −0.9 [−4.7 to 3.0]). At Week 48, 90.8% on DOR/3TC/TDF had HIV-1
RNA <50 copies/mL, demonstrating noninferiority versus baseline regimen at Week 24
(difference −3.8 [−7.9 to 0.3]).14 Participants were switched on Day 1 (immediate-switch group
[ISG]; n = 447) or at Week 24 (delayed-switch group [DSG]; n = 209). Long-term efficacy in the
extension arm at Week 144 showed virologic suppression (HIV RNA<50 copies/mL) in 80.1% of
ISG (351 out of 438) and 83.7% of DSG (175 out of 209) in FDA snapshot (intent-to-treat)
analysis.15

IMPAACT 2014 study data in ARV-naive or ARV-experienced virologically suppressed adolescents

suggest favorable antiviral effect comparable to adult data.8 A total of 45 participants, 43
virologically suppressed (50% on EFV-based ART) and 2 ARV-naive adolescents with mean age 15
years (12–17 years), were treated with DOR/3TC/TDF. At Week 24, 42 out of 45 (93.3%; 95%
confidence interval [CI], 81.7–98.6) achieved or maintained HIV-1 RNA <40 copies/mL in FDA
snapshot (intent-to-treat) analysis, while 42 out of 43 (97.7%; 95% CI, 87.7–99.9) achieved or
maintained HIV-1 RNA <40 copies/mL in observed failure (on-treatment) analysis.5

Pharmacokinetics
The PKs of DOR have been evaluated in treatment-naive adults aged ≥18 years and both treatment-
naive and treatment-experienced adolescents. A Phase 2 trial evaluated DOR across a dose range of
0.25 times to 2 times the recommended dose in treatment-naive participants with HIV who also
received FTC/TDF. No exposure-response relationship for efficacy was reported for DOR.11

Toxicity
In trials that compared DOR-based regimens and EFV-based regimens, central nervous system
(CNS) AEs (dizziness, sleep disorder and disturbances, and altered sensorium) occurred less
frequently among the patients who received DOR than among those who received EFV. In the dose-
finding trial, CNS AEs were reported in 26.9% of patients on DOR-based regimens, compared with
47.2% of patients on EFV-based regimens at Week 24.9 In the integrated safety analysis from the
DRIVE-FORWARD and DRIVE-AHEAD trials, 25.5% of patients on DOR-based regimens
experienced CNS AEs at Week 48, compared with 55.9% of patients on EFV-based regimes.11,16

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-84
Neither DRIVE-FORWARD nor DRIVE-AHEAD included an integrase strand transfer inhibitor–
based regimen as an active control. Fewer participants who received DOR-based regimens
experienced diarrhea than those treated with DRV/r-based regimens (12.4% vs. 22.5%, respectively).
In the DRIVE-SHIFT study, among adults who were receiving a ritonavir-boosted PI at study entry,
mean reductions in fasting low-density lipoprotein cholesterol and non-high-density lipoprotein
cholesterol at Week 24 were significantly greater in people who received DOR/3TC/TDF compared
with the baseline PI-based regimen with 3TC/TDF (P < 0.0001).14 The reduction in fasting lipids was
maintained through Week 144 in the extension arm of the DRIVE-SHIFT study.15 Similarly, the
96 weeks of data from the DRIVE-FORWARD trial supported greater mean reductions in low-
density lipoprotein cholesterol (HDL-C) (−14.6 mg/dL [95% CI, −18.2 to −11.0]) and non-high-
density lipoprotein cholesterol (18.4 mg/dL [95% CI, −22.5 to −14.3]) among participants in the
DOR arm than among those in the DRV/r arm.12 At Week 96 in the DRIVE-AHEAD trial, fasting
HDL-C levels increased among participants in the EFV/FTC/TDF arm (mean increases of 10.8 and
15.0 mg/dL) but not among participants treated with DOR/3TC/TDF (−0.6 and −2.1 mg/dL),
respectively, while the mean changes from baseline in total cholesterol/HDL-C ratio were similar
between both arms13 (−0.12 for DOR/3TC/TDF and −0.10 for EFV/FTC/TDF; treatment difference,
−0.04; 95% CI, −0.23–0.15).

In the IMPAACT 2014 study of 43 treatment-experienced and 2 ARV-naive adolescents aged 12 to

<18 years on DOR/3TC/TDF at Week 24, there were no Grade 4 AEs, serious AEs, or premature
study discontinuation due to AEs. The single drug-related Grade 1 AE was dizziness, and nine
participants had the following drug-unrelated Grade 3 AEs: increased alanine aminotransferase
(n = 1); increased creatinine with decreased estimated glomerular filtration rate (eGFR) (n = 2);
decreased eGFR (n = 1); gastroenteritis (n = 1); diarrhea (n = 1); and increased blood pressure
(n = 4).5

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-85
References

1. Boyle A, Moss CE, Marzolini C, Khoo S. Clinical pharmacodynamics, pharmacokinetics,

and drug interaction profile of doravirine. Clin Pharmacokinet. 2019;58(12):1553-1565.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31388941.

2. Khalilieh SG, Yee KL, Sanchez RI, et al. Doravirine and the potential for CYP3A-
mediated drug-drug interactions. Antimicrob Agents Chemother. 2019;63(5). Available
at: https://www.ncbi.nlm.nih.gov/pubmed/30783000.

3. Greaves W, Wan H, Yee KL, Kandala B, Vaddady P, Hwang C. Doravirine exposure and
HIV-1 suppression after switching from an efavirenz-based regimen to
doravirine/lamivudine/tenofovir disoproxil fumarate. Antimicrob Agents Chemother.
2019;63(12):e01298-01219. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31548188.

4. Best B, Yee K, Farhad M, et al. Pharmacokinetics, safety and tolerability of doravirine in

adolescents with HIV-1. Poster 39. Presented at: 11th International Workshop on HIV &
Pediatrics 2019; 2019. Mexico City, Mexico. Available at:
https://www.impaactnetwork.org/publications/abstracts?search_api_fulltext=&field_publicati
on_study=&field_conference=&page=70

5. Melvin AJ, Best B, Muresan P, et al. IMPAACT 2014 24-week PK and safety of
Doravirine/3TC/TDF in adolescents with HIV-1. Abstract 604. Presented at: Conference
on Retroviruses and Opportunistic Infections; 2021. Virtual Conference. Available at:
https://www.croiconference.org/abstract/impaact-2014-24-week-pk-and-safety-of-doravirine-
3tc-tdf-in-adolescents-with-hiv-1.

6. Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate) [package insert]. Food

and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210807s008lbl.pdf.

7. Doravirine [package insert]. Food and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210806s007lbl.pdf.

8. Ann J. Melvin BB, Petronella Muresan, Sarah Pasyar, Hedy Teppler, Kelly Yee, Katie
McCarthy, Rachel Scheckter, Hong Wan, Lina De Montigny, Linda Aurpibul, Pradthana
Ounchanum, Avy Violari, Nicole Tobin, Ellen Townley. IMPAACT 2014 24-week PK
and safety of Doravirine/3TC/TDF in Adolescents with HIV-1. Presented at: Conference
on Retroviruses and Opportnistic Infections 2021. Virtual Available at:
https://www.croiconference.org/abstract/impaact-2014-24-week-pk-and-safety-of-
doravirine-3tc-tdf-in-adolescents-with-hiv-1/.

9. Gatell JM, Morales-Ramirez JO, Hagins DP, et al. Doravirine dose selection and 96-week
safety and efficacy versus efavirenz in antiretroviral therapy-naive adults with HIV-1
infection in a Phase IIb trial. Antivir Ther. 2019;24(6):425-435. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31355775.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-86
 10. Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in
antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 48-week results of a
randomised, double-blind, phase 3, non-inferiority trial. Lancet HIV. 2018;5(5):e211-
e220. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29592840.

11. Orkin C, Squires KE, Molina JM, et al. Doravirine/lamivudine/tenofovir disoproxil

fumarate is non-inferior to efavirenz/emtricitabine/tenofovir disoproxil fumarate in
treatment-naive adults with human immunodeficiency virus-1 infection: week 48 results
of the DRIVE-AHEAD trial. Clin Infect Dis. 2019;68(4):535-544. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30184165.

12. Molina JM, Squires K, Sax PE, et al. Doravirine versus ritonavir-boosted darunavir in
antiretroviral-naive adults with HIV-1 (DRIVE-FORWARD): 96-week results of a
randomised, double-blind, non-inferiority, phase 3 trial. Lancet HIV. 2020;7(1):e16-e26.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31740348.

13. Orkin C, Squires KE, Molina JM, et al. Doravirine/lamivudine/tenofovir disoproxil

fumarate (TDF) versus efavirenz/emtricitabine/TDF in treatment-naive adults with
human immunodeficiency virus type 1 infection: week 96 results of the randomized,
double-blind, phase 3 DRIVE-AHEAD Noninferiority Trial. Clin Infect Dis.
2021;73(1):33-42. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33336698.

14. Johnson M, Kumar P, Molina JM, et al. Switching to doravirine/lamivudine/tenofovir

disoproxil fumarate (DOR/3TC/TDF) maintains HIV-1 virologic suppression through 48
weeks: results of the DRIVE-SHIFT Trial. J Acquir Immune Defic Syndr.
2019;81(4):463-472. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30985556.

15. Kumar P, Johnson M, Molina JM, et al. Brief report: switching to DOR/3TC/TDF
maintains HIV-1 virologic suppression through week 144 in the DRIVE-SHIFT trial. J
Acquir Immune Defic Syndr. 2021;87(2):801-805. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33633036.

16. Thompson M, Orkin C, Molina JM, et al. Once-daily doravirine for initial treatment of
adults living with HIV-1: an integrated safety analysis. Clin Infect Dis. 2019;70(7):1336-
1343 Available at: https://www.ncbi.nlm.nih.gov/pubmed/31121013.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-87
Efavirenz (EFV, Sustiva)
Updated: April 11,2023
Reviewed: April 11,2023

Formulations
Capsules: 50 mg, 200 mg

Tablet: 600 mg

Generic Formulations
• 50-mg and 200-mg capsules
• 600-mg tablet

Fixed-Dose Combination (FDC) Tablets

• [Atripla and generic] Efavirenz 600 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg
• [Symfi and generic] Efavirenz 600 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg
• [Symfi Lo] Efavirenz 400 mg/lamivudine 300 mg/tenofovir disoproxil fumarate 300 mg

When using FDC tablets, refer to other sections of the Drug Appendix for information about the individual components of the FDC. See
also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum Body Weights and Considerations for Use in Children
and Adolescents.
For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Neonatal Dose • Rash, which is generally mild and transient
• Efavirenz (EFV) is not approved for use in neonates. • Central nervous system (CNS) symptoms, such as
fatigue, poor sleeping patterns, insomnia, vivid dreams,
Pediatric Dose impaired concentration, agitation, seizures, depression,
• EFV capsules can be opened and the contents used as a sprinkle suicidal ideation, late-onset ataxia, and encephalopathy
preparation for infants and children who are unable to swallow • Gynecomastia
capsules.
• Hepatotoxicity
Infants and Children Aged 3 Months to <3 Years and Weighing ≥3.5 kg
• Corrected QT prolongation
• The Panel on Antiretroviral Therapy and Medical Management of
• Use of EFV may produce false-positive results with some
Children Living With HIV (the Panel) does not recommend the use of
cannabinoid and benzodiazepine tests.
EFV in children aged 3 months to <3 years due to highly variable
pharmacokinetics in this age group.
Special Instructions
• If the use of EFV is unavoidable due to a clinical situation, the Panel • EFV capsules and tablets can be swallowed whole, or
suggests using investigational doses of EFV in this age group (see EFV capsules can be administered by sprinkling the
Table A in the Pharmacokinetics and Dosing: Infants and Children Aged contents of an opened capsule on food, as described
<3 Years section below). below.
• Bedtime dosing is recommended, particularly during the
first 2 to 4 weeks of therapy, to improve tolerability of
CNS side effects.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-88
 Children Aged ≥3 Years and Weighing ≥10 kg • Administer EFV, Atripla, Symfi, or Symfi Lo on an empty
stomach. Avoid administration with a high-fat meal
Once-Daily Doses of Efavirenz by Weight
because this has the potential to increase absorption.
• The U.S. Food and Drug Administration cautions that
Weight EFV Dosea,b
EFV should not be used during the first trimester of
10 kg to <15 kg 200 mg pregnancy because of potential teratogenicity. However,
after a review of updated evidence regarding
15 kg to <20 kg 250 mg teratogenicity risks, the Perinatal Guidelines do not
restrict use of EFV in female adolescents and adults who
20 kg to <25 kg 300 mg are pregnant or who may become pregnant.
25 kg to <32.5 kg 350 mg
Instructions for Using the Efavirenz Capsule as a
32.5 kg to <40 kg 400 mg Sprinkle Preparation With Food or Formula

≥40 kg 600 mg • Hold capsule horizontally over a small container and

carefully twist open to avoid spillage.
aThe dose in mg can be dispensed in any combination of capsule
strengths. Capsules may be administered by sprinkling the contents onto • Gently mix capsule contents with 1 to 2 teaspoons of an
an age-appropriate food (see Special Instructions below). age-appropriate soft food (e.g., applesauce, grape jelly,
b Some
yogurt) or reconstituted infant formula at room
experts recommend a dose of EFV 367 mg per m2 of body surface temperature.
area (maximum dose 600 mg) due to concerns about underdosing at the
upper end of each weight band (see the Pediatric Use section below for • Administer within 30 minutes of mixing and do not
details). Weight bands approximate a dose of EFV 367 mg per m2 of body consume additional food or formula for 2 hours after
surface area, with a maximum dose of 600 mg. administration.

Child and Adolescent (Weighing ≥40 kg) and Adult Dose Metabolism/Elimination
• EFV 600 mg once daily • Cytochrome P450 (CYP) 2B6 is the primary enzyme for
EFV metabolism. CYP2A6, CYP3A4, CYP3A5, and
[Atripla] Efavirenz 600 mg/Emtricitabine/Tenofovir Disoproxil
uridine-glucuronyl-transferases also contribute to
Fumarate (TDF)
metabolism.
Child and Adolescent (Weighing ≥40 kg) and Adult Dose
• CYP3A and CYP2B6 inducer in vivo
• One tablet once daily
• Interpatient variability in EFV exposure can be explained
• Take on an empty stomach. in part by polymorphisms in CYP, particularly in CYP2B6.
Slower metabolizers are at higher risk of toxicity. See the
[Symfi] Efavirenz 600 mg/Lamivudine/TDF Therapeutic Drug Monitoring section below for
information about the management of mild or moderate
Child and Adolescent (Weighing ≥40 kg) and Adult Dose
toxicity.
• One tablet once daily
Efavirenz Dosing in Patients With Hepatic Impairment
• Take on an empty stomach.
• EFV is not recommended for patients with moderate or
[Symfi Lo] Efavirenz 400 mg/Lamivudine/TDF severe hepatic impairment.

Child and Adolescent (Weighing ≥35 kg) and Adult Dose Atripla, Symfi, and Symfi Lo Dosing in Patients With
Renal Impairment
• One tablet once daily
• Because Atripla, Symfi, and Symfi Lo are FDC products
• Take on an empty stomach. containing TDF, lamivudine, and/or emtricitabine that
require dose adjustments based on renal function, they
Note: Symfi Lo has not been studied in children (sexual maturity ratings should not be used in patients with creatinine clearance
[SMRs] 1–3), and major interindividual variability in EFV plasma <50 mL/min or in patients on dialysis.
concentrations has been found in pediatric patients in a multiethnic
setting. The 400-mg dose of EFV may be too low in children or
adolescents with SMRs 1 to 3 who weigh ≥40 kg. The use of therapeutic
drug monitoring is suggested by some Panel members when Symfi Lo is

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-89
 used in pediatric patients who weigh ≥40 kg (see the Therapeutic Drug
Monitoring section below).

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Coadministration of efavirenz (EFV) with drugs that are primarily metabolized by
cytochrome P450 (CYP) 2C9, CYP2C19, CYP2B6, or CYP3A isozymes may result in altered
plasma concentrations of the coadministered drugs. Drugs that induce CYP3A and CYP2B6
activity would be expected to increase the clearance of EFV, resulting in lower plasma
concentrations. There is potential for multiple drug interactions with EFV. Importantly, dose
adjustment or the addition of ritonavir may be necessary when EFV is used in combination with
atazanavir (ATV), lopinavir/ritonavir (LPV/r), or maraviroc (MVC).
• Before EFV is administered, a patient’s medication profile should be reviewed carefully for
potential drug interactions with EFV.
• Corrected QT (QTc) prolongation has been observed with the use of EFV.1,2 An alternative to
EFV should be considered in patients who are receiving a drug that has a known risk of Torsades
de Pointes or in patients who are at higher risk of Torsades de Pointes.

Major Toxicities
• More common: Skin rash and increased transaminase levels. Central nervous system (CNS)
abnormalities—such as dizziness, somnolence, insomnia, abnormal dreams, confusion, abnormal
thinking, impaired concentration, amnesia, agitation, depersonalization, hallucinations, euphoria,
and seizures—have been reported, primarily in adults. See Table 17a. Antiretroviral Therapy–
Associated Adverse Effects and Management Recommendations—Central Nervous System
Toxicity for information on managing these toxicities.
• Rare: QTc prolongation has been observed with the use of EFV, and Torsades de Pointes has been
reported with EFV use.3 An association between EFV and suicidal ideation, suicide, and
attempted suicide (especially among those with a history of mental illness or substance abuse) was
found in one retrospective analysis of four comparative trials in adults. This association, however,
was not found in analyses of two large observational cohorts.

Resistance
The International Antiviral Society–USA maintains a list of updated resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
EFV has been approved by the U.S. Food and Drug Administration (FDA) for use as part of
antiretroviral (ARV) therapy in children aged ≥3 months and weighing ≥3.5 kg. The FDA has also

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-90
approved the use of Symfi Lo, the fixed-dose combination of EFV 400 mg/lamivudine (3TC)
300 mg/tenofovir disoproxil fumarate (TDF) 300 mg, in children weighing ≥35 kg.

Efficacy in Clinical Trials

EFV-based regimens have proven virologically superior or noninferior to a variety of regimens in
adults, including those containing LPV/r, nevirapine, rilpivirine, ATV, elvitegravir, raltegravir, and
MVC.4-10 EFV was shown to be inferior to dolutegravir (DTG) in the SINGLE trial in adults, which
compared the virologic response of DTG plus abacavir/3TC with the virologic response of
EFV/TDF/emtricitabine (FTC) at Weeks 48 and 144. The differences were most likely due to more
drug discontinuations in the EFV group.11

In clinical trials in adults and children with HIV, EFV used in combination with two nucleoside
reverse transcriptase inhibitors (NRTIs) has been associated with excellent virologic response. FDA
approval of Symfi (EFV 600 mg/3TC/TDF) was based on the results from a clinical trial that
compared the use of TDF with the use of stavudine when each drug was administered with 3TC and
EFV.12 This trial showed that these regimens were similarly effective. The 96-week results of the
Evaluation of Novel Concepts in Optimization of antiRetroviral Efficacy (ENCORE) 1 trial, a
randomized trial in adults, showed that EFV 400 mg used in combination with TDF and FTC was
noninferior to EFV 600 mg used in combination with TDF and FTC.13 EFV used in combination
either with two NRTIs or with an NRTI and a protease inhibitor has been studied in children and has
shown virologic potency and safety comparable to what has been seen in adults.14-16

FDA approval of Symfi Lo was based on a comparison between EFV 400 mg and EFV 600 mg, both
taken with FTC 200 mg plus TDF 300 mg in 630 ARV-naive adult participants with a mean age of
36 years (range 18–69 years). Sixty-eight percent of participants were male, 37% were of African
heritage, 33% were of Asian ethnicity, 17% were Hispanic, and 13% were White. This study showed
similar rates of viral load suppression and toxicities among participants in each group.13 Because
EFV clearance is related to age and CYP2B6 polymorphisms, and because allele frequency varies by
ethnicity, some members of the Panel on Antiretroviral Therapy and Medical Management of
Children Living with HIV (the Panel) suggest using therapeutic drug monitoring (TDM) when using
Symfi Lo in pediatric patients weighing ≥40 kg.

Pharmacokinetics: Pharmacogenomics
Genetic polymorphisms in the genes that code for enzymes involved in the metabolism of EFV may
alter enzyme activity, which causes a high degree of interpatient variability in drug exposure.
CYP2B6 is the primary enzyme for EFV metabolism, and pediatric patients with the CYP2B6-516-
T/T genotype have reduced metabolism, resulting in higher EFV levels in these patients than in those
with the G/G or G/T genotypes.17-21 The CYP2B6-516-T/T allele frequency varies by ethnicity. In a
study of adults from the United States and Italy, this allele had a frequency of 24.4% among White
study participants, a frequency of 31.3% among Black study participants, and a frequency of 34.9%
among Hispanic study participants.22 A retrospective study of pediatric patients in a multiethnic,
high-income setting confirmed that EFV plasma concentrations can vary among patients. The
interindividual variability could be explained in large part by polymorphisms in drug metabolizing
genes, as well as by age at treatment initiation and time since treatment initiation.23 International
Material Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1070 has shown that aggressive
dosing with approximately 40 mg/kg of EFV using opened capsules resulted in therapeutic EFV
concentrations in 58% of children aged <3 years with the G/G or G/T genotypes, but excessive

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-91
exposure occurred in those with the T/T genotype.21,24 Optimal dosing may require pretreatment
CYP2B6 genotyping in children aged <3 years (see Pharmacokinetics and Dosing: Infants and
Children Aged <3years discussion below).20,21,24

Other variants—CYP2B6 alleles and variant CYP2A6 alleles—have been found to influence EFV
concentrations in adults and children.20,25-28

Pharmacokinetics and Dosing: Infants and Children Aged <3 Years

The Panel does not recommend the use of EFV in children aged 3 months to <3 years.
Pharmacokinetic (PK) data in children aged <3 years or weighing <14 kg have shown that it is
difficult to achieve target trough concentrations (C trough ) in this age group.18,29 IMPAACT P1070
studied children aged <3 years with HIV and tuberculosis (TB) coinfection using doses of EFV that
were determined by weight band based on CYP2B6-516-G/G and -G/T genotypes: children with G/G
and G/T genotypes were considered extensive metabolizers (EMs), and children with T/T genotypes
were considered slow metabolizers (SMs) (see Table A below). When doses were used without
regard to genotype, a dose of approximately 40 mg/kg per day resulted in therapeutic EFV
concentrations in an increased proportion of study participants with G/G or G/T genotypes but
excessive exposure in a high proportion of participants with T/T genotypes. This dose is higher than
the FDA-approved dose of EFV.24 Therefore, doses were modified so that infants and young children
with the T/T genotype received a reduced dose. The doses listed for P1070 in Table A are
investigational.

A study evaluated the PKs of EFV in children aged <3 years who had TB/HIV coinfection and were
receiving anti-TB treatment with rifampicin, isoniazid, pyrazinamide, and ethambutol. The findings
from this study reinforced the use of CYP2B6-516 genotype-directed EFV dosing and showed that,
in general, the EFV weight-band dose did not need to be modified further for children aged <40
months.21,30

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-92
Investigational Dosing for Children Aged 3 Months to <3 Years by CYP2B6
Genotype
Table A. Comparison of Efavirenz Doses Used in P1070 and the FDA-Recommended Doses

Protocol P1070 Dosing Protocol P1070 Dosing FDA-Approved Dosing for

for Patients With for Patients With Children Aged 3 Months to
Weight
CYP2B6-516-G/G and CYP2B6-516-T/T <3 Years (Without Regard
-G/T Genotypes (EMs)a Genotype (SMs)a to CYP2B6 Genotype)
5 kg to <7 kg 300 mg 50 mg 150 mg
7 kg to <7.5 kg 400 mg 100 mg 150 mg
7.5 kg to <10 kg 400 mg 100 mg 200 mg
10 kg to <14 kg 400 mg 100 mg 200 mg
14 kg to <15 kg 500 mg 150 mg 200 mg
15 kg to ≤17 kg 500 mg 150 mg 250 mg
a Investigational doses are based on the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) study
P1070.24,30 Evaluation of CYP2B6 genotype is required before initiating efavirenz (EFV). Therapeutic drug level monitoring is
recommended, with a trough concentration measured 2 weeks after initiating EFV and again at age 3 years for a possible dose
adjustment.
Key: CYP = cytochrome P450; EM = extensive metabolizer; SM = slow metabolizer

The FDA-approved doses of EFV for use in infants and children aged 3 months to <3 years were
derived from a population PK model that was based on data from older subjects in the Pediatric
AIDS Clinical Trials Group (PACTG) 1021 and PACTG 382, as well as from data collected during
AI266-922, a study that assessed the PKs, safety, and efficacy of using capsule sprinkles in children
aged 3 months to 6 years (see Table A). The FDA-approved doses are lower than the CYP2B6 EM
doses and higher than the CYP2B6 SM doses from the P1070 study. PK modeling, based on P1070
PK data, was used to generate estimates of the percentage of participants who were likely to reach
therapeutic EFV target concentrations on FDA-indicated doses, according to the participants’
genotypes.24 The study reported that an estimated one-third of EM children who received the FDA-
approved dose would experience subtherapeutic EFV exposures, and more than half of SM children
who received the FDA-approved dose would have area under the curve (AUC) values that were
above the target range.

The Panel does not recommend use of EFV in children aged 3 months to <3 years. If the clinical
situation demands the use of EFV, the Panel recommends determining CYP2B6 genotype prior to
use (see a list of laboratories that perform this test). Patients should be classified as extensive
CYP2B6-516-G/G and -G/T genotype metabolizers or slow CYP2B6-516-T/T genotype metabolizers
to guide dosing, as indicated by the investigational doses from IMPAACT study P1070 (see
Table A). Whether the doses used are investigational or approved by the FDA, EFV plasma
concentrations should be measured 2 weeks after initiating EFV (see the Therapeutic Drug
Monitoring section below). The mid-dose EFV plasma concentration target of 1.0 mg/L to 4.0 mg/L
derived from adult clinical monitoring data also, typically, is applied to C trough A study of 128
African children (aged 1.7–13.5 years) suggests that the concentration at 24 hours (C 24h ) threshold
for increased risk of unsuppressed viral load31 is C 24h 0.65 mg/L. Consultation with an expert in
pediatric HIV infection is recommended before adjusting the dose. In addition, when following the

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-93
P1070 investigational dose recommendations, some experts would measure EFV concentrations at
age 3 years before transitioning the child to the recommended dose for children aged ≥3 years.

Pharmacokinetics: Children Aged ≥3 Years and Adolescents

Even with the use of FDA-approved pediatric dosing in children aged ≥3 years, EFV concentrations
can be suboptimal.17,32-36 Therefore, some experts recommend using TDM in patients who are
receiving EFV and possibly using higher doses in young children, especially in certain clinical
situations, such as virologic rebound or lack of response in an adherent patient. In one study in which
the EFV dose was adjusted in response to measurement of the AUC, the median administered dose
was EFV 13 mg/kg (367 mg per m2 of body surface area), and the range was from 3 mg/kg to
23 mg/kg (69–559 mg per m2 of body surface area).37

Toxicity: Children Versus Adults

The toxicity profile for EFV differs for adults and children. One adverse effect (AE) commonly seen
in children is rash, which was reported in up to 40% of children and 27% of adults.38 The rash is
usually maculopapular, pruritic, mild to moderate in severity, and rarely requires drug
discontinuation. Onset is typically during the first 2 weeks of treatment. Although severe rash and
Stevens-Johnson syndrome have been reported, they are rare.

Multiple studies in adults have shown that EFV use is associated with low vitamin D levels, and
several studies have found an association between EFV use and low bone mineral density.39-42
Efavirenz induces CYP3A4 and CYP24 enzymes that may affect vitamin D homeostasis. Because of
these findings, the Panel recommends measurement of vitamin D in patients receiving EFV and
vitamin D supplementation for those with vitamin D deficiency (see Table 17j.Osteopenia and
Osteoporosis).

In adults, CNS symptoms are commonly reported and affected 29.6% of patients in one meta-
analysis of randomized trials.43 These symptoms usually occur early in treatment and rarely require
drug discontinuation, but they sometimes can persist for months. Administering EFV at bedtime
appears to decrease the occurrence and severity of these neuropsychiatric AEs. For patients who can
swallow capsules or tablets, ensuring that EFV is taken on an empty stomach also reduces the
occurrence of neuropsychiatric AEs. In several studies, the incidence of neuropsychiatric AEs was
correlated with EFV plasma concentrations, and the symptoms occurred more frequently in patients
with higher concentrations.44-47 The ENCORE1 study in adults demonstrated that a dose of EFV
400 mg is associated with fewer AEs and a noninferior virologic response when compared with the
recommended 600-mg dose of EFV.13,48 A Tanzanian study of children aged 6 to 12 years showed
that those who were receiving EFV, especially doses of EFV that were higher than or equal to those
recommended by the World Health Organization, had more anxiety and more difficulty concentrating
at school than children who were receiving alternative ARV medications.49 Adverse CNS events
occurred in 14% of children who received EFV in clinical studies50 and in 30% of children51 with
plasma EFV concentrations >4 mg/L. Late-onset neurotoxicity, including ataxia and encephalopathy,
may occur months to years after initiating EFV. Some events of late-onset neurotoxicity have
occurred in patients with certain CYP2B6 genetic polymorphisms who received standard doses of
EFV. These polymorphisms have been associated with slow metabolism of EFV and increased EFV
levels (see the package insert for EFV).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-94
An association between EFV and suicidal ideation, suicide, and attempted suicide (especially among
those with a history of mental illness or substance abuse) was found in a retrospective analysis of
four comparative trials in adults and in the Strategic Timing of AntiRetroviral Treatment (START)
Trial, a prospective analysis of adults.52,53 This association, however, was not found in the analyses
of two large observational cohorts,54,55 and no cases of suicide were reported in a systematic review
of randomized trials.43 In patients with pre-existing psychiatric conditions, EFV should be used
cautiously.

Toxicity: QTc Prolongation

The effect of EFV on the QTc interval was evaluated in a study of 58 healthy adult participants; a
variety of CYP2B6 polymorphisms was represented within this group. A positive relationship
between EFV concentration and QTc prolongation was observed.1 Clinicians should consider using
an alternative to EFV in patients who are receiving a drug that has a known risk of Torsades de
Pointes (e.g., quinidine, clarithromycin) or in patients who are at higher risk for Torsades de Pointes.2

Therapeutic Drug Monitoring

It is reasonable for a clinician to use TDM to determine whether a patient is experiencing toxicity,
because the concentration of EFV is higher than the normal therapeutic range for some toxicities.56,57
Dose reduction or drug discontinuation would be considered appropriate management of drug
toxicity. Dose reduction is best performed in consultation with an expert in pediatric HIV. Also,
TDM should be considered when administering EFV to children aged 3 months to <3 years due to
increased oral clearance and variable PK properties in this young age group. TDM should also be
considered when using a lower dose of EFV—such as the dose found in Symfi Lo—in children
weighing ≥40 kg. Two weeks after initiating EFV in patients aged <3 years, clinicians should
measure the plasma concentration of EFV. In cases where a dose adjustment may be necessary,
clinicians should consult an expert in pediatric HIV infection prior to adjusting the dose. If a child
initiated EFV at an investigational dose at <3 years of age, some experts would also measure plasma
concentration at age 3 years, after the child transitions to the recommended dose for children aged
≥3 years.

The currently accepted minimum effective concentration of EFV is a mid-dose concentration (C 12h )
>1 mg/L in adults, and concentrations of >4.0 mg/L are associated with CNS side effects.45 However,
the validity of using a single target has been called into question.58 In addition, a lower limit of C 12h
>0.7mg/L was most predictive of virologic outcome in a study of 180 adults.59 Findings from a study
of 128 African children (aged 1.7–13.5 years) suggest that the C 24h threshold for increased risk of
unsuppressed viral load is C 24h 0.65 mg/L.31

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-95
References

1. Abdelhady AM, Shugg T, Thong N, et al. Efavirenz inhibits the human ether-a-go-go
related current (hERG) and induces QT interval prolongation in CYP2B6*6*6 allele
carriers. J Cardiovasc Electrophysiol. 2016;27(10):1206-1213. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27333947.

2. Efavirenz (Sustiva) [package insert]. Food and Drug Administration. 2019. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/020972s057,021360s045lbl.
pdf.

3. Castillo R, Pedalino RP, El-Sherif N, Turitto G. Efavirenz-associated QT prolongation

and Torsade de Pointes arrhythmia. Ann Pharmacother. 2002;36(6):1006-1008.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/12022902.

4. Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with

efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial
therapy for patients infected with HIV. J Acquir Immune Defic Syndr. 2004;36(5):1011-
1019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15247553.

5. Torti C, Maggiolo F, Patroni A, et al. Exploratory analysis for the evaluation of

lopinavir/ritonavir-versus efavirenz-based HAART regimens in antiretroviral-naive HIV-
positive patients: results from the Italian MASTER cohort. J Antimicrob Chemother.
2005;56(1):190-195. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15917286.

6. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment
of HIV-1 infection. N Engl J Med. 2008;358(20):2095-2106. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18480202.

7. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus
efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a
multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796-806.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19647866.

8. Cooper DA, Heera J, Goodrich J, et al. Maraviroc versus efavirenz, both in combination
with zidovudine-lamivudine, for the treatment of antiretroviral-naive subjects with
CCR5-tropic HIV-1 infection. J Infect Dis. 2010;201(6):803-813. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20151839.

9. Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus
efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the
phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic
Syndr. 2012;60(1):33-42. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22343174.

10. Nunez M, Soriano V, Martin-Carbonero L, et al. SENC (Spanish efavirenz vs. nevirapine
comparison) trial: a randomized, open-label study in HIV-infected naive individuals. HIV
Clin Trials. 2002;3(3):186-194. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12032877.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-96
11. Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine
for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and
week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic
Syndr. 2015;70(5):515-519. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26262777.

12. Margot NA, Lu B, Cheng A, Miller MD, Study 903 Team. Resistance development over
144 weeks in treatment-naive patients receiving tenofovir disoproxil fumarate or
stavudine with lamivudine and efavirenz in Study 903. HIV Med. 2006;7(7):442-450.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/16925730.

13. ENCORE1 Study Group, Carey D, Puls R, et al. Efficacy and safety of efavirenz 400 mg
daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-
controlled, non-inferiority ENCORE1 study. Lancet Infect Dis. 2015;15(7):793-802.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25877963.

14. Funk MB, Notheis G, Schuster T, et al. Effect of first line therapy including efavirenz
and two nucleoside reverse transcriptase inhibitors in HIV-infected children. Eur J Med
Res. 2005;10(12):503-508. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16356864.

15. McKinney RE, Jr., Rodman J, Hu C, et al. Long-term safety and efficacy of a once-daily
regimen of emtricitabine, didanosine, and efavirenz in HIV-infected, therapy-naive
children and adolescents: Pediatric AIDS clinical trials group protocol P1021. Pediatrics.
2007;120(2):e416-423. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17646352.

16. Starr SE, Fletcher CV, Spector SA, et al. Combination therapy with efavirenz, nelfinavir,
and nucleoside reverse-transcriptase inhibitors in children infected with human
immunodeficiency virus type 1. Pediatric AIDS Clinical Trials Group 382 Team. N Engl
J Med. 1999;341(25):1874-1881. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/10601506.

17. Saitoh A, Fletcher CV, Brundage R, et al. Efavirenz pharmacokinetics in HIV-1-infected

children are associated with CYP2B6-G516T polymorphism. J Acquir Immune Defic
Syndr. 2007;45(3):280-285. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17356468.

18. Bolton C, Samson P, Capparelli E, Bwakura-Dangarembizi M, Jean-Philippe P, et al.

Strong influence of CYP2B6 genotypic polymorphisms on EFV pharmacokinetics in
HIV+ children <3 years of age and implications for dosing. Presented at: Conference on
Retroviruses and Opportunistic Infections; 2013. Atlanta, GA.

19. Salem AH, Fletcher CV, Brundage RC. Pharmacometric characterization of efavirenz
developmental pharmacokinetics and pharmacogenetics in HIV-infected children.
Antimicrob Agents Chemother. 2014;58(1):136-143. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24145522.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-97
20. Bienczak A, Cook A, Wiesner L, et al. The impact of genetic polymorphisms on the
pharmacokinetics of efavirenz in African children. Br J Clin Pharmacol. 2016;82(1):185-
198. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26991336.

21. Nikanjam M, Tran L, Chadwick EG, et al. Impact of CYP2B6 genotype, tuberculosis
therapy, and formulation on efavirenz pharmacokinetics in infants and children under 40
months of age. AIDS. 2022;36(4):525-532. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34873089.

22. Haas DW, Smeaton LM, Shafer RW, et al. Pharmacogenetics of long-term responses to
antiretroviral regimens containing efavirenz and/or nelfinavir: an Adult AIDS Clinical
Trials Group Study. J Infect Dis. 2005;192(11):1931-1942. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16267764.

23. Soeria-Atmadja S, Osterberg E, Gustafsson LL, et al. Genetic variants in CYP2B6 and
CYP2A6 explain interindividual variation in efavirenz plasma concentrations of HIV-
infected children with diverse ethnic origin. PLoS One. 2017;12(9):e0181316. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/28886044.

24. Bolton Moore C, Capparelli EV, Samson P, et al. CYP2B6 genotype-directed dosing is
required for optimal efavirenz exposure in children 3-36 months with HIV infection.
AIDS. 2017;31(8):1129-1136. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28323755.

25. di Iulio J, Fayet A, Arab-Alameddine M, et al. In vivo analysis of efavirenz metabolism

in individuals with impaired CYP2A6 function. Pharmacogenet Genomics.
2009;19(4):300-309. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19238117.

26. Arab-Alameddine M, Di Iulio J, Buclin T, et al. Pharmacogenetics-based population

pharmacokinetic analysis of efavirenz in HIV-1-infected individuals. Clin Pharmacol
Ther. 2009;85(5):485-494. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19225447.

27. Gandhi M, Greenblatt RM, Bacchetti P, et al. A single-nucleotide polymorphism in

CYP2B6 leads to >3-fold increases in efavirenz concentrations in plasma and hair among
HIV-infected women. J Infect Dis. 2012;206(9):1453-1461. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22927450.

28. Holzinger ER, Grady B, Ritchie MD, et al. Genome-wide association study of plasma
efavirenz pharmacokinetics in AIDS clinical trials group protocols implicates several
CYP2B6 variants. Pharmacogenet Genomics. 2012;22(12):858-867. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23080225.

29. Capparelli E, Rochon-Duck M, Robbins B, et al. Age-related pharmacokinetics of

efavirenz solution. Presented at: 16th Conference on Retroviruses and Opportunistic
Infections (CROI); 2009. Montreal, Canada.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-98
30. Bwakura Dangarembizi M, Samson P, Capparelli EV, et al. Establishing dosing
recommendations for efavirenz in HIV/TB-coinfected children younger than 3 years. J
Acquir Immune Defic Syndr. 2019;81(4):473-480. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31241542.

31. Bienczak A, Denti P, Cook A, et al. Plasma efavirenz exposure, sex, and age predict
virological response in HIV-infected African children. J Acquir Immune Defic Syndr.
2016;73(2):161-168. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27116047.

32. Ren Y, Nuttall JJ, Egbers C, et al. High prevalence of subtherapeutic plasma
concentrations of efavirenz in children. J Acquir Immune Defic Syndr. 2007;45(2):133-
136. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17417100.

33. Hirt D, Urien S, Olivier M, et al. Is the recommended dose of efavirenz optimal in young
West African human immunodeficiency virus-infected children? Antimicrob Agents
Chemother. 2009;53(10):4407-4413. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19635964.

34. Viljoen M, Gous H, Kruger HS, Riddick A, Meyers TM, Rheeders M. Efavirenz plasma
concentrations at 1, 3, and 6 months post-antiretroviral therapy initiation in HIV type 1-
infected South African children. AIDS Res Hum Retroviruses. 2010;26(6):613-619.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/20507205.

35. Fillekes Q, Natukunda E, Balungi J, et al. Pediatric underdosing of efavirenz: a

pharmacokinetic study in Uganda. J Acquir Immune Defic Syndr. 2011;58(4):392-398.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/21926634.

36. Cressey TR, Aurpibul L, Narkbunnam T, et al. Pharmacological assessment of efavirenz

weight-band dosing recommendations in HIV-infected Thai children. J Acquir Immune
Defic Syndr. 2013;62(1):e27-29. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23262981.

37. Fletcher CV, Brundage RC, Fenton T, et al. Pharmacokinetics and pharmacodynamics of
efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve
controlled trial. Clin Pharmacol Ther. 2008;83(2):300-306. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17609682.

38. Larru B, Eby J, Lowenthal ED. Antiretroviral treatment in HIV-1 infected pediatric
patients: focus on efavirenz. Pediatric Health Med Ther. 2014;5:29-42. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25937791.

39. Welz T, Childs K, Ibrahim F, et al. Efavirenz is associated with severe vitamin D
deficiency and increased alkaline phosphatase. AIDS. 2010;24(12):1923-1928. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/20588161.

40. Hamzah L, Tiraboschi JM, Iveson H, et al. Effects on vitamin D, bone and the kidney of
switching from fixed-dose tenofovir disoproxil fumarate/emtricitabine/efavirenz to

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-99
 darunavir/ritonavir monotherapy: a randomized, controlled trial (MIDAS). Antivir Ther.
2016;21(4):287-296. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26460504.

41. Wohl DA, Orkin C, Doroana M, et al. Change in vitamin D levels and risk of severe
vitamin D deficiency over 48 weeks among HIV-1-infected, treatment-naive adults
receiving rilpivirine or efavirenz in a Phase III trial (ECHO). Antivir Ther.
2014;19(2):191-200. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24430534.

42. Dave JA, Cohen K, Micklesfield LK, Maartens G, Levitt NS. Antiretroviral therapy,
especially efavirenz, is associated with low bone mineral density in HIV-infected South
Africans. PLoS One. 2015;10(12):e0144286. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26633015.

43. Ford N, Shubber Z, Pozniak A, et al. Comparative safety and neuropsychiatric adverse
events associated with efavirenz use in first-line antiretroviral therapy: A systematic
review and meta-analysis of randomized trials. J Acquir Immune Defic Syndr.
2015;69(4):422-429. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25850607.

44. Gutierrez F, Navarro A, Padilla S, et al. Prediction of neuropsychiatric adverse events

associated with long-term efavirenz therapy, using plasma drug level monitoring. Clin
Infect Dis. 2005;41(11):1648-1653. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16267739.

45. Marzolini C, Telenti A, Decosterd LA, Greub G, Biollaz J, Buclin T. Efavirenz plasma
levels can predict treatment failure and central nervous system side effects in HIV-1-
infected patients. AIDS. 2001;15(1):71-75. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11192870.

46. Treisman GJ, Kaplin AI. Neurologic and psychiatric complications of antiretroviral
agents. AIDS. 2002;16(9):1201-1215. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12045485.

47. Wintergerst U, Hoffmann F, Jansson A, et al. Antiviral efficacy, tolerability and

pharmacokinetics of efavirenz in an unselected cohort of HIV-infected children. J
Antimicrob Chemother. 2008;61(6):1336-1339. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18343800.

48. Encore Study Group, Puls R, Amin J, et al. Efficacy of 400 mg efavirenz versus standard
600 mg dose in HIV-infected, antiretroviral-naive adults (ENCORE1): a randomised,
double-blind, placebo-controlled, non-inferiority trial. Lancet. 2014;383(9927):1474-
1482. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24522178.

49. Van de Wijer L, McHaile DN, de Mast Q, et al. Neuropsychiatric symptoms in Tanzanian
HIV-infected children receiving long-term efavirenz treatment: a multicentre, cross-
sectional, observational study. Lancet HIV. 2019;6(4):e250-e258. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30770324.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-100
50. Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine
and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-
analysis. AIDS. 2013;27(9):1403-1412. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23343913.

51. Puthanakit T, Tanpaiboon P, Aurpibul L, Cressey TR, Sirisanthana V. Plasma efavirenz

concentrations and the association with CYP2B6-516G >T polymorphism in HIV-
infected Thai children. Antivir Ther. 2009;14(3):315-320. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19474465.

52. Mollan KR, Smurzynski M, Eron JJ, et al. Association between efavirenz as initial
therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or
completed suicide: an analysis of trial data. Ann Intern Med. 2014;161(1):1-10. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/24979445.

53. Arenas-Pinto A, Grund B, Sharma S, et al. Risk of suicidal behavior with use of
efavirenz: results from the strategic timing of antiretroviral treatment trial. Clin Infect
Dis. 2018;67(3):420-429. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29538636.

54. Smith C, Ryom L, Monforte A, et al. Lack of association between use of efavirenz and
death from suicide: evidence from the D:A:D study. J Int AIDS Soc. 2014;17(4 Suppl
3):19512. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25394021.

55. Napoli AA, Wood JJ, Coumbis JJ, Soitkar AM, Seekins DW, Tilson HH. No evident
association between efavirenz use and suicidality was identified from a disproportionality
analysis using the FAERS database. J Int AIDS Soc. 2014;17:19214. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25192857.

56. van Luin M, Gras L, Richter C, et al. Efavirenz dose reduction is safe in patients with
high plasma concentrations and may prevent efavirenz discontinuations. J Acquir
Immune Defic Syndr. 2009;52(2):240-245. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19593159.

57. Acosta EP, Gerber JG, Adult Pharmacology Committee of the AIDS Clinical Trials
Group. Position paper on therapeutic drug monitoring of antiretroviral agents. AIDS Res
Hum Retroviruses. 2002;18(12):825-834. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12201904.

58. Dickinson L, Amin J, Else L, et al. Comprehensive pharmacokinetic, pharmacodynamic

and pharmacogenetic evaluation of once-daily efavirenz 400 and 600 mg in treatment-
naive HIV-infected patients at 96 weeks: results of the ENCORE1 study. Clin
Pharmacokinet. 2015. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26715213.

59. Orrell C, Bienczak A, Cohen K, et al. Recommended Efavirenz concentration for

therapeutic drug monitoring Is too high. Presented at: Conference on Retroviruses and
Opportunistic Infections; 2016. Boston, MA.:

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-101
Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-102
Etravirine (ETR, Intelence)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Tablets: 25 mg, 100 mg, 200 mg

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Neonate and Infant Dose • Nausea
• Etravirine (ETR) is not approved for use in neonates or infants. • Diarrhea

Child Dose • Rash, including Stevens-Johnson syndrome

• ETR is not approved for use in children aged <2 years. • Hypersensitivity with rash, constitutional
symptoms, and, sometimes, organ dysfunction,
Etravirine Dosing Table for Antiretroviral Therapy–Experienced including hepatic failure
Children and Adolescents Aged 2 to 18 Years and Weighing
≥10 kg Special Instructions
Body Weight Twice-Daily Dose • ETR tablets are sensitive to moisture; store the
tablets at room temperature in the original
10 kg to <20 kg 100 mg container with desiccant.
20 kg to <25 kg 125 mg • Always administer ETR with food. Area under the
curve of ETR is decreased by about 50% when
25 kg to <30 kg 150 mg
the drug is taken on an empty stomach. The type
≥30 kg 200 mg of food does not affect the exposure to ETR.
• Swallowing ETR tablets whole is the preferred
• ETR is approved for use in children and adolescents who are means of administration. Although the package
treatment experienced. The Panel on Antiretroviral Therapy and insert contains instructions for dispersing ETR
Medical Management of Children Living With HIV recommends tablets in water or other liquids, using this
that ETR is used as part of a regimen that includes a administration method generally results in lower
ritonavir (RTV)-boosted protease inhibitor (PI) (see Efficacy in ETR exposures compared with swallowing tablets
Clinical Trials and Drug Interactions below). whole. Children who receive dispersed ETR
• Cobicistat-boosted PIs, non-nucleoside reverse transcriptase tablets should switch to swallowing tablets whole
inhibitors, bictegravir, and elvitegravir/cobicistat should not be as soon as developmentally able.
used with ETR. Raltegravir and dolutegravir should only be used
with ETR with RTV-boosted atazanavir, darunavir, or lopinavir. Metabolism/Elimination
Adult Dose for Antiretroviral Therapy–Experienced Patients • ETR is an inducer of cytochrome P450 (CYP) 3A4
and an inhibitor of CYP2C9, CYP2C19, and
• ETR 200 mg twice daily with food. P-glycoprotein. It is a substrate for CYP3A4,
CYP2C9, and CYP2C19.
• ETR is involved in multiple interactions with
antiretroviral agents and other drugs (see Drug
Interactions below).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-103
 Etravirine Dosing in Patients With Hepatic
Impairment
• No dose adjustment is required when using ETR
in patients with mild or moderate hepatic
insufficiency. No dosing information is available
for patients with severe hepatic impairment.

Etravirine Dosing in Patients With Renal

Impairment
• No dose adjustment is required when using ETR
in patients with renal impairment.

Drug Interactions
Additional information about drug interactions is available in Adult and Adolescent Antiretroviral
Guidelines and the HIV Drug Interaction Checker.

• Etravirine (ETR) is associated with multiple drug interactions. A patient’s medication profile
should be carefully reviewed for potential drug interactions before ETR is administered.
• ETR should not be administered with tipranavir/ritonavir, fosamprenavir/ritonavir, unboosted
protease inhibitors (PIs), or cobicistat-boosted PIs.1
• ETR should not be administered with other non-nucleoside reverse transcriptase
inhibitors (NNRTIs) (i.e., nevirapine [NVP], efavirenz [EFV], rilpivirine, doravirine).
• ETR should not be administered with bictegravir or elvitegravir/cobicistat. ETR reduces the
trough concentration of raltegravir2 (RAL) and dolutegravir (DTG). RAL and DTG should be
used with ETR only when these drugs are coadministered with atazanavir/ritonavir,
darunavir/ritonavir, or lopinavir/ritonavir.

Major Toxicities
• More common: Nausea, diarrhea, and mild rash. Rash occurs most commonly during the first
6 weeks of therapy. Rash generally resolves after 1 week to 2 weeks on continued therapy. A
history of NNRTI-related rash does not appear to increase the risk of developing rash with ETR.
However, patients who have a history of severe rash with prior NNRTI use should not receive
ETR.
• Less common (more severe): Peripheral neuropathy, severe rash, hypersensitivity
reactions (HSRs), and erythema multiforme all have been reported. Instances of severe rash have
included Stevens-Johnson syndrome, and HSRs have included constitutional symptoms and
organ dysfunction, including hepatic failure. Discontinue ETR immediately if signs or symptoms
of severe skin reactions or HSRs develop (including severe rash or rash accompanied by fever,
general malaise, fatigue, muscle or joint aches, blisters, oral lesions, conjunctivitis, facial edema,
hepatitis, and eosinophilia). Clinicians should monitor a patient’s clinical status, including levels
of liver transaminases, and initiate appropriate therapy when necessary. Continuing to use ETR
after the onset of severe rash may result in a life-threatening reaction. People who have a history
of severe rash while using NVP or EFV should not receive ETR.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-104
Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
ETR is approved by the U.S. Food and Drug Administration for use in antiretroviral therapy (ART)-
experienced children and adolescents aged 2 to 18 years.

Efficacy in Clinical Trials

In the Paediatric study of Intelence As an NNRTI Option (PIANO) study,3 ART-experienced
children aged 6 years to <18 years received ETR with a ritonavir (RTV)-boosted PI as part of an
optimized background regimen. At Week 24, 67% of these participants had plasma HIV RNA
concentrations <400 copies/mL, and 52% had HIV RNA <50 copies/mL. At Week 48, 56% of the
participants had HIV RNA <50 copies/mL and a mean increase in their CD4 T lymphocyte (CD4)
cell counts of 156 cells/mm3 from baseline. At Week 48, 68% of children aged 6 years to <12 years
had plasma HIV RNA <50 copies/mL, whereas only 48% of adolescents aged 12 years to <18 years
achieved a plasma viral load of <50 copies/mL.

In a retrospective study of 23 adolescents and young adults in Spain receiving ETR-based therapy,
78% of participants achieved HIV RNA <50 copies/mL at a median of 48.4 weeks of follow-up.4 A
separate pooled analysis of treatment-experienced children and adolescents <18 years of age on ETR-
based therapy showed 69% (85/124) with follow-up data through 12 months achieved HIV RNA
<50 copies/mL, and 80% (99/124) achieved HIV RNA <400 copies/mL.5

In the International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1090 trial,6
ART-experienced children aged ≥2 years to <6 years received ETR with an RTV-boosted PI as part
of an optimized background regimen. Participants received ETR at a dose of 100 mg twice daily
(10 kg to <20 kg) or 125 mg twice daily (20 kg to <25 kg). At Week 48, 75% had an HIV-1 RNA
<400 copies/mL or a >2-log reduction in HIV-1 RNA from baseline. The mean increase in CD4
count and CD4 percentage over 48 weeks was 298.5 cells/mm3 and 5.2%, respectively. Due to the
PIANO and IMPAACT P1090 study findings, if ETR is utilized to treat an ART-experienced child or
adolescent, the Panel on Antiretroviral Therapy and Medical Management of Children Living With
HIV (the Panel) recommends that ETR is part of a regimen that includes an RTV-boosted PI plus an
optimized background regimen.

Pharmacokinetics
In a Phase 1 dose-finding study that involved children aged 6 to 17 years, 17 children were given
ETR 4 mg/kg twice daily. The study reported that two pharmacokinetic (PK) parameters—area under
the curve for 12 hours postdose (AUC 0–12h ) and minimum plasma concentration (C min )—were lower
than the corresponding parameters observed in adults during previous studies.7 However, a higher
dose (ETR 5.2 mg/kg twice daily; maximum 200 mg per dose) yielded acceptable parameters and
was chosen for evaluation in the Phase 2 PIANO study. Exposures (mean AUC 0–12h ) remained lower
in older adolescents than in adults and younger children, and exposures were lower in Asian

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-105
participants than in either White or Black participants. In the PIANO study, children and adolescents
with ETR concentrations in the lowest quartile (<2,704 ng·h/mL or pre-dose concentration [C 0h ]
<145 ng/mL) were less likely to achieve sustained virologic responses (defined as plasma viral loads
<50 copies/mL) after 48 weeks of treatment than those with ETR concentrations in the upper three
quartiles.8

Table A. Pharmacokinetic Parameters in Children, Adolescents, and Adults Receiving

Etravirine Twice Daily With an Optimized Background Regimen, Including a Ritonavir-
Boosted Protease Inhibitor8

Mean ETR AUC 0–12h Mean ETR C 0h

Population
(ng·h/mL) (ng/mL)
Children Aged 6–11 Years (n = 41) 5,684 377

Adolescents Aged 12–17 Years (n = 60) 4,895 325

Adults (n = 575) 5,506 393

Key: AUC 0–12h = area under the curve for 12 hours postdose; C 0h = pre-dose concentration; ETR = etravirine

IMPAACT P1090 examined the PK and safety of ETR in treatment-experienced children with HIV
aged ≥2 years to <6 years.6 All participants received ETR as part of an optimized background
regimen, which included a RTV-boosted PI. The tablets were swallowed whole or dispersed in
liquid. ETR was initially given at a dose of 5.2 mg/kg twice daily to a cohort of six children;
however, at this dose, the geometric mean ETR AUC 0–12h values fell below the target range of 60%
of the values seen in adults. Subsequent participants were given twice-daily doses of ETR that were
determined by weight band: children weighing 10 kg to <20 kg were given 100 mg twice daily, and
children weighing 20 kg to <25 kg were given 125 mg twice daily.

The protocol-specified PK targets for ETR were achieved at these doses; the geometric mean
AUC 0–12h was 3,823 ng·hr/mL, which was within the target range of 2,713 ng·hr/mL to
6,783 ng·hr/mL (60% to 150% of the AUC 0–12h value seen in adults). However, considerable
intersubject variability was observed, with 5 (33.3%) of 15 participants having AUC 0–12h values that
were below the 10th percentile for the adult AUC 0–12h range (<2,350 ng·hr/mL). The ETR AUC 0–12h
values were significantly lower in children who received dispersed tablets than in children who
swallowed intact tablets: 2,919 ng·hr/mL (n = 11) versus 10,982 ng·hr/mL (n = 3), respectively
(P = 0.0008). The Panel recommends that children swallow tablets whole (rather than dispersed in
liquid) as soon as developmentally able.

Six children with HIV aged 1 year to <2 years also were enrolled in IMPAACT P1090. Although the
ETR exposures satisfied protocol-defined PK targets (AUC 0–12h between 2,713 ng·hr/mL and
6,783 ng·hr/mL), they were lower in these children compared with historical data in adults and
adolescents (geometric mean ETR AUC 0–12h of 3,328 ng·hr/mL). Virologic failure, which was
defined as a confirmed viral load of ≥400 copies/mL or less than a 2-log reduction in HIV-1 RNA
from baseline, occurred in four of six children by Week 48. Thus, the Panel does not recommend the
use of ETR in those younger than 2 years of age.

Given that both the PIANO and IMPAACT P1090 trials were conducted in children receiving RTV-
boosted PIs as part of their optimized background regimens, the Panel recommends using ETR as
part of a regimen that includes an RTV-boosted PI.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-106
Toxicity
In the PIANO study, rash and diarrhea were the most common adverse drug reactions that were
deemed to be possibly related to the use of ETR. Rash (Grade 2 or higher) occurred in 13% of
pediatric subjects and emerged at a median of 10 days, lasting a median of 7 days. Rash was
observed more frequently in female patients (13 of 64 patients; 20.3%) than in male patients (2 of
37 patients; 5.4%).8 In IMPAACT P1090, adverse drug reactions that were reported for children
aged ≥2 years to <6 years were comparable in frequency, type, and severity to those reported for
adults. Twelve participants (46.2%) developed Grade 1 or 2 rashes within the first 48 weeks of ETR,
but no subject discontinued the study prematurely due to rash. Diarrhea occurred in 8 (30.8%) of
26 patients.6

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-107
References

1. Molto J, Curran A, Miranda C, et al. Pharmacokinetics of darunavir/cobicistat and

etravirine alone and co-administered in HIV-infected patients. J Antimicrob Chemother.
2018;73(3):732-737. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29237008.

2. Do VT, Higginson RT, Fulco PP. Raltegravir dosage adjustment in HIV-infected patients
receiving etravirine. Am J Health Syst Pharm. 2011;68(21):2049-2054. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/22011983.

3. Tudor-Williams G, Cahn P, Chokephaibulkit K, et al. Etravirine in treatment-

experienced, HIV-1-infected children and adolescents: 48-week safety, efficacy and resistance
analysis of the phase II PIANO study. HIV Med. 2014;15(9):513-524. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/24589294.

4. Briz V, Palladino C, Navarro M, et al. Etravirine-based highly active antiretroviral

therapy in HIV-1-infected paediatric patients. HIV Med. 2011;12(7):442-446. Available at:
http://www.ncbi.nlm.nih.gov/pubmed/21395964.

5. European P, Paediatric Infections Cohort Collaboration E, Lyons A, et al. Outcomes of

etravirine-based antiretroviral treatment in treatment-experienced children and adolescents living
with HIV in Europe and Thailand. Antivir Ther. 2022;27(3):13596535221092182. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/36029009.

6. MacBrayne CE, Rutstein RM, Wiznia AA, et al. Etravirine in treatment-experienced

HIV-1-infected children 1 year to less than 6 years of age. AIDS. 2021;35(9):1413-1421.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/33831904.

7. Konigs C, Feiterna-Sperling C, Esposito S, et al. Pharmacokinetics and short-term safety

and tolerability of etravirine in treatment-experienced HIV-1-infected children and adolescents.
AIDS. 2012;26(4):447-455. Available at: http://www.ncbi.nlm.nih.gov/pubmed/22156961.

8. Kakuda TN, Brochot A, Green B, et al. Pharmacokinetics and

pharmacokinetic/pharmacodynamic relationships of etravirine in HIV-1-infected, treatment-
experienced children and adolescents in PIANO. J Clin Pharmacol. 2016;56(11):1395-1405.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27060341.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-108
Nevirapine (NVP, Viramune)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Oral Suspension: 10 mg/mL

Tablets: Immediate-release 200-mg tablets; extended-release (XR) 100-mg and 400-mg tablets

Generic Formulations
• 10 mg/mL suspension
• Immediate-release 200-mg tablets
• XR 400-mg tablets

The oral suspension formulation of nevirapine (brand name Viramune) is not typically stocked in local pharmacies or hospitals.
Clinicians should direct pharmacies to ask their drug wholesaler to order it from the Boehringer-Ingleheim distribution center.
The distribution center should be able to ship the formulation directly to the pharmacy.

Dosing Recommendations Selected Adverse Events

Note: Nevirapine (NVP) is often used as part of newborn antiretroviral • Rash, including Stevens-Johnson
regimens to prevent perinatal transmission of HIV. See Antiretroviral syndrome
Management of Newborns With Perinatal HIV Exposure or HIV Infection.
• Symptomatic hepatitis, including fatal
Child and Adolescent Dose hepatic necrosisb

• In most situations, NVP is given once daily for 2 weeks to allow • Severe systemic hypersensitivity
autoinduction of the enzymes involved in its metabolism. This may not be syndrome with potential for multisystem
necessary in children aged <2 years.a organ involvement and shock

• See Special Considerations for Dosing: Neonates and Premature Infants Special Instructions
below.
• The oral suspension must be shaken well
Immediate-Release Tablets and Oral Suspension before administering, and it should be
Gestational Age of 32 to <34 Weeks stored at room temperature.

• Birth to age 2 weeks: NVP 2 mg/kg per dose twice daily (no lead-in • NVP can be given with or without food.
dosing)a • NVP-associated skin rash usually occurs
• Age 2 to 4 weeks: NVP 4 mg/kg per dose twice daily within the first 6 weeks of therapy. If rash
occurs during the initial 14-day lead-in
• Age 4 to 6 weeks: NVP 6 mg/kg per dose twice daily period, do not increase the dose until the
rash resolves (see Major Toxicities below).
• Age >6 weeks: NVP 200 mg/m2 of body surface area (BSA) per dose twice
daily; only make this dose increase for infants with confirmed HIV • Extended-release tablets must be
infection. swallowed whole. They cannot be crushed,
chewed, or divided.
• This dosing strategy is recommended by the Panel on Antiretroviral
Therapy and Medical Management of Children Living with HIV (the Panel) • If NVP dosing is interrupted for >14 days,
based on the review of pharmacokinetic (PK) modeling and simulation NVP should be restarted with once-daily
data. This dosing strategy has not been evaluated in clinical trials and is dosing for 14 days, followed by escalation
not approved by the U.S. Food and Drug Administration (FDA). to the full, twice-daily regimen (see Dosing
Considerations: Lead-In Dosing below).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-109
 Gestational Age of 34 to <37 Weeks • Most cases of NVP-associated hepatic
toxicity occur during the first 12 weeks of
• Birth to age 1 week: NVP 4 mg/kg per dose twice daily (no lead-in dosing)a
therapy; frequent clinical and laboratory
• Age 1 week to 4 weeks: NVP 6 mg/kg per dose twice daily monitoring, including liver function tests, is
important during this period (see Major
• Age >4 weeks: NVP 200 mg/m2 of BSA per dose twice daily; only make Toxicities below).
this dose increase for infants with confirmed HIV infection.
• This dosing strategy is recommended by the Panel based on the review of Metabolism/Elimination
PK and safety data on this regimen from clinical trials. This dosing strategy
is not approved by the FDA. • NVP is a substrate and inducer of
cytochrome P450 (CYP) 3A4 and
Gestational Age of ≥37 Weeks to Age of <1 Month CYP2B6. More than 80% of a NVP dose is
eliminated in urine as uridine diphosphate
• Birth to age 4 weeks: NVP 6 mg/kg per dose twice daily (no lead-in glucuronosyltransferase (UGT)-derived
dosing)a glucuronidated metabolites.
• Age >4 weeks: NVP 200 mg/m2 of BSA per dose twice daily; only make Nevirapine Dosing in Patients With
this dose increase for infants with confirmed HIV infection. Hepatic Impairment
• This dosing strategy is recommended by the Panel based on the review of • NVP should not be administered to
PK and safety data on this regimen from clinical trials. This dosing strategy patients with moderate or severe hepatic
is not approved by the FDA. impairment.
Aged ≥1 Month to <8 Years Nevirapine Dosing in Patients With Renal
• NVP 200 mg/m2 of BSA per dose twice daily after lead-in dosing.a In Failure Who Are Receiving Hemodialysis
children aged ≤2 years, some experts initiate NVP without lead-in dosing • An additional dose of NVP should be given
(maximum dose of immediate-release tablets is NVP 200 mg twice daily). following each dialysis session.
Aged ≥8 Years
• NVP 120 mg to 150 mg/m2 of BSA per dose twice daily after lead-in
dosinga (maximum dose of immediate-release tablets is NVP 200 mg twice
daily).
• When adjusting the dose for a growing child, the mg dose need not be
decreased as the child reaches age 8 years; rather, the mg dose can be
left static to achieve the appropriate mg-per-m2 dose as the child grows, if
no adverse effects emerge.

Extended-Release Tablets
Aged ≥6 Years
• Patients aged ≥6 years who are already taking immediate-release NVP
tablets twice daily can be switched to extended-release NVP tablets
without lead-in dosing.a

Body Surface Area Dosing for Extended-Release Nevirapine

Tablets

Body Surface Area Once-Daily Dose

0.58 m2 to 0.83 m2 NVP 200 mg (two 100-mg tablets)
0.84 m2 to 1.16 m2 NVP 300 mg (three 100-mg tablets)
≥1.17 m2 NVP 400 mg (one 400-mg tablet)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-110
 Adolescent and Adult Dose
• NVP 200 mg twice daily or NVP 400 mg with the extended-release tablets
once daily after lead-in dosing.a,b

Nevirapine Used in Combination with Lopinavir/Ritonavir

• A higher dose of lopinavir/ritonavir may be needed in patients who also are
receiving NVP (see the Lopinavir/Ritonavir section).
a NVP is usually initiated at a lower dose that is increased in a stepwise fashion. NVP induces cytochrome P450 metabolizing
enzymes, which results in increased drug clearance. The stepwise increase in dose decreases the occurrence of rash.
Clinicians generally should initiate therapy with the immediate-release tablet formulation once daily instead of twice daily for the
first 14 days of therapy. If no rashes or other adverse effects emerge after 14 days of therapy, increase the dose of NVP to the
age-appropriate full dose of the immediate-release tablet formulation administered twice daily. For example, the recommended
oral dose for pediatric patients aged ≥1 month to <8 years is NVP 200 mg/m2 of BSA once daily for the first 14 days, followed by
NVP 200 mg/m2 of BSA twice daily thereafter. However, in children aged ≤2 years, some experts initiate NVP without lead-in
dosing (see the Dosing Considerations: Lead-In Dosing and Special Considerations for Dosing: Neonates and Premature
Infants sections below). In patients who are already receiving the full, twice-daily dose of the immediate-release tablets,
extended-release tablets can be used without the lead-in period. Patients must swallow extended-release tablets whole. They
must not be chewed, crushed, or divided. Patients must never take more than one form of NVP at the same time. The dose
should not exceed NVP 400 mg daily.
b Severe,
life-threatening, and, in rare cases, fatal hepatotoxicity—including fulminant and cholestatic hepatitis, hepatic necrosis,
and hepatic failure—have occurred in patients who were taking NVP. These toxicities are less common in children than adults.
Most cases occur during the first 12 weeks of therapy and may be associated with rash or other signs or symptoms of
hypersensitivity reaction (HSR). NVP should be discontinued and not restarted in children or adults who develop
symptomatic hepatitis, severe transaminase elevations, or HSRs.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Nevirapine (NVP) is metabolized by and induces hepatic CYP3A and CYP2B6;
autoinduction of metabolism occurs in 2 to 4 weeks of NVP dosing, leading to a 1.5-fold to
twofold increase in NVP clearance. Multiple drug interactions with NVP are possible. Some
genetic polymorphisms of CYP2B6 are associated with increased NVP plasma concentrations.
The prevalence of CYP2B6 polymorphisms varies among populations and may contribute to
differences in NVP exposure. See the Efavirenz section for more information on how
polymorphisms can alter metabolic enzyme activity.
• NVP should not be coadministered to patients who are receiving atazanavir (ATV) (with or
without ritonavir), because NVP substantially decreases ATV exposure.
• NVP increases the metabolism of lopinavir (LPV). A dose adjustment of LPV is recommended
when the two drugs are coadministered (see the Lopinavir/Ritonavir section).
• Before NVP is initiated, a patient’s medication profile should be carefully reviewed for potential
drug interactions.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-111
Major Toxicities
The following toxicities are seen with chronic dosing, not during single-dose NVP prophylaxis.

