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 ............................................................................................................................... xi
Financial Disclosure ........................................................................................................................................ xiii
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 Labor in People with Unknown HIV Status ....................................................................................B-6
HIV Testing During the Postpartum Period ....................................................................................................................B-7
Preventing HIV Transmission During Infant Feeding .......................................................................................C-1
Overview of Counseling and Management ................................................................................................................... C-3
Factors Affecting Decisions About Infant Feeding ........................................................................................................ C-8
Safety of Antiretroviral Drugs During Breastfeeding ..................................................................................................... C-11
Diagnosis of HIV Infection in Infants and Children.....................................................................................C-21
Diagnosis of HIV in Infants and Children ..................................................................................................................... C-22
Timing of Diagnostic Testing in Infants with Perinatal HIV Exposure .......................................................................... C-23
Table 3: Recommended Virologic Testing Schedules for Infants With Perinatal and
Breastfeeding Exposure to HIV .............................................................................................................................. C-26
Diagnostic Testing in Children with Postnatal HIV Exposure ...................................................................................... C-28
Diagnostic Testing in Children with Non-perinatal HIV Exposure or Children with Perinatal
HIV Exposure Aged >24 Months ................................................................................................................................. C-30
Virologic Assays to Diagnose HIV Infection in Infants Younger Than 18 Months with
Perinatal HIV-1 Exposure ............................................................................................................................................ C-31
Other Issues ................................................................................................................................................................ C-32
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

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

 Table 6. Sample Schedule for Clinical and Laboratory Monitoring of Children Before
and After Initiation of Antiretroviral Therapy ............................................................................................................. D-9
Table 7. Primary U.S. Food and Drug Administration–Approved Assays for Monitoring Viral Load ....................... D-11
When to Initiate Antiretroviral Treatment in Children with HIV Infection .................................................... E-1
What to Start: Antiretroviral Treatment Regimens Recommended for Initial Therapy in
Infants and Children with HIV ......................................................................................................................... F-1
Criteria Used for Recommendations .............................................................................................................................. F-1
Factors to Consider When Selecting an Initial Regimen ................................................................................................ F-2
Table A. Factors to Consider When Selecting an Antiretroviral Treatment Regimen for Children ............................ F-3
Panel Recommendations for Initial ART Regimens in Infants and Children .................................................................. F-5
Planning for Transitions in ART Regimens .................................................................................................................... F-5
Selection of Dual-Nucleoside Reverse Transcriptase Inhibitor Backbone as Part of Initial
Antiretroviral Therapy Regimens .................................................................................................................................... F-6
Recommended Initial ART Regimens for Infants from Birth to <30 Days of Age .......................................................... F-7
Table B. Advantages and Disadvantages of Anchor Drugs Recommended for Initial Antiretroviral Therapy
Regimens in Infants From Birth to <30 Days of Age ................................................................................................. F-9
Recommended Initial ART Regimens for Infants and Children Aged ≥30 Days to <2 Years ...................................... F-11
Recommended Initial ART Regimens for Children Aged ≥2 Years to <12 Years ....................................................... F-14
Recommended Regimens for Children and Adolescents Aged ≥12 Years ................................................................. F-17
Table 8. Antiretroviral Treatment Regimens Recommended for Initial Therapy for HIV Infection in
Infants and Children: Birth to <12 Years of Age ..................................................................................................... F-20
Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended for
Initial Antiretroviral Therapy in Infants and Children ............................................................................................... F-25
What Not to Start: Regimens Not Recommended for Initial Antiretroviral Therapy in
Infants and Children ...................................................................................................................................... F-37
Antiretroviral Drugs and Drug Combinations Not Recommended for Initial Therapy in Children ................................ F-37
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-42
Table 11. Antiretroviral Regimens or Components That Are Never Recommended for
Treating HIV in Children and Adolescents ............................................................................................................... F-43
Antiretroviral Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to HIV............. G-1
Table 12. Transmission Risk Assessment by HIV RNA Levels and Antenatal Time Period ................................... G-4
Table 13. Antiretroviral Management for Infants With In Utero or Intrapartum Exposure to HIV.............................. G-7
Table 13.1. Drug Dosing Recommendations for Antiretroviral Prophylaxis and Presumptive HIV Therapy in Infants
With In Utero or Intrapartum Exposure to HIV......................................................................................................... G-10
Table 14. Antiretroviral Management of Infants With Exposure to HIV During Breastfeeding................................. G-19

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

 Table 14.1. Antiretroviral Prophylaxis Dosing for Infants Who Are Breastfed........................................................ G-21
Figure 1. Algorithm for Antiretroviral Management of Infants With In Utero or Intrapartum HIV Exposure by Risk of HIV
Transmission............................................................................................................................................................ G-6
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
Sexually Transmitted Infections in Adolescents ............................................................................................................ H-4
Contraception, Pregnancy, and Antiretroviral Therapy ................................................................................................. H-5
Special Considerations for Adolescents with HIV Who Are Sexual and Gender 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-3
Strategies to Improve and Support Adherence ............................................................................................................... I-3
Regimen-Related Strategies ........................................................................................................................................... I-4
Family-Related Adherence Strategies............................................................................................................................. I-4
Health Care Provider–Related Strategies ....................................................................................................................... I-6
Table 15. Approaches for Monitoring Medication Adherence ..................................................................................... I-8
Table 16. Strategies to Improve Adherence to Antiretroviral Medications .................................................................. I-9
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-21
Table 17c. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Gastrointestinal Effects ............................................................................................................... J-28
Table 17d. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Hematologic Effects .................................................................................................................... J-33
Table 17e. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Hepatic Events............................................................................................................................ J-39
Table 17f. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Insulin Resistance, Asymptomatic Hyperglycemia, and Diabetes Mellitus ................................. J-46

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection iii
 Table 17g. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Lactic Acidosis ............................................................................................................................ J-51
Table 17h. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Lipodystrophies and Weight Gain ............................................................................................... J-55
Table 17i. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Nephrotoxic Effects ..................................................................................................................... J-64
Table 17j. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Osteopenia and Osteoporosis .................................................................................................... J-70
Table 175k. Antiretroviral Therapy–Associated Adverse Effects and Management
Recommendations—Rash and Hypersensitivity Reactions ......................................................................................... J-77
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-6
Recognizing and Managing Antiretroviral Treatment Failure ....................................................................K-22
Categories of Treatment Failure.................................................................................................................................. K-22
Table 19. Discordance Among Virologic, Immunologic, and Clinical Responses ....................................................K-25
Management of Virologic Failure................................................................................................................................. K-26
Therapeutic Options to Achieve Complete Virologic Suppression After Virologic Failure ........................................... K-27
Management Options When Two Fully Active Agents Cannot Be Identified or Administered ..................................... K-30
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-31
Antiretroviral Treatment Interruption in Children with HIV ........................................................................K-40
Unplanned Treatment Interruptions............................................................................................................................. K-40
Structured Treatment Interruptions ............................................................................................................................. K-41
Short-Cycle Therapy Strategies .................................................................................................................................. K-42
Conclusion .................................................................................................................................................................. K-43
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-36
Tenofovir Disoproxil Fumarate................................................................................................................................. L-58
Zidovudine ............................................................................................................................................................... L-72
Non-Nucleoside Analogue Reverse Transcriptase Inhibitors ....................................................................................... L-82
Doravirine ................................................................................................................................................................ L-83

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

 Efavirenz.................................................................................................................................................................. L-90
Etravirine ............................................................................................................................................................... L-105
Nevirapine ............................................................................................................................................................. L-111
Rilpivirine ............................................................................................................................................................... L-122
Protease Inhibitors ..................................................................................................................................................... L-133
Atazanavir .............................................................................................................................................................. L-134
Darunavir ............................................................................................................................................................... L-146
Lopinavir/Ritonavir ................................................................................................................................................. L-159
Entry and Fusion Inhibitors......................................................................................................................................... L-175
Fostemsavir ........................................................................................................................................................... L-176
Ibalizumab ............................................................................................................................................................. L-182
Maraviroc ............................................................................................................................................................... L-186
Capsid Inhibitor ......................................................................................................................................................... L-191
Lenacapavir .......................................................................................................................................................... L-192
Integrase Inhibitors ..................................................................................................................................................... L-197
Bictegravir .............................................................................................................................................................. L-198
Cabotegravir .......................................................................................................................................................... L-209
Dolutegravir ........................................................................................................................................................... L-217
Elvitegravir ............................................................................................................................................................. L-236
Raltegravir ............................................................................................................................................................. L-249
Pharmacokinetic Enhancers....................................................................................................................................... L-264
Cobicistat ............................................................................................................................................................... L-265
Ritonavir ................................................................................................................................................................ L-271
Fixed-Dose Combinations .......................................................................................................................................... L-277
Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or
as a Co-packaged Formulation, by Drug Class ..................................................................................................... L-278
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-281
Archived Drugs .......................................................................................................................................................... L-287
Didanosine ............................................................................................................................................................ L-288
Enfuvirtide............................................................................................................................................................. L-293
Fosamprenavir ...................................................................................................................................................... L-297
Indinavir ................................................................................................................................................................ L-302
Nelfinavir............................................................................................................................................................... L-307
Saquinavir ............................................................................................................................................................. L-313
Stavudine.............................................................................................................................................................. L-318

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

 Tipranavir.............................................................................................................................................................. L-327
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
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 Log10 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 Guidelines
Updated: December 19, 2024
Reviewed: December 19, 2024

December 19, 2024

The Panel on Antiretroviral Therapy and Medical Management of Children Living With HIV has
reviewed and updated three sections of the Guidelines for the Use of Antiretroviral Agents in
Pediatric HIV Infection that are developed in collaboration with the Panel on Treatment of HIV in
Pregnancy and Prevention of Perinatal Transmission (the Panels). These sections have been revised
to include new data and publications where relevant. Key updates are summarized below.

Preventing HIV Transmission During Infant Feeding

• Bulleted recommendations now include information from the text on counseling about the infant
feeding options of formula feeding, use of banked donor milk, or breastfeeding.
Recommendations also address clinical management if viremia is identified.
o In the case of a detectable viral load during breastfeeding, the Panels recommend
breastfeeding be stopped temporarily or discontinued and replacement feeding initiated while
the viral load is rechecked; causes for the viremia are assessed, and, when applicable,
adherence counseling is reinforced (AII). Most experts recommend permanent
discontinuation of breastfeeding when HIV RNA is ≥200 copies/mL (CIII).
o Depending on the level and persistence of viremia during breastfeeding, next steps may
include initiating or modifying infant antiretroviral (ARV) prophylaxis, permanently stopping
breastfeeding, and considering the need for additional infant HIV testing.
o If the repeat viral load is undetectable, a joint decision should be made by the parent and
providers about whether breastfeeding may resume (AIII).

Diagnosis of HIV Infection in Infants and Children

• Section text and Table 3. Recommended Virologic Testing Schedules for Infants With Perinatal
and Breastfeeding Exposure to HIV have been revised to align with changes in Antiretroviral
Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to HIV.
• The Panels recommend virologic diagnostic testing at birth using an HIV nucleic acid test, which
should generally be performed for all infants with perinatal HIV exposure but is not necessary for
infants at low risk of HIV acquisition (HIV RNA levels <50 copies/mL from 20 weeks of
gestation through delivery put infants at low risk of HIV acquisition). Birth testing should be
performed in infants at low risk of HIV acquisition if there is a plan to breastfeed or there are
concerns about loss to follow-up (BIII).

Antiretroviral Management of Infants With In Utero, Intrapartum or

Breastfeeding Exposure or HIV Infection
• This section has been extensively revised, and the title has been updated to reflect changes in
recommendations, associated content about infant ARV management according to risk from in

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

 utero and intrapartum HIV exposure, and guidance for infant ARV prophylaxis during
breastfeeding.
• The Panels have added Table 12. Transmission Risk Assessment by HIV RNA Levels and
Antenatal Time Period, which summarizes risk of transmission from exposure during three
antenatal time periods. Because robust data are not available to define thresholds of risk across
pregnancy, the Panels have selected time points balancing available data with implications for
clinical management. Transmission risk categories inform ARV choice and management of
prophylaxis and presumptive HIV therapy for infants with HIV exposure.
• Revised criteria for infant risk of HIV infection from in utero or intrapartum exposure and
recommended ARV management are summarized in Figure 1. Algorithm for Antiretroviral
Management of Infants With In Utero or Intrapartum HIV Exposure by Risk of HIV
Transmission and Table 13. Antiretroviral Management for Infants With In Utero or Intrapartum
Exposure to HIV. The Panels recommend the following:
o Viremia (HIV RNA ≥50 copies/mL) in the 4 weeks prior to delivery puts infants at higher risk of
HIV infection from in utero or intrapartum exposure. Infants in this category should be provided
a three-drug ARV regimen, administered from birth for 2 to 6 weeks, that serves as
presumptive HIV therapy or enhanced prophylaxis. If the duration of the three-drug regimen
is shorter than 6 weeks, zidovudine (ZDV) should be continued alone to complete a total of 6
weeks of prophylaxis (AII).
o HIV RNA levels <50 copies/ml from 20 weeks of gestation through delivery put infants at
low risk of in utero and intrapartum HIV acquisition. These infants should receive ZDV
alone for a duration of 2 weeks (AII).
o Infants not meeting the criteria for high or low risk should have ARV regimens and durations
based on case-specific factors related to the level and timing of viremia during the pregnancy
(AII).
• The section now includes updated recommendations and expanded content about ARV
prophylaxis for infants who are being breastfed. Recommendations of the Panels are summarized
in a new table, Table 14. Antiretroviral Management of Infants With Exposure to HIV During
Breastfeeding.
o For infants with low risk of HIV acquisition during breastfeeding, some Panel members do
not recommend extended ARV prophylaxis; however, other Panel members do recommend
extended ARV prophylaxis with either nevirapine or lamivudine (CIII). The Panels did not
reach consensus.
o Infants are considered at low risk of transmission during breastfeeding when (1) the
breastfeeding woman is receiving antiretroviral therapy and has had sustained virologic
suppression (HIV RNA <50 copies/mL) for at least 3 months prior to delivery and (2) the
provider and parent are confident that the breastfeeding woman will maintain ART adherence
during breastfeeding (AII).
• Bulleted recommendations and associated content have been added to provide guidance
about infant ARV prophylaxis or use of presumptive HIV therapy when the breastfeeding
woman experiences new viremia or there are concerns about future risk of viremia.
• Table 14.1. Antiretroviral Prophylaxis Dosing for Infants Who Are Breastfed has been
revised to provide updated dosing information and to address infant ARV management for
scenarios when a breastfeeding woman develops viremia or is diagnosed with HIV during

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection vii
 breastfeeding.

June 27, 2024

Clinical and Laboratory Monitoring of Pediatric HIV Infection
• The section has been updated to address recommended baseline screening tests for coinfections
and opportunistic infections (e.g., tuberculosis, hepatitis B virus, hepatitis C virus,
cytomegalovirus). See Table 6. Sample Schedule for Clinical and Laboratory Monitoring of
Children Before and After Initiation of Antiretroviral Therapy and the Pediatric Opportunistic
Infection Guidelines.

When to Initiate Antiretroviral Treatment in Children with HIV Infection

• If a child with HIV has not initiated antiretroviral treatment (ART), the Panel recommends that
ART initiation be discussed and strongly encouraged at every visit.
• When there are concerns about optimal timing of ART initiation relative to treatment of
opportunistic infections (e.g., cryptococcal meningitis, tuberculous meningitis, disseminated
Mycobacterium avium complex disease), timing should be discussed with a pediatric HIV
specialist.
• New data provide additional evidence supporting the neurodevelopmental and immune benefits
associated with early initiation of ART.

What to Start: Antiretroviral Treatment Regimens Recommended for Initial

Therapy in Infants and Children with HIV
• The section has been revised to present and discuss Panel recommendations for initial ART
regimens by age group (i.e., birth to <30 days, ≥30 days to <2 years, ≥2 to <12 years, and
≥12 years) rather than by antiretroviral (ARV) drug class. Content has been added within new
subsections to address practical considerations in ARV drug and regimen selection and
implementation of initial ART. Some content is deliberately repeated across the age groups.
• Two new tables have been added to the section: Table A. Factors to Consider When Selecting an
Antiretroviral Treatment Regimen for Children and Table B. Advantages and Disadvantages of
Anchor Drugs Recommended for Initial Antiretroviral Therapy Regimens in Infants from Birth
to <30 days of Age. Table 8. Antiretroviral Treatment Regimens Recommended for Initial
Therapy for HIV Infection in Infants and Children: Birth to <12 Years of Age has been
reorganized to present Preferred and Alternative regimens and ARV drugs by age group to
follow the revised structure of the section.
• Nevirapine- and raltegravir-based regimens continue to be recommended as Preferred ART for
infants aged <30 days. Lopinavir/ritonavir (LPV/r)-based ART is now recommended as an
Alternative regimen for infants in this age group if they have reached a postmenstrual age of
42 weeks and a postnatal age of at least 14 days; LPV/r was previously a Preferred ARV for
infants.
• To avoid delays in initiating treatment in neonates, abacavir (ABC) is now recommended as an
Alternative rather than a Preferred nucleoside reverse transcriptase inhibitor for infants aged <30

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection viii
 days who test negative for the HLA-B*5701 allele.
• The Panel now recommends second-generation integrase strand transfer inhibitor (INSTI)-based
regimens with dolutegravir (DTG) or bictegravir (BIC) as the Preferred anchor drugs for initial
ART in infants and children aged ≥30 days and weighing ≥3 kg whenever possible. DTG is
approved for children aged ≥30 days and weighing ≥3 kg, and BIC is approved for children aged
≥2 years and weighing ≥14 kg. Protease inhibitor (PI)-based regimens are recommended as
Alternative options. Non-nucleoside reverse transcriptase inhibitor-based regimens are
recommended as Alternative options only if needed for resistance or intolerance to INSTIs and
PIs.

What Not to Start: Regimens Not Recommended for Initial Antiretroviral

Therapy in Infants and Children
• Because elvitegravir (EVG) has a lower genetic barrier to the development of resistance
compared to second-generation INSTIs (i.e., DTG, BIC), the Panel no longer recommends EVG
as an Alternative ARV for initial ART regimens in children.
• Lenacapavir (LEN), a capsid inhibitor, has been added to this section. LEN is U.S. Food and
Drug Administration (FDA) approved for use in heavily treatment-experienced adults with
multidrug-resistant HIV-1; it is not approved for initial ART or for use in children.

Special Considerations for Antiretroviral Therapy Use in Adolescents with HIV

• Trauma experience is high among people with HIV generally and among youth with perinatally
acquired HIV. Interest in the adoption of trauma-informed care (TIC) practices for people with
HIV is emerging; however, research evaluating TIC interventions is limited, and efficacy is
mixed. Providers may consider utilizing TIC principles for youth who have experienced trauma.

Adherence to Antiretroviral Therapy in Children and Adolescents with HIV

• The Panel recommends discussing the option of long-acting injectable ART to facilitate and
support adherence with eligible patients and their caregivers.

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.
• 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 recommendations for ARV options in the context of treatment failure.
• Boxed recommendations in Antiretroviral Treatment Interruption in Children with HIV have
been updated to underscore that treatment interruption is not recommended as a strategy to
confirm diagnosis or to assess remission or cure in clinical settings.

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

 o The section has been updated to expand content about mitigating unplanned interruptions in
treatment (e.g., by clinicians working closely with families and providing anticipatory
guidance around potential short-term interruptions from such events as vacation, travel, or
summer camps).
o Guidance for Non-HIV-Specialized Providers Caring for People with HIV Who Have Been
Displaced by Disasters (Such as a Hurricane) addresses the care of children when
unforeseeable events, such as natural disasters, displace them from their primary HIV care
programs.

Appendix A: Pediatric Antiretroviral Drug Information

Drug sections and fixed-dose combination (FDC) tables, 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 FDA approvals of
new formulations and FDCs. Significant changes are summarized below:

• The dispersible FDC ABC/DTG/emtricitabine (Triumeq PD) now has FDA-approved dosing for
use in infants and children aged ≥3 months and weighing ≥6 kg to <25 kg (see Dolutegravir,
Abacavir, and Emtricitabine).
• Information about DTG dispersible tablet (Tivicay) dosing for infants and children with first-
generation INSTI resistance has been added to the Dolutegravir section.
• Based on available data, cautions about the use of DTG in pregnancy due to concerns about
neural defects have been removed from the package inserts for products containing DTG.
• Ritonavir (RTV) oral solution has been discontinued, but the pediatric formulation of 100-mg
powder packets is still available for children who are not able to swallow pills (see Ritonavir).
• Because the minimum dose of the powdered formulation of RTV is now 100 mg, doses of RTV-
boosted atazanavir (ATV/r) and RTV-boosted darunavir (DRV/r) requiring <100 mg RTV have
been removed or updated. Dosing for ATV/r is available for children weighing ≥15 kg. Dosing
for DRV/r is available for children weighing ≥20 kg. See Atazanavir and Darunavir.
• A new drug section has been added for the capsid inhibitor lenacapavir. LEN is FDA approved
for use in adults with multidrug-resistant HIV infection who are heavily treatment experienced.
• The recent FDA approval of rilpivirine tablets for oral suspension (Edurant PED) will be
addressed in the next update of the Rilpivirine section.