• More common: Skin rash (some severe cases have required hospitalization, and some cases have
been life-threatening, including instances of Stevens-Johnson syndrome and toxic epidermal
necrolysis), fever, nausea, headache, and elevated hepatic transaminases. In the two largest case
series of NVP-induced Stevens-Johnson syndrome in children, the incidence rate was estimated
between 1.4% and 7.1%.1,2 NVP should be discontinued and not restarted in children or adults
who develop severe rash, rash with constitutional symptoms (i.e., fever, oral lesions,
conjunctivitis, or blistering), or rash with elevated levels of hepatic transaminases.
NVP-associated skin rash usually occurs within the first 6 weeks of therapy. If rash occurs during
the initial 14-day lead-in period, do not increase the dose until rash resolves. However, the risk of
developing NVP resistance with extended lead-in dosing is unknown, and this concern must be
weighed against the current antiviral response and a patient’s overall ability to tolerate the
regimen.
• Less common (more severe): These toxicities are less common in children than adults. Most cases
occur during the first 12 weeks of therapy and may be associated with rash or other signs or
symptoms of hypersensitivity reaction (HSR). Risk factors for NVP-related hepatic toxicity in
adults include baseline elevation in serum transaminase levels, hepatitis B or hepatitis C virus
infection, female sex, and higher CD4 T lymphocyte (CD4) cell count at time of therapy
initiation (CD4 count >250 cells/mm3 in adult females and >400 cells/mm3 in adult males).
Children with CD4 percentages >15% have a threefold increase in the risk of rash and
hepatotoxicity after initiating NVP.3 HSRs have been reported, including, but not limited to,
severe rash or rash accompanied by fever, blisters, oral lesions, conjunctivitis, facial edema,
muscle or joint aches, general malaise, and significant hepatic abnormalities. NVP should be
discontinued and not restarted in children or adults who develop symptomatic hepatitis, severe
transaminase elevations, or HSRs.
• Less common (more severe): In a cross-sectional study of 201 children with HIV aged 6 to
16 years, 43% of whom had hypertension, the use of NVP was associated with left ventricular
hypertrophy (LVH) (adjusted odds ratio 3.14; confidence interval 1.13–8.72; P = 0.03) but not
left ventricular diastolic dysfunction.4 The median duration on antiretroviral therapy (ART) in
this cohort was 4.7 years (interquartile range 2.6–6.4 years). Most participants (76.6%) were
receiving a regimen that included two nucleoside reverse transcriptase inhibitors and a
non-nucleoside reverse transcriptase inhibitor (NNRTI). However, the use of NVP was not
associated with LVH in a more recent study by the same authors. LVH has been associated with
NVP use in adults.5,6

Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-112
Pediatric Use
Approval
NVP is approved by the U.S. Food and Drug Administration (FDA) for treatment of HIV in children
from infancy (aged ≥15 days) onward and remains a mainstay of ART, especially in resource-limited
settings.7-15 The extended-release tablet formulation has been approved by the FDA for use in
children aged ≥6 years.

Efficacy in Clinical Trials

Randomized clinical trials in children have demonstrated that lopinavir/ritonavir (LPV/r) is superior
to NVP in young children but not in older children. IMPAACT P1060 demonstrated the superiority
of LPV/r over NVP in children aged <3 years, as have observational studies. PENPACT-1 and
PROMOTE-pediatrics showed no differences in virologic outcomes between an NNRTI-based
regimen (with either NVP or efavirenz [EFV]) and a protease inhibitor (PI)-based regimen in older
children with HIV.16-22

In infants and children who were previously exposed to a single dose of NVP to prevent perinatal
HIV transmission, NVP-based ART is less likely to control viral load than LPV/r-based ART. In
IMPAACT P1060, 153 children with HIV and previous exposure to NVP for perinatal prophylaxis
(mean age 0.7 years) were randomly assigned to treatment with zidovudine (ZDV) and
lamivudine (3TC) plus either NVP or LPV/r. At 24 weeks post-randomization, 24% of children in the
NVP arm had experienced virologic failure compared with 7% of children in the LPV/r arm
(P = 0.0009); virologic failure was defined as <1 log 10 decrease in HIV RNA during Weeks 12 to 24
or HIV RNA >400 copies/mL at Week 24. When all primary endpoints were considered, including
virologic failure, death, and treatment discontinuation, the PI arm remained superior; 40% of children
in the NVP arm met a primary endpoint compared with 22% of children in the LPV/r arm
(P = 0.027).19 Similar results were reported in a randomized trial that compared NVP and LPV/r in
children aged 6 to 36 months who had not been previously exposed to NVP. This finding suggests
that LPV/r-based therapy is superior to NVP-based therapy for infants, regardless of past NVP
exposure.16

Extended-release NVP tablets (400 mg) were approved by the FDA for use in children aged ≥6 years
in November 2012. Trial 1100.1518 was an open-label, multiple-dose, nonrandomized, crossover
trial performed in 85 pediatric participants with HIV. The participants had received at least 18 weeks
of immediate-release NVP tablets and had plasma HIV RNA <50 copies/mL prior to enrollment.
Participants were stratified according to age (3 years to <6 years, 6 years to <12 years, and 12 years
to <18 years). Participants received immediate-release NVP tablets for 11 weeks. Participants were
then treated with NVP extended-release tablets once daily in combination with other
antiretroviral (ARV) drugs for 10 days, after which steady-state pharmacokinetics (PKs) were
determined.23 Forty participants who completed the initial part of the study were enrolled in an
optional extension phase of the trial, which evaluated the safety and antiviral activity of extended-
release NVP tablets through a minimum of 24 weeks of treatment. Of the 40 participants who entered
the treatment extension phase, 39 completed at least 24 weeks of treatment. After 24 weeks or more
of treatment with extended-release tablets,24 all 39 participants continued to have plasma HIV RNA
<50 copies/mL.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-113
General Dosing Considerations
Body surface area (BSA) has traditionally been used to guide NVP dosing in infants and young
children. It is important to avoid underdosing NVP, because a single point mutation (K103N) in the
HIV genome may confer NNRTI resistance to both NVP and EFV. Younger children (aged ≤8 years)
have higher apparent oral clearance than older children. To achieve drug exposures that are
comparable to those seen in children aged >8 years, younger children require higher doses of NVP
than older children.12,13 Because of this, it is recommended that children aged <8 years receive NVP
200 mg/m2 of BSA per dose twice daily (the maximum dose of the immediate-release tablet
formulation is NVP 200 mg twice daily) or NVP 400 mg/m2 of BSA administered once daily as the
extended-release tablet formulation (the maximum dose of the extended-release tablet formulation is
NVP 400 mg once daily). For children aged ≥8 years, the recommended dose of the immediate-
release tablet formulation is NVP 120 mg/m2 of BSA per dose (with a maximum dose of NVP
200 mg) administered twice daily. The maximum dose of the extended-release tablet formulation is
NVP 400 mg once daily for children aged ≥6 years.

When adjusting the dose for a growing child, the milligram dose need not be decreased (from NVP
200 mg to NVP 120 mg/m2 of BSA) as the child reaches 8 years of age; rather, the milligram dose
can be left static if no adverse effects emerge and the dose achieves the appropriate mg/m2 of BSA
dose as the child grows. Some practitioners dose NVP at 150 mg/m2 of BSA every 12 hours or NVP
300 mg/m2 of BSA once daily if using the extended-release tablets, regardless of age, as
recommended in the FDA-approved product label. Regardless of age, the maximum dose should
never exceed NVP 200 mg twice daily for immediate-release formulations of NVP or NVP 400 mg
once daily for extended-release formulations of NVP.

Dosing Considerations: Lead-In Dosing

Underdosing during the lead-in period may have potentially contributed to the poorer performance of
NVP in the IMPAACT P1060 trial. This potential for underdosing, which can increase the risk of
resistance, has led to a re-evaluation of lead-in dosing in children who have never received NVP.
Traditionally, NVP is initiated with an age-appropriate dose that is given only once daily instead of
twice daily (NVP 200 mg/m2 of BSA in infants aged ≥15 days and children aged <8 years, using the
immediate-release formulations) during the first 2 weeks of treatment to allow the autoinduction of
the liver enzymes CYP3A and CYP2B6, which are involved in NVP metabolism.

Studies have previously indicated potential for greater drug toxicity without lead-in dosing; however,
most of these studies have been performed in adult cohorts.25 The CHAPAS-1 trial26 randomized
211 children to initiate ART with immediate-release NVP without a lead-in dose (participants
received an age-appropriate dose twice daily) or with a lead-in dose (participants received an
age-appropriate dose once daily) for 2 weeks, followed by the standard twice-daily dosing of the
immediate-release formulation of NVP. Children were followed for a median of 92 weeks (with a
range of 68–116 weeks), and no difference emerged in the frequency of Grade 3 or 4 adverse events
between the two groups. The group that initiated NVP without a lead-in dose had a statistically
significant increase in the incidence of Grade 2 rash, but most participants were able to continue
NVP therapy after a brief interruption. Through 96 weeks, a similar percentage of participants in both
groups reached the CD4 count and virologic failure endpoints.

After children had been on NVP for 2 weeks, investigators conducted a substudy that examined NVP
plasma concentrations 3 to 4 hours after a morning dose of NVP. Among children aged <2 years, 3 of

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-114
23 children (13%) who initiated at full dose had subtherapeutic NVP levels (<3 mg/L) at 2 weeks
compared with 7 of 22 children (32%) who initiated at half dose (P = 0.16). No rash events occurred
in the substudy group of participants aged <2 years; in the parent CHAPAS study, a strong age effect
on rash occurrence was seen, with the risk of rash increasing with age. These findings suggest that a
lead-in dose may not be necessary in young patients.27

The standard practice has been to reinitiate half-dose NVP for another 2 weeks in children who have
interrupted therapy for 7 days or longer; however, given the current understanding of NVP
resistance, the half-life of CYP enzymes,28 and the results of CHAPAS-1, the Panel on Antiretroviral
Therapy and Medical Management of Children Living with HIV (the Panel) recommends restarting
full-dose NVP in children who interrupt therapy for 14 days or less.

Special Considerations for Dosing: Neonates and Premature Infants

The PK and safety of NVP during the first weeks of life were evaluated as part of IMPAACT P1115.
This study demonstrated that NVP dosed at 6 mg/kg twice daily for infants ≥37 weeks gestational
age (GA) and 4 mg/kg twice daily for 1 week and 6 mg/kg twice daily thereafter for infants 34 to
<37 weeks GA achieved concentrations appropriate for treatment.29 Among 438 infants (389 infants
≥37 weeks GA), measured NVP concentrations were above the minimum HIV treatment target
(3 mcg/mL) in 90% of infants at Week 1 and 87% of infants at Week 2. Grade 3 and 4 adverse events
possibly related to treatment occurred in 7% of infants (with neutropenia and anemia being the most
common) but did not lead to NVP cessation.

PK modeling and simulation were performed with partial data from IMPAACT P1106 and P1115 to
determine appropriate NVP dosing in premature infants 32 to <34 weeks GA. GA and postnatal age
were significantly correlated with NVP oral clearance; thus the authors recommended a GA-based
starting dose for premature infants treated with NVP and a stepwise increase in dosing at 2-week
intervals.30 These data might underestimate potential drug toxicity in infants of 32 to <34 weeks GA,
because the doses used to develop the model were lower than the doses now recommended. NVP is
shown to be safe in infants >34 weeks GA, so the risk of toxicity in infants 32 to <34 weeks GA
seems low. The Panel considers that this risk–benefit ratio may justify the use of this dose in
premature infants 32 to <34 weeks GA.

The Early Infant Treatment Study in Botswana started 40 infants with HIV ≥35 weeks GA on NVP
6 mg/kg twice daily (without lead-in dosing) along with ZDV and 3TC at a median age 2 days
(range 1–5 days). NVP was switched to LPV/r at Week 2, 3, 4, or 5 according to delivery GA.
Although NVP trough concentrations were below the therapeutic target (3,000 mg/mL) for 50% of
2-week measurements, 37 of 40 infants (92.5%) had an HIV RNA decline.31 Providers who consider
initiating treatment in premature infants or in infants aged <2 weeks should weigh the risks and
benefits of using unapproved ART dosing and should incorporate case-specific factors, such as
exposure to ARV prophylaxis.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-115
References
1. Dziuban EJ, Hughey AB, Stewart DA, et al. Stevens-Johnson syndrome and HIV in children
in Swaziland. Pediatr Infect Dis J. 2013;32(12):1354-1358. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23743542.

2. du Toit JD, Kotze K, van der Westhuizen HM, Gaunt TL. Nevirapine-induced Stevens-
Johnson syndrome in children living with HIV in South Africa. South Afr J HIV Med.
2021;22(1):1182. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33824730.

3. Kea C, Puthanakit T, et al. Incidence and risk factors for nevirapine related toxicities among
HIV-infected Asian children randomized to starting ART at different CD4%. Abstract
MOPE240. Presented at: 6th IAS Conference on HIV Pathogenesis, Treatment and
Prevention; 2011. Rome, Italy,. Available at:

4. Majonga ED, Rehman AM, Simms V, et al. High prevalence of echocardiographic

abnormalities in older HIV-infected children taking antiretroviral therapy. AIDS.
2018;32(18):2739-2748. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30289814.

5. Pombo M, Olalla J, Del Arco A, et al. Left ventricular hypertrophy detected by

echocardiography in HIV-infected patients. Eur J Intern Med. 2013;24(6):558-561. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/23664642.

6. Majonga ED, Rehman AM, McHugh G, et al. Incidence and progression of

echocardiographic abnormalities in older children with human immunodeficiency virus and
adolescents taking antiretroviral therapy: a prospective cohort study. Clin Infect Dis.
2020;70(7):1372-1378. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31054255.

7. Janssens B, Raleigh B, Soeung S, et al. Effectiveness of highly active antiretroviral therapy in

HIV-positive children: evaluation at 12 months in a routine program in Cambodia.
Pediatrics. 2007;120(5):e1134-1140. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17954553.

8. King JR, Nachman S, Yogev R, et al. Efficacy, tolerability and pharmacokinetics of two
nelfinavir-based regimens in human immunodeficiency virus-infected children and
adolescents: pediatric AIDS clinical trials group protocol 403. Pediatr Infect Dis J.
2005;24(10):880-885. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16220085.

9. Krogstad P, Lee S, Johnson G, et al. Nucleoside-analogue reverse-transcriptase inhibitors

plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human
immunodeficiency virus type 1. Clin Infect Dis. 2002;34(7):991-1001. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11880966.

10. Luzuriaga K, McManus M, Mofenson L, et al. A trial of three antiretroviral regimens in HIV-
1-infected children. N Engl J Med. 2004;350(24):2471-2480. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15190139.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-116
11. Luzuriaga K, Bryson Y, McSherry G, et al. Pharmacokinetics, safety, and activity of
nevirapine in human immunodeficiency virus type 1-infected children. J Infect Dis.
1996;174(4):713-721. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8843207.

12. Luzuriaga K, Bryson Y, Krogstad P, et al. Combination treatment with zidovudine,

didanosine, and nevirapine in infants with human immunodeficiency virus type 1 infection. N
Engl J Med. 1997;336(19):1343-1349. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/9134874.

13. Mirochnick M, Clarke DF, Dorenbaum A. Nevirapine: pharmacokinetic considerations in

children and pregnant women. Clin Pharmacokinet. 2000;39(4):281-293. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/11069214.

14. Verweel G, Sharland M, Lyall H, et al. Nevirapine use in HIV-1-infected children. AIDS.
2003;17(11):1639-1647. Available at: https://pubmed.ncbi.nlm.nih.gov/12853746.

15. Wiznia A, Stanley K, Krogstad P, et al. Combination nucleoside analog reverse transcriptase
inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-
experienced HIV-infected children: week 24 results of a randomized controlled trial--PACTG
377. Pediatric AIDS Clinical Trials Group 377 Study Team. AIDS Res Hum Retroviruses.
2000;16(12):1113-1121. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10954886.

16. Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavir-boosted lopinavir for
HIV-infected children. N Engl J Med. 2012;366(25):2380-2389. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22716976.

17. Babiker A, Castro nee Green H, Compagnucci A, et al. First-line antiretroviral therapy with a
protease inhibitor versus non-nucleoside reverse transcriptase inhibitor and switch at higher
versus low viral load in HIV-infected children: an open-label, randomised phase 2/3 trial.
Lancet Infect Dis. 2011;11(4):273-283. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21288774.

18. Ruel TD, Kakuru A, Ikilezi G, et al. Virologic and immunologic outcomes of HIV-infected
Ugandan children randomized to lopinavir/ritonavir or nonnucleoside reverse transcriptase
inhibitor therapy. J Acquir Immune Defic Syndr. 2014;65(5):535-541. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24326597.

19. Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with
peripartum nevirapine exposure. N Engl J Med. 2010;363(16):1510-1520. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20942667.

20. Kamya MR, Mayanja-Kizza H, Kambugu A, et al. Predictors of long-term viral failure
among ugandan children and adults treated with antiretroviral therapy. J Acquir Immune
Defic Syndr. 2007;46(2):187-193. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/17693883.

21. Lowenthal ED, Ellenberg JH, Machine E, et al. Association between efavirenz-based
compared with nevirapine-based antiretroviral regimens and virological failure in HIV-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-117
 infected children. JAMA. 2013;309(17):1803-1809. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23632724.

22. Kekitiinwa A, Spyer M, et al. Virologic resonse to efavirenz vs. neviraopine-containing ART
in the ARROW trial. Presented at: 21st Conference on Retroviruses and Opportunistic
Infections (CROI); 2014. Boston, MA.

23. Giaquinto C, Anabwani G, Feiterna-Sperling C, et al. Steady-state pharmacokinetics of

nevirapine extended-release tablets in HIV-1-infected children and adolescents: an open-
label, multiple-dose, cross-over study. Pediatr Infect Dis J. 2014;33(7):e173-179. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/24378938.

24. Anabwani G, Konigs C, Giaquinto C, et al. Nevirapine extended-release formulation tablets

in HIV-1-infected children--long-term follow-up. Clin Infect Dis. 2015;61(3):476-479.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25917636.

25. Havlir D, Cheeseman SH, McLaughlin M, et al. High-dose nevirapine: safety,

pharmacokinetics, and antiviral effect in patients with human immunodeficiency virus
infection. J Infect Dis. 1995;171(3):537-545. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/7533197.

26. Mulenga V, Cook A, Walker AS, et al. Strategies for nevirapine initiation in HIV-infected
children taking pediatric fixed-dose combination "baby pills" in Zambia: a randomized
controlled trial. Clin Infect Dis. 2010;51(9):1081-1089. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20868279.

27. Fillekes Q, Mulenga V, Kabamba D, et al. Is nevirapine dose escalation appropriate in young,
african, HIV-infected children? AIDS. 2013;27(13):2111-2115. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23595153.

28. Magnusson MO, Dahl ML, Cederberg J, Karlsson MO, Sandstrom R. Pharmacodynamics of
carbamazepine-mediated induction of CYP3A4, CYP1A2, and Pgp as assessed by probe
substrates midazolam, caffeine, and digoxin. Clin Pharmacol Ther. 2008;84(1):52-62.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/17971810.

29. Ruel TD, Capparelli EV, Tierney C, et al. Pharmacokinetics and safety of early nevirapine-
based antiretroviral therapy for neonates at high risk for perinatal HIV infection: a phase 1/2
proof of concept study. Lancet HIV. 2020;S2352-3018(20):30274-30275. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33242457.

30. Bekker A, Hanan N, Violari A, et al. Population pharmacokinetics of nevirapine in preterm

infants and prediction of doses needed for treatment in combination with other antiretrovirals.
Presented at: 11th International Workshop on HIV Pediatrics; 2019. Mexico City, Mexico.
Available at: https://www.impaactnetwork.org/ias-2019.

31. Maswabi K, Ajibola G, Bennett K, et al. Safety and efficacy of starting antiretroviral therapy
in the first week of life. Clin Infect Dis. 2020;ciaa02. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31927562.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-118
Rilpivirine (RPV, Edurant)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Tablet: 25 mg

Fixed-Dose Combination Tablets

• [Complera] Emtricitabine 200 mg/rilpivirine 25 mg/tenofovir disoproxil fumarate 300 mg
• [Juluca] Dolutegravir 50 mg/rilpivirine 25 mg
• [Odefsey] Emtricitabine 200 mg/rilpivirine 25 mg/tenofovir alafenamide 25 mg

When using fixed-dose combination (FDC) tablets, refer to other sections of Appendix A: Pediatric Antiretroviral Drug
Information for information about the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-
Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and Considerations for Use in Children
and Adolescents.

Co-packaged Formulations
• [Cabenuva Kit] Cabotegravir 400 mg/2 mL (200 mg/mL) and rilpivirine 600 mg/2 mL (300 mg/mL) suspension for
intramuscular injection
• [Cabenuva Kit] Cabotegravir 600 mg/3 mL (200 mg/mL) and rilpivirine 900 mg/3 mL (300 mg/mL) suspension for
intramuscular injection

When using the co-packaged formulation, refer to the Cabotegravir section for additional information.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Neonate and Infant Dose • Depression
• Rilpivirine (RPV) is not approved for use in neonates or • Insomnia
infants.
• Headache
Children Aged <12 Years • Rash, which can be severe and include DRESS (drug
• RPV is not approved for use in children aged <12 years (for reaction [or rash] with eosinophilia and systemic
more information, see the Pharmacokinetics section symptoms)
below). • Hepatotoxicity
Child and Adolescent (Aged ≥12 Years and Weighing • Altered adrenocorticotropic hormone stimulation test of
≥35 kg) and Adult Dose uncertain clinical significance
• RPV 25 mg once daily with a meal in antiretroviral
therapy (ART)-naive patients who have HIV RNA
≤100,000 copies/mL or in patients who are virologically
suppressed (HIV RNA <50 copies/mL) with no history of
virologic failure or resistance to RPV and other
antiretroviral (ARV) drugs in the new regimen.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-119
 [Complera] Emtricitabine/Rilpivirine/Tenofovir Disoproxil
Fumarate (TDF) Special Instructions
Child and Adolescent (Aged ≥12 Years and Weighing • Do not start RPV in patients with HIV RNA
≥35 kg) and Adult Dose >100,000 copies/mL because of the increased risk of
virologic failure.
• One tablet once daily with a meal in ART-naive patients
with baseline viral loads ≤100,000 copies/mL. One tablet • RPV concentrations are significantly increased when
once daily also can be used to replace the current ARV either RPV or dolutegravir (DTG)/RPV is administered
regimen in patients who are currently on their first or with a moderate- or high-fat meal.1 Patients must be able
second regimen and who have been virologically to take RPV (or DTG/RPV) with a meal of at least
suppressed (HIV RNA <50 copies/mL) for at least 6 months 500 calories on a regular schedule (a protein drink alone
with no history of treatment failure and no known mutations does not constitute a meal).
associated with resistance to the individual components of • Do not use RPV with other non-nucleoside reverse
Complera. transcriptase inhibitors.
[Juluca] Dolutegravir/Rilpivirine • Do not use RPV with proton pump inhibitors
(e.g., omeprazole, pantoprazole).
Adult Dose
• Antacids should only be taken at least 2 hours before or
• One tablet once daily with a meal as a complete regimen to
at least 4 hours after RPV.
replace the current ARV regimen in patients who have
been virologically suppressed (HIV RNA <50 copies/mL) on • H2 receptor antagonists (e.g., cimetidine, famotidine)
a stable ARV regimen for at least 6 months with no history should only be administered at least 12 hours before or
of treatment failure and no known mutations associated at least 4 hours after RPV.
with resistance to the individual components of Juluca.
• Use RPV with caution when coadministering it with a
• Not approved for use in children or adolescents (see the drug that has a known risk of prolonging the QTc interval
Simplification of Treatment section below). or causing Torsades de Pointes (for more information,
see CredibleMeds).
[Odefsey] Emtricitabine/Rilpivirine/Tenofovir Alafenamide
(TAF) • Screen patients for hepatitis B virus (HBV) infection
before using FDC tablets that contain TDF or TAF.
Child and Adolescent (Aged ≥12 Years and Weighing Severe acute exacerbation of HBV infection can occur
≥35 kg) and Adult Dose when TDF or TAF are discontinued, see Tenofovir
• One tablet once daily with a meal in ART-naive patients Disoproxil Fumarate and Tenofovir Alafenamide.
with HIV RNA ≤100,000 copies/mL. One tablet once daily Therefore, hepatic function and hepatitis B viral load
also can be used to replace a stable ARV regimen in should be monitored for several months after therapy
patients who have been virologically suppressed (HIV RNA with TDF or TAF is discontinued in patients with HBV.
<50 copies/mL) for at least 6 months with no history of • Refer to Cabotegravir for special instructions when using
treatment failure and no known mutations associated with CAB and RPV for IM injection.
resistance to the individual components of Odefsey.

[Cabenuva] Cabotegravir (CAB) and Rilpivirine (RPV) Kit Metabolism/Elimination

Child and Adolescent (Aged ≥12 Years and Weighing • Cytochrome P450 3A substrate.
≥35 kg) and Adult Dose • Refer to Cabotegravir for information about the IM CAB
• Cabenuva is a two-drug co-packaged product for and RPV regimen.
intramuscular (IM) injection that is approved by the
U.S. Food and Drug Administration as a complete regimen Rilpivirine Dosing in Patients With Hepatic Impairment
for the treatment of HIV-1 in patients with HIV RNA levels • No dose adjustment is necessary in patients with mild or
<50 copies/mL on a stable ARV regimen with no history of moderate hepatic impairment.
treatment failure and no known or suspected resistance to
CAB or RPV. Rilpivirine Dosing in Patients With Renal Impairment
• RPV decreases tubular secretion of creatinine and
slightly increases measured serum creatinine, but it does
not affect glomerular filtration.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-120
 • Oral lead-in dosing for at least 28 days can be used to • No dose adjustment is necessary in patients with mild or
assess tolerability prior to initiating IM CAB and RPV moderate renal impairment. However, RPV should be
injections or patients can proceed directly to IM CAB and used with caution in patients with severe renal
RPV on the last day of their current ARV regimen. impairment or end-stage renal disease. These patients
should be monitored more frequently for adverse events;
• Refer to Cabotegravir for dosing information. renal dysfunction may alter drug absorption, distribution,
• Long-acting CAB and RPV for IM injection is not approved and metabolism, leading to increased RPV
for children aged <12 years. concentrations.
• The FDC tablet Complera should not be used in
patients with creatinine clearance (CrCl) <50 mL/min,
and the FDC tablet Odefsey should not be used in
patients with CrCl <30 mL/min. Patients with CrCl
<30 mL/min who are taking Juluca should be monitored
closely.
• When using Complera, see the Tenofovir Disoproxil
Fumarate section of the guidelines; when using Odefsey,
see the Tenofovir Alafenamide section.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Rilpivirine (RPV) is a cytochrome P450 (CYP) 3A substrate, and concentrations

may be affected when administered with CYP3A-modulating medications.
• A patient’s medication profile should be carefully reviewed for potential drug interactions before
RPV is administered.
• Coadministering RPV with drugs that increase gastric pH may decrease plasma concentrations of
RPV.
o Antacids should only be taken at least 2 hours before or at least 4 hours after RPV.
o H2 receptor antagonists should only be administered at least 12 hours before or at least
4 hours after RPV.
o Do not use RPV with proton pump inhibitors.
• All the rifamycins significantly reduce RPV plasma concentrations; coadministration of rifampin
and oral RPV is contraindicated. For patients who are concomitantly receiving rifabutin and
oral RPV, the dose of RPV should be doubled to 50 mg once daily and taken with a meal.
Intramuscular (IM) RPV given with IM CAB is contraindicated with rifampin, rifabutin, and
rifapentine.
• In a cohort of adolescent patients, RPV exposure was two to three times greater when RPV was
administered in combination with darunavir/ritonavir (DRV/r) than when RPV was administered
alone.2

Major Toxicities
• More common: Insomnia, headache, rash

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-121
• Less common (more severe): Depression or mood changes, suicidal ideation
In studies of adults, 7.3% of patients who were treated with RPV showed a change in adrenal
function characterized by an abnormal 250-microgram adrenocorticotropic hormone (ACTH)
stimulation test (peak cortisol level <18.1 micrograms/dL). In a study of adolescents, 6 out of
30 patients (20%) developed this abnormality.3 The clinical significance of these results is unknown.
• Rare: RPV drug-induced liver injury has been reported.4

Resistance
The International Antiviral Society–USA (IAS–USA) maintains a list of updated HIV drug resistance
mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each
mutation.

Transmitted drug resistance to second-generation non-nucleoside reverse transcriptase

inhibitors (NNRTIs) may be present in infants and children who have recently received a diagnosis
of HIV.

Pediatric Use
Approval
With the viral load and antiretroviral (ARV) resistance restrictions noted above, RPV (Edurant) used
in combination with other ARV agents, the fixed-dose combination (FDC) tablet
emtricitabine/rilpivirine/tenofovir disoproxil fumarate (FTC/RPV/TDF; Complera), the FDC tablet
emtricitabine/rilpivirine/tenofovir alafenamide (FTC/RPV/TAF; Odefsey) and the long-acting
regimen of cabotegravir (CAB) and RPV for IM injection (IM CAB and RPV; Cabenuva) are all
approved by the U.S. Food and Drug Administration (FDA) for use in persons aged ≥12 years and
weighing ≥35 kg. The FDC tablet dolutegravir/rilpivirine (DTG/RPV; Juluca) is not approved for use
in pediatric or adolescent patients at the time of this review.

Efficacy in Clinical Trials

An RPV-containing regimen has been compared to an efavirenz (EFV)-containing regimen in two
large clinical trials in adults—ECHO and THRIVE. In both studies, RPV was shown to be non-
inferior to EFV. Patients with pretreatment HIV viral loads ≥100,000 copies/mL who received RPV
had higher rates of virologic failure than those who received EFV. These findings resulted in FDA
approval for initial therapy with RPV only in patients with HIV viral loads ≤100,000 copies/mL.5-8

A study of antiretroviral therapy (ART)-naive adolescents aged 12 to 18 years demonstrated that

RPV 25 mg, given once daily in combination with two nucleoside reverse transcriptase
inhibitors (NRTIs), was well tolerated over 48 weeks. In studies of adolescents with baseline viral
loads ≤100,000 copies/mL, 86% had a virologic response at 24 weeks and 79% had a virologic
response at 48 weeks. In adolescents with baseline viral loads >100,000 copies/mL, 38% had a
virologic response at 24 weeks and 50% had a virologic response at 48 weeks.9

Patients must be able to take RPV on a regular schedule and with a full meal, which may limit its
usefulness for some adolescents with irregular schedules. The FDC formulation Odefsey is a small
pill and can be useful for certain patients who have difficulty swallowing pills and want to switch

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-122
from a multipill regimen, and who do not have any drug resistance mutations that are associated with
the components of Odefsey.

A Spanish multicenter observational study enrolled 17 adolescents (aged <18 years) who acquired
HIV perinatally to receive FTC/RPV/TDF (Complera) as part of an off-label medication use
program. At the time of enrollment, 12 patients were on a protease inhibitor-based regimen, 4 were
on an NNRTI-based regimen, and 1 had not received ART. After a median follow-up of 90 weeks
(for participants with undetectable viral loads at baseline) or 40 weeks (for participants with
detectable viral loads at baseline), 86% and 89% of patients, respectively, achieved and maintained
an undetectable viral load. None of the patients discontinued RPV-based therapy because of adverse
events (AEs); no skin rashes or central nervous system (CNS)-related events were observed. In
addition, serum lipids improved, and two adolescents with a history of insomnia and abnormal
dreams while receiving EFV-based therapy did not report similar problems while receiving RPV-
based therapy.10

Another study evaluated 102 virologically-suppressed Thai adolescents who were switched from an
EFV- to an RPV-based therapy. Ninety-four of the adolescents remained virologically suppressed
through 48 weeks; six experienced virologic failure. Overall, RPV was well tolerated. No
improvement in EFV-related symptoms (e.g., sleep, mood, dizziness, headache, concentration) was
observed, and no change in quality of life or depression scores could be documented; however, there
were significant improvements in some assessments of cognitive and executive function as measured
at week 24.11

Pharmacokinetics
The pharmacokinetics (PKs), safety, and efficacy of RPV in children aged <12 years have not been
established but are currently being studied in patients aged 6 years to <12 years and weighing ≥17 kg
(ClinicalTrials.gov identifier NCT00799864). The Panel on Antiretroviral Therapy and Medical
Management of Children Living With HIV (the Panel) has agreed that the use of RPV may be
appropriate in certain children aged <12 years and weighing ≥35 kg. However, the Panel
advises consulting an expert in pediatric HIV infection prior to prescribing RPV for a child in this
age and weight group.

An international (India, Thailand, Uganda, and South Africa) Phase 2 trial, Pediatric Study in
Adolescents Investigating a New NNRTI TMC278 (PAINT), investigated a 25-mg dose of RPV
given in combination with two NRTIs in ARV-naive adolescents aged 12 years to <18 years who
weighed ≥32 kg and who had viral loads ≤100,000 copies/mL.9 In the dose-finding phase of the
study, 11 youth aged >12 years to ≤15 years and 12 youth aged >15 years to ≤18 years underwent
intensive PK assessment after they took an observed dose of RPV with a meal. PKs were comparable
to those in adults; results are listed in the table below.12

Table A. Rilpivirine Pharmacokinetics in Adults and Adolescents Aged 12 Years to

<18 Years

Adolescents
Parameter Adults
Aged 12 Years to <18 Years
Dose RPV 25 mg once daily RPV 25 mg once daily

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-123
 Adolescents
Parameter Adults
Aged 12 Years to <18 Years
Number of Participants Studied 679 34

AUC 24h (ng·h/mL)

Mean ± SD 2,235 ± 851 2,424 ± 1,024

Median (Range) 2,096 (198–7,307) 2,269 (417–5,166)

C 0h (ng/mL)
Mean ± SD 79 ± 35 85 ± 40

Median (Range) 73 (2–288) 79 (7–202)

Source: Adapted from Rilpivirine [package insert]. Food and Drug Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/202022s014lbl.pdf
Key: AUC 24h = area under the curve after 24 hours; C 0h = plasma concentration just prior to next dose; RPV = rilpivirine;
SD = standard deviation

In a PK study of youth aged 13 to 23 years who received RPV,2 RPV exposure was comparable to
the exposure observed during the PAINT study in patients who received 25-mg doses of RPV
without DRV/r and substantially higher than the exposure observed in those who received 25-mg
doses of RPV with DRV/r (RPV area under the curve in this study was 6,740 ng·h/mL). No dose
adjustments are currently recommended for adults when RPV is coadministered with DRV/r, where a
similar twofold to threefold increase in RPV exposure has been reported.3

RPV has been reported to have fewer CNS AEs than EFV, and it has been promoted as a replacement
ARV drug for some patients who experience CNS effects while receiving EFV. However, concern
exists that the prolonged half-life of EFV might result in residual drug levels that could have an
impact on RPV levels. A Thai study evaluated 20 Thai adolescents 4 weeks after they switched from
EFV to RPV. The PK parameters of RPV in this study population were comparable to those in
previous pediatric (PAINT) and adult (ECHO/THRIVE) PK substudies. No virologic failure was
detected at 12 or 24 weeks, and no patients discontinued RPV because of AEs.13

Simplification of Treatment
Juluca is an FDC tablet that contains DTG 50 mg and RPV 25 mg. The results from two trials in
adults (SWORD-1 and SWORD-2) supported FDA approval of DTG/RPV as a complete regimen for
treatment simplification or maintenance therapy in certain patients. The two identical SWORD trials
enrolled 1,024 patients with suppressed viral replication who had been on stable ART for at least
6 months and had no history of treatment failure or evidence of resistance mutations that are
associated with DTG or RPV. The participants were randomized to receive DTG/RPV (“early
switch”) or to continue their suppressive ARV regimen. After 48 weeks of treatment, 95% of patients
in both arms maintained HIV RNA <50 copies/mL.14 After 52 weeks, the participants who had been
randomized to continue their suppressive ARV regimen were switched to DTG/RPV (“late switch”).
At 148 weeks of treatment, 84% of the early switch patients and 90% of the late switch patients
remained virologically suppressed, and only 11 patients receiving dual therapy (DTG/RPV) met
virologic failure criteria. No integrase inhibitor resistance was identified.15 More AEs were reported,
and more AEs led to treatment discontinuation in the DTG/RPV arm during the comparative

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-124
randomized phase. In a subgroup of SWORD study patients whose original ARV regimen contained
TDF, small but statistically significant increases in hip and spine bone mineral density were
observed.16 Although DTG/RPV as Juluca is not approved for use in adolescents, the doses of both
component drugs that make up Juluca are approved for use in adolescents. This product may be
appropriate for certain adolescents; however, because the strategy of treatment simplification has not
been evaluated in adolescents, who may have difficulties adhering to therapy, the Panel does not
recommend using Juluca in adolescents and children until more data are available.

Long-Acting Injectable Rilpivirine

A long-acting IM injectable formulation of RPV has recently been approved for coadministration
with IM CAB as a complete ARV regimen for children and adolescents aged ≥12 years and weighing
≥35 kg and adults with HIV RNA levels <50 copies/mL, on a stable ARV regimen, with no history
of treatment failure, and no known or suspected resistance to CAB or RPV.17 This formulation has
been evaluated in adults as monthly or every-2 month intramuscular injections following an initial
oral, lead-in daily dose for 4 weeks to assess toxicity.18-20 These studies in adult patients
demonstrated non-inferior efficacy to standard oral therapy and good participant satisfaction and
tolerability through 96 weeks. A follow-on study demonstrated that dosing IM CAB and RPV every
2 months in virally suppressed participants provided similar safety and efficacy to monthly injections
through 48 weeks.21 Additionally, an extension of one study evaluated the benefit of oral lead-in
therapy prior to initiating IM CAB and RPV, demonstrating that initial oral therapy can be optional
based on the needs and desires of persons initiating treatment.22 IMPAACT study 2017, More
Options for Children and Adolescents (MOCHA), is currently evaluating the safety, tolerability,
acceptability, and PK profile of this injectable regimen in adolescents weighing ≥35 kg
(ClinicalTrials.gov identifier NCT03497676) and has reported acceptable PKs and safety for the
single IM products administered monthly and good acceptability by both adolescents and their
parents.23,24 However, MOCHA has not completed evaluating the dual injectable regimen long term,
and clinical experience with IM CAB and RPV remains limited. See the Cabotegravir section for
more information about this regimen.

Toxicity
In the PAINT study, the observed AEs were similar to those reported in adults (e.g., somnolence,
nausea, vomiting, abdominal pain, dizziness, headache). The incidence of depressive disorders was
19.4% (7 of 36 participants) compared to 9% in the Phase 3 trials in adults. The incidence of Grade 3
and 4 depressive disorders was 5.6% (2 of 36 participants).3

Six out of 30 adolescents (20%) with a normal ACTH stimulation test at baseline developed an
abnormal test during the trial. No serious AEs, deaths, or treatment discontinuations were attributed
to adrenal insufficiency. The clinical significance of abnormal ACTH stimulation tests is not known,
but this finding warrants further evaluation.3

Crushing Tablets for Enteral Administration

Some cases report DTG/RPV tablets’ being crushed and successfully administered via an enteral
tube.25 If DTG/RPV is administered via enteral tube, care should be taken to disperse the tablets
completely and flush the tube to avoid clogging.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-125
References

1. Mehta R, Piscitelli J, Wolstenholme A, et al. The effect of moderate- and high-fat meals
on the bioavailability of dolutegravir/rilpivirine fixed-dose combination tablet. Clin
Pharmacol. 2020;12:49-52. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32607002.

2. Foca M, Yogev R, Wiznia A, et al. Rilpivirine pharmacokinetics without and with

darunavir/ritonavir once daily in adolescents and young adults. Pediatr Infect Dis J.
2016;35(9):e271-274. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27187753.

3. Rilpivirine (Edurant) [package insert]. Food and Drug Administration. 2022. Available
at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/202022s016lbl.pdf.

4. Lee MJ, Berry P, D'Errico F, Miquel R, Kulasegaram R. A case of rilpivirine drug-

induced liver injury. Sex Transm Infect. 2020;96(8):618-619. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31974214.

5. Cohen CJ, Andrade-Villanueva J, Clotet B, et al. Rilpivirine versus efavirenz with two
background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive
adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial.
Lancet. 2011;378(9787):229-237. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21763935.

6. Cohen CJ, Molina JM, Cahn P, et al. Efficacy and safety of rilpivirine (TMC278) versus
efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the
phase 3 double-blind randomized ECHO and THRIVE trials. J Acquir Immune Defic
Syndr. 2012;60(1):33-42. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22343174.

7. Cohen CJ, Molina JM, Cassetti I, et al. Week 96 efficacy and safety of rilpivirine in
treatment-naive, HIV-1 patients in two Phase III randomized trials. AIDS.
2013;27(6):939-950. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23211772.

8. Molina JM, Cahn P, Grinsztejn B, et al. Rilpivirine versus efavirenz with tenofovir and
emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3
randomised double-blind active-controlled trial. Lancet. 2011;378(9787):238-246.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/21763936.

9. Lombaard J, Bunupuradah T, Flynn PM, et al. Rilpivirine as a treatment for HIV-infected

antiretroviral-naive adolescents: week 48 safety, efficacy, virology and pharmacokinetics.
Pediatr Infect Dis J. 2016;35(11):1215-1221. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27294305.

10. Falcon-Neyra L, Palladino C, Navarro Gomez ML, et al. Off-label use of rilpivirine in
combination with emtricitabine and tenofovir in HIV-1-infected pediatric patients: a
multicenter study. Medicine (Baltimore). 2016;95(24):e3842. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27310962.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-126
11. Phongsamart W, Jantarabenjakul W, Chantaratin S, et al. Switching efavirenz to
rilpivirine in virologically suppressed adolescents with HIV: a multi-centre 48-week
efficacy and safety study in Thailand. J Int AIDS Soc. 2022;25(1):e25862. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35001501.

12. Crauwels H, Hoogstoel A, Vanveggel S, et al. Rilpivirine pharmacokinetics in HIV-1-

infected adolescents: a substudy of PAINT (Phase II trial). Presented at: Conference on
Retroviruses and Opportunistic Infections; 2014. Boston, MA. Available at:
https://www.croiconference.org/sessions/rilpivirine-pharmacokinetics-hiv-1-infected-
adolescents-substudy-paint-phase-ii-trial.

13. Jantarabenjakul W, Anugulruengkitt S, Kasipong N, et al. Pharmacokinetics of rilpivirine

and 24-week outcomes after switching from efavirenz in virologically suppressed HIV-1-
infected adolescents. Antivir Ther. 2018;23(3):259-265. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28994660.

14. Llibre JM, Hung CC, Brinson C, et al. Efficacy, safety, and tolerability of dolutegravir-
rilpivirine for the maintenance of virological suppression in adults with HIV-1: phase 3,
randomised, non-inferiority SWORD-1 and SWORD-2 studies. Lancet.
2018;391(10123):839-849. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29310899.

15. van Wyk J, Orkin C, Rubio R, et al. Brief Report: Durable suppression and low rate of
virologic failure 3 years after switch to dolutegravir + rilpivirine 2-drug regimen: 148-
week results from the SWORD-1 and -2 randomized clinical trials. J Acquir Immune
Defic Syndr. 2020;85(3):325-330. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32675772.

16. McComsey GA, Lupo S, Parks D, et al. Switch from tenofovir disoproxil fumarate
combination to dolutegravir with rilpivirine improves parameters of bone health. AIDS.
2018;32(4):477-485. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29239893.

17. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-

release injectable suspension), co-packaged for intramuscular use [package insert]. Food
and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212888s002lbl.pdf.

18. Margolis DA, Gonzalez-Garcia J, Stellbrink HJ, et al. Long-acting intramuscular

cabotegravir and rilpivirine in adults with HIV-1 infection (LATTE-2): 96-week results
of a randomised, open-label, phase 2b, non-inferiority trial. Lancet.
2017;390(10101):1499-1510. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28750935.

19. Orkin C, Oka S, Philibert P, et al. Long-acting cabotegravir plus rilpivirine for treatment
in adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3
FLAIR study. Lancet HIV. 2021;8(4):e185-e196. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33794181.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-127
20. Swindells S, Lutz T, Van Zyl L, et al. Week 96 extension results of a Phase 3 study
evaluating long-acting cabotegravir with rilpivirine for HIV-1 treatment. AIDS.
2022;36(2):185-194. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34261093.

21. Overton ET, Richmond G, Rizzardini G, et al. Long-acting cabotegravir and rilpivirine
dosed every 2 months in adults with HIV-1 infection (ATLAS-2M), 48-week results: a
randomised, multicentre, open-label, phase 3b, non-inferiority study. Lancet.
2021;396(10267):1994-2005. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33308425.

22. Orkin C, Bernal Morell E, Tan DHS, et al. Initiation of long-acting cabotegravir plus
rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection:
week 124 results of the open-label phase 3 FLAIR study. Lancet HIV. 2021;8(11):e668-
e678. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34656207.

23. Lowenthal E, Chapman J, Calabrese K, et al. Adolescent and parent experiences with
long-acting injectables in the MOCHA study. Presented at: Conference on Retroviruses
and Opportunistic Infections; 2022. Virtual Conference. Available at:
https://www.croiconference.org/abstract/adolescent-and-parent-experiences-with-long-
acting-injectables-in-the-mocha-study.

24. Moore CB, Capparelli E, Calabrese K, et al. Safety and PK of long-acting cabotegravir
and rilpivirine in adolescents. Presented at: Conference on Retroviruses and
Opportunistic Infections 2022. Virtual Conference. Available at:
https://www.croiconference.org/abstract/safety-and-pk-of-long-acting-cabotegravir-and-
rilpivirine-in-adolescents.

25. Turley SL, Fulco PP. Enteral administration of twice-daily dolutegravir and rilpivirine as
a part of a triple-therapy regimen in a critically ill patient with HIV. J Int Assoc Provid
AIDS Care. 2017;16(2):117-119. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28198203.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-128
Appendix A: Pediatric Antiretroviral Drug Information
Protease Inhibitors
Atazanavir (ATV, Reyataz)

Darunavir (DRV, Prezista)

Lopinavir/Ritonavir (LPV/r, Kaletra)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-129
Atazanavir (ATV, Reyataz)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Powder Packet: 50 mg/packet

Capsules: 150 mg, 200 mg, 300 mg

Generic Formulations
• 150-mg, 200-mg, and 300-mg capsules

Fixed-Dose Combination Tablets

• [Evotaz] Atazanavir 300 mg/cobicistat 150 mg

Capsules and powder packets are not interchangeable.

For additional information, see Drugs@FDA: FDA-Approved Drugs or DailyMed.

Dosing Recommendations Selected Adverse Events

Neonate Dose • Indirect hyperbilirubinemia
• Atazanavir (ATV) is not approved for use in neonates and • Prolonged electrocardiogram PR interval, first-degree
infants aged <3 months. ATV should not be administered symptomatic atrioventricular block in some patients
to neonates because of risks associated with
hyperbilirubinemia (e.g., bilirubin-induced neurologic • Nephrolithiasis
dysfunction). • Increased serum transaminases
Infant and Child Dose • Hyperlipidemia (occurs primarily with RTV boosting)
Powder Formulation of Atazanavira
Special Instructions
• The powder formulation of ATV must be administered with
ritonavir (RTV). • Administer ATV with food to enhance absorption.

• The powder formulation is not approved for use in infants • Capsules and powder packets are not interchangeable.
aged <3 months or weighing <5 kg. • Do not open capsules.
Atazanavir Powder Dosing Table for Infants and Children • Because ATV can prolong the PR interval of the
Aged ≥3 Months and Weighing ≥5 kga electrocardiogram, use ATV with caution in patients with
preexisting cardiac conduction system disease or with
Weight Once-Daily Dose other drugs that are known to prolong the PR interval
(e.g., calcium channel blockers, beta-blockers, digoxin,
5 kg to <15 kg ATV 200 mg (four packets) plus RTV verapamil).
80 mg (1 mL oral solution) with food
• ATV absorption is dependent on low gastric pH;
15 kg to <25 kgb ATV 250 mg (five packets) plus RTV therefore, when ATV is administered with medications
80 mg (1 mL oral solution) with food that alter gastric pH, dosing adjustments may be
indicated (see the Drug Interactions section in the ATV
package insert).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-130
 • The plasma concentration and, therefore, the therapeutic
Capsule Formulation of Atazanavira effect of ATV can be expected to decrease substantially
• ATV capsules are not approved for use in children aged when ATV is coadministered with proton-pump
<6 years or weighing <15 kg. inhibitors (PPIs). Antiretroviral therapy (ART)-naive
patients who are receiving any PPI should receive a
Atazanavir/Ritonavir Capsule Dosing Table for Children dose of that PPI that is equivalent to no more than a
and Adolescents Aged ≥6 Years and Weighing ≥15 kg 20-mg dose of omeprazole. PPIs should be taken
approximately 12 hours before taking boosted ATV.
Weight Once-Daily Dose Coadministration of ATV with PPIs is not recommended
in ART-experienced patients.
<15 kg Capsules not recommended
• Patients with hepatitis B virus or hepatitis C virus
15 kg to <35 kg ATV/r 200 mg/100 mg, both with foodc infections and patients who had marked elevations in
transaminase levels before treatment may have an
≥35 kg ATV/r 300 mg/100 mg, both with foodc
increased risk of further elevations in transaminase
levels or hepatic decompensation.
ART-Naive Patients Who Are Unable to Tolerate Ritonavir
• ATV oral powder contains phenylalanine, which can be
Child and Adolescent (Aged ≥13 Years and Weighing harmful to patients with phenylketonuria. Each packet of
≥40 kg) and Adult Dose oral powder contains 35 mg of phenylalanine.
• ATV 400 mg (capsule formulation only) once daily with food Powder Administration
• ATV powder is not an option, because it must be • Mix ATV oral powder with at least 1 tablespoon of soft
administered with RTV. food (e.g., applesauce, yogurt). Oral powder mixed with
• For the capsule formulation, although the U.S. Food and a beverage (at least 30 mL of milk or water) may be used
Drug Administration (FDA) does not recommend the use of for older infants who can drink from a cup. For young
unboosted ATV in children aged <13 years, adolescents infants (aged <6 months) who cannot eat solid food or
aged ≥13 years and weighing ≥40 kg may be prescribed drink from a cup, oral powder should be mixed with at
unboosted ATV if they are not concurrently taking tenofovir least 10 mL of infant formula and administered using an
disoproxil fumarate (TDF) or tenofovir alafenamide (TAF). oral dosing syringe.

• To achieve target drug concentrations, adolescents may • Administer RTV immediately following powder
require doses of ATV that are higher than those administration.
recommended for use in adults (see Pediatric Use below). • Administer the entire dose of oral powder within 1 hour of
• The Panel on Antiretroviral Therapy and Medical preparation.
Management of Children Living with HIV does not
recommend the use of unboosted ATV. Metabolism/Elimination

ART-Naive and ART-Experienced Patients • ATV is a substrate and inhibitor of cytochrome

P450 (CYP) 3A4 and an inhibitor of CYP1A2, CYP2C9,
Child and Adolescent (Weighing ≥35 kg) and Adult Dose and uridine diphosphate glucuronosyltransferase 1A1.
• Atazanavir/ritonavir (ATV/r) 300 mg/100 mg once daily with
Atazanavir Dosing in Patients With Hepatic Impairment
food.d
• ATV should be used with caution in patients with mild or
• Atazanavir/cobicistat (ATV/c) 300 mg/150 mg once daily
moderate hepatic impairment. Consult the
with food, administered as single agents simultaneously or
manufacturer’s prescribing information for the dose
as the coformulated drug Evotaz.e
adjustment in patients with moderate impairment.
• Both ATV/r and ATV/c must be used in combination with
• ATV should not be used in patients with severe hepatic
other antiretroviral drugs.
impairment.
[Evotaz] Atazanavir/Cobicistat
Atazanavir Dosing in Patients With Renal Impairment
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• No dose adjustment is required for patients with renal
• One tablet once daily with food impairment.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-131
 • ATV should not be given to ART-experienced patients
with end-stage renal disease who are on hemodialysis.
amg/kg dosing is higher for the ATV powder packets than for the capsules. In P1020A, children of similar age and size who
were taking ATV powder had lower exposures than those who were taking ATV capsules.
bChildren weighing ≥25 kg who cannot swallow ATV capsules may receive ATV 300 mg oral powder (six packets) plus RTV
100 mg oral solution, both administered once daily with food.
c Either RTV capsules or RTV oral solution can be used.
dAdult patients who cannot swallow capsules may take ATV oral powder once daily with food using the adult dose for the
capsules. ATV oral powder should be administered with RTV.
eSee the Cobicistat section for important information about toxicity, drug interactions, and monitoring of patients who receive
cobicistat (COBI) and the combination of COBI and TDF.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Atazanavir (ATV) is both a substrate and an inhibitor of the cytochrome

P450 (CYP) 3A4 enzyme system and has significant interactions with drugs that are highly
dependent on CYP3A4 for metabolism. ATV also competitively inhibits CYP1A2 and CYP2C9.
ATV is a weak inhibitor of CYP2C8. ATV inhibits the glucuronidation enzyme uridine
diphosphate glucuronosyl transferase (UGT1A1). Because of the potential for multiple drug
interactions with ATV, a patient’s medication profile should be carefully reviewed for potential
drug interactions before administering ATV.
• Nucleoside reverse transcriptase inhibitors (NRTIs): Tenofovir disoproxil fumarate (TDF)
decreases ATV plasma concentrations. Only atazanavir/ritonavir (ATV/r) or
atazanavir/cobicistat (ATV/c) should be used in combination with TDF. The effect of tenofovir
alafenamide (TAF) on unboosted ATV is unknown; thus, only ATV/r or ATV/c should be used
with TAF.
• Non-nucleoside reverse transcriptase inhibitors: Efavirenz (EFV), etravirine (ETR), and
nevirapine (NVP) decrease ATV plasma concentrations significantly. NVP and ETR should not
be administered to patients who are receiving ATV (with or without a booster). Although the
combination of EFV and ATV/r is not commonly used in clinical practice, EFV may be used in
combination with ritonavir (RTV)-boosted ATV 400 mg in antiretroviral therapy (ART)-naive
patients. ATV/r should be taken with food, and EFV should be taken on an empty stomach,
preferably at bedtime. Coadministering ATV/r and EFV in ART-experienced patients is not
recommended, because this combination is expected to result in suboptimal ATV exposure in
these patients.
• Integrase strand transfer inhibitors: ATV is an inhibitor of UGT1A1 and may increase plasma
concentrations of raltegravir (RAL). This interaction may not be clinically significant.
• Absorption: ATV absorption is dependent on low gastric pH. The dose for ATV should be
adjusted when it is administered with medications that alter gastric pH. Guidelines for the
appropriate doses of ATV to use with antacids, H2 receptor antagonists, and proton-pump
inhibitors in adults are complex and can be found in the package insert for ATV. No information
is available on the appropriate doses of ATV to use in children when the drug is coadministered
with medications that alter gastric pH.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-132
• Coadministering cobicistat (COBI)—a CYP3A4 inhibitor—and medications that are metabolized
by CYP3A4 may increase the plasma concentrations of these medications. This may increase the
risk of clinically significant adverse reactions (including life-threatening or fatal reactions) that
are associated with the concomitant medications. Coadministration of COBI, ATV, and CYP3A4
inducers may lead to lower exposures of COBI and ATV, a loss of efficacy of ATV, and possible
development of resistance.1 Coadministering COBI and ATV with some antiretroviral (ARV)
agents (e.g., with ETR, with EFV in ART-experienced patients, or with another ARV drug that
requires pharmacokinetic [PK] enhancement, such as another protease inhibitor [PI] or
elvitegravir) may result in decreased plasma concentrations of that agent, leading to loss of
therapeutic effect and the development of resistance.

Major Toxicities
• More common: Indirect hyperbilirubinemia that can result in jaundice or icterus but is not a
marker of hepatic toxicity. Headache, fever, arthralgia, depression, insomnia, dizziness, nausea,
vomiting, diarrhea, and paresthesia.
• Less common: Prolongation of the electrocardiogram PR interval. Abnormalities in
atrioventricular (AV) conduction are generally limited to first-degree AV block, but second-
degree AV block has been reported. Rash is generally mild or moderate, but in rare cases
includes life-threatening Stevens-Johnson syndrome. Fat maldistribution and lipid abnormalities
may be less common than with other PIs. The use of ATV/r is associated with lipid
abnormalities, but to a lesser extent than with other boosted PIs.
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting
diabetes mellitus, spontaneous bleeding in hemophiliacs, and elevation in serum transaminases.
Chronic kidney disease, including biopsy-proven cases of granulomatous interstitial nephritis that
were associated with the deposition of ATV drug crystals in the renal parenchyma have occurred.
Nephrolithiasis and cholelithiasis have been reported. Hepatotoxicity (patients with hepatitis B
virus or hepatitis C virus infections are at increased risk of hepatotoxicity).

Resistance
The International Antiviral Society–USA maintains a list of updated resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
ATV is approved by the U.S. Food and Drug Administration (FDA) for use in infants (aged
≥3 months and weighing ≥5 kg), children, and adolescents. ATV coformulated with COBI (as
Evotaz) has been approved by the FDA for use in pediatric patients weighing ≥35 kg.

Efficacy
Studies in ART-naive adults have shown that ATV/r is as effective as EFV and lopinavir/ritonavir
(LPV/r) when these drugs are administered with two NRTIs.2-5 In AIDS Clinical Trials Group
(ACTG) A5257, ATV/r was compared to darunavir/ritonavir (DRV/r) or RAL, each administered

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-133
with a TDF/emtricitabine backbone. Although all three regimens had equal virologic efficacy, the
regimen that contained ATV/r was discontinued more frequently than the other regimens because of
toxicity but most often because of hyperbilirubinemia or gastrointestinal complaints.6

International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT)/Pediatric AIDS

Clinical Trials Group (PACTG) P1020 enrolled 195 ART-naive and ART-experienced patients with
HIV aged 3 months to 21 years. Capsule and powder formulations of ATV given with and without
RTV boosting were investigated in this open-label study; area under the curve (AUC) targeting was
used to direct dose finding. Of the 195 patients enrolled, 142 patients received ATV-based treatment
at the final recommended dose. Among these patients, 58% were ART-naive. At Week 48, 69.5% of
the ART-naive patients and 43.3% of the ART-experienced patients had HIV viral loads
≤400 copies/mL.7,8

Two open-label clinical trials in infants and children, PRINCE-1 and PRINCE-2, studied a powder
formulation of ATV that was administered once daily and boosted with liquid RTV.9-11 In total,
134 infants and children aged ≥3 months and weighing between 5 kg and 35 kg were evaluated.
Using a modified intent-to-treat analysis, 28 of 52 ARV-naive patients (54%) and 41 of 82 ART-
experienced patients (50%) had HIV RNA <50 copies/mL at Week 48. The median increase
from baseline in absolute CD4 T lymphocyte cell count at 48 weeks of therapy was 215 cells/mm3
(a 6% increase) in ARV-naive patients and 133 cells/mm3 (a 4% increase) in ARV-experienced
patients.

Pharmacokinetics and Dosing

Oral Capsule

The results of the IMPAACT/PACTG 1020A trial in children and adolescents indicate that, in the
absence of RTV boosting, ATV can achieve protocol-defined PK targets—but only when used at
higher doses (on a mg per kg body weight or mg per m2 of body surface area basis) than the doses
that are currently recommended in adults. In IMPAACT/PACTG 1020A, children aged >6 years to
<13 years required a dose of 520 mg per m2 of body surface area per day of the ATV capsule
formulation to achieve PK targets.8 Unboosted ATV at this dose was well tolerated in those aged
<13 years who were able to swallow capsules.12 The approved dose for adults is ATV 400 mg once
daily without RTV boosting; however, adolescents aged >13 years required a dose of ATV 620 mg
per m2 of body surface area per day.8 In this study, the AUCs for the unboosted arms were similar to
those seen in the ATV/r arms, but the maximum plasma concentration (C max ) was higher and the
minimum plasma concentration (C min ) was lower in the unboosted arms. Median doses of ATV, both
with and without RTV boosting, from IMPAACT/PACTG 1020A are outlined in the table below.
When administering unboosted ATV to pediatric patients, therapeutic drug monitoring is
recommended to ensure that adequate ATV plasma concentrations have been achieved. A minimum
target trough concentration for ATV is 150 ng/mL.13 Higher target trough concentrations may be
required in PI-experienced patients. IMPAACT P1058, a study of unboosted ATV PKs in ART-
experienced children, concluded that once-daily ATV 400 mg provided suboptimal exposure and that
administering higher, unboosted doses or splitting the daily dose into twice-daily doses warranted
investigation in ART-experienced children, adolescents, and young adults.14

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-134
Table A. Summary of Atazanavir Dosing Information Obtained from IMPAACT/PACTG
1020A

Age Range ATV Given with RTV ATV Median Dose (mg/m2)a ATV Median Dose (mg)
6–13 years No 509 475
6–13 years Yes 206 200
>13 years No 620 900
>13 years Yes 195 350
a These doses satisfied protocol-defined area under the curve/pharmacokinetic parameters and met all acceptable safety
targets. These doses differ from those recommended by the manufacturer. Therapeutic drug monitoring was used to determine
patient-specific dosing in this trial.
Source: Kiser JJ, Rutstein RM, Samson P, et al. Atazanavir and atazanavir/ritonavir pharmacokinetics in HIV-infected infants,
children, and adolescents. AIDS. 2011;25(12):1489-96.
Key: ATV = atazanavir; RTV = ritonavir

In the report of the IMPAACT/PACTG P1020A data, ATV satisfied PK criteria at a dose of 205 mg
per m2 of body surface area in pediatric subjects when administered with RTV.12 A study of a model-
based approach that used ATV concentration-time data from three adult studies and one pediatric
study (P1020A),15 along with subsequent additional adjusted modeling,16 informed the use of the
following weight-based ATV/r doses that are listed in the current FDA-approved product label for
children aged ≥6 years to <18 years:

• Weighing 15 kg to <35 kg: ATV/r 200 mg/100 mg

• Weighing ≥35 kg: ATV/r 300 mg/100 mg

Cobicistat as a Pharmacokinetic Enhancer

COBI (as Tybost) is approved by the FDA at the 150-mg dose for use with ATV 300 mg in children
and adolescents weighing ≥35 kg. A study of 14 adolescents, aged 12 to 18 years, showed that COBI
is a safe and effective PK enhancer when used in combination with ATV and two NRTIs in
adolescent patients.17 PK findings from this study are summarized in Table B below.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-135
Table B. Pharmacokinetic Parameters for Atazanavir Administered with Cobicistat (as
Tybost) in Pediatric Patients Aged 12 to 18 Years and Adults

ATV COBI
PK Parametersa
Pediatric Patients Adult Patients Pediatric Patients Adult Patients
(n = 12) (n = 30) (n = 12) (n = 30)
AUC tau μg∙h/mL 49.48 (49.1) 39.96 (52.1) 12.11 (44.7) 9.65 (41.8)
Geometric mean (CV%)
C max μg/mL 4.32 (49.9) 3.54 (45.8) 1.28 (31.7) 1.28 (35.6)
Geometric mean (CV%)
C tau μg/mL 0.91 (96.4) 0.58 (84.7) 0.09 (156.2) 0.04 (112.7)
Geometric mean (CV%)
a The information in this table comes from the Tybost package insert.10
Key: ATV = atazanavir; AUC tau = area under the concentration time curve over the dosing interval; C max = maximum serum
concentration; C tau = trough serum concentration at the end of the dosing interval; COBI = cobicistat; CV = coefficient of
variation; PK = pharmacokinetic

Oral Powder

The unboosted ATV powder arms in IMPAACT/PACTG P1020A were closed, because participants
were unable to achieve target exposures. For the IMPAACT/PACTG P1020A trial, AUC targets
(30,000 ng·hr/mL to 90,000 ng·hr/mL) were established based on exposures in adults in early studies
of unboosted ATV. In IMPAACT/PACTG P1020A, children aged 3 months to 2 years who were in
the boosted ATV powder cohorts and who received a daily dose of ATV 310 mg per m2 of body
surface area achieved average ATV exposures that approached, but did not meet, protocol targets.
Variability in exposures was high, especially among the very young children of 3 months to 2 years
in this study.8

Assessment of the PKs, safety, tolerability, and virologic response of ATV oral powder for FDA
approval was based on data from two open-label, multicenter clinical trials:

• PRINCE-1, which enrolled pediatric patients aged 3 months to <6 years;9 and
• PRINCE-2, which enrolled pediatric patients aged 3 months to <11 years.10

In total, 134 treated patients (weighing 5 kg to <35 kg) from both studies were evaluated during the
FDA approval process. All patients in the PRINCE trials were treated with boosted ATV and two
NRTIs. Children received an oral solution that contained ATV and RTV. Doses were assigned
according to the child’s weight:

• Weighing 5 kg to <10 kg: ATV 150 mg or ATV 200 mg and RTV 80 mg

• Weighing 10 kg to <15 kg: ATV 200 mg and RTV 80 mg
• Weighing 15 kg to <25 kg: ATV 250 mg and RTV 80 mg
• Weighing 25 kg to <35 kg: ATV 300 mg and RTV 100 mg

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-136
No new safety concerns were identified during these trials. Table C lists the PK parameters that were
measured during the PRINCE trials, including mean AUC, for the weight ranges that correspond to
the recommended doses.

Table C. Pharmacokinetic Parameters for Atazanavir Powder in Children (PRINCE-1 and

PRINCE-2) versus Capsules in Young Adults and Adults

PRINCE Triala ATV/r

Dose: Dose: Dose: Dose: Dose:
150 mg/ 200 mg/ 200 mg/ 250 mg/ 300 mg/
PK Young Adult Adult
80 mg 80 mg 80 mg 80 mg 100 mg
Parameters Studyb Study
Weighing: Weighing: Weighing: Weighing: Weighing:
5 kg to 5 kg to 10 kg to 15 kg to ≥25 kg to
<10 kg <10 kg <15 kg <25 kg <35 kg
AUC 32,503 39,519 50,305 55,687 44,329 35,971 46,073
ng·h/mL (61) (54) (67) (45) (63) (30,853–41,898) (66)
Meanc (CV%
n = 20 n = 10 n = 18 n = 31 n=8 n =22 n =10
or 95% CI)
C 24h ng/mL 336 550 572 686 468 578 636
Meanc (CV% (76) (60) (111) (68) (104) (474–704) (97)
or 95% CI)
n = 20 n = 10 n = 18 n = 31 n=8 n = 22 n = 10
a This information comes from the Reyataz package insert.10
b The young adults also were receiving tenofovir disoproxil fumarate.7
c Means are geometric means.
Key: ATV/r = atazanavir/ritonavir; AUC = area under the curve; CI = confidence interval; CV = coefficient of variation;
PK = pharmacokinetic

In these PK studies, although the PK targets were met in all patients using ATV powder except those
who received ATV/r 150 mg/80 mg in the 5 kg to <10 kg weight band, the coefficients of variation
were large, especially among the youngest patients.

Transitioning from Powder to Capsules

For children who reach a weight ≥25 kg while taking the powder, ATV 300 mg powder (six packets)
plus RTV 100 mg oral solution, both administered once daily with food, may be used. ATV capsules
should be used for children who can swallow pills. Bioavailability is higher for the capsules than for
the powder; therefore, a lower mg/kg dose is recommended when using capsules. Opened capsules
have not been studied and should not be used.

Toxicity
In the IMPAACT/PACTG 1020A trial, 9% of patients enrolled had a total bilirubin ≥5.1 times the
upper limit of normal,12 whereas 9% of patients enrolled in the PRINCE studies had a total bilirubin
≥2.6 times the upper limit of normal.9,11 The most common laboratory abnormality during the
PRINCE trials was elevated amylase levels, which occurred in 33% of patients.10 Three children
(2%) had treatment-related cardiac disorders during the PRINCE trials; one child discontinued

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-137
therapy because of QT corrected for heart rate (QTc) prolongation, and two experienced first-degree
AV block.9,11 In IMPAACT/PACTG P1020A, three children (3%) had QTc prolongations
>470 msec; two of these children came off the study, and all were asymptomatic.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-138
References

1. Cobicistat (Tybost) [package insert]. Food and Drug Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203094s016lbl.pdf.

2. Squires K, Lazzarin A, Gatell JM, et al. Comparison of once-daily atazanavir with

efavirenz, each in combination with fixed-dose zidovudine and lamivudine, as initial
therapy for patients infected with HIV. J Acquir Immune Defic Syndr. 2004;36(5):1011-
1019. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15247553.

3. Malan DR, Krantz E, David N, et al. Efficacy and safety of atazanavir, with or without
ritonavir, as part of once-daily highly active antiretroviral therapy regimens in
antiretroviral-naive patients. J Acquir Immune Defic Syndr. 2008;47(2):161-167.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/17971713.

4. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir

versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and
emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week
efficacy and safety results of the CASTLE study. Lancet. 2008;372(9639):646-655.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/18722869.

5. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir

compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and
emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week
efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr.
2010;53(3):323-332. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20032785.

6. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside
reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive
volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern
Med. 2014;161(7):461-471. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25285539.

7. Kiser JJ, Fletcher CV, Flynn PM, et al. Pharmacokinetics of antiretroviral regimens
containing tenofovir disoproxil fumarate and atazanavir-ritonavir in adolescents and
young adults with human immunodeficiency virus infection. Antimicrob Agents
Chemother. 2008;52(2):631-637. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18025112.

8. Kiser JJ, Rutstein RM, Samson P, et al. Atazanavir and atazanavir/ritonavir

pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS.
2011;25(12):1489-1496. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21610486.

9. Strehlau R, Donati AP, Arce PM, et al. PRINCE-1: safety and efficacy of atazanavir
powder and ritonavir liquid in HIV-1-infected antiretroviral-naive and -experienced
infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26066346.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-139
10. Reyataz (Atazanavir) [package insert]. Food and Drug Administration. 2020. Available
at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021567s044,206352s008lbl.
pdf.

11. Cotton MF, Liberty A, Torres-Escobar I, et al. Safety and efficacy of atazanavir powder
and ritonavir in HIV-1-infected infants and children from 3 months to <11 years of age:
the PRINCE-2 study. Pediatr Infect Dis J. 2018;37(6):e149-e156. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29206747.

12. Rutstein RM, Samson P, Fenton T, et al. Long-term safety and efficacy of atazanavir-
based therapy in HIV-infected infants, children and adolescents: the pediatric AIDS
clinical trials group protocol 1020A. Pediatr Infect Dis J. 2015;34(2):162-167. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/25232777.

13. Gonzalez de Requena D, Bonora S, Canta F, et al. Atazanavir Ctrough is associated with
efficacy and safety at 24 weeks: definition of therapeutic range. Abstract 60. Presented at:
6th International Workshop on Clinical Pharmacology of HIV Therapy; 2005. Quebec
City, Canada. Available at:
https://www.researchgate.net/profile/Maria_Grazia_Milia2/publication/267256045_Ataza
navir_Ctrough_is_associated_with_efficacy_and_safety_definition_of_therapeutic_range
/links/560106c808ae07629e52b5e1/Atazanavir-Ctrough-is-associated-with-efficacy-and-
safety-definition-of-therapeutic-range.pdf?origin=publication_detail.

14. Cressey TR, Hazra R, Wiznia A, et al. Pharmacokinetics of unboosted atazanavir in

treatment-experienced HIV-infected children, adolescents and young adults. Pediatr
Infect Dis J. 2016;35(12):1333-1335. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27583590.

15. Hong Y, Kowalski KG, Zhang J, et al. Model-based approach for optimization of
atazanavir dose recommendations for HIV-infected pediatric patients. Antimicrob Agents
Chemother. 2011;55(12):5746-5752. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21930880.

16. Sevinsky H, Cirincione B, Raybon J. Challenges in developing a population PK model

describing the PK of atazanavir and supporting dose selection in HIV infected pediatric
subjects. Presented at: The Seventh American Conference on Pharmacometrics 2016.
Bellevue, WA.

17. McFarland EJ, Heresi GP, Batra J, et al. Pharmacokinetics, safety, and efficacy of ATV
or DRV with COBI in adolescents. Presented at: Conference on Retroviruses and
Opportunistic Infections; 2017. Seattle, WA.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-140
Darunavir (DRV, Prezista)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Oral Suspension: 100 mg/mL

Tablets: 75 mg, 150 mg, 600 mg, 800 mg

Fixed-Dose Combination (FDC) Tablets

• [Prezcobix] Darunavir 800 mg/cobicistat 150 mg
• [Symtuza] Darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg

When using FDC tablets, refer to other sections of the Drug Appendix for information about the individual components of the
FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum Body Weights and
Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Note: Darunavir (DRV) should not be used without a • Skin rash, including Stevens-Johnson syndrome and
pharmacokinetic enhancer (boosting agent). Ritonavir (RTV) erythema multiforme
may be used as the boosting agent in children and adults.
Cobicistat (COBI) may be used as a boosting agent with DRV • Hepatotoxicity
in children weighing ≥40 kg and in adults. • Diarrhea, nausea
Neonate/Infant Dose • Headache
• DRV is not approved for use in neonates/infants. • Hyperlipidemia, transaminase elevation, hyperglycemia
Child Dose • Fat maldistribution
Aged <3 Years
Special Instructions
• Do not use DRV in children aged <3 years or weighing
≤10 kg. In juvenile rats, DRV caused convulsions and death; • Once-daily DRV is not generally recommended for use
these events have been attributed to immaturity of the in children aged <12 years or weighing <40 kg. Dosing
blood–brain barrier and liver metabolic pathways. estimates for these patients were based on limited
data, and limited clinical experience exists with this
Aged ≥3 Years to <12 Years dosing schedule in this age group.
• Dosing recommendations in the table below are for children • Once-daily DRV should not be used if any one of the
aged ≥3 years to <12 years and weighing ≥10 kg who are following resistance-associated mutations is present:
antiretroviral therapy–naive or treatment-experienced and V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V,
with or without resistance testing results that demonstrate I84V, or L89V.
that they have at least one mutation that is associated with
• DRV must be administered with food, which
DRV resistance.
increases DRV plasma concentrations by about 30%.
• DRV contains a sulfonamide moiety. Use DRV with
caution in patients with known sulfonamide allergies.
• Pediatric dosing requires coadministration of tablets of
different strengths to achieve the recommended dose
for each weight band. It is important to provide careful

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-141
 Twice-Daily Darunavir and Ritonavir Doses for Children instructions to caregivers when recommending a
Aged 3 Years to <12 Years and Weighing ≥10 kg combination of different-strength tablets.
• Store DRV tablets and oral suspension at room
Dose
Weight temperature (25ºC or 77ºF). The suspension must be
(Twice Daily With Food)a shaken well before dosing.
10 kg to <11 kgb DRV 200 mg (2.0 mL) plus RTV 32 mg • Screen patients for hepatitis B virus (HBV) infection
(0.4 mL) before using FDC tablets that contain emtricitabine
11 kg to <12 kgb DRV 220 mg (2.2 mL) plus RTV 32 mg (FTC) or tenofovir alafenamide (TAF). Severe acute
(0.4 mL)c exacerbation of HBV infection can occur when FTC or
TAF are discontinued; therefore, liver function should
12 kg to <13 kgb DRV 240 mg (2.4 mL) plus RTV 40 mg be monitored for several months after patients with
(0.5 mL)c HBV infection stop taking FTC or TAF.
13 kg to <14 kgb DRV 260 mg (2.6 mL) plus RTV 40 mg
(0.5 mL)c Metabolism/Elimination
14 kg to <15 kg DRV 280 mg (2.8 mL) plus RTV 48 mg • Cytochrome P450 3A4 substrate and inhibitor
(0.6 mL)c
Darunavir Dosing in Patients With Hepatic Impairment
15 kg to <30 kg DRV 375 mg (combination of tablets or
3.8 mL)d plus RTV 48 mg (0.6 mL)d • DRV is primarily metabolized by the liver. Caution
should be used when administering DRV to patients
30 kg to <40 kg DRV 450 mg (combination of tablets or with hepatic impairment. DRV is not recommended in
4.6 mL)d,e plus RTV (100 mg tablet or patients with severe hepatic impairment.
powder or 1.25 mL)b
≥40 kg DRV 600 mg (tablet or 6 mL) plus RTV Darunavir Dosing in Patients With Renal Impairment
100 mg (tablet or 1.25 mL) • No DRV dose adjustment is required in patients with
moderate renal impairment (creatinine clearance
Child and Adolescent (Aged ≥12 Years and Weighing ≥30 30–60 mL/min).
to <40 kg) Dose for Treatment-Naive or Treatment- • The FDC Symtuza is not recommended for use in
Experienced Patients With or Without at Least One patients with an estimated creatinine clearance
Mutation Associated With Darunavir Resistance <30 mL/min.
• DRV 450 mg (using a combination of tablets) plus RTV
100 mg, both twice daily with food

Child and Adolescent (Aged ≥12 years and Weighing

≥40 kg)e and Adult Dose for Treatment-Naive or Treatment-
Experienced Patients With No Mutations Associated With
Darunavir Resistance
• DRV 800 mg (using a tablet or combination of tablets) plus
RTV 100 mg, both once daily with food

Child and Adolescent (Weighing ≥40 kg) and Adult Dose

for Treatment-Naive or Treatment-Experienced Patients
With No Mutations Associated With Darunavir Resistance
• DRV 800 mg (tablet) plus COBIf 150 mg (tablet) or the
coformulation Prezcobix, once daily with food

Child and Adolescent (Weighing ≥40 kg) and Adult Dose

for Treatment-Experienced Patients With at Least One
Mutation Associated With Darunavir Resistance
• DRV 600 mg plus RTV 100 mg, both twice daily with food

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-142
 • The use of COBI is not recommended with DRV 600 mg
twice daily.

[Prezcobix] Darunavir/Cobicistat
Child and Adolescent (Weighing ≥40 kg) and Adult Dose for
Treatment-Naive or Treatment-Experienced Patients With No
Mutations Associated With Darunavir Resistance
• One tablet once daily with food

[Symtuza] Darunavir/Cobicistat/Emtricitabine/Tenofovir
Alafenamide (TAF)
Child and Adolescent (Weighing ≥40 kg) and Adult Dose
• One tablet once daily with food in ARV-naive patients or in
patients who have been virologically suppressed (HIV RNA
<50 copies/mL) for at least 6 months with no known
mutations associated with resistance to DRV or tenofovir.
a Once-daily dosing of DRV is approved by the U.S. Food and Drug Administration (FDA), but the Panel on Antiretroviral
Therapy and Medical Management of Children Living With HIV (the Panel) does not generally recommend using this dosing
schedule in children (see Frequency of Administration below).
b Note that the dose in children weighing 10 kg to 15 kg is DRV 20 mg/kg plus RTV 3 mg/kg of body weight per dose, which is
higher than the weight-adjusted dose in children with higher body weights.
c RTV 80 g/mL oral solution.
d The volumes for the 375-mg and 450-mg DRV doses are rounded for suspension-dose convenience.
e SomePanel members recommend using the FDA-approved dose of once-daily DRV 675 mg (administered using a
combination of tablets) plus RTV 100 mg once daily for adolescents weighing ≥30 kg to <40 kg (see Table B below).
fSee the Cobicistat section for important information about toxicity, drug interactions, and monitoring in patients who receive
COBI.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Darunavir (DRV) is primarily metabolized by cytochrome P450 (CYP) 3A4. Both
ritonavir (RTV) and cobicistat (COBI) are inhibitors of CYP3A4, thereby increasing the plasma
concentration of DRV. Coadministration of DRV plus RTV (DRV/r) or DRV plus COBI (DRV/c)
with drugs that are highly dependent on CYP3A clearance creates potential for multiple drug–drug
interactions and may be associated with suboptimal efficacy or serious and/or life-threatening
events.
• Coadministration of several drugs, including other protease inhibitors and rifampin, is
contraindicated with DRV/r and DRV/c. A study involving adults with HIV suggested that
etravirine (ETR) may reduce serum DRV concentrations by induction of CYP3A5, which is more
commonly expressed in individuals of African descent.1 Before administering DRV with a
pharmacokinetic (PK) enhancer (boosting agent), a patient’s medication profile should be
carefully reviewed for potential drug interactions.
• When twice-daily DRV/r was used in combination with tenofovir disoproxil fumarate (TDF) in
13 patients with HIV aged 13 to 16 years, both TDF and DRV exposures were lower than those

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-143
 found in adults treated with the same combination.2 No dose adjustment is recommended when
using DRV/r with TDF, but caution is advised and therapeutic drug monitoring (TDM) may be
useful. Data from the International Maternal Pediatric Adolescent AIDS Clinical
Trials (IMPAACT) protocol P1058A indicate that coadministering once-daily DRV/r with once-
daily or twice-daily ETR in children, adolescents, and young adults aged 9 years to <24 years did
not have a significant effect on DRV plasma concentrations.3 When DRV/r was coadministered
with ETR twice daily in pediatric patients, target concentrations for both DRV and ETR were
achieved.4 DRV PKs were not affected when DRV was coadministered with rilpivirine (RPV) in a
study of adolescents and young adults.5 DRV/r coadministration increased RPV exposure twofold
to threefold; close monitoring for RPV-related adverse events is advisable.

Major Toxicities
• More common: Diarrhea, nausea, vomiting, abdominal pain, headache, and fatigue.

• Less common: Skin rash, including erythema multiforme and Stevens-Johnson syndrome; fever
and elevated levels of hepatic transaminases; lipid abnormalities; and crystalluria.

• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting

diabetes mellitus, and spontaneous bleeding in hemophiliacs. Hepatic dysfunction, particularly in
patients with underlying risk factors, such as hepatitis B or hepatitis C virus coinfection.

Resistance
The International Antiviral Society–USA maintains a list of updated HIV drug resistance mutations,
and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
DRV/r is approved by the U.S. Food and Drug Administration (FDA) as a component of
antiretroviral (ARV) therapy in treatment-naive and treatment-experienced children aged ≥3 years.

DRV is approved by the FDA to be administered with COBI (Tybost) boosting in pediatric patients
weighing ≥40 kg. The fixed-dose combinations (FDCs) DRV/c (Prezcobix) and
Symtuza (DRV/c/emtricitabine/tenofovir alafenamide) are also approved by the FDA for use in
pediatric patients weighing ≥40 kg.

Efficacy in Clinical Trials

In an international, multisite clinical trial (TMC114-TiDP29-C228) that enrolled treatment-
experienced children aged 3 years to <6 years, 17 (81%) of 21 children who received DRV/r twice
daily had viral loads <50 copies/mL at Week 48.6-8

A randomized, open-label, multicenter pediatric trial8 that evaluated twice-daily DRV/r among
80 treatment-experienced children aged 6 years to <18 years reported that 66% of patients had
plasma HIV RNA <400 copies/mL and 51% had HIV RNA <50 copies/mL at Week 24.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-144
Once-daily DRV/r has been investigated in a small study involving 12 treatment-experienced
children aged 6 to 12 years who had maintained HIV viral loads <50 copies/mL for at least
6 months.9 All but one child continued to have undetectable viral loads during a median of
11.6 months of follow-up (range 0.5–14.2 months). The remaining child had detectable viral load
measurements between 20 copies/mL and 200 copies/mL on three occasions during a 3-month
period before, again, becoming undetectable without a change in regimen.

In one study, 12 participants aged 12 to 17 years received DRV/r once daily.10 After 48 weeks, all but
one participant had viral loads <50 copies/mL.

Pharmacokinetics and Dosing

Pharmacokinetics in Children Aged 3 Years to <6 Years
Twenty-one children aged 3 years to <6 years and weighing 10 kg to <20 kg received twice-daily
DRV/r oral suspension. These children had experienced virologic failure on their previous ARV
regimens and had fewer than three DRV resistance mutations, confirmed by genotypic testing.6,7,11
The DRV area under the curve (AUC 0–12h ), measured as a percent of the adult AUC value,6,7,11 was
128% overall: 140% in children weighing 10 kg to <15 kg and 122% in children weighing 15 kg to
<20 kg.

Pharmacokinetics in Children Aged >6 Years

Initial pediatric PK evaluation of DRV tablets and RTV oral solution or tablets was based on a
Phase 2 randomized, open-label, multicenter study that enrolled 80 treatment-experienced children
and adolescents aged 6 years to <18 years and weighing ≥20 kg.12 Part 1 of the trial used a weight-
adjusted dose of DRV (9 mg/kg to 15 mg/kg) and RTV (1.5 mg/kg to 2.5 mg/kg) twice daily,
approximating the standard adult dose of DRV/r 600 mg/100 mg twice daily on a per-weight basis.
This dose resulted in inadequate drug exposure in the pediatric population studied, with a 24-hour
AUC (AUC 24h ) that was 81% of the AUC 24h observed in adults and a pre-dose concentration (C 0h )
that was 91% of the C 0h observed in adults. A pediatric dose that was 20% to 33% higher than the
directly scaled adult dose was needed to achieve a drug exposure that was similar to that found in
adults, and this was the dose selected for Part 2 of the study. The higher dose used for the safety and
efficacy evaluation was DRV 11 mg/kg to 19 mg/kg and RTV 1.5 mg/kg to 2.5 mg/kg twice daily.
This dose resulted in a DRV AUC 24h of 123.3 mcg·h/mL (range 71.9–201.5 mcg·h/mL) and a C 0h of
3,693 ng/mL (range 1,842–7,191 ng/mL), representing 102% and 114% of the respective values in
adults. Doses were given twice daily and were stratified into body-weight bands of 20 kg to <30 kg
and 30 kg to <40 kg. The current weight-band doses of twice-daily DRV/r for treatment-experienced
pediatric patients weighing >20 kg to <40 kg were selected using the findings from the safety and
efficacy portion of this study (see Table A below).

A small study that involved 12 treatment-experienced children aged 6 to 12 years examined the PKs
and efficacy of DRV/r once daily administered in combination with abacavir and lamivudine.9 All
participants had maintained HIV plasma viral loads <50 copies/mL for at least 6 months prior to
beginning this regimen. The weight-based doses used for once-daily DRV/r were based on a prior
modeling study:13 600 mg/100 mg for patients weighing 15 kg to 30 kg, 675 mg/100 mg for patients
weighing 30 kg to 40 kg, and 800 mg/100 mg for patients weighing >40 kg. The geometric mean
AUC 0–24h was below the study target of 80% of the value seen in adults (63.1 mg·h/L vs.
71.8 mg·h/L), but the trough values that were observed at 23.1 hours to 25.1 hours after the previous

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-145
dose exceeded the trough plasma concentration recommended for treatment-experienced adults
(0.55 mg/L).14 One child developed neuropsychiatric symptoms (anxiety and hallucinations) and was
removed from study. This child did not have an excessive exposure to DRV; the AUC 0–24 was
47.8 mg·h/L.

Table A. Darunavir Pharmacokinetics With Twice-Daily Administration With Ritonavir

and Optimized Background Therapy in Children, Adolescents, and Adults

AUC 12h
C 0h (ng/mL)
Population n Dose of DRV/r (mcg·h/mL)
Mediana
Mediana
Children Weighing 10 kg to <15 kga 13 20 mg/kg/3 mg/kg 66.0 3,533
Children Weighing 10 kg to <15 kga 4 25 mg/kg/3 mg/kg 116.0 8,522
Children Weighing 15 kg to <20 kga 11 20 mg/kg/3 mg/kg 54.2 3,387
Children Weighing 15 kg to <20 kga 14 25 mg/kg/3 mg/kg 68.6 4,365
Children Aged 6 Years to <12 Yearsb Determined by weight
24 56.4 3,354
bandsb
Adolescents Aged 12 Years to Determined by weight
50 66.4 4,059
<18 Yearsb bandsb
Adults Aged >18 Years
285/278/119 600 mg/100 mg 54.7–61.7 3,197–3,539
(Three studies)
a Source: U.S. Food and Drug Administration. FDA clinical pharmacologic review of darunavir. 2011. Available at:

https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/UCM287674.pdf.
b DRV/r was administered at doses of 375 mg/50 mg twice daily for patients weighing 20 kg to <30 kg, 450 mg/60 mg twice daily
for patients weighing 30 kg to <40 kg, and 600 mg/100 mg twice daily for patients weighing ≥40 kg. Data from the 2008 FDA
pharmacokinetics review. Available at:
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResources/ucm129567.pdf.
c Source: Darunavir [package insert]. Food and Drug Administration. 2016. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021976s043,202895s017lbledt.pdf.
Key: AUC 12h = 12-hour area under the curve; C 0h = pre-dose concentration; DRV/r = darunavir/ritonavir

Dosing
Pharmacokinetic Enhancers

DRV should not be used without a PK enhancer (boosting agent). RTV may be used as a boosting
agent in children and adults. COBI may be used as a boosting agent in children weighing ≥40 kg and
adults.

A study that enrolled 19 Thai children used the RTV 100-mg capsule twice daily as the boosting dose
for twice-daily DRV 375 mg (in children weighing 20 kg to <30 kg), 450 mg (in children weighing
30 kg to 40 kg), and 600 mg (in children weighing ≥40 kg).15 The DRV exposures with RTV 100 mg
twice daily were similar to those obtained in the studies with lower (<100 mg) doses of liquid
RTV.12,15 The tolerability and PK data from this small study support the use of RTV 100 mg for
boosting using either the powder or tablet formulation in children weighing ≥20 kg, particularly in
instances where the lower-dose formulations are unavailable or a child does not tolerate the liquid

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-146
RTV formulation. No data are available on the safety and tolerability of using the RTV 100-mg tablet
or powder formulation in children weighing <20 kg.

Data on the dosing of DRV/c are available primarily for adult patients.16 Data on once-daily use of
the FDC tablet DRV/c 800 mg/150 mg (Prezcobix) showed bioavailability that was comparable to
the bioavailability observed with the use of DRV/r 800 mg/100 mg once daily.14

In an open-label switch study, eight adolescent patients with a median age of 14 years (range
12–17 years) who received DRV/c had DRV exposures (AUC tau ) that were similar to those observed
in adults, except for a lower trough concentration at the end of the dosing interval (C tau ). The median
DRV C tau (494 ng/mL) was above the protein binding-adjusted half-maximal inhibitory
concentration for wild-type virus (55 ng/mL). Adolescent patients in this study received the adult
dose of COBI 150 mg daily. DRV dosing was based on weight, with patients who weighed ≥40 kg
receiving DRV 800 mg once daily and patients who weighed 30 kg to <40 kg receiving DRV 675 mg
once daily. In this small sample, 95.5% of patients had HIV RNA <50 copies/mL at Week 12. COBI
appeared to be well tolerated with no discontinuations due to adverse events.17

Frequency of Administration
In February 2013, the FDA approved the use of once-daily DRV for treatment-naive children and for
treatment-experienced children without DRV resistance-associated mutations (see Table B below).
Population PK modeling and simulation were used to develop recommendations for once-daily
dosing in younger pediatric subjects aged 3 years to <12 years and weighing 10 kg to <40 kg.7,18
Currently, limited data exist on the efficacy of once-daily DRV/r dosing in treatment-naive or
treatment-experienced children aged <6 years. Therefore, the Panel on Antiretroviral Therapy and
Medical Management of Children Living With HIV (the Panel) generally recommends dosing DRV/r
twice daily in children aged ≥3 years to <12 years (see Once-Daily Administration in Children Aged
<12 Years and Weighing <40 kg below). The Panel recommends that once-daily DRV/r be used only
in treatment-naive and treatment-experienced adolescents weighing ≥40 kg who do not have
mutations that are associated with DRV resistance. If DRV and RTV are used once daily in children
aged <12 years, the Panel recommends conducting a PK evaluation of plasma concentrations of DRV
and closely monitoring viral load.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-147
Table B. Food and Drug Administration–Approved Dosing for Pediatric Patients Aged
≥3 Years and Weighing >10 kg Who Are Treatment Naive or Treatment Experienced With
No Darunavir Resistance-Associated Mutations

Note: The Panel generally recommends dosing DRV plus RTV twice daily in children aged ≥3 years
to <12 years.

Weight Dose (Once Daily with Food)

10 kg to <11 kga DRV 350 mg (3.6 mL)b plus RTV 64 mg (0.8 mL)c
11 kg to <12 kga DRV 385 mg (4 mL)b plus RTV 64 mg (0.8 mL)c
12 kg to <13 kga DRV 420 mg (4.2 mL)b plus RTV 80 mg (1 mL)c
13 kg to <14 kga DRV 455 mg (4.6 mL)b plus RTV 80 mg (1 mL)c
14 kg to <15 kga DRV 490 mg (5 mL)b plus RTV 80 mg (1 mL)c
15 kg to <30 kg DRV 600 mg (tablet, combination of tablets, or 6 mL) plus RTV 100 mg (tablet, powder, or 1.25 mL)c
30 kg to <40 kg DRV 675 mg (combination of tablets or 6.8 mL)b,d plus RTV 100 mg (tablet or 1.25 mL)c
≥40 kg DRV 800 mg (tablet, combination of tablets, or 8 mL)d plus RTV 100 mg (tablet or 1.25 mL)c
aThe dose in children weighing 10 kg to 15 kg is DRV 35 mg/kg and RTV 7 mg/kg per dose, which is higher than the weight-
adjusted dose in children with higher weights.
bDRV 100 mg/mL oral suspension; the 350-mg, 385-mg, 455-mg, 490-mg, and 675-mg DRV doses are rounded for suspension-
dose convenience.
c RTV 80 mg/mL oral solution.
d The 6.8-mL and 8-mL DRV doses can be taken as two administrations (3.4 mL and 4 mL, respectively) once daily by refilling
the oral dosing syringe supplied by the manufacturer or as one administration once daily if a larger syringe is provided by a
pharmacy or provider.
Key: DRV = darunavir; RTV = ritonavir

Once-Daily Administration in Children Aged <12 Years and Weighing <40 kg

During the TMC114-C228 trial, the researchers investigated once-daily dosing of DRV for 2 weeks;
DRV PKs were evaluated in treatment-experienced children aged 3 years to <12 years as part of a
substudy. After the conclusion of the substudy, the participants switched back to a twice-daily
regimen.18,19 The DRV/r dose for once-daily use, which was based on PK simulation and which did
not include a relative bioavailability factor, was DRV 40 mg/kg coadministered with approximately
7 mg/kg of RTV for children weighing <15 kg and DRV/r 600 mg/100 mg once daily for children
weighing ≥15 kg.18,19 The PK data obtained from 10 children aged 3 to 6 years in this substudy (see
Table C below) were included as part of the population PK modeling and simulation that was used to
determine the FDA-approved dose for once-daily DRV/r in children aged 3 years to <12 years.

In a small study in which DRV/r was administered once daily to 12 treatment-experienced children
aged 6 to 12 years,9 the geometric mean AUC 0–24h achieved was below the study target of 80% of the
value seen in adults (63.1 mg·h/L vs. 71.8 mg·h/L). Trough values exceeded the plasma
concentration that is recommended for treatment-experienced patients (0.55 mg/L). Despite the FDA
dosing guidelines, the Panel generally recommends dosing DRV/r twice daily in children aged
≥3 years to <12 years. The Panel makes this recommendation because of the small data set used for

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-148
once-daily DRV/r PK modeling and the limited amount of data on the use of once-daily DRV/r in
children aged <12 years.

Table C. Pharmacokinetics of Once-Daily Darunavir in Children Aged 3 to 6 Years After

2 Weeks of Therapy With Ritonavir and Optimized Background Therapy

Children Aged 3 to 6 Years Adults

PK Parameter
(n = 10)19 (n = 335)
DRV AUC 24h geometric mean, ng·h/mL (SD) 115 (40.6) 89.7 (27.0)
DRV C 0h geometric mean, ng/mL (SD) 3,029 (1,715) 2,027 (1,168)
Key: AUC 24h = 24-hour area under the curve; C 0h = pre-dose concentration; DRV = darunavir; PK = pharmacokinetic;
SD = standard deviation
Once-Daily Administration in Adolescents Aged ≥12 Years and Weighing ≥40 kg

A substudy of once-daily dosing of DRV/r 800 mg/100 mg demonstrated that DRV exposures in
12 treatment-naive adolescents (aged 12–17 years and weighing ≥40 kg) were similar to those seen in
adults treated with once-daily DRV (see Table D below).20 After 48 weeks, 83.3% of patients had
viral loads <50 copies/mL and 91.7% had viral loads <400 copies/mL.10 Interestingly, no relationship
was observed between DRV AUC 24h and C 0h and virologic outcome (HIV RNA <50 copies/mL) in
this study. DRV exposures were found to be similar to those observed in adults with once-daily
dosing in another study in which a single dose of DRV 800 mg with RTV 100 mg was administered
to 24 subjects with a median age of 19.5 years (range 14–23 years).21 However, DRV exposures were
slightly below the lower target concentrations in adolescent patients aged 14 to 17 years (n = 7)
within the cohort, suggesting that higher doses may be needed in younger adolescents. A single case
report involving a highly treatment-experienced adolescent patient suggests that using an increased
DRV dose with standard RTV boosting and employing TDM can lead to virologic suppression.

Table D. Darunavir Pharmacokinetics With Once-Daily Administration in Adolescents

Aged ≥12 Years and Adults Aged >18 Years

AUC 24h a C 0h (ng/mL)

Population n Dose of DRV/r (mcg·h/L) Median
Median
Adolescents Aged 12–17 Years
(Mean age 14.6 years)20 12 800 mg/100 mg 86.7 2,141

Adolescents and Adults Aged

14–23 Years 24 800 mg/100 mg 69.5 1,300
(Mean age 19.5 years)21
Adults Aged >18 Years
335/280 800 mg/100 mg 87.8–87.9 1,896–2,041
(Two studies)a
aSource: Darunavir [package insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021976Orig1s063lbl.pdf.
Key: AUC 24h = 24-hour area under the curve; C 0h = pre-dose concentration; DRV/r = darunavir/ritonavir

The efficacy of once-daily DRV has been established within a limited number of studies in small
cohorts of adolescents that reported long-term data on virologic and immunologic outcomes.10,22

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-149
References

1. Belkhir L, Elens L, Zech F, et al. Interaction between darunavir and etravirine is partly
mediated by CYP3A5 polymorphism. PLoS One. 2016;11(10):e0165631. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27788239.

2. King JR, Yogev R, Jean-Philippe P, et al. Steady-state pharmacokinetics of tenofovir-

based regimens in HIV-infected pediatric patients. Antimicrob Agents Chemother.
2011;55(9):4290-4294. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21670182.

3. Larson KB, Cressey TR, Yogev R, et al. Pharmacokinetics of once-daily

darunavir/ritonavir with and without etravirine in human immunodeficiency virus-
infected children, adolescents, and young adults. J Pediatric Infect Dis Soc.
2016;5(2):131-137. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27199469.

4. Cressey TR, Yogev R, Wiznia A, et al. Pharmacokinetics of darunavir/ritonavir with

etravirine both twice daily in human immunodeficiency virus-infected adolescents and
young adults. J Pediatric Infect Dis Soc. 2017;6(3):294-296. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27103489.

5. Foca M, Yogev R, Wiznia A, et al. Rilpivirine pharmacokinetics without and with

darunavir/ritonavir once daily in adolescents and young adults. Pediatr Infect Dis J.
2016;35(9):e271-274. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27187753.

6. Violari A, Bologna R, Kumarasamy N, et al. Safety and efficacy of darunavir/ritonavir in

treatment-experienced pediatric patients: week 48 results of the ARIEL trial. Pediatr
Infect Dis J. 2015;34(5):e132-137. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25719453.

7. Darunavir (Prezista) [package insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021976s059,202895s029lbl.
pdf.

8. Darunavir/cobicistat (Prezcobix) [package insert]. Food and Drug Administration. 2021.

Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/205395s020lbl.pdf.

9. Bastiaans DET, Geelen SPM, Visser EG, et al. Pharmacokinetics, short-term safety and
efficacy of the approved once-daily darunavir/ritonavir dosing regimen in HIV-infected
children. Pediatr Infect Dis J. 2018;37(10):1008-1010. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29474261.

10. Flynn P, Komar S, Blanche S, et al. Efficacy and safety of darunavir/ritonavir at 48

weeks in treatment-naive, HIV-1-infected adolescents: results from a phase 2 open-label
trial (DIONE). Pediatr Infect Dis J. 2014;33(9):940-945. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25361024.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-150
11. Food and Drug Administration. Clinical pharmacology review of darunavir. 2011.
Available at:
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentReso
urces/UCM287674.pdf.

12. Blanche S, Bologna R, Cahn P, et al. Pharmacokinetics, safety and efficacy of

darunavir/ritonavir in treatment-experienced children and adolescents. AIDS.
2009;23(15):2005-2013. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19724191.

13. Brochot A, Kakuda TN, Van De Casteele T, et al. Model-based once-daily

darunavir/ritonavir dosing recommendations in pediatric HIV-1-infected patients aged ≥3
to <12 years. CPT Pharmacometrics Syst Pharmacol. 2015;4(7):406-414. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26312164.

14. Kakuda TN, Brochot A, Tomaka FL, Vangeneugden T, Van De Casteele T, Hoetelmans
RM. Pharmacokinetics and pharmacodynamics of boosted once-daily darunavir. J
Antimicrob Chemother. 2014;69(10):2591-2605. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24951533.

15. Chokephaibulkit K, Prasitsuebsai W, Wittawatmongkol O, et al. Pharmacokinetics of

darunavir/ritonavir in Asian HIV-1-infected children aged ≥7 years. Antivir Ther.
2012;17(7):1263-1269. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22954687.

16. Cobicistat (Tybost) [package insert]. Food and Drug Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203094s016lbl.pdf.

17. McFarland E, Heresi G, Batra J, et al. Pharmacokinetics, safety, and efficacy of atv or drv
with cobi in adolescents. Abstract 425. Presented at: Conference on Retroviruses and
Opportunistic Infections; 2017. Seattle, Washington. Available at:
https://www.croiconference.org/sessions/pharmacokinetics-safety-and-efficacy-atv-or-
drv-cobi-adolescents.

18. Prezista drug label. Clinical review of darunavir [package insert]. Food and Drug
Administration. 2012. Available at:
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentReso
urces/UCM346671.pdf.

19. Kakuda TN, Brochot A, van de Casteele T, Opsomer M, Tomaka F. Establishing

darunavir dosing recommendations in treatment-naive and treatment-experienced
pediatric patients. Presented at: 14th Clinical Pharmacology Workshop on HIV; 2013.
Amsterdam, Netherlands. Available at:
https://www.natap.org/2013/Pharm/Pharm_19.htm.

20. Flynn P, Blanche S, Giaquinto C, et al. . 24-week efficacy, safety, tolerability and
pharmacokinetics of darunavir/ritonavir once daily in treatment-naïve adolescents aged
12 to < 18 years in DIONE. Abstract # PP_2. Presented at: 3rd International Workshop
on HIV Pediatrics; 2011. Rome, Italy. Available at:
https://www.natap.org/2011/IAS/IAS_40.htm.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-151
21. King J, Hazra R, et al. Pharmacokinetics of darunavir 800 mg with ritonavir 100mg once
daily in HIV+ adolescents and young adults. Presented at: Conference on Retroviruses
and Opportunistic Infections 2013. Atlanta, GA.

22. Chokephaibulkit K, Rungmaitree S, Phongsamart W, et al. Pharmacokinetics and efficacy

of darunavir/ritonavir once daily in virologically suppressed, treatment-experienced HIV-
infected children. HIV Med. 2014;15(8):511-512. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25138061.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-152
Lopinavir/Ritonavir (LPV/r, Kaletra)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Oral Solution
• [Kaletra] Lopinavir 80 mg/mL and ritonavir 20 mg/mL (contains 42.4% alcohol by volume and 15.3% propylene glycol by
weight/volume)

Film-Coated Tablets
• [Kaletra] Lopinavir 100 mg/ritonavir 25 mg
• [Kaletra] Lopinavir 200 mg/ritonavir 50 mg

When using fixed-dose combination (FDC) tablets, refer to other sections of the Drug Appendix for information about the
individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets: Minimum
Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Neonate (Aged <14 Days) Dose • Gastrointestinal (GI) intolerance, nausea, vomiting,
diarrhea, alteration of taste
• Lopinavir/ritonavir (LPV/r) is not approved by the U.S. Food and
Drug Administration (FDA) for use in neonates before a • Hyperlipidemia, especially hypertriglyceridemia
postmenstrual age of 42 weeks and a postnatal age of at least
14 days. • Elevated transaminases
• Hyperglycemia
Dosing for Individuals Who Are Not Receiving Concomitant
Nevirapine, Efavirenz, Fosamprenavir, or Nelfinavir • PR interval prolongation
Infant (Aged 14 Days to 12 Months) Dose • QT interval prolongation and Torsades de Pointes
• Once-daily dosing is not recommended. • Risk of toxicity—including life-threatening
cardiotoxicity—is increased in premature infants
• LPV/r 300 mg/75 mg per m2 of body surface area per dose twice
(see Major Toxicities below)
daily. This approximates LPV/r 16 mg/4 mg (both per kg body
weight) twice daily. Use of this dose in infants aged <12 months
is associated with lower LPV trough levels than those found in Special Instructions
adults; LPV dosing should be adjusted for growth at frequent
intervals (see Pharmacokinetics and Dosing below). • LPV/r tablets can be administered without regard to
food; administration with or after meals may
Child and Adolescent (Aged >12 Months to 18 Years) Dose enhance GI tolerability.
• Once-daily dosing is not recommended. • LPV/r tablets must be swallowed whole. Do not
• LPV/r 300 mg/75 mg per m2 of body surface area per dose twice crush or split tablets.
daily (maximum dose LPV/r 400 mg/100 mg twice daily, except • LPV/r oral solution should be administered with food
as noted below). For patients weighing <15 kg, this dose because a high-fat meal increases absorption.
approximates LPV/r 13 mg/3.25 mg (both per kg body weight)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-153
 twice daily. For patients weighing ≥15 kg to 45 kg, this dose • The poor palatability of LPV/r oral solution is difficult
approximates LPV/r 11 mg/2.75 mg (both per kg body weight) to mask with flavorings or foods (see Formulations
twice daily. This dose is routinely used by many clinicians and is below).
the preferred dose for antiretroviral therapy (ART)-experienced
patients who could harbor virus with decreased LPV • LPV/r oral solution can be kept at room temperature
susceptibility (see Pharmacokinetics and Dosing). (up to 77 ºF or 25 ºC) if used within 2 months. If
kept refrigerated (36 ºF to 46 ºF or 2 ºC to 8 ºC),
• LPV/r 230 mg/57.5 mg per m2 of body surface area per dose LPV/r oral solution remains stable until the
twice daily can be used in antiretroviral (ARV)-naive patients expiration date printed on the label.
aged >1 year. For patients weighing <15 kg, this dose
approximates LPV/r 12 mg/3 mg per kg body weight given twice • Children aged <18 years who receive once-daily
daily. For patients weighing ≥15 kg to 40 kg, this dose dosing of LPV/r have shown considerable variability
approximates LPV/r 10 mg/2.5 mg per kg body weight given in plasma concentrations and have a higher
twice daily. This lower dose should not be used in treatment- incidence of diarrhea. Therefore, once-daily dosing
experienced patients who could harbor virus with decreased is not recommended for this age group.
LPV susceptibility. • Use of LPV/r once daily is contraindicated if three
or more of the following LPV resistance–associated
Weight-Band Dosing for Lopinavir 100-mg/Ritonavir 25-mg substitutions are present: L10F/I/R/V, K20M/N/R,
Pediatric Tablets in Children and Adolescents L24I, L33F, M36I, I47V, G48V, I54L/T/V,
V82A/C/F/S/T, and I84V. This is because higher
Recommended Number of LPV/r 100-mg/25-mg Tablets LPV trough concentrations may be required to
Given Twice Daily suppress resistant virus.
Dosing target 300 mg/m2 per dose 230 mg/m2 per dose
given twice daily given twice daily Metabolism/Elimination
Body Weight • Cytochrome P450 3A4 substrate and inhibitor.
15 kg to 20 kg 2 2
>20 kg to 25 kg 3 2 Lopinavir/Ritonavir Dosing in Patients With
>25 kg to 30 kg 3 3 Hepatic Impairment
>30 kg to 35 kg 4a 3 • LPV/r is eliminated primarily by hepatic metabolism.
>35 kg to 45 kg 4a 4a Use caution when administering LPV to patients
>45 kg 4 or 5
a b 4a with hepatic impairment. No dosing information is
a Two tablets that each contain LPV/r 200 mg/50 mg can be currently available for children or adults with hepatic
substituted for the four LPV/r 100-mg/25-mg tablets in children who insufficiency.
are capable of swallowing a larger tablet.
• In the coformulation of LPV/r, ritonavir acts as a
bIn patients who weigh >45 kg and who are receiving concomitant pharmacokinetic enhancer, not as an ARV agent.
nevirapine (NVP), efavirenz (EFV), fosamprenavir (FPV), or Ritonavir inhibits the metabolism of LPV and
nelfinavir (NFV), the FDA-approved adult dose is LPV/r increases LPV plasma concentrations.
500 mg/125 mg twice daily, given as a combination of two tablets
of LPV/r 200 mg/50 mg and one tablet of LPV/r 100 mg/25 mg.
Alternatively, three tablets of LPV/r 200 mg/50 mg can be used for
ease of dosing.

Adult (Aged >18 Years) Dose

• LPV/r 800 mg/200 mg once daily; or
• LPV/r 400 mg/100 mg twice daily
• Do not use once-daily dosing in children; adolescents; in
patients receiving concomitant therapy with NVP, EFV, FPV, or
NFV; or in patients with three or more LPV-associated mutations
(see Special Instructions for a list of mutations).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-154
 Dosing for Individuals With Three or More Lopinavir-
Associated Mutations (See Special Instructions for List)
• LPV/r 400 mg/100 mg twice daily

Dosing for Individuals Receiving Concomitant Nevirapine or

Efavirenz
• These drugs induce LPV metabolism and reduce LPV plasma
levels. Increased LPV/r dosing is required with concomitant
administration of these drugs. Once-daily dosing should not be
used in these patients.

Child and Adolescent (Aged >12 Months to 18 Years) Dose

• LPV/r 300 mg/75 mg per m2 of body surface area per dose twice
daily. See the table above for weight-band dosing when using
tablets.

Adult (Aged >18 Years) Dose

• The FDA-approved dose is LPV/r 500 mg/125 mg twice daily,
given as a combination of two tablets of LPV/r 200 mg/50 mg
and one tablet of LPV/r 100 mg/25 mg. Alternatively, three
tablets of LPV/r 200 mg/50 mg can be used for ease of dosing.
Once-daily dosing should not be used.

Lopinavir/Ritonavir Used in Combination With Maraviroc

• Maraviroc doses may need modification (see the Maraviroc
section).

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Lopinavir/ritonavir (LPV/r) is a cytochrome P450 (CYP) 3A4 substrate and inhibitor
with the potential for multiple drug interactions. Coadministering LPV/r with drugs that induce
CYP3A4 may decrease LPV plasma concentrations, whereas coadministering LPV/r with other
CYP3A4 inhibitors may increase LPV plasma concentrations. Coadministering LPV/r with other
CYP3A4 substrates may require dose adjustments and additional monitoring.

Before initiating therapy with LPV/r, a patient’s medication profile should be carefully reviewed
for potential drug interactions. In patients treated with LPV/r, fluticasone (a commonly used
inhaled and intranasal steroid) should be avoided, and an alternative steroid should be used. Drug
interactions with antituberculous drugs are common. Coadministration of LPV/r with the
antituberculosis drug rifampin—a strong CYP3A4 inducer—may lead to suboptimal LPV
levels.1-3 Patients who are receiving both LPV/r and antituberculous drugs may need a dose
adjustment for LPV/r, or they may need to switch to an antiretroviral (ARV) regimen that does
not include LPV/r.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-155
Major Toxicities
• More common: Diarrhea, headache, asthenia, nausea and vomiting, rash, insulin resistance.4
Hyperlipidemia, especially hypercholesterolemia and hypertriglyceridemia,5-7 which may be
more pronounced in girls than in boys.8 LPV requires a higher dose of ritonavir than some other
protease inhibitors (PIs); this higher dose may exacerbate these adverse events (AEs).
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting
diabetes mellitus, hemolytic anemia, spontaneous and/or increased bleeding in hemophiliacs,
pancreatitis, elevation in serum transaminases, hepatitis (which has been life-threatening in rare
cases). PR interval prolongation, QT interval prolongation, and Torsades de Pointes may occur.
• Special populations—neonates: An increased risk of toxicity in premature infants has been
reported, including cases of transient symptomatic adrenal insufficiency,9,10 life-threatening
bradyarrhythmias and cardiac dysfunction (including complete atrioventricular block,
bradycardia, and cardiomyopathy),11-13 lactic acidosis, acute renal failure, central nervous system
depression, and respiratory depression. These toxicities may be caused by the drug itself and/or
by the inactive ingredients in the oral solution,13 which include propylene glycol (15.3%) and
ethanol (42.4%). Transient asymptomatic elevation in 17-hydroxyprogesterone levels also has
been reported9 in term newborns treated at birth with LPV/r. The pharmacokinetics (PKs) and
safety of LPV/r were studied in IMPAACT P1106, an opportunistic, multi-arm, Phase 4
prospective study in newborns who received ARV and anti-tuberculosis medicines in clinical
care. A total of 25 neonates with HIV were enrolled, with a median birth weight of 2,130 g
(interquartile range [IQR] 1,775–2,630 g) and a median gestational age of 35 weeks
(IQR 32–37 weeks). Neonates received LPV/r solution at a dose of 300 mg/75 mg per m2 twice
daily, which was well tolerated and not associated with any treatment-related AEs, even in
13 newborns who initiated therapy prior to 42 weeks postmenstrual age at a mean postnatal age
of 37 days (range 13–61 days).14

Resistance
The International Antiviral Society–USA maintains a list of HIV drug resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
LPV/r is approved by the U.S. Food and Drug Administration (FDA) for use in children, including
neonates who have attained a postmenstrual age of 42 weeks and a postnatal age of at least 14 days.
The potential benefit of using LPV/r in premature infants who have not met these age thresholds
must be carefully balanced with the risk of metabolic and cardiac toxicity. In pediatric patients
receiving LPV/r at a dose of 300 mg/75 mg per m2 twice daily, lower LPV exposure has been
observed in infants aged <6 weeks relative to older children.15

Efficacy
Clinical trials involving antiretroviral therapy (ART)-naive adults have shown that regimens that
contain LPV/r plus two nucleoside reverse transcriptase inhibitors (NRTIs) are comparable to a

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-156
variety of other regimens, including regimens that contain atazanavir, darunavir (DRV),
fosamprenavir (FPV), saquinavir/ritonavir, or efavirenz (EFV). Studies also have shown that
regimens that contain LPV/r plus two NRTIs are superior to regimens that contain nelfinavir (NFV)
and inferior to regimens that contain DRV.16-24

LPV/r has been studied in both ART-naive and ART-experienced children and has demonstrated
durable virologic activity and acceptable toxicity.25-33

Pharmacokinetics
General Considerations
Children have lower LPV/r exposure than adults when treated with doses that are directly scaled for
body surface area. The directly scaled dose approximation of the adult dose in children is calculated
by dividing the adult dose by the typical adult body surface area of 1.73 m2. For the adult dose of
LPV/r 400 mg/100 mg, the scaled pediatric dose would be approximately LPV/r 230 mg/57.5 mg
per m2 of body surface area. However, younger children have higher LPV clearance and need higher
doses to achieve LPV exposures that are similar to those seen in adults treated with standard doses.
To achieve a trough concentration (C trough ) similar to that observed in adults, the pediatric dose needs
to be increased 30% greater than the dose that is directly scaled for body surface area. LPV
exposures in infants15,27,32 are compared to those in older children25 and adults34 in Table A below.

Table A. Pharmacokinetics of Lopinavir/Ritonavir by Age

Infants at Infants at
Infantsa at
Adults Children Children 6 Weeks to 14 Days to
PK Parameters 12 Months
(n = 19)34 (n = 12)25 (n = 15)25 6 Months <6 Weeks
(n = 20)32
(n = 18)27 (n = 9)15
LPV Dose 400 mg 230 mg/m2 300 mg/m2 300 mg/m2 300 mg/m2 300 mg/m2

AUC 0-12 92.6 72.6 116.0 101.0 74.5 43.4

(mcg·hr/mL)
C max (mcg/mL) 9.8 8.2 12.5 12.1 9.4 5.2

C trough (mcg/mL) 7.1 4.7 7.9 4.9 2.7 2.5

C min (mcg/mL) 5.5 3.4 6.5 3.8 2.0 1.4

a This
column contains unreported data that were originally generated for a published study. The data were provided by Edmund
Capparelli, Pharm.D., in a personal communication (April 18, 2012).
Note: Values are means, and PK parameters refer to the LPV component; all data come from studies wherein none of the
participants received non-nucleoside reverse transcriptase inhibitors as part of their antiretroviral therapy.
Key: AUC = area under the curve; C max = maximum concentration; C min = minimum concentration; C trough = trough
concentration; LPV = lopinavir; mcg = microgram; mg = milligram; mL = milliliter; PK = pharmacokinetic

Models suggest that diet, body weight, and postnatal age are important factors in LPV PKs, with
higher bioavailability as dietary fat increases during the first year of life35 and clearance slowing by
age 2.3 years.36 A study from the United Kingdom and Ireland compared outcomes of LPV/r
treatment with either 230 mg per m2 of body surface area per dose or 300 mg per m2 of body surface

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-157
area per dose in children aged 5.6 to 12.8 years at the time of LPV/r initiation. The findings
suggested that the higher dose was associated with improved long-term viral load suppression.37

Pharmacokinetics and Dosing

14 Days to 12 Months (Without Concurrent Nevirapine, Efavirenz,
Fosamprenavir, or Nelfinavir)
The PKs of the oral solution at approximately LPV/r 300 mg/75 mg per m2 of body surface area per
dose twice daily were evaluated in infants aged <6 weeks15 and infants aged 6 weeks to 6 months.27
Even at this higher dose, C trough levels were highly variable, but they were lower in infants than in
children aged >6 months. C trough levels were lower in infants aged ≤6 weeks than in infants aged
6 weeks to 6 months. By age 12 months, LPV area under the curve (AUC) was similar to that found
in older children.32 Because infants grow rapidly in the first months of life, it is important to optimize
LPV dosing by adjusting the dose at frequent intervals. Given the safety of doses as high as 400 mg
per m2 of body surface area in older children and adolescents,28 some practitioners anticipate rapid
infant growth and prescribe doses somewhat higher than the 300 mg per m2 of body surface area dose
to allow for projected growth between clinic appointments.

12 Months to 12 Years (Without Concurrent Nevirapine, Efavirenz,

Fosamprenavir, or Nelfinavir)
Lower C trough values have been observed in children receiving LPV/r 230 mg/57.5 mg per m2 of body
surface area per dose twice daily than in children receiving LPV/r 300 mg/75 mg per m2 of body
surface area per dose twice daily (see Table A above).24 Therefore, some clinicians choose to initiate
therapy in children aged 12 months to 12 years using LPV/r 300 mg/75 mg per m2 of body surface
area per dose twice daily (when LPV/r is given without nevirapine [NVP], EFV, FPV, or NFV),
rather than the FDA-approved dose of LPV/r 230 mg/57.5 mg per m2 of body surface area per dose
twice daily.

For infants receiving LPV/r 300 mg/75 mg per m2 of body surface area per dose twice daily,
immediate dose reduction at age 12 months is not recommended; many practitioners would allow
patients to “grow into” the dose of LPV/r 230 mg/57.5 mg per m2 of body surface area per dose twice
daily as they gain weight over time. Some practitioners would continue the infant dose (LPV/r
300 mg/75 mg per m2 of body surface area per dose twice daily) while using the LPV/r liquid
formulation.

Pharmacokinetics and Dosing With Concurrent Nevirapine, Efavirenz,

Fosamprenavir, or Nelfinavir
In both children and adults, the LPV C trough is reduced by concurrent treatment with non-nucleoside
reverse transcriptase inhibitors (NNRTIs) or concomitant FPV or NFV. Higher doses of LPV are
recommended when the drug is given in combination with NVP, EFV, FPV, or NFV. In 14 children
who were treated with LPV/r 230 mg/57.5 mg per m2 of body surface area per dose twice daily plus
NVP,25 the mean LPV C trough was 3.77 ± 3.57 mcg/mL. Not only are these trough plasma
concentrations lower than those found in adults treated with standard doses of LPV/r, but the
variability in concentration is much higher in children than in adults.25,38 In a study of 15 children
with HIV aged 5.7 to 16.3 years who were treated with LPV/r 300 mg/75 mg per m2 of body surface

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-158
area per dose twice daily plus EFV 14 mg/kg body weight per dose once daily, there was a 34-fold
interindividual variation in LPV C trough values. Five of 15 children (33%) had LPV 12-hour C trough
values that were <1.0 mcg/mL, the plasma concentration needed to inhibit wild-type HIV.39 A PK
study in 20 children aged 10 to 16 years who were treated with LPV/r 300 mg/75 mg per m2 of body
surface area twice daily plus EFV 350 mg per m2 of body surface area once daily reported only one
patient (6.6%) with subtherapeutic LPV C trough values,40 perhaps because the trial used an EFV dose that
was approximately 11 mg/kg body weight40 instead of the 14 mg/kg body weight dose used in the trial
discussed above.39

Dosing
Once Daily
A single daily dose of LPV/r 800 mg/200 mg is approved by the FDA for treatment of HIV in
treatment-naive adults aged >18 years. However, once-daily administration cannot be
recommended for use in children in the absence of therapeutic drug monitoring (TDM); once-
daily administration may be successful in select, closely monitored children.41 There is high
interindividual variability in drug exposure for LPV/r, and trough plasma concentrations may fall
below the therapeutic range for wild-type virus, as demonstrated in studies of ARV-naive children
and adolescents.42-45 The currently available tablet formulation of LPV/r has lower variability in trough
levels than the previously used soft-gel formulation.45,46 An international, randomized, open-label trial
attempted to demonstrate that once-daily LPV/r dosing was noninferior to twice-daily LPV/r dosing in
children and adolescents with HIV. This trial was unsuccessful, because a greater number of children
and adolescents who received once-daily doses had viral loads ≥50 copies/mL within 48 weeks.47

Dosing and Its Relation to Efficacy

LPV/r is effective in treatment-experienced patients with severe immune suppression,48,49 although
heavily pretreated patients may be slower to reach undetectable viral loads49,50 and may have less-
robust CD4 T lymphocyte (CD4) percentage responses.51

The relationship between LPV exposure and the susceptibility of the HIV-1 isolate is a key
component of successful treatment. The ratio of C trough to half maximal effective concentration
(EC 50 ) is called the inhibitory quotient (IQ), and in both adults and children treated with LPV/r, viral
load reduction is more closely associated with IQ than with either C trough or EC 50 alone.52-54 One
study investigated the use of the IQ as a guide for therapy by administering higher doses of LPV/r to
children and adolescents until a target IQ of 15 was reached. This study showed that doses of LPV/r
400 mg/100 mg per m2 of body surface area per dose twice daily (without FPV, NFV, NVP, or EFV)
and LPV/r 480 mg/120 mg per m2 of body surface area per dose twice daily (with NVP or EFV) were
safe and tolerable.28 Results of a modeling study suggest that standard doses of LPV/r may be
inadequate for treatment-experienced children and indicate the potential utility of TDM when LPV/r
is used in children who were previously treated with PIs.55 An LPV plasma concentration of
≥1 mcg/mL is cited as a minimum target C trough ,56-58 but this C trough may not adequately control
viremia in patients with multiple LPV resistance mutations.59,60

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-159
Formulations
Palatability
The poor palatability of the LPV/r oral solution can be a significant challenge to medication
adherence for some children and families. Numbing the taste buds with ice chips before or after
administering the solution, masking the taste of the solution by administering it with sweet or tangy
foods (e.g., chocolate syrup, peanut butter), or having the pharmacist flavor the solution prior to
dispensing it are examples of interventions that may improve tolerability. Alternative pediatric
formulations are currently being developed.61,62

Do Not Use Crushed Tablets

LPV/r tablets must be swallowed whole. Crushed tablets are slowly and erratically absorbed and
result in significantly reduced AUC, maximum concentration (C max ), and C trough compared with
swallowing the whole tablet. The variability of the reduced exposure with the crushed tablets (5–75%
reduction in AUC) means that a dose modification cannot be relied on to overcome the reduced
absorption. Crushed tablets cannot be recommended for use.63 In a PK study that used a generic adult
formulation of LPV/r manufactured in Thailand, 21 of 54 children were administered cut (not
crushed) pills and had adequate LPV C trough measurements.46

Toxicity
Children treated with LPV/r may have less-robust weight gain and smaller increases in CD4
percentage than children treated with NNRTI-based regimens.30,64-68 However, one study did not
observe this difference in the effect of LPV/r on CD4 count,69 and another study found that the
difference did not persist after a year of therapy.33 Some studies found no differences between the
weight gain of children treated with LPV/r and those treated with EFV.67,70 Switching to an EFV-
based regimen at or after age 3 years removed the risk of LPV-associated metabolic toxicity, with no
loss of virologic control (see Table 16 in Modifying Antiretroviral Regimens in Children with
Sustained Virologic Suppression on Antiretroviral Therapy).67,68 Bone mineral density improved
when children were treated with EFV-containing regimens instead of regimens that contained
LPV/r.71 Among 212 children randomized to either remain on an LPV/r-based regimen or switch to
an EFV-containing regimen, osteocalcin—a biochemical marker of bone turnover—was higher in the
LPV/r group than the EFV group at both 8 weeks and 2 years post-randomization. Levels of C-
telopeptide of type 1 collagen (CTx) and procollagen type I N-terminal propeptide did not differ
between the two groups.72 In a separate study, among 220 children with HIV (mean age 6.38 years),
lower bone mass was observed in children on LPV/r-based regimens than those with EFV-based
regimens over 2 years of follow-up.73

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-160
References

1. Salerno SN, Capparelli EV, McIlleron H, et al. Leveraging physiologically based

pharmacokinetic modeling to optimize dosing for lopinavir/ritonavir with rifampin in
pediatric patients. Pharmacotherapy. 2022;10.1002/phar.2703. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35607886.

2. Chishala Chabala, Anna Turkova, Kapasa M, et al. Suboptimal lopinavir exposure on 8-

hourly LPV/R 4:1 in HIV/TB co-infected children. Presented at: Conference on
Retroviruses and Opportunistic Infections 2022. Virtual. Available at:
https://www.croiconference.org/wp-
content/uploads/sites/2/posters/2022/CROI2022_Poster_733.pdf.

3. T.G. Jacobs, V. Mumbiro, C. Moraleda, et al. Suboptimal lopinavir exposure in infants 1-

12 months on rifampicin treatment receiving double-dosed or semi-superboosted
lopinavir/ritonavir; results from the EMPIRICAL trial. Presented at: AIDS 2022; 2022.
Montreal, Canada. Available at:
https://programme.aids2022.org/Abstract/Abstract/?abstractid=12648.

4. Dejkhamron P, Unachak K, Aurpibul L, Sirisanthana V. Insulin resistance and lipid

profiles in HIV-infected Thai children receiving lopinavir/ritonavir-based highly active
antiretroviral therapy. J Pediatr Endocrinol Metab. 2014;27(5-6):403-412. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24259240.

5. Arpadi S, Shiau S, Strehlau R, et al. Metabolic abnormalities and body composition of

HIV-infected children on lopinavir or nevirapine-based antiretroviral therapy. Arch Dis
Child. 2013;98(4):258-264. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23220209.

6. Ige OO, Yilgwan CS, Ebonyi AO, et al. Serum lipid and glucose profiles in HIV-positive
Nigerian children. J Virus Erad. 2017;3(3):157-162. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28758024.

7. Patel K, Lindsey J, Angelidou K, Aldrovandi G, Palumbo P, Team IPS. Metabolic effects

of initiating lopinavir/ritonavir-based regimens among young children. AIDS.
2018;32(16):2327-2336. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30102656.

8. Shiau S, Kuhn L, Strehlau R, et al. Sex differences in responses to antiretroviral treatment

in South African HIV-infected children on ritonavir-boosted lopinavir- and nevirapine-
based treatment. BMC Pediatr. 2014;14:39. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24521425.

9. Simon A, Warszawski J, Kariyawasam D, et al. Association of prenatal and postnatal

exposure to lopinavir-ritonavir and adrenal dysfunction among uninfected infants of HIV-
infected mothers. JAMA. 2011;306(1):70-78. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21730243.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-161
10. Kariyawasam D, Peries M, Foissac F, et al. Lopinavir-ritonavir impairs adrenal function
in infants. Clin Infect Dis. 2019;71(4):1030-1039. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31633158.

11. Lopriore E, Rozendaal L, Gelinck LB, Bokenkamp R, Boelen CC, Walther FJ. Twins
with cardiomyopathy and complete heart block born to an HIV-infected mother treated
with HAART. AIDS. 2007;21(18):2564-2565. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18025905.

12. McArthur MA, Kalu SU, Foulks AR, Aly AM, Jain SK, Patel JA. Twin preterm neonates
with cardiac toxicity related to lopinavir/ritonavir therapy. Pediatr Infect Dis J.
2009;28(12):1127-1129. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19820426.

13. Food and Drug Administration. Serious health problems seen in premature babies given
keletra (lopinavir/ ritonavir) oral solution. 2011. Available at:
https://www.fda.gov/Drugs/DrugSafety/ucm246002.htm.

14. Bekker A, Hanan N, Cababasay M, et al. Pharmacokinetics and safety of

lopinavir/ritonavir solution in HIV-infected newborns. Abstract 841. Presented at:
Conference on Retroviruses and Opportunistic Infections 2018. Boston, Massachusetts.
Available at: https://www.croiconference.org/sessions/pharmacokinetics-and-safety-
lopinavirritonavir-solution-hiv-infected-newborns.

15. Chadwick EG, Pinto J, Yogev R, et al. Early initiation of lopinavir/ritonavir in infants
less than 6 weeks of age: pharmacokinetics and 24-week safety and efficacy. Pediatr
Infect Dis J. 2009;28(3):215-219. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19209098.

16. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the
initial treatment of HIV infection. N Engl J Med. 2002;346(26):2039-2046. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12087139.

17. Eron J, Jr., Yeni P, Gathe J, Jr., et al. The KLEAN study of fosamprenavir-ritonavir
versus lopinavir-ritonavir, each in combination with abacavir-lamivudine, for initial
treatment of HIV infection over 48 weeks: a randomised non-inferiority trial. Lancet.
2006;368(9534):476-482. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16890834.

18. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir

versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and
emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week
efficacy and safety results of the CASTLE study. Lancet. 2008;372(9639):646-655.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/18722869.

19. Ortiz R, Dejesus E, Khanlou H, et al. Efficacy and safety of once-daily

darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients
at week 48. AIDS. 2008;22(12):1389-1397. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18614861.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-162
20. Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment
of HIV-1 infection. N Engl J Med. 2008;358(20):2095-2106. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18480202.

21. Pulido F, Estrada V, Baril JG, et al. Long-term efficacy and safety of fosamprenavir plus
ritonavir versus lopinavir/ritonavir in combination with abacavir/lamivudine over 144
weeks. HIV Clin Trials. 2009;10(2):76-87. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19487177.

22. Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine

for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and
week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic
Syndr. 2015;70(5):515-519. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26262777.

23. Orkin C, DeJesus E, Khanlou H, et al. Final 192-week efficacy and safety of once-daily
darunavir/ritonavir compared with lopinavir/ritonavir in HIV-1-infected treatment-naive
patients in the ARTEMIS trial. HIV Med. 2013;14(1):49-59. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23088336.

24. Molina JM, Andrade-Villanueva J, Echevarria J, et al. Once-daily atazanavir/ritonavir

compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and
emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week
efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr.
2010;53(3):323-332. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20032785.

25. Saez-Llorens X, Violari A, Deetz CO, et al. Forty-eight-week evaluation of

lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected
children. Pediatr Infect Dis J. 2003;22(3):216-224. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12634581.

26. De Luca M, Miccinesi G, Chiappini E, Zappa M, Galli L, De Martino M. Different

kinetics of immunologic recovery using nelfinavir or lopinavir/ritonavir-based regimens
in children with perinatal HIV-1 infection. Int J Immunopathol Pharmacol.
2005;18(4):729-735. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16388722.

27. Chadwick EG, Capparelli EV, Yogev R, et al. Pharmacokinetics, safety and efficacy of
lopinavir/ritonavir in infants less than 6 months of age: 24 week results. AIDS.
2008;22(2):249-255. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18097227.

28. Robbins BL, Capparelli EV, Chadwick EG, et al. Pharmacokinetics of high-dose
lopinavir-ritonavir with and without saquinavir or nonnucleoside reverse transcriptase
inhibitors in human immunodeficiency virus-infected pediatric and adolescent patients
previously treated with protease inhibitors. Antimicrob Agents Chemother.
2008;52(9):3276-3283. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18625762.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-163
29. Violari A, Cotton MF, Gibb DM, et al. Early antiretroviral therapy and mortality among
HIV-infected infants. N Engl J Med. 2008;359(21):2233-2244. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19020325.

30. Palumbo P, Lindsey JC, Hughes MD, et al. Antiretroviral treatment for children with
peripartum nevirapine exposure. N Engl J Med. 2010;363(16):1510-1520. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20942667.

31. Reitz C, Coovadia A, Ko S, et al. Initial response to protease-inhibitor-based

antiretroviral therapy among children less than 2 years of age in South Africa: effect of
cotreatment for tuberculosis. J Infect Dis. 2010;201(8):1121-1131. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20214476.

32. Chadwick EG, Yogev R, Alvero CG, et al. Long-term outcomes for HIV-infected infants
less than 6 months of age at initiation of lopinavir/ritonavir combination antiretroviral
therapy. AIDS. 2011;25(5):643-649. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21297419.

33. Barlow-Mosha L, Angelidou K, Lindsey J, et al. Nevirapine- versus lopinavir/ritonavir-

based antiretroviral therapy in HIV-infected infants and young children: long-term
follow-up of the IMPAACT P1060 randomized trial. Clin Infect Dis. 2016;63(8):1113-
1121. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27439527.

34. Kaletra (lopinavir/ritonavir) [package insert]. Food and Drug Administration. 2020.
Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/021251s059,021906s054lbl.
pdf.

35. Nikanjam M, Chadwick EG, Robbins B, et al. Assessment of lopinavir pharmacokinetics

with respect to developmental changes in infants and the impact on weight band-based
dosing. Clin Pharmacol Ther. 2012;91(2):243-249. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22190064.

36. Urien S, Firtion G, Anderson ST, et al. Lopinavir/ritonavir population pharmacokinetics

in neonates and infants. Br J Clin Pharmacol. 2011;71(6):956-960. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21564164.

37. Donegan K, Doerholt K, Judd A, et al. Lopinavir dosing in HIV-infected children in the
United Kingdom and Ireland. Pediatr Infect Dis J. 2013;32(1):45-50. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23076384.

38. Verweel G, Burger DM, Sheehan NL, et al. Plasma concentrations of the HIV-protease
inhibitor lopinavir are suboptimal in children aged 2 years and below. Antivir Ther.
2007;12(4):453-458. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17668553.

39. Bergshoeff AS, Fraaij PL, Ndagijimana J, et al. Increased dose of lopinavir/ritonavir
compensates for efavirenz-induced drug-drug interaction in HIV-1-infected children.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-164
 J Acquir Immune Defic Syndr. 2005;39(1):63-68. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15851915.

40. King JR, Acosta EP, Yogev R, et al. Steady-state pharmacokinetics of lopinavir/ritonavir
in combination with efavirenz in human immunodeficiency virus-infected pediatric
patients. Pediatr Infect Dis J. 2009;28(2):159-161. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19106779.

41. Gondrie IPE, Bastiaans DET, Fraaij PLA, et al. Sustained viral suppression in HIV-
infected children on once-daily lopinavir/ritonavir in clinical practice. Pediatr Infect Dis
J. 2017;36(10):976-980. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28475554.

42. Rosso R, Di Biagio A, Dentone C, et al. Lopinavir/ritonavir exposure in treatment-naive

HIV-infected children following twice or once daily administration. J Antimicrob
Chemother. 2006;57(6):1168-1171. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16606636.

43. van der Lee M, Verweel G, de Groot R, Burger D. Pharmacokinetics of a once-daily

regimen of lopinavir/ritonavir in HIV-1-infected children. Antivir Ther. 2006;11(4):439-
445. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16856617.

44. la Porte C, van Heeswijk R, Mitchell CD, Zhang G, Parker J, Rongkavilit C.

Pharmacokinetics and tolerability of once- versus twice-daily lopinavir/ritonavir
treatment in HIV-1-infected children. Antivir Ther. 2009;14(4):603-606. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19578247.

45. van der Flier M, Verweel G, van der Knaap LC, et al. Pharmacokinetics of lopinavir in
HIV type-1-infected children taking the new tablet formulation once daily. Antivir Ther.
2008;13(8):1087-1090. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19195335.

46. Puthanakit T, Chokephaibulkit K, Suntarattiwong P, et al. Therapeutic drug monitoring

of lopinavir in human immunodeficiency virus-infected children receiving adult tablets.
Pediatr Infect Dis J. 2010;29(1):79-82. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19858772.

47. Paediatric European Network for Treatment of AIDS. Once vs. twice-daily
lopinavir/ritonavir in HIV-1-infected children. AIDS. 2015;29(18):2447-2457. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/26558544.

48. Resino S, Bellon JM, Ramos JT, et al. Salvage lopinavir-ritonavir therapy in human
immunodeficiency virus-infected children. Pediatr Infect Dis J. 2004;23(10):923-930.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/15602192.

49. Resino S, Bellon JM, Munoz-Fernandez MA, Spanish Group of HIV Infection.
Antiretroviral activity and safety of lopinavir/ritonavir in protease inhibitor-experienced
HIV-infected children with severe-moderate immunodeficiency. J Antimicrob
Chemother. 2006;57(3):579-582. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/16446377.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-165
50. Resino S, Galan I, Perez A, et al. Immunological changes after highly active
antiretroviral therapy with lopinavir-ritonavir in heavily pretreated HIV-infected children.
AIDS Res Hum Retroviruses. 2005;21(5):398-406. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15929702.

51. Larru B, Resino S, Bellon JM, et al. Long-term response to highly active antiretroviral
therapy with lopinavir/ritonavir in pre-treated vertically HIV-infected children. J
Antimicrob Chemother. 2008;61(1):183-190. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18025025.

52. Casado JL, Moreno A, Sabido R, et al. Individualizing salvage regimens: the inhibitory
quotient (Ctrough/IC50) as predictor of virological response. AIDS. 2003;17(2):262-264.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/12545089.

53. Delaugerre C, Teglas JP, Treluyer JM, et al. Predictive factors of virologic success in
HIV-1-infected children treated with lopinavir/ritonavir. J Acquir Immune Defic Syndr.
2004;37(2):1269-1275. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15385734.

54. Hsu A, Isaacson J, Brun S, et al. Pharmacokinetic-pharmacodynamic analysis of

lopinavir-ritonavir in combination with efavirenz and two nucleoside reverse
transcriptase inhibitors in extensively pretreated human immunodeficiency virus-infected
patients. Antimicrob Agents Chemother. 2003;47(1):350-359. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12499212.

55. Rakhmanina N, van den Anker J, Baghdassarian A, Soldin S, Williams K, Neely MN.
Population pharmacokinetics of lopinavir predict suboptimal therapeutic concentrations
in treatment-experienced human immunodeficiency virus-infected children. Antimicrob
Agents Chemother. 2009;53(6):2532-2538. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19258274.

56. Moholisa RR, Schomaker M, Kuhn L, et al. Plasma lopinavir concentrations predict
virological failure in a cohort of South African children initiating a protease-inhibitor-
based regimen. Antivir Ther. 2014;19(4):399-406. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24518130.

57. Moholisa RR, Schomaker M, Kuhn L, et al. Effect of lopinavir and nevirapine
concentrations on viral outcomes in protease inhibitor-experienced HIV-infected
children. Pediatr Infect Dis J. 2016;35(12):e378-e383. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27583591.

58. Aurpibul L, Teerananchai S, Prasitsuebsai W, et al. Therapeutic drug monitoring of

lopinavir in HIV-infected children on second-line antiretroviral therapy in Asia. Ther
Drug Monit. 2016;38(6):791-795. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27749514.