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

Members of the HHS Panel on Antiretroviral Therapy
and Medical Management of Children Living with HIV
Updated: June 27, 2024
Reviewed: June 27, 2024

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, MD, MS 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 Northwestern University Feinberg School of Medicine, Chicago, IL

Rana Chakraborty, MD, PhD, MS University of Miami Miller School of Medicine, Miami, FL

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

Summer Drake, DO Los Angeles, CA

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

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

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

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 System, Bronx, NY

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

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

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

Nicole H. Tobin, MD University of California, Los Angeles, Los Angeles, CA

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

Nickolas Agathis, MD, MPH U.S. Food and Drug Administration, Silver Spring, MD

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

Katrina Byrd, MD, MS Centers for Disease Control and Prevention, Atlanta, GA

Dwight E. Yin, MD, PhD National Institutes of Health, Rockville, MD

Non-voting Observers
Adam Bartlett, MBBS, MPHTM, PhD, Sydney Children’s Hospital, Randwick, New South Wales, Australia
FRACP
Australasian Society for HIV, Viral Hepatitis, and Sexual Health Medicine,
Sydney, Australia

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

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 xii
HHS Panel on Antiretroviral Therapy and
Medical Management of Children Living with HIV
Financial Disclosure
Updated: June 27, 2024
Reviewed: June 27, 2024

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

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 ViiV Healthcare Research Support

Drake, Summer M None N/A

Golatt, Mindy HHS None N/A

Hazra, Rohan ES None N/A

Khaitan, Alka M None N/A

McAuley, James B. M None N/A

Melvin, Ann J. CC None N/A

Momper, Jeremiah M None N/A

Neilan, Anne 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. ViiV/GSK 1. Research Support

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection xiii
 Name Panel Status Company Relationship
2. Gilead Sciences 2. Research Support

Ruel, Theodore D. CC 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

Tobin, Nicole H. M None NA

Weinberg, Geoffrey A. M Merck Honoraria

Yin, Dwight E. M None N/A

Key: C = Chair; CC = Co-chair; 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 xiv
Introduction
Updated: June 27, 2024
Reviewed: June 27, 2024

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 (PK) of ARV agents in children. The U.S.
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—

• Pregnancy and Postpartum HIV Testing and Identification of Perinatal and Postnatal HIV
Exposure
• Diagnosis of HIV Infection in Infants and Children
• Antiretroviral Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to
HIV
• Preventing HIV Transmission During Infant Feeding

Since the guidelines were first developed in 1993 (with the support of the François-Xavier Bagnoud
Center, Rutgers School of Nursing, 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A-1
effective initial and subsequent regimens. Treatment strategies focus on early initiation of potent
ARV regimens that 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 ART 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 Panel members are also considered. These

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection A-2
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 U.S. Department of
Health and Human Services (HHS) agencies: the Centers for Disease Control and
Prevention (CDC), 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
Table 1. Outline of the Guidelines Development Process

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 interventions to
prevent perinatal transmission (the Perinatal Guidelines); ART for 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 PK 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,
2018. 2020. 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, et al. 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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/32741214.

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

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

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://pubmed.ncbi.nlm.nih.gov/26743091.

13. Flynn PM, Abrams EJ. Growing up with perinatal HIV. AIDS. 2019;33(4):597-603.
Available at: https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/27749662.

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

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

Technical Requirements of Pharmaceuticals for Human Use; Overview.: 2022.Available
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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://pubmed.ncbi.nlm.nih.gov/22025597.

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

population guidance for industry [package insert]. Food and Drug Administration. 2018.
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ances/UCM530012.pdf.

19. ICH Harmonized Guidelines: Pediatric Extrapoloation E11A [package insert]. Food and
Drug Administration. 2022. Available at: https://www.fda.gov/regulatory-
information/search-fda-guidance-documents/e11a-pediatric-extrapolation.

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: February 20, 2025
Reviewed: February 20, 2025

Panel’s Recommendations
• HIV testing is recommended for all sexually active people and should be a routine component of pre-pregnancy care (AII).
• For all pregnancies, opt-out HIV testing should be done 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).
• For all pregnancies, partners should be referred for HIV testing when their status is unknown (AIII).
• Repeat HIV testing in the third trimester is recommended during pregnancies in which there are negative initial HIV tests
and increased risk of acquiring HIV, including pregnancies in which the care is received in facilities that have an HIV
incidence of ≥1 case per 1,000 patients experiencing pregnancy 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 when there is a sexually transmitted infection during pregnancy, when there are signs
and symptoms of acute HIV infection, or when there is 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 when HIV status is undocumented as well as
when HIV tests were negative early in pregnancy but there is increased risk of HIV infection and there was no retest 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 HIV Care.
• 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 there is a positive HIV test result during labor and delivery or postpartum, a maternal HIV-1/HIV-2 antibody
differentiation assay and an HIV RNA assay should be performed (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 maternal HIV test results 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 standard maternal HIV
diagnostic testing should be offered 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 Infants With In Utero, Intrapartum, or
Breastfeeding Exposure to HIV for guidance.
o When there is an initial positive HIV test during labor or delivery or immediately postpartum and there are plans to
breastfeed, the Panel on Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission recommends
against breastfeeding. Breast milk should be expressed and stored appropriately until all supplemental HIV tests are
reviewed and are negative (AI).

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to Reduce Perinatal HIV Transmission in the United States B-1
 • When there is increased risk of HIV acquisition postpartum, HIV testing and PrEP should be offered. If breastfeeding is
occurring, consult an HIV specialist regarding frequency of HIV testing for the breastfeeding dyad (AIII).
• Maternal HIV test results 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 maternal HIV status 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

Incident HIV infection during pregnancy, postpartum, or 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
• 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.

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to Reduce Perinatal HIV Transmission in the United States B-2
 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. 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 HIV status is undocumented during labor.
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 risk of acute HIV infection during pregnancy, particularly late in pregnancy,
because there may be a negative result for HIV immunoassays during 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.

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to Reduce Perinatal HIV Transmission in the United States B-3
Discordant or False Positive HIV Test Results
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 when there is 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) or as
early as possible in pregnancy. In the United States, approximately 20% to 34% of infants with
perinatal HIV exposure were born to mothers whose HIV diagnosis was not known before
pregnancy.6 Early diagnosis provides the best opportunity to improve maternal health and pregnancy
outcomes and to prevent infant acquisition of HIV. Universal voluntary HIV testing is recommended
as the standard of care during all pregnancies 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 HIV testing should be performed during pregnancy wherever care is
provided (including emergency departments and prenatal clinics) to avoid missed opportunities to
identify HIV infection. Repeat HIV testing should be performed in the third trimester when there is
increased risk of acquiring HIV or when living in areas of high HIV incidence. Repeat testing is also
recommended when a sexually transmitted infection (STI) is diagnosed during pregnancy, or when
symptoms and signs of acute HIV infection are present. When HIV status is unknown or
undocumented during labor, providers should test for HIV 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, HIV testing provides an opportunity for clinicians to initiate a discussion about
preventive interventions, including educating and counseling about pre-exposure prophylaxis (PrEP)
when there is risk for acquiring HIV during pregnancy. See Pre-exposure Prophylaxis (PrEP) to

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to Reduce Perinatal HIV Transmission in the United States B-4
Prevent HIV During Periconception, Antepartum, and Postpartum Periods and guidance available on
CDC’s Pre-exposure Prophylaxis (PrEP) webpage for more information.

Determining HIV status before pregnancy or during the antenatal period enables:

• Provision of 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 during pregnancy and HIV care 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 Infants With In Utero,
Intrapartum, or Breastfeeding Exposure to HIV);
• Shared decision-making on infant feeding choice, specifically breastfeeding or use of
replacement feeding (see Preventing HIV Transmission During Infant Feeding); 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 Infants With In Utero,
Intrapartum, or Breastfeeding Exposure to HIV, and Table 6. What to Start: Initial Antiretroviral
Regimens During Pregnancy When Antiretroviral Therapy Has Never Been Received).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 notification that HIV testing will be performed as part of routine pregnancy care unless
the choice is made 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 during pregnancy, 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 parental consent. In some areas, this applies to all newborns; in others, it applies only when
prenatal or intrapartum maternal testing has been declined.

Repeat HIV Testing in the Third Trimester

Repeat HIV testing during the third trimester, before 36 weeks of gestation, is recommended when
there were negative results on the initial HIV tests during pregnancy and:

• There is high risk of acquiring HIV (i.e., injection drug use or sex with people who inject drugs,
exchange of sex for money or drugs, sex partner with HIV who has a detectable or unknown HIV
viral load, new sex partner or more than one sex partner during the current pregnancy,7 suspected
or diagnosed STI during pregnancy,10 recent immigration from a high-burden HIV setting,
partner who either recently immigrated from a high-burden HIV setting or recently traveled to
such a setting); or

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• Health care is being provided by facilities where prenatal screening identifies one or more HIV
cases per 1,000 patients experiencing pregnancy screened or the jurisdiction of residence (state or
county) has an elevated incidence rate of HIV in females aged 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
• The states or territories of residence have statutes or regulations that require third-trimester HIV
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 State-level clinical guidelines may also recommend third-trimester HIV
testing (e.g., New York). Clinicians should check current requirements and recommendations in
their jurisdictions; or
• There are 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
• There is self-perception as being at increased risk for HIV infection (regardless of whether or not
any of the above criteria apply). When testing is declined earlier in pregnancy, providers should
offer 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 HIV acquisition risk during pregnancy 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

When determining the timing of repeat HIV testing in the third trimester, some clinicians conduct
testing at or around 28 weeks of gestation in conjunction with the recommended timing of syphilis
testing. This approach limits the number of blood draws and allows adequate time for syphilis
treatment and congenital syphilis prophylaxis. Some clinicians also conduct a third test for HIV at
the time of delivery hospitalization admission.

HIV Testing During Labor When HIV Status is Unknown

When HIV status is undocumented during labor or HIV testing was negative early in pregnancy but
there is an increased risk of HIV infection and there was no retesting in the third trimester, expedited
HIV testing should be performed.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 during labor.
An HIV RNA assay should also be performed when there is 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
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• 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
• 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 a maternal HIV RNA
assay 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) 7 days a week. If possible,
results of HIV RNA assays should be available in 24 hours or less.
• When there is a positive HIV test result or suspected acute HIV infection during labor, provide
counseling about HIV test results and implications for care.
o Initiate intravenous zidovudine during labor (see Intrapartum HIV Care).
o Immediately initiate presumptive HIV therapy appropriate for infants who are at high risk of
perinatal HIV transmission (see Antiretroviral Management of Infants With In Utero,
Intrapartum, or Breastfeeding Exposure to HIV or contact the National Clinician
Consultation Center Perinatal HIV/AIDS hotline).
o When there are plans to breastfeed, the Panel on Treatment of HIV During Pregnancy and
Prevention of Perinatal Transmission strongly advises against initiating breastfeeding given
the high risk of perinatal transmission. Breast milk should be expressed and stored
appropriately; it should not be used for infant feeding unless all supplemental HIV test results
are reviewed and determined to be negative (see Preventing HIV Transmission During Infant
Feeding).

HIV Testing During the Postpartum Period

When there has been no testing for HIV during pregnancy or labor, expedited testing during the
immediate postpartum period should be offered. 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 HIV testing is requested postpartum or there is increased risk of HIV acquisition
(e.g., injection drug use or sex with people who inject drugs, exchange of sex for money or drugs, sex
partner with HIV who has a detectable or unknown HIV viral load, new sex partner or more than one
sex partner during the current pregnancy,7 suspected or diagnosed STI during pregnancy,10 recent
immigration from a high-burden HIV setting, partner that either recently immigrated from a high-
burden HIV setting or recently traveled to such a setting) HIV testing and PrEP should be offered.
See Pre-exposure Prophylaxis (PrEP) to Prevent HIV During Periconception, Antepartum, and
Postpartum Periods for more information. If breastfeeding is occurring, consult an HIV specialist
regarding frequency of HIV testing in the breastfeeding dyad.

When an initial maternal or infant HIV test is positive or there is high suspicion of acute HIV
infection, 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 Infants With In Utero, Intrapartum, or Breastfeeding Exposure to
HIV). Providers should counsel 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 HIV negative maternal testing
is confirmed. If supplemental test results are negative and acute HIV is excluded, infant ARV drugs
can be discontinued. In the absence of ongoing HIV exposure, breastfeeding can be initiated.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States B-7
Consultation with a pediatric HIV specialist is strongly recommended if questions remain about the
potential for acute infection while lactating or ongoing infant risk of HIV exposure.

Infant HIV Testing When Maternal HIV Test Results Are Unavailable
When maternal HIV test results are unavailable (e.g., testing declined 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 maternal HIV test results are unavailable, the infant 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 Infants With In
Utero, Intrapartum, or Breastfeeding Exposure to HIV for guidance), and standard maternal HIV
diagnostic testing should be offered 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 when considering becoming pregnant, during all pregnancies and
postpartum periods when there have been previous negative HIV tests, and when breastfeeding.
When there are risk factors for HIV acquisition before, during, and after pregnancy, prevention
counseling and appropriate interventions should be provided, including PrEP if indicated36,37 (see
Prepregnancy Counseling and Care and Pre-exposure Prophylaxis [PrEP] to Prevent HIV During
Periconception, Antepartum, and Postpartum Periods for more information). When there is acute
HIV during pregnancy or lactation, there is an increased risk of perinatal transmission; acute HIV
also increase risk for sexual transmission of HIV (see Early [Acute and Recent] HIV Infection). 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. When acute
HIV infection is possible and breastfeeding is ongoing, counsel about the Panel’s recommendation to
cease breastfeeding immediately until HIV infection is confirmed or excluded.38 Breast milk can be
expressed and stored appropriately while HIV diagnostic testing is completed. Expressed breast milk
should not be used for infant feeding until all supplemental HIV test results are reviewed and
determined to be negative. Breastfeeding can resume if HIV infection is excluded and there is no
ongoing risk. Care during pregnancy or breastfeeding for the breastfeeding dyad when there is acute
or early HIV should follow the recommendations in the Perinatal Guidelines (see Early [Acute and
Recent] HIV Infection, Antiretroviral Management of Infants With In Utero, Intrapartum, or
Breastfeeding Exposure to HIV, and Preventing HIV Transmission During Infant Feeding).

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 confirmed HIV, including infants with confirmed HIV. Reporting infants
who have been exposed to HIV allows the appropriate public health functions to be accomplished.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States B-8
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and antiretroviral use: systematic review of prospective studies of discordant couples.
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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 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 AIDS.
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.

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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.

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.

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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. Abuogi L, Noble L, Smith C, et al. Infant feeding for persons living with and at risk for HIV
in the United States: clinical report. Pediatrics. 2024. Available at:
https://pubmed.ncbi.nlm.nih.gov/38766700.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States B-12
Preventing HIV Transmission During Infant Feeding
Updated: December 19, 2024
Reviewed: December 19, 2024

Panel’s Recommendations
• When there is potential for perinatal HIV transmission, evidence-based, patient-centered counseling should be provided
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, inform 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 through breastfeeding.
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.
• Replacement feeding with formula or banked pasteurized donor human milk is recommended to eliminate the risk of HIV
transmission through breastfeeding when ART is not being taken and/or viral suppression has not been achieved during
pregnancy (at a minimum throughout the third trimester), as well as at delivery (AI).
• When ART is being taken for HIV and a sustained undetectable viral load is achieved, counseling about the options of
formula feeding, use of banked donor milk, or breastfeeding should be provided. Those who choose to breastfeed should
be supported in this decision (AIII).
• If formula feeding is chosen, providers should support in this decision. Providers should ask about potential barriers to
formula feeding and explore ways to address them (AIII).
• In the case of a detectable viral load during breastfeeding, the Panel on Treatment of HIV in Pregnancy and Prevention
of Perinatal Transmission and the Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV
recommend breastfeeding be stopped temporarily or discontinued and replacement feeding initiated while the viral load
is rechecked, causes for the viremia are assessed, and, when applicable, adherence counseling is reinforced (AII) (see
Situations to Consider Stopping or Modifying Breastfeeding in the text below). Most experts recommend permanent
discontinuation of breastfeeding when HIV RNA is ≥200 copies/mL (CIII).
o Depending on the level and persistence of viremia , next steps may include initiating or modifying infant antiretroviral
prophylaxis, permanently stopping breastfeeding, and considering the need for additional infant HIV testing (see
Antiretroviral Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to HIV, Table 14.
Antiretroviral Management of Infants With Exposure to HIV During Breastfeeding, and Table 3. Recommended Virologic
Testing Schedules for Infants With Perinatal and Breastfeeding Exposure to HIV in Diagnosis of HIV Infection in Infants
and Children).
o If the repeat parental viral load is undetectable, a joint decision should be made by the parent and providers about
whether breastfeeding may resume (AIII).
• Engaging Child Protective Services or similar agencies is not an appropriate response to infant feeding choices impacted
by HIV (AIII).
• Clinicians are encouraged to consult the National Perinatal HIV/AIDS Hotline (1-888-448-8765) with HIV-related
questions about infant feeding (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

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-1
Counseling about infant feeding is an integral component of HIV care during pregnancy and
postpartum. Ideally, this counseling should begin before pregnancy, continue during pregnancy, and
be reviewed again after delivery. Patient-centered counseling should assess opinions and plans about
infant feeding, engage in shared decision-making, and assist in implementing plans for infant
feeding. Previously, replacement feeding with properly prepared formula or banked, pasteurized
donor human milk was recommended as the only option for infant feeding in the United States
because it is generally available and eliminates any risk of HIV transmission through breastfeeding.
However, breastfeeding provides certain benefits to the breastfeeding dyad 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 a sustained undetectable HIV viral load.1-4

The Panel on Treatment of HIV in Pregnancy and Prevention of Perinatal Transmission and the Panel
on Antiretroviral Therapy and Medical Management of Children Living With HIV (the Panels)
recommend that clinicians engage parents in patient-centered counseling and shared decision-making
regarding infant feeding. In 2024, the American Academy of Pediatrics published an updated opinion
on breastfeeding in the context of HIV, stating “pediatricians should be prepared to offer a family-
centered, nonjudgmental, harm reduction approach to support people with HIV on ART with
sustained viral suppression below 50 copies per mL who desire to breastfeed.”4 As part of this
process, providers and parents should discuss both replacement feeding and breastfeeding and
address 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 throughout the duration of
breastfeeding, particularly if viral load becomes detectable (see Table 14. Antiretroviral Management
of Infants With Exposure to HIV During Breastfeeding and Table 14.1. Antiretroviral Prophylaxis
Dosing for Infants Who Are Breastfed in Antiretroviral Management of Infants With In Utero,
Intrapartum, or Breastfeeding Exposure to HIV). Counseling should also address issues related to
breast health (e.g., mastitis), mixed feeding, and weaning.

Panel recommendations are in line with the opinions of multiple experts and community
organizations that have called for a patient-centered approach to infant feeding decision-making and
providing access to the information, support, and tools parents need to make informed infant feeding
decisions.4-13 A 2016 survey of 93 clinicians in the United States who provide specialty care to
women with HIV found that one-third of the providers were aware that women in their care breastfed
their infants after being advised not to do so.14 These findings underscore the importance of open
communication and shared decision-making that provide an opportunity to understand patients’
values and infant feeding preferences, thus allowing appropriate care and support for breastfeeding
dyads.

Most of the data on HIV transmission via breast milk come from studies conducted in low- and
middle-income countries. However, there is growing interest in breastfeeding by people with HIV
and health care providers in the United States and other higher-income countries. Data about
breastfeeding with HIV in these settings are limited but have been explored in a number of studies. A
2020 case series 15 described breastfeeding of three infants with perinatal HIV exposure in Canada.
Eight observational studies published after that time have reported on groups of 7 to 72 breastfeeding
infants estimated to reflect a total of 184 to 214 unique infants in Germany,16,17 Italy,18 Switzerland,19
and the United States and Canada.20-23 In these publications, participants who breastfed were on
ART, generally started before or in the first trimester of pregnancy, and were documented to be
virally suppressed (viral load <50 to <400 copies/mL) at the time of delivery and/or in late
pregnancy. A few cases of low-level viremia were reported postpartum, with cessation of

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-2
breastfeeding in most instances. Infant ARV prophylaxis varied within and across study locations,
including no ARV prophylaxis, zidovudine (ZDV) and/or nevirapine (NVP) for 4 to 6 weeks after
birth, or continuing prophylaxis through one month after weaning. Some centers chose therapeutic
dosing with three-drug ARV regimens for either the first 4 to 6 weeks after birth or through weaning.
Although none of the studies identified cases of HIV transmission related to breastfeeding, the
studies were not designed to evaluate transmission (see the subsection on Risk of Transmission
below), the number of participating infants was small, and follow-up has not been completed for all
participants. Some infants are still breastfeeding, and a small number were lost to follow-up.
Challenges during breastfeeding—including mastitis, inadequate milk supply with need for formula
supplementation, episodes of detectable viral load, and difficulty weaning—require further study to
inform optimal management.

Clinicians who provide HIV care who have questions about infant feeding or are considering
breastfeeding are encouraged to consult with an expert and/or the National Perinatal HIV/AIDS
Hotline (1-888-448-8765).

Overview of Counseling and Management

When ART for HIV is being taken with a consistently suppressed viral load during pregnancy (at a
minimum during the third trimester) and at the time of delivery, the Panel recommends counseling
about the options of formula feeding, banked donor milk, or breastfeeding and supporting in infant
feeding decisions.

When ART is not being taken and/or a suppressed viral load is not achieved 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 sometimes, 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.

Other countries have updated their guidelines for management of breastfeeding in the context of
HIV: Switzerland in 2018,19 Australia in 2021,24 the United Kingdom in 202010 and 2022,25 and
Canada in 2023.26 A number of institutions in the United States have developed their own protocols
for counseling and providing HIV care when there is an interest in breastfeeding.20,27-29 Although
these country guidelines and institution-level protocols have some differences, they all entail
common elements: standardized counseling regarding infant feeding options during HIV care, a
multidisciplinary team-based approach, lactation support, adherence counseling and support, and
close monitoring of the breastfeeding dyad.25 Approaches to infant prophylaxis are quite variable (see
Antiretroviral Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to
HIV). In a provider survey conducted in 2021, institutional protocols supporting breastfeeding with
HIV were rare but were associated with higher degrees of provider comfort when patients chose to
breastfeed.30

Special Concerns
Engaging Child Protective Services or similar agencies is not an appropriate response to infant
feeding choices impacted by HIV.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-3
There have been numerous reports that after expressing interest in or intention to breastfeed,
providers threatened to make a report to Child Protective Services or actually did so. Such
engagements can be extremely harmful to families; can exacerbate the stigma and discrimination
associated with HIV; and are disproportionately applied to minoritized individuals, including Black,
Indigenous, and other people of color.31-33

Other Considerations
Patients should be asked nonjudgmental questions about their self-expression, including how they
want to be referred to as a parent (e.g., mother, father, another name), and how they want to describe
infant feeding (e.g., breastfeeding, another name). Some patients may desire to feed their infants their
own milk, although some may find it dysphoric.34 Counseling about infant feeding options, as
discussed in this section, should be provided to all pregnancies impacted by HIV. There are no
evidence-based guidelines on timing of restarting testosterone after giving birth or while
breastfeeding. In one published case report of restarting testosterone 13 months postpartum while
still lactating, the calculated milk-to-plasma ratio was under 1.0, the calculated relative infant dose
was under 1%, the infant had no observable side effects, and the infant serum testosterone
concentrations remained undetectable.35

Approach to Counseling
Health care providers who provide HIV care during pregnancy or prepregnancy should initiate
conversations about infant feeding early in pregnancy, or 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 breast milk. Less than 1 of 100 breastfed
infants would be expected to acquire HIV through breast milk when ART is being taken and a
sustained undetectable viral load is achieved while lactating; however, the risk is not zero. What
information can I provide to help you decide?”