59. van Zyl GU, van Mens TE, McIlleron H, et al. Low lopinavir plasma or hair
concentrations explain second-line protease inhibitor failures in a resource-limited

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-166
 setting. J Acquir Immune Defic Syndr. 2011;56(4):333-339. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/21239995.

60. Court R, Gordon M, Cohen K, et al. Random lopinavir concentrations predict resistance
on lopinavir-based antiretroviral therapy. Int J Antimicrob Agents. 2016;48(2):158-162.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27345268.

61. Food and Drug Administration. NDA 205425 tentative approval 2015. 2015. Available
at:
https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/205425Orig1s000TAltr.
pdf

62. Kekitiinwa A, Musiime V, Thomason MJ, et al. Acceptability of lopinavir/r pellets

(minitabs), tablets and syrups in HIV-infected children. Antivir Ther. 2016;21(7):579-
585. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27128199.

63. Best BM, Capparelli EV, Diep H, et al. Pharmacokinetics of lopinavir/ritonavir crushed
versus whole tablets in children. J Acquir Immune Defic Syndr. 2011;58(4):385-391.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/21876444.

64. Coovadia A, Abrams EJ, Stehlau R, et al. Reuse of nevirapine in exposed HIV-infected
children after protease inhibitor-based viral suppression: a randomized controlled trial.
JAMA. 2010;304(10):1082-1090. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20823434.

65. Violari A, Lindsey JC, Hughes MD, et al. Nevirapine versus ritonavir-boosted lopinavir
for HIV-infected children. N Engl J Med. 2012;366(25):2380-2389. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22716976.

66. Lindsey JC, Hughes MD, Violari A, et al. Predictors of virologic and clinical response to
nevirapine versus lopinavir/ritonavir-based antiretroviral therapy in young children with
and without prior nevirapine exposure for the prevention of mother-to-child HIV
transmission. Pediatr Infect Dis J. 2014;33(8):846-854. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25222305.

67. Murnane PM, Strehlau R, Shiau S, et al. Switching to efavirenz versus remaining on
ritonavir-boosted lopinavir in HIV-infected children exposed to nevirapine: long-term
outcomes of a randomized trial. Clin Infect Dis. 2017;65(3):477-485. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28419200.

68. Coovadia A, Abrams EJ, Strehlau R, et al. Efavirenz-based antiretroviral therapy among
nevirapine-exposed HIV-infected children in South Africa: a randomized clinical trial.
JAMA. 2015;314(17):1808-1817. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26529159.

69. Dahourou DL, Amorissani-Folquet M, Malateste K, et al. Efavirenz-based simplification

after successful early lopinavir-boosted-ritonavir-based therapy in HIV-infected children
in Burkina Faso and Cote d'Ivoire: the MONOD ANRS 12206 non-inferiority

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-167
 randomised trial. BMC Med. 2017;15(1):85. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28434406.

70. Achan J, Kakuru A, Ikilezi G, et al. Growth recovery among HIV-infected children
randomized to lopinavir/ritonavir or NNRTI-based antiretroviral therapy. Pediatr Infect
Dis J. 2016;35(12):1329-1332. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27580060.

71. Arpadi SM, Shiau S, Strehlau R, et al. Efavirenz is associated with higher bone mass in
South African children with HIV. AIDS. 2016;30(16):2459-2467. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27427876.

72. Shiau S, Yin MT, Strehlau R, et al. Bone turnover markers in children living with HIV
remaining on ritonavir-boosted lopinavir or switching to efavirenz. Bone.
2020;138:115500. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32590137.

73. Shen Y, Shiau S, Strehlau R, et al. Persistently lower bone mass and bone turnover
among South African children living with well-controlled HIV. AIDS. 2021;35(13):2137-
2147. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34127577.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-168
Appendix A: Pediatric Antiretroviral Drug Information
Entry and Fusion Inhibitors
Fostemsavir (FTR, Rukobia)

Ibalizumab (IBA, Trogarzo)

Maraviroc (MVC, Selzentry)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-169
Fostemsavir (FTR, Rukobia)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Extended-release tablet: 600 mg

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Child and Adolescent (Aged <18 years) • QTc (corrected QT) prolongation with higher than recommended dosages
Dose
• Increased hepatic transaminases in patients with hepatitis B or hepatitis C
• The safety and efficacy of using coinfection
fostemsavir (FTR) in children and
adolescents aged <18 years have not Special Instructions
been established.
• Can be taken with or without food.
Adult Dose
• Extended-release tablet must be swallowed whole. Do not chew, crush, or split
• One tablet twice daily tablets.
• Should not be coadministered with strong cytochrome P450 (CYP) 3A4 inducers
of metabolism, such as rifampin, carbamazepine, phenytoin, and phenobarbital.
• Potential for multiple drug interactions. Check concomitant medications before
prescribing FTR.
• Tablets have a slight odor similar to vinegar.

Metabolism/Elimination
• FTR tromethamine is a prodrug of temsavir (TMR), an HIV-1 gp120-directed
attachment inhibitor.
• FTR is rapidly converted to TMR after oral administration. Metabolic pathways of
TMR include hydrolysis (esterases) (36.1% of oral dose), oxidation (CYP3A4)
(21.1% of oral dose), and uridine diphosphate glucotransferase (UDG) (<1% of
oral dose).
• TMR is a substrate of CYP3A, esterases, P-glycoprotein, and breast cancer
resistance protein (BCRP).
• TMR is an inhibitor of organic anion transporter (OAT) P1B1 and OATP1B3;
TMR and two of its metabolites are inhibitors of BCRP.

Fostemsavir Dosing in Patients With Hepatic Impairment

• No dose adjustment is required in patients with mild-to-severe hepatic
impairment.

Fostemsavir Dosing in Patients With Renal Impairment

• No dose adjustment is required in patients with renal impairment or those on
hemodialysis.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-170
Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Coadministration with strong cytochrome P450 3A inducers is contraindicated,

because the plasma concentrations of the active metabolite, temsavir (TMR), are significantly
reduced, which could result in loss of virologic efficacy.
• Cardiac toxicity: Caution is required when used in combination with drugs that are associated
with prolongation of the QTc interval of the echocardiogram.
• Oral contraceptives: Do not exceed 30 mcg ethinyl estradiol daily. The combination may
increase ethinyl estradiol concentrations and risk of thrombosis.
• HMG-CoA reductase inhibitors (statins): TMR may increase plasma concentrations of statins,
including rosuvastatin, atorvastatin, fluvastatin, pitavastatin, and simvastatin. Use the lowest
possible starting dose of statin and monitor for statin-associated adverse effects.
• Hepatitis C virus direct-acting antivirals: TMR may increase plasma concentrations of
grazoprevir and voxilaprevir due to organic anion transporting polypeptide (OATP) 1B1/3
inhibition.
• Other antiretroviral agents: Drug interaction studies of FTR in combination with
darunavir/cobicistat, darunavir/ritonavir, etravirine, and maraviroc have been conducted in
healthy volunteers. FTR given in combination with these other ARVs was generally well
tolerated, and no dose adjustments were required.1,2

Major Toxicities
• More common: The most common adverse reactions (≥5%) reported include nausea, fatigue, and
diarrhea.
• Less common: QTc prolongation with higher than recommended doses.3 Increased hepatic
transaminases in patients with hepatitis B or hepatitis C coinfection.

Resistance
The International AIDS Society–USA maintains a list of HIV drug resistance mutations and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

TMR showed reduced antiviral activity against HIV subtype AE (the predominate subtype found in
Southeast Asia but not commonly found elsewhere in the world). Treatment-emergent glycoprotein
(gp120) genotypic substitutions at four key sites (S375, M434, M426, and M475) have been found in
evaluable subjects with virologic failure in clinical trials. However, overall frequency of
polymorphisms previously associated with the potential to reduce susceptibility to TMR is low and
should not be a barrier to its usage in patients with multidrug resistance.4

Pediatric Use
Fostemsavir (FTR) is a HIV-1 gp120-directed attachment inhibitor that is not approved for use in
pediatric patients. FTR was approved by the U.S. Food and Drug Administration in 2020 for use in

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-171
adults in combination with other antiretroviral (ARV) drugs, with approval limited to heavily
treatment-experienced adults with multidrug-resistant HIV failing their current (ARV) regimen due
to resistance, intolerance, or safety considerations.5 A pharmacokinetic and safety study of FTR in
children and adolescents ≥20 kg will soon be open to enrollment (PENTA Foundation:
NCT04648280).

Efficacy in Clinical Trials

The safety and efficacy of FTR in heavily treatment-experienced adults with HIV were evaluated in
the BRIGHTE trial, a Phase 3, double-blind placebo-controlled trial. A total of 371 participants were
enrolled into two cohorts (randomized and nonrandomized), depending on remaining treatment
options. The randomized cohort included 272 participants, with at least one fully active drug in at
least one but no more than two ARV classes that could be added to FTR. Participants received either
FTR or a placebo twice daily for 8 days, in addition to their failing ARV regimen. On Day 8,
participants treated with FTR had a significantly greater decrease in levels of HIV-RNA than those
taking the placebo (0.79 versus 0.17 log 10 copies, respectively).6 After Day 8, all participants
received FTR as part of an optimized regimen. In results reported through 48 weeks,6 54% of
participants had an HIV viral load of <40 copies/mL. At Week 96, 60% of participants5,7 had HIV
viral loads of <40 copies/mL and a mean increase in CD4 T lymphocyte (CD4) cell counts of
205 cells/mm3. In 51% (27 out of 53) of evaluable subjects with virologic failure, treatment-emergent
gp120 genotypic substitutions were detected at four key sites (S375, M434, M426, and M475). In the
randomized cohort, virologic response rates increased over time, between the 24-week and 96-week
analyses. Response rates were associated with better susceptibility scores for new optimized
treatment regimens.8 Patients with the lowest CD4 counts at baseline were more likely to experience
serious adverse events or death.8

An additional nonrandomized cohort of 99 patients who had no active drugs as treatment options but
had FTR added to an optimized ARV regimen was studied. Of these, 38% achieved an HIV viral
load of <40 copies/mL at 48 weeks.6 For this cohort, at 96 weeks,5 37% of participants had HIV viral
loads of <40 copies/mL, and the mean increase in CD4 counts was 119 cells/mm3.

Improvements in patient-reported outcomes in health-related quality of life were observed among

participants in both cohorts of the BRIGHTE trial at 48 weeks.9

Mechanism of Action
FTR tromethamine is a prodrug of TMR, an HIV-1 gp120-directed attachment inhibitor. FTR is
rapidly converted to TMR after oral administration. TMR binds directly to the HIV-1 gp120 and
prevents viral attachment and subsequent entry of virus into host T cells. FTR has a novel mechanism
of action and no in vitro cross-resistance with other ARVs, and it can be used regardless of HIV-1
tropism.4

Pharmacokinetics
FTR is pre-systemically metabolized to the active moiety TMR by alkaline phosphatase in the
luminal surface of the small intestine, and then TMR is rapidly absorbed. In healthy adults, the
estimated t ½ is approximately 11 hours.10

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-172
References

1. Moore K, Thakkar N, Magee M, et al. Pharmacokinetics of temsavir, the active moiety of the
HIV-1 attachment inhibitor prodrug, fostemsavir, coadministered with cobicistat, etravirine,
darunavir/cobicistat, or darunavir/ritonavir with or without etravirine in healthy participants.
Antimicrob Agents Chemother. 2022;66(4):e0225121. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35315687.
2. Wire MB, Magee M, Ackerman P, Llamoso C, Moore K. Evaluation of the pharmacokinetic
drug-drug interaction between the antiretroviral agents fostemsavir and maraviroc: a single-
sequence crossover study in healthy participants. HIV Res Clin Pract. 2021;23(1):1-8.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/35285786.
3. Lagishetty C, Moore K, Ackerman P, Llamoso C, Magee M. Effects of temsavir, active
moiety of antiretroviral agent fostemsavir, on QT interval: results from a Phase I study and
an exposure-responses analysis. Clin Transl Sci. 2020;13(4):769-776. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32027457.
4. Gartland M, Arnoult E, Foley BT, et al. Prevalence of gp160 polymorphisms known to be
related to decreased susceptibility to temsavir in different subtypes of HIV-1 in the Los
Alamos National Laboratory HIV Sequence Database. J Antimicrob Chemother.
2021;76(11):2958-2964. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34297843.
5. Fostemsavir (Rukobia) [package insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/212950s000lbl.pdf.
6. Kozal M, Aberg J, Pialoux G, et al. Fostemsavir in adults with multidrug-resistant HIV-1
infection. N Engl J Med. 2020;382(13):1232-1243. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32212519.
7. Gartland M, Cahn P, DeJesus E, et al. Week 96 genotypic and phenotypic results of the
fostemsavir Phase 3 BRIGHTE study in heavily treatment-experienced adults living with
multidrug-resistant HIV-1. Antimicrob Agents Chemother. 2022;66(6):e0175121. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/35502922.
8. Ackerman P, Thompson M, Molina JM, et al. Long-term efficacy and safety of fostemsavir
among subgroups of heavily treatment-experienced adults with HIV-1. AIDS.
2021;35(7):1061-1072. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33946085.
9. Anderson SJ, Murray M, Cella D, et al. Patient-reported outcomes in the Phase III BRIGHTE
trial of the HIV-1 attachment inhibitor prodrug fostemsavir in heavily treatment-experienced
individuals. The Patient -Centered Outcomes Research 2021. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34180035.
10. Magee M, Slater J, Mannino F, Ackerman P, Llamoso C, Moore K. Effect of renal and
hepatic impairment on the pharmacokinetics of temsavir, the active moiety of fostemsavir. J
Clin Pharmacol. 2021;61(7):939-953. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33368327.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-173
Ibalizumab (IBA, Trogarzo)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Single-Dose Vial for Intravenous Administration: 200 mg/1.33 mL (150 mg/mL) in a single-dose vial. Each single-dose vial
contains the following inactive ingredients: L-histidine, polysorbate 80, sodium chloride, and sucrose.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Child and Adolescent Dose • Diarrhea, dizziness, nausea, rash
• The safety and efficacy of using ibalizumab (IBA) in • Immune reconstitution inflammatory syndrome
children and adolescents has not been established.
• In studies of cynomolgus macaque monkeys, IBA use during
Adult Dose pregnancy was associated with reversible immunosuppression
(CD4+ T and B cell lymphopenia) in offspring with IBA exposure
• A single-loading dose infusion of IBA 2,000 mg in utero. Whether this association exists for infants of women treated
administered intravenously (IV) over 30 minutes is with IBA during pregnancy is unknown.
followed by a maintenance dose of IBA 800 mg
administered IV over 15 minutes every 2 weeks. • Potential for immunogenicity in the form of anti-IBA antibodies

• U.S. Food and Drug Administration approval of IBA Special Instructions

is limited to heavily treatment-experienced adults
with multidrug-resistant HIV infection who are • The solution in the vial must be diluted in 0.9% sodium chloride
experiencing treatment failure on their current injection and administered by IV infusion.
regimen.
• Using aseptic technique, withdraw 1.33 mL from each vial and
• IBA is used in combination with other antiretroviral transfer into a 250-mL bag of 0.9% sodium chloride for IV injection.
drugs. Other IV diluents must not be used.
• Once diluted, the solution should be administered immediately. If not
used immediately, the solution can be stored at room temperature
for up to 4 hours or refrigerated for up to 24 hours. Refrigerated
solution should be allowed to stand at room temperature for at least
30 minutes but no more than 4 hours prior to administration.
• Diluted solution is administered as an IV infusion, not as a bolus or
IV push.

Metabolism/Elimination
• Monoclonal antibodies are metabolized to peptides and amino acids.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Ibalizumab (IBA) is a humanized IgG4 monoclonal antibody that blocks HIV entry into CD4 T
lymphocyte (CD4) cells. Based on IBA’s mechanism of action and target-mediated drug

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-174
 disposition, drug–drug interactions are not expected. However, no drug interaction studies have
been conducted.1

Major Toxicities
• More common: Rash, diarrhea, headache, nausea, dizziness, depression1,2
• Less common (more severe): Immune reconstitution inflammatory syndrome (IRIS),
hypersensitivity reaction1

Resistance
HIV has shown reduced susceptibility to IBA, as defined by a decrease in maximum percent
inhibition, when HIV loses N-linked glycosylation sites in the V5 loop of glycoprotein 120.1-3

Phenotypic and genotypic test results showed no evidence of cross-resistance between IBA and any
U.S. Food and Drug Administration (FDA)–approved classes of antiretroviral (ARV) drugs.4 IBA
exhibits ARV activity against R5-tropic, X4-tropic, and dual-tropic HIV.4

Pediatric Use
Approval
IBA is not approved by the FDA for use in pediatric patients. IBA was approved by the FDA in 2018
for use in adults in combination with other ARV drugs, with approval limited to heavily treatment-
experienced adults with multidrug-resistant HIV who are experiencing treatment failure on their
current regimen.5 IBA has an orphan drug designation exempting the requirement for pediatric
studies under the Pediatric Research Equity Act. The FDA requested that the company create a
registry to collect prospective data in individuals exposed to IBA during pregnancy to monitor
maternal and pregnancy outcomes, including adverse effects on the developing fetus, neonate, and
infant. Healthcare providers are encouraged to report these adverse events to Theratechnologies by
calling 1 (833)-23-THERA (1-833-23-4372).

Efficacy in Clinical Trials

Trial Tai Med Biologics (TMB-301) was conducted in 40 adults aged 23 to 65 years who had body
weights ranging from 50 kg to 130 kg, had resistance to ARV drugs from three classes, had been
treated for at least 6 months on stable ARV regimens, had viral loads >1,000 copies/mL, and had
viral sensitivity to at least one ARV drug.3,5 Participants continued their current ARV regimens and
received a 2,000-mg loading dose of IBA on Day 7 of the study. One week after the loading dose,
participants optimized their ARV regimens. Participants received IBA 800 mg on Day 21 and every
2 weeks thereafter. At Week 25, 43% of participants achieved suppressed viral loads1,3 of
<50 copies/mL. At Week 48 of an open-label extension study, 24 participants were taking IBA and
their optimized ARV regimen. Sixteen of 27 participants (59%) had viral loads <50 copies/mL at
48 weeks.6,7

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-175
Mechanism of Action
IBA is a recombinant humanized monoclonal antibody that blocks HIV from infecting CD4 cells. It
does this by binding to domain 2 of the CD4 receptor, which interferes with the post-attachment steps
that allow HIV virus particles to enter host cells and prevent the viral transmission that occurs via
cell–cell fusion.1,7 IBA does not interfere with CD4-mediated immune functions because it binds to a
conformational epitope located primarily in domain 2 of the extracellular portion of the CD4
receptor, away from Major Histocompatibility Complex II molecule binding sites.

Embryo-Fetal Toxicity
In an enhanced pre- and post-natal development study, pregnant cynomolgus monkeys were
administered intravenous doses of IBA, and significant changes in infant monkey immune cell levels
were found (CD4+ T cell and B cell lymphocytopenia) that were attributed to in utero IBA
exposure.1 The lymphocyte changes correlated with infant monkey IBA serum concentrations and
appeared to return to near-normal levels when IBA concentrations were nearly undetectable. One
treatment-group infant monkey died from a systemic viral infection with secondary superficial
bacterial infection that was acquired during the postnatal period. Despite the low incidence of death
(1 of 20 infant monkeys), the death may be related to IBA-induced immunosuppression.1

Based on these animal data, IBA may cause reversible immunosuppression (CD4+ T cell and B cell
lymphocytopenia) in infants born to mothers treated with IBA during pregnancy. Immune
phenotyping of the peripheral blood and expert consultation are recommended to provide guidance
regarding monitoring and management of exposed infants based on the degree of
immunosuppression observed. Furthermore, the safety of administering live or live-attenuated
vaccines to infants with in utero IBA exposure and abnormal lymphocyte levels is unknown.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-176
References

1. Ibalizumab-uiyk (Trogarzo) [package insert]. Food and Drug Administration. 2021.

Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/761065s011lbl.pdf.

2. Iacob SA, Iacob DG. Ibalizumab targeting CD4 receptors, an emerging molecule in HIV
therapy. Front Microbiol. 2017;8:2323. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29230203.

3. Emu B, Fessel J, Schrader S, et al. Phase 3 study of ibalizumab for multidrug-resistant

HIV-1. N Engl J Med. 2018;379(7):645-654. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30110589.

4. Weinheimer S, Cohen Z, Marsolais C, Lewis S. Ibalizumab susceptibility in patient HIV

isolates resistant to antiretrovirals. Abstract 561. Presented at: Conference on
Retroviruses and Opportunistic Infections 2018. Boston, Massachusetts. Available at:
https://www.croiconference.org/sessions/ibalizumab-susceptibility-patient-hiv-isolates-
resistant-antiretrovirals.

5. Food and Drug Administration. FDA clinical pharmacology biopharmaceutics reviews.

2018. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/TROGARZO_761065_TOC.c
fm.

6. Emu B, Fessel J, Schrader S, et al. Forty-eight-week safety and efficacy on-treatment

analysis of ibalizumab in patients with multi-drug resistant HIV-1. Open Forum Infect
Dis. 2017;4(Suppl 1):S38-S39. Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632088.

7. Gulick RM. Investigational antiretroviral drugs: what is coming down the pipeline. Top
Antivir Med. 2018;25(4):127-132. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29689540.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-177
Maraviroc (MVC, Selzentry)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Oral Solution: 20 mg/mL

Tablets: 25 mg, 75 mg, 150 mg, 300 mg

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

• Maraviroc (MVC) is approved by the U.S. Food and Drug • Nausea, vomiting
Administration (FDA) for use, in combination with other
antiretroviral agents, for the treatment of CCR5-tropic HIV-1 • Abdominal pain, diarrhea
infection in infants born full term weighing ≥2 kg, children, • Cough
adolescents, and adults.
• Upper respiratory tract infections
Recommended Maraviroc Dose for Full-Term Infants • Fever
and Treatment-Experienced Children and Adolescents
Weighing ≥2 kg: Tablets or Oral Solution • Rash
• Hepatotoxicity (which may be preceded by severe rash
Twice- Oral and/or other signs of systemic allergic reaction)
Weight Band Daily Solution Tablets
Dosing 20 mg/mL • Postural hypotension (generally seen in patients with
severe renal insufficiency)
Recommended doses when MVC is given with non-interacting • Dizziness
drugs, such as nucleoside reverse transcriptase inhibitors
(NRTIs), nevirapine (NVP), enfuvirtide (T-20), and
raltegravir (RAL)
Special Instructions

2 kg to <4 kg 30 mg 1.5 mL N/A • MVC is recommended for use in patients who have only
CCR5-tropic HIV-1. Before using MVC, conduct testing
4 kg to <6 kg 40 mg 2 mL N/A with an HIV tropism assay (see Drug-Resistance
Testing in the Adult and Adolescent Antiretroviral
6 kg to 100 mg 5 mL One 25-mg tablet
Guidelines) to exclude the presence of CXCR4-tropic or
<10 kg and one 75-mg
mixed/dual-tropic HIV. Do not use MVC if CXCR4-tropic
tablet
or mixed/dual-tropic HIV is present.
10 kg to 14 kg 150 mg 7.5 mL One 150-mg tablet
• MVC can be given without regard to food.
14 kg to 200 mg 10 mL One 150-mg tablet • Instruct patients on how to recognize symptoms of
<30 kg and two 25-mg allergic reactions or hepatitis.
tablets
• Use caution when administering MVC to patients with
30 kg to 300 mg 15 mL One 300-mg tablet underlying cardiac disease.
<40 kg
≥40 kg 300 mg 15 mL One 300-mg tablet

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-178
 Recommended doses when MVC is given with potent Metabolism/Elimination
cytochrome P450 (CYP) 3A inhibitors (with or without a potent
CYP3A inducer), including all protease inhibitors (PIs) • MVC is a substrate of CYP3A4. If a patient is receiving
antiretroviral agents or other medications that act as
2 kg to Not recommended. Data are insufficient to CYP3A inducers or inhibitors, the dose of MVC should
<10 kg make dosing recommendations for infants be adjusted accordingly.
weighing <10 kg and receiving a potent P450
CYP3A inhibitor. Maraviroc Dosing in Patients With Hepatic Impairment
10 kg to 50 mg 2.5 mL Two 25-mg tablets • Use caution when administering MVC to patients with
<20 kg hepatic impairment; MVC concentrations may be
increased in these patients.
20 kg to 75–80 mg 4 mL One 75-mg tablet
<30 kg Maraviroc Dosing in Patients With Renal Impairment
30 kg to 100 mg 5 mL One 25-mg tablet • No data recommend specific doses of MVC for pediatric
<40 kg and one 75-mg patients with mild or moderate renal impairment. MVC
tablet is contraindicated for pediatric patients with severe
≥40 kg 150 mg 7.5 mL One 150-mg tablet renal impairment or end-stage renal disease who are
on regular hemodialysis and who are receiving potent
Recommended doses when MVC is given with potent CYP3A CYP3A inhibitors.
inducers (without a potent CYP3A inhibitor), including efavirenz • Refer to the manufacturer’s prescribing information for
(EFV) and etravirine (ETR) the appropriate doses to use in adolescent and adult
Infants and Not recommended. Data are insufficient to patients with renal impairment.
children and make dosing recommendations.
adolescents
in all weight
bands

Recommended Maraviroc Dose for Adults: Tablets

When Coadministered With Dose

Non-interacting concomitant medications, 300 mg
including NRTIs, T-20, NVP, and RAL twice daily

Potent CYP3A inhibitors (with or without a 150 mg

potent CYP3A inducer), including all PIs twice daily

Potent CYP3A inducers (without a potent 600 mg

CYP3A inhibitor), including EFV and ETR twice daily

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Absorption: Absorption of maraviroc (MVC) is slightly reduced with ingestion of a high-fat meal.
Food restrictions were not part of either the adult trials (which used the tablet formulation) or the
pediatric trial (which used both the tablet and oral solution formulations) that demonstrated the
efficacy, antiviral activity, and safety of MVC. Therefore, MVC can be given with or without food.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-179
• Metabolism: MVC is a cytochrome P450 (CYP) 3A and p-glycoprotein (P-gp) substrate and
requires dose adjustments when administered with medications that modulate CYP3A or P-gp. A
patient’s medication profile should be carefully reviewed for potential drug interactions before
MVC is administered; recommended MVC doses are based on concomitant medications and their
anticipated effect on MVC metabolism.

Major Toxicities
• More common: Cough, fever, upper respiratory tract infections, rash, musculoskeletal symptoms,
abdominal pain, vomiting, diarrhea, and headache. Dizziness occurred in 12.2% of adults but only
3.2% of children when MVC was administered twice daily.
• Less common (more severe): Hepatotoxicity has been reported; some cases were preceded by
evidence of a systemic allergic reaction (including pruritic rash, eosinophilia, or elevated levels
of immunoglobulin). Serious adverse events (AEs) occurred in <2% of MVC-treated adult
patients and included cardiovascular abnormalities (e.g., angina, heart failure, myocardial
infarction), hepatic cirrhosis or failure, cholestatic jaundice, viral meningitis, pneumonia,
myositis, osteonecrosis, and rhabdomyolysis.

Mechanism of Action
MVC is a CCR5 receptor antagonist that selectively binds to the human chemokine receptor CCR5
on the cell membrane, preventing interaction between HIV-1 gp120 and CCR5 tropic HIV-1,
inhibiting viral entry into the cell.

Resistance
An HIV tropism assay should be performed before MVC is administered to a patient. Clinical failure
may also represent the outgrowth of CXCR4-using (naturally resistant) HIV variants. However, in
circumstances when MVC is needed for presumptive HIV therapy for full-term neonates at high risk
of perinatal HIV transmission, initiation of MVC should not be deferred until assay results are
available, and consultation with an HIV expert is recommended.

Pediatric Use
Approval
MVC is approved by the U.S. Food and Drug Administration (FDA) for treatment in full-term infants
weighing ≥2 kg, as well as children, adolescents, and adults who have a CCR5-tropic HIV virus
when used in conjunction with other antiretroviral drugs.1,2

Pharmacokinetics and Efficacy

The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT 2007) study
evaluated the pharmacokinetics (PK) and safety of MVC added to a 6-week prophylactic
antiretroviral regimen to prevent perinatal HIV transmission of HIV among infants born to mothers
living with HIV.2 Analyses were stratified by exposure to efavirenz (EFV), either in utero or through
breastmilk, versus non-EFV exposure. The MVC exposure target was average plasma
concentration (C avg ) ≥75 ng/mL, as determined by adult treatment studies. MVC oral solution was

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-180
dosed at 8 mg/kg twice daily for the first 6 weeks of life. Among 25 infants with evaluable PK data,
12 of whom were EFV-exposed, 67% of the EFV-exposed infants achieved a C avg ≥75 ng/mL at
Week 1, whereas 77% of the EFV-unexposed infants had a C avg ≥75 ng/mL. At Week 4, the
proportion of infants achieving a C avg ≥75 ng/mL declined to 42% among EFV-exposed infants and
31% among EFV-unexposed infants. No infants in the study met safety endpoints or discontinued
MVC during the study and no infants acquired HIV. The FDA recommendation for MVC dosing
among children >6 weeks of life but younger than 2 years of age is based on modeling using PK data
from the IMPAACT 2007 study. When considering the use of MVC for neonates and infants, a
pediatric HIV specialist should be consulted.

PK, safety, and efficacy of MVC for treatment-experienced children, ages 2 years to <18 years and
weighing ≥10 kg, who had plasma HIV RNA >1,000 copies/mL, were examined in an international
dose-finding and efficacy study (A4001031). Of the 103 children who participated in the study, 51%
had HIV-1 subtype C, 25% had subtype B, and 23% had other subtypes.

In this trial, the MVC dose was based on body surface area and the composition of the patient’s
optimized background therapy. Most participants (90 of 103 participants [87%]) received MVC in
combination with potent CYP3A inhibitors; 10 participants received MVC with noninteracting
medications; and only 3 participants received MVC with CYP3A inducers (without CYP3A
inhibitors). The key pharmacologic target (geometric mean C avg of >100 ng/mL) was achieved with
both the tablet and oral solution formulation of MVC.3

From a mean baseline plasma HIV RNA concentration of 4.4 log 10 copies/mL, a decrease of
≥1.5 log 10 occurred in all four age-based cohorts. Only two participants discontinued the study due to
AEs. The most common MVC-related AEs through 48 weeks were diarrhea (which occurred in
20.3% of participants), vomiting (19.8%), and upper respiratory infections (16.2%). At Week 48,
48% of participants had HIV RNA <48 copies/mL.3 The absolute CD4 T lymphocyte cell count and
percentage increased in all four subgroups of the study, with overall median increases of
192 cells/mm3 (interquartile range [IQR] 92–352 cells/mm3) and 4% (IQR 1% to 8%), respectively.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-181
References
1. Maraviroc (Selezentry) [package insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022128Orig1s019,208984Orig1s002l
bl.pdf.

2. Rosebush JC, Best BM, Chadwick EG, et al. Pharmacokinetics and safety of maraviroc in
neonates. AIDS. 2021;35(3):419-427. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33252481.

3. Giaquinto C, Mawela MP, Chokephaibulkit K, et al. Pharmacokinetics, safety and efficacy of

maraviroc in treatment-experienced pediatric patients infected with CCR5-tropic HIV-1. Pediatr
Infect Dis J. 2018;37(5):459-465. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29023357.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-182
Appendix A: Pediatric Antiretroviral Drug Information
Integrase Inhibitors
Bictegravir (BIC)

Cabotegravir (CAB, Vocabria)

Dolutegravir (DTG, Tivicay)

Elvitegravir (EVG)

Raltegravir (RAL, Isentress)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-183
Bictegravir (BIC)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Bictegravir is available only in a fixed-dose combination (FDC) tablet.

FDC Tablet
• [Biktarvy]
o Bictegravir 50 mg/emtricitabine 200 mg/tenofovir alafenamide 25 mg
o Bictegravir 30 mg/emtricitabine 120 mg/tenofovir alafenamide 15 mg

When using FDC tablets, refer to other sections of Appendix A: Pediatric Antiretroviral Drug Information for information about
the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and
Co-packaged Formulations: Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

[Biktarvy] Bictegravir/Emtricitabine/Tenofovir Alafenamide • Diarrhea, nausea, headache
(BIC/FTC/TAF)
Neonate or Child Aged <2 years and Weighing <14 kg Special Instructions
• No data currently are available on the appropriate dose of • Administer Biktarvy with or without food. See the
Biktarvy in children aged <2 years and weighing <14 kg. Drug Interactions section below for guidance when
Studies are being conducted to develop an age-appropriate administering Biktarvy with antacids or iron or
formulation and identify the appropriate dose for this age and calcium supplements.
weight group. • For children unable to swallow a whole tablet, the
tablet can be split and each part taken separately, as
Child (Aged ≥2 years), Adolescent, and Adult Dose
long as all parts are swallowed within approximately
• One tablet once daily with or without food. 10 minutes. Dissolving tablets may be an alternative,
but crushing tablets is not recommended.
Body Weight Dose
• Screen patients for hepatitis B virus (HBV) infection
≥14 to <25 kg BIC 30 mg/FTC 120 mg/TAF 15 mg before using FTC or TAF. Severe acute exacerbation
of HBV can occur when discontinuing FTC or TAF;
≥25 kg BIC 50 mg/FTC 200 mg/TAF 25 mg therefore, monitor hepatic function for several months
after halting therapy with FTC or TAF.
• The U.S. Food and Drug Administration approved Biktarvy for
use in only antiretroviral therapy–naive patients or to replace Metabolism/Elimination
the current antiretroviral (ARV) regimen in patients who have
been virologically suppressed (HIV RNA <50 copies/mL) on a • BIC is metabolized by cytochrome P450 3A4 and
stable ARV regimen and who have no history of treatment uridine diphosphate glucuronosyltransferase
failure and no known mutations associated with resistance to (UGT1A1).
the individual components of Biktarvy. Some members on the
Panel on Antiretroviral Therapy and Medical Management of Biktarvy Dosing in Patients With Hepatic
Children Living With HIV (the Panel) recommend the use of Impairment
Biktarvy in patients with prior treatment failure and who have • Biktarvy is not recommended for use in patients
virus containing the M184V mutation but no other known with severe hepatic impairment.
mutations associated with resistance to the individual

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-184
 components of Biktarvy (see Efficacy in Clinical Trials in Adults Biktarvy Dosing in Patients With Renal Impairment
below).
• Biktarvy is not recommended for use in patients
with estimated creatinine clearance <30 mL/min. See
the Biktarvy product label for use in patients on
dialysis.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Bictegravir (BIC) is a substrate of cytochrome P450 (CYP) 3A4 and uridine
diphosphate glucuronosyltransferase (UGT) 1A1. TAF is a substrate of P-glycoprotein and
UGT1A1. Coadministration of the fixed-dose combination (FDC) tablet
bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF [Biktarvy]) and rifampin is
contraindicated.1,2
• Renal effects: BIC is an inhibitor of organic cation transporter 2 and multidrug and toxin
extrusion protein 1, so it decreases tubular secretion of creatinine. This increases serum creatinine
and reduces estimated glomerular filtration rate (eGFR) with no change in glomerular function.
Drugs that decrease renal function could reduce clearance of FTC.
• Absorption: Administering BIC concurrently with antacids lowers the plasma concentrations of
BIC. This phenomenon occurs because of the formation of complexes in the gastrointestinal tract
and not because of changes in gastric pH. Chelation by high concentrations of divalent cations—
such as iron—decreases absorption of integrase strand transfer inhibitors (INSTIs), including
elvitegravir and BIC. For this reason, Biktarvy should be administered at least 2 hours before or
6 hours after antacids and supplements or multivitamins that contain iron, calcium, aluminum,
magnesium, and/or zinc3 when Biktarvy is given on an empty stomach. Biktarvy and antacids or
supplements that contain calcium or iron can be taken together with food.

Major Toxicities
• More common: Diarrhea, nausea, headache. In two clinical trials, total bilirubin increased by up
to 2.5 times the upper limit of normal in 12% of patients who received Biktarvy. In general,
however, bilirubin increase was quite mild and did not lead to drug discontinuations in these
trials.2 BIC may cause an increase in creatine kinase concentration. One patient out of 201 in a
post-marketing observational study in adults experienced thrombocytopenia,4 and one participant
out of 100 in a prospective cohort study in children and adolescents experienced
insomnia/anxiety5 leading to drug discontinuation. Other neuropsychiatric and central nervous
system manifestations have been reported in adults (see Table 17a. Antiretroviral Therapy–
Associated Adverse Effects and Management Recommendations—Central Nervous System
Toxicity). Weight gain has been reported in adults who were receiving Biktarvy (see Table 17h.
Antiretroviral Therapy-Associated Adverse Effects and Management Recommendations—
Lipodystrophies and Weight Gain).
• Less common (more severe): Severe immune reconstitution inflammatory syndrome may be more
common with INSTIs than with other antiretroviral (ARV) agents.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-185
Resistance
The International Antiviral Society–USA maintains a list of HIV drug resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
BIC, available as part of the FDC tablet Biktarvy, containing BIC 50 mg/FTC 200 mg/TAF 25 mg,
was approved by the U.S. Food and Drug Administration (FDA) in 2018 for use in adults and in
2019 for use in children or adolescents weighing ≥25 kg. Biktarvy, containing BIC 30 mg/FTC
120 mg/TAF 15 mg was approved by the FDA in 2021 for use in children aged ≥2 years and
weighing ≥14 to <25kg. Biktarvy is FDA approved for patients who have no ARV treatment history
or to replace current ARV regimens in patients who have been virologically suppressed (HIV RNA
<50 copies/mL) on a stable ARV regimen for at least 3 months, with no history of treatment failure
and no known mutations associated with resistance to the individual components of the FDC.2
However, some members of the Panel on Antiretroviral Therapy and Medical Management of
Children Living With HIV (the Panel) recommend the use of Biktarvy in patients with prior
treatment failure and who have virus containing the M184V mutation but no other known mutations
associated with resistance to the individual components of Biktarvy (see Efficacy in Clinical Trials in
Adults below).

Efficacy in Clinical Trials in Adults

In a short-term Phase 1 study, BIC monotherapy at doses of BIC 50 mg or BIC 100 mg was well
tolerated. Three out of eight participants in both of these dosing groups achieved HIV RNA
<50 copies/mL within 11 days.6 The efficacy (defined as viral load suppression to HIV RNA
<50 copies/mL) and safety (as measured by the incidence of study drug discontinuation or death) of
Biktarvy were similar to the efficacy and safety of comparator regimens in two Phase 3 randomized
trials in treatment-naive adults. Viral load suppression occurred in 89% of participants who received
coformulated BIC 50 mg/FTC 200 mg/TAF 25 mg (n = 320) and in 93% of participants who
received a regimen of dolutegravir (DTG) 50 mg plus FTC 200 mg plus TAF 25 mg (n = 325). Study
drug discontinuation occurred in 1% of participants in both groups.

In a separate trial, viral load suppression occurred in 92% of participants who received
BIC/FTC/TAF (n = 314) and in 93% of participants who received coformulated abacavir
600 mg/dolutegravir 50 mg/lamivudine 300 mg (ABC/DTG/3TC) (n = 315). Study drug
discontinuation was not reported for any of the participants who received BIC/FTC/TAF, although it
did occur in 1% of participants who received ABC/DTG/3TC.2,7 Studies that randomized
virologically suppressed patients who were on stable ARV regimens to either continue their current
regimens or switch to coformulated BIC/FTC/TAF have shown that BIC/FTC/TAF has similar safety
and efficacy to existing regimens. Viral load suppression occurred in 94% of participants who were
randomized to switch to BIC/FTC/TAF (n = 282) and in 95% of participants who continued taking
ABC/DTG/3TC (n = 281). Study drug discontinuation was reported in 2% of participants who
received BIC/FTC/TAF and 1% of participants who received ABC/DTG/3TC. Ninety-two percent of
participants who were randomized to switch to BIC/FTC/TAF (n = 290) achieved viral load
suppression, whereas 89% of participants who continued receiving atazanavir-based or darunavir-
based combination ARV regimens (n = 287) achieved viral load suppression. Study drug

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-186
discontinuation occurred in 1% of participants in both groups.2 Similar BIC/FTC/TAF efficacy has
been demonstrated in historically underrepresented populations, including Black and female
populations with HIV.8,9

Initial studies in participants switching to BIC/FTC/TAF from stable antiretroviral therapy (ART)
required undetectable viral load for 3 or 6 months and no proven or presumed preexisting resistance
to any of the components of BIC/FTC/TAF.2,10,11 Further analysis of data from these studies used
proviral genotyping and showed presence of M184V/I mutation in 54 (10%) of 543 BIC/FTC/TAF-
treated participants. Presence of this mutation did not affect viral load suppression, with Week 48
HIV RNA <50 copies/mL in 52 (96%) of 54 participants with archived M184V/I mutations
compared with Week 48 HIV RNA <50 copies/mL in 561 (98%) of 570 participants without the
mutation.12 A study to measure the effect of preexisting nucleoside reverse transcriptase inhibitor
(NRTI) mutations on virologic outcome in participants switching from a stable regimen to
BIC/FTC/TAF showed Week 48 HIV RNA <50 copies/mL in 223 (94%) of 237 participants without
M184V/I resistance and in 42 (89%) of 47 participants with M184V/I mutations at baseline.13,14 At
Week 48, HIV RNA <50 copies/mL was maintained in 199 (93%) of 213 participants with no NRTI
resistance mutation and in 66 (93%) of 71 participants with any NRTI resistance mutation, including
K65R/E/N, any number of thymidine analogue mutations (M41L, D67N, K70R, L210W, T215F/Y,
and K219Q/E/R/N), T69 insertions, T69D, K70E/G/M/Q/S/T, L74I/V, V75A/S/M/T, Y115F,
Q151M, or M184V/I.13 That study required pre-enrollment virologic suppression for 6 months in
those with suspected NRTI resistance and 3 months for those without suspected NRTI resistance.15 In
an analysis of participant data pooled from six clinical trials switching virologically suppressed
adults with HIV to BIC/FTC/TAF, 98% (179/182) of participants with pre-existing M184V/I and
99% (2,012/2,034) of all participants (with or without M184V/I) had an HIV-1 RNA viral load
<50 copies/mL at their last on-treatment visit, with no treatment-emergent resistance to
BIC/FTC/TAF.15-17 In practice, Panel members have used BIC/FTC/TAF even in patients with
detectable viral load, prior ARV failure, or virus containing the M184V mutation but no other known
mutations associated with resistance to the individual components of Biktarvy. This practice is based
on the premise that the ability to simplify multi-pill or multi-dose regimens to a single small pill,
once daily, can overcome potential resistance barriers with definite adherence benefits.18

Pharmacokinetics
Pharmacokinetic (PK) studies of Biktarvy containing BIC 50 mg have been performed in adults,
adolescents aged 12 years to <18 years who weigh ≥35 kg, and children aged 6 years to <12 years
who weigh ≥25 kg. PK studies of “low-dose” Biktarvy, which contains BIC 30 mg, have been
performed in children aged ≥2 years weighing 14 to <25 kg.19 These studies show a higher BIC
maximum serum concentration (C max ) in the younger cohorts than in the older cohorts, perhaps
because the administered dose is higher on a mg/kg basis (see Table A below). The lower trough
serum concentration (C tau ) and higher C max in the younger age/lower body weight cohorts suggest
more rapid clearance in children and adolescents than in adults. In the cohorts with body weight19
≥14 to <25 kg and body weight5 ≥35 kg, there is a lower geometric mean ratio when C tau is compared
to adult values, and the lower 90% confidence interval suggests that some patients have quite rapid
clearance (see Table B below). These PK observations raise the concern that some of the patients in
the youngest age/lowest body weight cohorts may experience suboptimal trough concentrations,
which may lead to less “pharmacologic forgiveness” in persons with lower adherence (see Table B
below).20

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-187
Table A. Bictegravir Pharmacokinetics in Children, Adolescents, and Adults With HIV

Children Children Adolescents

Aged ≥2 Years Aged 6 Years to Aged 12 Years to
PK Parameters Adults2
and Weighing ≥14 <12 Years and <18 Years and
to <25 kg19 Weighing ≥25 kg5 Weighing ≥35 kg5
Dose (mg) 30 50 50 50
Dose for Lowest Weight 2.14 2 1.43 1.25a
in the Cohort (mg/kg)
AUC tau ng•h/mL 109,000 (24) 128,000 (28) 89,100 (31) 102,000 (26.9)
Mean (CV%)
C max ng/mL 10,100 (21) 9,460 (24) 6,240 (27) 6,150 (22.9)
Mean (CV%)
C tau ng/mL 2,000 (78) 2,360 (39) 1,780 (44) 2,610 (35)
Mean (CV%)
a This dose was calculated using 40 kg as the lowest weight for adults.

Key: AUC tau = area under the concentration time curve over the dosing interval; C max = maximum serum concentration;
C tau = trough serum concentration at the end of the dosing interval; CV = coefficient of variation; PK = pharmacokinetic

Table B. Bictegravir Pharmacokinetics in Children and Adolescents With HIV

Dose for Lowest GMR% (90% CI) Compared to Adult Valuesa

Dose
Cohort Characteristics Weight in Cohort
(mg)
(mg/kg) AUC tau C max C tau
Aged ≥2 Years and 30 2.14 109 (96.7–122) 166 (149–184) 67.7 (49.6–92.4)
Weighing ≥14 to <25 kg19
Aged 6 Years to <12 Years 50 2 125 (117–134) 153 (143–163) 88.9 (80.6–98.0)
and Weighing ≥25 kg5
Aged 12 Years to <18 Years 50 1.43 86 (80–93) 100 (94–107) 65.4 (58.3–73.3)
and Weighing ≥35 kg5
a In this table, child and adolescent pharmacokinetic (PK) values are compared to the PK values of adults who received

bictegravir 50 mg. The dose for the lowest weight in the adult cohort was 1.25 mg/kg; this was calculated using 40 kg as the
lowest weight for adults.
Key: AUC tau = area under the concentration time curve over the dosing interval; C max = maximum serum concentration;
C tau = trough serum concentration at the end of the dosing interval; CI = confidence interval; GMR = geometric mean ratio

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-188
Use of Biktarvy in Children and Adolescents Weighing ≥25 kg
BIC 50 mg/FTC 200 mg/TAF 25 mg (Biktarvy) was administered to adolescents aged 12 years to
<18 years who weighed ≥35 kg (maximum body weight 56.1 kg) and who had had viral loads of
<50 copies/mL for ≥6 months on their previous ARV regimens. The drug was well tolerated and was
associated with a fall in eGFR similar to that seen in adults. This decrease in eGFR was considered to
be from changes in tubular secretion of creatinine and was not a true change in glomerular function.
In comparing cohorts of children (body weight ≥14 kg to <25 kg) and adolescents (body weight
≥35 kg) to adult cohorts the geometric mean ratio of C tau was noted to be lower (see Tables A and B
above). All 50 participants in the study had viral loads <50 copies/mL at Week 24, and 49 of 50 had
viral loads <50 copies/mL at week 48.5

BIC 50 mg/FTC 200 mg/TAF 25 mg was administered to children aged 6 years to <12 years who
weighed ≥25 kg and who had had viral loads <50 copies/mL for ≥6 months on their current ARV
regimens.5 Despite a high area under the curve (AUC) and C max (see Table A above), the drug
combination was well tolerated, with a fall in eGFR similar to that seen in adult studies. One
participant stopped the study drug because of insomnia and anxiety. The geometric mean ratio of C tau
compared with adult values (see Table B above) showed trough concentrations similar to those seen
in adults.5 All 50 participants in the study had viral loads <50 copies/mL at Week 24 and 49 of 50
had viral loads <50 copies/mL at Week 48.5

Use of Biktarvy in Children Weighing ≥14 to <25 kg

Biktarvy tablets consisting of BIC 30 mg/FTC 120 mg/TAF15 mg were administered to children
aged ≥2 years weighing ≥14 to <25 kg and who had viral loads <50 copies/mL on stable ART. PK
evaluation showed high AUC and C max , similar to those in patients aged 6 years to <12 years who
weighed ≥25 kg, a similarly low C tau (see Table A above), and a lower geometric mean ratio when
C tau was compared with adult values (see Table B above).19 In general, the low-dose tablet was well
tolerated over 55 weeks in the 22 children studied.21 Adverse events considered related to the study
drug included transient neutropenia (n = 2) and abdominal pain (n = 3).21 At 24 weeks, the median
change in CD4 cell count was a decrease of 100 cells/μL, and the change in CD4 percentage was an
increase of 0.5%. HIV RNA at <50 copies/mL was maintained in 20 of 22 participants at 24 weeks.21

Dosing: Splitting, Dissolving, or Crushing Biktarvy Tablets

The product label states that for children who are unable to swallow a whole tablet, the tablet can be
split and each part taken separately, as long as all parts are ingested within approximately
10 minutes.2

In a Phase 1 open-label, single-dose, three-period crossover randomized trial of 18 adult participants

without HIV, the bioavailability of Biktarvy (BIC 50 mg/FTC 200 mg/TAF 25 mg) was evaluated in
fasting participants who received Biktarvy dissolved in water, crushed in applesauce, or as a solid
tablet. Dissolved tablet plasma concentration AUC was considered bioequivalent for all antiretroviral
components. Although the dissolved tablet C max was considered bioequivalent for BIC and FTC, the
TAF C max 90% lower confidence limit was not (dissolved vs. solid ratio, 96% [90% confidence
interval (CI), 74–124%]). For crushed tablets mixed with applesauce, the BIC component was
considered bioequivalent for AUC and C max . However, crushed FTC and TAF AUC and C max were
lower than that of solid tablets, with FTC C max (crushed vs. solid ratio, 70% [90% CI, 63–78%]),

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-189
TAF AUC (84% [90% CI, 69–103%]), and TAF C max (66% [90% CI, 51–85%]) failing to meet
bioequivalence criteria. Crushing Biktarvy tablets may lead to suboptimal FTC and TAF exposures.22

Dissolving BIC/FTC/TAF tablets may be an alternative method of administration, but crushing

tablets is not recommended. In the clinical literature, case reports in adults with HIV receiving
crushed BIC/FTC/TAF describe inconsistent virological and resistance outcomes.17,23-26 These cases
varied in underlying comorbidities, baseline viral loads, adherence, method of crushing and
dissolving tablets, administration (i.e., orally vs. via a tube), and instructions about polyvalent cation
and food administration.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-190
References

1. Custodio J, West SK, Collins S, et al. Pharmacokinetics of bictegravir administered twice

daily in combination with rifampin. Presented at: Conference on Retroviruses and
Opportunistic Infections; 2018. Boston, MA. Available at:
https://www.croiconference.org/sessions/pharmacokinetics-bictegravir-administered-
twice-daily-combination-rifampin.
2. Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) [package insert]. Food and
Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210251s015lbl.pdf.
3. Rock AE, DeMarais PL, Vergara-Rodriguez PT, Max BE. HIV-1 virologic rebound due
to coadministration of divalent cations and bictegravir. Infect Dis Ther. 2020;9(3):691-
696. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32623580.
4. Hayes E, Derrick C, Smalls D, Smith H, Kremer N, Weissman S. Short-term adverse
events with BIC/FTC/TAF: postmarketing study. Open Forum Infect Dis.
2020;7(9):ofaa285. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32908943.
5. Gaur AH, Cotton MF, Rodriguez CA, et al. Fixed-dose combination bictegravir,
emtricitabine, and tenofovir alafenamide in adolescents and children with HIV: week 48
results of a single-arm, open-label, multicentre, phase 2/3 trial. Lancet Child Adolesc
Health. 2021;5(9):642-651. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34302760.
6. Gallant JE, Thompson M, DeJesus E, et al. Antiviral activity, safety, and
pharmacokinetics of bictegravir as 10-day monotherapy in HIV-1-infected adults.
J Acquir Immune Defic Syndr. 2017;75(1):61-66. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28196003.
7. Gallant J, Lazzarin A, Mills A, et al. Bictegravir, emtricitabine, and tenofovir
alafenamide versus dolutegravir, abacavir, and lamivudine for initial treatment of HIV-1
infection (GS-US-380-1489): a double-blind, multicentre, phase 3, randomised controlled
non-inferiority trial. Lancet. 2017;390(10107):2063-2072. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28867497.
8. Hagins D, Kumar P, Saag M, et al. Switching to bictegravir/emtricitabine/tenofovir
alafenamide in Black Americans with HIV-1: a randomized phase 3b, multicenter, open-
label study. J Acquir Immune Defic Syndr. 2021;88(1):86-95. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34397746.
9. Orkin C, Ajana F, Kityo C, et al. Brief report: efficacy and safety of
bictegravir/emtricitabine/tenofovir alafenamide in females living with HIV: an integrated
analysis of 5 trials. J Acquir Immune Defic Syndr. 2021;88(4):393-398. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34506342.
10. Daar ES. Virology and immunology of acute HIV type 1 infection. AIDS Res Hum
Retroviruses. 1998;14 Suppl 3:S229-234. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/9814948.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-191
 11. Molina JM, Ward D, Brar I, et al. Switching to fixed-dose bictegravir, emtricitabine, and
tenofovir alafenamide from dolutegravir plus abacavir and lamivudine in virologically
suppressed adults with HIV-1: 48 week results of a randomised, double-blind,
multicentre, active-controlled, phase 3, non-inferiority trial. Lancet HIV. 2018;5(7):e357-
e365. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29925489.
12. Andreatta K, Willkom M, Martin R, et al. Switching to bictegravir/emtricitabine/
tenofovir alafenamide maintained HIV-1 RNA suppression in participants with archived
antiretroviral resistance including M184V/I. J Antimicrob Chemother. 2019;74(12):3555-
3564. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31430369.
13. Sax PE, Rockstroh JK, Luetkemeyer AF, et al. Switching to bictegravir, emtricitabine,
and tenofovir alafenamide in virologically suppressed adults with HIV. Clin Infect Dis.
2020;ciaa988. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32668455.
14. Acosta RK, Willkom M, Andreatta K, et al. Switching to
bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) from dolutegravir
(DTG)+F/TAF or DTG+F/tenofovir disoproxil fumarate (TDF) in the presence of pre-
existing NRTI resistance. J Acquir Immune Defic Syndr. 2020;85(3):363-371. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/32701823.
15. Sax PE, Rockstroh JK, Luetkemeyer AF, et al. Switching to bictegravir, emtricitabine,
and tenofovir alafenamide in virologically suppressed adults with human
immunodeficiency virus. Clin Infect Dis. 2021;73(2):e485-e493. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32668455.
16. Chamberlain N, Mena L, Brock JB. Case report: emergent resistance in a treatment-naive
person with human immunodeficiency virus under bictegravir-based therapy. Open
Forum Infect Dis. 2021;8(6):ofab297. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34189182.
17. Rowe SM, Clary JC, Drummond M, Derrick C, Sanasi K, Bookstaver PB. Increased viral
load in a hospitalized patient on treatment with crushed
bictegravir/emtricitabine/tenofovir alafenamide: a case report and review of the literature.
Am J Health Syst Pharm. 2022;79(16):1330-1336. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/35511892.
18. Levy ME, Griffith C, Ellenberger N, et al. Outcomes of integrase inhibitor-based
antiretroviral therapy in a clinical cohort of treatment-experienced children, adolescents
and young adults with HIV infection. Pediatr Infect Dis J. 2020;39(5):421-428. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/32176183.
19. Majeed S, German P, West SK, et al. B/F/TAF low-dose tablet relative bioavailability in
HVs and PK in children with HIV. Abstract #841. Presented at: Conference on
Retroviruses and Opportunistic Infections 2020. Boston, MA. Available at:
https://www.natap.org/2020/CROI/croi_111.htm
20. Shuter J. Forgiveness of non-adherence to HIV-1 antiretroviral therapy. J Antimicrob
Chemother. 2008;61(4):769-773. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18256112.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-192
 21. Natukunda E, Rodriguez C, McGrath E, et al. B/F/TAF in virologically suppressed
adolescents and children: two-year outcomes in 6 to <18 year olds and six-month
outcomes in toddlers. Presented at: 13th International Workshop on HIV Pediatrics 2021.
virtual meeting. Available at: https://www.natap.org/2021/IAS/IAS_80.htm.
22. Hocqueloux L, Lefeuvre S, Bois J, et al. Bioavailability of dissolved and crushed single
tablets of bictegravir, emtricitabine, tenofovir alafenamide in healthy adults: the
SOLUBIC randomized crossover study. J Antimicrob Chemother. 2022;78(1):161-168.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/36322475.
23. Ferrandez JS, Garcia AL, Alonso-Vega GG, Gonzalez AO, Garcia TM. Successful
bictegravir/emtricitabine/tenofovir alafenamide treatment in a HIV patient with
swallowing difficulties. Ann Pharmacother. 2021;55(4):556-557. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32862660.
24. Fulco PP. Crushed bictegravir/emtricitabine/tenofovir alafenamide in a human
immunodeficiency virus-positive patient with esophageal cancer. Am J Health Syst
Pharm. 2020;77(7):509-510. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32207818.
25. Lozano AB, Chueca N, de Salazar A, et al. Failure to bictegravir and development of
resistance mutations in an antiretroviral-experienced patient. Antiviral Res.
2020;179:104717. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31982483.
26. Roa PE, Bazzi R. Crushed bictegravir/emtricitabine/tenofovir alafenamide in a human
immunodeficiency virus-positive patient with pancreatic cancer. Int J STD AIDS.
2022;33(1):97-98. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34787026.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-193
Cabotegravir
Updated: April 11, 2023
Reviewed: April 11, 2023

Cabotegravir (CAB, Vocabria)

Cabotegravir for Intramuscular Injection (CAB, Apretude)
Cabotegravir and Rilpivirine for Intramuscular Injections (IM CAB and RPV,
Cabenuva)

Formulations
Tablets
• [Vocabria] Cabotegravir: 30 mg

Single-Dose Vial for Intramuscular Injection

• [Apretude] Cabotegravir 600-mg/3-mL (200-mg/mL) suspension for intramuscular injection for use as HIV pre-exposure
prophylaxis only

Co-Packaged Formulation
• [Cabenuva Kit] Cabotegravir 400-mg/2-mL (200-mg/mL) and rilpivirine 600-mg/2-mL (300-mg/mL) suspension for
intramuscular injection (each drug packaged in a separate syringe)
• [Cabenuva Kit] Cabotegravir 600-mg/3-mL (200-mg/mL) and rilpivirine 900-mg/3-mL (300-mg/mL) suspension for
intramuscular injection (each drug packaged in a separate syringe)

When using the co-packaged formulation, refer to the Rilpivirine section for additional information.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

[Apretude] Cabotegravir for Intramuscular Injection • Depression
• Cabotegravir (CAB) 600 mg/3 mL for intramuscular (IM) injection • Insomnia
is approved by the U.S. Food and Drug Administration (FDA) for
use as HIV pre-exposure prophylaxis (PrEP) in adults and • Headache
adolescents weighing ≥35 kg; an oral dosing lead-in period of • Rash (can be severe and include drug reaction with
approximately 1 month is optional. See package insert for eosinophilia and systemic symptoms) or
additional information about dosing and administration of CAB as hypersensitivity
PrEP; this indication is not addressed in the Pediatric
Antiretroviral Guidelines. • Hepatotoxicity
• Altered adrenocorticotropic hormone stimulation test of
[Cabenuva] Cabotegravir and Rilpivirine for intramuscular
uncertain clinical significance
injection (IM CAB and RPV)
Pediatric Dose • Injection site reactions

• CAB tablets and co-packaged IM CAB and RPV are not FDA • Creatine phosphokinase elevation following IM
approved for the treatment of HIV in children aged <12 years. injection
• Weight gain

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-194
 Child and Adolescent (Aged ≥12 Years and Weighing ≥35 kg) and
Adult Dose Special Instructions
• CAB and RPV is a two-drug co-packaged product for IM injection • Coadministering oral RPV with drugs that increase
that is FDA approved as a complete regimen for the treatment of gastric pH may decrease plasma concentrations of
HIV-1 in patients with HIV RNA levels <50 copies/mL on a stable RPV. Refer to the RPV package insert for specific
antiretroviral (ARV) regimen, with no history of treatment failure, instructions regarding use of these products during the
and no known or suspected resistance to CAB or RPV. oral lead-in dosing.

• Oral lead-in dosing with CAB and RPV for at least 28 days can be • If monthly injections are missed or delayed by more
used to assess tolerability prior to initiating IM CAB and RPV than 7 days and oral therapy has not been taken,
injections, or patients can proceed directly to IM CAB and RPV on clinically reassess the patient to determine if
the last day of their current ARV regimen. resumption of injection dosing remains appropriate.
Refer to the package insert for information about
• Refer to the package insert for instructions about changing the managing planned and unplanned missed doses.
frequency of IM injections, i.e., from monthly to every-2-month • IM CAB and RPV is a complete regimen.
dosing or from every-2-month to monthly dosing. Coadministration with other ARV drugs is not
recommended.
Oral Lead-In Dosing
• When IM CAB and RPV injections are stopped,
o CAB 30 mg orally and RPV 25 mg orally once daily with a
residual concentrations may remain measurable for up
meal for at least 28 days.
to 12 months or longer. It is essential to initiate an
Dosing for Monthly Administration of IM CAB and RPV alternative, fully suppressive ARV regimen no later
than 1 month after the final injections of IM CAB and
o On the last day of oral lead-in therapy or the current oral ARV RPV.
regimen, a loading dose of CAB 600 mg (3 mL) and RPV
900 mg (3 mL) should be given as two separate IM injections • Use CAB and RPV with caution when coadministering
in separate ventrogluteal sites. it with a drug that has a known risk of prolonging the
QTc interval or causing Torsades de Pointes (for more
o Continuation therapy of CAB 400 mg (2 mL) and RPV 600 mg information, see CredibleMeds).
(2 mL) IM is given 1 month after the loading dose and once a
month thereafter, with allowance for a ±7-day administration Metabolism/Elimination
window.
• CAB is metabolized by uridine diphosphate-
Dosing for Every-2-Month Administration of IM CAB and glucuronosyl transferase 1A1 (UGT1A1).
RPV
• RPV is a cytochrome P450 3A substrate.
o To initiate every-2-month dosing, CAB 600 mg (3 mL) and
RPV 900 mg (3 mL) should be given as two separate IM Dosing in Patients With Hepatic Impairment
injections in separate ventrogluteal sites on the last day of oral
lead-in or the current oral ARV regimen and 1 month after the • No dose adjustment of CAB or IM CAB and RPV is
initial injections. necessary in patients with mild or moderate hepatic
impairment.
o After these two initiation injections 1 month apart for 2 months,
continuation therapy with IM CAB 600 mg (3 mL) and RPV Dosing in Patients With Renal Impairment
900 mg (3 mL) is administered every 2 months, with allowance
for a ±7-day administration window. • RPV decreases tubular secretion of creatinine and
slightly increases measured serum creatinine, but it
Patients should be monitored for approximately 10 minutes for post- does not affect glomerular filtration.
injection reactions. A 23-gauge, 1.5-inch IM needle is • No dose adjustment of CAB or IM CAB and RPV is
recommended for the injection and is provided in the packaging. necessary in patients with mild or moderate renal
Longer, 2-inch needles (not included with packaging) should be impairment. However, IM CAB and RPV should be
used in patients with a body mass index >30 kg/m2. The Panel on used with caution in patients with severe renal
Antiretroviral Therapy and Medical Management of Children Living impairment or end-stage renal disease. These patients
With HIV recommends that providers review instructions available should be monitored more frequently for adverse
with the package insert prior to beginning IM administration of CAB events.
and RPV. In-person training also may be helpful and can be
requested from the manufacturer (ViiV).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-195
Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Cabotegravir (CAB) is metabolized primarily by uridine diphosphate-glucuronosyl

transferase 1A1 (UGT1A1). Drugs that are strong inducers of UGT1A1 may decrease CAB
concentrations and decrease effectiveness.
• Rilpivirine (RPV) is a cytochrome P450 (CYP) 3A substrate, and RPV concentrations may be
affected when administered with CYP3A-modulating medications.
• A patient’s medication profile should be carefully reviewed for potential drug interactions before
CAB plus RPV is administered.
• CAB and RPV are both highly protein bound and unlikely to be removed by hemodialysis.
• Coadministering oral RPV with drugs that increase gastric pH may decrease plasma
concentrations of RPV.
o Antacids should not be taken less than 2 hours before or less than 4 hours after oral RPV.
o H2 receptor antagonists should not be administered less than 12 hours before or less than
4 hours after oral RPV.
o Do not use oral RPV with proton pump inhibitors.
• Rifamycin drugs significantly reduce CAB and RPV plasma concentrations. For patients who are
concomitantly receiving rifabutin and oral RPV, the dose of RPV should be doubled to 50 mg
once daily and taken with a meal. Coadministration of the following drugs is contraindicated:
o Rifampin and oral RPV
o Rifampin or rifapentine and CAB
o Rifabutin and intramuscular (IM) CAB and RPV

Major Toxicities
• More common: Injection site reactions, insomnia, headache, rash, elevated creatine
phosphokinase serum concentrations
• More common: In studies of adults, 7.3% of patients who were treated with RPV showed a
change in adrenal function characterized by an abnormal 250-microgram adrenocorticotropic
hormone stimulation test (peak cortisol level <18.1 micrograms/dL). In a study of adolescents,
6 of 30 patients (20%) developed this abnormality.1 The clinical significance of these results is
unknown.
• Less common (more severe): Depression or mood changes, suicidal ideation
• Rare: Hepatotoxicity, post-injection reactions, including dyspnea, agitation, abdominal cramping,
flushing, sweating, oral numbness, and changes in blood pressure
• Rare: RPV drug-induced liver injury has been reported.2

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-196
Resistance
The International Antiviral Society–USA maintains a list of updated HIV Drug Resistance
Mutations, and the Stanford University HIV Drug Resistance Database offers a discussion of each
mutation.

Pediatric Use
Approval
CAB oral tablets (Vocabria) and co-packaged CAB and RPV for injection (Cabenuva) are approved
by the U.S. Food and Drug Administration (FDA) for the treatment of HIV in children or adolescents
aged ≥12 years and weighing ≥ 35 kg (2022) and adults (2021). They are not approved for use in
children aged <12 years. CAB tablets were approved by the FDA in 2021 for use in adults as part of
the oral lead-in prior to beginning injectable IM CAB and RPV or as an oral interim treatment when
patients miss planned injections.1,3 CAB and RPV co-packaged extended-release injectable
suspensions for IM use are approved for use in patients (monthly or every 2 months) who are
virologically suppressed on a stable antiretroviral (ARV) regimen with no history of virologic failure
or known resistance affecting either of the component drugs.1

In December 2021, the FDA approved CAB IM (Apretude) for HIV pre-exposure prophylaxis (PrEP)
in adults and adolescents weighing at least 35 kg; an oral lead-in period of approximately 1 month
may be used to assess safety and tolerability but is optional. Refer to the package insert for additional
information about dosing and administration,4 and see the Centers for Disease Control and
Prevention Guidelines for Pre-exposure Prophylaxis for the Prevention of HIV in the United States
(PDF) for further information about the use of CAB for PrEP.

Efficacy and Pharmacokinetics in Clinical Trials

Clinical Trials in Pediatric Patients 12 years to <18 years

The safety and efficacy of CAB, an HIV-1 integrase inhibitor, given in combination with RPV, a
non-nucleoside reverse transcriptase inhibitor (NNRTI), has been characterized in a series of clinical
trials conducted in adults, which form the basis for approval.

International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Study 2017, More
Options for Children and Adolescents (MOCHA), is currently in progress to evaluate the safety,
tolerability, acceptability, and pharmacokinetics of this injectable regimen in adolescents (MOCHA
Trial) and has reported initial results leading to FDA approval in this age group. MOCHA evaluated
23 virologically suppressed adolescents on stable therapy who received either a 4-week lead-in of
oral CAB followed by IM CAB 600 mg at Week 4 and 400 mg at Weeks 8 and 12 (n = 8) or a lead-in
of oral RPV followed by IM RPV 900 mg at Week 4 and 600 mg at Weeks 8 and 12 (n = 13).
Injection site reactions were observed but none led to treatment discontinuations. Two adolescents
experienced Grade 3 adverse events, one due to insomnia (CAB arm) and one due to hypersensitivity
reaction to oral RPV which led to discontinuation.5 In a concurrent assessment of adolescent and
parental experiences with IM treatment in MOCHA, overall perceptions of the injectable treatment
were favorable. Of the 21 adolescents who received all three study injections, >90% “definitely” or
“probably” wanted to continue IM treatment.6 It should be noted, however, that none of the MOCHA
participants received both monthly IM CAB and monthly IM RPV as a dual complete regimen, and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-197
clinical experience with this product remains very limited. The Panel on Antiretroviral Therapy and
Medical Management of Children Living With HIV notes that significant questions remain regarding
the use of IM CAB and RPV in pediatric patients, including whether an oral lead-in is beneficial in
the adolescent population, whether there are additional adverse effects specific to the pediatric
population, whether the use of a two-drug nucleoside-sparing regimen for children with significant
ARV treatment history is appropriate, and what potential implementation challenges might exist.

Clinical Trials in Adults

The Phase 3 Antiretroviral Therapy as Long-Acting Suppression (ATLAS) study randomized stable,
virologically suppressed adults to receive either CAB and RPV (n = 308) or continue their oral
antiretroviral therapy (ART) (n = 308). Patients assigned to CAB and RPV initiated therapy with an
oral regimen for 4 weeks prior to beginning monthly IM injections. The initial assessment at
48 weeks demonstrated that switching to monthly IM CAB and RPV was noninferior to continuing a
three-drug oral therapy. After 48 weeks, participants were allowed to transition to injections every
2 months in a follow-up study (ATLAS-2M, see below); 52 patients remaining on the original
ATLAS study were included in the 96-week analysis. Adverse events were more common among
patients receiving injectable ART; injection site reactions were common, but only 1% withdrew from
the study because of these events.7 The ATLAS-2M trial randomized participants to monthly IM
CAB 400 mg and RPV 600 mg (n = 523) or every-2-month injections of CAB 600 mg and RPV
900 mg (n = 522); it enrolled both new patients and those continuing from the ATLAS trial. After
96 weeks, the every-2-month injections were noninferior to monthly injections, with 11 (2%)
confirmed virologic failures in the every-2-month injection group and 6 (1%) in the monthly
injection group. No new safety signals were identified, and the rate of injection site reactions—the
most common adverse event—were similar across treatment arms. Of those failing the every-2-
month injection regimen, a majority had NNRTI resistance–associated mutations.8

The First Long-Acting Injectable Regimen (FLAIR) study enrolled 631 treatment-naive adults and
initiated treatment with a standard oral ARV regimen consisting of dolutegravir/abacavir/lamivudine
(DTG/ABC/3TC) for 20 weeks. Those patients with documented HIV-1 RNA <50 copies/mL after
16 weeks were randomized to either continue oral DTG/ABC/3TC (n = 283) or switch to oral CAB
and RPV for 4 weeks, followed by monthly injections of CAB and RPV (n = 283). After 96 weeks of
randomized therapy, nine participants (3.2%) in each arm had HIV RNA >50 copies/mL. Adverse
events were common in both treatment groups, but adverse events leading to withdrawal from the
study were observed in only 14 (5%) participants in the IM CAB and RPV group and 4 (1%) in the
oral standard care group. Injection site reactions were the most common adverse events, reported by
245 (88%) participants in the IM CAB and RPV group, and lasted a median of 3 days.9 The FLAIR
study was extended to include an assessment of switching those participants remaining in the oral
ARV arm after 120 weeks to IM CAB and RPV either with or without the initial oral lead-in phase.
There were no differences between the lead-in group and the direct-to-injection group in terms of
safety, tolerability, or efficacy through an additional 24 weeks on the study.10

These studies demonstrated noninferiority of switching to monthly IM CAB and RPV compared to
continuing oral ART. In all studies, adult patients expressed a high degree of treatment satisfaction
and preference for the IM CAB and RPV regimen. Although documented virologic failure with the
IM CAB and RPV regimen has been rare to date, investigators have attempted to assess the baseline
factors associated with treatment failure. In a multivariate analysis of the adult IM CAB and RPV
Phase 3 trials, presence of at least two baseline factors of RPV resistance–associated mutations, HIV-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-198
1 subtype A6/A1, and body mass index >30 kg/m2 was associated with increased risk of virologic
failure at 48 weeks.11

Pharmacokinetics
IM CAB reaches its maximum plasma concentration in adults in about 7 days and has a mean half-
life of 5.6 to 11.5 weeks. Measurable levels of CAB can be detected in plasma for up to a year or
longer. Due to this prolonged drug exposure, it is essential to initiate an alternative, fully suppressive
ARV regimen no later than 1 month after the final injections of CAB and RPV to minimize the
potential risk of developing viral resistance.1 The PK profiles observed in adolescents enrolled in
MOCHA were comparable to those observed in adults receiving monthly IM CAB and RPV in the
ATLAS and FLAIR studies described above.5

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-199
References
1. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release
injectable suspension), co-packaged for intramuscular use [package insert]. Food and Drug
Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212888s002lbl.pdf.

2. Lee MJ, Berry P, D'Errico F, Miquel R, Kulasegaram R. A case of rilpivirine drug-induced

liver injury. Sex Transm Infect. 2020;96(8):618-619. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31974214.

3. Vocabria (cabotegravir) tablets,for oral use [package insert]. Food and Drug Administration.
2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/212887s005s006lbl.pdf.

4. Apretude (cabotegravir extended-release injectable suspension), for intramuscular use

[package insert]. Food and Drug Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/215499s000lbl.pdf.

5. Moore CB, Capparelli E, Calabrese K, et al. Safety and PK of long-acting cabotegravir and
rilpivirine in adolescents. Presented at: Conference on Retroviruses and Opportunistic
Infections; 2022. Virtual Conference. Available at:
https://www.croiconference.org/abstract/safety-and-pk-of-long-acting-cabotegravir-and-
rilpivirine-in-adolescents.

6. Lowenthal E, Chapman J, Calabrese K, et al. Adolescent and parent experiences with long-
acting injectables in the MOCHA study. Presented at: Conference on Retroviruses and
Opportunistic Infections; 2022. Virtual Conference. Available at:
https://www.croiconference.org/abstract/adolescent-and-parent-experiences-with-long-
acting-injectables-in-the-mocha-study

7. Swindells S, Lutz T, Van Zyl L, et al. Week 96 extension results of a Phase 3 study
evaluating long-acting cabotegravir with rilpivirine for HIV-1 treatment. AIDS.
2022;36(2):185-194. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34261093.

8. Jaeger H, Overton ET, Richmond G, et al. Long-acting cabotegravir and rilpivirine dosed
every 2 months in adults with HIV-1 infection (ATLAS-2M), 96-week results: a randomised,
multicentre, open-label, phase 3b, non-inferiority study. Lancet HIV. 2021;8(11):e679-e689.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/34648734.

9. Orkin C, Oka S, Philibert P, et al. Long-acting cabotegravir plus rilpivirine for treatment in
adults with HIV-1 infection: 96-week results of the randomised, open-label, phase 3 FLAIR
study. Lancet HIV. 2021;8(4):e185-e196. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33794181.

10. Orkin C, Bernal Morell E, Tan DHS, et al. Initiation of long-acting cabotegravir plus
rilpivirine as direct-to-injection or with an oral lead-in in adults with HIV-1 infection: week
124 results of the open-label phase 3 FLAIR study. Lancet HIV. 2021;8(11):e668-e678.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/34656207.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-200
11. Cutrell AG, Schapiro JM, Perno CF, et al. Exploring predictors of HIV-1 virologic failure to
long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS. 2021;35(9):1333-
1342. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33730748.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-201
Dolutegravir (DTG, Tivicay, Tivicay PD)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Tablets
• Dispersible tablets for oral suspension [Tivicay PD] 5 mg
• Film-coated tablets [Tivicay] 10 mg, 25 mg, 50 mg

Fixed-Dose Combination Tablets

• [Dovato] Dolutegravir 50 mg/lamivudine 300 mg
• [Juluca] Dolutegravir 50 mg/rilpivirine 25 mg
• [Triumeq] Abacavir 600 mg/dolutegravir 50 mg/lamivudine 300 mg
• [Triumeq PD] Abacavir 60 mg/dolutegravir 5 mg/lamivudine 30 mg

When using fixed-dose combination (FDC) tablets, refer to other sections of Appendix A: Pediatric Antiretroviral Drug
Information for information about the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose
Combination Tablets: Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

All formulations and fixed-dose combinations of • Insomnia
dolutegravir (DTG) are U.S. Food and Drug Administration (FDA)
approved for use in treatment-naive or treatment-experienced • Headache
pediatric, adolescent, and adult patients naive to integrase • Neuropsychiatric symptoms (i.e., depression and/or
strand transfer inhibitor (INSTI) drug class. The Panel on suicidal thoughts or actions), especially in patients
Antiretroviral Therapy and Medical Management of Children with a history of psychiatric illness
Living With HIV endorse the use of DTG as appropriate for some
children with prior INSTI use (See Management of Children • Rare cases of hypersensitivity reactions (HSRs),
Receiving Antiretroviral Therapy [MCRAT] 1 and 2). including rash and drug reaction (or rash) with
eosinophilia and systemic symptoms, constitutional
Neonate Dose symptoms, and organ dysfunction (including liver
injury)
• Dolutegravir (DTG) is not approved by the FDA for use in neonates.

[Tivicay PD] Dolutegravir Dispersible Tablets

Infant (Aged ≥4 Weeks and Weighing ≥3 kg), Child, and Adolescent
Dose Special Instructions
• DTG may be taken without meals.
Recommended Dosea of
Pediatric Number of • DTG should be taken 2 hours before or 6 hours after
Dolutegravir Dispersible
Body Weight 5-mg Tablets taking cation-containing antacids or laxatives,
Tablets
sucralfate, oral iron supplements, oral calcium
3 kg to <6 kg 5 mg once daily 1 supplements, or buffered medications.
6 kg to <10 kg 15 mg once daily 3

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-202
 10 kg to <14 kg 20 mg once daily 4 • For DTG dispersible tablets, fully disperse the
dispersible tablets in 5 mL of drinking water (if using
14 kg to <20 kg 25 mg once daily 5 one or three tablets) or in 10 mL of drinking water (if
using four, five, or six tablets) in the supplied cup;
≥20 kg 30 mg once daily 6 swirl the suspension so that no lumps remain. After
a If certain drugs that induce uridine diphosphate glucuronyl full dispersion and within 30 minutes of mixing,
transferase (UGT) 1A or cytochrome P450 (CYP) 3A are administer the oral suspension. Rinse the dosing cup
coadministered, administer DTG dispersible tablets twice daily (see with a small amount of water, and give this additional
the Drug Interactions section below). water to the child to ensure the child takes the full
dose and no medication remains in the dosing cup.
[Tivicay] Dolutegravir Film-Coated Tablets • DTG dispersible tablets may be swallowed whole. If
Child and Adolescent (Weighing ≥14 kg) more than one tablet is required, swallow one tablet
at a time to reduce the risk of choking. DTG
• DTG film-coated tablets and DTG dispersible tablets are not dispersible tablets should not be chewed or crushed.
bioequivalent and are not interchangeable on a milligram-per-
milligram basis. Each formulation has different doses. • For ABC/DTG/3TC dispersible tablets, fully disperse
them in 20 mL of drinking water in the supplied cup
Dosing of Film-Coated Tablets for Pediatric Patients Weighing and swirl the suspension so that no lumps remain.
≥14 kg Who Can Swallow Tablets After full dispersion and within 30 minutes of mixing,
administer the oral suspension. Rinse the dosing cup
Pediatric Recommended Dosea Number of with a small amount of water, and give this additional
Body Weight of Dolutegravir Tablets water to the child to ensure the child takes the full
Film­Coated Tablets dose and no medication remains in the dosing cup.
ABC/DTG/3TC dispersible tablets should not be
14 kg to <20 kg 40 mg once daily 4 x 10 mg swallowed whole, chewed, or crushed.
≥20 kg 50 mg once daily 1 x 50 mg • No data exist regarding dispersion in breast milk or
any vehicles other than water.
aIf certain drugs that induce UGT1A or CYP3A are coadministered,
administer DTG tablets twice daily (see the Drug Interactions section • In patients who have difficulty swallowing the film-
below). coated tablets whole, 50-mg tablets may be either
split into halves followed by immediate ingestion of
Some infants may have received raltegravir as presumptive HIV both halves of the tablet, or crushed and added to a
therapy prior to diagnosis. These infants and other infants and small amount of semisolid food or liquid, all of which
children with HIV who have received INSTIs are candidates to switch should be consumed immediately.1
to once-daily DTG if they are virologically suppressed or have no
mutations associated with resistance to INSTIs. • The efficacy of DTG 50 mg twice daily is reduced in
patients with certain combinations of INSTI-
Adult Dose resistance mutations (see the Resistance section
below).
• One 50-mg DTG film-coated tablet once daily
• Screen patients for hepatitis B virus (HBV)
• If certain drugs that induce UGT1A or CYP3A are coadministered, infection before using FDC tablets that contain
administer DTG 50 mg twice daily (see the Drug Interactions lamivudine (3TC). Severe acute exacerbations of
section below). HBV can occur after discontinuation of 3TC. Patients
• Adults who are INSTI-experienced with certain INSTI-associated with HBV/HIV coinfection who receive Dovato will
resistance mutations or clinically suspected INSTI resistance should require additional treatment for chronic HBV
receive 50 mg DTG twice daily. infection.
• For any FDC tablets containing abacavir (ABC), test
[Dovato] Dolutegravir/Lamivudine
patients for the HLA-B*5701 allele before starting
Adult Dose therapy to predict the risk of HSRs. Patients who test
• One tablet once daily with or without food as a complete regimen in positive for the HLA-B*5701 allele should not be
antiretroviral (ARV)-naive adults with no known mutations given an ABC-containing FDC. Patients with no prior
associated with resistance to the individual components of Dovato HLA-B*5701 testing who are tolerating an ABC-
containing regimen do not need to be tested. See
Abacavir.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-203
 [Juluca] Dolutegravir/Rilpivirine
Metabolism/Elimination
Adult Dose
• UGT1A1 and CYP3A substrate. Also, a substrate of
• One tablet once daily with a meal as a complete regimen to replace
UGT1A3, UGT1A9, BCRP, and P-gp in vitro. Drugs
the current ARV regimen in patients who have been virologically
that induce these enzymes and transporters may
suppressed (HIV RNA <50 copies/mL) on a stable ARV regimen for
decrease plasma concentrations of DTG. Drugs that
at least 6 months, with no history of treatment failure, and no known
inhibit these enzymes may increase DTG plasma
mutations associated with resistance to the individual components
concentrations.
of Juluca
Dolutegravir Dosing in Patients With Hepatic
[Triumeq PD] Abacavir/Dolutegravir/Lamivudine
Impairment
Child Weighing ≥10 kg to <25 kg
• No dose adjustment is necessary in patients with
• Dispersible Triumeq PD tablets are FDA-approved for children mild or moderate hepatic impairment. Due to the lack
weighing ≥10 to < 25 kg. They are not recommended for children of data, DTG is not recommended for use in
weighing ≥25 kg. patients with severe hepatic impairment.
• Administer the appropriate number of tablets for a child’s weight • FDC tablets containing ABC or 3TC should not be
once daily dispersed in 20 mL of water, see Special Instructions. used in patients with impaired hepatic function.
Triumeq PD tablets should not be swallowed whole, chewed, cut, or
crushed. Dolutegravir Dosing in Patients With Renal
Impairment
Weight-Band Dosing of Triumeq PD Tablets for Children
• DTG decreases tubular secretion of creatinine and
Weighing ≥10 kg
increases measured serum creatinine without
affecting glomerular filtration.
Number of
Recommended
Weight Triumeq PD • No dose adjustment is required in INSTI-naive
Daily Dose
Tablets patients with mild, moderate, or severe renal
impairment, or in INSTI-experienced patients with
10 kg to <14 kg ABC 240 mg, DTG 20 mg, 4 mild or moderate renal impairment.
3TC 120 mg
• Use DTG with caution in INSTI-experienced patients
14 kg to <20 kg ABC 300 mg, DTG 25 mg, 5
with severe renal impairment (creatinine
3TC 150 mg
clearance [CrCl] <30 mL/min), because DTG
20 kg to <25 kg ABC 360 mg, DTG 30 mg, 6 concentrations will be decreased. The cause of this
3TC 180 mg decrease is unknown.
≥25 kg Use Triumeq. See below. • FDC tablets containing 3TC (Dovato, Triumeq PD,
and Triumeq) should not be used in patients who
• For use in patients who are ARV naive or ARV experienced (but have CrCl <30 mL/min or patients who are on
INSTI naive) and who are not being treated with UGT1A1 or CYP3A dialysis because the doses of 3TC cannot be
inducers adjusted. Data about the FDC DTG/3TC (Dovato)
• See the Abacavir section for special instructions about testing for suggest that patients with a sustained creatinine
abacavir (ABC) hypersensitivity. clearance 30–49 mL/min may experience a higher
3TC exposure and should be monitored for
[Triumeq] Abacavir/Dolutegravir/Lamivudine hematologic toxicities and potential FDC
discontinuation and subsequent adjustment of the
Child and Adolescent (Weighing ≥25 kg) and Adult Dose treatment regimen. See package inserts for
• One tablet once daily with or without food additional information.

• For use in patients who are ARV naive or ARV experienced (but
INSTI naive) and who are not being treated with UGT1A1 or CYP3A
inducers
• See the Abacavir section for special instructions about testing for
ABC hypersensitivity.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-204
Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Dolutegravir (DTG) is a uridine diphosphate glucuronyl transferase (UGT) 1A and

cytochrome P450 (CYP) 3A substrate and may require dose adjustments when administered with
UGT1A-modulating or CYP3A-modulating medications. DTG dosing should be adjusted to
twice daily (i.e., twice the usual dose) when coadministered with drugs such as efavirenz and
rifampin. Because etravirine (ETR) significantly reduces plasma concentrations of DTG, DTG
should not be administered with ETR without coadministration of atazanavir (ATV)/ritonavir,
darunavir/ritonavir, or lopinavir/ritonavir, which counteract this effect on DTG concentrations.
DTG should not be administered with nevirapine because of insufficient data on interactions
between these drugs. See the product label for a full listing of significant drug–drug interactions.
• ATV is an inhibitor of UGT1A1. In a recent pharmacologic survey of adult patients who were
receiving DTG, patients who also received ATV had plasma concentrations of DTG that were
twofold to fourfold higher than those of patients who received other antiretroviral (ARV) drugs.2
• Before administering DTG, clinicians should carefully review a patient’s medication profile for
potential drug interactions.

Major Toxicities
• More common: Insomnia and headache. Weight gain and increased body mass index (BMI) have
been reported in adults who received DTG in clinical trials and in some pediatric and adolescent
cohorts (see Table 17h. Lypodystrophies and Weight Gain).3-6
• Less common (more severe): Hypersensitivity reactions characterized by rash, constitutional
symptoms, and sometimes organ dysfunction; neuropsychiatric symptoms, especially in patients
with a history of psychiatric illness. Multiple post-marketing reports note that neuropsychiatric
adverse events (AEs) have occurred following the initiation of DTG-based therapy in adults.7,8
• Immune reconstitution inflammatory syndrome (IRIS): In retrospective observational studies,
severe cases of IRIS that required hospitalization appeared to be more frequent in patients who
presented with advanced HIV disease and who initiated treatment with integrase strand transfer
inhibitors (INSTIs), particularly DTG.9,10 This phenomenon is presumed to be linked to the rapid
decline in HIV RNA observed in patients receiving INSTI-based therapy.
• Rare: Hepatotoxicity has been reported; two cases of liver injury were presumed to be related to
the use of DTG. One of these cases required liver transplantation.11,12
• Rare: A single case of drug reaction (or rash) with eosinophilia and systemic symptoms
(DRESS) has been reported.13
• The DTG package insert includes cautions about the use of DTG during the first trimester of
pregnancy due to potential teratogenicity. The Perinatal Guidelines recommend DTG as a
Preferred drug for use during pregnancy and when trying to conceive. Although early data raised
concerns about a possible higher rate of neural tube defects (NTDs) among infants born to
mothers who received DTG at the time of conception, more recent data from expanded and
ongoing surveillance found the prevalence of NTDs was identical in women receiving DTG and
those receiving other ARVs at the time of conception.14

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-205
Resistance
The International Antiviral Society–USA maintains a list of updated resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

The efficacy of DTG 50 mg twice daily is reduced in patients with the INSTI-resistance Q148
substitution plus two or more additional INSTI-resistance mutations.

Pediatric Use
Approval
DTG is approved by the FDA for use, in combination with other ARV drugs, in pediatric patients at
least 4 weeks of age and weighing at least 3 kg who are treatment naive or treatment experienced but
INSTI naive (see Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-
Packaged Formulations: Minimum Body Weights and Considerations for Use in Children and
Adolescents). Pediatric patients weighing ≥20 kg may take the DTG 50-mg film-coated tablets if
they are able to swallow tablets. The combination tablet abacavir/dolutegravir/lamivudine
(ABC/DTG/3TC; Triumeq) is approved by the FDA for use in children and adolescents weighing
≥25 kg. Dispersible ABC/DTG/3TC tablets (Triumeq PD) are FDA approved for use in children
weighing ≥10 kg to <25 kg. The combination tablets dolutegravir/rilpivirine (DTG/RPV; Juluca) and
dolutegravir/lamivudine (DTG/3TC; Dovato) are not approved by the FDA for use in children or
adolescents.

Formulation Differences: Film-Coated Tablet Compared to Dispersible Tablet

DTG is currently available as either film-coated tablets or dispersible tablets (tablets for oral
suspension). The dispersible tablet has 60% to 80% greater bioavailability in adults than the film-
coated tablet,15 so recommended doses using the dispersible tablet cannot be directly compared to
those using the film-coated tablets. The drug exposure provided by the 50-mg film-coated tablet is
approximately equal to that of DTG 30 mg administered as dispersible tablets.

Efficacy and Pharmacokinetics

Pediatric Patients 4 Weeks to <18 years
IMPAACT P1093 is an ongoing, multinational, open-label trial of DTG in children with HIV.
Results of pharmacokinetic (PK), safety, and efficacy assessments have been reported sequentially
for different age and weight cohorts as data became available; similarly, dosing recommendations
have been revised sequentially.16-18 Dosing recommendations that previously included the 25-mg
film-coated tablets have been replaced with other formulations.

Data from IMPAACT P1093 Cohort 1 (aged 12 years to <18 years) and Cohort 2 (6 years to
<12 years) provide support for use of DTG film-coated tablets in pediatric patients weighing ≥14 kg;
Cohort 3 (2 to <6 years), Cohort 4 (6 months to <2 years), and Cohort 5 (4 weeks to <6 months)
provide evidence supporting the use of DTG 5-mg dispersible tablets. Seventy-five study participants
ranging in age from 1 month to 214 months received the currently approved dose (determined by
weight and age) of DTG film-coated tablets or dispersible tablets. Eighty percent of participants were
treatment-experienced, but all were INSTI naive. Among these 75 patients who received either DTG

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-206
film-coated tablets or DTG dispersible tablets, according to the approved dosing recommendations
for their weight band, 42 received DTG for at least 48 weeks. At Week 48, 69% of participants
achieved HIV RNA <50 copies/mL, and 79% achieved HIV RNA <400 copies/mL. The median CD4
T lymphocyte count (percent) increase from baseline to Week 48 was 141 cells/mm3 (7%). Overall,
the safety profile in P1093 participants was comparable to that observed in adults, and both
formulations were well tolerated by pediatric patients. The effectiveness observed in the trial was
comparable to that of treatment-experienced adult subjects.19

Sixteen adolescents in Cohort 1 have remained on P1093 through 144 weeks, with 43% and 35% of
participants achieving and maintaining HIV RNA levels <400 copies/mL and <50 copies/mL,
respectively. Genotypic testing was available at the time of treatment failure for 6 of the
13 participants experiencing treatment failure; one of these adolescents developed DTG resistance.20

A subsequent analysis of a larger group of 73 participants in Cohorts 3 through 5 (4 weeks to

<6 years of age), who received the final proposed dose and of whom 87.7% were treatment
experienced, confirmed safety as assessed to 48 weeks with no Grade 3 or higher adverse events
attributed to DTG. At 48 weeks, of 68 participants with HIV RNA data, 91% and 68% achieved HIV
RNA <400 copies/mL and <50 copies/mL, respectively.18

The Once-daily DTG based ART in Young people vS Standard thErapY (ODYSSEY) trial,
conducted by the Pediatric European Network for the Treatment of AIDS (PENTA), enrolled both
treatment-naive and treatment-experienced pediatric patients from the European Union, Thailand,
and several African countries; this trial initially evaluated doses approved by the European Medicines
Agency at the time the trial started. A total of 707 children aged <18 years were enrolled;
311 children started DTG as first-line therapy, and 396 started DTG as second-line therapy.21 As
assessed by 96 weeks, DTG-based ART as both first-line therapy and second-line therapy in children
was superior to standard care.22 Results from the younger ODYSSEY cohort of children weighing
between 3 and 14 kilograms showed superiority of DTG-based ART compared to other regimens, of
which over 70% were protease inhibitor (PI)-based regimens.22-24

Nested PK substudies within ODYSSEY also evaluated simplified pediatric dosing that aligned with
the World Health Organization’s (WHO) recommended weight bands. PK data are available from a
cohort of children weighing >25 kg who switched to the DTG 50-mg film-coated tablet. Data from
another ODYSSEY cohort reported on children weighing 20 kg to <25 kg who received either the
DTG 50-mg film-coated tablet or DTG 30 mg administered as six 5-mg dispersible tablets. Both of
these doses achieved area-under-the-curve (AUC) and maximum plasma concentration (C max ) values
that were higher than adult PK reference values but still acceptable. Both doses achieved trough
plasma concentration (C trough ) values that were slightly lower than adult reference values and
exhibited greater variability but were determined to be acceptable.25 Later-enrolling ODYSSEY
cohorts included children weighing 3 kg to <20 kg. Children weighing 14 kg to <20 kg received
25 mg and were enrolled first, then children weighing 3 kg to <6 kg and younger than 6 months
received 5 mg DTG, 3 kg to <6 kg and older than 6 months received 10 mg, 6 kg to <10 kg received
15 mg, and 10 kg to <14 kg received 20 mg. For all weight bands, the DTG exposure (AUC 0–24 ) was
comparable to or higher than the target values in adults receiving the approved dose but within an
acceptable safety margin.

A total of 19 children <20 kg experienced Grade 3 or higher adverse events, including two deaths
(one kwashiorkor and one accidental trauma) assessed as unrelated to the study drug. Eleven

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-207
participants experienced serious adverse events, 69% of which were due to infectious diseases. Long-
term safety and effectiveness assessments in the ODYSSEY trial are ongoing.

Combined PK data from P1093 and ODYSSEY across all age/weight cohorts form the basis for the
current FDA dose recommendations and are summarized in Table A below. These data support the
administration of either 30 mg as dispersible tablets or 50 mg as a film-coated tablet in patients
weighing ≥20 kg. In addition, modeling and simulations that included UGT1A1 maturation in infants
were used to support the dose of DTG in infants at least 4 weeks of age and weighing at least 3 kg.
Dosing in neonates is under investigation.

Table A: Summary of Pharmacokinetic Parameters in Pediatric HIV-1-Infected

Participants (Pooled Analyses for IMPAACT P1093 and ODYSSEY Trials)

Pharmacokinetic Parameter
Geometric Mean (% CV)

Doseb of DTG FCT or C max AUC 0–24h C 24h

Weight Banda DTG DT n (mcg/mL) (mcg·h/mL) (ng/mL)
3 kg to <6 kg DTG DT 8 3.80 (34) 49.37 (49) 962 (98)
5 mg once daily
6 kg to <10 kg DTG DT 17 5.27 (50) 57.17 (76) 706 (177)
15 mg once daily
10 kg to <14 kg DTG DT 13 5.99 (33) 68.75 (48) 977 (100)
20 mg once daily
14 kg to <20 kg DTG DT 19 5.97 (42) 58.97 (44) 725 (75)
25 mg once daily
20 kg to <25 kg DTG DT 9 7.16 (26) 71.53 (26) 759 (73)
30 mg once daily
≥20 kg DTG FCT 49 4.92 (40) 54.98 (43) 778 (62)
50 mg once daily
Adultsc DTG FCT 3.67 (20) 53.6 (27) 1,110 (46)
50 mg once daily
Adultsc DTG FCT 4.15 (29) 75.1 (35) 2,120 (47)
50 mg twice daily
a Data are from two weight-band-based pharmacokinetic substudies in the ODYSSEY trial.
b The bioavailability of DTG tablets for oral suspension is approximately 1.6-fold that of DTG film-coated tablets.
c Adult pharmacokinetic data are based on population pharmacokinetic analyses from clinical trials.19
Key: AUC 0–24 = 24-hour area under the curve; C max = maximum plasma concentration; C trough = trough plasma concentration;
CV = coefficient of variation, DTG DT = dolutegravir dispersible tablets; DTG FCT = dolutegravir film-coated tablets

Efficacy and safety of DTG-based regimens have been evaluated in multiple observational pediatric
cohorts. Additional long-term efficacy and safety data for this age/weight group come from a
retrospective, multicenter French cohort study that evaluated 134 children and adolescents who
received DTG-based ART for at least 12 months. Most participants were ART experienced (90.3%)
but naive from integrase inhibitors (90.3%) and had virologic suppression at baseline (63.4%).26

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-208
Virologic failure occurred in 43 participants (32%) and occurred more frequently when baseline viral
load was ≥50 copies/mL (67.4% vs. 22.0%, P < 0.01). Resistance mutations to DTG emerged in one
patient with virologic failure.26

Another cohort of adolescents in Barcelona, Spain, received the fixed-dose combination (FDC)
product ABC 600 mg/DTG 50 mg/3TC 300 mg (Triumeq). Of the 12 patients described, one
received Triumeq for initial ART, 6 received Triumeq for treatment simplification, and 5 received
Triumeq because of previous treatment failure. Nine of the 12 patients achieved or maintained viral
suppression after switching to Triumeq; three patients failed to achieve suppression because of
suboptimal adherence. Of note, patients complained about the size of the tablet, and six patients
reported having to crush or split the tablet to swallow it (see Appendix A, Table 2. Antiretroviral
Fixed-Dose Combination Tablets and Co-Packaged Formulations: Minimum Body Weights and
Considerations for Use in Children and Adolescents).27

The Baylor Tanzania Centres of Excellence program began rolling out DTG to children and
adolescents in 2019 and recently reported preliminary results on their experience.28 Of the
1,703 children and adolescents initiating DTG between March 2019 and November 2020, 57%
received tenofovir disoproxil fumarate (TDF)/3TC/DTG, 39% received ABC/DTG/3TC, and 4%
received zidovudine/3TC/DTG. They reported no severe toxicity and no discontinuations of DTG.
By the end of the study period, 92.4% of patients on DTG had documented viral suppression,
including 85.6% (149 of 174 patients) of those not previously suppressed on their original regimen.

The dispersible tablet formulation of the FDC ABC 60 mg/DTG 5 mg/3TC 30 mg (Triumeq PD) has
been studied in IMPAACT P2019 to confirm dosing of the three-drug FDC in pediatric patients
younger than 12 years (NCT03760458). In P2019, children are being dosed in five weight bands
aligned with WHO-preferred weight bands. Results of the initial PK and safety assessments for
35 participants in weight bands ≥6 kg demonstrated acceptable PK parameters and tolerability for all
cohorts and confirmed dosing according to WHO weight bands. No Grade 3 or 4 adverse events were
reported, and no participant discontinued the study drug because of adverse events. The study is
continuing to collect safety and efficacy data through 48 weeks.29,30

Pediatric Postmarketing Safety Studies

As long-term data are analyzed from the ODYSSEY trial, additional comparative safety information
has been reported. The investigators reported a small number of neuropsychiatric AEs in the
707 children and adolescents randomized to DTG, not significantly different from those reported in
study participants receiving standard care. However, participants receiving DTG were more likely to
have suicidal ideation than those receiving standard care. Suicidal thoughts were reported by
13 participants receiving DTG, but none were reported among those receiving standard care;
however, these symptoms were described as transient and did not lead to changes in ART.31 In a
subset of ODYSSEY participants aged 6 to <18 years, vitamin B12 and folate levels were measured
to investigate a potential mechanism of reported neural tube defects among pregnant women
receiving DTG. No differences were identified in vitamin B12 levels across study arms, although
plasma and RBC folate levels were lower among participants receiving standard care.32

Reports of weight gain among adults enrolled in clinical trials prompted similar studies to investigate
metabolic effects of DTG in adolescents. A group of investigators in Eswatini analyzed BMI
measurements retrospectively from a cohort of 460 virally suppressed adolescents switching to a
DTG-based regimen (either ABC/DTG/3TC or TDF/3TC/DTG). In this cohort, both weight-for-age

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-209
z-score and BMI-for-age z-score decreased slightly before transition to DTG but increased during the
year after DTG was initiated. The rate of BMI increase per year was calculated to be about twofold
greater than the normal rate in the full cohort, and about 2.8-fold greater among female adolescents.4
A retrospective, single-center study of 97 children and adolescents who received a DTG-based
regimen for at least 12 months in France showed that trajectories of BMI z-score change 12 months
pre- versus 12 months post-DTG were similar, except in subjects with baseline BMI ≥50th
percentile, whose rate of BMI z-score change was lower post-DTG (difference: −0.23; p = 0.04).33
Another group measured multiple body fat parameters and cholesterol/lipid profiles in Italian
adolescents switched from a PI- or non-nucleoside reverse transcriptase inhibitor-based regimen to a
DTG-based regimen (ABC/DTG/3TC). Although BMI, body fat percentage, and limb fat percentage
remained the same, trunk fat and trunk fat/total body fat ratio increased significantly. Total
cholesterol and low density lipoproteins decreased, while serum triglycerides decreased early in the
study and then increased by the end of the study.3 A small, single-center cohort in Australia
identified similar increases in BMI among adolescents switched to either DTG- or TAF-containing
regimens.5 Another retrospective analysis of a cohort of children and adolescents in the District of
Columbia who were initiated on INSTIs also identified a pattern of increasing BMI-for-age z-scores,
with a mean rate of change of +0.19 z-score units per year.6 The ODYSSEY investigators also
assessed weight, height, and BMI over the course of their prospective, randomized study. At
Week 96, they found that weight, height, and BMI-for-age z-score increased in children receiving
DTG compared with those receiving standard care, with the adjusted difference in means of 1 kg,
0.8 cm, and 0.14 z-score units, respectively. The investigators noted that the differences between
treatment groups were relatively small, emerged early, and stabilized within the 2-year study
period.24 Based on these data, weight gain may be observed in adolescents receiving DTG, as
observed in adults; the long-term clinical significance of these changes are unclear, and further
studies are needed in adolescents and children receiving DTG.

Simplification of Treatment
Two trials in adults (Regimen Switch to Dolutegravir + Rilpivirine from Current Antiretroviral
Regimen in Human Immunodeficiency Virus Type 1 Infected and Virologically Suppressed Adults,
SWORD-1 and SWORD-2) supported the approval of a DTG 50-mg/RPV 25­mg FDC tablet as a
complete regimen for treatment simplification or maintenance therapy in selected patients. The two
identical SWORD trials enrolled 1,024 virologically suppressed patients who had been on stable
ART for at least 6 months and who had no history of treatment failure or evidence of resistance
mutations. The participants were randomized either to receive DTG/RPV or to continue their
suppressive ARV regimen. After 48 weeks of treatment, 95% of patients in both arms maintained
HIV RNA levels <50 copies/mL.34 After 52 weeks, the participants who had been randomized to
continue their suppressive ARV regimen were switched to DTG/RPV. At 148 weeks, 84% of the
early-switch patients and 90% of the late-switch patients remained virologically suppressed, and only
11 patients receiving dual therapy met virologic failure criteria. No INSTI resistance was identified.35
During the comparative randomized phase of the study, more AEs were reported and led to
discontinuation in the DTG/RPV arm. In a subgroup of the SWORD study, small but statistically
significant increases in hip and spine bone mineral density and bone turnover markers were observed
in patients whose original ARV regimen contained TDF.36 The approval of DTG 50 mg/3TC 300 mg
as a complete regimen was supported by data from two randomized, double-blind, controlled trials
(Efficacy, Safety, and Tolerability Study Comparing Dolutegravir Plus Lamivudine With
Dolutegravir Plus Tenofovir/Emtricitabine in Treatment naïve HIV Infected Subjects, GEMINI-1 and
GEMINI-2) in ARV-naive adults with HIV. GEMINI-1 and GEMINI-2 are identical 148-week trials
that enrolled a total of 1,433 adults with HIV who had plasma HIV RNA levels between 1,000

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-210
copies/mL and ≤500,000 copies/mL at screening and no evidence of major resistance mutations or
hepatitis B virus infection. Participants were randomized to receive either DTG plus 3TC or DTG
plus 3TC/TDF. During 96 weeks of treatment, 86% of patients who received DTG plus 3TC and
89.5% of patients who received DTG plus 3TC/TDF achieved HIV RNA levels <50 copies/mL.
Patients who received DTG plus 3TC had a lower rate of adverse drug reactions (19.6%) than those
who received DTG plus 3TC/TDF (25%).37

Although neither Juluca nor Dovato is approved by the FDA for use in adolescents, the doses of the
component drugs that make up these FDC tablets are approved for use in adolescents. The Panel on
Antiretroviral Therapy and Medical Management of Children Living With HIV (the Panel) usually
endorses the use of adult formulations in adolescents, and these products may be appropriate for use
in certain adolescents. The use of DTG/RPV regimens could be useful in patients in whom there is
concern for toxicity from nucleoside reverse transcriptase inhibitors. However, the Panel notes that
adolescents may have difficulties adhering to therapy and suggests considering close monitoring with
viral load testing (see the Treatment Simplification section of Management of Children Receiving
Antiretroviral Therapy).

Crushing Film-Coated Tablets for Administration

Dispersible tablets are now considered the preferred formulation for pediatric patients weighing
<20 kg, and film-coated tablets should not be used in children weighing <14 kg. In patients who have
difficulty swallowing whole tablets and in children weighing >14 kg, when the preferred dispersible
tablets are not available, the 10-mg and 50-mg tablets either may be split into halves followed by
immediate ingestion of both halves of the tablet, or crushed and added to a small amount of
semisolid food or liquid, all of which should be consumed immediately.1 In healthy adults, the use of
crushed tablets resulted in slightly higher exposures than the use of whole tablets.38 No information
exists on the impact of splitting or crushing film-coated tablets on palatability. Some case reports
describe DTG-containing film-coated tablets being crushed and successfully administered via
orogastric tube39 or nasogastric tube.40 If DTG is administered via enteral tube, care should be taken
to disperse the tablets completely and flush the tube to avoid clogging.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-211
References
1. Duggan JM, Akpanudo B, Shukla V, Gutterson G, Eitniear L, Sahloff EG. Alternative
antiretroviral therapy formulations for patients unable to swallow solid oral dosage forms.
Am J Health Syst Pharm. 2015;72(18):1555-1565. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26346211.

2. Cattaneo D, Minisci D, Cozzi V, et al. Dolutegravir plasma concentrations according to

companion antiretroviral drug: unwanted drug interaction or desirable boosting effect?
Antivir Ther. 2017;22(4):353-356. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28008867.

3. Giacomet V, Lazzarin S, Manzo A, et al. Body fat distribution and metabolic changes in
a cohort of adolescents living with HIV switched to an antiretroviral regimen containing
dolutegravir. Pediatr Infect Dis J. 2021;40(5):457-459. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33847293.

4. Thivalapill N, Simelane T, Mthethwa N, et al. Transition to dolutegravir is associated

with an increase in the rate of body mass index change in a cohort of virally suppressed
adolescents. Clin Infect Dis. 2021;73(3):e580-e586. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33119739.

5. Yeoh DK, Campbell AJ, Bowen AC. Increase in body mass index in children with HIV,
switched to tenofovir alafenamide fumarate or dolutegravir containing antiretroviral
regimens. Pediatr Infect Dis J. 2021;40(5):e215-e216. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/33847305.

6. Koay WLA, Dirajlal-Fargo S, Levy ME, et al. Integrase strand transfer inhibitors and
weight gain in children and youth with perinatal human immunodeficiency virus in the
DC cohort. Open Forum Infect Dis. 2021;8(7):ofab308. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34295943.

7. Elzi L, Erb S, Furrer H, et al. Adverse events of raltegravir and dolutegravir. AIDS.
2017;31(13):1853-1858. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28692533.

8. Fettiplace A, Stainsby C, Winston A, et al. Psychiatric symptoms in patients receiving

dolutegravir. J Acquir Immune Defic Syndr. 2017;74(4):423-431. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27984559.

9. Dutertre M, Cuzin L, Demonchy E, et al. Initiation of antiretroviral therapy containing

integrase inhibitors increases the risk of IRIS requiring hospitalization. J Acquir Immune
Defic Syndr. 2017;76(1):e23-e26. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28418992.

10. Wijting IEA, Wit F, Rokx C, et al. Immune reconstitution inflammatory syndrome in
HIV infected late presenters starting integrase inhibitor containing antiretroviral therapy.
EClinicalMedicine. 2019;17:100210. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31891143.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-212
11. Wang B, Abbott L, Childs K, et al. Dolutegravir-induced liver injury leading to sub-acute
liver failure requiring transplantation: a case report and review of literature. Int J STD
AIDS. 2018;29(4):414-417. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29059031.

12. Christensen ES, Jain R, Roxby AC. Abacavir/dolutegravir/lamivudine (Triumeq)-induced

liver toxicity in a human immunodeficiency virus-infected patient. Open Forum Infect
Dis. 2017;4(3):ofx122. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28748198.

13. Martin C, Payen MC, De Wit S. Dolutegravir as a trigger for DRESS syndrome? Int J
STD AIDS. 2018;29(10):1036-1038. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29621952.

14. R. Zash., L.B. Holmes., M. Diseko., et al. Update on neural tube defects with
antiretroviral exposure in the Tsepamo Study, Botswana. Presented at: 24th International
AIDS Conference; 2022. Montreal, Canada. Available at:
https://www.natap.org/2022/IAC/IAC_31.htm.

15. Parasrampuria R, Adkison K, Wolstenholme A, et al. Comparison of relative

bioavailavility of tivicay immediate release and dispersible pediatric tablets to
immeediate release tivivcay adult tablets. Presented at: 19th International Workshop on
Clinical Pharmacology of Antiviral Therapy; 2018. Baltimore, MD.

16. Viani RM, Alvero C, Fenton T, et al. Safety, pharmacokinetics and efficacy of
dolutegravir in treatment-experienced HIV-1 infected adolescents: 48-week results from
IMPAACT P1093. Pediatr Infect Dis J. 2015;34(11):1207-1213. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26244832.

17. Wiznia A, Alvero C, Fenton T, et al. IMPAACT 1093: dolutegravir in 6- to 12-year-old

HIV-infected children: 48-week results. Presented at: Conference on Retroviruses and
Opporotunistic Infections; 2016. Boston, MA. Available at:
https://www.natap.org/2016/CROI/croi_86.htm

18. Ruel TD, Acosta EP, Liu JP, et al. Pharmacokinetics, safety, tolerability, and antiviral
activity of dolutegravir dispersible tablets in infants and children with HIV-1 (IMPAACT
P1093): results of an open-label, phase 1-2 trial. Lancet HIV. 2022;9(5):e332-e340.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/35489377.

19. Tivicay and tivicay PD (dolutegravir) [package insert]. Food and Drug Administration.
2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/204790s030,213983s003lbl.
pdf.

20. Viani RM, Ruel T, Alvero C, et al. Long-term safety and efficacy of dolutegravir in
treatment-experienced adolescents with human immunodeficiency virus infection: results
of the IMPAACT P1093 study. J Pediatric Infect Dis Soc. 2020;9(2):159-165. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/30951600.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-213
21. Moore CL, Turkova A, Mujuru H, et al. ODYSSEY clinical trial design: a randomised
global study to evaluate the efficacy and safety of dolutegravir-based antiretroviral
therapy in HIV-positive children, with nested pharmacokinetic sub-studies to evaluate
pragmatic WHO-weight-band based dolutegravir dosing. BMC Infect Dis. 2021;21(1):5.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/33446115.

22. Amuge P, Lugemwa A, Wynne B, et al. Once-daily dolutegravir-based antiretroviral

therapy in infants and children living with HIV from age 4 weeks: results from the below
14 kg cohort in the randomised ODYSSEY trial. Lancet HIV. 2022;9(9):e638-e648.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/36055295.

23. Turkova A, White E, Mujuru HA, et al. Dolutegravir as first- or second-line treatment for
HIV-1 infection in children. N Engl J Med. 2021;385(27):2531-2543. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34965338.

24. Turkova A, Kityo C, Mujuru HA, et al. Weight gain in children and adolescents on
dolutegravir vs. standard of care in the ODYSSEY trial. Abstract PEB202. Presented at:
11th IAS Conference on HIV Science; 2021. Virtual Conference. Available at:
https://theprogramme.ias2021.org/Abstract/Abstract/1311

25. Bollen PDJ, Moore CL, Mujuru HA, et al. Simplified dolutegravir dosing for children
with HIV weighing 20 kg or more: pharmacokinetic and safety substudies of the
multicentre, randomised ODYSSEY trial. Lancet HIV. 2020;7(8):e533-e544. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/32763217.

26. Frange P, Blanche S, Veber F, Avettand-Fenoel V. Dolutegravir in the long term in

children and adolescents: frequent virological failure but rare acquired genotypic
resistance. HIV Med. 2021;22(10):958-964. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34369051.

27. Bossacoma Busquets F, Noguera-Julian A, Sanchez E, Fortuny C. Dolutegravir plus

abacavir/lamivudine works in adolescents, but size matters. J Antimicrob Chemother.
2017;72(10):2958-2960. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29091219.

28. Bacha J, Mayalla B, Chodota M, Jiwa N, Campbell L. The road to success is paved with
dolutegravir: dolutegravir treatment success among children and adolescents living the
HIV (CALHIV) at the Baylor Tanzania Centre of Excellence. Abstract OAB0504.
Presented at: 11th IAS Conference on HIV Science; 2021. Virtual Conference. Available
at: https://onlinelibrary.wiley.com/doi/10.1002/jia2.25755

29. Brooks KM, Kiser JJ, Samson P, et al. Pharmacokinetics and safety of dispersible and
immediate release FDC abacavir/dolutegravir/lamivudine in children with HIV weighing
≥14 kg: preliminary results from IMPAACT 2019. Abstract PEBLB15 Presented at: 11th
IAS Conference on HIV Science; 2021. Virtual Conference. Available at:
https://theprogramme.ias2021.org/Abstract/Abstract/2385

30. Brooks C, Kiser JJ, Rani Y, et al. PK & safety of dispersible ABC/DTG/3TC in children
with HIV 6 to <14kg. Presented at: Conference on Retroviruses and Opportunistic

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-214
 Infections; 2022. Virtual Conference. Available at:
https://www.natap.org/2022/CROI/croi_20.htm

31. Turkova A, Kekitiinwa A, White E, et al. Neuropsychiatric manifestations and sleep

disturbances in children and adolescents randomised to dolutegravir-based ART vs.
standard-of-care in the ODYSSEY trial. Abstract OAB0404. Presented at: 11th IAS
Conference on HIV Science; 2021. Virtual Conference. Available at:
https://onlinelibrary.wiley.com/doi/10.1002/jia2.25755

32. Barlow-Mosha L, Ahimbisibwe G, Chappell E, et al. Effect of dolutegravir on folate and

vitamin B12 status among HIV-infected children and adolescents in the ODYSSEY trial.
Abstract PEB203. Presented at: 11th IAS Conference on HIV Science; 2021. Virtual
Conference. Available at: https://theprogramme.ias2021.org/Abstract/Abstract/1496

33. Frange P, Avettand-Fenoel V, Veber F, Blanche S. No overall impact on body mass

index for age change after dolutegravir initiation in a French paediatric cohort. HIV Med.
2022;23(9):1019-1024. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35306718.

34. Llibre JM, Hung CC, Brinson C, et al. Phase III SWORD 1&2: switch to DTG+RPV
maintains virologic suppression through 48 wks. Presented at: Conference on
Retroviruses and Opportunistic Infections; 2017. Seattle, WA. Available at:
https://www.natap.org/2017/CROI/croi_11.htm

35. van Wyk J, Orkin C, Rubio R, et al. Durable suppression and low rate of virologic failure
3 years after switch to dolutegravir + rilpivirine 2-drug regimen: 148-week results from
the SWORD-1 and -2 randomized clinical trials. J Acquir Immune Defic Syndr.
2020;85(3):325-330. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32675772.

36. McComsey GA, Lupo S, Parks D, et al. Switch from tenofovir disoproxil fumarate
combination to dolutegravir with rilpivirine improves parameters of bone health. AIDS.
2018;32(4):477-485. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29239893.

37. Cahn P, Madero JS, Arribas JR, et al. Durable efficacy of dolutegravir plus lamivudine in
antiretroviral treatment-naive adults with HIV-1 infection: 96-week results from the
GEMINI-1 and GEMINI-2 randomized clinical trials. J Acquir Immune Defic Syndr.
2020;83(3):310-318. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31834000.

38. Roskam-Kwint M, Bollen P, Colbers A, Duisenberg-van Essenberg M, Harbers V,

Burger D. Crushing of dolutegravir fixed-dose combination tablets increases dolutegravir
exposure. J Antimicrob Chemother. 2018;73(9):2430-2434. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29796595.

39. Turley SL, Fulco PP. Enteral administration of twice-daily dolutegravir and rilpivirine as
a part of a triple-therapy regimen in a critically ill patient with HIV. J Int Assoc Provid
AIDS Care. 2017;16(2):117-119. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28198203.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-215
40. Chrdle A, Jerhotova Z, Vacik M, Linka M, Chmelik V. Crushed
dolutegravir/abacavir/lamivudine given via nasogastric tube in gastric outlet obstruction
caused by cancer resulted in rapid viral load suppression. Int J STD AIDS. 2019;30(1):94-
98. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30231834.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-216
Elvitegravir (EVG)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Tablet: Discontinued by the manufacturer. Elvitegravir is available only in fixed-dose combination (FDC) tablets.

FDC Tablets
• [Genvoya] Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg
• [Stribild] Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg

When using FDC tablets, refer to other sections of the Appendix A: Pediatric Antiretroviral Drug Information for information
about the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets
and Co-packaged Formulations: Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

[Genvoya] Genvoya- and Stribild-Associated Adverse Events
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir
Alafenamide (EVG/c/FTC/TAF) • Nausea

Child (Weighing <14 kg) Dose • Diarrhea

• No data exist on the dosing of EVG/c/FTC/TAF for • Fatigue

children weighing <14 kg. • Headache
Child (Weighing ≥14 to <25 kg) Elvitegravir-Associated Adverse Events
• Limited data currently exist on the appropriate dose • Diarrhea
of Genvoya in children ≥14 kg to <25 kg. Studies are
being conducted to assess the safety and efficacy of Tenofovir Alafenamide–Specific Adverse Events
a low-dose tablet with EVG 90 mg/COBI 90 mg/FTC
120 mg/TAF 6 mg. • Increased levels of low-density lipoprotein cholesterol, high-
density lipoprotein cholesterol, triglycerides, and total
Child and Adolescent (Weighing ≥25 kg) and Adult cholesterol
Dose • Glomerular and proximal renal tubular dysfunction
• One tablet once daily with food in antiretroviral
therapy (ART)-naive patients. This dose of Genvoya Tenofovir Disoproxil Fumarate–Specific Adverse Events
also can be used to replace the current • Glomerular and proximal renal tubular dysfunction
antiretroviral (ARV) regimen in patients who have
been virologically suppressed (HIV RNA • Decreased bone mineral density
<50 copies/mL) on a stable ART regimen for at least • Flatulence
6 months with no history of treatment failure and no
known mutations associated with resistance to the Cobicistat-Specific Adverse Events
individual components of Genvoya.
• Benign increases in serum creatinine levels (reductions in
estimated glomerular filtration) due to inhibition of tubular
secretion of creatinine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-217
 [Stribild]
Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Special Instructions
Disoproxil Fumarate (EVG/c/FTC/TDF) • Administer both Genvoya and Stribild with food.
Child and Adolescent (Weighing <35 kg) Dose • Genvoya and Stribild should be administered at least 4 hours
• No data exist on the appropriate dose of Stribild for before or after antacids and supplements or multivitamins that
children or adolescents weighing <35 kg. contain iron, calcium, aluminum, and/or magnesium.
• When using Genvoya (contains TAF) or Stribild, (contains
Adolescent (Weighing ≥35 kg and Sexual Maturity
TDF), monitor estimated creatinine clearance (CrCl), urine
Rating [SMR] 4 or 5) and Adult Dose
glucose, and urine protein at baseline and every 3 to 6 months
• One tablet once daily with food in ART-naive while on therapy. In patients who are at risk of renal
patients. This dose of Stribild also can be used to impairment, also monitor serum phosphate. Patients with an
replace the current ARV regimen in patients who increase in serum creatinine levels >0.4 mg/dL should be
have been virologically suppressed (HIV RNA closely monitored for renal safety.
<50 copies/mL) on a stable ART regimen for at least
• Screen patients for hepatitis B virus (HBV) infection before
6 months with no history of treatment failure and no
using FTC, TDF, or TAF. Severe acute exacerbation of HBV
known mutations associated with resistance to the
can occur when FTC, TDF, or TAF are discontinued; therefore,
individual components of Stribild.
monitor hepatic function for several months after stopping
therapy with FTC, TDF, or TAF.
• For information on crushing and cutting tablets, see the
Information on Crushing and Liquid Drug Formulations table
from Toronto General Hospital.

Metabolism/Elimination
• EVG is metabolized by cytochrome P450 (CYP) 3A4 and is a
modest inducer of CYP2C9.
• EVG is available only in combination with the pharmacokinetic
enhancer (boosting agent) cobicistat in Stribild or Genvoya.
Refer to the Cobicistat, TDF, and TAF sections for further
details on these components.

Elvitegravir Dosing in Patients With Hepatic Impairment

• Stribild and Genvoya should not be used in patients with
severe hepatic impairment.

Elvitegravir Dosing in Patients With Renal Impairment

• Stribild should not be initiated in patients with estimated CrCl
<70 mL/min, and it should be discontinued in patients with
estimated CrCl <50 mL/min. FTC and TDF require dose
adjustments in these patients, and these adjustments cannot
be achieved with an FDC tablet.
• Genvoya is not recommended in patients with estimated
CrCl 15 to <30 mL/min or in patients with estimated CrCl
<15 mL/min who are not receiving chronic hemodialysis.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-218
• Absorption: Elvitegravir (EVG) plasma concentrations are lower with concurrent administration
of divalent cations due to the formation of complexes in the gastrointestinal tract and not due to
changes in gastric pH. Therefore, Stribild and Genvoya should be administered at least 4 hours
before or after administering antacids and supplements or multivitamins that contain iron,
calcium, aluminum, and/or magnesium.1

• Metabolism: Stribild and Genvoya contain EVG and cobicistat (COBI). EVG is metabolized
predominantly by cytochrome P450 (CYP) 3A4, secondarily by uridine diphosphate glucuronyl
transferase 1A1/3, and by oxidative metabolism pathways. EVG is a moderate inducer of
CYP2C9. COBI is a strong inhibitor of CYP3A4 and a weak inhibitor of CYP2D6. In addition,
COBI inhibits the adenosine triphosphate-dependent transporters, P-glycoprotein and the breast
cancer resistance protein, and the organic anion-transporting (OAT) polypeptides OATP1B1 and
OATP1B3. See the Cobicistat section for a more detailed summary of drug interactions. Multiple
drug interactions are possible when using both EVG and COBI. Neither Stribild nor Genvoya
should be administered concurrently with products or regimens that contain ritonavir (RTV)
because of the similar effects of COBI and RTV on CYP3A4 metabolism. Coadministration of
medications that induce or inhibit CYP3A4 may respectively decrease or increase exposures of
EVG and COBI. Coadministration of medications that are CYP3A4 substrates may result in
clinically significant adverse reactions that are severe, life-threatening, or fatal, or may result in
loss of therapeutic effect if dependent on conversion to an active metabolite due to CYP3A4
inhibition by COBI.

• Renal elimination: Drugs that decrease renal function or compete for active tubular secretion
could reduce clearance of tenofovir, in the form of tenofovir alafenamide (TAF) or tenofovir
disoproxil fumarate (TDF), or emtricitabine (FTC). Concomitant use of nephrotoxic drugs should
be avoided when using Genvoya or Stribild. COBI inhibits MATE1, which increases serum
creatinine levels up to 0.4 mg/dL from baseline in adults. Creatinine-based calculations of
estimated glomerular filtration rate (GFR) will be altered, but the actual GFR might be only
minimally changed.2 Significant increases in serum creatinine levels >0.4 mg/dL from baseline
may represent renal toxicity and should be evaluated. People who experience a confirmed
increase in serum creatinine levels should be closely monitored for renal toxicity; clinicians
should monitor creatinine levels for further increases and perform a urinalysis to look for
evidence of proteinuria or glycosuria.3

Major Toxicities
• More common: Nausea, diarrhea, fatigue, headache, flatulence

• Less common (more severe): Lactic acidosis and severe hepatomegaly with steatosis, including
fatal cases, have been reported in patients receiving nucleoside reverse transcriptase inhibitors,
including TDF and FTC. TDF caused bone toxicity (osteomalacia and reduced bone mineral
density [BMD]) in animals when given in high doses. Decreases in BMD have been reported in
both adults and children who were taking TDF; the clinical significance of these changes is not
yet known. Evidence of renal toxicity has been observed in patients taking TAF or TDF,
including a higher incidence of glycosuria, proteinuria, phosphaturia, and/or calciuria; increases
in the levels of serum creatinine and blood urea nitrogen; and decreases in serum phosphate
levels. Numerous case reports of renal tubular dysfunction have been reported in patients
receiving TAF or TDF; patients at increased risk of renal dysfunction should be closely
monitored if they are being treated with Genvoya or Stribild. This nephrotoxicity may be more

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-219
 pronounced in patients with preexisting renal disease.3 Although postmarketing cases of renal
impairment have been reported with TAF, Genvoya, which contains TAF, has an improved bone
and renal safety profile in children and adults when compared to Stribild, which contains TDF.4,5
However, Genvoya is associated with greater increases in lipid levels than Stribild, according to
findings from large-scale clinical trials in adults.6

Resistance
The International Antiviral Society–USA maintains a list of updated HIV drug resistance mutations
and the Stanford University HIV Drug Resistance Database offers a discussion of each mutation. There
is phenotypic cross-resistance between EVG and raltegravir (RTV).7

Pediatric Use
Approval
Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide [EVG/c/FTC/TAF]) is
approved by the U.S. Food and Drug Administration (FDA) for use in antiretroviral (ARV)-naive
children and adolescents with HIV weighing ≥25 kg with any sexual maturity rating (SMR). It also
can be used to replace the current ARV regimen in those who have been virologically suppressed
(HIV RNA <50 copies/mL) on a stable ARV regimen for at least 6 months with no history of
treatment failure and no known mutations associated with resistance to the individual components of
Genvoya.6

Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate [EVG/c/FTC/TDF]) is

approved by the FDA as a complete regimen for use in children and adolescents aged ≥12 years and
weighing ≥35 kg. However, the Panel on Antiretroviral Therapy and Medical Management of
Children Living With HIV recommends limiting the use of Stribild to adolescents with SMRs of 4 or
5 due to concerns about decreased BMD in pre-pubertal patients. It can also be used to replace the
current ARV regimen in those who have been virologically suppressed (HIV RNA <50 copies/mL)
on a stable ARV regimen for at least 6 months with no history of treatment failure and no known
mutations associated with resistance to the individual components of Stribild.8

Efficacy in Clinical Trials in Adults

EVG/c/FTC/TDF was found to be noninferior to efavirenz/emtricitabine/TDF (EFV/FTC/TDF)9-11
and atazanavir/ritonavir (ATV/r) plus FTC/TDF in adults through 144 weeks of treatment.12-14 In
studies comparing EVG/c/FTC/TDF or EVG/c/FTC/TAF over 48 weeks in 1,733 adults, those
receiving EVG/c/FTC/TAF had significantly smaller mean serum creatinine increases (0.08 vs.
0.12 mg/dL; P < 0.0001), significantly less proteinuria (median percent change in protein −3% vs.
+20%; P < 0.0001), and a significantly smaller decrease in BMD at the spine (mean percent change
−1.30% vs. −2.86%; P < 0.0001) and hip (−0.66% vs. −2.95%; P < 0.0001).5 Larger increases in
fasting lipid levels were observed with EVG/c/FTC/TAF than with EVG/c/FTC/TDF; the median
increases in levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein
cholesterol, and triglycerides were all higher in patients who received EVG/c/FTC/TAF.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-220
Use of Elvitegravir in Children and Adolescents Weighing ≥25 kg
Studies of EVG/c/FTC/TDF and EVG/c/FTC/TAF in children with HIV aged ≥12 years and
weighing ≥35 kg have demonstrated safety and efficacy similar to that seen in adults through
24 weeks and 48 weeks of study, respectively; these formulations are approved by the FDA for use in
this age/weight group.15 EVG/c/FTC/TDF is not approved to treat children weighing <35 kg.
EVG/c/FTC/TAF is preferred over EVG/c/FTC/TDF when treating children with SMRs 1 to 3
because EVG/c/FTC/TAF carries a lower risk of renal and bone toxicity than EVG/c/FTC/TDF.6
Long-term bone safety data through 96 weeks with EVG/c/FTC/TAF in adolescents weighing ≥35 kg
revealed no concerns for toxicity in this age group on the basis of BMD (median change from
baseline spine BMD height-age [HA] z-score +0.14 and total body less head [TBLH] HA z-score of
−0.07) and serum biomarkers of bone formation and resorption.16

EVG/c/FTC/TAF is FDA-approved to treat children with any SMR weighing ≥25 kg; this approval
was based on 24 weeks of data in 23 children.17 In this study, children who had been virologically
suppressed (HIV RNA <50 copies/mL) for at least 6 months were switched from their current
regimens to EVG/c/FTC/TAF. No study discontinuations occurred due to medication toxicity, but a
concerning decline in CD4 T lymphocyte (CD4) cell counts was observed in all 23 children over the
first 24 weeks of EVG/c/FTC/TAF treatment. CD4 counts declined by a median of 130 cells/mm3
(with a range of −472 cells/mm3 to 266 cells/mm3) from baseline. However, after enrolling additional
children (for a total of 52 participants), the median CD4 count decline at 48 weeks was 25 cells/mm3
and at 96 weeks was 45 cells/mm3.18 Additionally, the CD4 percentage did not significantly change
across Weeks 24, 48, and 96.19 The mechanism for the reduction in CD4 count is unclear, and this
reduction has only been reported in this study. Plasma exposures of all four drugs were higher in
these children than the plasma exposures seen in historical data from adults, but no association was
identified between plasma exposures of the four components of EVG/c/FTC/TAF and CD4 counts.20
Long-term bone safety data with EVG/c/FTC/TAF through 96 weeks revealed no concerns for
toxicity in this cohort on the basis of BMD (median change from baseline spine BMD HA z-score of
−0.2 and TBLH HA z-score of −0.32) and serum biomarkers of bone formation and resorption.19

A retrospective analysis of integrase strand transfer inhibitor (INSTI) use in children and adolescents
showed that 83.7% (61/73) of patients on an EVG/c-containing therapy continued their prescribed
regimen through the end of the study follow-up period (median [interquartile range] 2.0 [1.4–2.7]
years of exposure). Treatment interruption due to virologic occurred in 4.1% (3/73) of those on
EVG/c, which was comparable to that of dolutegravir (DTG)-based regimens (3.7% [5 of
134 participants]) and lower than RAL-based regimens (17.3% [19 of 110 participants]). Two of the
participants who experienced virologic failures with EVG had major INSTI drug resistance
mutations, but both attained virologic suppression after switching to regimens containing
darunavir (DRV) or DRV with DTG.21

Use of Elvitegravir in Children Weighing 14 to <25 kg

EVG/c/FTC/TAF is not approved to treat children weighing <25 kg.3,6 A pharmacokinetic (PK),
safety, and efficacy study with a low-dose tablet in children aged ≥2 years and weighing ≥14 kg to
<25 kg is ongoing.22 In this study, children had to be virologically suppressed (HIV RNA
<50 copies/mL) for at least 6 months prior to entry. Virologic suppression was maintained19 in
27 (100%) of 27 children at Week 16, 26 (96%) of 27 children at Week 24, and 26 (96%) of
27 children at Week 48. No participant discontinued the study drug because of adverse events or met
criteria for resistance analyses through Week 48. CD4 counts decreased19 by a mean of

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-221
187 cells/mm3 between baseline and Week 48, although the CD4 percentage did not differ (mean
[standard deviation] change of 0.0 [<5.0]). At least 90% of children reported that swallowing the
low-dose tablet was “easy” or “super easy” and perceived the tablet size when swallowing as “okay”
at baseline, Week 4, and Week 24.22 Long-term bone safety data with the low-dose formulation
through 48 weeks revealed no concerns for bone safety in this cohort on the basis of BMD (median
change from baseline in spine BMD HA z-score +0.14 and TBLH HA z-score of −0.06) and serum
biomarkers of bone formation and resorption.16

Pharmacokinetics
EVG/c/FTC/TDF (Stribild)

The PKs of EVG 150 mg, COBI 150 mg, FTC 200 mg, and TDF 300 mg as a fixed-dose
combination (FDC) tablet were evaluated in 14 treatment-naive adolescents with HIV between
12 and <18 years of age and weighing ≥35 kg.23 EVG area under the plasma concentration versus
time curve over the dosing interval (AUC tau ) and peak concentrations (C max ) were 30% higher (90%
confidence interval [CI], 105-162%) and 42% higher (90% CI, 116-173%), respectively, in
comparison to historical data in adults. EVG concentrations at the end of the dosing interval (C tau )
were 6% higher (90% CI, 70-160%) than in adults, and approximately ninefold higher than the
protein-adjusted 95% inhibitory concentration (PA-IC 95 ) of 44.5 ng/mL for EVG. COBI, FTC, and
TFV exposures were comparable to those measured in adults.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-222
Table A. Pharmacokinetics of EVG, COBI, FTC, and TFV From TDF (Stribild) in
Adolescents With HIV Aged 12 to <18 Years and Weighing ≥35 kg

Adolescents
Aged 12 to
Adultsa23 % GLSM Ratio
<18 Years and
Component Parameter
Weighing ≥35 kg23 (90% CI)23
n GLSM n GLSM
EVG AUC tau (ng∙h/mL) 14 28,500 419 21,900 130 (105,162)
C max (ng/mL) 14 2,390 419 1,690 142 (116,173)
C tau (ng/mL) 14 410 419 387 106 (70,160)
COBI AUC tau (ng∙h/mL) 14 9,200 483 8,729 105 (78,142)
C max (ng/mL) 14 1,275 483 1,179 108 (84,139)
C tau (ng/mL) 14 19 483 18 107 (66,173)
FTC AUC tau (ng∙h/mL) 14 14,509 61 12,106 120 (103,139)
C max (ng/mL) 14 2,124 61 1,814 117 (101,136)
C tau (ng/mL) 14 98 61 104 94 (79,113)
TFV AUC tau (ng∙h/mL) 14 4,281 419 3,114 137 (121,156)
C max (ng/mL) 14 409 419 313 131 (110,155)
C tau (ng/mL) 14 84 419 68 123 (109,138)
a Results from Phases 2 and 3 studies in adults with HIV receiving elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil
fumarate.
Key: AUC tau = area under the plasma concentration versus time curve over the dosing interval; CI = confidence interval;
C max = maximum observed plasma concentration of drug; C tau = observed drug concentration at the end of the dosing interval;
COBI = cobicistat; EVG = elvitegravir; FTC = emtricitabine; GLSM = geometric least squares mean; kg = kilogram;
mL = milliliter; ng = nanogram; TFV = tenofovir

EVG/c/FTC/TAF (Genvoya)

The PK of EVG 150 mg, COBI 150 mg, FTC 200 mg, and TAF 10 mg as an FDC tablet have been
evaluated in adolescents 12 to <18 years of age weighing ≥35 kg23 and children 6 to <12 years of age
weighing ≥25 kg.17 AUC tau , C max , and C tau for EVG, COBI, FTC, TAF, and TFV were comparable to
or higher than those measured in adults with HIV in both cohorts (see Tables B and C below).

The PK of a low-dose FDC tablet containing EVG 90 mg, COBI 90 mg, FTC 120 mg, and TAF 6 mg
were evaluated in 27 children with HIV weighing ≥14 kg and <25 kg.22 EVG and TAF AUC tau were
higher in comparison to historical data in adults receiving full-strength Genvoya (see Tables B and C
below). EVG C tau was 21% lower (90% CI [53.1-117%]) in children versus adults but was
approximately 4.4-fold higher and ninefold higher than the PA-IC 95 and PA-IC 50 for wild-type virus,
respectively. However, EVG C tau measured in this cohort was lower than those previously measured

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-223
in children and adolescents weighing ≥25 kg with EVG at the 150-mg dose. COBI, FTC, and TFV
exposures were all comparable to or higher than historical data in adults.