When breastfeeding with HIV is being considered, providers should engage 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 the breastfeeding dyad) 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.

People with HIV desire to be counseled about safe infant feeding practices and have their questions
answered without judgment.27,36 Community-based organizations have developed patient-facing
materials to assist decisions around infant feeding options during pregnancy.37 When the choice is
made to breastfeed, counseling should include the importance of adherence to ART, sustained viral
suppression during pregnancy and breastfeeding, and engagement in postpartum care. Points to
address are listed below:

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-4
• 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.
• When ART for HIV is being taken with a sustained undetectable viral load, counsel about the
options of formula feeding, use of banked donor milk, or breastfeeding. Those who choose to
breastfeed should be supported in this decision.
• For those who choose to breastfeed, exclusive breastfeeding (no formula or other foods) through
the first 6 months is recommended. It is important to acknowledge that there may be intermittent
need to give formula (e.g., infant weight loss, milk supply not yet established, not having enough
stored milk, transient increases in viral load).
• 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 HIV Management and Follow-
Up).
• Access to a provider who is a breastfeeding specialist certified by the Academy of Breastfeeding
Medicine (when available) or a lactation consultant with expertise in supporting breastfeeding
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
higher-resource settings and when adherent to ART with sustained viral suppression starting
early in pregnancy.
• Breastfeeding provides numerous health benefits such as reduction in hypertension, type 2
diabetes, and breast and ovarian cancers and benefits for the breastfed infant such reduction in
asthma, gastroenteritis and otitis media,.38
Some providers and/or institutions have chosen to require a signed form acknowledging the
counseling provided; others have felt this practice is too stigmatizing and prefer to document the
infant feeding discussion in the patient’s chart without requiring a signed form.
Approach to Management
If the decision is made to breastfeed, several measures should be taken to reduce the possibility of
HIV transmission. Care of the breastfeeding dyad should be coordinated prior to delivery among the
maternity care provider, HIV provider, infant provider, breastfeeding specialist certified by the
Academy of Breastfeeding Medicine (when available), lactation consultant, and social worker,
all of whom may need education about new approaches to infant feeding with HIV.20,26-30
Recommendations for management include the following:

• Support 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.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-5
 o Ensure continued access to ARV medications throughout the breastfeeding period,
recognizing that patients may have changes to insurance status and may need support
applying for assistance programs.
o Provide early active referral to a supportive lactation consultant, preferably a breastfeeding
medicine provider when available, beginning prenatally or at delivery and continuing until
breastfeeding is well established. The lactation consultant should be 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 after giving birth and may affect ART adherence. Postpartum depression
occurs more frequently with HIV compared to without HIV39 (see Postpartum HIV
Management and Follow-Up).
• Document sustained viral suppression before delivery and throughout breastfeeding.
o No data exist to inform the appropriate frequency of viral load testing while breastfeeding.
One approach is to monitor the plasma viral load of the parent every 1 to 2 months during
breastfeeding.21,40
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 viral load becomes detectable, switching to replacement feeding is recommended (see
Situations to Consider Stopping or Modifying Breastfeeding below). There are no data that
clearly define a specific viral load threshold for permanent discontinuation of breastfeeding.
Most experts recommend permanent discontinuation of breastfeeding when viral load is ≥200
copies/mL. Guidance about infant ARV management when viremia develops during
breastfeeding is provided in Antiretroviral Prophylaxis for Infants Exposed to Detectable
HIV RNA During Breastfeeding in Antiretroviral Management of Infants With In Utero,
Intrapartum, or Breastfeeding Exposure to HIV; see Table 14. Antiretroviral Management of
Infants With Exposure to HIV or Exposure During Breastfeeding and Table 14.1
Antiretroviral Prophylaxis Dosing for Infants Who Are Breastfed.
• Recommend exclusive breastfeeding in the first 6 months of life, followed by the introduction of
complementary foods (e.g, solids) with continued breastfeeding, if desired.38 Some parents may
choose to stop breastfeeding and switch to formula prior to 6 months of age.
o Provide support for exclusive breastfeeding, acknowledging that there may be scenarios
where formula supplementation is needed. There is no evidence that formula supplementation
increases the risk of HIV acquisition in the breastfed infant in the context of parental ART
and viral suppression. 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).41,42 The highest risk in these
studies was from very early introduction of solids (before 2 months of age).41,43 Whether this
remains a risk factor when viral suppression is sustained during breastfeeding has not been
studied.
o If supplementation is needed during a hospital stay, prioritize the use of pasteurized donor
human milk when feasible.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-6
• Administer appropriate ARV prophylaxis starting at birth; see Antiretroviral Prophylaxis for
Breastfeeding Infants, Table 14. Antiretroviral Management of Infants With Exposure to HIV or
Exposure During Breastfeeding and Table 14.1 Antiretroviral Prophylaxis Dosing for Infants
Who Are Breastfed in Antiretroviral Management of Infants With In Utero, Intrapartum, or
Breastfeeding Exposure to HIV.
• If detectable viral load develops during breastfeeding, the Panels recommend that breastfeeding
be temporarily stopped or discontinued and replacement feeding initiated. Additional infant ARV
prophylaxis and infant testing are also recommended, see Situations to Consider Stopping or
Modifying Breastfeeding, below, Table 14, Table 14.1, and Table 3. Recommended Virologic
Testing Schedules for Infants With Perinatal and Breastfeeding Exposure to HIV
• Provide guidance on good breast care, including strategies to avoid and promptly resolve over-
production of breast milk, 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
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,44-46 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.47 Information about HIV testing for infants who are being breastfed is available in
Diagnosis of HIV Infection in Infants and Children (see Table 3. Recommended Virologic
Testing Schedules for Infants With Perinatal and Breastfeeding Exposure to HIV).

Situations to Consider Stopping or Modifying Breastfeeding

Situations may arise in which there is a need to temporarily stop or discontinue breastfeeding and
initiate replacement feeding, such as a detectable viral load or developing mastitis or bleeding nipples
during breastfeeding. If the situation is temporary, some options to consider while expressing breast
milk until the condition has resolved or viral load becomes undetectable include: (1) giving
previously stored expressed milk from a date when viral suppression was achieved while
encouraging pumping and discarding breast milk to ensure that breastfeeding can resume; (2)
pumping and flash heating breast milk before feeding it to the infant; (3) providing replacement
feeding with formula or pasteurized donor human milk while encouraging pumping and discarding
breast milk to ensure that breastfeeding can resume; or (4) permanently stopping breastfeeding. Flash
heating, which has been documented to eliminate HIV from breast milk, 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.48,49 Once cooled to room
temperature, milk can be given to the infant 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 viral load that becomes detectable while breastfeeding, the Panels recommend
temporarily stopping or discontinuing breastfeeding and initiating replacement feeding, using one of
the options described above, engaging in shared decision-making, assessing the etiology of the

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-7
viremia, and repeating the viral load. Due to the risk of postnatal transmission associated with
viremia during breastfeeding, the Panels advise immediate cessation of breastfeeding if viral load
becomes detectable; this guidance is more directive than counseling when ART is being taken with
sustained viral suppression. Most experts recommend permanent discontinuation of breastfeeding
when HIV RNA is ≥200 copies/mL. The exact association between degree and duration of viremia
and lactational transmission is not known. In situations where viremia is low and an addressable
cause has been identified, the added risk of short-term continued breastfeeding until a repeat viral
load is available is likely to be low.

Any viremia is an opportunity to review the risks and benefits of continued breastfeeding, adherence
strategies, and other considerations, such as ARV prophylaxis for the breastfeeding infant (see Table
14. Antiretroviral Management of Infants With Exposure to HIV During Breastfeeding and Table
14.1. Antiretroviral Prophylaxis Dosing for Infants Who Are Breastfed in Antiretroviral Management
of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to HIV). If the repeat viral load is
undetectable, a joint decision should be made by the parent and the clinician about whether
breastfeeding may resume. If the repeat viral load remains detectable, support should be provided to
continue replacement feeding.

The Diagnosis of HIV Infection in Infants and Children section provides guidance about HIV
diagnostic testing for infants who are being breastfed. If after counseling, the choice is made to
continue to breastfeeding with viremia, the parent and provider should remain engaged; the provider
should offer guidance on 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 nucleic acid test (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: Antiretroviral Treatment Regimens
Recommended for Initial Therapy in Infants and Children With HIV 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.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-8
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 the Centers for Disease Control and Prevention
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 infants and avoiding the monetary costs of
formula, benefits to breastfeeding include decreased risk of hypertension; type 2 diabetes; and breast,
endometrial, and ovarian cancers.38 An exclusive focus on the risk of perinatal HIV transmission via
breastfeeding fails to acknowledge the health benefits of lactating and the health benefits that may be
lost by prohibiting breastfeeding with HIV.

Access 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.50 These outcomes 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.51 These issues should be
considered as part of counseling and support for decisions around infant feeding 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 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.52

Cultural Considerations
Environmental, social, familial, and personal pressures to consider breastfeeding may be faced during
pregnancy.5,12,50,53-58 Many factors affect a woman’s decision to breastfeed her infant; these include
bonding; maternal and infant health benefits; social, cultural, and religious factors; and concerns
about HIV-related stigma and disclosure.19,23,54

Some women, especially those from a country or cultural background where breastfeeding is the
norm, fear that not breastfeeding will lead to disclosure of their HIV status.5,57,58 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.13

Risk of HIV Transmission to Infants Through Breastfeeding

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.59,60 The mechanisms of HIV transmission by
breastfeeding are not fully understood.61,62 This lack of current knowledge, and the fact that rare HIV

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-9
transmissions during breastfeeding have occurred when breast milk and/or plasma HIV viral load
was undetectable, complicate decision-making.63,64.

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.65-69 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. A systematic review and meta-analysis
published in 2017 identified six studies with ART started at some point during pregnancy and
continued for at least 6 months postpartum that provided estimates of postnatal transmission rates,
excluding peripartum infections diagnosed before 6 weeks of age. The pooled postnatal transmission
rate at 6 months was 1.1% (95% confidence interval, 0.32% to 1.85%), with substantial
heterogeneity. Transmission rates in the included studies ranged from 0.2% to 3.1%.70

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. 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 daily oral
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.71 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.63

Smaller studies have also looked at HIV transmission in the context of maternal ART and viral load
monitoring. 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.72

In a prospective follow-up of 475 breastfeeding mother–infant pairs in Zimbabwe, there were two
postpartum transmissions, both from women with HIV RNA levels >1,000 copies/mL.73 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. When maternal
plasma viral load remained <100 copies/mL during breastfeeding, there were no occurrences of
infant HIV acquisition.64

There have been at least five additional published cases of HIV transmission when maternal viral
load was <50 copies/mL close to the time of transmission. Two cases are from an observational study
in Malawi. In one, ART was started 8 weeks before delivery, and maternal plasma RNA was
<37 copies/mL at 1 month, 3 months, 6 months, and 12 months postpartum. The infant was breastfed
until 9 months of age and tested positive for HIV at 12 months of age after testing negative at months

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-10
1, 3, and 6. HIV RNA measured in the breast milk was 293 copies/mL at 1 month postpartum and
<37 copies/mL at months 3 and 6. In the second case, ART was started 14 weeks before delivery, and
maternal plasma RNA was <37 copies/mL at 1 month and 3 months postpartum. The infant tested
positive for HIV at 3 months of age, after testing negative at 1 month. HIV RNA measured in the
breast milk was <37 copies/mL at 1 month postpartum and 90 copies/mL at 3 months.74

The Mma Bana study in Botswana compared triple nucleoside reverse transcriptase inhibitor (NRTI)
therapy (abacavir, ZDV, and lamivudine [3TC]) to protease inhibitor (PI)–based therapy
(lopinavir/ritonavir plus ZDV and 3TC). There were two lactational transmissions where maternal
plasma and breast milk RNA were <50 copies/mL at 1 and 3 months postpartum, both in the NRTI
arm. In one case, ART was started 4 weeks before delivery and viral load was elevated at delivery;
the infant tested positive for HIV at 94 days of life after testing negative at 28 days. In the other case,
ART was started 14 weeks before delivery and HIV RNA was <50 copies/mL at delivery, although
issues with adherence were reported; the infant tested positive for HIV at 91 days of life after testing
negative at 21 days.75 In DOLPHIN-2 (Dolutegravir in Pregnant HIV Mothers and Their Neonates),
which compared dolutegravir- versus efavirenz (EFV)-based ART started in the third trimester, out
of 268 mother–infant pairs, there was one breastfeeding HIV transmission in the EFV group. HIV
was diagnosed in the infant at 72 weeks of age (16 months), and maternal viral load was <50
copies/mL at 12 weeks, 24 weeks, 48 weeks, and 72 weeks postpartum.1,2,63,71

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 seven continued to
breastfeed with ongoing counseling and frequent viral load checks. There were no cases of HIV
transmission via breastfeeding.76

Safety of Antiretroviral Drugs During Breastfeeding

Parents are often concerned about infant exposure to ARV medications through breast milk. The non-
nucleoside reverse transcriptase inhibitors (NNRTIs) NVP, EFV, and etravirine have been detected
in breast milk; however, the levels of these ARV medications that have been detected in breast milk
are lower than those seen in maternal plasma. Among 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.77 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 the breastfed infant.77-79 Emtricitabine and 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).77 A subanalysis 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

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-11
with lower levels of the virus in both compartments and a lower incidence of viral transmission
during breastfeeding.80 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.81 For more details on the passage of ARV medications 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.82 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.83 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.84

The rates of serious adverse events among infants who receive ARV prophylaxis during
breastfeeding are low (see Safety of Antiretroviral Drugs for Infant Prophylaxis in Antiretroviral
Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to HIV). 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
infant adverse events were observed between study arms.1,66 In breastfed infants in the PROMISE
study, week 26 mean lumbar spine bone mineral content was lower in infants in the maternal ART
group than in the infant NVP group. This difference (about 0.23 g) was less than one-half standard
deviation, considered unlikely to be clinically relevant. No infant renal safety concerns were
observed.85 An infant who acquires HIV while breastfeeding is at risk for developing ARV
medication resistance due to subtherapeutic drug levels in breast milk.71,86-88 A longitudinal
retrospective study of Kenyan women with HIV from the pre-ART era showed no statistically
significant difference in the composition of the bacterial microbiome of breast milk from women
receiving combination antiretroviral (cART) and those receiving no ARV medications during
breastfeeding.89

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.66 For additional
information, see Safety of Antiretroviral Drugs for Infant Prophylaxis in Antiretroviral Management
of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to HIV. 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.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-12
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44. Kuhn L, Aldrovandi GM, Sinkala M, et al. Effects of early, abrupt weaning on HIV-free survival
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45. 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:
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46. Kuhn L, Kim HY, Walter J, et al. HIV-1 concentrations in human breast milk before and after
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47. King CC, Kourtis AP, Persaud D, et al. Delayed HIV detection among infants exposed to
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48. Israel-Ballard K, Chantry C, Dewey K, et al. Viral, nutritional, and bacterial safety of flash-
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49. 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.

50. 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:
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51. Hinson TD, Skinner AC, Spatz DL. Subject matter experts identify health equity concerns in
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52. Murray A, Hall A, Weaver J, Kremer F. Methods for estimating locations of housing units served
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53. Levison J, Weber S, Cohan D. Breastfeeding and HIV-infected women in the United States: harm
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54. 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.
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55. 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://pubmed.ncbi.nlm.nih.gov/26757986.

56. 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
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57. 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.
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58. 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:
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59. 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://pubmed.ncbi.nlm.nih.gov/10703779.

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60. World Health Organization. HIV Transmission through breastfeeding: a review of available
evidence; 2007 update. 2008. Available at:
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61. 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.
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62. Waitt C, Low N, Van de Perre P, et al. 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://pubmed.ncbi.nlm.nih.gov/29960731.

63. 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://pubmed.ncbi.nlm.nih.gov/34108383.

64. 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://pubmed.ncbi.nlm.nih.gov/27846071.

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

66. 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:
https://pubmed.ncbi.nlm.nih.gov/20554982.

67. 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: https://pubmed.ncbi.nlm.nih.gov/22196945.

68. 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: https://pubmed.ncbi.nlm.nih.gov/26603917.

69. 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: https://pubmed.ncbi.nlm.nih.gov/21237718.

70. Bispo S, Chikhungu L, Rollins N, et al. Postnatal HIV transmission in breastfed infants of HIV-
infected women on ART: a systematic review and meta-analysis. J Int AIDS Soc.
2017;20(1):21251. Available at: https://pubmed.ncbi.nlm.nih.gov/28362072.

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71. 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://pubmed.ncbi.nlm.nih.gov/34467974.

72. 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://pubmed.ncbi.nlm.nih.gov/29781882.

73. Zijenah LS, Bandason T, Bara W, et al. Impact of Option B(+) combination antiretroviral therapy
on mother-to-child transmission of HIV-1, maternal and infant virologic responses to
combination antiretroviral therapy, and maternal and infant mortality rates: a 24-month
prospective follow-up study at a primary health care clinic, in Harare, Zimbabwe. AIDS Patient
Care STDS. 2022;36(4):145-152. Available at: https://pubmed.ncbi.nlm.nih.gov/35438521.

74. Giuliano M, Andreotti M, Liotta G, et al. Maternal antiretroviral therapy for the prevention of
mother-to-child transmission of HIV in Malawi: maternal and infant outcomes two years after
delivery. PLoS One. 2013;8(7):e68950. Available at: https://pubmed.ncbi.nlm.nih.gov/23894379.

75. 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:
https://pubmed.ncbi.nlm.nih.gov/20554983.

76. 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://pubmed.ncbi.nlm.nih.gov/34723927.

77. 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://pubmed.ncbi.nlm.nih.gov/29309634.

78. 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://pubmed.ncbi.nlm.nih.gov/27676257.

79. 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://pubmed.ncbi.nlm.nih.gov/26679247.

80. 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://pubmed.ncbi.nlm.nih.gov/30570527.

81. 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://pubmed.ncbi.nlm.nih.gov/31539371.

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82. 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.

83. 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://pubmed.ncbi.nlm.nih.gov/33544759.

84. 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://pubmed.ncbi.nlm.nih.gov/32573842.

85. Vhembo T, Baltrusaitis K, Tierney C, et al. Bone and renal health in infants with or without
breastmilk exposure to tenofovir-based maternal antiretroviral treatment in the PROMISE
randomized trial. J Acquir Immune Defic Syndr. 2023;93(5):431-437. Available at:
https://pubmed.ncbi.nlm.nih.gov/37199427.

86. 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: https://pubmed.ncbi.nlm.nih.gov/21460326.

87. 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: https://pubmed.ncbi.nlm.nih.gov/21468304.

88. Aebi-Popp K, Kahlert CR, Crisinel PA, et al. Transfer of antiretroviral drugs into breastmilk: a
prospective study from the Swiss Mother and Child HIV Cohort Study. J Antimicrob Chemother.
2022;77(12):3436-3442. Available at: https://pubmed.ncbi.nlm.nih.gov/36177836.

89. Maqsood R, Skidmore PT, Holland LA, et al. Dynamic changes in breast milk microbiome in the
early postpartum period of Kenyan women living with HIV are influenced by antibiotics but not
antiretrovirals. Microbiol Spectr. 2022;10(2):e0208021. Available at:
https://pubmed.ncbi.nlm.nih.gov/35384692.

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Diagnosis of HIV Infection in Infants and Children
Updated: December 19, 2024
Reviewed: December 19, 2024

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 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).
• An assay that detects HIV non–B subtype viruses or Group O infections (e.g., an HIV RNA NAT or a total DNA/RNA test)
is recommended for use in infants and children perinatally exposed to known or suspected non–B subtype virus or Group
O infections (AII).
• Virologic diagnostic testing using an HIV NAT (see Table 3 below) is recommended for all infants with perinatal HIV
exposure at the following ages:
o Birth (AII)
 The test at birth generally should be performed in all infants with perinatal HIV exposure but is not necessary for
infants at low risk of HIV acquisition (HIV RNA levels <50 copies/mL from 20 weeks of gestation through delivery
put infants at low risk of HIV acquisition). Birth testing should be performed in infants at low risk of HIV acquisition
if there are plans to breastfeed or there are concerns about loss to follow-up (BIII).
o 14 to 21 days (AII)
o 1 to 2 months (AII)
o 4 to 6 months (AII)
• For infants who receive presumptive HIV therapy, additional virologic diagnostic testing is recommended 2 to 6 weeks after
antiretroviral (ARV) drugs are discontinued (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 (and no
positive virologic tests), with one negative test obtained at age ≥1 month (and at least 2–6 weeks after discontinuation of
infant ARVs) 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 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
(AII).
• 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 if the gap between
the tests at ages 1 to 2 months and 4 to 6 months is greater than 3 months. See Preventing HIV Transmission During
Infant Feeding.
o Virologic diagnostic testing should be performed at least 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 and 4 to 6 months after cessation (BII).
Infants with potential HIV exposure after birth (e.g., diagnosis of HIV during breastfeeding, premasticated feeding, sexual
abuse, contaminated blood products, percutaneous exposure) require additional testing using HIV antigen/antibody and/or
HIV NAT assays, based on age at time of exposure and the maternal HIV status at delivery (AII).

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-21
 • Age-appropriate HIV testing is also recommended for infants and children with signs and/or symptoms of HIV, even in the
absence of documented or suspected HIV exposure (AII).
• For children aged ≥18 months, HIV antibody (or HIV antigen/antibody) tests are recommended for diagnostic testing (AII).
o When early (acute or recent) HIV infection is suspected, additional testing with an HIV NAT may be necessary to
diagnose HIV infection (AII).
Note: The National Perinatal HIV Hotline 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 all by age 4 to 6 months. Antibody tests, including
antigen/antibody combination immunoassays, do not establish the presence of HIV in infants because
HIV antibodies that have been transferred transplacentally may be detected (i.e., false positive);
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
antiretroviral therapy (ART) through transplacental transfer of antiretroviral (ARV) drugs to the fetus
during pregnancy 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 A 2019 systematic review
provides additional information on the global and regional molecular epidemiology of Group M
subtype infections and recombinants among subtypes.4 Newer HIV RNA PCR assays are usually
“dual-target” assays, which target two separate highly conserved regions on the HIV genome. Dual-
target HIV assays are better than older RNA assays at detecting non–subtype B HIV infection and
Group O strains5-10 (See Clinical and Laboratory Monitoring of Pediatric HIV Infection).

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 with known perinatal HIV exposure.
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 aged
<18 months.11-13 Children with perinatal HIV exposure who are aged ≥18 months occasionally have
residual HIV antibodies from the antepartum period; definitive confirmation of HIV infection in
children in this age group who remain HIV antibody–positive should be based on a NAT (see Special

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to Reduce Perinatal HIV Transmission in the United States C-22
Situations below). Diagnosis in children aged ≥18 months relies primarily on HIV antibody and
antigen/antibody tests (see Diagnostic Testing in Children with Postnatal HIV Exposure below).1

An infant who has a positive HIV antibody test but the maternal HIV status is unknown (see
Pregnancy and Postpartum HIV Testing and Identification of Perinatal and Postnatal 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,3 and
receive presumptive HIV therapy as soon as possible (see Antiretroviral Management of Infants with
In Utero, Intrapartum, or Breastfeeding Exposure to HIV).

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 <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 ART is being taken and viral suppression is achieved and sustained
during pregnancy and postpartum.

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), one negative virologic test at age ≥8
weeks at least 2 weeks after discontinuing multidrug ARV prophylaxis/presumptive therapy, or one
negative HIV antibody test at age ≥6 months.1, 3

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 infant ARVs) 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.14 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).

Virologic Testing at Birth

Virologic testing at birth provides insights about the timing of HIV transmission and supports early
HIV diagnosis for rapid initiation of ART when indicated (see When to Initiate Antiretroviral
Treatment in Children With HIV Infection in the Pediatric Antiretroviral Guidelines). Infants who
have a positive virologic test result at or before age 48 hours are considered to have early (in utero)

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to Reduce Perinatal HIV Transmission in the United States C-23
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.15-17

In addition to early HIV diagnosis, results of birth testing are used in clinical decisions about infant
ARV management. Negative HIV virologic testing at birth would rule out in utero infection and
allow de-escalation of a three-drug presumptive HIV therapy regimen for some infants. See Table 13
and associated content in Antiretroviral Management of Infants With In Utero, Intrapartum, or
Breastfeeding Exposure to HIV.

Virologic testing at birth should generally be performed for all infants with perinatal HIV exposure
but is not necessary for infants who are at low risk of infection (HIV RNA levels <50 copies/mL
from 20 weeks gestation through delivery put infants at low risk of HIV acquisition) unless there are
plans to breastfeed. When breastfeeding is planned for an infant at low risk of HIV acquisition, a
birth test provides baseline information, should the infant subsequently have a positive test. Virologic
testing at birth should also be considered whenever there are concerns that the newborn may be lost
to follow-up without testing.

Specimens for HIV testing at birth should be obtained before or immediately after initiating an ARV
drug regimen; however, presumptive HIV therapy or ARV prophylaxis 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 Age 14 to 21 Days

Some children with perinatal HIV exposure can have a positive NAT between 14 and 21 days of
age.3 Early identification of infection permits transition from presumptive HIV therapy to treatment
doses of ART (see When to Initiate Antiretroviral Treatment in Children With HIV Infection 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 infants with perinatal HIV exposure. 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.18 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 suggest
performing an additional virologic test 2 to 6 weeks after ARV drugs are discontinued (i.e., at age
8–12 weeks when the infant receives 6 weeks of prophylaxis), 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.18, 19 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.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-24
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.

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.20, 21

Antibody Testing at Age ≥18 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.

Virologic Testing for Infants With Perinatal HIV Exposure Who Are Being
Breastfed
Some may choose to breastfeed with HIV (see Preventing HIV Transmission During Infant Feeding).
A descriptive study of 72 people with HIV who breastfed their infants in North America reported
high variability in policies, infant ARV prophylaxis, and infant and parental testing practices among
institutions and noted the need to identify best care practices.22 Table 3 summarizes the
recommended diagnostic testing schedule for infants who are being breastfed. 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 to provide baseline information should the infant subsequently have a
positive test. 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 at least
every 3 months during breastfeeding. At cessation of breastfeeding, virologic diagnostic testing
should be performed at 4 to 6 weeks and 4 to 6 months after breastfeeding has ended, regardless of
the age of the child when breastfeeding is discontinued. If the infant is receiving extended ARV
prophylaxis during breastfeeding, an additional test should be done at least 2 weeks after cessation of
ARV prophylaxis. If an infant’s virologic test result is positive, a repeat test should be performed as
soon as possible and ART should be initiated.

No data exist to inform the appropriate frequency of maternal viral load testing during breastfeeding.
One approach is to monitor plasma viral load every 1 to 2 months during breastfeeding. Additional
infant virologic testing using an HIV NAT is indicated if the maternal viral load becomes detectable
during breastfeeding (for infant ARV prophylaxis considerations, see Table 14 and Table 14.1 in
Antiretroviral Management for Infants With In Utero, Intrapartum, or Breastfeeding Exposure to
HIV). If maternal viral load is detectable and breastfeeding continues, 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, irrespective of when breastfeeding ends,

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to Reduce Perinatal HIV Transmission in the United States C-25
virologic testing should be performed at 4 to 6 weeks and 4 to 6 months after cessation of
breastfeeding. If the breastfed infant is receiving presumptive HIV therapy or ARV prophylaxis, this
virologic testing should be performed at least 2 weeks after discontinuation of infant ARV
administration. Consultation with an expert and/or the National Perinatal HIV Hotline (8884488765)
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 Preventing HIV
Transmission During Infant Feeding.

Table 3. Recommended Virologic Testing Schedules for Infants With Perinatal and
Breastfeeding Exposure to HIV

Infants With Perinatal HIV Exposurea

Risk Category Age at HIV NATb,c Testing
Infants at High Risk of HIV Acquisition Birth
Infants with perinatal HIV exposure to— 14–21 days
• Viremia (HIV RNA ≥50 copies/mL) in the 4 weeks prior to 1–2 months
delivery
2–3 months (see note below)
• Early (acute or recent) HIV during pregnancy or HIV 4–6 months
diagnosed in labor or postpartum
All infants at high risk of perinatal HIV transmission should
Note: Viremia can be documented by a laboratory or have specimens obtained for HIV testing at birth before or
presumed by other clinical factors (e.g., new diagnosis, ART immediately after initiating an ARV drug regimen; however,
adherence challenges, stopping ART prior to delivery). presumptive HIV therapy should not be delayed.
Note: Additional virologic testing is recommended 2 to
6 weeks after infant ARV drugs are discontinued (i.e., at age
2 to 3 months if the infant receives 6 weeks of ARV drugs).
If an infant’s NAT test result is positive, a repeat test should
be performed as soon as possible and ART should be
initiated.
Infants at Low Risk of HIV Acquisition Who Are Not Birth (see note below)
Being Breastfed
14–21 days
Infants with perinatal HIV exposure to—
1–2 months (see note below)
• Sustained viral suppression (<50 copies/mL) from
4–6 months
20 weeks of gestation through delivery
Note: A birth test generally should be performed but is not
Note: Ideally, sustained viral suppression is documented by
necessary for infants at low risk of HIV acquisition unless
HIV RNA testing, including at least two consecutive tests
there are concerns that the newborn could be lost to follow-
obtained at least 4 weeks apart with HIV RNA
up without further testing.
<50 copies/mL, but can be based on the clinical judgment of
providers. Note: For infants at low risk of HIV acquisition, testing may
be timed to occur at least 2 weeks after cessation of ZDV
prophylaxis.
Infants Not Meeting Criteria for High or Low Risk of HIV For all infants in this group, a NAT should be obtained at
Acquisition birth and the NAT testing schedule for infants at high risk of
HIV acquisition (shown above) should be followed.
• In these clinical scenarios, some infants may receive
presumptive HIV therapy and others may receive only
ZDV prophylaxis.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-26
 The timing of virologic testing 2 to 6 weeks after ARV drugs
are discontinued will vary based on the duration of infant
ARV drugs.
See Table 13 and Table 13.1 in Antiretroviral Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure
to HIV for information about presumptive HIV therapy and ZDV prophylaxis, including duration of ARV drugs.

Infants With Perinatal HIV Exposure at Low Risk of HIV Acquisition Who Are Being Breastfed
Guidance for Virologic Testing During Age at HIV NATb,c Testing
Breastfeeding
From Birth to Age 6 Months Birth
A NAT test at birth is recommended for infants with perinatal 14–21 days
HIV exposure who are at low risk of HIV acquisition and are
1–2 months (see note below)
being breastfed.
4–6 months
Note: NAT testing of the infant should be performed at least
every 3 months during breastfeeding. An additional virologic
test should be performed if the gap between the tests at
ages 1 to 2 months and 4 to 6 months is greater than 3
months.
In addition to the standard time points after birth, NAT
testing also should be performed at 4 to 6 weeks and 4 to
6 months after cessation of breastfeeding, regardless of the
age when breastfeeding ends.
If Breastfeeding Continues Beyond 6 Months of Age NAT testing of the infant should be performed at least every
3 months during breastfeeding and at 4 to 6 weeks and 4 to
6 months after cessation of breastfeeding, regardless of the
age when breastfeeding ends.

If Viremia Develops While Breastfeeding (a detectable Prompt NAT testing of the infant
viral load)
Additional testing time points are based on the clinical
scenario and use of infant ARV prophylaxis or presumptive
HIV therapy; see Table 14 in Antiretroviral Management of
Infants With In Utero, Intrapartum, or Breastfeeding
Exposure to HIV.
If there is a detectable maternal viral load and breastfeeding
continues, some Panel members would recommend monthly
virologic testing of the infant as an approach to early
detection of HIV infection during ongoing exposure.
Consultation with an expert is recommended to determine
the need for infant ARV prophylaxis or presumptive HIV
therapy and additional testing time points.
Consultation with an expert and/or the National Perinatal HIV Hotline (888-448-8765) is recommended for questions about
HIV diagnostic testing for infants with perinatal HIV exposure who are being breastfed.
See Table 14 in Antiretroviral Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to HIV for
information about extended ARV prophylaxis and presumptive HIV therapy during breastfeeding.
See Preventing HIV Transmission During Infant Feeding for additional guidance about breastfeeding.
a Thistable summarizes standard time points for HIV virologic diagnostic testing of infants according to risk of perinatal
acquisition.

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to Reduce Perinatal HIV Transmission in the United States C-27
b HIV RNA or HIV DNA NATs that directly detect HIV.
cIf maternal HIV-2 infection is suspected or confirmed, infant testing for HIV-2 can follow the same schedule (see Virologic
Assays to Diagnose HIV-2 Infections below).
Key: ART = antiretroviral therapy; ARV = antiretroviral; NAT = nucleic acid test; ZDV = zidovudine

Diagnostic Testing in Children With Postnatal HIV Exposure

Infants and children with potential HIV exposure after birth (e.g., HIV diagnosed during
breastfeeding, premasticated feeding, sexual abuse, contaminated blood products, percutaneous
exposure) require age-appropriate testing. Infants with perinatal HIV exposure who have these
additional exposures after birth require HIV NAT testing for diagnosis. Infants aged <18 months who
were not exposed to HIV at delivery and infants aged ≥18 months who have these potential
exposures require HIV antigen/antibody testing, unless the time between potential exposure and
testing indicates that the patient is in the window for seroconversion, when an HIV NAT is more
sensitive. Repeat testing may still be required (see Pregnancy and Postpartum HIV Testing and
Identification of Perinatal and Postnatal HIV Exposure for additional information).

New HIV Diagnosis While Breastfeeding

Infants may be exposed to HIV through breastfeeding if acute or primary maternal HIV infection
occurs or when pre-existing HIV infection was not diagnosed during pregnancy or postpartum.23
Diagnosis of HIV during breastfeeding should prompt health care professionals to counsel to
discontinue breastfeeding immediately to reduce the risk of postnatal transmission to the infant. In
these situations, infant virologic diagnostic testing using an HIV NAT is recommended immediately
and 14 to 21 days, 4 to 6 weeks, and 4 to 6 months after the infant’s last exposure to breast milk
(i.e., cessation of breastfeeding). A virologic test also should be performed at least 2 weeks after
cessation of presumptive HIV therapy if provided (see ARV Management of Infants With In Utero,
Intrapartum, or Breastfeeding Exposure to HIV). Duplicate tests are not needed if some of these time
points overlap with standard post-natal testing. For additional information, consult the National
Perinatal HIV Hotline (1­888­448­8765).

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.24-30 If this occurs in children with perinatal HIV
exposure aged <18 months with prior negative virologic tests, it will be necessary for such children
to undergo virologic diagnostic testing because they may have residual HIV antibodies from the
antepartum period (see Special Situations below).

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

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to Reduce Perinatal HIV Transmission in the United States C-28
body piercing present a potential risk of HIV transmission, no reported cases of HIV transmission
from these activities have been documented.31

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 ≥18 months relies primarily on HIV antibody and
antigen/antibody tests.1, 32 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.33 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.34
• 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.

For information on diagnosis of HIV-2 infection, see Virologic Assays to Diagnose HIV-2 Infections
below.

Special Situations
Late Seroreversion (Aged ≥18 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 HIV antibodies from the
antepartum period up to age 24 months. These children are called late seroreverters.35-38 In one study,
14% of children with HIV exposure who did not have HIV infection seroreverted after age
18 months.38 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.39 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. 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.

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to Reduce Perinatal HIV Transmission in the United States C-29
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.

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.40-42 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.

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 age 1 month, 3 months, and 6 months and is comparable to the
specificity of HIV DNA PCR.19 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

The sensitivity of HIV RNA assays is affected by maternal antenatal ART or ARV drugs
administered to the infant as prophylaxis or presumptive therapy.43 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.19 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.44 Further studies are necessary to evaluate
the sensitivity of HIV RNA assays during receipt of multidrug ARV prophylaxis or presumptive HIV
therapy in infants when maternal antenatal ART was received.

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.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-30
An HIV qualitative RNA assay is an alternative diagnostic test that can be used for infant testing.16,
45-49

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 age 1 month, 3 months, and 6 months. Studies have shown that HIV DNA PCR assays
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 age 3 months and 6 months.3, 16

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.18 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
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.50 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.51 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.52

The AMPLICOR® HIV-1 DNA test has been used widely for diagnosis of HIV in infants perinatally
exposed to 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. 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.53 Data from the CDC
National HIV Surveillance System (NHSS) showed that the number of non–U.S. born children with
HIV living in the United States 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.54 In an evaluation of infants who received a perinatal HIV infection diagnosis in New York

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-31
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 1999.55 Among a group of 40 children who visited a pediatric HIV
clinic in 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.56 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.57 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.58 Non–subtype B and Group O strains may be seen in countries with
links to these geographical regions.59-63 The geographical distribution of HIV groups is available at
the HIV Sequence Database.

Current HIV RNA PCR assays and the qualitative diagnostic RNA assays are better at detecting non–
subtype B HIV infection and the less-common Group O strains than older RNA assays5-10, 49 (see
Clinical and Laboratory Monitoring of Pediatric HIV Infection). The increased sensitivity is due to
amplification of more than one highly conserved region of the HIV genome. HIV DNA assays,
though generally less sensitive, may be more sensitive in detecting HIV infection when the infant is
receiving ART because identification is based on detection of cell-associated DNA in whole blood or
dried blood spots and does not rely on active viral replication.16, 64

A qualitative RNA assay, a quantitative RNA assay, or a total DNA/RNA (total nucleic acid) test
should be used for infant testing in addition to a DNA PCR assay when evaluating an infant exposed
to HIV infection linked to an area that is endemic for non–subtype B HIV or Group O strains, such as
Africa or Southeast Asia. These additional tests are also indicated 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.65-69

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States C-32
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.70-72
HIV­2 infection also is well documented in France and Portugal, which have large numbers of
immigrants from these regions.73, 74 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-1.75-77 (See HIV-2 Infection and
Pregnancy.)

HIV-2 should be suspected if HIV infection is linked to an area that is endemic for HIV-2 infection
or if HIV test results are suggestive of HIV-2 infection (i.e., 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).78

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 exposed to 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.79, 80 Clinicians should consult with an expert in pediatric HIV infection when
caring for infants with suspected or known exposure to HIV-2.70, 81

The diagnosis of HIV-2 in children with only non-perinatal exposure or in children with perinatal
exposure aged ≥18 months should also follow the Centers for Disease Control and Prevention and
Association of Public Health Laboratories 2014 laboratory testing guidelines, which recommend
using an HIV-1/HIV-2 antibody differentiation immunoassay that distinguishes between HIV-1 and
HIV-2 antibodies for supplemental testing. 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.79, 80

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Clinical and Laboratory Monitoring of Pediatric
HIV Infection
Updated: June 27, 2024
Reviewed: June 27, 2024

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).
• 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, have sustained virologic suppression and
CD4 count values that are well above the threshold for opportunistic infection risk, and have stable clinical status (AII).
Viral load measurement every 3 to 4 months is generally recommended to monitor ART adherence (AIII).
• 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). See Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines.
• 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).
• 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).
• 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*). See Co-Receptor Tropism Assays in the Adult and Adolescent Antiretroviral
Guidelines.
• 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.
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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-1
Laboratory monitoring of children with HIV poses unique and challenging issues. In particular, the
normal ranges of CD4 T lymphocyte (CD4) cell counts and plasma HIV RNA 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 Are
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. Children with HIV should have a complete, age-appropriate medical history
and physical examination (see Table 6 below). Their growth and development should be evaluated
for signs of HIV-associated abnormalities. Testing also should be performed to assess for HIV-
associated conditions, including the following:

• Anemia, leukopenia, thrombocytopenia

• Hypoalbuminemia
• Nephropathy (urinalysis)
• Renal insufficiency (creatinine)
• Hyperglycemia
• Hepatic transaminitis

Baseline screening tests for coinfections and opportunistic infections (OIs), including tests for the
following, should be performed:

• Tuberculosis, with tuberculin skin test if aged <2 years, or an interferon gamma release assay if
aged ≥2 years
• Hepatitis B virus (HBV), with HBV surface antibody, HBV surface antigen, and HBV core
antibody tests
• Hepatitis C virus (HCV), with HCV nucleic acid (HCV RNA) testing if aged <18 months or
HCV antibody if aged >18 months
• Cytomegalovirus (CMV), with CMV antibody tests if aged >12 months

Monitoring for OIs 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
gastrointestinal parasites, 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-2
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, sexual maturity rating, 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) 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. 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.

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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-3
A 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.

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 

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

Technology requirements (internet access, equipment, skills) 

Legal and administrative guidelines for visit documentation and billing  
aCooperative 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.

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.

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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-5
The Adult and Adolescent Antiretroviral Guidelines—Laboratory Testing currently supports
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

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

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

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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-6
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.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, Table B,
and Table C in Appendix D: Supplemental Information). Children with higher baseline CD4
percentages, younger ages (<4 years), or early ART initiation25 can potentially recover normal CD4
counts, whereas children with severe baseline immune suppression may not achieve normal CD4
levels with ART.26-28 Although CD4 cells decline as a result of HIV infection, CD8 T lymphocyte
(CD8) cells expand soon after infection. In adults with HIV, low CD4/CD8 ratios are a prognostic
indicator for serious non-AIDS events.29 In children with perinatal HIV, the CD4/CD8 ratio inversely
correlates with immune activation, senescence, and exhaustion.29 Some clinicians find CD4/CD8
ratios useful for gauging overall immune dysfunction. 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 Antiretroviral Treatment in Children with HIV Infection).

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 log10 copies to reach a stable lower
level (the virologic set point) approximately 6 to 12 months after acute infection.30,31 In adults with
HIV, the virologic set point correlates with the subsequent risk of disease progression or death in the
absence of therapy.32

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, and then slowly declines until age 4 to 5 years.33-34,35
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.36

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.37 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.37-40

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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-7
<20 copies/mL to 75 copies/mL) (see Table 7 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 ART41 and generally defined as up to 200 copies/mL, but they may be as high as
500 copies/mL in children on ART42; 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.

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.43-45 Moreover,
because of biologic variability, only differences >0.7 log10 copies/mL (a fivefold difference) in
infants aged <2 years and differences >0.5 log10 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 immigrant and adopted children who are born outside the United States or to
non–U.S.-born parents.43,46-50

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.51-54 In addition, some human genetic polymorphisms are associated with
drug toxicity or AEs (e.g., using HLA-B*5701 testing to predict ABC hypersensitivity)55; 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.

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 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 Monthsd ARV
Regimens)

Medical History
and Physical      
Examinatione,f

Adherence
    
Evaluationf

CD4 Countd     

Plasma Viral
    
Loadg

Resistance
 
Testing

CBC with
     
Differentiald

Chemistriesd,h      

Lipid Paneli   

Random Plasma
 
Glucosej

Urinalysis   

HBV Screeningk  

Pregnancy Test
for Youth and
Young Adults of   
Childbearing
Potentiall

HLA-B*5701m 

HCV Screeningn 

TB Screeningo  

CMV Abp  
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.