Table B. Pharmacokinetics of EVG, COBI, FTC, TAF, and TFV (Genvoya) in Children
and Adolescents With HIV Between 2 to <18 Years of Age and Weighing ≥14 kg

Children Children Adolescents

Aged ≥2 Years Aged 6 to Aged 12 to
Adultsa15,17
and Weighing <12 Years and <18 Years and
Component Parameter ≥14 to <25 kg22 Weighing ≥25 kg17 Weighing ≥35 kg15

Mean Mean Mean

n GLSM n n n
(%CV) (%CV) (%CV)
EVG AUC tau (ng∙h/mL) 27 29,900 22 33,814 (58%) 24 23,840 (26%) 19 22,800 (35%)
C max (ng/mL) 27 2,850 23 3,055 (39%) 24 2,230 (19%) 19 2,100 (34%)
C tau (ng/mL) 27 195 23 370 (119%) 24 301 (81%) 19 290 (62%)
COBI AUC tau (ng∙h/mL) 27 12,300 20 15,891 (52%) 23 8,241 (36%) 19 9,500 (34%)
C max (ng/mL) 27 1,270 23 2,079 (47%) 24 1,202 (35%) 19 1,500 (28%)
C tau (ng/mL) 27 16.6 23 96 (169%) 15 25 (180%) 19 20 (85%)
FTC AUC tau (ng∙h/mL) 27 18,600 22 20,629 (19%) 24 14,424 (24%) 19 11,714 (17%)
C max (ng/mL) 27 2,810 23 3,397 (27%) 24 2,265 (23%) 19 2,056 (20%)
C tau (ng/mL) 27 77.4 23 115 (24%) 23 102 (39%) 19 95 (47%)
TAF AUC tau (ng∙h/mL) 27 344 23 333 (45%) 24 189 (56%) 539 206 (72%)
C max (ng/mL) 27 218 23 313 (61%) 24 167 (64%) 539 162 (51%)
TFV AUC tau (ng∙h/mL) 27 327 23 440 (21%) 23 288 (19%) 841 293 (27%)
C max (ng/mL) 27 19.1 23 26 (21%) 23 18 (24%) 841 15 (26%)
C tau (ng/mL) 27 11.1 23 15 (25%) 23 10 (21%) 841 11 (29%)
TFV-DP in C 0h (fmol/106
PBMCS — — — — 12 222 (94%) 21 121 (91%)
cells)
a Adult pharmacokinetic parameters for elvitegravir, cobicistat, and emtricitabine were derived from intensive pharmacokinetic

analysis from Phase 2 study 102; data for tenofovir alafenamide and tenofovir were from population pharmacokinetic analyses in
Phase 3 studies 104 and 111.
Key: AUC tau = area under the plasma concentration versus time curve over the dosing interval; C 0h = concentration at
time 0 (pre-dose); C max = maximum observed plasma concentration of drug; C tau = observed drug concentration at the end of
the dosing interval; COBI = cobicistat; CV = coefficient of variation; EVG = elvitegravir; fmol = femtomole; FTC = emtricitabine;
GLSM = geometric least squares mean; kg = kilogram; mL = milliliter; ng = nanogram; PBMCs = peripheral blood mononuclear
cells; TAF = tenofovir alafenamide; TFV = tenofovir; TFV-DP = tenofovir-diphosphate

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-224
Table C. Comparisons of EVG, COBI, FTC, TAF, and TFV (Genvoya) Pharmacokinetics
in Children and Adolescents With HIV Between 2 and <18 Years of Age and Weighing
≥14 kg to Adult Values

% GLSM (90% CI) Compared with Adult Valuesa

Children
Component Parameter Children
Aged ≥2 Years and
Dose Weighing ≥14 to Dose Aged 6 to <12 Years and
(mg) <25 kg17 (mg) Weighing ≥25 kg22
EVG AUC tau (ng∙h/mL) 139 (112,172) 134 (104,173)
C max (ng/mL) 90 143 (113,180) 150 141 (115,173)
C tau (ng/mL) 79 (53,117) 86 (55,133)
COBI AUC tau (ng∙h/mL) — 158 (126,198)
C max (ng/mL) 90 — 150 127 (98,165)
C tau (ng/mL) — 171 (95,310)
FTC AUC tau (ng∙h/mL) — 175 (160,192)
C max (ng/mL) 120 — 200 164 (145,184)
C tau (ng/mL) — 125 (107,146)
TAF AUC tau (ng∙h/mL) 193 (166,224) 171 (147,199)
C max (ng/mL) 150 (116,195) 182 (146,225)
TFV AUC tau (ng∙h/mL) 6 — 10 152 (142,163)
C max (ng/mL) — 173 (161,186)
C tau (ng/mL) — 143 (132,155)
a Adultpharmacokinetic parameters for elvitegravir, cobicistat, and emtricitabine were derived from intensive pharmacokinetic
analysis from Phase 2 study 102; data for tenofovir alafenamide and tenofovir were from population pharmacokinetic analyses in
Phase 3 studies 104 and 111.
Key: AUC tau = area under the plasma concentration versus time curve over the dosing interval; C max = maximum observed
plasma concentration of drug; COBI = cobicistat; C tau = observed drug concentration at the end of the dosing interval;
CI = confidence interval; EVG = elvitegravir; FTC = emtricitabine; GLSM = geometric least squares mean; kg = kilogram;
mL = milliliter; mg = milligram; ng = nanogram; TAF = tenofovir alafenamide; TFV = tenofovir

Formulations
EVG is an INSTI that is metabolized by CYP3A4. EVG is only available in the FDC products
Stribild24 or Genvoya,6 both of which contain COBI (see below). COBI itself does not have ARV
activity, but it is a CYP3A4 inhibitor that acts as a PK enhancer, similar to RTV.25

Coadministration of Elvitegravir, Cobicistat, and Darunavir

The combination of Stribild or Genvoya plus DRV may provide a low pill-burden regimen for
antiretroviral therapy-experienced individuals. However, an unfavorable drug interaction between
EVG/c and DRV is possible, and the available data on the magnitude of the interaction are
conflicting. Data on the efficacy of the combination in adults also are conflicting.26-32

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-225
The most rigorous drug interaction study, performed in HIV-seronegative adults, found 21% lower
DRV trough concentrations (C trough ) and 52% lower EVG C trough with DRV 800 mg plus EVG/c
150 mg/150 mg once daily compared to the administration of either darunavir/cobicistat
800 mg/150 mg once daily or EVG/c 150 mg/150 mg once daily alone.26 The actual C trough were
1,050 ng/mL for DRV and 243 ng/mL for EVG.

Despite the findings of the aforementioned drug interaction study in HIV-seronegative adults, the
most rigorous efficacy evaluation found that among 89 treatment-experienced adults who were
receiving five-tablet ARV regimens, 96.6% achieved virologic suppression (HIV RNA
<50 copies/mL) 24 weeks after simplifying their regimens to a two-tablet regimen of Genvoya plus
DRV 800 mg once daily.30 Intensive PK sampling was performed in 15 of these patients (17%).
Mean DRV and EVG C trough were 1,250 ng/mL and 464 ng/mL, respectively.

Given the uncertainty around the true magnitude of the drug interaction and the absence of data in
children, this combination should be used with caution in children.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-226
References

1. Ramanathan S, Mathias A, Wei X, et al. Pharmacokinetics of once-daily boosted

elvitegravir when administered in combination with acid-reducing agents. J Acquir
Immune Defic Syndr. 2013;64(1):45-50. Available at:
https://journals.lww.com/jaids/Fulltext/2013/09010/Pharmacokinetics_of_Once_Daily_B
oosted.8.aspx.

2. German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate
in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr.
2012;61(1):32-40. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22732469.

3. Stribild (elvitegravir, cobicitstat, emtricitabine, tenofovir disoproxil fumarate) [package

insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203100s035lbl.pdf.

4. Sharma S, Gupta S, Majeed S, et al. Exposure-safety of tenofovir in pediatic HIV-

infected participants: comparison of tenofovir alafenamide & tenofovir disoproxil
fumarate. Abstract 23. Presented at: 10th International Workshop on HIV Pediatrics
2018. Amsterdam, The Netherlands. Available at:
https://academicmedicaleducation.com/meeting/international-workshop-hiv-pediatrics-
2018/slide-set/32wsharma?check_logged_in=1.

5. Sax PE, Wohl D, Yin MT, et al. Tenofovir alafenamide versus tenofovir disoproxil
fumarate, coformulated with elvitegravir, cobicistat, and emtricitabine, for initial
treatment of HIV-1 infection: two randomised, double-blind, Phase 3, non-inferiority
trials. Lancet. 2015;385(9987):2606-2615. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25890673.

6. Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) [package insert].

Food and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207561s029lbl.pdf.

7. Garrido C, Villacian J, Zahonero N, et al. Broad phenotypic cross-resistance to

elvitegravir in HIV-infected patients failing on raltegravir-containing regimens.
Antimicrob Agents Chemother. 2012;56(6):2873-2878. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22450969.

8. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) [package

insert]. Food and Drug Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203100s036lblet.pdf.

9. Sax PE, DeJesus E, Mills A, et al. Co-formulated elvitegravir, cobicistat, emtricitabine,

and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial
treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of
results after 48 weeks. Lancet. 2012;379(9835):2439-2448. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22748591.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-227
10. Zolopa A, Sax PE, DeJesus E, et al. A randomized double-blind comparison of
coformulated elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate versus
efavirenz/emtricitabine/tenofovir disoproxil fumarate for initial treatment of HIV-1
infection: analysis of week 96 results. J Acquir Immune Defic Syndr. 2013;63(1):96-100.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/23392460.

11. Wohl DA, Cohen C, Gallant JE, et al. A randomized, double-blind comparison of single-
tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF versus single-tablet
regimen efavirenz/emtricitabine/tenofovir DF for initial treatment of HIV-1 infection:
analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65(3):e118-120.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/24256630.

12. Rockstroh JK, Dejesus E, Henry K, et al. A randomized, double-blind comparison of co-
formulated elvitegravir/cobicistat/emtricitabine/tenofovir versus ritonavir-boosted
atazanavir plus co-formulated emtricitabine and tenofovir DF for initial treatment of
HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr.
2013;62(5):483-486. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23337366.

13. DeJesus E, Rockstroh JK, Henry K, et al. Co-formulated elvitegravir, cobicistat,

emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus
co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of
HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet.
2012;379(9835):2429-2438. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22748590.

14. Clumeck N, Molina JM, Henry K, et al. A randomized, double-blind comparison of

single-tablet regimen elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-
boosted atazanavir plus emtricitabine/tenofovir DF for initial treatment of HIV-1
infection: analysis of week 144 results. J Acquir Immune Defic Syndr. 2014;65(3):e121-
124. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24346640.

15. Gaur AH, Kizito H, Prasitsueubsai W, et al. Safety, efficacy, and pharmacokinetics of a
single-tablet regimen containing elvitegravir, cobicistat, emtricitabine, and tenofovir
alafenamide in treatment-naive, HIV-infected adolescents: a single-arm, open-label trial.
Lancet HIV. 2016;3(12):e561-e568. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27765666.

16. Rakhmanina N GC, Natukunda E, Kosalaraksa P, Anugulruengkitt S, Shao Y, Maxwell

H, O’Connor C, et al. Effects of long-term treatment with
elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate (E/C/F/TAF) on
bone safety parameters in children and adolescents living with HIV [Abstract 64].
Presented at: International Workshop on HIV Pediatrics 2021. Virtual Meeting. Available
at: https://academicmedicaleducation.com/meeting/international-workshop-hiv-
pediatrics-2021/abstract.

17. Natukunda E, Gaur A, Kosalaraksa P, et al. Safety, efficacy, and pharmacokinetics of

single-tablet elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in
virologically suppressed, HIV-infected children: a single-arm, open-label trial. Lancet

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-228
 Child Adolescent Health. 2017;1(1):27-34. Available at:
https://www.sciencedirect.com/science/article/pii/S2352464217300093?via%3Dihub.

18. Rakhmanina N, Natukunda E, Kosalaraksa P, Batra J, Gaur A, et al. Safety and efficacy
of E/C/F/TAF in virologically suppressed, HIV-infected children through 96 weeks.
Abstract 22. Presented at: 11th International Workshop on HIV Pediatrics; 2019. Mexico
City, Mexico.

19. Anugulruengkitt S, A. Gaur, P. Kosalaraksa, A. Liberty, Y. Shao, et al. . Long-term

safety & efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate
(E/C/F/TAF) single-tablet regimen in children and adolescents living with HIV [abstract
4]. Presented at: International Workshop on HIV Pediatrics 2021. Virtual Meeting.
Available at: https://www.natap.org/2021/IAS/IAS_79.htm.

20. Bell T, Baylor M, Rhee S, et al. FDA analysis of CD4+ cell count declines observed in
HIV-infected children treated with elvitegravir/cobicistat/emtricitabine/tenofovir
alafenamide. Open Forum Infect Dis. 2018;5. Available at:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6253452/

21. Torres-Fernandez D, Jimenez de Ory S, Fortuny C, et al. Integrase inhibitors in children

and adolescents: clinical use and resistance. J Antimicrob Chemother. 2022;77(10):2784-
2792. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35971971.

22. Natukunda E, Liberty A, Strehlau R, et al. Safety, pharmacokinetics and efficacy of low-
dose E/C/F/TAF in virologically suppressed children ≥2 years old living with HIV.
Abstract OALB0101. Presented at: International AIDS Conference; 2020. Virtual
Meeting. Available at: https://academicmedicaleducation.com/meeting/international-
workshop-hiv-pediatrics-2020/abstract/safety-pharmacokinetics-and-efficacy.

23. Stribild (elvitegravir, cobicitstat, emtricitabine, tenofovir disoproxil fumarate) [package

insert]. Food and Drug Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203100s036lblet.pdf.

24. Tybost (cobicistat) [package insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/203094s015lbl.pdf.

25. Ramanathan S, Wang H, Szwarcberg J, Kearney BP. Safety/tolerability,

pharmacokinetics, and boosting of twice-daily cobicistat administered alone or in
combination with darunavir or tipranavir. Abstract P-08. Presented at: 13th International
Workshop on Clinical Pharmacology of HIV Therapy. 2012. Barcelona, Spain. Available
at: https://www.natap.org/2012/pharm/Pharm_28.htm.

26. Diaz A, Moreno A, Gomez-Ayerbe C, et al. Role of EVG/COBI/FTC/TDF (Quad) plus

darunavir regimen in clinical practice Presented at: 21st International AIDS Conference
(AIDS 2016). 2016. Durban, South Africa.

27. Gutierrez-Valencia A, Benmarzouk-Hidalgo OJ, Llaves S, et al. Pharmacokinetic

interactions between cobicistat-boosted elvitegravir and darunavir in HIV-infected

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-229
 patients. J Antimicrob Chemother. 2017;72(3):816-819. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27999051.

28. Harris M, Ganase B, Watson B, Harrigan PR, Montaner JSG, Hull MW. HIV treatment
simplification to elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate
(E/C/F/TDF) plus darunavir: a pharmacokinetic study. AIDS Res Ther. 2017;14(1):59.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29096670.

29. Huhn GD, Tebas P, Gallant J, et al. A randomized, open-label trial to evaluate switching
to elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide plus darunavir in treatment-
experienced HIV-1-infected adults. J Acquir Immune Defic Syndr. 2017;74(2):193-200.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/27753684.

30. Naccarato MJ, Yoong DM, Fong IW, Gough KA, Ostrowski MA, Tan DHS.
Combination therapy with tenofovir disoproxil
fumarate/emtricitabine/elvitegravir/cobicistat plus darunavir once daily in antiretroviral-
naive and treatment-experienced patients: a retrospective review. J Int Assoc Provid
AIDS Care. 2018;17:2325957417752260. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29385867.

31. Ricard F, Wong A, Lebouche B, et al. Low darunavir concentrations in patients receiving
Stribild (elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate) and darunavir
once daily. Abstract 50. Presented at: 16th International Workshop on Clinical
Pharmacology of HIV and Hepatitis Therapy; 2015. Washington, DC. Available at:
https://www.natap.org/2015/Pharm/Pharm_04.htm.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-230
Raltegravir (RAL, Isentress)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Tablet: 400 mg (film-coated poloxamer tablet)

High-Dose (HD) Tablet: 600 mg (film-coated poloxamer tablet)

Chewable Tablets: 100 mg (scored) and 25 mg

Granules for Oral Suspension: Single-use packet of 100 mg of raltegravir, suspended in 10 mL of water for a final
concentration of 10 mg/mL

Film-coated tablets, chewable tablets, and oral suspension are not interchangeable.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Note: No dosing information is available for preterm infants or • Rash, including Stevens-Johnson syndrome,
infants weighing <2 kg at birth. See Table 13 in Antiretroviral hypersensitivity reaction, and toxic epidermal necrolysis
Management of Newborns With Perinatal HIV Exposure or HIV
Infection for information about using raltegravir (RAL) for the • Nausea, diarrhea
prevention of perinatal HIV transmission. • Headache, dizziness, fatigue
Neonate (Weighing ≥2 kg) Dosea,b • Insomnia
Raltegravir Oral Suspension Dosing Table for Full-Term • Fever
Neonates From Birth to Age 4 Weeks
• Creatine phosphokinase elevation, muscle weakness,
Neonates Aged ≥37 Weeks and Weighing ≥2 kg and rhabdomyolysis

Weight Volume (Dose) of Suspensionb Special Instructions

Birth to 1 Week of Age: Approximately • RAL can be given without regard to food.
Once-Daily Dosing 1.5 mg/kg per dose • Coadministration or staggered administration of
2 kg to <3 kg 0.4 mL (4 mg) once daily aluminum-containing and magnesium-containing
antacids is not recommended with any RAL
3 kg to <4 kg 0.5 mL (5 mg) once daily formulations.
4 kg to <5 kg 0.7 mL (7 mg) once daily • Significant drug interactions are more likely to occur
when the RAL HD formulation is used once daily. The
1–4 Weeks of Age: following drugs should not be coadministered with
Approximately 3 mg/kg per dose
Twice-Daily Dosing once-daily RAL HD dosing: calcium carbonate
antacids, rifampin, tipranavir/ritonavir, and etravirine.
2 kg to <3 kg 0.8 mL (8 mg) twice daily
• Chewable tablets can be chewed, crushed (before
3 kg to <4 kg 1 mL (10 mg) twice daily
administration), or swallowed whole.
4 kg to <5 kg 1.5 mL (15 mg) twice daily
• Film-coated tablets, including HD tablets, must be
a RAL is metabolized by uridine diphosphate glucuronyl swallowed whole.
transferase (UGT) 1A1, and enzyme activity is low at birth; enzyme
• The chewable tablets and oral suspension have better
activity increases rapidly during the next 4–6 weeks of life.
bioavailability than the film-coated tablets. Because the

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-231
 b For neonates, most of the prepared oral suspension will be formulations are not interchangeable, do not substitute
discarded. The volume for the required dose is much smaller than chewable tablets or oral suspension for film-coated
the 10 mL suspension that is prepared. tablets. See specific recommendations for proper
dosing of different formulations.
Note: If the mother has taken RAL 2–24 hours prior to delivery, the
neonate’s first dose should be delayed until 24–48 hours after • The chewable tablets should be stored in the original
birth. package with a desiccant to protect them from moisture.
• Instructions for preparing and administering the
Infant >4 Weeks of Age and Child (Weighing ≥3 kg to <20 kg) chewable tablet as a crushed tablet are as follows:
Dose Place the tablet(s) in a small, clean cup. For each tablet,
• For children weighing 3–20 kg, either oral suspension or add a teaspoon (~5 mL) of liquid (e.g., water, juice, or
chewable tablets can be used. breast milk). Within 2 minutes, the tablet(s) will absorb
the liquid and fall apart. Using a spoon, crush any
Raltegravir Oral Suspension Dosing Table for Patients Aged remaining pieces of the tablet(s). Immediately
>4 Weeksa administer the entire dose orally. If any portion of the
dose is left in the cup, add another teaspoon (~5 mL) of
Note: The maximum dose of oral suspension is 10 mL
liquid, swirl, and administer immediately.
(RAL 100 mg) twice daily.
• The chewable tablets contain phenylalanine, a
Twice-Daily Volume (Dose) component of aspartame. Phenylalanine can be harmful
Weight to patients with phenylketonuria, and the necessary
of Suspensionb
dietary adjustments should be made in consultation with
3 kg to <4 kg 2.5 mL (25 mg) twice daily a metabolic specialist.
4 kg to <6 kg 3 mL (30 mg) twice daily • The oral suspension comes in a kit that includes
6 kg to <8 kg 4 mL (40 mg) twice daily instructions for use, mixing cups, oral dosing syringes,
and 60 foil packets. Detailed instructions for preparation
8 kg to <10 kg 6 mL (60 mg) twice daily are provided in the Instructions for Use document.1
10 kg to <14 kg 8 mL (80 mg) twice daily Each single-use foil packet contains 100 mg of RAL,
which will be suspended in 10 mL of water for a final
14 kg to <20 kg 10 mL (100 mg) twice daily concentration of RAL 10 mg/mL. Gently swirl the mixing
a The weight-based dose recommendation for the oral suspension cup for 45 seconds in a circular motion to mix the
powder into a uniform suspension.
is based on a dose of approximately RAL 6 mg/kg per dose twice
daily. • Do not shake the oral suspension. Dose should be
administered within 30 minutes of mixing; unused
bFor neonates, most of the prepared oral suspension will be
solution should be discarded as directed in the
discarded, because the volume for the required dose is much
Instructions for Use document. For neonates, most of
smaller than 10 mL.
the prepared oral suspension will be discarded,
Child and Adolescent Dose for Chewable Tablets, Film-Coated because the volume for the required dose is much
Tablets, and HD Tablets smaller than 10 mL.

Children Weighing ≥3 kg Metabolism/Elimination

• Weighing <25 kg • UGT1A1-mediated glucuronidation
o Chewable tablets twice daily. See the table below for
chewable tablet doses. Raltegravir Dosing in Patients With Hepatic
Impairment
• Weighing ≥25 kg
• No dose adjustment is necessary for patients with mild-
o RAL 400-mg, film-coated tablets twice daily or chewable to-moderate hepatic insufficiency who are receiving
tablets twice daily. See the table below for chewable tablet RAL twice daily.
doses.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-232
 Children and Adolescents Weighing ≥40 kg • No studies have been conducted on the use of RAL HD
in patients with hepatic impairment. Therefore,
• Two RAL 600-mg HD tablets (1,200 mg) once daily
administering RAL HD is not recommended in patients
• This dose is for antiretroviral therapy–naive or virologically with hepatic impairment.
suppressed patients who are on an initial dose of RAL 400 mg
• The effect of severe hepatic impairment on RAL
twice daily.
pharmacokinetics has not been studied.
Chewable Tablet Dosing Tablea
Raltegravir Dosing in Patients With Renal Impairment
Note: The maximum dose of chewable tablets is RAL 300 mg twice
daily. • No dose adjustment is necessary in patients with any
degree of renal impairment.
Twice-Daily Number of Chewable
Weight
Dose Tablets
3 kg to <6 kg RAL 25 mg 1 tablet (25 mg)
6 kg to <10 kg RAL 50 mg 2 tablets (25 mg)
10 kg to <14 kg RAL 75 mg 3 tablets (25 mg)
14 kg to <20 kg RAL 100 mg 1 tablet (100 mg)
20 kg to <28 kg RAL 150 mg 1½ tabletsb (100 mg)
28 kg to <40 kg RAL 200 mg 2 tablets (100 mg)
≥40 kg RAL 300 mg 3 tablets (100 mg)
a The weight-based dose recommendation for the chewable tablet

is based on a dose of approximately RAL 6 mg/kg per dose twice

daily.
b TheRAL 100-mg chewable tablet can be divided into equal
halves.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: The major route of raltegravir (RAL) elimination is mediated through

glucuronidation by uridine diphosphate glucuronyl transferase (UGT) 1A1.
• Coadministering RAL with inducers of UGT1A1—such as rifampin and tipranavir—may result
in reduced plasma concentrations of RAL. Inhibitors of UGT1A1—such as atazanavir (ATV)—
may increase plasma concentrations of RAL. No dosing modifications are recommended when
RAL is coadministered with atazanavir/ritonavir (ATV/r) or tipranavir/ritonavir (TPV/r).
However, RAL high-dose (HD) tablets should not be coadministered with TPV/r.
• In adults, an increased dose of RAL is recommended when it is coadministered with rifampin.
For adults receiving rifampin, the recommended RAL dose is 800 mg twice daily. Do not
coadminister rifampin with once-daily RAL HD tablets. In children aged 4 weeks to <12 years
who had tuberculosis (TB)/HIV coinfection and were taking rifampin, RAL 12 mg/kg per dose
twice daily of the chewable tablet formulation safely achieved pharmacokinetic (PK) targets.2,3 In
a single case report of a 6-month-old infant receiving RAL oral granules for suspension and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-233
 rifampicin for TB prophylaxis, 3 to 4 times the currently recommended dose of 12 mg/kg twice
daily was needed4 to achieve target trough concentrations (C trough ) >0.022 mg/L.
• Aluminum-containing antacids and magnesium-containing antacids may reduce RAL plasma
concentrations and should not be coadministered with RAL.
• Significant drug interactions may be more likely to occur with RAL HD once daily. C trough in
adults is approximately 30% lower with RAL HD 1,200 mg once daily than with RAL 400 mg
twice daily. A lower C trough increases the potential for clinically significant drug interactions with
interfering drugs that decrease RAL exposure and further lower C trough . In addition to aluminum-
containing and magnesium-containing antacids, the following drugs should not be
coadministered with the RAL HD formulation: calcium carbonate antacids, rifampin, TPV/r,
and etravirine. The impact of other strong inducers of drug-metabolizing enzymes on RAL is
unknown; coadministration with phenytoin, phenobarbital, and carbamazepine is not
recommended.
• Before administering RAL, clinicians should carefully review a patient’s medication profile for
potential drug interactions with RAL.

Major Toxicities
• More common: Nausea, headache, dizziness, diarrhea, fatigue, itching, insomnia.
• Less common: Abdominal pain, vomiting. Patients with chronic active hepatitis B virus infection
and/or hepatitis C virus infection are more likely to experience a worsening adverse events (AEs)
grade from baseline for laboratory abnormalities of aspartate aminotransferase (AST), alanine
aminotransferase (ALT), or total bilirubin than patients who are not coinfected.
• Rare: Moderate-to-severe increase in creatine phosphokinase levels. Use RAL with caution in
patients who are receiving medications that are associated with myopathy and rhabdomyolysis.
Anxiety, depression, and paranoia, especially in those with a history of these conditions. Rash
(including Stevens-Johnson syndrome), hypersensitivity reaction, and toxic epidermal necrolysis.
Thrombocytopenia. Cerebellar ataxia. Hepatic failure (with and without associated
hypersensitivity) in patients with underlying liver disease and/or concomitant medications.

Resistance
The International AIDS Society–USA maintains a list of updated HIV resistance mutations, and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
RAL is an integrase strand transfer inhibitor that is approved by the U.S. Food and Drug
Administration (FDA) for use in combination with other antiretroviral (ARV) drugs for the treatment
of HIV in pediatric patients weighing ≥2 kg. The current pediatric FDA approval and dose
recommendations are based on evaluations of 122 patients aged ≥4 weeks to 18 years who
participated in IMPAACT P1066 and 42 full-term neonates who were treated for ≤6 weeks starting
from birth and followed for a total of 24 weeks during IMPAACT P1110.5

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-234
The FDA has approved RAL HD, which allows once-daily dosing, for use in children and
adolescents weighing ≥40 kg.

Efficacy in Clinical Trials

RAL has been evaluated in adults in three large, randomized clinical trials: STARTMRK,
SPRING-2, and AIDS Clinical Trials Group (ACTG) A5257. STARTMRK compared the safety and
efficacy of a RAL-containing regimen and an efavirenz (EFV)-containing regimen. At 48 weeks,
RAL was noninferior to EFV. However, more patients discontinued EFV during the longer follow-up
periods of 4 and 5 years, and RAL was found to be virologically and immunologically superior to
EFV.6-8 Results from the SPRING-2 study in treatment-naive adults showed that RAL and
dolutegravir (DTG) were equally effective and had similar safety profiles.9 ACTG A5257 compared
RAL to ATV/r and darunavir/ritonavir; all regimens had equivalent virologic efficacy, but RAL had
better tolerability.10 The ONCEMRK study compared RAL 1,200 mg once daily (taken as two 600-
mg RAL HD tablets) to RAL 400 mg twice daily in treatment-naive adults (see the results for the
ONCEMRK study in the following section). Once-daily dosing of RAL using the HD tablets was
approved by the FDA for adults and children weighing ≥40 kg who are either treatment naive or
virologically suppressed on a twice-daily RAL regimen.

RAL was studied in infants, children, and adolescents in IMPAACT P1066, an open-label trial that
evaluated PKs, safety, tolerability, and efficacy. In 96 participants aged 2 to 18 years who were
mostly antiretroviral therapy (ART) experienced, 79.1% of the patients achieved a favorable viral
load response (i.e., viral loads <400 copies/mL or ≥1 log 10 decline in viral load) while receiving the
currently recommended dose of RAL. Infants and toddlers aged ≥4 weeks to <2 years also were
enrolled in IMPAACT P1066 and received treatment with RAL oral suspension. At Weeks 24 and
48, 61% of the participants (14 of 23 infants and toddlers) had HIV viral loads11-13 <400 copies/mL.

Efficacy and Pharmacokinetics of Once-Daily Dosing in Children and Adults

RAL PKs exhibit considerable intrasubject and intersubject variability.14,15 Current PK targets are
based on results from a clinical trial in adults (QDMRK) in which treatment-naive patients with HIV
were randomized to receive RAL 800 mg once daily or RAL 400 mg twice daily. After 48 weeks of
treatment, the percent of patients who achieved HIV RNA viral loads <50 copies/mL was 83% in the
once-daily group, compared with 89% in the twice-daily group. Patients in the once-daily arm with
C trough concentrations <45 nM (20 ng/mL) were at greater risk of experiencing treatment failure.14,15
Overall drug exposures were similar in both groups, but the association between higher risk of
treatment failure and lower C trough concentrations suggests that maintaining RAL trough plasma
concentrations >45 nM (20 ng/mL) is important for efficacy.14,15

Once-daily dosing with RAL 1,200 mg was found to be as effective as dosing with RAL 400 mg
twice daily. In the ONCEMRK study, 797 treatment-naive adults were randomized to receive either
RAL 1,200 mg once daily (taken as two 600-mg tablets) or RAL 400 mg twice daily plus tenofovir
disoproxil fumarate plus emtricitabine. After 48 weeks, 89% of participants on the once-daily dose
and 88% of participants on the twice-daily dose reached viral loads of <40 copies/mL.
Discontinuation rates due to AEs were not different between the two groups.16 In May 2017, once-
daily dosing of RAL using the HD tablets was approved by the FDA for adults and children weighing
≥40 kg who are either treatment naive or virologically suppressed on a twice-daily RAL regimen.
The use of once-daily dosing with the HD tablets has not been studied in pediatric patients.
Population PK modeling and simulations of once-daily dosing with RAL HD tablets predict that this

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-235
dosing schedule will produce drug exposures similar to those observed in adult patients during
ONCEMRK.5,17

Dosing with three 400-mg RAL tablets once daily and dosing with two 600-mg RAL HD tablets
once daily are expected to produce similar PK profiles. In adults enrolled in ONCEMRK, the C trough
concentrations were approximately 30% lower in participants taking once-daily RAL HD tablets than
in those taking RAL 400 mg twice daily. Because of this, once-daily dosing of RAL has a greater
potential for significant drug interactions; coadministering once-daily RAL with drugs that decrease
drug exposure may further decrease C trough . The highest concentration (C max ) is approximately six
times higher in patients receiving RAL 1,200 mg once daily than in those receiving RAL 400 mg
twice daily, with a twofold higher area under the curve (AUC).

Although modeling and simulations for pediatric patients indicate that PK targets are met using the
once-daily RAL 1,200-mg dose, no clinical data exist on the use of this dose in children weighing
<50 kg. Six children in IMPAACT P1066 had drug exposures that were similar to those observed in
ONCEMRK, but all six children weighed >50 kg. Dose-related central nervous system toxicities—
such as insomnia or hyperactivity—may occur in children who are exposed to very high
concentrations of RAL.5

Efficacy and Pharmacokinetics in Children

IMPAACT P1066 evaluated the PKs, safety, and efficacy of RAL in treatment-experienced children
aged 4 weeks to 18 years. A summary of RAL steady-state PK parameters, following administration
of the recommended twice-daily doses (approximately 6 mg/kg twice daily), can be found in Table A
below.12,13

Table A. Raltegravir Steady-State Pharmacokinetic Parameters in Pediatric Patients

Following Administration of Recommended Twice-Daily Doses: IMPAACT P1066

Geometric Mean Geometric Mean

Body Weight Formulation Dose Na (% CVb) (% CVb)
AUC 0-12h (μM·h)c,d C 12h (nM)c,d
≥25 kg Film-coated tablet 400 mg twice daily 18 14.1 (121%) 233 (157%)
≥25 kg Chewable tablet Weight-based dosinge 9 22.1 (36%) 113 (80%)
11 kg to <25 kg Chewable tablet Weight-based dosinge 13 18.6 (68%) 82 (123%)
3 kg to <20 kg Oral suspension Weight-based dosinge 19 24.5 (43%) 113 (69%)
a Number of patients with intensive PK results at the final recommended dose
b Geometric coefficient of variation
cPharmacokinetic targets for film-coated tablets and chewable tablets: AUC 0–12h 14–25 µM·h (6–11 mg·h/L); C 12h nM ≥33 nM
(14.7 ng/mL)
d Pharmacokinetic targets for oral suspension: AUC 0–12h 14–45 µM·h (6–20 mg·h/L); C 12h nM ≥75 nM (33.3 ng/mL)
e To approximate 6 mg/kg twice daily
Key: AUC = area under the curve; AUC 0–12h = AUC from time zero to 12 hours after drug administration; C 12h = concentration at
12 hours (trough); CV = coefficient of variation

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-236
Children Aged 2 Years to 18 Years
IMPAACT P1066 was a Phase 1/2 open-label, multicenter study that evaluated the PK profile,
safety, tolerability, and efficacy of various formulations of RAL in ART-experienced children and
adolescents with HIV aged 2 to 18 years. RAL was administered in combination with an optimized
background ARV regimen.13,18 Subjects received either the RAL 400-mg, film-coated tablet
formulation twice daily (patients aged 6–18 years and weighing ≥25 kg) or the chewable tablet
formulation at a dose of RAL 6 mg/kg twice daily (patients aged 2 years to <12 years). In IMPAACT
P1066, the initial dose-finding stage included an intensive PK evaluation in various age cohorts
(Cohort 1: 12 years to <19 years; Cohort 2: 6 years to <12 years; Cohort 3: 2 years to <6 years).
Doses were selected with the aim of achieving target PK parameters that were similar to those seen in
adults: PK targets were a geometric mean (GM) AUC 0–12h of 14 µM·h to 25 µM·h and a GM 12-hour
concentration (C 12h ) >33 nM. Additional participants were then enrolled in each age cohort to
evaluate the long-term efficacy, tolerability, and safety of RAL.

A total of 126 treatment-experienced participants were enrolled, with 96 participants receiving the
final recommended dose of RAL. Only treatment-experienced patients were eligible to enroll, and the
optimized regimen was determined by the site investigators. Adolescents tended to be more treatment
experienced and have more advanced disease than those in the younger cohorts, with 75% having the
Centers for Disease Control and Prevention Category B or C classification of HIV infection. Ninety-
six participants completed 48 weeks of treatment. Seventy-nine percent of participants achieved HIV
RNA <400 copies/mL, and 57% of participants achieved HIV RNA <50 copies/mL, with a mean
CD4 T lymphocyte (CD4) count increase13 of 156 cells/mm3 (4.6%). Among 36 subjects who
experienced virologic failure, the development of drug resistance and/or poor adherence were
contributing factors. Genotypic resistance data were available for 34 patients who experienced
virologic failure, and RAL-associated mutations were detected in 12 out of 34 of those patients. The
frequency, type, and severity of AEs through Week 48 were comparable to those observed in adult
studies. AEs were commonly reported, but few serious AEs were considered to be drug related.
Patients with AEs that were considered to be drug related included one patient with Grade 3
psychomotor hyperactivity, abnormal behavior, and insomnia, as well as one patient with a Grade 2
allergic rash on Day 17 and Grade 3 ALT and Grade 4 AST laboratory elevations after Day 122.
There were no discontinuations due to AEs and no drug-related deaths.13 Overall, RAL was well
tolerated when administered as a film-coated tablet twice daily in subjects aged 6 years to <19 years
and as chewable tablets at a dose of approximately 6 mg/kg twice daily in subjects aged 2 years to
<12 years, with favorable virologic and immunologic responses.19

Children Aged ≥4 Weeks to <2 Years

IMPAACT P1066 studied 26 infants and toddlers aged 4 weeks to <2 years who were administered
the granules for RAL oral suspension in combination with an optimized background ARV regimen.
All subjects had previously received ARV drugs to prevent perinatal transmission and/or treat HIV,
and 69% had baseline plasma HIV RNA exceeding 100,000 copies/mL. PK targets for Cohort IV
(6 months to <2 years) and Cohort V (4 weeks to <6 months) were modified to a GM AUC 0–12h of
14 µM·h to 45 µM·h and a GM C 12h ≥75 nM (33.3 ng/mL). These targets were modified so that an
estimated >90% of patients would have C 12h above the 45 nM threshold. By Week 48, two subjects
experienced AEs that were thought to be related to the study drug: one patient experienced a serious
erythematous rash that resulted in permanent discontinuation of RAL, and one patient experienced
immune reconstitution inflammatory syndrome. Virologic success, defined as ≥1 log 10 decline in
HIV RNA or <400 copies/mL at 48 weeks, was achieved in >87% of participants. At 48 weeks of

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-237
follow up, 45.5% of subjects had HIV RNA <50 copies/mL and mean CD4 count increases of
527.6 cells/mm3 (7.3%). Four subjects in Cohort 4 experienced virologic failure by Week 48, and one
participant had a RAL-associated resistance mutation. Overall, the granules for oral suspension, at a
dose of approximately RAL 6 mg/kg twice daily, were well tolerated and had good efficacy.12

Long-Term Follow Up in Children

The IMPAACT P1066 study team reported results regarding the safety and efficacy of different RAL
formulations at 240 weeks in children enrolled in this multicenter trial.20 Eligible participants were
children aged 4 weeks to 18 years who had previously been treated with ART and who were
experiencing virologic failure at the time of enrollment. RAL was added to an optimized ARV
regimen in all participants. RAL was well tolerated, and few serious clinical or laboratory safety
events were noted during the study.20

The proportion of participants who achieved virologic success at 240 weeks varied by the RAL
formulation used: 19 of 43 children (44.2%) who received RAL 400-mg tablets; 24 of 31 children
(77.4%) who received chewable tablets; and 13 of 15 children (86.7%) who received the oral
granules for suspension. RAL resistance was documented in 19 of 50 patients (38%) who
experienced virologic rebound after initial suppression. These results suggest that younger children
with less treatment experience are more likely to have sustained virologic suppression, whereas older
children with an extensive treatment history are more likely to experience treatment failure and
develop resistance to RAL. Poor adherence among adolescents may have contributed to the lower
efficacy observed in older children who received the RAL 400-mg tablets.20

Neonates Aged <4 Weeks

RAL is metabolized by UGT1A1, the same enzyme that is responsible for the elimination of
bilirubin. UGT enzyme activity is low at birth, and RAL elimination is prolonged in neonates.
Washout PKs of RAL in neonates born to pregnant women with HIV were studied in IMPAACT
P1097.21 The neonatal plasma half-life of RAL was highly variable, ranging from 9.3 to 184 hours.
This suggests that neonatal development may impact UGT1A1 enzyme activity, redistribution,
and/or enterohepatic recirculation of RAL. RAL competes with unconjugated bilirubin for albumin
binding sites. When RAL plasma concentrations are extremely high, unconjugated bilirubin may be
displaced from albumin by RAL and cross the blood–brain barrier, leading to bilirubin-induced
neurologic dysfunction. The effect of RAL on neonatal bilirubin binding is unlikely to be clinically
significant, unless concentrations that are 50-fold to 100-fold higher than typical peak concentrations
are reached (approximately 5,000 ng/mL).22

IMPAACT P1110 was a Phase 1, multicenter trial that enrolled full-term neonates with or without
in utero RAL exposure at risk of acquiring HIV. RAL-exposed neonates were those whose mothers
received RAL within 2 to 24 hours of delivery. For RAL-exposed neonates, the initial dose of RAL
was delayed until 12 to 60 hours after delivery. The study design included two cohorts: Cohort 1
infants received two RAL doses that were administered 1 week apart, and Cohort 2 infants received
daily RAL doses for the first 6 weeks of life. PK data from Cohort 1 and from older infants and
children were combined in a population PK model, and simulations were used to select the following
RAL dosing regimen for evaluation in infants in Cohort 2: RAL 1.5 mg/kg daily, starting within
48 hours of life and continuing through Day 7; RAL 3 mg/kg twice daily on Days 8 to 28 of life; and
RAL 6 mg/kg twice daily after 4 weeks of age.23 Protocol exposure targets for each subject were

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-238
AUC 0–24hr 12 mg·h/L to 40 mg·h/L, AUC 0–12hr 6 mg·h/L to 20 mg·h/L, and C 12h or C 24h >33 ng/mL.
Safety was assessed using clinical and laboratory evaluations.21,24,25

Twenty-six RAL-naive infants and 10 RAL-exposed infants were enrolled in Cohort 2; 25 RAL-
naive infants and 10 RAL-exposed infants had evaluable PK results and safety data. Results for the
RAL-naive infants and RAL-exposed infants who were enrolled in Cohort 2 are contained in Table B
below.25

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-239
Table B. Raltegravir Pharmacokinetic Parameters for Raltegravir-Naive and Raltegravir-
Exposed Neonates

Initial Dose: Initial Dose: Days 15–18: Days 15–18:

RAL 1.5 mg/kg RAL 1.5 mg/kg RAL 3.0 mg/kg RAL 3.0 mg/kg
Once Daily Once Daily Twice Daily Twice Daily
PK Parameter
RAL-Naive RAL-Exposed RAL-Naive RAL-Exposed
(n = 25)d (n = 10) (n = 24)e (n = 10)f

GM (CV%) GM (CV%) GM (CV%) GM (CV%)

AUC 0–24h (mg·h/L)a 38.2 (42.0%) 42.9 (25.3%) — —
AUC 0–12h (mg·h/L) — — 14.3 (49.5%) 18.3 (62.8%)
C trough (ng/mL)b 948 (84.0%) 946 (74.0%) 176 (162.1%) 274 (176.4%)
C max (ng/mL)c 2,350 (36.5%) 2,565 (23.1%) 2,849 (47.5%) 3,667 (46.3%)
T max (hours) 5.4 (71.5%) 3.8 (88.8%) 2.3 (77.1%) 1.9 (52.3%)
T 1/2 (hours) 15.8 (101.4%) 14.4 (69.5%) 2.5 (34.1%) 2.9 (20.7%)
a AUC targets: AUC 0–24h 12–40 mg·h/L and AUC 0–12h 6–20 mg·h/L.
b C trough concentration >33 ng/mL. For initial dose, C last collected at 24 hours was used. For Days 15–18, C 12h was estimated
when the 12 hours post-dose sample was collected earlier than 12 hours after dosing (the protocol specified a sample collection
time of 8–12 hours post dose).
c C max <8,724 ng/mL
d AUC 0–24h could not be estimated for one infant.
e AUC 0–12h and C trough could not be estimated for one infant with delayed absorption.
f AUC 0–12h and C max could not be estimated for one infant with incomplete sample collection.
Key: AUC = area under the curve; AUC 0–12h = AUC from time zero to 12 hours after drug administration; AUC 0–24h = AUC from
time zero to 24 hours after drug administration; C last = last measurable plasma concentration; C max = maximum concentration;
C trough = trough concentration; CV = coefficient of variation; GM = geometric mean; PK = pharmacokinetic; RAL = raltegravir;
T 1/2 = half-life; T max = time to reach maximum concentration

Daily RAL was safe and well tolerated during the first 6 weeks of life. Infants were treated for up to
6 weeks from birth and followed for a total of 24 weeks. All GM protocol exposure targets were met.
In some infants, AUC 0–24h following the initial dose was slightly above the target range, but this is
considered acceptable given the rapid increase in RAL metabolism during the first week of life. The
PK targets and the safety guidelines were met for both RAL-naive and RAL-exposed infants in
Cohort 2 using the specified dosing regimen. No drug-related clinical AEs were observed. Three
laboratory AEs were reported among the RAL-naive infants: Grade 4 transient neutropenia occurred
in one infant who received a zidovudine-containing regimen; two bilirubin elevations (one Grade 1
and one Grade 2) were considered nonserious and did not require specific therapy.5 Among the RAL-
exposed infants, four infants exhibited Grade 3 or 4 toxicities: anemia in one infant, neutropenia in
one infant, and hyperbilirubinemia in two infants. No specific therapy was required to treat these
toxicities, and no infants required phototherapy or exchange transfusion for hyperbilirubinemia.

Results from IMPAACT P1110 confirmed the PK modeling and simulation submitted for FDA
approval and labeling. Neonates born to mothers who received RAL 2 to 24 hours prior to delivery

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-240
should have their first dose of RAL delayed until 24 to 48 hours after birth.24,25 The timing of
administration of the initial dose of RAL to infants born to patients receiving DTG- or bictegravir-
containing regimens has not been studied. In a single case report of a neonate born to a mother
receiving an intensified regimen of DTG 50 mg twice daily for viremia close to the time of delivery,
prolonged neonatal DTG concentrations were observed.26 These findings suggest that a similar delay
in the first dose of RAL until 24 to 48 hours after birth may be indicated in neonates born to patients
receiving an INSTI-containing oral regimen to avoid potential toxicity. Results of ongoing studies
IMPAACT 2023 (DTG neonatal PK and safety study) and IMPAACT 2026 (washout PK in infants
born to mothers receiving bictegravir) may provide PK data that can inform future recommendations.

The current RAL dosing regimen with two dose changes in the first month of life may be challenging
for some families. To simplify medication teaching and minimize dosing changes, some experts
increase to the 3 mg/kg twice-daily dose on Day 4 or 5 of life. Because many infants receiving RAL
as part of presumptive HIV therapy will have a longer hospital stay following birth by cesarean
section, this dosing change can generally be made at the time of hospital discharge.

RAL can be safely administered to full-term infants using the daily dosing regimen that was studied
in IMPAACT P1110. This regimen is not recommended for use in preterm infants. RAL elimination
kinetics in preterm and low-birth-weight neonates after maternal dosing was studied in IMPAACT
P1097.27 Sixteen mothers and their 18 low-birth-weight neonates (<2.5 kg) were enrolled. Median
(range) RAL elimination half-life was 24.4 hours (10.1–83) hours (n = 17). A PK model
incorporating slower clearance in preterm neonates demonstrated that a reduction in RAL dosing is
required in this population.27

Two case reports of preterm infants who received RAL to prevent perinatal transmission have been
published.28,29 These case reports involved one infant born at a gestational age of 24 weeks and
6 days who weighed 800 g and another infant born at 33 weeks gestation who weighed 1,910 g. In
both infants, intermittent dosing of RAL was done using real-time therapeutic drug monitoring in the
neonatal intensive care unit.28,29 Less-frequent dosing was required because RAL elimination was
significantly delayed in these preterm infants. RAL PKs and safety must be studied in preterm infants
before RAL can be safely used without real-time PK monitoring in this population.

Formulations
The PKs of RAL in adult patients with HIV who swallowed intact 400-mg tablets were compared
with those observed in patients who chewed the 400-mg, film-coated tablets because of swallowing
difficulties. Drug absorption was significantly higher among patients who chewed the tablets,
although the palatability was rated as poor.30 In adult volunteers, the PKs of RAL 800 mg taken once
daily by chewing was compared with the PKs of two doses of RAL 400 mg taken every 12 hours by
swallowing. Participants who took RAL by chewing had significantly higher drug exposure and
reduced PK variability than those who swallowed whole tablets according to current
recommendations.31 According to the manufacturer, the film-coated tablets must be swallowed
whole.

The RAL chewable tablet and oral suspension have higher oral bioavailability than the 400-mg, film-
coated tablet, according to a comparative study in healthy adult volunteers.32 Compared with the
RAL 400-mg tablet formulation, the RAL 600-mg tablet has higher relative bioavailability.5,33
Interpatient and intrapatient variability for PK parameters of RAL are considerable, especially with
the film-coated tablets.5,34 Because of differences in the bioavailability of various formulations, the

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-241
dosing recommendations for each formulation differ, and the formulations are not interchangeable.
When prescribing RAL, clinicians should refer to the appropriate dosing table for the chosen
formulation. The use of RAL chewable tablets as dispersible tablets in children aged <2 years has
been studied in IMPAACT P1101 for infants and toddlers with TB/HIV coinfection who received
rifampin as part of their TB treatment. The use of RAL chewable tablets dispersed in water at a dose
of RAL 12 mg/kg per dose twice daily safely achieved PK targets.2,35 The RAL chewable tablets are
now approved for use in infants and young children 4 weeks of age and older and weighing at least
2 kg.36 An in vitro evaluation demonstrated that the chewable tablets are stable in various liquids,
including water, apple juice, and breast milk.36 The chewable tablets may be crushed and mixed with
a small amount of liquid to facilitate administration (see Special Instructions above).

Palatability was evaluated as part of IMPAACT P1066. Both chewable tablets and oral granules for
suspension were thought to have acceptable palatability. Seventy-three percent of those surveyed
reported no problems with chewable tablets; 82.6% reported no problems with administering the oral
granules.12,13 The acceptability and feasibility of administering RAL granules for oral suspension in a
low-resource setting has been studied in clinics in South Africa and Zimbabwe. With proper training
by health care personnel, caregivers were able to prepare the suspension safely and accurately.37,38

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-242
References
1. Mills A, Myers L, Raudenbush C, et al. A health literate patient-focused approach to the
redesign of the raltegravir (ISENTRESS) pediatric kit and instructions for use. Pediatr Infect
Dis J. 2022;41(1):51-56. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34694252.
2. Meyers T, Samson P, Acosta EP, et al. Pharmacokinetics and safety of a raltegravir-
containing regimen in HIV-infected children aged 2–12 years on rifampicin for tuberculosis.
AIDS. 2019;33(14):2197-2203. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31689263.
3. Krogstad P, Samson P, Acosta EP, et al. Pharmacokinetics and safety of a raltegravir-
containing regimen in children aged 4 weeks to 2 years living with human immunodeficiency
virus and receiving rifampin for tuberculosis. J Pediatric Infect Dis Soc. 2021;10(2):201-204.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/32448902.
4. van der Veer MA, Jacobs TG, Bukkems LH, et al. Pharmacokinetic interaction between
raltegravir and rifampicin in an infant with HIV exposed to active TB: a case report. Antivir
Ther. 2022;27(4):13596535221119932. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/36062614.
5. Raltegravir (Isentress ) [package insert]. Food and Drug Administration. 2020. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022145s042,203045s016,20578
6s008lblrpl.pdf.
6. Lennox JL, DeJesus E, Lazzarin A, et al. Safety and efficacy of raltegravir-based versus
efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a
multicentre, double-blind randomised controlled trial. Lancet. 2009;374(9692):796-806.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19647866.
7. DeJesus E, Rockstroh JK, Lennox JL, et al. Efficacy of raltegravir versus efavirenz when
combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected patients: week-192
overall and subgroup analyses from STARTMRK. HIV Clin Trials. 2012;13(4):228-232.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/22849964.
8. Rockstroh JK, DeJesus E, Lennox JL, et al. Durable efficacy and safety of raltegravir versus
efavirenz when combined with tenofovir/emtricitabine in treatment-naive HIV-1-infected
patients: final 5-year results from STARTMRK. J Acquir Immune Defic Syndr.
2013;63(1):77-85. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23412015.
9. Raffi F, Jaeger H, Quiros-Roldan E, et al. Once-daily dolutegravir versus twice-daily
raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week
results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis.
2013;13(11):927-935. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24074642.
10. Lennox JL, Landovitz RJ, Ribaudo HJ, et al. Efficacy and tolerability of 3 nonnucleoside
reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers
infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med.
2014;161(7):461-471. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25285539.
11. Briz V, Leon-Leal JA, Palladino C, et al. Potent and sustained antiviral response of
raltegravir-based highly active antiretroviral therapy in HIV type 1-infected children and
adolescents. Pediatr Infect Dis J. 2012;31(3):273-277. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22330165.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-243
 12. Nachman S, Alvero C, Acosta EP, et al. Pharmacokinetics and 48-week safety and efficacy
of raltegravir for oral suspension in human immunodeficiency virus type-1-infected children
4 weeks to 2 years of age. J Pediatric Infect Dis Soc. 2015;4(4):e76-83. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26582887.
13. Nachman S, Zheng N, Acosta EP, et al. Pharmacokinetics, safety, and 48-week efficacy of
oral raltegravir in HIV-1-infected children aged 2 through 18 years. Clin Infect Dis.
2014;58(3):413-422. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24145879.
14. Rizk ML, Hang Y, Luo WL, et al. Pharmacokinetics and pharmacodynamics of once-daily
versus twice-daily raltegravir in treatment-naive HIV-infected patients. Antimicrob Agents
Chemother. 2012;56(6):3101-3106. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22430964.
15. Rizk ML, Du L, Bennetto-Hood C, et al. Population pharmacokinetic analysis of raltegravir
pediatric formulations in HIV-infected children 4 weeks to 18 years of age. J Clin
Pharmacol. 2015;55(7):748-756. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25753401.
16. Cahn P, Sax PE, Squires K, et al. Raltegravir 1200 mg once daily vs 400 mg twice daily, with
emtricitabine and tenofovir disoproxil fumarate, for previously untreated HIV-1 infection:
week 96 results from ONCEMRK, a randomized, double-blind, noninferiority trial. J Acquir
Immune Defic Syndr. 2018;78(5):589-598. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29771789.
17. Food and Drug Administration. Raltegravir clinical pharmacology review. 2017. Available
at:
https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResource
s/UCM562849.pdf.
18. Larson KB, King JR, Acosta EP. Raltegravir for HIV-1 infected children and adolescents:
efficacy, safety, and pharmacokinetics. Adolesc Health Med Ther. 2013;4:79-87. Available
at: https://www.ncbi.nlm.nih.gov/pubmed/24600298.
19. Tuluc F, Spitsin S, Tustin NB, et al. Decreased PD-1 expression on CD8 lymphocyte subsets
and increase in CD8 Tscm cells in children with HIV receiving raltegravir. AIDS Res Hum
Retroviruses. 2016;33:133-142. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/27615375.
20. Nachman S, Alvero C, Teppler H, et al. Safety and efficacy at 240 weeks of different
raltegravir formulations in children with HIV-1: a phase 1/2 open label, non-randomised,
multicentre trial. Lancet HIV. 2018;5(12):e715-e722. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30527329.
21. Clarke DF, Acosta EP, Rizk ML, et al. Raltegravir pharmacokinetics in neonates following
maternal dosing. J Acquir Immune Defic Syndr. 2014;67(3):310-315. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25162819.
22. Clarke DF, Wong RJ, Wenning L, Stevenson DK, Mirochnick M. Raltegravir in vitro effect
on bilirubin binding. Pediatr Infect Dis J. 2013;32(9):978-980. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23470680.
23. Clarke DF, Mirochnick M, Acosta EP, et al. Use of modeling and simulations to determine
raltegravir dosing in neonates: a model for safely and efficiently determining appropriate

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-244
 neonatal dosing regimens: IMPAACT P1110. J Acquir Immune Defic Syndr. 2019;82(4):392-
398. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31658182.
24. Lommerse J, Clarke D, Kerbusch T, et al. Maternal-neonatal raltegravir population
pharmacokinetics modeling: implications for initial neonatal dosing. CPT Pharmacometrics
Syst Pharmacol. 2019;8(9):643-653. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31215170.
25. Clarke DF, Acosta EP, Cababasay M, et al. Raltegravir (RAL) in neonates: dosing,
pharmacokinetics (PK), and safety in HIV-1-exposed neonates at risk of infection
(IMPAACT P1110). J Acquir Immune Defic Syndr. 2020;84(1):70-77. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31913995.
26. Jacobs TG, Schouwenburg S, Penazzato M, et al. What babies need: accelerating access to
current and novel antiretroviral drugs in neonates through pharmacokinetic studies. Lancet
HIV. 2022;9(9):e649-e657. Available at: https://www.ncbi.nlm.nih.gov/pubmed/35863363.
27. Clarke DF, Lommerse J, Acosta EP, et al. Impact of low birth weight and prematurity on
neonatal raltegravir pharmacokinetics: IMPAACT P1097. J Acquir Immune Defic Syndr.
2020;85:626-634. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32925360.
28. Trahan MJ, Lamarre V, Metras ME, Kakkar F. Use of triple combination antiretroviral
therapy with raltegravir as empiric HIV therapy in the high-risk HIV-exposed newborn.
Pediatr Infect Dis J. 2018;38(4):410-412. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30882734.
29. Kreutzwiser D, Sheehan N, Dayneka N, et al. Therapeutic drug monitoring guided raltegravir
dosing for prevention of vertical transmission in a premature neonate born to a woman living
with perinatally acquired HIV. Antivir Ther. 2017;22(6):545-549. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/28198351.
30. Cattaneo D, Baldelli S, Cerea M, et al. Comparison of the in vivo pharmacokinetics and in
vitro dissolution of raltegravir in HIV patients receiving the drug by swallowing or by
chewing. Antimicrob Agents Chemother. 2012;56(12):6132-6136. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22964253.
31. Cattaneo D, Cossu MV, Fucile S, et al. Comparison of the pharmacokinetics of raltegravir
given at 2 doses of 400 mg by swallowing versus one dose of 800 mg by chewing in healthy
volunteers: a randomized, open-label, 2-period, single-dose, crossover phase 1 study. Ther
Drug Monit. 2015;37(1):119-125. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24988438.
32. Brainard D, Gendrano N, Jin B, et al. A pharmacokinetic comparison of adult and pediatric
formulations of RAL in healthy adults. Presented at: Conference on Retroviruses and
Opportunistic Infections (CROI); 2010. San Francisco, CA.
33. Krishna R, Rizk ML, Larson P, Schulz V, Kesisoglou F, Pop R. Single- and multiple-dose
pharmacokinetics of once-daily formulations of raltegravir. Clin Pharmacol Drug Dev.
2018;7(2):196-206. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28419778.
34. Siccardi M, D’Avolio A, Rodriguez-Novoa S, et al. Intrapatient and interpatient
pharmacokinetic variability of raltegravir in the clinical setting. Ther Drug Monit.
2012;34(2):232-235. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22406652.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-245
 35. Krogstad P, Samson P, Acosta E, et al. Pharmacokinetics of raltegravir in HIV/TB cotreated
infants and young children. Presented at: Conference on Retroviruses and Opportunistic
Infections 2020. Boston, MA.
36. Teppler H, Thompson K, Chain A, Mathe M, Nachman S, Clarke D. Crushing of raltegravir
(RAL) chewable tablets for adminstration in infants and young children. Presented at:
International Workshop on HIV Pediatrics; 2017. Paris, France.
37. Archary M, Zanoni BC, Lallemant M, Suwannaprom P, Clarke D, Penazzato M.
Acceptability and feasibility of using raltegravir oral granules for suspension for the
treatment of neonates in a low resource setting. Pediatr Infect Dis J. 2020;39(1):57-60.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31815839.
38. Katirayi L, Stecker C, Andifasi P, et al. Optimising neonatal antiretroviral therapy using
raltegravir: a qualitative analysis of healthcare workers’ and caregivers’ perspectives. BMJ
Paediatr Open. 2022;6(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/36053612.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-246
Appendix A: Pediatric Antiretroviral Drug Information
Pharmacokinetic Enhancers
Cobicistat (COBI, Tybost)

Ritonavir (RTV, Norvir)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-247
 Cobicistat (COBI, Tybost)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Tablet: 150 mg

Fixed-Dose Combination (FDC) Tablets

• [Evotaz] Atazanavir 300 mg/cobicistat 150 mg
• [Genvoya] Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg
• [Prezcobix] Darunavir 800 mg/cobicistat 150 mg
• [Stribild] Elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg
• [Symtuza] Darunavir 800 mg/cobicistat 150 mg/emtricitabine 200 mg/ tenofovir alafenamide 10 mg

When using FDC tablets, refer to other sections of Appendix A: Pediatric Antiretroviral Drug Information for information about
the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets:
Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Cobicistat Is a Pharmacokinetic Enhancer • COBI is an inhibitor of renal tubular transporters of
creatinine. This increases serum creatinine and reduces
• The only use of cobicistat (COBI) is as a
the estimated glomerular filtration rate, with no change in
pharmacokinetic (PK) enhancer (boosting agent) for
glomerular function.
certain protease inhibitors (PIs) and integrase strand
transfer inhibitors. COBI is not interchangeable with
ritonavir (RTV) and has no antiviral activity. Special Instructions
• COBI 150 mg is not interchangeable with RTV, but it has
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
a PK boosting effect that is comparable to RTV 100 mg.
• COBI 150 mg with atazanavir (ATV) 300 mg administered
• Drug interactions may differ between RTV and COBI,
at the same time with food
because COBI is a stronger P-glycoprotein inhibitor and
Child and Adolescent (Weighing ≥40 kg) and Adult Dose lacks some of the induction effects of RTV.

• COBI 150 mg with darunavir (DRV) 800 mg administered • Do not administer COBI with RTV or with FDC tablets
at the same time with food that contain COBI.
• COBI is not recommended for use with more than one
[Evotaz] Atazanavir/Cobicistat ARV drug that requires PK enhancement (e.g., elvitegravir
Child and Adolescent (Weighing ≥35 kg) and Adult Dose used in combination with a PI).

• One tablet once daily with food • Using COBI with PIs other than once-daily ATV 300 mg or
DRV 800 mg is not recommended.
• Use in combination with other antiretroviral (ARV) drugs.
• Patients with a confirmed increase in serum creatinine
>0.4 mg/dL from baseline should be closely monitored for
renal safety.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-248
 [Genvoya] Elvitegravir/Cobicistat/Emtricitabine (FTC)/ • When using COBI in combination with TDF, monitor serum
Tenofovir Alafenamide (TAF) creatinine, urine protein, and urine glucose at baseline and
every 3 to 6 months while the patient is receiving therapy
Child (Weighing ≥14 to <25 kg)
(see Table 17i. Nephrotoxic Effects). In patients who are at
• Limited data currently exist on the appropriate dose of risk of renal impairment, serum phosphate also should be
Genvoya in children ≥14 kg to <25 kg. Studies are monitored.
currently being conducted to assess the safety and
• For information on crushing and cutting tablets, see
efficacy of a low-dose tablet with elvitegravir (EVG)
Information on Crushing and Liquid Drug Formulations
90 mg/COBI 90 mg/FTC 120 mg/TAF 6 mg.
(PDF) from Toronto General Hospital.
Child and Adolescent (Weighing ≥25 kg) and Adult Dose
Metabolism/Elimination
• One tablet once daily with food
• COBI is a strong inhibitor of cytochrome P450 (CYP) 3A4
[Prezcobix] Darunavir/Cobicistat and a weak inhibitor of CYP2D6.
Child and Adolescent (Weighing ≥40 kg) and Adult Dose Cobicistat Dosing in Patients With Hepatic Impairment
• One tablet once daily with food • COBI does not require dose adjustment in patients with
• Use in combination with other ARV drugs. mild-to-moderate hepatic impairment. No data are
available in patients with severe hepatic impairment.
[Stribild] Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Dosing recommendations for medications that are
Disoproxil Fumarate (TDF) coadministered with COBI should be followed.1
Child and Adolescent (Weighing ≥35 kg) and Adult Dose • Genvoya, Prezcobix, Stribild, and Symtuza are not
recommended in patients with severe hepatic
• One tablet once daily with food
impairment.1
• The Panel on Antiretroviral Therapy and Medical
• Evotaz is not recommended in patients with any degree
Management of Children Living With HIV recommends
of hepatic impairment.
using Stribild only in patients with sexual maturity ratings of
4 or 5. Cobicistat Dosing in Patients With Renal Impairment
[Symtuza] Darunavir/Cobicistat/Emtricitabine/TAF • COBI does not require a dose adjustment in patients with
renal impairment, including those with severe renal
Child and Adolescent (Weighing ≥40 kg) and Adult Dose
impairment. Dosing recommendations for medications that
• One tablet once daily with food are coadministered with COBI should be followed.
• The use of COBI plus TDF is not recommended in
patients with creatinine clearance (CrCl) <70 mL/min.
Dose adjustments for TDF are required for patients with
CrCl <50 mL/min, and the necessary dose adjustments for
TDF when this drug is used with COBI have not been
established in this group of patients.
• Genvoya2 is not recommended in patients with estimated
CrCl 15 to <30 mL/min, or in patients with estimated CrCl
<15 mL/min who are not receiving chronic hemodialysis.
• Stribild3 should not be initiated in patients with estimated
CrCl <70 mL/min and should be discontinued in patients
with estimated CrCl <50 mL/min. The dose adjustments
required for emtricitabine and TDF in these patients
cannot be achieved with an FDC tablet.
• Symtuza4 is not recommended in patients with estimated
CrCl <30 mL/min.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-249
 Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Metabolism of cobicistat (COBI) is mainly via cytochrome P450 (CYP) 3A4 and, to
a lesser degree, CYP2D6. COBI is a strong inhibitor of CYP3A4 and a weak inhibitor of
CYP2D6. COBI also inhibits breast cancer resistance protein, P-glycoprotein (P-gp), the organic
anion transporting polypeptides OATP1B1 and OATP1B3, and multidrug and toxin extrusion 1.
Unlike ritonavir, COBI does not demonstrate any enzyme-inducing effects. The potential exists
for multiple drug interactions when using COBI. Before COBI is administered, a patient’s
medication profile should be carefully reviewed for potential interactions and overlapping
toxicities with other drugs. Coadministration of medications that induce or inhibit CYP3A4 may
respectively decrease or increase exposures of COBI and coformulated antiretroviral
medications. Coadministration of medications that are CYP3A4 substrates may result in
clinically significant adverse reactions that are severe, life-threatening, or fatal, or may result in
loss of therapeutic effect if dependent on conversion to an active metabolite due to CYP3A4
inhibition by COBI.1
• Nucleoside reverse transcriptase inhibitors: COBI is a strong P-gp inhibitor; thus, a dose of
tenofovir alafenamide (TAF) 10 mg combined with COBI produces tenofovir (TFV) exposures
that are similar to those produced by TAF 25 mg without COBI.5 COBI increases plasma TFV
exposures by 23% when it is coadministered with TDF; thus, renal safety should be monitored in
patients who are receiving this combination.1,6
• Non-nucleoside reverse transcriptase inhibitors: Efavirenz, etravirine, and nevirapine should not
be used with COBI.
• Protease inhibitors: Using COBI as a dual booster for elvitegravir (EVG) and darunavir (DRV)
has been studied in people with and without HIV, and the evidence is conflicting. When EVG
plus COBI plus DRV was administered to people without HIV, the trough concentration (C trough )
of EVG was 50% lower than the C trough seen in people who received
elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/c/FTC/TDF) without
DRV.7 When EVG/c/FTC/TAF was administered with DRV to patients with HIV, both DRV and
EVG concentrations were comparable to those seen in historic controls.8
• Integrase inhibitors: In one small study, dolutegravir (DTG) C trough was 107% higher when DTG
was administered with darunavir/cobicistat (DRV/c) than when it was administered with
darunavir/ritonavir.9 Bictegravir (BIC) area under the curve increases 74% when BIC is
administered with DRV/c.10
• Corticosteroids: Increased serum concentrations of corticosteroids can occur when
corticosteroids and COBI are coadministered; this can lead to clinically significant adrenal
suppression. Adrenal suppression occurs regardless of whether the corticosteroids are
administered orally or by some other route (e.g., intranasal, inhaled, interlaminar, intraarticular)
and regardless of whether the corticosteroids are administered routinely or intermittently. A
possible exception is beclomethasone, which appears to be a relatively safe option with inhaled
or intranasal administration.11,12

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-250
 Major Toxicities
• More common: Nausea, vomiting, diarrhea, abdominal pain, anorexia
• Less common (more severe): New onset renal impairment or worsening of renal impairment when
used with TAF or TDF; rhabdomyolysis; increased amylase and lipase levels.

Resistance
Not applicable because COBI has no antiviral activity.

Pediatric Use
Approval
COBI is a pharmacokinetic (PK) enhancer of antiretroviral drugs that is available as a single agent or
a component of fixed-dose combination products. COBI, as a component of Stribild, is approved by
the U.S. Food and Drug Administration (FDA) at the adult dose for use in children and adolescents
aged ≥12 years and weighing ≥35 kg.3 The Panel on Antiretroviral Therapy and Medical
Management of Children Living With HIV recommends limiting the use of Stribild to those with a
sexual maturity rating of 4 or 5. COBI, as a component of Genvoya, is approved by the FDA at the
adult dose for use in children weighing ≥25 kg.2 The FDA has not approved COBI as a component of
Genvoya for use in children <25 kg, but an ongoing PK, safety, and efficacy study is underway with
a low-dose tablet in children weighing ≥14 kg to <25 kg (see the Elvitegravir section). COBI alone
(as Tybost) is approved by the FDA at the adult dose for use in children weighing ≥35 kg when used
in combination with ATV, and in children weighing ≥40 kg when used in combination with DRV.1
COBI, coformulated with ATV (as Evotaz),13 is approved by the FDA at the adult dose for use in
children and adolescents weighing ≥35 kg. COBI, coformulated with DRV (as Prezcobix)14 and as a
component of Symtuza,4 is approved by the FDA at the adult dose in children and adolescents
weighing ≥40 kg.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-251
 References

1. Cobicistat (Tybost) [package insert]. Food and Drug Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203094s016lbl.pdf.

2. Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide) [package insert].

Food and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/207561s029lbl.pdf.

3. Stribild (elvitegravir, cobicitstat, emtricitabine, tenofovir disaproxil fumarate) [package

insert]. Food and Drug Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203100s036lblet.pdf.

4. Symtuza (Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide) [package

insert]. Food and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210455s022lbl.pdf.

5. Ramanathan S, Wei X, Custudio J, et al. Pharmacokinetics of a novel

EVG/COBI/FTC/GS-7340 single tablet regimen. Abstract O-13. Presented at: 13th
International Workshop on Clinical Pharmacology of HIV Therapy; 2012. Barcelona,
Spain. Available at: https://www.natap.org/2012/pharm/Pharm_24.htm.

6. Custodio J, Garner W, Jin F, et al. Evaluation of the drug interaction potential between
the pharmacokinetic enhancer and tenofovir disoproxil fumarate in healthy subjects.
Presented at: 14th International Workshop on Clinical Pharmacology of HIV Therapy;
2013. Amsterdam, The Netherlands.

7. Ramanathan S, Wang H, Szwarcberg J, Kearney BP. Safety/tolerability,

pharmacokinetics, and boosting of twice-daily cobicistat administered alone or in
combination with darunavir or tipranavir. Abstract abstract P-08. Presented at: 13th
International Workshop on Clinical Pharmacology of HIV Therapy; 2012. Barcelona,
Spain. Available at: https://www.natap.org/2012/pharm/Pharm_28.htm.

8. Gutierrez-Valencia A, Trujillo-Rodriguez M, Fernandez-Magdaleno T, Espinosa N,

Viciana P, Lopez-Cortes LF. Darunavir/cobicistat showing similar effectiveness as
darunavir/ritonavir monotherapy despite lower trough concentrations. J Int AIDS Soc.
2018;21(2). Available at: https://www.ncbi.nlm.nih.gov/pubmed/29430854.