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
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.
ePay 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).
fVirtual visits may be appropriate at some time points, particularly for adherence assessments and for visits for established
patients, see Table 4 above.
gSome 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).
h Chemistries 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.
iIf 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.
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 Baseline HBV screening is recommended with HBsAb, HBsAg, and HBcAb. HBV screening is also 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 in the Perinatal Guidelines.
m Conduct 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).
nBaseline hepatitis C screening is recommended with HCV nucleic acid (HCV RNA) testing if aged <18 months or Hepatitis C
antibody if aged >18 months. If HCV testing is positive, refer to the Infectious Diseases Society of America HCV in Children
guidelines for management.
o TB screening is recommended at baseline and annually with tuberculin skin test if aged <2 years or interferon gamma
release assay if aged >2 years (see Mycobacterium tuberculosis in the Pediatric Opportunistic Infection Guidelines).
pCMV antibody testing is recommended at age 1 year (or at baseline evaluation if aged >1 year at initial visit) and then
annually for CMV-seronegative infants and children with HIV who are immunosuppressed (i.e., CD4 count <100 cells/mm3 or
CD4 percentage <10%) (see Cytomegalovirus in the Pediatric Opportunistic Infection Guidelines).
Key: 3TC = lamivudine; ABC = abacavir; ALT = alanine aminotransferase; ART = antiretroviral therapy; ARV = antiretroviral;
AST = aspartate aminotransferase; CAB = cabotegravir; CBC = complete blood count; CD4 = CD4 T lymphocyte;
CMV = cytomegalovirus; Cr = creatinine; FTC = emtricitabine; HBV = hepatitis B virus; HBsAb = HBV surface antibody;
HBsAg = HBV surface antigen; HBcAb = HBV core antibody; HCV = hepatitis C virus; HgbA1C = glycosylated hemoglobin;
RPV = rilpivirine; TAF = tenofovir alafenamide; TB = tuberculosis; TDF = tenofovir disoproxil fumarate

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-10
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 bioMérieux 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-11
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7. Dandachi D, Lee C, Morgan RO, et al. Integration of telehealth services in the healthcare
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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
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10. Regelmann MO, Conroy R, Gourgari E, et al. Pediatric endocrinology in the time of COVID-
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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.
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12. Arrow Trial team, Kekitiinwa A, Cook A, et al. Routine versus clinically driven laboratory
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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://pubmed.ncbi.nlm.nih.gov/23886048.

14. Hyle EP, Sax PE, Walensky RP. Potential savings by reduced CD4 monitoring in stable
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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
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16. Gaur AH, Flynn PM, Bitar W, Liang H. Optimizing frequency of CD4 assays in the era of
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17. Gale HB, Gitterman SR, Hoffman HJ, et al. Is frequent CD4+ T-lymphocyte count
monitoring necessary for persons with counts >=300 cells/µL and HIV-1 suppression? Clin
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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://pubmed.ncbi.nlm.nih.gov/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:
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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://pubmed.ncbi.nlm.nih.gov/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.
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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
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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:
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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.
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25. Schroter J, Anelone AJN, de Boer RJ, et al. Quantification of CD4 recovery in early-treated
infants living with HIV. J Acquir Immune Defic Syndr. 2022;89(5):546-557. Available at:
https://pubmed.ncbi.nlm.nih.gov/35485581.

26. Puthanakit T, Kerr S, Ananworanich J, et al. 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://pubmed.ncbi.nlm.nih.gov/19504731.

27. 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://pubmed.ncbi.nlm.nih.gov/18426371.

28. 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.

29. Ron R, Moreno E, Martinez-Sanz J, et al. CD4/CD8 ratio during human immunodeficiency
virus treatment: time for routine monitoring? Clin Infect Dis. 2023;76(9):1688-1696.
Available at: https://pubmed.ncbi.nlm.nih.gov/36883584.

30. 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://pubmed.ncbi.nlm.nih.gov/7629984.

31. Katzenstein TL, Pedersen C, Nielsen C, et al. Longitudinal serum HIV RNA quantification:
correlation to viral phenotype at seroconversion and clinical outcome. AIDS. 1996;10(2):167-
173. Available at: https://pubmed.ncbi.nlm.nih.gov/8838704.

32. 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://pubmed.ncbi.nlm.nih.gov/7887550.

33. 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.

34. 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://pubmed.ncbi.nlm.nih.gov/9652428.

35. 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://pubmed.ncbi.nlm.nih.gov/7699539.

36. Krogstad P, Uittenbogaart CH, Dickover R, et al. 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://pubmed.ncbi.nlm.nih.gov/10413650.

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37. 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://pubmed.ncbi.nlm.nih.gov/9129063.

38. 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://pubmed.ncbi.nlm.nih.gov/9182469.

39. 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://pubmed.ncbi.nlm.nih.gov/9182471.

40. 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://pubmed.ncbi.nlm.nih.gov/9508151.

41. 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://pubmed.ncbi.nlm.nih.gov/22438396.

42. 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://pubmed.ncbi.nlm.nih.gov/26529159.

43. 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://pubmed.ncbi.nlm.nih.gov/21068276.

44. 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://pubmed.ncbi.nlm.nih.gov/20884287.

45. 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://pubmed.ncbi.nlm.nih.gov/22692747.

46. 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://pubmed.ncbi.nlm.nih.gov/8656008.

47. 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://pubmed.ncbi.nlm.nih.gov/12380591.

48. 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

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 infants. Clin Infect Dis. 2002;34(3):417-418. Available at:
https://pubmed.ncbi.nlm.nih.gov/11774090.

49. 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://pubmed.ncbi.nlm.nih.gov/21767972.

50. 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://pubmed.ncbi.nlm.nih.gov/21164353.

51. 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://pubmed.ncbi.nlm.nih.gov/26991336.

52. 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://pubmed.ncbi.nlm.nih.gov/28323755.

53. 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.

54. Chala A, Kitabi EN, Ahmed JH, et al. Genetic and non-genetic factors influencing efavirenz
population pharmacokinetics among human immunodeficiency virus-1-infected children in
Ethiopia. CPT Pharmacometrics Syst Pharmacol. 2023. Available at:
https://pubmed.ncbi.nlm.nih.gov/36840416.

55. 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://pubmed.ncbi.nlm.nih.gov/28399804.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection D-16
When to Initiate Antiretroviral Treatment in Children
with HIV Infection
Updated: June 27, 2024
Reviewed: June 27, 2024

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 (AI*).
• 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).
o ART initiation should be discussed and strongly encouraged at every visit (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) initiation1-3
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) cell 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, tuberculous meningitis, and
disseminated Mycobacterium avium complex disease. Due to concerns regarding the risk of immune
reconstitution inflammatory syndrome, ART initiation may be deferred until the optimal timing
relative to treatment of these opportunistic infections. Timing of ART initiation in these cases should
be discussed with a pediatric HIV specialist (see Guidelines for the Prevention and Treatment of
Opportunistic Infections in Children with and Exposed to HIV). A recent retrospective review of
children and adolescents with HIV in six African countries between 2013 and 2020 showed that there

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-1
was no mortality difference if ART was initiated <2 weeks (n = 266) versus 2 weeks to 2 months
(n = 398) after starting anti-tuberculous therapy for pulmonary tuberculosis (TB).12 This finding
supporting ART initiation in pediatric patients within the first 2 weeks of treatment for TB is
consistent with World Health Organization Updated Recommendations on HIV Prevention, Infant
Diagnosis, Antiretroviral Initiation and Monitoring, March 2021,13 which advocate for ART
initiation within 2 weeks of TB treatment initiation for infants and children, except when signs and
symptoms of meningitis are present.

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,14 and
the presence of HIV-related signs and symptoms15—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) (see Appendix C. CDC Pedaitric HIV CD4 Cell Count/Percentage and
HIV-Related Disease Categorization)14
• The child develops new HIV-related clinical symptoms (see Appendix C. CDC Pedaitric HIV
CD4 Cell Count/Percentage and HIV-Related Disease Categorization)15
• 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%). Immediately initiating ART resulted in a
75% reduction in early mortality among these infants compared with delaying treatment until the
infants met clinical or immune criteria according to the 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 and lower morbidity compared with
those who started treatment later.16-20

In general, studies that evaluate later initiation of ART in children have a selection bias: 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 gain in height among children who
started ART immediately was reported.21 Similarly, other studies have reported an association
between younger age at initiation of ART and more rapid growth reconstitution.17,22-24 Studies

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-2
conducted in and outside the United States have reported an association between delayed ART
initiation and delay of pubertal development and menarche.25 Finally, among 32 youths with
perinatally acquired HIV (PHIV) 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.26

A proteomics study of children who initiated ART early (within 12 weeks of birth) versus later
(12–50 weeks after birth) identified a protein signature among later initiators associated with a
proinflammatory state. This proinflammatory state 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
Early infant initiation of ART has been associated with improved neurodevelopmental outcomes
compared with later initiation of ART. Examples include a CHER trial substudy in which infants
who initiated ART early had significantly better gross motor and neurodevelopmental profiles than
those whose therapy was deferred.27 Additionally, 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 ages 3 to 12 months.28 Among Kenyan children who
initiated ART within 1 year of birth (early ART; n = 54) versus 1.5 to 6 years after birth (late ART; n
= 27) between 2007 and 2009 and were prospectively assessed for neurocognitive outcomes at a
median age of 6.9 years, the children with later ART initiation had significantly higher odds of
impairment in global cognition, short-term memory, visuospatial processing, learning, planning,
nonverbal test performance, and motor skills (adjusted odds ratios 2.87–16.22; P values ≤ 0.05).29
Lastly, a study of South African infants with PHIV who initiated ART within 21 days of life (median
6 days) found that neurodevelopmental scores at approximately 11.5 months of age were within the
normal range for age in the domains of locomotor, personal–social, hearing and language, and
visual–motor.30

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
The IMPAACT 1115 Phase 1/2 proof-of-concept study of very early ART initiation began treatment
of 54 infants within 10 days of birth. CD4 counts were ≥1,500 cells/mm3, and CD4 percentages were
≥25% among 84% of infants at 24 weeks after treatment initiation and among 80% of infants at
48 weeks after treatment initation.31 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.32 Available data suggest that both children
and adults who initiate treatment with a higher CD4 percentage or CD4 count have better immune

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-3
recovery than patients who initiate treatment with lower CD4 percentages or CD4 counts.23,33-35
Among 1,236 children with PHIV 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%.36 Finally, earlier age at ART
initiation results in higher rates of CD4:CD8 ratio normalization and improved immunogenicity of
childhood vaccines.37-39

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.40-45

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.46
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.47-49 Among 27 children in the Early-treated Perinatally HIV-infected
Individuals: Improving Children’s Actual Life with Novel Immunotherapeutic Strategies (EPIICAL)
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.50 In the CHER study, early ART initiation
and longer duration of ART was associated with lower proviral DNA levels at age 5 years.51 Finally,
in the Early Infant Treatment Study in Botswana, 40 infants initiated ART at a median 2 days of life,
with 2 infants dying within 12 to 24 weeks of treatment initiation. Low reservoirs were noted among
the 38 who survived to 96 weeks, even though most infants experienced periods of detectable HIV-1
RNA between 24 to 96 weeks. Low pre-ART reservoir size was predictive of preserved CD4 count
and low viral reservoirs.52

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.40,53

The report of a prolonged remission in a child with PHIV in Mississippi generated discussion about
early initiation of ART as presumptive treatment in newborns at high risk of HIV acquisition.54,55
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.56 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 counts.57

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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection E-4
facilitate ART-free remission. Although a limited number of case reports describe lengthy remissions
in children with PHIV who have undergone treatment interruption, current ART has not been shown
to eradicate HIV infection, because HIV persists in CD4 cells and other long-lived cells.56-59 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 data for antiretroviral (ARV) drugs in full-term
infants aged <2 weeks and preterm infants aged ≤4 weeks, drug and dose selection in this age group
is challenging60,61 (see What to Start and Antiretroviral Management of Infants With In Utero,
Intrapartum, or Breastfeeding Exposure to HIV). 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.62,63 When drug concentrations are subtherapeutic—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.
However, in ART-naive children and adolescents with cryptococcal meningitis, tuberculous
meningitis, and disseminated Mycobacterium avium complex 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.64,65 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
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What to Start: Antiretroviral Treatment Regimens
Recommended for Initial Therapy in Infants and Children
with HIV
Updated: June 27, 2024
Reviewed: June 27, 2024

Panel’s Recommendations
• The selection of an initial antiretroviral regimen for the treatment of HIV infection in infants and children should be
individualized based on factors that include patient characteristics (e.g., age, weight), regimen characteristics (e.g., efficacy,
safety, tolerability), clinical and practical considerations, patient and family preferences, and the results of HIV resistance
testing (AIII) (see Table A below and Appendix A. Pediatric Antiretroviral Drug Information).
• For infants and children initiating treatment for HIV for the first time, the Panel on Antiretroviral Therapy and Medical
Management of Children Living with HIV recommends initiating antiretroviral treatment (ART) with three drugs: a dual–
nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) backbone plus an integrase strand transfer inhibitor anchor drug,
when possible. In some circumstances, an ART regimen of two NRTIs plus a non-nucleoside reverse transcriptase inhibitor or
a boosted protease inhibitor as the anchor drug may be indicated for initial treatment (AI*). See Table 8. Antiretroviral
Treatment Regimens Recommended for Initial Therapy for HIV Infection in Infants and Children 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/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 treatment (ART) regimens 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 viral load (plasma HIV RNA
concentration) and CD4 T lymphocyte (CD4) cell count. The Panel modifies recommendations on optimal
initial therapy for children as new data become available, new therapies or drug formulations are developed,
and additional toxicities are recognized.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-1
When developing recommendations for specific antiretroviral (ARV) 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. However, if pediatric data are lacking,
evidence in adolescents and adults is considered.
• The extent of pediatric experience with a specific drug or regimen.
• 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 ease of
administration, formulation options (e.g., syrups, powders, or granules vs. chewable tablets vs. pediatric
dispersible tablets), palatability, pill size, and number of pills or volume of oral solution needed for an
appropriate dose.
• Dosing frequency and food and fluid requirements.
• The potential for drug interactions with other medications.

ART regimens recommended for use in children with HIV should generally consist of a backbone of two
nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) plus a third active anchor drug from one of the
following classes: an integrase strand transfer inhibitor (INSTI), a non-nucleoside reverse transcriptase
inhibitor (NNRTI), or a protease inhibitor (PI) with a PK enhancer (also known as a booster; the two drugs
used for this purpose are cobicistat [COBI or c] and ritonavir [RTV or r]).

The Panel classifies recommended ARV drugs or ART regimens for initial treatment of HIV infection in
infants and children into one of two categories:

Preferred: ARV drugs or drug combinations are designated as Preferred for initial ART in ART-naive
infants and children when clinical trial data in children or, more often, in adults have demonstrated optimal
and durable efficacy and when pediatric studies using surrogate markers have demonstrated safety and
appropriate drug exposure. Age and weight requirements, formulations, dosing frequency, potential drug
interactions, and other factors are also considered when designating ARV drugs or ART regimens as
Preferred.

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
initial ART regimens in children if they are less effective or durable than a Preferred regimen in children or
adults; 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.

ARV drugs or regimens that are not recommended for initial ART in children are discussed in What Not to
Start: Regimens Not Recommended for Initial Antiretroviral Therapy in Children. For detailed pediatric
information on each drug, see Appendix A. Pediatric Antiretroviral Drug Information.

Factors to Consider When Selecting an Initial ART Regimen

ART regimens for infants and children should contain three fully active drugs for durable and potent
virologic suppression. When possible, the initial treatment should reflect an option that only requires once-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-2
daily dosing and minimizes the number of liquid formulations, dispersible tablets, or pills that must be
administered. Therefore, Panel recommendations reflect once-daily ARV regimens and single-tablet
regimens whenever feasible.

Panel recommendations about ARV drugs and drug combinations for initial ART regimens in infants and
children are influenced by the availability of FDA-approved drugs. FDA drug approvals of pediatric
formulations and approvals for the use of adult formulations in children are based on weight but include age
limitations for some drugs. Although age can be used as an initial guide when selecting ARV drugs for use in
infants and children, body weight is the preferred determinant for drug selection and drug dosing in infants
and children. Gestational age at birth and postnatal age must also be considered in the selection of some
drugs for infants. Many drugs that are recommended for use in young infants do not have dosing
recommendations for infants born prior to 37 weeks of gestational age (i.e., born preterm).

When making recommendations, the Panel considers efficacy and factors affecting the efficacy of a regimen,
age and weight requirements, potential toxicity, tolerability, and drug or regimen characteristics that affect
administration and adherence (e.g., formulations, pill size, dosing frequency). Table A below summarizes
factors to consider when selecting an ART regimen for infants and children. Details about ARV
formulations, fixed-dose combinations, dosing, and administration to infants and children are provided in
Appendix A. Pediatric Antiretroviral Drug Information. Advantages and disadvantages of ARV components
recommended for initial therapy in infants and children are summarized in Table B and Table 9 below.
Additional information is provided in the Adult and Adolescent Antiretroviral Guidelines (see Table B.
Advantages and Disadvantages of Antiretroviral Components Recommended as Initial Antiretroviral
Therapy).

The Panel recommends rapid initiation of ART (defined as initiating ART immediately or within days of
diagnosis), accompanied by a discussion about the importance of adherence and provision of adherence
support for all children with HIV (see When to Initiate Antiretroviral Treatment in Children with HIV
Infection and Adherence to Antiretroviral Therapy in Children and Adolescents with HIV).

Table A. Factors to Consider When Selecting an Antiretroviral Treatment Regimen for Children

Factors to Consider Key Questions and Comments

Acquired potential drug Are there any concerns that the childa may have HIV virus resistant to certain ARV
resistance drugs?
Age and weight Are dosing, PK, and safety information for an ARV drug available based on the child’s
weight and age?
Are there weight and/or age requirements for ARV drug use per FDA approvals or
Panel recommendations, including gestational age and postnatal age requirements?
Do efficacy and safety data support the choice of specific ARV drugs as part of an
initial ART regimen?
Is weight-band dosing information available? Weight-band dosing minimizes the need
for frequent dose adjustments.
Available formulations What drug formulations are available for potential treatment regimens (e.g., liquids,
dispersible tablets, film-coated tablets that must be swallowed whole, tablets that can
be crushed or split)?
If pills are available, what is the pill size?

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-3
 Are multiclass single-tablet regimens available? See Appendix A, 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.
Frequency of dosing Is a once-daily regimen possible?
Preparation and administration How complicated is preparing the medications needed for the ART regimen?
of medication by caregivers
What can be done to ensure that caregivers can safely and accurately administer the
medications?
Providers should complete the following:
• Provide medication teaching by trained medical staff.
• Provide correctly sized oral syringes.
• For liquids, ensure that bottles include stoppers to minimize spilling and medication
wastage.
• Provide medication calendars after discussing who will be administering the ART
and identifying the most convenient time for administration.
• Address any food restrictions or requirements for ARVs to be given with food.
• Repeat teaching at each clinic visit.
Palatability and tolerance How palatable and well tolerated is the regimen?
Ability to swallow pills Can this child swallow pills or be taught how to swallow pills?
The age that a child can learn the skill of swallowing pills varies. Usually, children aged
4 years and older can be taught to swallow pills.
Drug–drug interactions Does the child require chronic treatment for any other conditions (e.g., mental health
conditions, seizure disorders, tuberculosis)? If so, are there any potential drug
interactions? See the Adult and Adolescent Antiretroviral Guidelines and the HIV Drug
Interaction Checker.
Contraindications Are there contraindications to prescribing a specific ARV or ART regimen? For
example, a positive HLA-B*5701 allele test result is a contraindication for use of
abacavir.
Comorbidities Are there conditions or comorbidities that affect ARV choices for the drug regimen?
Examples include tuberculosis, hepatitis B virus infection, and, for adolescents,
pregnancy.
Toxicity What are the most common side effects and safety profiles for the ARV(s)? See
Appendix A. Pediatric Antiretroviral Drug Information.
Are there specific toxicity or side effect considerations for individual children (e.g.,
weight gain in children or adolescents who are overweight or obese, depression)?
Availability,b cost, and Are the medications and formulations needed readily available? Some new drugs or
insurance coverage pediatric formulations may not be available in certain areas, or concerns may exist
about maintaining a continuous supply.
Does the child have insurance coverage?
Are there co-pays and, if so, can the family afford the costs?
Does the regimen require prior authorization?
a For the sake of brevity, the term “child” encompasses infants, children, and prepubertal adolescents.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-4
b Because some ARV medications or pediatric formulations may not be available in certain hospitals or geographic areas, clinicians should
check availability and advocate for additions to formularies at local hospitals and/or pharmacies as needed.
Key: ART = antiretroviral therapy; ARV = antiretroviral; FDA = U.S. Food and Drug Administration; PK = pharmacokinetic

Panel Recommendations for Initial ART Regimens in Infants and Children

The following subsections group Panel recommendations for initial ART regimens for children, including
prepubertal adolescents, with HIV infection according to a child’s age (birth to <30 days, ≥30 days to
<2 years, ≥2 to <12 years, and ≥12 years). These guidelines provide recommendations for prepubertal
children and adolescents (i.e., those with sexual maturity ratings [SMR] of 1 to 3).1 The Adult and
Adolescent Guidelines2 address recommendations for postpubertal adolescents (i.e., those with an SMR of 4
and 5); see What to Start. It is important to point out that pediatric approvals for most drugs are now based
on specific weight parameters and that weight, rather than SMR, is a key determinant in ARV drug selection.

Preferred regimens for initial ART in infants aged <30 days with HIV-1 infection include a backbone of two
NRTIs. INSTI-based regimens (INSTI plus two NRTIs) plus an INSTI or a NNRTI as the anchor drug are
Preferred for initial ART in infants and children aged ≥30 days with HIV-1 infection whenever possible.
Preferred anchor drugs, by age and weight, are listed below with Alternative options discussed in
subsections by age group:

• Newborns and infants aged <30 days: nevirapine (NVP), regardless of weight, or raltegravir (RAL) if
weight ≥2 kg; see Table 8 below regarding gestational age considerations.
• Infants and children aged ≥30 days 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 (FTC)/tenofovir alafenamide
(TAF).
INSTI-based regimens have become the Preferred option for initial ART regimens in infants and children
(and adults) whenever possible due to their virologic efficacy, lack of drug interactions, and favorable
toxicity profile.3-6 This pediatric recommendation is consistent with recommendations for initial ART in
adults and adolescents (see the What to Start: Initial Combination Antiretroviral Regimens for People with
HIV section of the Adult and Adolescent Antiretroviral Guidelines). Adult comparative trials have shown
that INSTI-containing regimens have superior efficacy compared with PI-containing and NNRTI-containing
regimens,7,8 and an increasing number of studies have evaluated the PK, safety, tolerability, and efficacy of
these drugs in infants, children, and adolescents (see the Raltegravir, Dolutegravir, and Bictegravir sections).
RAL is a first-generation INSTI and is the only INSTI option FDA approved for use in infants aged <30
days. INSTI-based regimens using second-generation INSTIs that have greater efficacy and a higher barrier
to resistance than RAL (i.e., DTG or BIC depending on age and weight), are recommended for initial
therapy in children.

Planning for Transitions in ART Regimens

When initiating treatment in infants and children, it is recognized that there may be more potent drug
options, options with lower administration burden on a caregiver, and options with lower liquid volume
requirements or pill burden as an infant or child gains weight or increases in age and develops the ability to
swallow pills. This section briefly addresses planning regimen transitions. Information and recommendations
about the sequence and selection of ARV drugs after initial therapy are provided in other Guidelines
sections. Modifying Antiretroviral Regimens in Children with Sustained Viral Suppression on Antiretroviral

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-5
Therapy discusses modifications to simplify or optimize treatment or to manage a specific toxicity.
Recognizing and Managing Treatment Failure discusses situations where viral suppression has not been
reached on initial ARV therapy. Management of Medication Toxicity or Intolerance provides an overview of
management with links to toxicity tables (e.g., Lipodystrophies and Weight Gain, Dyslipidemia) that address
specific issues.

Selection of Dual–Nucleoside Reverse Transcriptase Inhibitor Backbone as Part of Initial

Antiretroviral Therapy Regimens
Dual-NRTI combinations form the backbone of ART regimens for the treatment of HIV in both adults and
children and are used in combination with an anchor drug from one of the following ARV classes: INSTIs,
PIs, or NNRTIs. Dual-NRTI backbones recommended by the Panel as part of Preferred or Alternative ART
regimens for children or for use in special circumstances are listed below, with links to sections in Appendix
A. Pediatric Antiretroviral Drug Information that provide detailed information about the formulations,
dosing, safety, and use of each drug in infants and children.

• (Zidovudine [ZDV] or abacavir [ABC]) plus (lamivudine [3TC] or FTC)

• TAF plus FTC for children weighing ≥14 kg. Some FDCs for complete ART regimens that include TAF
have varying weight and age requirements.
• Tenofovir disoproxil fumarate (TDF) for children aged ≥2 years and weighing ≥10 kg plus 3TC or FTC
Dual-NRTI selection is influenced by a child’s weight and age, as well as the availability of FDCs for NRTI
combinations or FDCs for complete ART regimens. The advantages and disadvantages of the different dual-
NRTI backbone options that are recommended for initial therapy in children are shown in Table 9 and
discussed briefly below.

ZDV has been shown to be safe and effective as part of ART regimens for infants and children; however,
hematologic toxicity (anemia, neutropenia, and/or thrombocytopenia) may affect its use in some children.9,10
Twice-daily dosing of ZDV is required for all ages. Other NRTIs that require only once-daily dosing in
children are available (e.g., ABC [for some age groups], FTC, TAF). Hematological toxicity and twice-daily
dosing requirements limit the long-term use of ZDV in children.

ABC is only approved by the FDA for use in children aged ≥3 months, but the Panel recommends use of
ABC from birth in full-term infants (see Abacavir).11,12 The Panel supports ABC dosing in neonates that is
based on PK simulation models and has been endorsed by the World Health Organization. A negative test for
the HLA-B*5701 allele must be obtained prior to use of ABC.

3TC and FTC are considered interchangeable as part of ART regimens; both are well tolerated and are
associated with few adverse effects (AEs). FTC can be substituted for 3TC as one component of a Preferred
dual-NRTI backbone (i.e., FTC plus ABC, TDF, or ZDV). Both 3TC and FTC select for the M184V
resistance mutation, which is 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 possible decreased viral
fitness.13,14

TDF-containing regimens are efficacious and well tolerated. However, reductions in bone mineral density
can manifest in children and adults soon after initiating TDF, the clinical significance of which is
unknown.15-20 This reduction in bone density is reversible with drug discontinuation. Although TDF is
associated with a decline in glomerular filtration rate, the effect is generally small, and severe glomerular

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-6
toxicity is rare.21,22 Irreversible renal failure is very rare, but cases have been reported.23 With long-term use
of TDF, renal toxicity can occur at the site of the proximal convoluted tubules, with clinical manifestations
ranging from asymptomatic proteinuria to progressively declining glomerular filtration rates.21,24 Before
starting treatment, clinicians should consider whether the benefits of using TDF outweigh the potential risks
described above. The combination of TDF with atazanavir (ATV)/r, darunavir (DRV)/r, or lopinavir (LPV)/r
increases plasma tenofovir concentrations and the risk of TDF-associated toxicity.25

TAF is only available in FDC tablets that must be swallowed. With TAF, the active drug tenofovir (TFV)
achieves higher intracellular concentrations and lower plasma concentrations than TDF. Bone and renal
toxicity associated with TDF is linked to higher plasma concentrations of TFV, which may explain why
these toxicities do not occur with TAF. Use of COBI- or RTV-boosted PIs in combination with TAF/FTC is
not recommended in children weighing <35 kg because these drugs can increase TAF exposure, and no data
are available on the use of this combination. In children and adolescents weighing ≥35 kg, boosted PIs can be
used with TAF/FTC.

Weight gain and increased risk for clinical obesity have been reported in adults with the use of TAF- and
INSTI-containing regimens,26,27 but these side effects have not been clearly demonstrated in children.28-30
Furthermore, use of TAF-containing regimens has also been associated with increased levels of total and
low-density lipoprotein cholesterol and triglycerides. When these concerns arise, regimens containing TDF
may be preferable. However, providers must consider the risks of proximal renal tubular injury, rare
irreversible renal failure, and decreased bone mineral density that can occur when TDF is used.

NRTI Backbone Selection with Hepatitis B Virus Coinfection

When selecting the NRTI backbone for an initial ART regimen, FTC, 3TC, TDF, and 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.

Recommended Initial ART Regimens for Infants from Birth to <30 Days of Age
Panel recommendations for the anchor drugs for Preferred and Alternative initial ART regimens in infants
aged <30 days (i.e., RAL, NVP, and LPV/r) reflect FDA approval by current weight and the infant’s
postmenstrual age (calculated as gestational age at birth plus postnatal age) at the time the ARV regimen or
specific ARV drug is initiated.

Preferred Regimens
• Term infants (≥37 weeks gestation) or preterm infants with a postmenstrual age ≥37 weeks at the time of
treatment initiation:
o NVP plus ZDV plus (3TC or FTC) or
o RAL (for infants weighing ≥2 kg) plus ZDV plus (3TC or FTC)
• Preterm infants with a postmenstrual age ≥32 weeks to <37 weeks at the time of treatment initiation:
o NVP plus ZDV plus (3TC or FTC)
• Preterm infants with a postmenstrual age <32 weeks at the time of treatment initiation:

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-7
 o Consultation with a pediatric HIV expert or the National Perinatal HIV/AIDS Hotline
(1­888­448­8765) is recommended.
Rationale
The Panel recommends RAL or NVP administered with an NRTI backbone of ZDV plus 3TC as an initial
regimen for the treatment of HIV-1 infection in infants. These regimens consist of ARV drugs that are FDA
approved, with extensive data on the safety and efficacy of their use in infants and children.31-37 The selection
of anchor drug and regimen will depend on several factors, such as ARV resistance during pregnancy, the
infant’s gestational age at birth, current postmenstrual age, weight at treatment initiation, the caregiver’s
perceived ease of preparing and dosing, availability of appropriate formulations, and availability of
medications in the outpatient setting. These have been summarized in Table B. Advantages and
Disadvantages of ARVs Recommended for Initial Antiretroviral Therapy in Infants From Birth to <30 Days
of Age below. Resistance testing should be performed at the time of HIV diagnosis and before initiation of
ART but should not delay treatment initiation. Initial ART regimens can be modified if needed based on
results (see Clinical and Laboratory Monitoring of Pediatric HIV Infection).

At the time of HIV diagnosis, some infants at high risk for HIV acquisition may have initiated
presumptive HIV therapy. The regimens recommended for presumptive HIV therapy are addressed in
Antiretroviral Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to HIV and are
the same as the ARV regimens recommended for treatment of HIV infection in neonates. Therefore, once the
diagnosis of HIV-1 is established in the neonate, the regimen for presumptive HIV therapy can be
continued—now as definitive ART—with virologic monitoring to establish successful viral suppression (see
Clinical and Laboratory Monitoring of Pediatric HIV Infection).

At the time of HIV diagnosis, some infants at low risk for HIV acquisition might be receiving ZDV
alone as prophylaxis. If the infant has a positive HIV nucleic acid test, a complete ART regimen should be
initiated without waiting for the results of a confirmatory test. In this case, ZDV may be continued with the
addition of a second NRTI and either RAL or NVP. If RAL or NVP is not an option, a LPV/r-based regimen
appropriate for the infant’s age and weight can be used (see Alternative Regimens below). If confirmatory
testing indicates the infant does not have HIV infection, ART can be discontinued.

Alternative Regimens
Alternative Anchor Drug

• Infants with a postmenstrual age ≥42 weeks and a postnatal age of ≥14 days
o LPV/r plus ZDV plus (3TC or FTC)
LPV/r: The Panel recommends LPV/r oral solution in combination with the NRTI backbone recommended in
Preferred Regimens above as an Alternative anchor drug for infants with a postmenstrual age of ≥42 weeks
of gestation and a postnatal age of >14 days. LPV/r oral solution contains 42.4% (volume/volume) alcohol
and 15.3% (weight/volume) propylene glycol. Use of this drug in infants before 42 weeks postmenstrual age
and before a postnatal age of 14 days, at a time when hepatic metabolic function and kidney excretory
function are maturing, can lead to accumulation of LPV, alcohol, and propylene glycol, resulting in serious
cardiac, renal, metabolic, or respiratory problems. For more information about LPV/r use in newborns, refer
to the Lopinavir/Ritonavir section in Appendix A. Pediatric Antiretroviral Drug Information.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-8
Alternative NRTI Backbone

• Term infants (≥37 weeks gestation)

o ABC plus (3TC or FTC) if HLA-B*5701 negative
ABC: A negative test for the HLA-B*5701 allele must be obtained prior to use of ABC. Although ABC is
not FDA approved for use in infants aged <3 months, the Panel recommends ABC as part of an Alternative
NRTI backbone for full-term infants from birth (see Abacavir). An ABC dosing recommendation using PK
simulation models has been endorsed by the World Health Organization using weight-band dosing for full-
term neonates. A recent study of infants with HIV in a South African cohort, stratified by age (<28 days and
≥28 days) and weight (<3 kg and ≥3 kg), demonstrated the safety and effectiveness of ABC in infants aged
<3 months and in neonates weighing <3 kg.11,12,38

Table B. Advantages and Disadvantages of Anchor Drugs Recommended for Initial Antiretroviral
Therapy Regimens in Infants From Birth to <30 Days of Age

Preferred and Advantages Disadvantages

Alternative Anchor
Drugsa
RAL • FDA-approved INSTI for use in term • First-generation INSTI with lower barrier
newborns weighing ≥2 kg to resistance than DTG or BIC
• Produces rapid reduction in viral load • Granule formulation requires a multistep
preparation before administration.
• Safe and well tolerated
• Caregivers must be taught how to
• Avoids use of NVP and exposure to properly prepare granule formulation.
another class of ARVs (NNRTIs) Explain that only a small volume of the
prepared granule suspension is used; the
rest must be discarded and cannot be
reused.
• Limited to use in term infants (≥37 weeks
of gestation) or preterm infants with a
postmenstrual age ≥37 weeks at the time
of treatment initiation
NVP • Available in convenient oral solution • Not a Preferred ARV outside the neonatal
period due to the potential for toxicity and
• Can be used in preterm newborns with a development of viral resistance, though it
gestational age ≥32 weeks can be used if clinically indicated
• Reduced virologic efficacy in young
infants, regardless of exposure to NVP as
part of a peripartum preventive regimen
• A single mutation can confer resistance to
this drug and, in some instances, to all
NNRTIs.
LPV/r • Available in convenient oral solution • Should not be administered to neonates
before a postmenstrual age of 42 weeks
• More durable than RAL or NVP (calculated as gestational age at birth plus

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-9
 Preferred and Advantages Disadvantages
Alternative Anchor
Drugsa
postnatal age) and a postnatal age <14
days
• Poor palatability and bitter taste may
cause incomplete dosing if infant spits it
out.
• Not a Preferred ARV outside the neonatal
period due to issues with palatability and
concerns about toxicity, though it can be
used if clinically indicated
aThis table focuses on advantages and disadvantages regarding the selection of anchor drugs for ART regimens used in infants aged <30
days. Additional information is available in Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended for Initial
Therapy in Infants and Children.

Key: ART = antiretroviral therapy; ARV = antiretroviral; BIC = bictegravir; DTG = dolutegravir; FDA = U.S. Food and Drug Administration;
INSTI = integrase strand transfer inhibitor; LPV/r = lopinavir/ritonavir; NNRTI = non-nucleoside reverse transcriptase inhibitor; NVP =
nevirapine; RAL = raltegravir

Practical and Clinical Considerations

The clinician should provide the infant’s caregiver with information about prescribed medications, including
names, doses, dose times, potential side effects, and how to properly administer the medications.
Appropriately sized oral syringes should be dispensed, and liquid medications should include bottle adapter
plugs to minimize wastage. Practice preparing and administering the medications should be completed and
documented in the medical record. This is especially important when RAL is prescribed because there is a
multistep process to prepare the infant dose using the oral granules for suspension (see Raltegravir). ARV
availability and complexity of preparation and administration may affect decisions about the use of NVP
versus RAL. It is recommended that a medication calendar be provided and that the caregiver be involved in
deciding the most convenient times for the medications to be administered. Clinicians should ensure that
insurance covers the prescribed ART regimen and that the infant’s local pharmacy stocks all components of
the regimen. For neonates who are initiating ART while still in the hospital, clinicians should provide
caregivers with the appropriate information and an initial supply of medications before discharge.

At each clinic visit, the clinician and caregiver should review the process of preparing the different liquid
formulations of the medications to ensure that correct volumes and doses are being administered. When
appropriate, weight-band dosing should be used and doses should be adjusted based on weight gain and age.
This is particularly important during the first weeks of life, when changes to drug metabolism and renal
function occur that impact appropriate dosing recommendations (see Appendix A. Pediatric Antiretroviral
Drug Information). Refills should be arranged with pharmacies that stock the ARV drugs.

Special Situations
• ARV Drug Resistance: Infants can acquire HIV infection with drug-resistant virus. Transmitted drug
resistance has been demonstrated with NNRTIs, NRTIs, PIs, and INSTIs, although transmitted resistance
to INSTIs is very rare.39 Therefore, when viral suppression was not achieved during pregnancy and drug
resistance is suspected, the parent’s ARV resistance data should be reviewed, if available, and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-10
 consultation with a pediatric HIV expert is recommended. In neonates, a Preferred ART regimen should
be commenced immediately; this may later be changed or modified based on the results of baseline
infant HIV genotyping (see Clinical and Laboratory Monitoring of Pediatric HIV Infection).
• HIV-2 Infection: ART regimens for infants with HIV-2 infection only or infants with HIV-2 and HIV-1
coinfection should include ARVs that are active against HIV-2. Because NNRTIs are not active against
HIV-2, NVP should not be used. A RAL-based regimen is recommended for infants with HIV-2 or with
HIV-2 and HIV-1 coinfection: RAL (for full-term infants weighing ≥2 kg) plus ZDV plus (3TC or FTC).
Consultation with a pediatric HIV expert or the National Perinatal HIV/AIDS Hotline (1­888­448­8765)
is recommended for the care of infants weighing <2 kg or with a gestational age <37 weeks.
Planning ARV Transitions
Although the ARV regimen started in the first 29 days of life can be continued, the Panel recommends that
consideration be given to changing the regimen to a DTG-containing regimen after the infant reaches the
appropriate age and weight; see Preferred Regimens for Children Aged ≥30 Days to <2 Years below. This
change should be considered because DTG has greater efficacy and durability than RAL or NVP,40 DTG
dispersible tablets are easier to prepare and administer than RAL granules, and DTG is available in a FDC
formulation.

Recommended Initial ART Regimens for Infants and Children Aged ≥30 Days to <2 Years
Preferred Regimens
• Aged ≥30 days to <2 years and weighing ≥3 kga
o DTG plus ABC plus (3TC or FTC) if HLA-B*5701 negative or
o DTG plus ZDV plus (3TC or FTC) or
• Aged ≥3 months to <2 years and weighing ≥6 kg to <25 kg
o DTG plus ABC plus 3TC as a FDC (Triumeq PD) if HLA-B*5701 negative
a
For infants aged ≥30 days who weigh <3 kg, therapy should be initiated using one of the regimens
described in Recommended Initial ART Regimens for Infants from Birth to <30 Days of Age above (e.g.,
NVP or RAL). Transition to a DTG-based regimen should be considered when the infant’s weight is ≥3 kg.

Rationale
It is assumed that all children in this age group are unable to swallow pills and will require treatment with
ARVs in liquid, dispersible tablet, powder packet, or chewable tablet formulations.

For infants and children weighing ≥3 kg who are starting ART at ≥30 days of age, the Panel recommends
initiation of an INSTI-based ART regimen using DTG plus two NRTIs. DTG is a second-generation INSTI
that has a higher barrier to resistance than RAL and is FDA approved for use in this age group. While there is
low potential for development of resistance with DTG, young infants may initially have very high HIV viral
loads and continue to have low-level viremia during the first year of life. The overall risk of developing
resistance with DTG-based ART in young infants is unknown.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-11
INSTIs have better efficacy and safety profiles than NNRTIs or PIs, and DTG has been studied extensively
in children.3,5 Importantly, the FDC of DTG/ABC/3TC has proven efficacy and a good safety profile, with
weight-band dosing that achieves PK targets.41

For infants aged ≥30 days to ≤6 weeks receiving presumptive HIV therapy with RAL or NVP plus two
NRTIs at the time of HIV diagnosis, the Panel recommends changing to one of the DTG-based regimens
listed above using DTG dispersible tablets. The liquid formulations of the NRTIs used as part of presumptive
HIV therapy (usually ZDV plus 3TC) can be continued; no change in NRTIs is required.

Alternative Regimens
Alternative Anchor Drugs

• LPV/r: LPV is available as an oral solution coformulated with RTV, and twice-daily dosing is
recommended. LPV/r should be administered with food to improve tolerability.34,42,43 Poor taste and
palatability of the oral solution may become an issue for young children and limit acceptance of this
regimen. LPV/r has a high genetic barrier to drug resistance. However, poor acceptance of formulation,
gastrointestinal side effects, and poor weight gain may limit its use in this age group.44
• ATV/r: ATV/r can be considered an Alternative to LPV/r in children weighing ≥15 kg.45 ATV and RTV
are available as separate powder packets that are mixed with either soft food or formula and administered
once daily. The powder formulation of ATV can be used in children weighing ≥15 kg to <25 kg. The
powder formulations have poor palatability and may be difficult to tolerate in this age group.
• NNRTIs: NVP could be considered if there is resistance or intolerance to both PIs and INSTIs. However,
NVP is generally not recommended as an initial treatment in this age group as the low genetic barrier to
resistance during a time of significant viremia may lead to drug resistance to all members of the NNRTI
class of drugs.35 Efavirenz (EFV) is not recommended for children <3 years of age due to highly variable
PK in young children, difficulty in determining an appropriate dose without therapeutic drug monitoring,
and side effects (i.e., neurologic toxicity).46
NRTI Backbones in Alternative Regimens

• Twice-daily dosing: An NRTI backbone of ZDV plus 3TC twice daily or ABC plus 3TC twice daily
allows for all medications to be administered at the same time when given in combination with LPV/r or
RAL. There is considerable experience with ZDV and 3TC in this age group. ABC is associated with less
bone marrow toxicity than ZDV and may be the Preferred NRTI for long-term use.
Practical and Clinical Considerations
DTG plus ZDV plus 3TC can be initiated immediately. However, due to the potential of ABC
hypersensitivity, a negative test for the HLA-B*5701 allele must be obtained before initiating a regimen of
DTG plus ABC plus 3TC. HLA-B*5701 should be included in the initial work-up for all infants and children
with HIV. ABC is not FDA approved for use in infants aged <3 months, but the Panel does recommend use
of twice-daily ABC for infants aged ≥30 days. In decisions about selecting ABC as a component of the initial
regimen for children aged <2 years, clinicians should consider concerns regarding delays initiating treatment
related to HLA-B*5701 testing versus the advantages of using an FDC.

For infants who are aged ≥30 days and ≥3 kg in weight, DTG is available as dispersible tablets that are
administered separately, along with the liquid formulations of ZDV and 3TC. For infants and children

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-12
weighing ≥6 kg to <25 kg who are initiating therapy at ≥3 months of age, DTG plus ABC plus 3TC is
available as dispersible FDC tablets (Triumeq PD) that can be administered once daily and provide a number
of advantages:

• Tablets are mixed in water (volume depends on the number of tablets needed for weight-band dosing; see
Dolutegravir for details about dosing and preparation).
• Once-daily dosing improves adherence to ARVs.
• Use of the FDC formulation avoids the need to measure and administer liquid ZDV and 3TC separately
and minimizes difficulties in accurately measuring the volumes needed.
• Use of the FDC minimizes the need to adjust doses frequently as the infant or child grows.
When teaching families about preparing the medications, it should be explained that dispersible tablets need
to be mixed in water because there is a lack of data about dispersing DTG or DTG/ABC/3TC dispersible
tablets in other liquids, such as formula or breast milk. With once-daily dosing, it is particularly important to
emphasize the critical importance of not missing any doses.

Special Situations
• DTG dispersible tablets not available: If DTG dispersible tablets are not available, RAL can be
administered using either the oral granules for suspension dispersed in water or as the chewable tablets
dispersed in juice or formula/milk.47 RAL oral granules for suspension require a multistep process to
prepare each dose, and twice-daily dosing is required. RAL also has a lower genetic barrier to resistance
compared to DTG.
• Identification of viral resistance: If viral resistance is identified in baseline genotype testing, the initial
ART regimen may need to be modified.
o INSTI resistance: If resistance to INSTIs is present, the regimen should consist of the NRTI
backbone plus a PI. Use of LPV/r is recommended in this situation, as it is coformulated with
ritonavir in a formulation suitable for administration in this age group. If there is multidrug ARV
resistance, consultation with a pediatric HIV expert is recommended.
o Presence of M184V resistance mutation: If the M184V/I mutation associated with FTC and 3TC is
present, these medications should be continued if the new regimen contains TDF, TAF, or ZDV. The
presence of this mutation may increase susceptibility to these NRTIs.
• HLA-B*5701 positive: ART regimens with ABC should not be given due to ABC-associated
hypersensitivity.
• Presence of HBV infection: In HIV/HBV coinfection, an ART regimen should include two NRTIs
active against HBV (see Selection of Dual–Nucleoside Reverse Transcriptase Inhibitor Backbone as Part
of Initial Antiretroviral Therapy Regimens above). However, regimens containing only one active NRTI
(3TC or FTC) may be used when children in this age group don’t meet the weight criteria for use of a
second NRTI active against HBV. They should be changed to a TAF/FTC-containing regimen as soon as
possible after they weigh ≥14 kg.
• HIV-2 infection: ART regimens for infants and children with HIV-2 infection only or those with HIV-
2/HIV-1 coinfection should include ARVs that are active against HIV-2. Consultation with a pediatric
HIV expert is recommended for the care of infants and children with HIV-2.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-13
Planning ARV Transitions
For infants aged ≥3 months and weighing ≥6 kg who initiated treatment on DTG plus ZDV plus (3TC or
FTC), the Panel recommends changing to a regimen of once-daily DTG plus ABC plus 3TC that is available
as dispersible FDC tablets (Triumeq PD) in order to simplify measurement of ARV doses and
administration. A negative test for the HLA-B*5701 allele must be obtained prior to initiation of an ABC-
containing regimen.