9. Gervasoni C, Riva A, Cozzi V, et al. Effects of ritonavir and cobicistat on dolutegravir

exposure: when the booster can make the difference. J Antimicrob Chemother.
2017;72(6):1842-1844. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28333266.

10. Zhang H, Custudio J, Wei X, et al. Clinical pharmacology of the HIV integrase strand
transfer inhibitor bictegravir. Abstract 40. Presented at: Conference on Retrovirsues and
Opportunistic Infections; 2017. Seattle, WA. Available at:
https://www.croiconference.org/sessions/clinical-pharmacology-hiv-integrase-strand-
transfer-inhibitor-bictegravir.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-252
 11. Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in HIV-positive
individuals taking protease inhibitors: a review of pharmacokinetics, case reports and
clinical management. HIV Med. 2013;14(9):519-529. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23590676.

12. Boyd SD, Hadigan C, McManus M, et al. Influence of low-dose ritonavir with and
without darunavir on the pharmacokinetics and pharmacodynamics of inhaled
beclomethasone. J Acquir Immune Defic Syndr. 2013;63(3):355-361. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23535292.

13. Evotaz (atazanavir/cobicistat ) [package insert]. Food and Drug Administration. 2020.
Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/206353s007lbl.pdf.

14. Prezcobix (darunavir/cobicistat) [package insert]. Food and Drug Administration. 2022.
Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/205395s024lbl.pdf.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-253
Ritonavir (RTV, Norvir)
Updated: April 11, 2023
Reviewed: April 11, 2023

Formulations
Oral Powder: 100 mg per packet

Oral Solution: 80 mg/mL. Oral solution contains 43% (v/v) ethanol and approximately 27% (w/v) propylene glycol.

Tablets: 100 mg

Generic Formulation
• 100-mg tablets

Fixed-Dose Combination (FDC) Solution

• [Kaletra] Lopinavir 80 mg/ritonavir 20 mg/mL. Oral solution contains 42.4% (v/v) ethanol and 15.3% (w/v) propylene glycol.

FDC Tablets
• [Kaletra] Lopinavir 100 mg/ritonavir 25 mg
• [Kaletra] Lopinavir 200 mg/ritonavir 50 mg

When using FDC tablets or solution, refer to other sections of Appendix A: Pediatric Antiretroviral Drug Information for
information about the individual components of the FDC. See also Appendix A, Table 2. Antiretroviral Fixed-Dose
Combination Tablets: Minimum Body Weights and Considerations for Use in Children and Adolescents.

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Ritonavir as a Pharmacokinetic Enhancer • Gastrointestinal (GI) intolerance, nausea, vomiting,
diarrhea
• Ritonavir (RTV) is used as a pharmacokinetic (PK) enhancer of
other protease inhibitors (PIs). The recommended dose of RTV • Hyperlipidemia, especially hypertriglyceridemia
varies and is specific to the drug combination selected. See other
sections of Appendix A: Pediatric Antiretroviral Drug Information • Hepatitis
for information about the recommended doses of RTV to use with • Hyperglycemia
specific PIs. RTV has antiviral activity, but it is not used as an
antiviral agent; instead, it is used as a PK enhancer of other PIs. • Fat maldistribution

Formulation Considerations
Special Instructions
• The RTV oral solution contains propylene glycol and ethanol.
• Administer RTV with food to increase absorption
• The oral powder is preferred over the oral solution for children and reduce the likelihood and severity of GI
who cannot swallow the tablets and who need a dose of at least adverse events.
RTV 100 mg because the oral powder does not contain
• Do not administer RTV with cobicistat (COBI) or
propylene glycol or ethanol.
drugs that contain COBI (e.g., Stribild, Genvoya,
• RTV oral powder should be used only for dosing increments of Prezcobix, Evotaz).
100 mg and cannot be used for doses <100 mg.
• Do not refrigerate RTV oral solution; store at 68°F
to 77°F (20°C to 25°C). Shake the solution well
before use.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-254
 [Kaletra] Lopinavir/Ritonavir • RTV oral powder should be mixed with a soft
food (e.g., applesauce, vanilla pudding) or a liquid
Infant, Child, Adolescent, and Adult Dose
(e.g., water, chocolate milk, infant formula) to help
• See the Lopinavir/Ritonavir section of Appendix A: Pediatric mitigate the bitter taste. Administer or discard the
Antiretroviral Drug Information for information. mixture within 2 hours of mixing.

To Increase Tolerability of Ritonavir Oral Solution

or Oral Powder in Children
• Mix the solution or powder with milk, chocolate
milk, ice cream, or vanilla or chocolate pudding.
• Before administering RTV, give a child ice chips, a
Popsicle, or spoonfuls of partially frozen orange or
grape juice concentrate to dull the taste buds.
Another option is to give a nonallergic child peanut
butter or hazelnut chocolate spread to coat the
mouth.1
• After administration, give foods with strong tastes
(e.g., maple syrup, cheese).
• Check a child’s food allergy history before making
these recommendations.
• Counsel caregivers or patients that the bad taste
will not be completely masked.

Metabolism/Elimination
• Cytochrome P450 (CYP) 3A and CYP2D6 inhibitor;
CYP1A2, CYP2B6, CYP2C9, CYP2C19, and
glucuronidation inducer. RTV inhibits the intestinal
transporter P-glycoprotein.

Ritonavir Dosing in Patients With Hepatic

Impairment
• RTV is primarily metabolized by the liver.
• No dose adjustment is necessary in patients with
mild or moderate hepatic impairment.
• No data exist on RTV dosing for adult or pediatric
patients with severe hepatic impairment. Use
caution when administering RTV to patients with
moderate-to-severe hepatic impairment.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• Metabolism: Ritonavir (RTV) is extensively metabolized by (and is one of the most potent
inhibitors of) hepatic cytochrome P450 (CYP) 3A. Also, RTV is a CYP2D6 inhibitor and a
CYP1A2, CYP2B6, CYP2C9, CYP2C19, and glucuronidation inducer. RTV inhibits the
intestinal transporter P-glycoprotein. There is potential for multiple drug interactions with RTV.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-255
• Before RTV is administered, a patient’s medication profile should be reviewed carefully for
potential interactions with RTV and overlapping toxicities with other drugs.
• RTV and cobicistat are not interchangeable. The potential drug interactions for these drugs are
different.2
• Avoid concomitant use of corticosteroids, including intranasal or inhaled fluticasone or inhaled
budesonide. Reduced elimination of steroids can increase steroid effects, leading to adrenal
insufficiency.3,4 Use caution when prescribing RTV with other inhaled steroids. Limited data
suggest that beclomethasone may be a suitable alternative to fluticasone when a patient who is
taking RTV requires an inhaled or intranasal corticosteroid.5,6 Iatrogenic Cushing’s syndrome
and suppression of the hypothalamic-pituitary axis secondary to the drug interaction between
RTV and local injection of triamcinolone has occurred.7,8 See Drug Interactions Between
Protease Inhibitors and Other Drugs in the Adult and Adolescent Antiretroviral Guidelines for
additional information.

Major Toxicities
• More common: Nausea, vomiting, diarrhea, headache, abdominal pain, anorexia, circumoral
paresthesia, abnormal lipid levels
• Less common (more severe): Exacerbation of chronic liver disease, fat maldistribution
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting
diabetes mellitus, spontaneous bleeding in hemophiliacs, pancreatitis. Cases of hepatitis,
including life-threatening cases, have been reported. Allergic reactions, including bronchospasm,
urticaria, and angioedema have occurred. Toxic epidermal necrolysis and Stevens-Johnson
syndrome have occurred.9

Resistance
Resistance to RTV is not clinically relevant when the drug is used as a pharmacokinetic (PK)
enhancer of other antiretroviral (ARV) medications.

Pediatric Use
Approval
RTV has been approved by the U.S. Food and Drug Administration for use in the pediatric
population.

Effectiveness in Practice
Use of RTV as the sole protease inhibitor (PI) in ARV therapy in children is not recommended. In
both children and adults, RTV is recommended as a PK enhancer for use with other PIs. RTV is a
CYP3A inhibitor and functions as a PK enhancer by slowing the metabolism of the PI.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-256
Dosing
Dosing regimens for RTV-boosted darunavir and atazanavir and coformulated
lopinavir/ritonavir (LPV/r) are available for pediatric patients. For more information about individual
PIs, see other sections of Appendix A: Pediatric Antiretroviral Drug Information.

Toxicity
Full-dose RTV has been shown to prolong the PR interval in a study of healthy adults who were
given RTV 400 mg twice daily.9 Potentially life-threatening arrhythmias have been reported in
premature infants who were treated with LPV/r; therefore, the use of LPV/r is generally not
recommended before a gestational age of 42 weeks (see Lopinavir/Ritonavir).10,11 Coadministration
of RTV with other drugs that prolong the PR interval (e.g., macrolides, quinolones, methadone)
should be undertaken with caution because it is unknown how coadministering any of these drugs
with RTV will affect the PR interval. In addition, RTV should be used with caution in patients who
may be at increased risk of developing cardiac conduction abnormalities, such as patients who have
underlying structural heart disease, conduction system abnormalities, ischemic heart disease, or
cardiomyopathy.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-257
References

1. Morris JB, Tisi DA, Tan DCT, Worthington JH. Development and palatability
assessment of norvir (ritonavir) 100 mg powder for pediatric population. Int J Mol Sci.
2019;20(7):1718. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30959935.

2. Marzolini C, Gibbons S, Khoo S, Back D. Cobicistat versus ritonavir boosting and

differences in the drug-drug interaction profiles with co-medications. J Antimicrob
Chemother. 2016;71(7):1755-1758. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26945713.

3. Bernecker C, West TB, Mansmann G, Scherbaum WA, Willenberg HS. Hypercortisolism

caused by ritonavir associated inhibition of CYP 3A4 under inhalative glucocorticoid
therapy. 2 case reports and a review of the literature. Exp Clin Endocrinol Diabetes.
2012;120(3):125-127. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22328106.

4. Peyro-Saint-Paul L, Besnier P, Demessine L, et al. Cushing’s syndrome due to interaction

between ritonavir or cobicistat and corticosteroids: a case-control study in the French
Pharmacovigilance Database. J Antimicrob Chemother. 2019;74(11):3291-3294.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/31369085.

5. Boyd SD, Hadigan C, McManus M, et al. Influence of low-dose ritonavir with and
without darunavir on the pharmacokinetics and pharmacodynamics of inhaled
beclomethasone. J Acquir Immune Defic Syndr. 2013;63(3):355-361. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23535292.

6. Saberi P, Phengrasamy T, Nguyen DP. Inhaled corticosteroid use in HIV-positive

individuals taking protease inhibitors: a review of pharmacokinetics, case reports and
clinical management. HIV Med. 2013;14(9):519-529. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23590676.

7. Dubrocq G, Estrada A, Kelly S, Rakhmanina N. Acute development of cushing syndrome

in an HIV-infected child on atazanavir/ritonavir based antiretroviral therapy. Endocrinol
Diabetes Metab Case Rep. 2017;2017:17-0076. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29118985.

8. Noe S, Jaeger H, Heldwein S. Adrenal insufficiency due to ritonavir-triamcinolone drug-

drug interaction without preceding Cushing’s syndrome. Int J STD AIDS.
2018;29(11):1136-1139. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29749880.

9. Changes to Norvir labeling. AIDS Patient Care STDS. 2008;22(10):834-835. Available

at: https://www.ncbi.nlm.nih.gov/pubmed/18924248.

10. Lopriore E, Rozendaal L, Gelinck LB, Bokenkamp R, Boelen CC, Walther FJ. Twins
with cardiomyopathy and complete heart block born to an HIV-infected mother treated
with HAART. AIDS. 2007;21(18):2564-2565. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18025905.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-258
11. McArthur MA, Kalu SU, Foulks AR, Aly AM, Jain SK, Patel JA. Twin preterm neonates
with cardiac toxicity related to lopinavir/ritonavir therapy. Pediatr Infect Dis J.
2009;28(12):1127-1129. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19820426.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-259
Appendix A: Pediatric Antiretroviral Drug Information
Fixed-Dose Combinations
Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or as a
Co-packaged Formulation, by Drug Class

Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged

Formulations: Minimum Body Weights and Considerations for Use in Children and Adolescents

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-260
Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or as a Co-packaged Formulation,
by Drug Class
Updated: April 11, 2023
Reviewed: April 11, 2023

PK
NRTIs NNRTIs INSTIs PIs
Brand Enhancers
Name
ABC 3TC ZDV FTC TDF TAFa DOR EFV RPV b BICa CABb DTG EVGa ATV DRV LPVc COBI RTV
NRTI
Cimduo X X
Combivir X X
Descovy X X
Epzicom X X
Temixys X X
Truvada X X

NRTI/NNRTI
Atripla X X X
Complera X X X
Delstrigo X X X
Odefsey X X X
Symfi or X X X
Symfi Lo

NRTI/INSTI
Biktarvy X X X
Dovato X X

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-261
 PK
NRTIs NNRTIs INSTIs PIs
Brand Enhancers
Name
ABC 3TC ZDV FTC TDF TAFa DOR EFV RPV b BICa CABb DTG EVGa ATV DRV LPVc COBI RTV
Triumeq X X X
Triumeq X X X
PD

NNRTI/INSTI
Juluca X X
Cabenuva X X

NRTI/INSTI/COBI
Genvoya X X X X
Stribild X X X X

NRTI/PI/COBI
Symtuza X X X X

PI/COBI
Evotaz X X
Prezcobix X X

PI/RTV
Kaletra X X
aTAF, BIC, and EVG are only available in FDC tablets. However, TAF 25 mg tablets (Vemlidy) are FDA-approved for treatment of HBV. In select circumstances, TAF might be
used as one component of a combination ARV regimen, with dosing recommendations similar to those for Descovy.
bCAB and RPV for intramuscular injection are available as a co-packaged product (Cabenuva); oral formulations of CAB and RPV for initial lead-in dosing must be prescribed
separately; see Cabotegravir and Rilpivirine.
c LPV is only available in FDC tablets or solution.
Key: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; ATV = atazanavir; BIC = bictegravir; CAB = cabotegravir; COBI = cobicistat; DOR = doravirine; DRV = darunavir;
DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; FDA = U.S. Food and Drug Administration; FDC = fixed-dose combination; FTC = emtricitabine; HBV = hepatitis B virus;

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-262
INSTI = integrase strand transfer inhibitor; LPV = lopinavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NRTI = nucleoside and nucleotide reverse transcriptase
inhibitor; PI = protease inhibitor; PK = pharmacokinetic; RPV = rilpivirine; RTV = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-263
Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights
and Considerations for Use in Children and Adolescents
Updated: April 11, 2023
Reviewed: April 11, 2023

General Considerations When Using Fixed-Dose Combination Products

Please see the individual drug sections under Pediatric Antiretroviral Drug Information for the recommended dosing of individual fixed-dose
combination (FDC) products.

FDC tablets and individual ARV drugs also can be looked up by drug name (brand name and generic) at DailyMed. Size is listed under the
Ingredients and Appearance section

For images of most of the FDC tablets listed in this table, see the Antiretroviral Medications section of the National HIV Curriculum. In addition, a
resource from the United Kingdom illustrates the relative sizes of FDC tablets and individual ARV drugs (see the ARV Chart at HIV i-BASE).
Although most of the drugs listed in the chart are the same as those in the United States, there are several differences: some formulations available
in the United States are not included; a few of the brand names are not the same as those listed in Appendix A, Table 2; and the chart includes a
formulation that is not available in the United States.

Integrase Strand Transfer Inhibitors (INSTIs)

• Bictegravir (BIC) and dolutegravir (DTG), second-generation INSTIs, have a higher barrier to resistance than the first-generation INSTIs,
elvitegravir (EVG) and raltegravir (RAL).
• For children weighing ≥10 kg, dolutegravir is available in once-daily FDC formulations of abacavir/dolutegravir/lamivudine (ABC/DTG/3TC).
If ABC/DTG/3TC is not an option, then single-entity DTG can be used in combination with other FDC tablets.
o ABC/DTG/3TC is available in two different formulations, with the appropriate formulation depending on weight. For children weighing
≥10 kg to <25 kg, ABC/DTG/3TC is available in a dispersible tablet, once-daily regimen (Triumeq PD); the number of tablets per dose
depends on the child’s weight. For children and adolescents weighing ≥25 kg, ABC/DTG/3TC is available as a once-daily single-tablet
regimen (Triumeq).
o Whether considering DTG in FDC or single-entity form, the film-coated tablets and dispersible tablets are not bioequivalent and, thus,
are not interchangeable on a milligram-per-milligram basis. Refer to Dolutegravir for dosing information.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-264
Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and
Considerations for Use in Children

• For children weighing ≥14 kg, bictegravir is available as the single-tablet, once-daily regimen bictegravir/emtricitabine/tenofovir alafenamide
(BIC/FTC/TAF; Biktarvy). There are two dosage strengths for pediatric use: one for use in children weighing ≥14 to <25 kg and another for
children and adolescents weighing ≥25 kg and adults.
• For children weighing ≥25 kg, elvitegravir is available as the single-tablet, once-daily regimen elvitegravir/cobicistat/emtricitabine/tenofovir
alafenamide (EVG/c/FTC/TAF; Genvoya). EVG/c/FTC/TAF (Genvoya) has more drug–drug interactions than ABC/DTG/3TC (Triumeq or
Triumeq PD) or BIC/FTC/TAF (Biktarvy).
• The two-drug, co-packaged regimen of long-acting cabotegravir and rilpivirine (CAB and RPV; Cabenuva) is approved by the U.S. Food and
Drug Administration (FDA) for use in children and adolescents aged ≥12 years and weighing ≥35 kg. CAB and RPV are administered by
intramuscular injection on a monthly or every-2-months schedule after an optional oral dose lead-in. See Cabotegravir for instructions about
dosing and administration.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

• ABC or TAF in combination with 3TC or FTC are favored over zidovudine/lamivudine (ZDV/3TC) because of the lower risk of NRTI)-
associated mitochondrial toxicity.
• Tenofovir disoproxil fumarate (TDF) is more potent than ABC at high viral loads (>100,000 copies/mL) when used in regimens that do not
contain an INSTI.
• TAF is favored over TDF because of the lower risk of TDF-associated bone and renal toxicity. TDF is not recommended for children with
sexual maturity ratings (SMRs) of 1 to 3 because of TDF-associated bone toxicity.
• For children weighing ≥14 kg who can swallow pills, FTC/TAF (Descovy) offers a once-daily alternative to twice-daily ZDV plus 3TC or ABC
plus 3TC.
• For children weighing ≥14 kg and ≤35 kg, FTC/TAF (Descovy) can be used in combination with an INSTI or NNRTI, but not with a protease
inhibitor; this restriction does not apply to regimens containing ZDV or ABC.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

• The FDC tablet doravirine/lamivudine/tenofovir disoproxil fumarate (DOR/3TC/TDF) is approved by the FDA for children and adolescents
weighing ≥35 kg who are antiretroviral (ARV) naive or virologically suppressed on a stable ARV regimen (see the Doravirine section).
• RPV has low potency at high viral loads (>100,000 copies/mL) and requires a high-fat meal for optimal absorption, so efavirenz (EFV) or an
INSTI are favored over RPV.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-265
Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and
Considerations for Use in Children

Fixed-Dose Combinations Available for Children and Adolescents

FDC by Class Minimum Body Pill Size (mm × mm)

Brand name and generica FDC Components Weight or Weight or Largest Food Requirements
products, when available Range (kg) or Ageb Dimension (mm)c

NRTI
Cimduo 3TC 300 mg/TDF 300 mg 35 kg 19 Take with or without food.

Combivir and 3TC 150 mg/ZDV 300 mg (scored tablet) 30 kg 18 × 7 Take with or without food.
Generic 3TC/ZDV
Descovy FTC 120 mg/TAF 15 mg With an INSTI or NNRTI N/A Take with or without food.
• 14 to < 25 kg
FTC 200 mg/TAF 25 mg With an INSTI or NNRTI 12.5 × 6.4 Take with or without food.
• 25 kg

With a Boosted PI
• 35 kg
Epzicom and ABC 600 mg/3TC 300 mg 25 kg 21 × 9 Take with or without food.
Generic ABC/3TC
Temixys 3TC 300 mg/TDF 300 mg 35 kg N/A Take with or without food.

Truvada FTC 100 mg/TDF 150 mg 17 to <22 kg 14 Take with or without food.

FTC 133 mg/TDF 200 mg 22 to <28 kg 16 Take with or without food.

FTC 167 mg/TDF 250 mg 28 to <35 kg 18 Take with or without food.

FTC 200 mg/TDF 300 mg 35 kg 19 × 8.5 Take with or without food.

NRTI/NNRTI
Atripla EFV 600 mg/FTC 200 mg/TDF 300 mg 40 kg 20 Take on an empty stomach.

Complera FTC 200 mg/RPV 25 mg/TDF 300 mg 35 kg and aged ≥12 years 19 Take with a meal.d

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-266
Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and
Considerations for Use in Children

FDC by Class Minimum Body Pill Size (mm × mm)

Brand name and generica FDC Components Weight or Weight or Largest Food Requirements
products, when available Range (kg) or Ageb Dimension (mm)c
Delstrigo DOR 100 mg/3TC 300 mg/TDF 300 mg 35 kg 19 Take with or without food.

Odefsey FTC 200 mg/RPV 25 mg/TAF 25 mg 35 kg and aged ≥12 years 15 Take with a meal.d

Symfi EFV 600 mg/3TC 300 mg/TDF 300 mg (scored tablet) 40 kg 23 Take on an empty stomach.

Symfi Lo EFV 400 mg/3TC 300 mg/TDF 300 mg 35 kge 21 Take on an empty stomach.

NRTI/INSTI
Biktarvy BIC 30 mg/FTC 120 mg/TAF 15 mg 14 to <25 kg N/A Take with or without food.

BIC 50 mg/FTC 200 mg/TAF 25 mg 25 kg 15 × 8 Take with or without food.

Dovato DTG 50 mg/3TC 300 mg Adultsf 19 Take with or without food.

Triumeq ABC 600 mg/DTG 50 mg/3TC 300 mg 25 kg 22 × 11 Take with or without food.

Triumeq PD ABC 60 mg/DTG 5 mg/3TC 30 mg 10 to < 25 kgg N/A (dispersible) Take with or without food.

NNRTI/INSTI
Cabenuvah Cabenuva 400 mg/600 mg kit contains CAB 35 kg and aged ≥12 years N/A See Cabotegravir for instructions
400 mg/2 mL vial and RPV 600 mg/2 mL vial about dosing and administration.

Cabenuva 600 mg/900 mg kit contains CAB 35 kg and aged ≥12 years N/A See Cabotegravir for instructions
600 mg/3 mL vial and RPV 900 mg/3 mL vial about dosing and administration.

Juluca DTG 50 mg/RPV 25 mg Adultsf 14 Take with a meal.d

NRTI/INSTI/COBI
Genvoya EVG 150 mg/COBI 150 mg/FTC 200 mg/TAF 10 mg 25 kg 19 × 8.5 Take with food.

Stribild EVG 150 mg/COBI 150 mg/FTC 200 mg/TDF 300 mg 35 kg and SMR of 4 or 5i 20 Take with food.

NRTI/PI/COBI

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-267
Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and
Considerations for Use in Children

FDC by Class Minimum Body Pill Size (mm × mm)

Brand name and generica FDC Components Weight or Weight or Largest Food Requirements
products, when available Range (kg) or Ageb Dimension (mm)c
Symtuza DRV 800 mg/COBI 150 mg/FTC 200 mg/TAF 10 mg 40 kg 22 Take with food.

PI/COBI
Evotaz ATV 300 mg/COBI 150 mg 35 kg 19 Take with food.

Prezcobix DRV 800 mg/COBI 150 mg 40 kg 23 Take with food.

PI/RTV
Kaletra LPV/r Oral Solution Post-Menstrual Age of 19 Take with or without food.
42 Weeks and a
• LPV 80 mg/mL and RTV 20 mg/mL
Postnatal Age of ≥14
Tablets Days

• LPV 200 mg/RTV 50 mg • No minimum weight

• LPV 100 mg/RTV 25 mg

a The possibility of planned and unplanned pregnancy should be considered when selecting an antiretroviral therapy (ART) regimen for an adolescent. When discussing ART options with
adolescents of childbearing potential and their caregivers, it is important to consider the benefits and risks of all ARV drugs and to provide the information and counseling needed to support
informed decision-making (see Table 7. Situation-Specific Recommendations for Use of Antiretroviral Drugs in Pregnant People and Nonpregnant People Who Are Trying to Conceive and
Appendix C: Antiretroviral Counseling Guide for Health Care Providers).
b Minimum body weight and age are those recommended by the FDA, unless otherwise noted.
cSizes or largest dimensions of generic drugs are not listed because they may vary by manufacturer; this information is available by looking up one of the drug components using
DailyMed.
d Patients must be able to take oral RPV with a meal of at least 500 calories on a regular schedule (a protein drink alone does not constitute a meal).
eBecause of pharmacokinetic concerns, the Panel recommends caution when using Symfi Lo in children and adolescents who have SMRs of 1 to 3 and weigh ≥40 kg (see the Efavirenz
section).
fThe Panel does not currently recommend using dolutegravir/lamivudine (DTG/3TC; Dovato) or dolutegravir/rilpivirine (DTG/RPV; Juluca) as a two-drug complete regimen in adolescents
and children. These FDC tablets could be used as part of a three-drug regimen in children who meet the minimum body weight requirements for each component drug.
g ABC/DTG/3TC is available in dispersible tablets (Triumeq PD) for children weighing ≥10 mg to <25 mg with the dosage and number of tablets based on weight. Refer to the Dolutegravir
section for exact dosage and instructions for administration. Dispersible tablets (Triumeq PD) are not recommended for children and adolescents weighing ≥25 kg.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-268
Appendix A, Table 2. Antiretroviral Fixed-Dose Combination Tablets and Co-packaged Formulations: Minimum Body Weights and
Considerations for Use in Children
hLong-acting CAB and RPV for intramuscular injection are available as a co-packaged product (Cabenuva); oral formulations of CAB and RPV for the optional initial lead-in dosing or
bridging between injections >7 days from the target injection window must be prescribed separately (see the Cabotegravir and Rilpivirine sections).
iAlthough Stribild is approved by the FDA for use in children and adolescents weighing ≥35 kg and age ≥12 years, the Panel does not recommend its use in children with SMRs of 1 to 3
given the availability of other INSTI-containing FDCs.
Key: 3TC = lamivudine; ABC = abacavir; ATV = atazanavir; BIC = bictegravir; CAB = cabotegravir; COBI = cobicistat; DOR = doravirine; DRV = darunavir; DTG = dolutegravir;
EFV = efavirenz; EVG = elvitegravir; FDA = U.S. Food and Drug Administration; FDC = fixed-dose combination; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor;
kg = kilogram; LPV = lopinavir; LPV/r = lopinavir/ritonavir; mg = milligram; mL = milliliter; mm = millimeter; N/A = information not available or not applicable; NNRTI = non-nucleoside
reverse transcriptase inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; the Panel = Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV;
PI = protease inhibitor; RPV = rilpivirine; RTV = ritonavir; SMR = sexual maturity rating; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-269
Appendix A: Pediatric Antiretroviral Drug Information
Archived Drugs
The Archived Drugs section of Appendix A: Pediatric Antiretroviral Drug Information provides
access to the last updated versions of drug sections that are no longer being reviewed by the Panel on
Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel). Archived
Drugs includes older antiretroviral drugs that the Panel does not recommend for use in children
because they have unacceptable toxicities, inferior virologic efficacy, a high pill burden,
pharmacologic concerns, and/or a limited amount of pediatric data.

Didanosine (ddl, Videx)

Enfuvirtide (T-20, Fuzeon)

Fosamprenavir (FPV, Lexiva)

Indinavir (IDV, Crixivan)

Nelfinavir (NFV, Viracept)

Saquinavir (SQV, Invirase)

Stavudine (d4t, Zerit)

Tipranavir (TPV, Aptivus)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-264
Didanosine (ddI, Videx)
Updated: May 22, 2018
Reviewed: May 22, 2018

Formulations
Pediatric Oral Solution: 10 mg/mL
Enteric-Coated (EC) Delayed-Release Capsules (EC Beadlets): 125 mg, 200 mg, 250 mg, and 400 mg

Generic Formulations
Delayed-Release Capsules: 125 mg, 200 mg, 250 mg, and 400 mg

For additional information, see Drugs@FDA.

Dosing Recommendations Selected Adverse Events

Note: Didanosine is no longer recommended by the Panel • Peripheral neuropathy
on Antiretroviral Therapy and Medical Management of
Children Living with HIV for use in children due to higher • Diarrhea, abdominal pain, nausea, vomiting
rates of adverse effects than other NRTIs. • Lactic acidosis and severe hepatomegaly with steatosis,
including fatal cases, have been reported (the risk is
Neonate/Infant Dose (Aged 2 Weeks to <3 Months) increased when didanosine is used in combination with
• 50 mg/m of body surface area every 12 hours. See dosing
2 stavudine).
section below for justification of this dose. • Pancreatitis (less common in children than in adults, more
common when didanosine is used in combination with
Infant Dose (Aged ≥3 Months to 8 Months) tenofovir disoproxil fumarate or stavudine)
• 100 mg/m2 of body surface area every 12 hours • Non-cirrhotic portal hypertension
Pediatric Dose of Oral Solution (Aged >8 Months) • Retinal changes, optic neuritis
• 120 mg/m2 of body surface area every 12 hours • Insulin resistance/diabetes mellitus
• Dose range: 90–150 mg/m2 of body surface area every
12 hours. Do not exceed maximum adult dose; see table Special Instructions
below.
• Administer didanosine on an empty stomach (30 minutes
• In treatment-naive children aged 3 years to 21 years, before or 2 hours after a meal). To improve adherence,
240 mg/m2 of body surface area once daily (oral solution or some practitioners administer didanosine without regard to
capsules) has resulted in viral suppression. timing of meals (see text below).

Pediatric Dose of Videx EC or Generic Capsules • Didanosine powder for oral solution contains antacids that
(Aged 6–18 Years and Weighing ≥20 kg) may interfere with the absorption of other medications,
including protease inhibitors (PIs). See individual PI for
instructions on timing of administration.
Body Weight Dose
• Shake didanosine oral solution well before use. Keep
20 kg to <25 kg 200 mg once daily
refrigerated; solution is stable for 30 days.
25 kg to <60 kg 250 mg once daily
≥60 kg 400 mg once daily

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-265
 Adolescent and Adult Dose
Metabolism/Elimination
Body Weight Dose • Renal excretion 50%
<60 kg 250 mg once daily • Decrease dosage in patients with impaired renal function.
≥60 kg 400 mg once daily Consult manufacturer’s prescribing information for
adjustment of dosage in accordance with creatinine
clearance.
Pediatric and Adolescent Dose of Didanosine when
Combined with Tenofovir Disoproxil Fumarate
• This combination should be avoided because of enhanced
didanosine toxicity, reports of immunologic nonresponse,
high rates of early virologic failure, and rapid selection of
resistance mutations (see the Adult and Adolescent
Guidelines).

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent Guidelines
and the HIV Drug Interaction Checker.

• Absorption: Antacids in didanosine oral solution can decrease the absorption of a number of
medications if given at the same time. Avoid giving other medications concurrently with
didanosine oral solution.
• Mechanism unknown: Didanosine serum concentrations are increased when didanosine is co-
administered with tenofovir disoproxil fumarate (TDF). This combination should be avoided.
• Renal elimination: Drugs that decrease renal function can decrease didanosine clearance.
• Overlapping toxicities: The combination of stavudine with didanosine may result in enhanced
toxicity. This combination should be avoided (see the Major Toxicities section below).

Major Toxicities
• More common: Diarrhea, abdominal pain, nausea, vomiting
• Less common (more severe): Peripheral neuropathy, electrolyte abnormalities, and
hyperuricemia. Lactic acidosis and hepatomegaly with steatosis, including fatal cases, have been
reported, and are more common when didanosine is used in combination with stavudine.
Pancreatitis (less common in children than in adults, more common when didanosine is used in
combination with TDF or stavudine) can occur. Increased liver enzymes, retinal depigmentation,
and optic neuritis have been reported. Decreases in CD4 T lymphocyte counts have been reported
when didanosine is used in combination with TDF.
• Rare: Non-cirrhotic portal hypertension, presenting clinically with hematemesis, esophageal
varices, ascites, and splenomegaly, and associated with increased transaminases, increased
alkaline phosphatase, and thrombocytopenia, has been associated with long-term didanosine use.1
• Possible risk of cancer after in-utero exposure: In a study of 15,163 children without HIV
infection who were exposed to at least one nucleoside reverse transcriptase inhibitor (NRTI) in
utero, 21 cancers were identified. Didanosine accounted for only 10% of prescriptions but was
associated with one-third of identified cancers, and, in multivariate analysis, didanosine was

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-266
 associated with a 5.5-fold (95% CI, 2.1–14.4) increased risk of cancer with first-trimester
exposure.2 Pregnant adolescents or sexually active female adolescents on didanosine should be
cautioned about this risk.

Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
Although didanosine is a Food and Drug Administration (FDA)-approved NRTI for use in children
as part of antiretroviral therapy, it is not recommended for in children due to its significant toxicity
and the availability of safer agents.

Dosing
Standard Dose in Children Aged >8 Months
The standard dose of didanosine oral solution in children aged >8 months is 120 mg/m2 of body
surface area twice daily.3,4 Doses higher than 180 mg/m2 of body surface area twice daily are
associated with increased toxicity.5

Special Considerations for Children Aged 2 Weeks to <8 Months

For infants aged 2 weeks to 8 months, the FDA recommends 100 mg/m2 of body surface area per
dose twice daily. However, because pharmacokinetic (PK) differences in younger infants (aged
2 weeks–3 months) compared with older children raise concerns for increased toxicity in this
younger age group, the Panel on Antiretroviral Therapy and Medical Management of Children
Living with HIV recommends a dose of 50 mg/m2 of body surface area twice daily for infants aged
2 weeks to 3 months, with an increase to 100 mg/m2 of body surface area per dose twice daily at
3 months, and finally increasing to 120 mg/m2 of body surface area per dose twice daily at age
8 months (as discussed above).

Frequency of Administration (Once Daily or Twice Daily)

In those aged >3 years, a once-daily dosing regimen may be preferable to promote adherence, and
multiple studies support the favorable PKs and efficacy of once-daily dosing of 240 mg/m2 of body
surface area.6

Food Restrictions
Although the prescribing information recommends taking didanosine on an empty stomach, this is
impractical for infants who must be fed frequently, and it may decrease medication adherence by
increasing regimen complexity. A comparison showed that systemic exposure measured by area
under the curve was similar whether didanosine oral solution was given to children with or without
food; absorption of didanosine administered with food was slower and elimination more prolonged.7

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-267
To improve adherence, some practitioners administer didanosine without regard to timing of meals.
Studies in adults suggest that didanosine can be given without regard to food.8,9 A European study
dosed didanosine oral solution as part of a four-drug regimen either 1 hour before or 1 hour after
meals, but allowed the extended-release formulation to be given without food restriction. The study
showed good virologic outcome with up to 96 weeks of follow-up.10

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-268
References
1. Scherpbier HJ, Terpstra V, Pajkrt D, et al. Noncirrhotic portal hypertension in perinatally
HIV-infected adolescents treated with didanosine-containing antiretroviral regimens in
childhood. Pediatr Infect Dis J. 2016. Available at
http://www.ncbi.nlm.nih.gov/pubmed/27167116.

2. Hleyhel M, Goujon S, Delteil C, et al. Risk of cancer in children exposed to didanosine in

utero. AIDS. 2016;30(8):1245-1256. Available at
http://www.ncbi.nlm.nih.gov/pubmed/26854809.

3. Fletcher CV, Brundage RC, Remmel RP, et al. Pharmacologic characteristics of indinavir,
didanosine, and stavudine in human immunodeficiency virus-infected children receiving
combination therapy. Antimicrob Agents Chemother. 2000;44(4):1029-1034. Available at
http://www.ncbi.nlm.nih.gov/pubmed/10722507.

4. Nacro B, Zoure E, Hien H, et al. Pharmacology and immuno-virologic efficacy of once-a-day

HAART in African HIV-infected children: ANRS 12103 phase II trial. Bull World Health
Organ. 2011;89(6):451-458. Available at http://www.ncbi.nlm.nih.gov/pubmed/21673861.

5. Butler KM, Husson RN, Balis FM, et al. Dideoxyinosine in children with symptomatic
human immunodeficiency virus infection. N Engl J Med. 1991;324(3):137-144. Available at
http://www.ncbi.nlm.nih.gov/pubmed/1670591.

6. King JR, Nachman S, Yogev R, et al. Single-dose pharmacokinetics of enteric-coated

didanosine in HIV-infected children. Antivir Ther. 2002;7(4):267-270. Available at
http://www.ncbi.nlm.nih.gov/pubmed/12553481.

7. Stevens RC, Rodman JH, Yong FH, Carey V, Knupp CA, Frenkel LM. Effect of food and
pharmacokinetic variability on didanosine systemic exposure in HIV-infected children.
Pediatric AIDS Clinical Trials Group Protocol 144 Study Team. AIDS Res Hum Retroviruses.
2000;16(5):415-421. Available at http://www.ncbi.nlm.nih.gov/pubmed/10772527.

8. Sanchez-Conde M, Palacios R, Sanz J, et al. Efficacy and safety of a once daily regimen with
efavirenz, lamivudine, and didanosine, with and without food, as initial therapy for HIV
Infection: the ELADI study. AIDS Res Hum Retroviruses. 2007;23(10):1237-1241. Available
at http://www.ncbi.nlm.nih.gov/pubmed/17961110.

9. Hernandez-Novoa B, Antela A, Gutierrez C, et al. Effect of food on the antiviral activity of

didanosine enteric-coated capsules: a pilot comparative study. HIV Med. 2008;9(4):187-191.
Available at http://www.ncbi.nlm.nih.gov/pubmed/18298579.

10. Scherpbier HJ, Bekker V, Pajkrt D, Jurriaans S, Lange JM, Kuijpers TW. Once-daily highly
active antiretroviral therapy for HIV-infected children: safety and efficacy of an efavirenz-
containing regimen. Pediatrics. 2007;119(3):e705-715. Available at
http://www.ncbi.nlm.nih.gov/pubmed/17308244.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-269
Enfuvirtide (T-20, Fuzeon)
Updated: May 22, 2018
Reviewed: May 22, 2018

Formulations
Lyophilized Powder for Injection: 108-mg vial of enfuvirtide. Reconstitution with 1.1 mL sterile water will deliver 90 mg/mL.
Convenience Kit: 60 single-use vials of enfuvirtide (108-mg vial reconstituted as 90 mg/mL), 60 vials of sterile water for
injection, 60 reconstitution syringes (3 mL), 60 administration syringes (1 mL), alcohol wipes

For additional information, see Drugs@FDA.

Dosage Recommendations Selected Adverse Events

Pediatric and Adolescent Dose (Aged 6–16 Years) • Local injection site reactions (e.g., pain, erythema,
induration, nodules and cysts, pruritus, ecchymosis) in up
Children Aged <6 Years
to 98% of patients.
• Not approved for use in children aged <6 years
• Increased rate of bacterial pneumonia (unclear
Children Aged ≥6 Years association).

• 2 mg/kg (maximum dose 90 mg [1 mL]) twice daily injected • Hypersensitivity reaction (HSR)—symptoms may include
subcutaneously (SQ) into the upper arm, anterior thigh, or rash, fever, nausea, vomiting, chills, rigors, hypotension, or
abdomen elevated serum transaminases. Rechallenge is not
recommended.
Adolescent (Aged >16 Years) and Adult Dose
• 90 mg (1 mL) twice daily injected SQ into the upper arm, Special Instructions
anterior thigh, or abdomen • Carefully instruct patient or caregiver in proper technique
for drug reconstitution and administration of SQ injections.
Enfuvirtide injection instructions are provided with
convenience kits.
• Allow reconstituted vial to stand until the powder goes
completely into solution, which could take up to
45 minutes. Do not shake.
• Once reconstituted, inject enfuvirtide immediately or keep
refrigerated in the original vial until use. Reconstituted
enfuvirtide must be used within 24 hours.
• Enfuvirtide must be given SQ; severity of reactions
increases if given intramuscularly.
• Give each injection at a site different from the preceding
injection site; do not inject into moles, scar tissue, bruises,
or the navel. Both the patient/caregiver and health care
provider should carefully monitor for signs and symptoms
of local infection or cellulitis.
• To minimize local reactions, apply ice or heat after
injection or gently massage injection site to better disperse
the dose. There are reports of injection-associated
neuralgia and paresthesia when alternative delivery
systems, such as needle-free injection devices, are used.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-270
 • Advise patients/caregivers of the possibility of a HSR;
instruct them to discontinue treatment and seek immediate
medical attention if a patient develops signs and symptoms
consistent with a HSR.

Metabolism/Elimination
• Catabolism to constituent amino acids.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent Guidelines
and the HIV Drug Interaction Checker.

There are no known significant drug interactions with enfuvirtide.

Major Toxicities
• More common: Almost all patients (87% to 98%) experience local injection site reactions
including pain and discomfort, induration, erythema, nodules and cysts, pruritus, and
ecchymosis. Reactions are usually mild to moderate in severity but can be more severe. Average
duration of local injection site reaction is 3 to 7 days but was >7 days in 24% of patients.
• Less common (more severe): Increased rate of bacterial pneumonia (unclear association).1 Pediatric
studies have lacked the statistical power to answer questions concerning enfuvirtide use and
increased risk of pneumonia.
• Rare: Hypersensitivity reactions (HSRs) (<1%) including fever, nausea and vomiting, chills,
rigors, hypotension, and elevated liver transaminases; immune-mediated reactions including
primary immune complex reaction, respiratory distress, glomerulonephritis, and Guillain-Barre
syndrome. Patients experiencing HSRs should seek immediate medical attention. Therapy should
not be restarted in patients with signs and symptoms consistent with HSRs.
• Pediatric specific: Local site cellulitis requiring antimicrobial therapy (up to 11% in certain
subgroups of patients in pediatric studies).2

Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Resistance testing must be ordered specifically for fusion inhibitors, as it is not performed on routine
genotypic or phenotypic assays.

Pediatric Use
Approval
Although enfuvirtide is Food and Drug Administration (FDA)-approved for use in children, it is not
commonly used because of its high cost, need for twice-daily subcutaneous (SQ) injections, and high

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-271
rate of injection site reactions. Use in deep salvage regimens3 has also declined with the availability
of integrase inhibitors and other entry inhibitors (such as maraviroc).

Pharmacokinetics
A single-dose pharmacokinetic evaluation study of enfuvirtide, given SQ to 14 children with HIV
aged 4 years to 12 years (PACTG 1005), identified that enfuvirtide 60 mg/m2 of body surface area
per dose resulted in a target trough concentration that approximated the equivalent of a 90-mg dose
delivered SQ to an adult (1000 mg/mL).4 In a second pediatric study of 25 children aged 5 years to
16 years, a 2-mg/kg dose (maximum 90 mg) of enfuvirtide given twice daily yielded drug
concentrations similar to 60 mg/m2 of body surface area dose independent of age group, body weight,
body surface area, and sexual maturation.5 The FDA-recommended dose of enfuvirtide for children
aged 6 to 16 years is 2 mg/kg (maximum 90 mg) administered SQ twice daily. Further data are
needed for dosing in children aged <6 years.

Efficacy
The safety and antiretroviral (ARV) activity of twice-daily SQ enfuvirtide administration at
60 mg/m2 per dose plus optimized background therapy (OBT) was evaluated over 96 weeks in
14 children aged 4 to 12 years who had failed to achieve viral suppression on multiple prior ARV
regimens (PACTG 1005). At 24 weeks 71% of the children had a >1.0 log reduction in viral load; 43%
and 21% had HIV RNA levels suppressed to <400 copies/mL and <50 copies/mL, respectively.
However, only 36% of children maintained virologic suppression (>1.0 log decrease in HIV RNA) at
Week 96. Most children had local injection site reactions.6 Significant improvements in CD4 T
lymphocyte (CD4) cell percentages and height z scores were observed in children receiving
enfuvirtide for 48 and 96 weeks.

T20-310, a Phase 1/2 study of enfuvirtide (2.0 mg/kg SQ, maximum 90 mg, twice daily) plus OBT,
enrolled 52 treatment-experienced children aged 3 to 16 years for 48 weeks. Only 64% of the
children completed 48 weeks of therapy. The median decrease in HIV RNA was
−1.17 log 10 copies/mL (n = 32) and increase in CD4 cell count was 106 cells/mm3 (n = 25). At
Week 8, treatment responses as measured by several plasma HIV RNA parameters were superior in
younger children (aged <11 years) compared with adolescents. Median increases in CD4 cell count
were 257 cells/mm3 in children and 84 cells/mm3 in adolescents. Local skin reactions were common
in all age groups (87% of study participants). The observed differential responses between children
and adolescents probably reflect unique challenges to adherence with the prescribed regimen.2

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-272
References
1. Kousignian I, Launay O, Mayaud C, et al. Does enfuvirtide increase the risk of bacterial
pneumonia in patients receiving combination antiretroviral therapy? J Antimicrob
Chemother. 2010;65(1):138-144. Available at
http://www.ncbi.nlm.nih.gov/pubmed/19903719.

2. Wiznia A, Church J, Emmanuel P, et al. Safety and efficacy of enfuvirtide for 48 weeks
as part of an optimized antiretroviral regimen in pediatric human immunodeficiency
virus 1-infected patients. Pediatr Infect Dis J. 2007;26(9):799-805. Available at
http://www.ncbi.nlm.nih.gov/pubmed/17721374.

3. Feiterna-Sperling C, Walter H, Wahn V, Kleinkauf N. A 12-year-old boy with multidrug-

resistant human immunodeficiency virus type 1 successfully treated with HAART including
ritonavir-boosted tipranavir oral solution and enfuvirtide. Eur J Med Res. 2009;14(1):44-46.
Available at http://www.ncbi.nlm.nih.gov/pubmed/19258211.

4. Church JA, Cunningham C, Hughes M, et al. Safety and antiretroviral activity of chronic
subcutaneous administration of T-20 in human immunodeficiency virus 1-infected children.
Pediatr Infect Dis J. 2002;21(7):653-659. Available at
http://www.ncbi.nlm.nih.gov/pubmed/12237598.

5. Bellibas SE, Siddique Z, Dorr A, et al. Pharmacokinetics of enfuvirtide in pediatric human

immunodeficiency virus 1-infected patients receiving combination therapy. Pediatr Infect Dis
J. 2004;23(12):1137-1141. Available at http://www.ncbi.nlm.nih.gov/pubmed/15626952.

6. Church JA, Hughes M, Chen J, et al. Long term tolerability and safety of enfuvirtide for
human immunodeficiency virus 1-infected children. Pediatr Infect Dis J. 2004;23(8):713-
718. Available at http://www.ncbi.nlm.nih.gov/pubmed/15295220.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-273
Fosamprenavir (FPV, Lexiva)
Updated: May 22, 2018
Reviewed: May 22, 2018

Formulations
Tablets: 700 mg
Oral Suspension: 50 mg/mL

For additional information, see Drugs@FDA.

Dosing Recommendations Selected Adverse Events

Pediatric Dose (Aged >6 Months to 18 Years) • Diarrhea, nausea, vomiting
• Unboosted fosamprenavir (without ritonavir) is Food and • Skin rash (fosamprenavir has a sulfonamide moiety.
Drug Administration (FDA)-approved for antiretroviral Stevens-Johnson syndrome and erythema multiforme
(ARV)-naive children aged 2 to 5 years, but not have been reported.)
recommended by the Panel on Antiretroviral Therapy and
Medical Management of Children Living with HIV (the • Headache
Panel) because of low exposures (see text below). • Hyperlipidemia, hyperglycemia
• Boosted fosamprenavir (with ritonavir) is FDA-approved for • Nephrolithiasis
ARV-naive infants ≥4 weeks and for treatment-experienced
infants ≥6 months; however, the Panel does not • Transaminase elevation
recommend use in infants aged <6 months because of • Fat maldistribution
similarly low exposures (see text below). If used in infants
as young as 4 weeks, it should only be administered to • Possible increased bleeding episodes in patients with
infants born at 38 weeks’ gestation or greater. hemophilia

Note: Once-daily dosing is not recommended for any

Special Instructions
pediatric patient.
• Fosamprenavir tablets with ritonavir should be taken with
Pediatric Dose (Aged ≥6 Months to 18 Years) food. Children should take the suspension with food.
Twice-Daily Dose Regimens by Weight for Pediatric • Patients taking antacids should take fosamprenavir at
Patients ≥6 Months Using Fosamprenavir Oral Suspension least 1 hour before or after antacid use.
with Ritonavir
• Fosamprenavir contains a sulfonamide moiety. The
Dose potential for cross sensitivity between fosamprenavir and
Weight other drugs in the sulfonamide class is unknown.
(Both Drugs Twice Dailya with Food)
Fosamprenavir should be used with caution in patients
<11 kg Fosamprenavir 45 mg/kg/dose plus ritonavir with sulfonamide allergy.
7 mg/kg/dose
• Shake oral suspension well before use. Refrigeration is
11 kg to Fosamprenavir 30 mg/kg/dose plus ritonavir not required.
<15 kg 3 mg/kg/dose
15 kg to Fosamprenavir 23 mg/kg/dose plus ritonavir
<20 kg 3 mg/kg/dose
≥20 kg Fosamprenavir 18 mg/kg/dose plus ritonavir
3 mg/kg/dose

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-274
 a Not to exceed the adult dose of fosamprenavir 700 mg plus
ritonavir 100 mg twice daily. Metabolism/Elimination
Note: When administered with ritonavir, the adult regimen of • The prodrug fosamprenavir is rapidly and almost
700 mg fosamprenavir tablets plus 100 mg ritonavir, both completely hydrolyzed to amprenavir by cellular
given twice daily, can be used in patients weighing ≥39 kg. phosphatases in the gut as it is absorbed.
Ritonavir tablets can be used in patients weighing ≥33 kg.
• Amprenavir is a cytochrome P (CYP) 450 3A4 inhibitor,
Adolescent and Adult Dose inducer, and substrate.

• Dosing regimen depends on whether the patient is ARV- Fosamprenavir Dosing in Patients with Hepatic
naive or ARV-experienced. Impairment

ARV-Naive Patients • Specific dose adjustments are recommended for adults

with mild, moderate, and severe hepatic impairment.
• Fosamprenavir 700 mg plus ritonavir 100 mg, both twice However, there are no data to support dosing
daily recommendations for pediatric patients with hepatic
impairment. Please refer to the package insert.
• Fosamprenavir 1400 mg plus ritonavir 100–200 mg, both
once daily Fosamprenavir Dosing in Patients with Renal
Impairment
Protease-Inhibitor-Experienced Patients
• No dose adjustment is required in patients with renal
• Fosamprenavir 700 mg plus ritonavir 100 mg, both twice
impairment.
daily.

Note: Once-daily administration of fosamprenavir plus

ritonavir is not recommended.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent Guidelines
and the HIV Drug Interaction Checker.

• Fosamprenavir may interact with a number of other drugs, and using ritonavir as a boosting agent
increases the potential for drug interactions. Before administration, a patient’s medication profile
should be carefully reviewed for potential drug interactions with fosamprenavir.

Major Toxicities
• More common: Vomiting, nausea, diarrhea, perioral paresthesia, headache, rash, lipid
abnormalities
• Less common (more severe): Life-threatening rash, including Stevens-Johnson syndrome, in <1%
of patients. Fat maldistribution, neutropenia, and elevated serum creatinine kinase levels.
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting
diabetes mellitus, spontaneous bleeding in hemophiliacs, hemolytic anemia, elevation in serum
transaminases, angioedema, and nephrolithiasis.
• Pediatric-specific: Vomiting was more frequent in children than in adults during clinical trials of
fosamprenavir with ritonavir (20% to 36% vs. 10%, respectively) and in trials of fosamprenavir
without ritonavir (60% vs. 16%, respectively). Neutropenia was also more common in children
across all the trials (15% vs. 3%, respectively).1

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-275
Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
Fosamprenavir is Food and Drug Administration (FDA)-approved for use in children as young as age
4 weeks, but the Panel on Antiretroviral Therapy and Medical Management of Children Living with
HIV (the Panel) recommends use only in children aged ≥6 months. Although unboosted
fosamprenavir has been approved by the FDA for antiretroviral-naive children aged 2 to 5 years, the
Panel does not recommend unboosted fosamprenavir for this—or any other—age group because of
low exposures and also because unboosted fosamprenavir may select for mutations associated with
resistance to darunavir.2

Efficacy and Pharmacokinetics

Dosing recommendations for fosamprenavir are based on three pediatric studies that enrolled more
than 200 children aged 4 weeks to 18 years. In two, open-label trials in both treatment-experienced
and treatment-naive children aged 2 to 18 years,3,4 fosamprenavir was well-tolerated and effective in
suppressing viral load and increasing CD4 T lymphocyte count. However, data were insufficient to
support a once-daily dosing regimen of fosamprenavir/ritonavir in children; therefore, once-daily
dosing is not recommended for pediatric patients.

Pharmacokinetics in Infants
In a study of infants, higher doses of both fosamprenavir and ritonavir were used in treatment-naive
infants as young as age 4 weeks and in treatment-experienced infants as young as age 6 months.1,5
Exposures in those aged <6 months were much lower than those achieved in older children and
adults and comparable to those seen with unboosted fosamprenavir (see table below). Given these
low exposures, limited data, large dosing volumes, unpleasant taste, and the availability of
alternatives for infants and young children, the Panel does not recommend fosamprenavir use in
infants aged <6 months.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-276
Table A. Fosamprenavir Dose and Amprenavir Exposure by Age Group

AUC 0-24h
(mcg*hr/mL) C min
Population Dose
Except Where (mcg/mL)
Noted
Infants Aged FPV 45 mg/kg plus RTV 10 mg/kg twice daily 26.6a 0.86
<6 Months

Children Aged FPV 30 mg/kg twice daily (no RTV) 22.3a 0.513
2 Years to <6 Years

Children Weighing FPV 45 mg/kg plus RTV 7 mg/kg twice daily 57.3 1.65
<11 kg

Children Weighing FPV 23 mg/kg FPV plus RTV 3 mg/kg twice daily 121.0 3.56
15 kg to <20 kg

Children Weighing FPV 18 mg/kg plus RTV 3 mg/kg twice daily 72.3–97.9 1.98–2.54
≥20 kg (maximum 700/100 mg)

Adults FPV 1400 mg twice daily (no RTV) 33 0.35

Adults FPV 1400 mg plus RTV 100–200 mg RTV once daily 66.4–69.4 0.86–1.45

Adults FPV 700 mg plus RTV 100 mg twice daily 79.2 2.12
a AUC 0-12 (mcg*hr/mL)
Key: AUC 0-24h = area under the curve for 24 hours post-dose; C min = minimum plasma concentration; FPV = fosamprenavir;
RTV = ritonavir
Note: Dose for those weighing 11 kg to <15 kg is based on population pharmacokinetic studies; therefore, AUC and C min are not
available.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-277
References
1. Fosamprenavir [package insert]. Food and Drug Administration. 2016. Available at
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/022116s023_21548-s39lbl.pdf.

2. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of
antiretroviral agents in adults and adolescents with HIV. 2022. Available at
https://clinicalinfo.hiv.gov/sites/default/files/guidelines/documents/guidelines-adult-
adolescent-arv.pdf.

3. Chadwick E, Borkowsky W, Fortuny C, et al. Safety and antiviral activity of

fosamprenavir/ritonavir once daily regimens in HIV-infected pediatric subjects ages 2 to 18
years (48-week interim data, study apv20003). Presented at: 14th Conference on Retroviruses
and Opportunistic Infections. 2007. Los Angeles, CA.

4. Fortuny C, Duiculescu D, Cheng K, et al. Pharmacokinetics and 48-week safety and antiviral
activity of fosamprenavir-containing regimens in HIV-infected 2- to 18-year-old children.
Pediatr Infect Dis J. 2014;33(1):50-56. Available at
http://www.ncbi.nlm.nih.gov/pubmed/23811744.

5. Cotton M, Cassim H, Pavia-Ruz N, et al. Pharmacokinetics, safety and antiviral activity of

fosamprenavir/ritonavir-containing regimens in HIV-infected children aged 4 weeks to 2
years-48-week study data. Pediatr Infect Dis J. 2014;33(1):57-62. Available at
http://www.ncbi.nlm.nih.gov/pubmed/23811743.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-278
Indinavir (IDV, Crixivan)
Updated: May 22, 2018
Reviewed: May 22, 2018

Formulations
Capsules: 100 mg, 200 mg, and 400 mg

For additional information, see Drugs@FDA.

Dosing Recommendations Selected Adverse Events

Neonate and Infant Dose • Nephrolithiasis
• Not approved for use in neonates/infants • Gastrointestinal intolerance, nausea
• Should not be administered to neonates because of the • Hepatitis
risks associated with hyperbilirubinemia (kernicterus)
• Indirect hyperbilirubinemia
Pediatric Dose • Hyperlipidemia
• Not approved for use in children • Hyperglycemia
• A range of indinavir doses (234–500 mg/m2 body surface • Fat maldistribution
area) boosted with low-dose ritonavir has been studied in
children (see text below). • Possible increased bleeding episodes in patients with
hemophilia
Adolescent and Adult Dose
• 800 mg indinavir plus 100 or 200 mg ritonavir every Special Instructions
12 hours
• When indinavir is given in combination with ritonavir,
• The Panel on Antiretroviral Therapy and Medical meal restrictions are not necessary.
Management of Children Living with HIV does not
recommend the use of indinavir in adolescents. • Adequate hydration is required to minimize risk of
nephrolithiasis (≥48 oz of fluid daily in adult patients).
• Indinavir capsules are sensitive to moisture; store at room
temperature (59–86ºF) in original container with
desiccant.

Metabolism/Elimination
• Cytochrome P450 3A4 (CYP3A4) inhibitor and substrate

Indinavir Dosing in Patients with Hepatic Impairment

• Dose should be decreased in patients with mild-to-
moderate hepatic impairment (recommended dose for
adults is 600 mg indinavir every 8 hours). No dosing
information is available for children with any degree of
hepatic impairment or for adults with severe hepatic
impairment.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-279
Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent Guidelines
and the HIV Drug Interaction Checker.

• Metabolism: Cytochrome P450 3A4 (CYP3A4) is the major enzyme responsible for metabolism.
There is potential for multiple drug interactions with indinavir.
• Avoid other drugs that cause hyperbilirubinemia, such as atazanavir.
• Before administration, a patient’s medication profile should be carefully reviewed for potential
drug interactions with indinavir.

Major Toxicities
• More common: Nephrolithiasis/urolithiasis with indinavir crystal deposit is reported more
frequently in children (29%) than in adults (12.4%).1 Interstitial nephritis and urothelial
inflammation has been commonly reported in adults.2 Nausea, abdominal pain, headache,
metallic taste, dizziness, asymptomatic hyperbilirubinemia (10%), lipid abnormalities, pruritus,
and rash.
• Less common (more severe): Fat maldistribution.
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting
diabetes mellitus, spontaneous bleeding in hemophiliacs, acute hemolytic anemia, and hepatitis
(life-threatening in rare cases).

Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
Indinavir has not been approved by the Food and Drug Administration for use in the pediatric
population. Although indinavir was one of the first protease inhibitors to be studied in children, its
use in pediatrics has never been common and is currently very rare.3 Indinavir is not recommended
by the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV for
use in children and adolescents because of its unfavorable toxicity profile, limited efficacy data, and
uncertain pharmacokinetics.

Efficacy and Pharmacokinetics

Both unboosted and ritonavir-boosted indinavir have been studied in children with HIV. In children,
an unboosted indinavir dose of 500 to 600 mg/m2 body surface area given every 8 hours results in
peak blood concentrations and area under the curve that are slightly higher than those in adults, but
trough concentrations are considerably lower. A significant proportion of children have trough
indinavir concentrations less than the 0.1 mg/L value associated with virologic efficacy in adults.4-7

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-280
Studies that investigated a range of indinavir/ritonavir doses in small groups of children have shown
that indinavir 500 mg/m2 body surface area plus ritonavir 100 mg/m2 body surface area twice daily is
probably too high,8 that indinavir 234 to 250 mg/m2 body surface area plus low-dose ritonavir twice
daily is too low,9,10 and that indinavir 400 mg/m2 body surface area plus ritonavir 100 to 125 mg/m2
body surface area twice daily results in exposures approximating those seen with indinavir 800 mg
plus ritonavir 100 mg twice daily in adults, albeit with considerable inter-individual variability and
high rates of toxicity.10-12

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-281
References
1. Indinavir [package insert]. Food and Drug Administration. 2015. Available at
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020685s077lbl.pdf.

2. Kopp JB, Falloon J, Filie A, et al. Indinavir-associated interstitial nephritis and urothelial
inflammation: clinical and cytologic findings. Clin Infect Dis. 2002;34(8):1122-1128.
Available at https://www.ncbi.nlm.nih.gov/pubmed/11915002.

3. Van Dyke RB, Patel K, Siberry GK, et al. Antiretroviral treatment of US children with
perinatally acquired HIV infection: temporal changes in therapy between 1991 and 2009 and
predictors of immunologic and virologic outcomes. J Acquir Immune Defic Syndr.
2011;57(2):165-173. Available at http://www.ncbi.nlm.nih.gov/pubmed/21407086.

4. Burger DM, van Rossum AM, Hugen PW, et al. Pharmacokinetics of the protease inhibitor
indinavir in human immunodeficiency virus type 1-infected children. Antimicrob Agents
Chemother. 2001;45(3):701-705. Available at http://www.ncbi.nlm.nih.gov/pubmed/11181346.

5. Fletcher CV, Brundage RC, Remmel RP, et al. Pharmacologic characteristics of indinavir,
didanosine, and stavudine in human immunodeficiency virus-infected children receiving
combination therapy. Antimicrob Agents Chemother. 2000;44(4):1029-1034. Available at
http://www.ncbi.nlm.nih.gov/pubmed/10722507.

6. Gatti G, Vigano A, Sala N, et al. Indinavir pharmacokinetics and parmacodynamics in

children with human immunodeficiency virus infection. Antimicrob Agents Chemother.
2000;44(3):752-755. Available at http://www.ncbi.nlm.nih.gov/pubmed/10681350.

7. Mueller BU, Sleasman J, Nelson RP, Jr., et al. A phase I/II study of the protease inhibitor
indinavir in children with HIV infection. Pediatrics. 1998;102(1 Pt 1):101-109. Available at
http://www.ncbi.nlm.nih.gov/pubmed/9651421.

8. van Rossum AM, Dieleman JP, Fraaij PL, et al. Persistent sterile leukocyturia is associated
with impaired renal function in human immunodeficiency virus type 1-infected children
treated with indinavir. Pediatrics. 2002;110(2 Pt 1):e19. Available at
http://www.ncbi.nlm.nih.gov/pubmed/12165618.

9. Plipat N, Cressey TR, Vanprapar N, Chokephaibulkit K. Efficacy and plasma concentrations

of indinavir when boosted with ritonavir in human immunodeficiency virus-infected Thai
children. Pediatr Infect Dis J. 2007;26(1):86-88. Available at
http://www.ncbi.nlm.nih.gov/pubmed/17195716.

10. Curras V, Hocht C, Mangano A, et al. Pharmacokinetic study of the variability of indinavir
drug levels when boosted with ritonavir in HIV-infected children. Pharmacology.
2009;83(1):59-66. Available at http://www.ncbi.nlm.nih.gov/pubmed/19052483.

11. Bergshoeff AS, Fraaij PL, van Rossum AM, et al. Pharmacokinetics of indinavir combined
with low-dose ritonavir in human immunodeficiency virus type 1-infected children.
Antimicrob Agents Chemother. 2004;48(5):1904-1907. Available at
http://www.ncbi.nlm.nih.gov/pubmed/15105157.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-282
12. Fraaij PL, Bergshoeff AS, van Rossum AM, Hartwig NG, Burger DM, de Groot R. Changes
in indinavir exposure over time: a case study in six HIV-1-infected children. J Antimicrob
Chemother. 2003;52(4):727-730. Available at http://www.ncbi.nlm.nih.gov/pubmed/12917234.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-283
Nelfinavir (NFV, Viracept)
Updated: May 22, 2018
Reviewed: May 22, 2018

Formulations
Tablets: 250 mg and 625 mg

For additional information, see Drugs@FDA.

Dosing Recommendations Selected Adverse Events

Note: The Panel on Antiretroviral Therapy and Medical • Diarrhea
Management of Children Living with HIV no longer
recommends nelfinavir-based regimens for use in children due • Hyperlipidemia
to inferior potency compared to other regimens. • Hyperglycemia
Neonate and Infant Dose • Fat maldistribution
• Nelfinavir should not be used for treatment in children aged • Serum transaminase elevations
<2 years.
Special Instructions
Pediatric Dose (Aged ≥2 Years)
• 45–55 mg/kg twice daily • Administer nelfinavir with meal or light snack.
• If co-administered with didanosine, administer nelfinavir
Adolescent and Adult Dose 2 hours before or 1 hour after didanosine.
• 1,250 mg (five 250-mg tablets or two 625-mg tablets) twice • Patients unable to swallow nelfinavir tablets can dissolve
daily the tablets in a small amount of water. Once tablets are
dissolved, mix the cloudy mixture well and consume it
immediately. The glass should be rinsed with water and the
rinse swallowed to ensure that the entire dose is
consumed. Tablets can also be crushed and administered
with pudding or other nonacidic foods.

Metabolism/Elimination
• Cytochrome P (CYP) 2C19 and 3A4 substrate
• Metabolized to active M8 metabolite
• CYP3A4 inhibitor

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent Guidelines
and the HIV Drug Interaction Checker.

• Metabolism: Cytochrome P (CYP) 2C19 and 3A4 substrate and CYP3A4 inhibitor. Ritonavir
boosting does not significantly increase nelfinavir concentrations, and co-administration of
nelfinavir with ritonavir is not recommended.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-284
• There is potential for multiple drug interactions with nelfinavir. Before administering nelfinavir,
carefully review a patient’s medication profile for potential drug interactions.

Major Toxicities
• More common: Diarrhea (most common), asthenia, abdominal pain, rash, lipid abnormalities
• Less common (more severe): Fat redistribution, exacerbation of chronic liver disease
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing
diabetes mellitus, spontaneous bleeding in patients with hemophilia, elevations in transaminases

Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
Nelfinavir is approved by the Food and Drug Administration (FDA) for use in children aged
≥2 years. Given the higher variability of nelfinavir plasma concentrations in infants and younger
children,1,2 nelfinavir is not approved for children aged <2 years. Despite being FDA-approved for
pediatric use, nelfinavir is not recommended for use in children and adolescents by the Panel on
Antiretroviral Therapy and Medical Management of Children Living with HIV, due to its limited
efficacy and uncertain pharmacokinetics (PK).

Efficacy in Pediatric Clinical Trials

Nelfinavir used in combination with other antiretroviral (ARV) drugs has been extensively studied in
children with HIV infection.3-10 In randomized trials of children aged 2 to 13 years receiving
nelfinavir as part of triple combination therapy, the proportion of patients with HIV RNA
<400 copies/mL through 48 weeks of therapy has been quite variable, ranging from 26% to 69%. The
antiviral response to nelfinavir is significantly less in children aged <2 years than in older
children.8,10,11 In clinical studies, virologic and immunologic response to nelfinavir-based therapy has
varied according to the patient’s age or prior treatment history, the number of drugs included in the
combination regimen, and the dose of nelfinavir used.

Pharmacokinetics: Exposure-Response Relationships

Nelfinavir’s relatively poor ability to control plasma viremia in infants and children in clinical trials
may be related to its lower potency when compared with other ARV drugs, as well as highly variable
drug exposure, metabolism, and poor palatability.12-14 The bioavailability of dissolved nelfinavir
tablets is comparable to that of tablets swallowed whole.3,15

Administration of nelfinavir with food increases nelfinavir exposure (area under the curve increases
by up to fivefold) and decreases PK variability when compared to the fasted state. Nelfinavir plasma
exposure may be even more unpredictable in pediatric patients than in adults due to the increased

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-285
clearance of nelfinavir observed in children and difficulties in taking nelfinavir with sufficient food
to improve bioavailability.

Nelfinavir is metabolized by multiple CYP450 enzymes, including CYP3A4 and CYP2C19. The
variability of drug exposure at any given dose is much higher for children than for adults,16 which
has been attributed—at least in part—to differences in the diets of children and adults. Two
population PK studies of nelfinavir and its active metabolite, M8, describe the large intersubject
variability observed in children.17,18 Furthermore, CYP2C19 genotype has been shown to affect
nelfinavir PK and the virologic responses in children with HIV.12

Several studies have demonstrated a correlation between nelfinavir trough concentrations and
virologic response. In both children and adults, an increased risk of virologic failure was associated
with low nelfinavir drug exposure, particularly with a nelfinavir minimum plasma concentration
(C min ) <1.0 mcg/mL.19-21

In a study of 32 children treated with a high dose of nelfinavir (a twofold increase of the
recommended dose), 80% of children with morning trough nelfinavir plasma concentration
>0.8 mcg/mL had HIV RNA concentrations <50 copies/mL at Week 48, compared with only 29% of
those with morning trough <0.8 mcg/mL.22 Children in the group with C trough <0.8 mcg/mL were
younger than the children in the group with C trough >0.8 mcg/mL (median ages in these groups were
3.8 years and 8.3 years, respectively).22 Therapeutic drug monitoring of nelfinavir plasma
concentrations, with appropriate adjustments for low drug exposure, has been shown to improve
virologic response in adults and children.18,19,23,24 Pediatric and adolescent and patients may require
doses higher than those recommended in adults to achieve higher plasma nelfinavir exposure.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-286
References
1. Capparelli EV, Sullivan JL, Mofenson L, et al. Pharmacokinetics of nelfinavir in human
immunodeficiency virus-infected infants. Pediatr Infect Dis J. 2001;20(8):746-751.
Available at http://www.ncbi.nlm.nih.gov/pubmed/11734735.