There are additional options for transitioning to other INSTI-containing preparations as children become
older and are able to swallow pills, such as the FDC BIC/FTC/TAF (Biktarvy), which can be used in children
aged ≥2 years and weighing ≥14 kg (see discussion in Recommended Initial ART Regimens for Children
Aged ≥2 Years to <12 Years below). The NRTI backbone FTC/TAF is available in a FDC (Descovy) that
can be used in combination with an anchor drug, such as DTG, in children weighing ≥14 kg who are able to
swallow pills.

Recommended Initial ART Regimens for Children Aged ≥2 Years to <12 Years
Preferred Regimens
In considering an initial ART regimen for children aged ≥2 years to <12 years, some children, particularly
younger children, may not be able to swallow pills, whereas older children may be able to take pills. It is
recommended that clinicians counsel families about teaching children how to swallow pills, as this increases
the number of ARV options and simplifies regimens.48 Children as young as 4 years of age can be taught
how to swallow pills. In addition to age and ability to swallow pills, the weight of the child must also be
taken into consideration. Therefore, the Panel recommendations for what regimen to start are presented for
children unable to swallow pills and those who are able. FDA-approved pill formulations are based on a
child’s weight, followed by recommendations for those who are able to swallow pills and the minimum
weight allowed for dosing. Please refer to Appendix A. Pediatric Antiretroviral Drug Information for specific
dosing of ARV drugs by weight band.

Preferred Regimens for Children Aged ≥2 Years to ≤12 Years Who Are Not Able to Swallow Pills

• DTG plus ABC plus 3TC in the dispersible FDC formulation (Triumeq PD) for children weighing 6 kg
to <25 kg if HLA-B*5701 negative or
o DTG film-coated tablets (Tivicay) plus ABC plus (3TC or FTC) in liquid formulations for children
weighing ≥25 kg if HLA-B*5701 negative (see Dolutegravir for special instructions about
administering DTG tablets to children who are not able to swallow pills)
• DTG plus FTC plus TAF for children weighing ≥14 kg (see Dolutegravir and Tenofovir Alafenamide for
available formulations of DTG [Tivicay, Tivicay PD], dosage strengths of FTC/TAF [Descovy], and
special instructions for administering DTG film-coated tablets and FTC/TAF tablets to children who are
not able to swallow pills) or
• DTG in dispersible tablets plus ZDV plus (3TC or FTC) in liquid formulations
The dispersible FDC tablet of DTG/ABC/3TC (Triumeq PD) is a once-daily regimen. A child must have a
negative HLA-B*5701 allele screening test prior to initiation of treatment to ensure that the child will not be
at risk for a hypersensitivity reaction to ABC.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-14
When the DTG/ABC/3TC dispersible FDC tablet cannot be used (i.e., it is not available or results of HLA-
B*5701 testing are unknown or positive) and the child weighs <14 kg at treatment initiation, the Panel
recommends initiating a regimen of DTG plus ZDV plus 3TC. DTG is available as dispersible tablets
(Tivicay PD) dosed once daily that can be used in children weighing 6 kg to <25 kg. ZDV and 3TC are both
available in liquid formulations and require twice-daily dosing. If DTG/ABC/3TC cannot be used and the
child weighs ≥14 kg, DTG plus FTC/TAF (Descovy) is recommended by the Panel. FTC/TAF (Descovy) is
available in two different-strength tablets, with the lower-strength tablet for children weighing ≥14 kg to
<25 kg.

Preferred Regimens for Children Aged ≥2 Years to ≤12 Years Who Are Able to Swallow Pills

For children weighing <14 kg, see regimens listed above for children who are not able to swallow pills.

• BIC plus FTC plus TAF (FDC BIC/FTC/TAF, Biktarvy) for children weighing ≥14 kg
• DTG plus FTC plus TAF (DTG, Tivicay, plus the FDC FTC/TAF, Descovy) for children weighing
≥14 kg
• DTG plus ABC plus 3TC (FDC DTG/ABC/3TC, Triumeq) for children weighing ≥25 kg if
HLA-B*5701 negative

Rationale
The Panel recommends initiating ART with a once-daily, single-tablet regimen of BIC/FTC/TAF (Biktarvy)
for children weighing ≥14 kg. Two different strengths of BIC/FTC/TAF tablets are available, with the lower-
strength tablet for children weighing ≥14 kg and <25 kg. The product label states that for children who are
unable to swallow a whole tablet, the BIC/FTC/TAF tablet can be split and each part taken separately, as
long as all parts are ingested within approximately 10 minutes.49

DTG/3TC/ABC (Triumeq) is another Preferred single-tablet regimen option for children weighing ≥25 kg;
however, the DTG/3TC/ABC pill is much larger than the BIC/FTC/TAF pill and might be more challenging
to swallow, particularly for younger children. If DTG/3TC/ABC is selected, documentation of a negative
HLA-B*5701 screening should occur prior to treatment initiation. For children weighing ≥14 kg, the film-
coated tablet of DTG (Tivicay) used in conjunction with the FDC tablets of FTC/TAF (Descovy) is also
recommended by the Panel.

The FDC of BIC/FTC/TAF (Biktarvy) has been studied in adolescents aged 12 years to <18 years and
weighing ≥35 kg (Cohort 1), children aged 6 years to <12 years and weighing ≥25 kg (Cohort 2), and
children aged ≥2 years and weighing ≥14 kg to <25 kg (Cohort 3). 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.50 Among children in Cohort 3, after
24 weeks, all 12 participants maintained viral suppression.

DTG, studied in the multinational open-label IMPAACT 1093 study3,51,52 and ODYSSEY4,10,53 has been
demonstrated to be safe, efficacious, and well tolerated in children. 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 aged <12 years (NCT03760458). In IMPAACT P2019,

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-15
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 World Health Organization
weight bands.41

Alternative Regimens
Anchor Drugs

When concern for INSTI resistance exists, the following anchor drugs represent Alternative treatment
options when paired with two fully active NRTIs.

• ATV plus RTV or COBI: ATV is available as a powder packet that should be mixed with solid food
and administered once daily. ATV powder should be coadministered with RTV once daily for a child
aged ≥2 years and weighing ≥15 kg to ≤25 kg. RTV is also available in powder packets; the powder
formulation has poor palatability and may be difficult to tolerate. For a child weighing ≥15 kg who is
able to swallow pills, the capsule formulation of ATV can be dosed once daily with the RTV tablets (i.e.,
ATV/r). Boosting ATV with COBI is only an option if the child weighs ≥35 kg and is able to swallow
pills. The FDC of COBI-boosted ATV (ATV/c) can be administered once daily.
• DRV plus RTV or COBI: DRV, dosed twice daily, is an option for children aged ≥3 years to <12 years
and weighing ≥20 kg. However, DRV requires a PK enhancer or boosting agent, such as RTV or COBI.
DRV is available as a solution or tablet that can be administered with a RTV powder packet or tablet.
Boosting DRV with COBI is only an option if the child weighs ≥40 kg. COBI-boosted DRV (DRV/c) is
available in a once-daily FDC (Prezcobix).
• NNRTIs: An NNRTI-based regimen using NVP, EFV, or doravirine (DOR) could be considered if there
is resistance or intolerance to both PIs and INSTIs. EFV is not recommended by the Panel for use in
children aged <3 years due to highly variable PK in young children, difficulty in determining an
appropriate dose without therapeutic drug monitoring, and side effects (i.e., neurologic toxicity) (see
Efavirenz). DOR is approved for use in children weighing ≥35 kg, and recent data found that once-daily
dosing of DOR/3TC/TDF was safe and well tolerated for maintaining viral suppression through
96 weeks in adolescents.54
Practical and Clinical Considerations
The availability of FDC formulations and method of administration are important considerations in the
selection of a Preferred initial regimen.

• BIC/FTC/TAF (Biktarvy) is a single-tablet regimen for children weighing ≥14 kg. The tablet may not be
crushed or dissolved; however, it can be split in half prior to dosing for ease of swallowing.
BIC/FTC/TAF is available in two formulations for children able to swallow pills, including BIC
30 mg/FTC 120 mg/TAF 15 mg for children weighing ≥14 kg to <25 kg and BIC 50 mg/FTC
200 mg/TAF 25 mg for children weighing ≥25 kg.
• ABC/DTG/3TC (Triumeq PD) are dispersible tablets that can be used in children weighing <25 kg and
should be dissolved in water. Each tablet contains all three drugs. The number of tablets per dose is
based on a child’s weight.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-16
• ABC/DTG/3TC (Triumeq) is a nondispersible, single-tablet regimen option for children weighing ≥25 kg
who are able to swallow whole pills. However, a disadvantage is the larger pill size, which can make
swallowing challenging compared with the other recommended options.
• DTG plus FTC/TAF is dosed once daily. DTG is available as dispersible tablets (Tivicay PD) and as a
film-coated tablet (Tivicay). FTC/TAF (Descovy) is available in two different strengths as a single tablet
to be swallowed. See Dolutegravir and Tenofovir Alafenamide for specific weight parameters and for
special instructions about administering these ARVs to children who are not able to swallow pills.
Special Situations
• Identification of viral resistance: If viral resistance is identified in baseline genotypic testing, the initial
ART regimen may need to be modified.
o INSTI resistance: If resistance to INSTIs is present, the regimen should consist of the NRTI
backbone plus a boosted PI. PI options include ATV or DRV, both of which should be boosted with
either RTV or COBI. See Alternative Regimens Anchor Drugs above for age and weight restrictions
for each PI in conjunction with its formulation and its boosting agent. If there is multidrug ARV
resistance, consultation with a pediatric HIV expert is recommended.
o Presence of M184V resistance mutation: 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 regimen
contains TDF, TAF, or ZDV. The presence of this mutation may increase susceptibility to these
NRTIs.
• HLA-B*5701 positive: ARV regimens with ABC should be avoided due to ABC-associated
hypersensitivity.
• Presence of HBV infection: The ART regimen should include two NRTIs active against HBV (see
Selection of Dual–Nucleoside Reverse Transcriptase Inhibitor Backbone as Part of Initial Antiretroviral
Therapy Regimens above). The Panel recommends the FDC FTC/TAF (Descovy) as the NRTI backbone
for children with HIV/HBV coinfection.
• HIV-2 infection: ART regimens for children with HIV-2 infection only or those with HIV-2/HIV-1
coinfection should include ARVs that are active against HIV-2. Consultation with a pediatric HIV expert
is recommended for the care of infants and children with HIV-2.

Planning ARV Transitions

Among children aged ≥2 years to <12 years who initiated treatment when they were unable to swallow pills
or whose weight precluded use of a pill option, once children can swallow pills and are of an appropriate age,
the Panel recommends transitioning to the once-daily FDC of BIC/FTC/TAF (Biktarvy), so long as there are
no contraindications.

Recommended Regimens for Children and Adolescents Aged ≥12 Years

Recommendations for initial ART regimens for adolescents are also addressed in What to Start in the
Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (see Adolescents and
Young Adults with HIV), with an overview provided here.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-17
Pubertal changes during adolescence encompass increased growth velocity, changes in body composition,
and development of secondary sexual characteristics. It is recognized that these changes can affect the PK
and pharmacodynamics of drugs. Adolescents with perinatal HIV infection are more likely to have delayed
puberty and growth compared to their uninfected peers.55 However, regimens recommended for initial ART
in the Adult and Adolescent Guidelines provide adequate drug exposure and are effective and safe when used
for people with HIV infection in this age bracket above a minimum weight, regardless of pubertal stage.

Preferred Regimens
For adolescents aged ≥12 years who do not have a history of using long-acting cabotegravir (CAB-LA) for
HIV preexposure prophylaxis (PrEP), Preferred ART regimens are listed below.

• BIC plus FTC plus TAF (FDC BIC/FTC/TAF, Biktarvy) for adolescents weighing ≥25 kg
• DTG plus ABC plus 3TC (FDC DTG/ABC/3TC, Triumeq) for adolescents weighing ≥25 kg
• DTG plus FTC plus TAF (FDC FTC/TAF, Descovy) for adolescents weighing ≥35 kg
DRV-based regimens are recommended for initial therapy in adolescents who previously received CAB-LA
for PrEP (see Alternative Regimens below).

In the unlikely event that some adolescents aged ≥12 years are not able to swallow pills or weigh <25 kg,
please refer to the Preferred regimens in the 2- to 12-year age group above and Table 8 below.

Rationale
The Preferred regimens (BIC/FTC/TAF and DTG/ABC/3TC) are consistent with the Panel’s
recommendations for the 2- to 12-year age group and are available as FDC single-tablet regimens that
contain the appropriate dose of the three drugs for the specified weight. These FDC regimens are also the
same as those recommended for use in adults and adolescents without delay in pubertal onset, allowing for
the continuation of the same initial Preferred regimen as patients transition through puberty in adolescence
to adulthood. The third regimen, DTG plus FTC plus TAF, is not a single-tablet regimen and has the
disadvantage of requiring use of two tablets for each dose.

The Adult and Adolescent Guidelines also recommend the two-drug regimen DTG/3TC as an option for
initial ART in some individuals (see What to Start). However, the Panel does not recommend a DTG/3TC
regimen for initial therapy in adolescents because data are limited about its use for this age group and there
are concerns about the efficacy and durability of two-drug ART regimens related to gaps or lapses in ARV
adherence common in adolescents.

Alternative Regimens
• DRV/c plus TAF plus FTC (FDC DRV/c/TAF/FTC, Symtuza) for adolescents weighing ≥40 kg
• DRV/c (FDC, Prezcobix) plus TDF/FTC (FDC, Truvada) for adolescents weighing ≥40 kg
Boosted DRV regimens are approved for use in adolescents and can be used if there are concerns about
INSTI resistance (e.g., adolescents diagnosed with HIV who have a history of CAB-LA use for PrEP). These
Alternative regimens give the provider a choice between using a TAF-containing regimen as a single daily
FDC tablet (first option) or a TDF-containing regimen consisting of two daily tablets (second option). These

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-18
alternate choices will be driven by concern for renal and bone disease in the patient (i.e., the need to avoid
TDF) or adverse weight or lipid issues in the patient (i.e., the need to avoid TAF).

Practical and Clinical Considerations

Clinicians should provide the education and support that caregivers and adolescents need in order to
administer or take ARVs correctly and adhere to the ART regimen (see Adherence to Antiretroviral Therapy
in Children and Adolescents with HIV). Adolescents may have difficulty adhering to daily oral medications.
Among many other factors, the number of pills and the pill size are important considerations. Additionally,
in considering the optimal regimen for initiation, the clinician should understand whether the adolescent will
be supervised to take treatment or is expected to take their treatment independently. Preferred initial therapy
with a single tablet dosed once daily helps maintain adherence and viral suppression. Biktarvy is one of the
smallest FDC single-tablet regimens currently available (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).

Several other issues unique to adolescents need to be addressed when initiating HIV treatment. Some may be
living with caregivers who are not aware of their diagnosis and may still be accessing care under their parent
or caregiver’s health insurance plan. Communications between health insurance companies and caregivers
can compromise confidentiality and result in accidental disclosure. Clinicians and social workers need to
work around this issue, and in some instances, assist the patient in establishing their own access to HIV drugs
and/or health insurance. Some adolescents may be emancipated and living on their own but need access to
affordable health insurance. In other instances, adolescents with HIV have been rejected by their families and
are homeless. Rapid initiation of HIV treatment, though desirable, may have to be deferred until social
barriers to adherence are addressed. Adolescents can have other comorbidities, such as depression and
increased risk for suicide. These issues are heightened in adolescents whose sexual/romantic attractions
and/or self-expression are less common. Food insecurity and other social determinants of health that can
affect an adolescent’s ability to safely initiate and adhere to HIV treatment should be evaluated and available
support offered, if possible. Finally, use of patient-centered language can be beneficial in establishing and
maintaining rapport with adolescents, facilitating sustained engagement in care. For additional information,
see Special Considerations for Antiretroviral Therapy Use in Adolescents with HIV and Adolescents and
Young Adults with HIV in the Adult and Adolescent Antiretroviral Guidelines.

Special Situations
Where weight gain and increased risk for clinical obesity is a concern, or the adolescent has a high-risk lipid
profile, a TAF-containing regimen may not be appropriate as a component of a preferred initial regimen (see
Selection of Dual–Nucleoside Reverse Transcriptase Inhibitor Backbone as Part of Initial Antiretroviral
Therapy Regimens above). A FDC single-tablet regimen containing the NNRTI DOR with a backbone of
TDF/FTC can be considered when initiating treatment in adolescents with these concerns.54 However,
providers must take into account the risks of proximal tubular injury, rare irreversible renal failure, and
decreased bone mineral density that can occur when TDF is used.

Planning ARV Transitions

Adherence to daily oral medications is particularly challenging for adolescents,56,57 with lower rates of
virologic suppression compared to adults.58 CAB and RPV (Cabenuva) is a two-drug long-acting ART
regimen administered as two intramuscular injections on a bimonthly schedule that is approved for
adolescents weighing ≥35 kg and adults with HIV who are virologically suppressed on an oral regimen.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-19
Although it is not an option for initial therapy, it provides an option for adolescents who wish to maintain
viral suppression without the need for daily oral medications. In select circumstances, some adolescents
experiencing difficulties with adherence to an oral ART regimen could receive intensive adherence support
to achieve viral suppression on their initial regimen as a bridge to switching to long-acting injectable CAB
and RPV (see Management of Children Receiving Antiretroviral Therapy: Modifying Antiretroviral
Regimens in Children with Sustained Virologic Suppression on Antiretroviral Therapy).59

Table 8. Antiretroviral Treatment Regimens Recommended for Initial Therapy for HIV Infection
in Infants and Children: Birth to <12 Years of Age

The Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV (the Panel)
designates regimens as Preferred based on efficacy, ease of administration, acceptable toxicity, and other
considerations. 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 (see Table A. Factors to Consider When Selecting an Antiretroviral Treatment Regimen for
Infants, Children and Adolescents and Table 9. Advantages and Disadvantages of Antiretroviral Components
Recommended for Initial Therapy in Infants and Children).

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. 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 Infants With In Utero, Intrapartum, or
Breastfeeding Exposure to HIV.

Children who are receiving effective and tolerable antiretroviral 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 additional
guidance about transitioning children to other regimens as they grow.

Panel recommendations for children and adolescents aged ≥12 years are not included in this table; see
Recommended Regimens for Children and Adolescents Aged ≥12 Years in the text.

See the Adult and Adolescent Antiretroviral Guidelines for recommendations about initial antiretroviral
therapy for adolescents.

Preferred Initial Regimens and ARV Drugs Based on Age and Weight at Time of Treatment Initiation
8A. Infants from Birth to <30 Days of Age
Panel Age and/or Weight Formulations and
Regimen or ARV Drug
Recommendationa,b Restrictionc Commentsc
Preferred ART NNRTI (NVP) or INSTI (RAL) plus two
regimens for infants NRTIs
≥37 weeks of
gestation and aged • NVP plus ZDV plus (3TC or FTC) or None All oral solutions
<30 days and
preterm infants with • RAL plus ZDV plus (3TC or FTC) ≥2 kg (RAL) RAL granules for oral
a postmenstrual age suspension plus oral

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-20
 of ≥37 weeks at solutions for ZDV plus (3TC
treatment initiation or FTC)

Preferred ART NNRTI (NVP) plus two NRTIs

regimen for preterm
• NVP plus ZDV plus (3TC or FTC) None All oral solutions
infants ≥32 to
<37 weeks of
gestation
Preferred ART Consultation with a pediatric HIV expert or the National Perinatal HIV/AIDS Hotline (1-888-448-8765) is
regimens for preterm recommended
infant <32 weeks of
gestation
Alternative ART PI (LPV/r) plus two NRTIs
regimens for infants
• LPV/r plus ZDV plus (3TC or FTC) Postmenstrual age ≥42 weeks All oral solutions
and a postnatal age of
>14 days (LPV/r)

Alternative NRTI • ABC plus (3TC or FTC) if HLA- ≥37 weeks of gestation All oral solutions
backbone for infants B*5701 negative
Use of ABCd requires
negative HLA-B*5701 testing.

Preferred Initial Regimens and ARV Drugs Based on Age and Weight at Time of Treatment Initiation
8B. Infants and Children Aged ≥30 Days to <2 Years
Panel Age and/or Weight Formulations and
Regimen or ARV Drug
Recommendationa,b Restrictionc Commentsc
Preferred ART INSTI (DTG)e,f plus two NRTIs
regimens for infants
• DTG plus ZDV plus (3TC or FTC) or DTG ≥30 days and ≥3 kg to DTG dispersible tablets plus
and children aged
<25 kg oral solutions (ABCd, ZDV,
≥30 days to <2 years
3TC, or FTC)
• DTG plus ABC plus (3TC or FTC) if DTG ≥30 days and ≥3 kg to
HLA-B*5701 negative <25 kg
• DTG/ABC/3TC in FDC if HLA-B*5701 ≥3 months and ≥6 kg to <25 DTG/ABC/3TC in FDC
negative kg (Triumeq PD) dispersible tablets (Triumeq
PD)
≥25 kg (Triumeq)
DTG/ABC/3TC FDC tablets if
≥25 kg (Triumeq). See
Dolutegravir for special
instructions if a child is
unable to swallow pills.