2. Mirochnick M, Stek A, Acevedo M, et al. Safety and pharmacokinetics of nelfinavir

coadministered with zidovudine and lamivudine in infants during the first 6 weeks of life.
J Acquir Immune Defic Syndr. 2005;39(2):189-194. Available at
http://www.ncbi.nlm.nih.gov/pubmed/15905735.

3. Aboulker JP, Babiker A, Chaix ML, et al. Highly active antiretroviral therapy started in
infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug
resistance outcome. AIDS. 2004;18(2):237-245. Available at
http://www.ncbi.nlm.nih.gov/pubmed/15075541.

4. King JR, Nachman S, Yogev R, et al. Efficacy, tolerability and pharmacokinetics of two
nelfinavir-based regimens in human immunodeficiency virus-infected children and
adolescents: pediatric AIDS clinical trials group protocol 403. Pediatr Infect Dis J.
2005;24(10):880-885. Available at http://www.ncbi.nlm.nih.gov/pubmed/16220085.

5. Krogstad P, Lee S, Johnson G, et al. Nucleoside-analogue reverse-transcriptase inhibitors

plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human
immunodeficiency virus type 1. Clin Infect Dis. 2002;34(7):991-1001. Available at
http://www.ncbi.nlm.nih.gov/pubmed/11880966.

6. Krogstad P, Wiznia A, Luzuriaga K, et al. Treatment of human immunodeficiency virus

1-infected infants and children with the protease inhibitor nelfinavir mesylate. Clin Infect
Dis. 1999;28(5):1109-1118. Available at http://www.ncbi.nlm.nih.gov/pubmed/10452644.

7. Luzuriaga K, McManus M, Mofenson L, et al. A trial of three antiretroviral regimens in

HIV-1-infected children. N Engl J Med. 2004;350(24):2471-2480. Available at
http://www.ncbi.nlm.nih.gov/pubmed/15190139.

8. Paediatric European Network for Treatment of AIDS (PENTA). Comparison of dual

nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in
children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial.
Lancet. 2002;359(9308):733-740. Available at
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract
&list_uids=11888583&query_hl=42.

9. Resino S, Larru B, Maria Bellon J, et al. Effects of highly active antiretroviral therapy with
nelfinavir in vertically HIV-1 infected children: 3 years of follow-up. Long-term response to
nelfinavir in children. BMC Infect Dis. 2006;6:107. Available at
http://www.ncbi.nlm.nih.gov/pubmed/16834769.

10. Scherpbier HJ, Bekker V, van Leth F, Jurriaans S, Lange JM, Kuijpers TW. Long-term
experience with combination antiretroviral therapy that contains nelfinavir for up to 7 years
in a pediatric cohort. Pediatrics. 2006;117(3):e528-536. Available at
http://www.ncbi.nlm.nih.gov/pubmed/16481448.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-287
11. Nelfinavir [package insert]. Food and Drug Administration. 2011. Available at
http://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020778s035,020779s056,021503
s017lbl.pdf.

12. Saitoh A, Capparelli E, Aweeka F, et al. CYP2C19 genetic variants affect nelfinavir
pharmacokinetics and virologic response in HIV-1-infected children receiving highly active
antiretroviral therapy. J Acquir Immune Defic Syndr. 2010;54(3):285-289. Available at
http://www.ncbi.nlm.nih.gov/pubmed/19890215.

13. Wu H, Lathey J, Ruan P, et al. Relationship of plasma HIV-1 RNA dynamics to baseline
factors and virological responses to highly active antiretroviral therapy in adolescents (aged
12–22 years) infected through high-risk behavior. J Infect Dis. 2004;189(4):593-601.
Available at
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract
&list_uids=14767811&query_hl=31.

14. Walmsley S, Bernstein B, King M, et al. Lopinavir-ritonavir versus nelfinavir for the initial
treatment of HIV infection. N Engl J Med. 2002;346(26):2039-2046. Available at
http://www.ncbi.nlm.nih.gov/pubmed/12087139.

15. Regazzi MB, Seminari E, Villani P, et al. Nelfinavir suspension obtained from nelfinavir
tablets has equivalent pharmacokinetic profile. J Chemother. 2001;13(5):569-574. Available
at http://www.ncbi.nlm.nih.gov/pubmed/11760223.

16. Gatti G, Castelli-Gattinara G, Cruciani M, et al. Pharmacokinetics and pharmacodynamics of

nelfinavir administered twice or thrice daily to human immunodeficiency virus type
1-infected children. Clin Infect Dis. 2003;36(11):1476-1482. Available at
http://www.ncbi.nlm.nih.gov/pubmed/12766843.

17. Hirt D, Urien S, Jullien V, et al. Age-related effects on nelfinavir and M8 pharmacokinetics:
a population study with 182 children. Antimicrob Agents Chemother. 2006;50(3):910-916.
Available at http://www.ncbi.nlm.nih.gov/pubmed/16495250.

18. Crommentuyn KM, Scherpbier HJ, Kuijpers TW, Mathot RA, Huitema AD, Beijnen JH.
Population pharmacokinetics and pharmacodynamics of nelfinavir and its active metabolite
M8 in HIV-1-infected children. Pediatr Infect Dis J. 2006;25(6):538-543. Available at
http://www.ncbi.nlm.nih.gov/pubmed/16732153.

19. Burger DM, Hugen PW, Aarnoutse RE, et al. Treatment failure of nelfinavir-containing triple
therapy can largely be explained by low nelfinavir plasma concentrations. Ther Drug Monit.
2003;25(1):73-80. Available at
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract
&list_uids=12548148&query_hl=15.

20. Gonzalez de Requena D, Nunez M, de Mendoza C, Jimenez-Nacher I, Soriano V. Nelfinavir

plasma concentrations in patients experiencing early failure with nelfinavir-containing triple
combinations. AIDS. 2003;17(3):442-444. Available at
http://www.ncbi.nlm.nih.gov/pubmed/12556700.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-288
21. Pellegrin I, Breilh D, Montestruc F, et al. Virologic response to nelfinavir-based regimens:
pharmacokinetics and drug resistance mutations (VIRAPHAR study). AIDS.
2002;16(10):1331-1340. Available at http://www.ncbi.nlm.nih.gov/pubmed/12131209.

22. Burger DM, Bergshoeff AS, De Groot R, et al. Maintaining the nelfinavir trough
concentration above 0.8 mg/L improves virologic response in HIV-1-infected children.
J Pediatr. 2004;145(3):403-405. Available at
http://www.ncbi.nlm.nih.gov/pubmed/15343199.

23. Burger D, Hugen P, Reiss P, et al. Therapeutic drug monitoring of nelfinavir and indinavir in
treatment-naive HIV-1-infected individuals. AIDS. 2003;17(8):1157-1165. Available at
http://www.ncbi.nlm.nih.gov/pubmed/12819517.

24. Fletcher CV, Brundage RC, Fenton T, et al. Pharmacokinetics and pharmacodynamics of
efavirenz and nelfinavir in HIV-infected children participating in an area-under-the-curve
controlled trial. Clin Pharmacol Ther. 2008;83(2):300-306. Available at
http://www.ncbi.nlm.nih.gov/pubmed/17609682.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-289
Saquinavir (SQV, Invirase)
Updated: May 22, 2018
Reviewed: May 22, 2018

Formulations
Capsules: 200 mg
Tablets: 500 mg

For additional information, see Drugs@FDA.

Dosing Recommendations Selected Adverse Events

Pediatric Dose • Gastrointestinal intolerance, nausea, diarrhea
• Not approved for use in infants, children, and adolescents • Elevated transaminases
aged <16 years.
• Hyperlipidemia
Adolescent and Adult Dose • Hyperglycemia
• Saquinavir should only be used in combination with • Fat maldistribution
ritonavir.
• PR interval prolongation, QT interval prolongation, and
• Saquinavir 1000 mg plus ritonavir 100 mg twice daily ventricular tachycardia (Torsades de Pointes)

Special Instructions
• Administer within 2 hours after a full meal.
• Sun exposure can cause photosensitivity reactions; advise
patients to use sunscreen or protective clothing.
• Pre-therapy electrocardiogram is recommended;
saquinavir is contraindicated in patients with a prolonged
QT interval.

Metabolism/Elimination
• Cytochrome P450 3A4 (CYP3A4) substrate and inhibitor
• 90% metabolized in the liver
• Use saquinavir with caution in patients who have hepatic
impairment; no dose adjustment recommended.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent Guidelines
and the HIV Drug Interaction Checker.

• Saquinavir is both a substrate and inhibitor of the cytochrome P 450 3A4 (CYP3A4) system.
Potential exists for multiple drug interactions. Saquinavir should not be coadministered with

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-290
 drugs that are highly dependent on CYP3A clearance, especially in cases where elevated plasma
concentrations of the coadministered drug can cause serious or life-threatening events.
• Before administration, a patient’s medication profile should be carefully reviewed for potential
drug interactions.

Major Toxicities
• More common: Diarrhea, abdominal discomfort, headache, nausea, paresthesia, skin rash, lipid
abnormalities
• Less common (more severe): Exacerbation of chronic liver disease, lipodystrophy
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of pre-existing
diabetes mellitus, spontaneous bleeding in patients with hemophilia, pancreatitis, and elevation in
serum transaminases. Saquinavir administered with ritonavir can lead to prolonged QT and/or PR
intervals with potential for heart block and ventricular tachycardia (Torsades de Pointes).

Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval
Saquinavir is not approved for use in children or adolescents aged <16 years.1

Efficacy
Saquinavir has been studied with nucleoside reverse transcriptase inhibitors and other protease
inhibitors in children with HIV.2-9 Saquinavir/ritonavir (SQV/r) and a dual-protease inhibitor
saquinavir/lopinavir/ritonavir regimen were considered for salvage therapy in children prior to the
emergence of the new classes of antiretroviral medications; these regimens are no longer
recommended.

Pharmacokinetics
Pharmacokinetic (PK) data from children who received SQV/r showed prohibitively low exposure in
children younger than 2 years.10 In children aged ≥2 years, a dose of saquinavir 50 mg/kg twice daily
in combination with ritonavir and lopinavir/ritonavir resulted in steady-state plasma trough
concentrations (Ctrough) similar to those seen adults.9,11 No clinical trials have collected data on the
efficacy of saquinavir doses <50 mg/kg in children.

Toxicity
In healthy adult volunteers, SQV/r dose and exposure were associated with increases in both QT and
PR intervals.1,12 Rare cases of Torsades de Pointes and complete heart block have been reported in
postmarketing surveillance. SQV/r is not recommended for adolescent and adult patients with any

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-291
of the following conditions: documented congenital or acquired QT prolongation, pretreatment QT
interval of >450 milliseconds, refractory hypokalemia or hypomagnesemia, complete atrioventricular
block without implanted pacemakers, at risk of complete atrioventricular block, or the use of other
drugs that prolong QT interval. An electrocardiogram (EKG) is recommended before initiation of
therapy with saquinavir and repeat EKGs should be considered during therapy.

Steady-state saquinavir exposures observed in one pediatric trial (NV20911) were substantially
higher than those seen in historical data from adults with QT and PR prolongation.1,12 Although no
EKG abnormalities have been reported among the small number of subjects in pediatric trials,
pediatric PK/pharmacodynamics modeling suggests that reducing the saquinavir dose in order to
minimize the risk of QT prolongation would decrease saquinavir efficacy in children. Pediatric
saquinavir dose recommendations that were both reliably effective and below the thresholds of
concern for QT and PR prolongation were not determined.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-292
References
1. Saquinavir [package insert]. Food and Drug Administration. 2015. Available at
http://www.accessdata.fda.gov/drugsatfda_docs/label/2015/020628s43-021785s19lbl.pdf.

2. Ananworanich J, Kosalaraksa P, Hill A, et al. Pharmacokinetics and 24-week efficacy/safety

of dual boosted saquinavir/lopinavir/ritonavir in nucleoside-pretreated children. Pediatr
Infect Dis J. 2005;24(10):874-879. Available at
http://www.ncbi.nlm.nih.gov/pubmed/16220084.

3. De Luca M, Miccinesi G, Chiappini E, Zappa M, Galli L, De Martino M. Different kinetics

of immunologic recovery using nelfinavir or lopinavir/ritonavir-based regimens in children
with perinatal HIV-1 infection. Int J Immunopathol Pharmacol. 2005;18(4):729-735.
Available at http://www.ncbi.nlm.nih.gov/pubmed/16388722.

4. Grub S, Delora P, Ludin E, et al. Pharmacokinetics and pharmacodynamics of saquinavir in

pediatric patients with human immunodeficiency virus infection. Clin Pharmacol Ther.
2002;71(3):122-130. Available at http://www.ncbi.nlm.nih.gov/pubmed/11907486.

5. Hoffmann F, Notheis G, Wintergerst U, Eberle J, Gurtler L, Belohradsky BH. Comparison of

ritonavir plus saquinavir- and nelfinavir plus saquinavir-containing regimens as salvage
therapy in children with human immunodeficiency type 1 infection. Pediatr Infect Dis J.
2000;19(1):47-51. Available at http://www.ncbi.nlm.nih.gov/pubmed/10643850.

6. Kline MW, Brundage RC, Fletcher CV, et al. Combination therapy with saquinavir soft
gelatin capsules in children with human immunodeficiency virus infection. Pediatr Infect Dis
J. 2001;20(7):666-671. Available at http://www.ncbi.nlm.nih.gov/pubmed/11465838.

7. Palacios GC, Palafox VL, Alvarez-Munoz MT, et al. Response to two consecutive protease
inhibitor combination therapy regimens in a cohort of HIV-1-infected children. Scandinavian
journal of infectious diseases. 2002;34(1):41-44. Available at
http://www.ncbi.nlm.nih.gov/pubmed/11874163.

8. Robbins BL, Capparelli EV, Chadwick EG, et al. Pharmacokinetics of high-dose lopinavir-
ritonavir with and without saquinavir or nonnucleoside reverse transcriptase inhibitors in
human immunodeficiency virus-infected pediatric and adolescent patients previously treated
with protease inhibitors. Antimicrob Agents Chemother. 2008;52(9):3276-3283. Available at
http://www.ncbi.nlm.nih.gov/pubmed/18625762.

9. Bunupuradah T, van der Lugt J, Kosalaraksa P, et al. Safety and efficacy of a double-boosted
protease inhibitor combination, saquinavir and lopinavir/ritonavir, in pretreated children at 96
weeks. Antivir Ther. 2009;14(2):241-248. Available at
http://www.ncbi.nlm.nih.gov/pubmed/19430099.

10. Haznedar J, Zhang A, Labriola-Tompkins E, et al. A pharmacokinetic study of ritonavir-

boosted saquinavir in HIV-infected children 4 months to <6 years old. Presented at: 17th
Conference on Retroviruses and Opportunistic Infections (CROI); February 16–19, 2010;
San Francisco, CA.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-293
11. Kosalaraksa P, Bunupuradah T, Engchanil C, et al. Double boosted protease inhibitors,
saquinavir, and lopinavir/ritonavir, in nucleoside pretreated children at 48 weeks. Pediatr
Infect Dis J. 2008;27(7):623-628. Available at
http://www.ncbi.nlm.nih.gov/pubmed/18520443.

12. Zhang X, Jordan P, Cristea L, et al. Thorough QT/QTc study of ritonavir-boosted saquinavir
following multiple-dose administration of therapeutic and supratherapeutic doses in healthy
participants. J Clin Pharmacol. 2012;52(4):520-529. Available at
http://www.ncbi.nlm.nih.gov/pubmed/21558456.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-294
Stavudine (d4T, Zerit)
Updated: May 22, 2018
Reviewed: May 22, 2018

Formulations
Powder for Oral Solution: 1 mg/mL
Capsules: 15 mg, 20 mg, 30 mg, and 40 mg

Generic Formulations
Powder for Oral Solution: 1 mg/mL
Capsules: 15 mg, 20 mg, 30 mg, and 40 mg

For additional information, see Drugs@FDA.

Dosing Recommendations Selected Adverse Events

Note: Stavudine is no longer recommended for use in • Associated with a higher risk of mitochondrial toxicity than
children by the Panel on Antiretroviral Therapy and Medical other NRTI drugs
Management of Children Living with HIV, because it causes
higher rates of adverse effects than other nucleoside reverse • Peripheral neuropathy is dose-related and occurs more
transcriptase inhibitors (NRTIs). frequently in patients who have advanced HIV disease or a
prior history of peripheral neuropathy, and in patients
Pediatric (Aged ≥14 Days and Weighing <30 kg) Dose receiving other drugs associated with neuropathy.

• 1 mg/kg per dose twice daily • Facial/peripheral lipoatrophy

• Pancreatitis
Adolescent (Weighing ≥30 kg) and Adult Dose
• Lactic acidosis/severe hepatomegaly with hepatic steatosis
• 30 mg per dose twice daily (higher incidence than with other NRTIs). The risk
increases when stavudine is used in combination with
didanosine.
• Dyslipidemia
• Insulin resistance, asymptomatic hyperglycemia
• Rapidly progressive ascending neuromuscular weakness
(rare)

Special Instructions
• Stavudine can be given without regard to food.
• Shake stavudine oral solution well before use. Keep
refrigerated; the solution is stable for 30 days.

Metabolism/Elimination
• Renal excretion 50%. Decrease dose in patients with renal
dysfunction.
• Stavudine is phosphorylated intracellularly to the active
metabolite stavudine triphosphate.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-295
Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent Guidelines
and the HIV Drug Interaction Checker.

• Renal elimination: Drugs that decrease renal function could decrease stavudine clearance.
• Other nucleoside reverse transcriptase inhibitors (NRTIs): Stavudine should not be
administered in combination with zidovudine because of virologic antagonism.
• Overlapping toxicities: The combination of stavudine and didanosine is not recommended
because of overlapping toxicities. Reported toxicities occur more frequently in adults and include
serious, even fatal, cases of lactic acidosis with hepatic steatosis with or without pancreatitis in
pregnant women.
• Ribavirin and interferon: Hepatic decompensation (sometimes fatal) has occurred in patients with
HIV/hepatitis C virus co-infection who are receiving antiretroviral therapy (ART), interferon, and
ribavirin.
• Doxorubicin: Simultaneous use of doxorubicin and stavudine should be avoided. Doxorubicin
may inhibit the phosphorylation of stavudine to its active form.

Major Toxicities
• More common: Headache, gastrointestinal disturbances, skin rashes, hyperlipidemia, fat
maldistribution
• Less common (more severe): Peripheral sensory neuropathy is dose-related. It occurs more
frequently in patients with advanced HIV disease, a prior history of peripheral neuropathy, and in
patients receiving other drugs associated with neuropathy. Pancreatitis. Lactic acidosis and severe
hepatomegaly with hepatic steatosis, including fatal cases, have been reported.1-3 The
combination of stavudine and didanosine may result in enhanced toxicity (increased risk of fatal
and nonfatal cases of lactic acidosis, pancreatitis, peripheral neuropathy, and hepatotoxicity),
particularly in adults, including pregnant persons—this combination should not be used. Risk
factors found to be associated with lactic acidosis in adults include female sex, obesity, and
prolonged nucleoside exposure.4
• Rare: Increased liver enzymes and hepatic toxicity, which may be severe or fatal. Neurologic
symptoms, including rapidly progressive ascending neuromuscular weakness, are most often seen
in the setting of lactic acidosis. Noncirrhotic portal hypertension with prolonged exposure.

Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-296
Pediatric Use
Approval
Although stavudine is Food and Drug Administration (FDA)-approved for use in infants aged
≥14 days and children, it is no longer recommended for use by the Panel on Antiretroviral Therapy
and Medical Management of Children Living with HIV because it carries a higher risk of adverse
effects associated with mitochondrial toxicity and a higher incidence of lipoatrophy than other
NRTIs.

Efficacy
Data from multiple pediatric studies of stavudine administered alone or in combination with other
antiretroviral (ARV) agents demonstrate that stavudine is associated with clinical and virologic
response.5-11 In resource-limited countries, stavudine is frequently a component of initial ART in
children, given with lamivudine and nevirapine. Stavudine is often a component of fixed-dose
combinations that are not available in the United States. In this setting, reported outcomes from
observational studies are good; data show substantial increases in the CD4 T lymphocyte (CD4) cell
count and complete viral suppression in 50% to 80% of treatment-naive children.12-15 In such a
setting, where pediatric patients are already predisposed to anemia because of malnutrition, parasitic
infestations, or sickle cell anemia, stavudine carries a lower risk of hematologic toxicity than
zidovudine, especially in patients receiving trimethoprim-sulfamethoxazole (TMP-SMX)
prophylaxis.16 Short-term use of stavudine in certain settings where access to other ARVs may be
limited remains an important strategy for treating HIV in children.17,18

Toxicity
Stavudine is associated with a higher rate of adverse events than zidovudine in adults and children
receiving ART.19,20 In a large pediatric natural history study (PACTG 219C), stavudine-containing
regimens had a modest—but significantly higher—rate of clinical and laboratory toxicities than
regimens containing zidovudine, with pancreatitis, peripheral neuropathy, and
lipodystrophy/lipoatrophy (fat maldistribution) associated more often with stavudine use.20

Lipodystrophy and Metabolic Abnormalities

Lipodystrophy syndrome (LS), and specifically lipoatrophy (loss of subcutaneous fat), are toxicities
associated with NRTIs, particularly stavudine, in adults and children.21-24 Stavudine use has
consistently been associated with a higher risk of lipodystrophy and other metabolic abnormalities
(e.g., insulin resistance) in multiple pediatric studies involving children.25-33 Improvements in (or
resolution of) lipodystrophy were reported in 22.9% to 73% of cases after discontinuation of
stavudine in two separate studies.30,34

Lactic acidosis with hepatic steatosis, including fatal cases, has been reported with use of nucleoside
analogues, including stavudine, alone or in combination with didanosine.1-3

Mechanism
Many of the stavudine-related adverse events are believed to be due to mitochondrial toxicity
resulting from inhibition of mitochondrial DNA polymerase gamma, with depletion of mitochondrial

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-297
DNA in fat, muscle, peripheral blood mononuclear cells, and other tissues.1,35-37 In a recent analysis
involving a large cohort of pediatric patients (PACTG protocols 219 and 219C), possible
mitochondrial dysfunction was associated with NRTI use, especially in children receiving stavudine
and/or lamivudine.38

World Health Organization Recommendations

The World Health Organization (WHO) cautions against using doses of stavudine that exceed 30 mg
twice daily. This is in contrast to the FDA-recommended dose of 40 mg twice daily in patients
weighing 60 kg or more.39,40 Studies comparing the efficacy and toxicity of the two doses have
consistently shown that both doses have similar efficacy. However, while the 30-mg dose shows
lower toxicity than the 40-mg dose, the overall incidence of toxicity with the 30-mg dose is
considered to be unacceptably high.41-45 WHO recommends that stavudine be phased out of use in all
patients because of concerns about unacceptable toxicity, even at the lower dose. Safer alternative
agents can be prescribed.

Pharmacokinetics
Current pediatric dosing recommendations are based on early pharmacokinetic (PK) studies designed
to achieve exposure (area under the curve) in children similar to that found in adults receiving a dose
with proven efficacy.46 Although WHO has recommended using a reduced dose in adults, a similar
dose reduction has not been suggested in children. A reduced pediatric dose has been proposed based
on PK modeling, but clinical data on intracellular concentrations of the active stavudine triphosphate
are lacking.47,48 Intracellular stavudine triphosphate concentrations have not been measured in
neonates.

Formulations
The pediatric formulation for stavudine oral solution requires refrigeration and has limited stability
once reconstituted. As an alternative dosing method for children, capsules can be opened and
dispersed in a small amount of water, with the appropriate dose drawn up into an oral syringe and
administered immediately. Because plasma exposure of stavudine is equivalent whether the drug is
administered in an intact or a dispersed capsule, dosing with the dispersal method can be used as an
alternative to the oral solution.49

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-298
References
1. Haugaard SB, Andersen O, Pedersen SB, et al. Depleted skeletal muscle mitochondrial DNA,
hyperlactatemia, and decreased oxidative capacity in HIV-infected patients on highly active
antiretroviral therapy. J Med Virol. 2005;77(1):29-38. Available at
http://www.ncbi.nlm.nih.gov/pubmed/16032748.

2. Koh MT. Unrecognized near-fatal hyperlactatemia in an HIV-infected infant exposed to

nucleoside reverse transcriptase inhibitors. Int J Infect Dis. 2007;11(1):85-86. Available at
http://www.ncbi.nlm.nih.gov/pubmed/16581278.

3. Hernandez Perez E, Dawood H. Stavudine-induced hyperlactatemia/lactic acidosis at a

tertiary communicable diseases clinic in South Africa. J Int Assoc Physicians AIDS Care
(Chic). 2010;9(2):109-112. Available at http://www.ncbi.nlm.nih.gov/pubmed/20484736.

4. Matthews LT, Giddy J, Ghebremichael M, et al. A risk-factor guided approach to reducing

lactic acidosis and hyperlactatemia in patients on antiretroviral therapy. PLoS One.
2011;6(4):e18736. Available at http://www.ncbi.nlm.nih.gov/pubmed/21494566.

5. Aboulker JP, Babiker A, Chaix ML, et al. Highly active antiretroviral therapy started in
infants under 3 months of age: 72-week follow-up for CD4 cell count, viral load and drug
resistance outcome. AIDS. 2004;18(2):237-245. Available at
http://www.ncbi.nlm.nih.gov/pubmed/15075541.

6. Kline MW, Dunkle LM, Church JA, et al. A phase I/II evaluation of stavudine (d4T) in
children with human immunodeficiency virus infection. Pediatrics. 1995;96(2 Pt 1):247-252.
Available at http://www.ncbi.nlm.nih.gov/pubmed/7630678.

7. Kline MW, Fletcher CV, Federici ME, et al. Combination therapy with stavudine and
didanosine in children with advanced human immunodeficiency virus infection:
pharmacokinetic properties, safety, and immunologic and virologic effects. Pediatrics.
1996;97(6 Pt 1):886-890. Available at http://www.ncbi.nlm.nih.gov/pubmed/8657531.

8. Kline MW, Van Dyke RB, Lindsey JC, et al. Combination therapy with stavudine (d4T) plus
didanosine (ddI) in children with human immunodeficiency virus infection. The Pediatric
AIDS Clinical Trials Group 327 Team. Pediatrics. 1999;103(5):e62. Available at
http://www.ncbi.nlm.nih.gov/pubmed/10224206.

9. Krogstad P, Lee S, Johnson G, et al. Nucleoside-analogue reverse-transcriptase inhibitors

plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human
immunodeficiency virus type 1. Clin Infect Dis. 2002;34(7):991-1001. Available at
http://www.ncbi.nlm.nih.gov/pubmed/11880966.

10. Nachman SA, Stanley K, Yogev R, et al. Nucleoside analogs plus ritonavir in stable
antiretroviral therapy-experienced HIV-infected children: a randomized controlled trial.
Pediatric AIDS Clinical Trials Group 338 Study Team. JAMA. 2000;283(4):492-498.
Available at http://www.ncbi.nlm.nih.gov/pubmed/10659875.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-299
11. Yogev R, Lee S, Wiznia A, et al. Stavudine, nevirapine and ritonavir in stable antiretroviral
therapy-experienced children with human immunodeficiency virus infection. Pediatr Infect
Dis J. 2002;21(2):119-125. Available at http://www.ncbi.nlm.nih.gov/pubmed/11840078.

12. Bolton-Moore C, Mubiana-Mbewe M, Cantrell RA, et al. Clinical outcomes and CD4 cell
response in children receiving antiretroviral therapy at primary health care facilities in
Zambia. JAMA. 2007;298(16):1888-1899. Available at
http://www.ncbi.nlm.nih.gov/pubmed/17954540.

13. Janssens B, Raleigh B, Soeung S, et al. Effectiveness of highly active antiretroviral therapy in
HIV-positive children: evaluation at 12 months in a routine program in Cambodia.
Pediatrics. 2007;120(5):e1134-1140. Available at
http://www.ncbi.nlm.nih.gov/pubmed/17954553.

14. Kamya MR, Mayanja-Kizza H, Kambugu A, et al. Predictors of long-term viral failure
among ugandan children and adults treated with antiretroviral therapy. J Acquir Immune
Defic Syndr. 2007;46(2):187-193. Available at
http://www.ncbi.nlm.nih.gov/pubmed/17693883.

15. Zhang F, Haberer JE, Zhao Y, et al. Chinese pediatric highly active antiretroviral therapy
observational cohort: a 1-year analysis of clinical, immunologic, and virologic outcomes.
J Acquir Immune Defic Syndr. 2007;46(5):594-598. Available at
http://www.ncbi.nlm.nih.gov/pubmed/18043313.

16. Okechukwu AA, Gambo D, Okechukwu IO. Prevalence of anaemia in HIV-infected children
at the University of Abuja Teaching Hospital, Gwagwalada. Niger J Med. 2010;19(1):50-57.
Available at http://www.ncbi.nlm.nih.gov/pubmed/20232757.

17. Kenny J, Musiime V, Judd A, Gibb D. Recent advances in pharmacovigilance of

antiretroviral therapy in HIV-infected and exposed children. Curr Opin HIV AIDS.
2012;7(4):305-316. Available at http://www.ncbi.nlm.nih.gov/pubmed/22678488.

18. Palmer M, Chersich M, Moultrie H, Kuhn L, Fairlie L, Meyers T. Frequency of stavudine

substitution due to toxicity in children receiving antiretroviral treatment in sub-Saharan
Africa. AIDS. 2013;27(5):781-785. Available at
http://www.ncbi.nlm.nih.gov/pubmed/23169331.

19. Robbins GK, De Gruttola V, Shafer RW, et al. Comparison of sequential three-drug regimens
as initial therapy for HIV-1 infection. N Engl J Med. 2003;349(24):2293-2303. Available at
http://www.ncbi.nlm.nih.gov/pubmed/14668455.

20. Van Dyke RB, Wang L, Williams PL, Pediatric ACTGCT. Toxicities associated with dual
nucleoside reverse-transcriptase inhibitor regimens in HIV-infected children. J Infect Dis.
2008;198(11):1599-1608. Available at http://www.ncbi.nlm.nih.gov/pubmed/19000014.

21. Joly V, Flandre P, Meiffredy V, et al. Increased risk of lipoatrophy under stavudine in
HIV-1-infected patients: results of a substudy from a comparative trial. AIDS.
2002;16(18):2447-2454. Available at http://www.ncbi.nlm.nih.gov/pubmed/12461419.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-300
22. European Paediatric Lipodystrophy Group. Antiretroviral therapy, fat redistribution and
hyperlipidaemia in HIV-infected children in Europe. AIDS. 2004;18(10):1443-1451.
Available at
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=15199321&query_hl=60.

23. Ene L, Goetghebuer T, Hainaut M, Peltier A, Toppet V, Levy J. Prevalence of lipodystrophy

in HIV-infected children: a cross-sectional study. Eur J Pediatr. 2007;166(1):13-21.
Available at http://www.ncbi.nlm.nih.gov/pubmed/16896646.

24. Haubrich RH, Riddler SA, DiRienzo AG, et al. Metabolic outcomes in a randomized trial of
nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment.
AIDS. 2009;23(9):1109-1118. Available at http://www.ncbi.nlm.nih.gov/pubmed/19417580.

25. Jacobson DL, Patel K, Siberry GK, et al. Body fat distribution in perinatally HIV-infected
and HIV-exposed but uninfected children in the era of highly active antiretroviral therapy:
outcomes from the Pediatric HIV/AIDS Cohort Study. Am J Clin Nutr. 2011;94(6):1485-
1495. Available at http://www.ncbi.nlm.nih.gov/pubmed/22049166.

26. Dapena M, Jimenez B, Noguera-Julian A, et al. Metabolic disorders in vertically

HIV-infected children: future adults at risk for cardiovascular disease. J Ped Endocrin Metab.
2012;25(5-6):529-535. Available at http://www.ncbi.nlm.nih.gov/pubmed/22876550.

27. Alam N, Cortina-Borja M, Goetghebuer T, et al. Body fat abnormality in HIV-infected

children and adolescents living in Europe: prevalence and risk factors. J Acquir Immune
Defic Syndr. 2012;59(3):314-324. Available at
http://www.ncbi.nlm.nih.gov/pubmed/22205436.

28. Kinabo GD, Sprengers M, Msuya LJ, et al. Prevalence of lipodystrophy in HIV-infected
children in Tanzania on highly active antiretroviral therapy. Pediatr Infect Dis J.
2013;32(1):39-44. Available at http://www.ncbi.nlm.nih.gov/pubmed/23038217.

29. Piloya T, Bakeera-Kitaka S, Kekitiinwa A, Kamya MR. Lipodystrophy among HIV-infected

children and adolescents on highly active antiretroviral therapy in Uganda: a cross sectional
study. J Int AIDS Soc. 2012;15(2):17427. Available at
http://www.ncbi.nlm.nih.gov/pubmed/22814353.

30. Aurpibul L, Puthanakit T, Taejaroenkul S, et al. Improvement of lipodystropy in children

after substitution of stavudine with zidovudine in NNRTI-based antiretroviral therapy,
Abstract #CDB437. Presented at: 6th IAS Conference on HIV Pathogenesis Treatment and
Prevention. 2011. Rome, Italy.

31. Innes SEV, van Niekerk M, Rabie H, et al. Prevalence and risk factors for lipoatrophy among
pre-pubertal African children on HAART, Abstract #CDB430. Presented at: 6th IAS
Conference on HIV Pathogensesis, Treatment and Prevention. 2011. Rome, Italy.

32. Cohen S, Innes S, Geelen SP, et al. Long-term changes of subcutaneous fat mass in
HIV-infected children on antiretroviral therapy: a retrospective analysis of longitudinal data
from two pediatric HIV-cohorts. PLoS One. 2015;10(7):e0120927. Available at
http://www.ncbi.nlm.nih.gov/pubmed/26148119.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-301
33. Fortuin-de Smidt M, de Waal R, Cohen K, et al. First-line antiretroviral drug discontinuations
in children. PLoS One. 2017;12(2):e0169762. Available at
https://www.ncbi.nlm.nih.gov/pubmed/28192529.

34. Sawawiboon N, Wittawatmongkol O, Phongsamart W, Prasitsuebsai W, Lapphra K,

Chokephaibulkit K. Lipodystrophy and reversal of facial lipoatrophy in perinatally
HIV-infected children and adolescents after discontinuation of stavudine. Int J STD AIDS.
2012;23(7):497-501. Available at http://www.ncbi.nlm.nih.gov/pubmed/22844004.

35. Blanco F, Garcia-Benayas T, Jose de la Cruz J, Gonzalez-Lahoz J, Soriano V. First-line

therapy and mitochondrial damage: different nucleosides, different findings. HIV Clin Trials.
2003;4(1):11-19. Available at http://www.ncbi.nlm.nih.gov/pubmed/12577192.

36. Cherry CL, Gahan ME, McArthur JC, et al. Exposure to dideoxynucleosides is reflected in
lowered mitochondrial DNA in subcutaneous fat. J Acquir Immune Defic Syndr.
2002;30(3):271-277. Available at
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list
_uids=12131563.

37. Sanchez-Conde M, de Mendoza C, Jimenez-Nacher I, Barreiro P, Gonzalez-Lahoz J,

Soriano V. Reductions in stavudine dose might ameliorate mitochondrial-associated
complications without compromising antiviral activity. HIV Clin Trials. 2005;6(4):197-202.
Available at http://www.ncbi.nlm.nih.gov/pubmed/16214736.

38. Crain MJ, Chernoff MC, Oleske JM, et al. Possible mitochondrial dysfunction and its
association with antiretroviral therapy use in children perinatally infected with HIV. J Infect
Dis. 2010;202(2):291-301. Available at http://www.ncbi.nlm.nih.gov/pubmed/20533872.

39. World Health Organization. Toxicity of reduced and standard doses of d4T. 2009. Available
at http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf.

40. World Health Organization. Rapid advice. Antiretroviral therapy for HIV infection in adults
and adolescents. 2009. Available at http://www.who.int/hiv/pub/arv/rapid_advice_art.pdf.

41. Pahuja M, Glesby M, Grobler A, et al. Effects of a reduced dose of stavudine (d4T) on the
incidence and severity of peripheral neuropathy in PLHIV in South Africa. Abstract
#WEPE0149. Presented at: IAS-AIDS. 2010.

42. Hoffmann CJ, Charalambous S, Fielding KL, et al. HIV suppression with stavudine 30 mg
versus 40 mg in adults over 60 kg on antiretroviral therapy in South Africa. AIDS.
2009;23(13):1784-1786. Available at http://www.ncbi.nlm.nih.gov/pubmed/19491652.

43. Pujades-Rodriguez M, Dantony E, Pinoges L, et al. Toxicity associated with stavudine dose
reduction from 40 to 30 mg in first-line antiretroviral therapy. PLoS One. 2011;6(11):e28112.
Available at http://www.ncbi.nlm.nih.gov/pubmed/22132226.

44. Brennan A, Maskew M, Sanne I, Fox M. The effect of 30 vs. 40 mg of stavudine vs.
tenofovir on treatment outcomes amongst HIV+ patients: Johannesburg, South Africa.
Abstract # 1098. Presented at: Conference on Retroviruses and Opportunistic Infections.
2013. Atlanta, GA.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-302
45. Maskew M, Westreich D, Fox MP, Maotoe T, Sanne IM. Effectiveness and safety of 30 mg
versus 40 mg stavudine regimens: a cohort study among HIV-infected adults initiating
HAART in South Africa. J Int AIDS Soc. 2012;15(1):13. Available at
http://www.ncbi.nlm.nih.gov/pubmed/22410312.

46. Kaul S, Kline MW, Church JA, Dunkle LM. Determination of dosing guidelines for
stavudine (2',3'-didehydro-3'-deoxythymidine) in children with human immunodeficiency
virus infection. Antimicrob Agents Chemother. 2001;45(3):758-763. Available at
http://www.ncbi.nlm.nih.gov/pubmed/11181356.

47. Sy SK, Innes S, Derendorf H, Cotton MF, Rosenkranz B. Estimation of intracellular

concentration of stavudine triphosphate in HIV-infected children given a reduced dose of
0.5 milligrams per kilogram twice daily. Antimicrob Agents Chemother. 2014;58(2):1084-
1091. Available at http://www.ncbi.nlm.nih.gov/pubmed/24295968.

48. Sy SK, Malmberg R, Matsushima A, et al. Effect of reducing the paediatric stavudine dose
by half: a physiologically-based pharmacokinetic model. Int J Antimicrob Agents.
2015;45(4):413-419. Available at http://www.ncbi.nlm.nih.gov/pubmed/25697412.

49. Innes S, Norman J, Smith P, et al. Bioequivalence of dispersed stavudine: opened versus
closed capsule dosing. Antivir Ther. 2011;16(7):1131-1134. Available at
http://www.ncbi.nlm.nih.gov/pubmed/22024529.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-303
Tipranavir (TPV, Aptivus)
Updated: May 22, 2018
Reviewed: May 22, 2018

Formulations
Oral Solution: 100 mg tipranavir/mL with 116 International Units (IU) vitamin E/mL
Capsules: 250 mg

For additional information, see Drugs@FDA.

Dosing Recommendations Selected Adverse Events

Note: Tipranavir must be boosted with ritonavir. The • Rare cases of fatal and nonfatal intracranial hemorrhage
ritonavir boosting dose used for tipranavir is higher than
• Skin rash (more common in children than adults)
the doses used for other protease inhibitors.
• Nausea, vomiting, diarrhea
Pediatric (Aged <2 Years) Dose
• Hepatotoxicity: elevated transaminases; clinical hepatitis
• Not approved for use in children aged <2 years
• Hyperlipidemia
Pediatric (Aged 2–18 Years) Dose • Hyperglycemia
Note: Not recommended for treatment-naive patients • Elevated creatine phosphokinase
Body Surface Area Dosing
Special Instructions
• Tipranavir/ritonavir (TPV/r) 375 mg/m2/150 mg/m2, both
twice daily (maximum dose is TPV/r 500 mg/200 mg, • Administer tipranavir and ritonavir together and with food.
both twice daily) • Tipranavir oral solution contains 116 IU vitamin E per mL,
which is significantly higher than the reference daily intake for
Weight-Based Dosing vitamin E. Patients taking the oral solution should avoid taking
• TPV/r 14 mg/kg/6 mg/kg, both twice daily (maximum any form of supplemental vitamin E that contains more
dose is TPV/r 500 mg/200 mg, both twice daily) vitamin E than found in a standard multivitamin.
• Tipranavir contains a sulfonamide moiety and should be used
Adult Dose
with caution in patients with sulfonamide allergy.
• TPV/r 500 mg (as two 250-mg capsules)/200 mg, both
• Store tipranavir oral solution at room temperature, 25°C
twice daily
(77°F); do not refrigerate or freeze. Oral solution must be
Note: Not recommended for treatment-naive patients used within 60 days after the bottle is first opened.
• Store unopened bottles of oral tipranavir capsules in a
refrigerator at 2°C to 8°C (36°F to 46°F). Once the bottle has
been opened, capsules can be kept at room temperature
(maximum of 77°F or 25°C) if used within 60 days.
• Use tipranavir with caution in patients who may be at
increased risk of intracranial hemorrhage, including
individuals with brain lesion, head trauma, recent
neurosurgery, coagulopathy, hypertension, or alcoholism, or
who use anticoagulant or antiplatelet agents (including
vitamin E).
• Use of tipranavir is contraindicated in patients with moderate
or severe hepatic impairment.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-304
 Metabolism/Elimination
• Cytochrome P450 3A4 (CYP3A4) inducer and substrate
• P-glycoprotein substrate

Tipranavir Dosing in Patients with Renal Impairment

• No dose adjustment is required.

Tipranavir Dosing in Patients with Hepatic Impairment

• No dose adjustment is required for mild hepatic impairment.
• Use of tipranavir is contraindicated in patients with moderate-
to-severe hepatic impairment.

Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent Guidelines
and the HIV Drug Interaction Checker.

• Tipranavir has the potential for multiple drug interactions. Co-administration of

tipranavir/ritonavir (TPV/r) with drugs that are highly dependent on cytochrome P (CYP) 3A for
clearance or are potent CYP3A inducers is contraindicated.
• Before tipranavir is administered, a patient’s medication profile should be carefully reviewed for
potential drug interactions.
• TPV/r is a potent enzyme inducer and has the potential to decrease plasma concentrations of
other antiretroviral drugs. TPV/r significantly decreases plasma concentrations of etravirine.
Etravirine and TPV/r should not be co-administered.
• TPV/r has been shown to decrease raltegravir concentrations. TPV/r dose adjustment is not
currently recommended when raltegravir is administered twice daily. However, TPV/r should
not be co-administered with raltegravir HD once daily because significantly lower raltegravir
concentrations are likely to occur.
• Tipranavir should be used with caution in patients who are receiving medications known to
increase the risk of bleeding, such as antiplatelet agents, anticoagulants, or high doses of
supplemental vitamin E.

Major Toxicities
• More common: Diarrhea, nausea, fatigue, headache, rash (which is more frequent in children than
in adults), and vomiting. Elevated transaminases, cholesterol, and triglycerides. Elevated creatine
phosphokinase.
• Less common (more severe): Lipodystrophy. Hepatotoxicity: clinical hepatitis and hepatic
decompensation, including some fatalities. Patients with chronic hepatitis B or hepatitis C
coinfection or elevations in transaminases are at increased risk of developing further
transaminase elevations or hepatic decompensation (approximately 2.5-fold risk). Epistaxis,
which is more common with oral solution than capsule formulation.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-305
• Rare: New-onset diabetes mellitus, hyperglycemia, ketoacidosis, exacerbation of preexisting
diabetes mellitus, spontaneous bleeding in hemophiliacs. Increased risk of intracranial
hemorrhage. Tipranavir should be used with caution in patients who may be at risk of increased
bleeding from trauma, surgery, or other medical conditions.

Resistance
The International AIDS Society–USA maintains a list of updated resistance mutations and the
Stanford University HIV Drug Resistance Database offers a discussion of each mutation.

Pediatric Use
Approval and General Considerations
Tipranavir is approved for use in children aged as young as 2 years and is available in a liquid
formulation.

Its indication is limited to those patients who are treatment-experienced and who have HIV strains
that are resistant to more than one protease inhibitor (PI).1 Tipranavir imposes a high pill burden on
patients taking tipranavir capsules and requires a higher dose of boosting ritonavir than the doses
used with other PIs. This increased dose of ritonavir is associated with a greater potential for drug
interactions and increased toxicity. In addition, tipranavir is associated with serious adverse events
(AEs) that limit its use to patients with few treatment options.

Efficacy
The Food and Drug Administration’s approval of tipranavir was based on a multicenter, pediatric
study of the safety, efficacy, and pharmacokinetics (PKs) of TPV/r in children with HIV
(PACTG 1051/BI-1182.14).2 This study enrolled 110 treatment-experienced children (with the
exception of three treatment-naive patients) aged 2 years to 18 years (with a median age of
11.7 years). Patients were randomized to receive two different dosing regimens. The higher dose of
TPV/r (375 mg/150 mg/m2 body surface area [BSA] twice daily) plus optimized background therapy
was associated with better virologic responses at 48 weeks, particularly in the older, more heavily
pretreated patients, when compared to the lower dose that was studied. A follow-up study of
PACTG 1051 participants evaluated the long-term safety, efficacy, and tolerability of TPV/r in
pediatric patients.3 At Week 288, most children were no longer receiving TPV/r. Reasons for
discontinuation included AEs, virologic failure, and nonadherence. The youngest patients who were
stable at Week 48 were more likely to still be on treatment after 5 years with continued efficacy.3

Pharmacokinetics
PK evaluation of the liquid formulation at steady state in children was assessed.4 In children aged
2 to <12 years, a dose of TPV/r 290 mg/115 mg/m2 BSA achieved tipranavir trough concentrations
that were consistent with those achieved in adults receiving standard TPV/r 500 mg/200 mg dosing.
However, children aged 12 to 18 years required a higher dose (375 mg/150 mg/m2 BSA, 30% higher
than the directly scaled adult dose) to achieve drug exposure similar to that seen in adults receiving
the standard TPV/r dose. Based on available data, a dose of TPV/r 375 mg/150 mg/m2 BSA twice
daily is recommended.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-306
Toxicity
AEs were similar between treatment groups in the multicenter, pediatric study.2 Twenty-five percent
of children experienced a drug-related serious AE, and 9% of patients discontinued study drugs
because of AEs. The most common AEs were gastrointestinal disturbances: 37% of participants had
vomiting and 24% had diarrhea. The most common Grade 3 through 4 laboratory abnormalities were
increases in the levels of creatine phosphokinase (11% of participants), alanine aminotransferase
(6.5% of participants), and amylase (7.5% of participants). In the long-term follow-up report for
PACTG 1051, incidence of AEs defined as drug-related was 55% to 65% regardless of age at entry,
with higher discontinuation rates due to AEs in the older age groups.3

Vitamin E is an excipient in the tipranavir oral solution, with a concentration of 116 international
units (IU) of vitamin E and 100 mg tipranavir per mL of solution. The recommended dose of
tipranavir (14 mg/kg body weight) results in a vitamin E dose of 16 IU/kg body weight per day,
significantly higher than the reference daily intake for vitamin E (which is 30 IU for adults and
approximately 6–22 IU for children and adolescents, depending on age of the child or adolescent)
and close to the upper limit of tolerability for children. In PACTG 1051, bleeding events were
reported more commonly in children receiving tipranavir oral capsules (14.3%) than in children
taking tipranavir oral solution (5.75%).2 Overall, the incidence of bleeding episodes (primarily
epistaxis) in pediatric patients observed in clinical trials was 7.5%.5

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-307
References
1. Courter JD, Teevan CJ, Li MH, Girotto JE, Salazar JC. Role of tipranavir in treatment of
patients with multidrug-resistant HIV. Ther Clin Risk Manag. 2010;6:431-441. Available at
http://www.ncbi.nlm.nih.gov/pubmed/20957134.

2. Salazar JC, Cahn P, Yogev R, et al. Efficacy, safety and tolerability of tipranavir
coadministered with ritonavir in HIV-1-infected children and adolescents. AIDS.
2008;22(14):1789-1798. Available at http://www.ncbi.nlm.nih.gov/pubmed/18753862.

3. Salazar JC, Cahn P, Della Negra M, et al. Efficacy and safety of tipranavir coadministered
with ritonavir in HIV-1-infected children and adolescents: 5 years of experience. Pediatr
Infect Dis J. 2014;33(4):396-400. Available at
http://www.ncbi.nlm.nih.gov/pubmed/23995585.

4. Sabo J, Cahn P, Della Negra M, et al. Population pharmacokinetic (PK) assessment of

systemic steady-state tipranavir (TPV) concentrations for HIV+ pediatric patients
administered tipranavir/ritonavir (TPV/r) 290/115 mg/m2 and 375/150 mg/m2 BID (BI
1192.14 and PACTG 1051 study team). Presented at: 13th Conference on Retroviruses and
Opportunistic Infections (CROI). 2006. Denver, CO.

5. Tipranavir [package insert]. Food and Drug Administration. 2015. Available at

https://www.accessdata.fda.gov/drugsatfda_docs/label/2005/021814lbl.pdf.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-308
Appendix B: Acronyms
Updated: April 11, 2023
Reviewed: April 11, 2023

Drug Name Abbreviations

Abbreviation Full Name

3TC lamivudine
ABC abacavir
ATV atazanavir
BIC bictegravir
CAB cabotegravir
COBI or /c cobicistat
d4T stavudine
ddI didanosine
DMPA depot medroxyprogesterone acetate
DOR doravirine
DRV darunavir
DTG dolutegravir
EFV efavirenz
ETR etravirine
EVG elvitegravir
FPV fosamprenavir
FTC emtricitabine
FTR fostemsavir
IBA ibalizumab
IDV indinavir
LPV lopinavir
MVC maraviroc
NFV nelfinavir
NVP nevirapine
RAL raltegravir
RPV rilpivirine
RTV or /r ritonavir

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-1
 Abbreviation Full Name
SQV saquinavir
T-20 enfuvirtide
TAF tenofovir alafenamide
TDF tenofovir disoproxil fumarate
TFV tenofovir
TFV-DP tenofovir diphosphate
Tris tris(hydroxymethyl)aminomethane
TMP-SMX trimethoprim sulfamethoxazole
TMR temsavir
TPV tipranavir
ZDV zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-2
General Terms

Acronym Term
°C degrees Celsius
°F degrees Fahrenheit
%v volume
25-OH-vitamin D 25-hydroxy vitamin D
AE adverse effect or adverse event
AHR adjusted hazard ratio
ALT alanine aminotransferase
ANC absolute neutrophil count
app mobile application
ART antiretroviral therapy
ARV antiretroviral
ASCVD atherosclerotic cardiovascular disease
AST aspartate aminotransferase
AUC area under the curve
AUC 12h 12-hour area under the curve
AUC 24h 24-hour area under the curve
AUC tau area under the concentration time curve over the dosing interval
AV atrioventricular
BCRP breast cancer resistance protein
BHIVA British HIV Association
BMD bone mineral density
BMI body mass index
BSA body surface area
C 0h pre-dose concentration
C 12h concentration at 12 hours
C 24h concentration at 24 hours
CAR chimeric antigen receptor
C avg average plasma concentration
CBC complete blood count
CD4 CD4 T lymphocyte
CDC Centers for Disease Control and Prevention

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-3
 Acronym Term
CI confidence interval
CK creatine kinase
C max maximum plasma concentration
C min minimum plasma concentration
CMV cytomegalovirus
CNS central nervous system
Cr creatinine
CrCl creatinine clearance
CT continuous therapy or continuous treatment
C tau concentration at the end of a dosing interval
C trough trough concentration
CT x C-telopeptide of type 1 collagen
CV coefficient of variation
CVDI cardiovascular disease
CYP cytochrome P450
CYP2B6 cytochrome P450 family 2 subfamily B member 6
DAIDS Division of AIDS (NIAID)
DBS dried blood spot
dL deciliter
DM diabetes mellitus
DNA deoxyribonucleic acid
DOT directly observed therapy
DRESS drug reaction (or rash) with eosinophilia and systemic symptoms
DSG delayed switch group
DSMB Data Safety Monitoring Board
DT dispersible tablet
DXA dual energy X-ray absorptiometry
E2D2 Every Dose, Every Day [Toolkit and App]
EBV Epstein-Barr virus
EC enteric-coated
EC 50 half maximal effective concentration
ECG electrocardiogram

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-4
 Acronym Term
EEG electroencephalogram
eGFR estimated glomerular filtration rate
EM erythema multiforme or extensive metabolizer
FCT film-coated tablet
FDA U.S. Food and Drug Administration
FDC fixed-dose combination
fL femtoliter
FLP fasting lipid profile
fmol femtomole
FPG fasting plasma glucose
g gram
g/dL grams per deciliter
G6PD glucose-6-phosphate dehydrogenase
GA gestational age
GFR glomerular filtration rate
GI gastrointestinal
GLSM geometric least squares mean
GM geometric mean
GMR geometric mean ratio
gp glycoprotein
gp120 glycoprotein 120
h hour
HA height age
HAV hepatitis A virus
HBV hepatitis B virus
HCV hepatitis C virus
HD high dose
HDL-C high-density lipoprotein cholesterol
Hgb hemoglobin
HgbA1c glycosylated hemoglobin
HHS U.S. Department of Health and Human Services
HIV RNA or HIV-1 RNA viral load

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-5
 Acronym Term
HLA human leukocyte antigen
HRSA Health Resources and Services Administration
HSR hypersensitivity reaction
HSV herpes simplex virus
IAS–USA International Antiviral Society–USA
IFPG impaired fasting plasma glucose
IGT impaired glucose tolerance
IM intramuscular
INSTI integrase strand transfer inhibitor
IQ inhibitory quotient
IQR interquartile range
IR insulin resistance
IRIS immune reconstitution inflammatory syndrome
ISG immediate switch group
IU international unit
IV intravenous
IVIG intravenous immune globulin
kg kilogram
L liter
LAI long-acting injectable
LBW low birth weight
LDL low-density lipoprotein
LDL-C low-density lipoprotein cholesterol
LFT liver function test
log 10 the logarithm to the base 10
LS lipodystrophy syndrome
LVH left ventricular hypertrophy
m2 square meter
mcg microgram
MCV mean cell volume
mDAART modified directly administered ART
MEMS Medication Event Monitoring System

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-6
 Acronym Term
mg milligram
min minute
mL milliliter
mm millimeter
mm3 cubic millimeter
mmol millimole
N/A not available or not applicable
NASBA nucleic acid sequence-based amplification
NAT nucleic acid test
ng nanogram
NHLBI National Heart, Lung, and Blood Institute
NHSS National HIV Surveillance System
NIH National Institutes of Health
nM nanometer
NNRTI non-nucleoside reverse transcriptase inhibitor
NRTI nucleoside reverse transcriptase inhibitor
NTD neural tube defect
OARAC Office of AIDS Research Advisory Council
OAT organic anion transporter
OATP organic anion transporter polypeptide
OBT optimized background therapy
OGTT oral glucose tolerance test
OI opportunistic infection
oz ounce
PA-IC 95 protein-adjusted IC 95
The Panel the Panel on Antiretroviral Therapy and Medical Management of Children
Living With HIV
PBMC peripheral blood mononuclear cell
PCP Pneumocystis jirovecii pneumonia
PCR polymerase chain reaction
PEP post-exposure prophylaxis
PG plasma glucose

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-7
 Acronym Term
P-gp P-glycoprotein
PI protease inhibitor
PK pharmacokinetic
POC point of care
PPI proton pump inhibitor
PrEP pre-exposure prophylaxis
PUFA polyunsaturated fatty acid
QTc corrected QT
RCT randomized controlled trial
RNA ribonucleic acid
RPG random plasma glucose
RR relative risk
RT-PCR reverse transcription polymerase chain reaction
SAM severe acute malnutrition
SCT short-cycle therapy
SD standard deviation
SJS Stevens-Johnson syndrome
SM slow metabolizers
SMR sexual maturity rating
SMS short message service
SOC standard of care
SQ subcutaneous
STI sexually transmitted infection
STR single-tablet regimen
T½ half-life
TB tuberculosis
TBLH total body less head
TC total cholesterol
TDM therapeutic drug monitoring
TEN toxic epidermal necrolysis
TG triglyceride
TMA transcription-mediated amplification

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-8
 Acronym Term
T max time to reach maximum concentration
U=U Undetectable = Untransmittable
UGT uridine diphosphate glucuronosyltransferase
UGT1A uridine diphosphate (UDP)-glucuronosyltransferase family 1 member A
complex
ULN upper limit of normal
v/v volume per volume
w weight
w/v weight per volume
WHO World Health Organization
XR extended release

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-9
Study and Trial Names

Acronym Name
ACTG AIDS Clinical Trials Group
AMP Adolescent Master Protocol
ANRS National Agency for AIDS Research (France)
ARROW AntiRetroviral Research fOr Watoto
ATHENA AIDS Therapy Evaluation in the Netherlands
ATLAS Antiretroviral Therapy as Long-Acting Suppression
ATN Adolescent Trials Network
BAN Breastfeeding, Antiretrovirals, and Nutrition
CHAPAS Children with HIV in Africa—Pharmacokinetics and Acceptability of
Simple second-line antiretroviral regimens
CHER Children with HIV Early Antiretroviral Therapy
CRAFFT Car, Relax, Alone, Forget, Friends, and Trouble
DIONE A Study to Evaluate Antiviral Activity of Darunavir + Ritonavir in HIV-1
Infected Adolescents
DolPHIN-2 Dolutegravir in Pregnant HIV Mothers and Their Neonates
ENCORE Evaluation of Novel Concepts in Optimization of antiRetroviral Efficacy
EPIICAL Early-treated Perinatally HIV-infected Individuals: Improving Children’s
Actual Life with Novel Immunotherapeutic Strategies
EPPICC European Pregnancy and Paediatric Infections Cohort Collaboration
FLAIR First Long-Acting Injectable Regimen
HPPM HIV Paediatric Prognostic Markers
HPTN HIV Prevention Trials Network
IeDEA International Epidemiology Databases to Evaluate AIDS
IMPAACT International Maternal Pediatric Adolescent AIDS Clinical Trials
MOCHA More Options for Children and Adolescents
NEVEREST Nevirapine Resistance Study
ODYSSEY Once-daily DTG based ART in Young people vS Standard thErapY
PACTG Pediatric AIDS Clinical Trials Group
PENPACT Trial run in collaboration between PENTA and PACTG/IMPAACT
PENTA Paediatric European Network for Treatment of AIDS
PEPFAR President’s Emergency Plan for AIDS Relief
PHACS Pediatric HIV/AIDS Cohort Study

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-10
 PIANO Paediatric study of Intelence As an NNRTI Option
PREDICT Early Versus Deferred Antiretroviral Therapy for Children Older Than 1
Year Infected with HIV
PROMISE Promoting Maternal and Infant Survival Everywhere Study
PROMOTE PEPFAR PROMise Ongoing Treatment Evaluation
SBIRT Screening, Brief Intervention, and Referral to Treatment
SMILE Strategy for Maintenance of HIV Suppression With Once Daily Integrate
Inhibitor+Darunavir/Ritonavir in Children
START Strategic Timing of AntiRetroviral Treatment

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-11
Appendix C: CDC Pediatric HIV CD4 Cell
Count/Percentage and HIV-Related Diseases
Categorization

Updated: Apr.11, 2022

Reviewed: Apr.11, 2022

Table A. HIV Infection Stage Based on Age-Specific CD4 Count or Percentage

Aged <1 Year Aged 1 Year to <6 Years Aged ≥6 Years

Stagea
Cells/mm3 % Cells/mm3 % Cells/mm3 %
1 ≥1,500 ≥34 ≥1,000 ≥30 ≥500 ≥26
2 750–1,499 26–33 500–999 22–29 200–499 14–25
3 <750 <26 <500 <22 <200 <14
a The stage is based primarily on the CD4 count; the CD4 count takes precedence over the CD4 percentage, and the
percentage is considered only when the count is missing. If a Stage 3–defining condition has been diagnosed (see Table 6),
then the stage is 3, regardless of CD4 test results.
Key: CD4 = CD4 T lymphocyte
Source: Centers for Disease Control and Prevention. Revised surveillance case definition for HIV infection—United States,
2014. MMWR 2014;63(No. RR-3):1-10.

Table B. HIV-Related Symptoms and Conditions

Mildly Symptomatic
Children with two or more of the following conditions, but none of the conditions listed in the Moderately Symptomatic
category, are considered mildly symptomatic:
• Lymphadenopathy (lymph nodes are ≥0.5 cm at more than two sites and/or bilateral at one site)
• Hepatomegaly
• Splenomegaly
• Dermatitis
• Parotitis
• Recurrent or persistent upper respiratory tract infection, sinusitis, or otitis media

Moderately Symptomatic
• Anemia (hemoglobin <8 g/dL [<80 g/L]), neutropenia (white blood cell count <1,000 per µL [<1.0 × 109 per L]), and/or
thrombocytopenia (platelet count <100 × 103 per µL [<100 × 109 per L]) persisting for ≥30 days
• Bacterial meningitis, pneumonia, or sepsis (single episode)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection N-1
 • Candidiasis, oropharyngeal (thrush), persisting for >2 months in children aged >6 months
• Cardiomyopathy
• CMV infection, with onset before age 1 month
• Diarrhea, recurrent or chronic
• Hepatitis
• HSV stomatitis, recurrent (more than two episodes within 1 year)
• HSV bronchitis, pneumonitis, or esophagitis with onset before age 1 month
• Herpes zoster (shingles) involving at least two distinct episodes or more than one dermatome
• Leiomyosarcoma
• Lymphoid interstitial pneumonia or pulmonary lymphoid hyperplasia complex
• Nephropathy
• Nocardiosis
• Persistent fever (lasting >1 month)
• Toxoplasmosis, onset before age 1 month
• Varicella, disseminated (complicated chickenpox)

AIDS-Defining Conditions
• Bacterial infections, multiple or recurrenta
• Candidiasis of bronchi, trachea, or lungs
• Candidiasis of esophagus
• Cervical cancer, invasive
• Coccidioidomycosis, disseminated or extrapulmonary
• Cryptococcosis, extrapulmonary
• Cryptosporidiosis, chronic intestinal (>1-month duration)
• CMV disease (other than liver, spleen, or lymph nodes), onset at age >1 month
• CMV retinitis (with loss of vision)
• Encephalopathy attributed to HIVb
• HSV: chronic ulcers (>1-month duration) or bronchitis, pneumonitis, or esophagitis (onset at age >1 month)
• Histoplasmosis, disseminated or extrapulmonary
• Isosporiasis, chronic intestinal (>1-month duration)
• Kaposi sarcoma
• Lymphoma, Burkitt (or equivalent term)
• Lymphoma, immunoblastic (or equivalent term)
• Lymphoma, primary (of brain)
• Mycobacterium avium complex or Mycobacterium kansasii, disseminated or extrapulmonary

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection N-2
 • Mycobacterium tuberculosis of any site, pulmonary, disseminated, or extrapulmonary
• Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
• Pneumocystis jirovecii (previously known as Pneumocystis carinii) pneumonia
• Pneumonia, recurrentc
• Progressive multifocal leukoencephalopathy
• Salmonella septicemia, recurrent
• Toxoplasmosis of brain, onset at age >1 month
• Wasting syndrome attributed to HIVb

a Only among children aged <6 years.

b Suggested diagnostic criteria for these illnesses, which might be particularly important for HIV encephalopathy and HIV
wasting syndrome, are described in the following references:
Centers for Disease Control and Prevention. 1994 Revised classification system for human immunodeficiency virus infection in
children less than 13 years of age. MMWR. 1994;43(No. RR-12).
Centers for Disease Control and Prevention. 1993 Revised classification system for HIV infection and expanded surveillance
case definition for AIDS among adolescents and adults. MMWR. 1992;41(No. RR-17).
c Only among adults, adolescents, and children aged ≥6 years.
Key: CMV = cytomegalovirus; HSV = herpes simplex virus
Modified from:
Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in
children less than 13 years of age. MMWR. 1994;43(No. RR-12).
Centers for Disease Control and Prevention: Revised Surveillance Case Definition for HIV Infection—United States, 2014.
MMWR. 2014;63(No. RR-3):1-10.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection N-3
Appendix D: Supplemental Information
Updated: Apr.11, 2022
Reviewed: Apr.11, 2022

Table A. Likelihood of Developing AIDS or Death Within 12 Months, by Age and CD4 T-
Cell Percentage or Log10 HIV-1 RNA Copy Number in HIV-Infected Children Receiving
No Therapy or Zidovudine Monotherapy

CD4 Percentage Log 10 HIV RNA Copy Number

Age 10% 20% 25% 30% 6.0 5.0 4.0

Percent Mortality (95% Confidence Interval)
6 Months 28.7 12.4 8.5 6.4 9.7 4.1 2.7
1 Year 19.5 6.8 4.5 3.3 8.8 3.1 1.7
2 Years 11.7 3.1 2.0 1.5 8.2 2.5 1.1
5 Years 4.9 0.9 0.6 0.5 7.8 2.1 0.7
10 Years 2.1 0.3 0.2 0.2 7.7 2.0 0.6
Percent Developing AIDS (95% Confidence Interval)
6 Months 51.4 31.2 24.9 20.5 23.7 13.6 10.9
1 Year 40.5 20.9 15.9 12.8 20.9 10.5 7.8
2 Years 28.6 12.0 8.8 7.2 18.8 8.1 5.3
5 Years 14.7 4.7 3.7 3.1 17.0 6.0 3.2
10 Years 7.4 2.2 1.9 1.8 16.2 5.1 2.2
Note: Table modified from: HIV Paediatric Prognostic Markers Collaborative Study Group. Lancet. 2003;362:1605-1611.

Table B. Death and AIDS/Death Rate per 100 Person-Years by Current Absolute CD4 Cell
Count andAge in HIV-Infected Children Receiving No Therapy or Zidovudine
Monotherapy (HIV Paediatric Prognostic Markers Collaborative Study) and Adult
Seroconverters (CASCADE Study)

Absolute CD4 Cell Count (cells/mm3)

Age (Years)
<50 50–99 100–199 200–349 350–499 500+
Rate of Death Per 100 Patient-Years
0–4 59.3 39.6 25.4 11.1 10.0 3.5
5–14 28.9 11.8 4.3 0.89 0.00 0.00
15–24 34.7 6.1 1.1 0.71 0.58 0.65
25–34 47.7 10.8 3.7 1.1 0.38 0.22
35–44 58.8 15.6 4.5 0.92 0.74 0.85
45–54 66.0 18.8 7.7 1.8 1.3 0.86
55+ 91.3 21.4 17.6 3.8 2.5 0.91

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection O-1
 Rate of AIDS or Death per 100 Patient-Years
0–4 82.4 83.2 57.3 21.4 20.7 14.5
5–14 64.3 19.6 16.0 6.1 4.4 3.5
15–24 61.7 30.2 5.9 2.6 1.8 1.2
25–34 93.2 57.6 19.3 6.1 2.3 1.1
35–44 88.1 58.7 25.5 6.6 4.0 1.9
45–54 129.1 56.2 24.7 7.7 3.1 2.7
55+ 157.9 42.5 30.0 10.0 5.1 1.8
Note: Table modified from: HIV Paediatric Prognostic Markers Collaborative Study and the CASCADE Collaboration. J Infect
Dis. 2008;197:398-404.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection O-2
Table C. Association of Baseline Human Immunodeficiency Virus (HIV) RNA Copy
Number and CD4T-Cell Percentage with Long-Term Risk of Death in HIV-Infected
Childrena

Deathsb
Baseline HIV RNAc (Copies/mL)
No. Patientsd
Baseline CD4 Percentage
Number Percentage

≤100,000
≥15% 103 15 (15%)
<15% 24 15 (63%)

>100,000
≥15% 89 32 (36%)
<15% 36 29 (81%)
aData from the Eunice Kennedy Shriver National Institute of Child Health and Human Development Intravenous Immunoglobulin
Clinical Trial.
b Mean follow-up: 5.1 years.
c Tested by NASBA® assay (manufactured by Organon Teknika, Durham, North Carolina) on frozen stored serum.
d Mean age: 3.4 years.
Source: Mofenson LM, Korelitz J, Meyer WA, et al. The relationship between serum human immunodeficiency virus type 1
(HIV-1) RNA level, CD4 lymphocyte percent, and long-term mortality risk in HIV-1-infected children. J Infect Dis.
1997;175(5):1029–1038.

Figure A. Estimated Probability of AIDS Within 12 Months by Age and CD4 Percentage in
HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy

Figure modified from Lancet 2003;362:1605-1611

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection O-3
Figure B. Estimated Probability of Death Within 12 Months by Age and CD4 Percentage in
HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy

Figure modified from Lancet 2003;362:1605-1611

Figure C. Death Rate per 100 Person-Years in HIV-Infected Children Aged 5 Years or
Older in the HIV Paediatric Prognostic Marker Collaborative Study and HIV-Infected
Seroconverting Adults from the CASCADE Study*

Figure modifed from: HIV Paediatric Prognostic Markers Collaborative Study and the CASCADE Collaboration. J Infect Dis.
2008;197:398-404.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection O-4
Figure D. Estimated Probability of AIDS Within 12 Months of Age and HIV RNA Copy
Number in HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy

Figure modified from Lancet 2003;362:1605-1611

Figure E. Estimated Probability of Death Within 12 Months of Age and HIV RNA Copy
Number in HIV-Infected Children Receiving No Therapy or Zidovudine Monotherapy

Figure modified from Lancet 2003;362:1605-1611

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection O-5