Alternative anchor • LPV/rf (boosted PI) Postmenstrual age ≥42 weeks LPV/r oral solution
drugs to replace DTG and postnatal age >14 days
in an ART regimen
with a Preferred NRTI
• ATV plus RTV (boosted PI) ATV ≥15 kg to <25 kg ATV is available in powder
backbone for infants
packets; RTV is available in
and children aged
100 mg tablets and 100 mg
≥30 days to <2 years
powder packets.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-21
 • NVP (NNRTI) NVP solution

<3 years

Preferred Initial Regimens and ARV Drugs Based on Age and Weight at Time of Treatment Initiation
8C. Children Aged ≥2 Years to <12 Years
Panel Age and/or Weight Formulations and
Regimen or ARV Drug
Recommendationa,b Restrictionc Commentsc
Preferred ART INSTI (DTG) plus two NRTIs For children who are
regimens for children unable to swallow pills
aged ≥2 years to <12
years who are • DTG/ABC/3TC in FDC if HLA-B*5701 ≥3 months and 3 kg to <25 kg DTG/ABC/3TC in FDC
unable to swallow negative (Triumeq PD) dispersible tablets (Triumeq
pills PD)

• DTG plus ZDV plus (3TC or FTC) ≥30 days and ≥3 kg (DTG) DTG dispersible tablets plus
oral solutions (ZDV, 3TC, or
FTC)

• DTG plus FTC/TAF; FTC/TAF in ≥30 days and ≥3 kg (DTG) TAF available as FTC/TAF in
FDC (Descovy) FDC (Descovy) only; not
≥14 kg to <25 kg (FTC/TAF)
available as an individual
drug. See Tenofovir
Alafenamide for special
instructions about
administering FTC/TAF to
children who are not able to
swallow pills.
For children who are ≥25 kg
and unable to swallow pills,
see Dolutegravir and
Tenofovir Alafenamide for
special instructions about
administering DTG 50 mg
and FTC/TAF (200 mg
FTC/25 mg TAF).

Preferred ART INSTI (BIC or DTG) plus two NRTIs For children who are able
regimens for children to swallow pills

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-22
 aged ≥2 years to <12 • BIC plus FTC plus TAF in FDCg,h Aged ≥2 years and ≥14 kg to BIC is only available in the
years who are able <25 kg (BIC 30 mg/FTC FDC BIC/FTC/TAF.
to swallow pills 120 mg/TAF 15 mg)
≥25 kg (BIC 50 mg/FTC The product label states that
200 mg/TAF 25 mg) for children who are unable
to swallow a whole tablet, the
BIC/FTC/TAF tablet can be
split and each part taken
separately, as long as all
parts are ingested within
approximately 10 minutes;
see Bictegravir.

• DTG plus ZDV plus (3TC or FTC) ≥14 kg (DTG tablets, Tivicay)

• DTG plus ABC plus 3TC in FDC if ≥25 kg DTG/ABC/3TC in FDC

HLA-B*5701 negative tablets (Triumeq)

• DTG plus FTC/TAF; FTC/TAF in Aged ≥30 days and ≥3 kg TAF available as FTC/TAF in
FDC (Descovy)i (DTG) FDC (Descovy) only; not
available as an individual
≥14 kg (FTC/TAF)
drug. See Tenofovir
Alafenamide.

Alternative anchor • ATV powder plus RTV powder ≥15 kg to ≤ 25 kg ATV is available in 50 mg
drugs in an ART (boosted PI) powder packets; RTV is
regimen with a available in 100 mg powder
Preferred NRTI packets.
backbone for
ATV and RTV powder can be
children aged ≥2
mixed with soft food or liquid.
years to <12 yearsi
• ATV capsules plus RTV tablets ≥15 kg
(boosted PI)
• ATV plus COBI in FDC tablet (ATV/c, ≥35 kg
boosted PI)

• DRV plus RTV (boosted PI) ≥20 kg DRV is available in an oral

solution or tablets to be taken
• DRV plus COBI in FDC tablet ≥40 kg
with RTV powder or tablets.
(DRV/c, boosted PI)

• NVP None NVP solution or immediate

release tablets
• NVP XR Aged ≥6 years

• EFV Aged ≥3 years and ≥10 kg EFV capsules can be opened

and used as a sprinkle
formulation for children who
are unable to swallow pills.

• DOR ≥35 kg Available as a single tablet

regimen (DOR/3TC/TDF)
a Panel recommendations summarized in this table are for children with HIV-1 infection.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-23
bRecommendations for ARV drugs or ART regimens to be used in special circumstances are addressed in the text (e.g., ARV resistance,
HBV coinfection).
cAdditional information about FDCs is available in Appendix A. Pediatric Antiretroviral Drug Information, 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.
d ABC 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 result should be available. An FDC
tablet that contains ABC/3TC (Epzicom and generic) is available for use in children weighing ≥25 kg.
eIf DTG dispersible tablets are not available, RAL can be administered using either the oral granules for suspension dispersed in water or
as the chewable tablets dispersed in juice, formula, or milk.
f An NRTI backbone of ZDV plus 3TC twice daily or ABC plus 3TC twice daily allows for all medications to be administered at the same
time when given in combination with LPV/r or RAL. There is considerable experience with ZDV and 3TC in this age group. ABC is
associated with less bone marrow toxicity than ZDV and may be the preferred NRTI for long-term use.
g There are two different strengths of BIC/FTC/TAF tablets, with the lower-strength tablet for children weighing ≥14 kg and <25 kg.
hThe product label for BIC/FTC/TAF (Biktarvy) states that for children who are unable to swallow a whole tablet, the BIC/FTC/TAF tablet
can be split and each part taken separately, as long as all parts are ingested within approximately 10 minutes.
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. 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.
Key: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; ART = antiretroviral therapy; ATV = atazanavir; BIC = bictegravir; DOR =
doravirine; DRV = darunavir; DTG = dolutegravir; EFV = efavirenz; FTC = emtricitabine; INSTI = integrase strand transfer inhibitor; HBV =
hepatitis B virus; 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; TDF = tenofovir
disoproxil fumarate; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-24
Table 9. Advantages and Disadvantages of Antiretroviral Components Recommended for Initial
Therapy in Infants and Children

See Appendix A. Pediatric Antiretroviral Drug Information and Table 7. Antiretroviral Regimen
Considerations for Initial Therapy Based on Specific Clinical Scenarios in the Adult and Adolescent
Antiretroviral Guidelines for more information. For detailed information about drug interactions, see Drug–
Drug Interactions and ARV class-specific tables 24a-24g and 25a-25b in Adult and Adolescent Antiretroviral
Guidelines, the HIV Drug Interaction Checker, and updated prescribing information.

Note: Drugs within each ARV class are listed in alphabetical order.

ARV Class/
Advantages Disadvantages
Agent(s)
All INSTIs INSTI Class Advantages INSTI Class Disadvantages
• Well tolerated • Possible weight gain in adults, especially Black/African
American women
• Potential for multiple drug interactions due to metabolism
via hepatic enzymes (e.g., CYP3A4, UGT1A1).
Information about drug interactions is available in the
Adult and Adolescent Antiretroviral Guidelines and the
HIV Drug Interaction Checker.
• Oral absorption can be reduced by simultaneous
administration with drugs or supplements containing
polyvalent cations.

BIC • Once-daily administration • The FDC tablet is not recommended for patients with
hepatic impairment or an estimated CrCl <30 mL/min.
• No food requirement
• CNS side effects, particularly sleep disturbances.
• Coformulated with TAF/FTC (see Appendix A, Depression and suicidal ideation (rare; usually in
Table 1. Antiretrovirals Available in Fixed-Dose patients with preexisting psychiatric conditions).
Combination Tablets or as a Co-packaged
Formulation, by Drug Class) • CYP3A4 and UGT1A1 substrate (but not a CYP3A4
inducer or inhibitor); potential for drug–drug interactions
• Higher barrier to resistance than RAL
• Inhibits tubular secretion of creatinine resulting in an
increase in serum creatinine without affecting glomerular
function. This is generally benign but can be
misinterpreted by clinicians not aware of this side effect.
Added follow-up may be required in patients with
underlying renal disease.

DTG • Once-daily administration • UGT1A1 substrate; potential for drug–drug interactions.

• No food requirement • CNS side effects, particularly sleep disturbances.
Depression and suicidal ideation (rare; usually in
• Coformulated with ABC/FTC and with 3TC (see patients with preexisting psychiatric conditions).
Appendix A, Table 1. Antiretrovirals Available in
Fixed-Dose Combination Tablets or as a Co- • Inhibits tubular secretion of creatinine resulting in an
packaged Formulation, by Drug Class) increase of serum creatinine without affecting glomerular
function. This is generally benign but can be
• Single-agent DTG pills are available in several misinterpreted by clinicians not aware of this side effect.
doses and are small in size.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-25
 ARV Class/
Advantages Disadvantages
Agent(s)
• DTG and the FDC ABC/DTG/3TC are available Added follow-up may be required in patients with
as dispersible tablets for suspension. underlying renal disease.
• Higher barrier to resistance than RAL

RAL • No food requirement • Lower barrier to resistance than boosted PI-, BIC-, or
DTG-based regimens
• Available in tablet, chewable tablet, and oral
granules for suspension formulations • Oral absorption of RAL can be reduced by simultaneous
administration with drugs or supplements containing
• Chewable tablets can be crushed and mixed with polyvalent cations.
various liquids for infants aged ≥4 weeks who
weigh ≥3 kg. • UGT1A1 substrate; potential for drug interaction
• Favorable lipid profile • Depression and suicidal ideation (rare; usually in
patients with preexisting psychiatric conditions)
• Increases in creatine kinase, myopathy, and
rhabdomyolysis have been reported.
• Potential for rare systemic allergic reaction or hepatitis
• Granule formulation requires a multistep preparation
before administration; caregiver must be taught how to
properly prepare this formulation.
• Higher pill burden than other INSTI-based regimens. No
FDC formulation.

All NNRTIs NNRTI Class Advantages NNRTI Class Disadvantages

• Longer half-life allows for once daily dosing of • Prevalence of NNRTI-resistant viral strains in ART-naive
DOR, EFV, and RPV. patients and the drugs’ low barrier for the development
of resistance. A single mutation can confer resistance,
• Lower risk of dyslipidemia and fat maldistribution with cross-resistance between EFV and NVP.
than PIs
• Rare but serious and potentially life-threatening cases of
• PI-sparing skin rash (including SJS) and hepatic toxicity. All
• Lower pill burden than PIs for children taking the NNRTIs pose this risk, but the risk is greatest with NVP;
solid formulation; easier to use and adhere to these toxic effects have not been reported in neonates.
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 as a single-drug tablet and • DOR is contraindicated when coadministered with drugs
coformulated with TDF/FTC (see Appendix A, that are strong cytochrome P450 (CYP)3A enzyme
Table 1. Antiretrovirals Available in Fixed-Dose inducers (see Doravirine).
Combination Tablets or as a Co-packaged
Formulation, by Drug Class) • Potential for CYP3A4 drug interactions

• No food requirement • Treatment-emergent DOR resistance mutations may

confer resistance to certain NNRTIs.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-26
 ARV Class/
Advantages Disadvantages
Agent(s)
• Has continued antiviral activity in the setting of
some NNRTI mutations
• Favorable lipid profile
• Not associated with weight gain compared with
boosted DRV or EFV

EFV • Once-daily administration • CNS side effects, including dizziness, abnormal dreams,
headache, depression, suicidality, insomnia,
• Available as a single-drug tablet and somnolence. Bedtime dosing is recommended to reduce
coformulated with TDF/FTC and TDF/3TC (see CNS effects.
Appendix A, Table 1. Antiretrovirals Available in
Fixed-Dose Combination Tablets or as a Co- • Rash (generally mild); QTc prolongation, dyslipidemia
packaged Formulation, by Drug Class)
• Potential for CYP3A4 drug interactions
• Can give with food (but avoid high-fat meals).
Usually recommended to be taken on an empty • No commercially available liquid formulation
stomach. • Limited data on dosing for children aged <3 years
• Capsules can be opened and added to food. • No data on dosing for children aged <3 months

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 available. regimen
• No food requirement • Higher incidence of rash/HSR than other NNRTIs
• 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 as single-drug tablet and coformulated
with TDF/FTC and TAF/FTC (see Appendix A, • Food requirement. Must be taken with a ≥500 kcal meal
Table 1. Antiretrovirals Available in Fixed-Dose at a consistent time each day; this may affect
Combination Tablets or as a Co-packaged adherence.
Formulation, by Drug Class)
• Potential for CYP3A4 drug interactions
• RPV oral absorption is reduced with increased gastric
pH. Use of RPV with PPIs is contraindicated; see Adult
Drug–Drug Interactions for dosing recommendations
when RPV is coadministered with H2 blocker or
antacids.
• Low barrier to resistance
• Side effects include depression, headache, skin rash,
and QTc prolongation.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-27
 ARV Class/
Advantages Disadvantages
Agent(s)
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)
• Higher barrier to resistance than NNRTIs and Information about drug interactions is available in the
RAL. Resistance to PIs requires multiple Adult and Adolescent Antiretroviral Guidelines and the
mutations. HIV Drug Interaction Checker.
• When combined with a dual-NRTI backbone, a • Higher pill burden than NRTI-based or NNRTI-based
regimen that contains a PI targets HIV at two regimens for patients taking solid formulations.
steps of viral replication by inhibiting the activity
of viral reverse transcriptase and protease • Poor palatability of liquid preparations, which may affect
enzymes. adherence.
• Most PIs require RTV or COBI boosting, resulting in
drug–drug interactions that are associated with RTV or
COBI.

ATV/r and ATV/c • Once-daily dosing • No liquid formulation

Unboosted ATV • Powder formulation is available for young • Food requirement

children.
• Indirect hyperbilirubinemia is common but asymptomatic.
• ATV has less effect on TG and total cholesterol Scleral icterus may be distressing to the patient, which
levels than other PIs (but RTV boosting may be may affect adherence. Other side effects include
associated with elevations in these parameters). cholelithiasis, nephrolithiasis, and PR interval
prolongation.
• Must be used with caution in patients with preexisting
conduction system defects (can prolong the PR interval
of an ECG)
• ATV boosted with RTV or COBI is recommended. Both
RTV and COBI are associated with a large number of
drug–drug interactions. CYP3A4 substrate and inhibitor.
• ATV absorption is reduced when ATV is given with acid-
lowering therapies.
• COBI inhibits active tubular secretion of creatinine and
can increase serum creatinine without affecting renal
glomerular function. This is generally benign but can be
misinterpreted by clinicians not aware of this side effect.
Added follow-up may be required in patients with
underlying renal disease.

DRV/c or DRV/r • Can be used once daily in children aged ≥12 • Pediatric pill burden high with current tablet dose
years. formulations
• Liquid formulation is available. • Food requirement
• DRV requires a boosting agent. • Must be boosted with RTV or COBI to achieve adequate
plasma concentrations.
• Available as single-drug tablet and coformulated
as DRV/c and DRV/c/TAF/FTC (see Appendix A,

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-28
 ARV Class/
Advantages Disadvantages
Agent(s)
Table 1. Antiretrovirals Available in Fixed-Dose • Contains sulfa moiety. The potential for cross-sensitivity
Combination Tablets or as a Co-packaged between DRV and other drugs in sulfonamide class is
Formulation, by Drug Class) unknown. Other side effects include hyperlipidemia and
increase in transaminases.
• RTV and COBI are associated with a large number of
potential drug–drug interactions.
• COBI inhibits active tubular secretion of creatinine and
can increase serum creatinine without affecting renal
glomerular function. This is generally benign but can be
misinterpreted by clinicians not aware of this side effect.
Added follow-up may be required in patients with
underlying renal disease.
• 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–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.
• No food requirement
• ABC use has been associated with CV disease and
• Available in FDC tablets (see Appendix A, cardiac events in some, but not all, observational studies
Table 1. Antiretrovirals Available in Fixed-Dose conducted in adults.
Combination Tablets or as a Co-packaged
Formulation, by Drug Class)

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 or as a Co-packaged
Formulation, by Drug Class)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-29
 ARV Class/
Advantages Disadvantages
Agent(s)
• Active against HBV; a recommended dual-NRTI
option for patients with HBV/HIV coinfection

TDF plus (3TC or • Once-daily dosing for TDF • Limited pediatric experience
FTC)
• Resistance is slow to develop.
• Potential bone and renal toxicity
• Lower risk of mitochondrial toxicity than other
NRTIs
• No food requirement
• TDF is 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 or as a Co-packaged
Formulation, by Drug Class)
• Active against HBV; a recommended dual-NRTI
option for patients with HBV/HIV coinfection.

ZDV plus (3TC or • Extensive pediatric experience • Bone marrow suppression and lipoatrophy with ZDV
FTC)
• Coformulations of ZDV and 3TC are available for • ZDV requires twice-daily dosing.
children weighing ≥30 kg.
• Palatable liquid formulations
• No food requirement
• FTC is available as a palatable liquid formulation
that can be administered once daily.

Key: 3TC = lamivudine; ABC = abacavir; AE = adverse event; ATV = atazanavir; BIC = bictegravir; BSA = body surface area; CNS =
central nervous system; COBI = cobicistat; CrCl = creatinine clearance; CYP = cytochrome P450; DOR = doravirine; DRV = darunavir;
DTG = dolutegravir; ECG = electrocardiogram; EFV = efavirenz; FDC = fixed-dose combination; FTC = emtricitabine;
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; NVP = nevirapine; PI = protease inhibitor;
RAL = raltegravir; RPV = rilpivirine; RTV = ritonavir; SJS = Stevens-Johnson Syndrome; TAF = tenofovir alafenamide; TDF = tenofovir
disoproxil fumarate; TFV = tenofovir; TG = triglyceride; ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-30
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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.
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10. Peadiatric 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://pubmed.ncbi.nlm.nih.gov/11888583.

11. Bekker A, Decloedt EH, Slade G, et al. 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://pubmed.ncbi.nlm.nih.gov/32697327.

12. 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-
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13. Borroto-Esoda K, Vela JE, Myrick F, et al. In vitro evaluation of the anti-HIV activity and
metabolic interactions of tenofovir and emtricitabine. Antivir Ther. 2006;11(3):377-384.
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14. Ross L, Parkin N, Chappey C, et al. Phenotypic impact of HIV reverse transcriptase M184I/V
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15. Gafni RI, Hazra R, Reynolds JC, et al. Tenofovir disoproxil fumarate and an optimized
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16. Giacomet V, Mora S, Martelli L, et al. A 12-month treatment with tenofovir does not impair
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17. Hazra R, Gafni RI, Maldarelli F, et al. Tenofovir disoproxil fumarate and an optimized
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18. Hazra R, Balis FM, Tullio AN, et al. Single-dose and steady-state pharmacokinetics of tenofovir
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19. Gallant JE, Staszewski S, Pozniak AL, et al. Efficacy and safety of tenofovir DF vs stavudine in
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21. Hall AM. Update on tenofovir toxicity in the kidney. Pediatr Nephrol. 2013;28(7):1011-1023.
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22. Cooper RD, Wiebe N, Smith N, et al. Systematic review and meta-analysis: renal safety of
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23. Wood SM, Shah SS, Steenhoff AP, et al. Tenofovir-associated nephrotoxicity in two HIV-
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24. Andiman WA, Chernoff MC, Mitchell C, et al. Incidence of persistent renal dysfunction in
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26. Bosch B, Akpomiemie G, Chandiwana N, et al. Weight and metabolic changes after switching
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27. Venter WDF, Sokhela S, Simmons B, et al. Dolutegravir with emtricitabine and tenofovir
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disoproxil fumarate for initial treatment of HIV-1 infection (ADVANCE): week 96 results from
a randomised, phase 3, non-inferiority trial. Lancet HIV. 2020;7(10):e666-e676. Available at:
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28. Frange P, Avettand-Fenoel V, Veber F, Blanche S. No overall impact on body mass index for
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29. Belfrage E, Soeria-Atmadja S, Naver L. Growth, weight gain and BMI in virally suppressed
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30. O'Rourke J, Townsend CL, Milanzi E, et al. Effectiveness and safety of tenofovir alafenamide in
children and adolescents living with HIV: a systematic review. J Int AIDS Soc.
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31. 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://pubmed.ncbi.nlm.nih.gov/24326597.

32. 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://pubmed.ncbi.nlm.nih.gov/30527329.

33. 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://pubmed.ncbi.nlm.nih.gov/20823434.

34. 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://pubmed.ncbi.nlm.nih.gov/27439527.

35. 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://pubmed.ncbi.nlm.nih.gov/22716976.

36. Kuhn L, Strehlau R, Shiau S, et al. Early antiretroviral treatment of infants to attain HIV
remission. EClinicalMedicine. 2020;18:100241. Available at:
https://pubmed.ncbi.nlm.nih.gov/31993578.

37. Persaud D, Bryson Y, Nelson BS, et al. HIV-1 reservoir size after neonatal antiretroviral therapy
and the potential to evaluate antiretroviral-therapy-free remission (IMPAACT P1115): a phase
1/2 proof-of-concept study. Lancet HIV. 2024;11(1):e20-e30. Available at:
https://pubmed.ncbi.nlm.nih.gov/38061376.

38. de Waal R, Rabie H, Technau KG, et al. Abacavir safety and effectiveness in young infants with
HIV in South African observational cohorts. Antivir Ther. 2023;28(2):13596535231168480.
Available at: https://pubmed.ncbi.nlm.nih.gov/37038365.

39. Francois K, Van Onacker JD, Jordan MR, et al. First case report of a perinatally HIV-infected
infant with HIV resistance to dolutegravir associated with tenofovir/lamivudine/dolutegravir use
in mothers. AIDS. 2023;37(13):2097-2099. Available at:
https://pubmed.ncbi.nlm.nih.gov/37755428.

40. Townsend CL, O'Rourke J, Milanzi E, et al. Effectiveness and safety of dolutegravir and
raltegravir for treating children and adolescents living with HIV: a systematic review. J Int AIDS
Soc. 2022;25(11):e25970. Available at: https://pubmed.ncbi.nlm.nih.gov/36377082.

41. Brooks KM, Kiser JJ, Ziemba L, et al. Pharmacokinetics, safety, and tolerability of dispersible
and immediate-release abacavir, dolutegravir, and lamivudine tablets in children with HIV

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-34
 (IMPAACT 2019): week 24 results of an open-label, multicentre, phase 1-2 dose-confirmation
study. Lancet HIV. 2023;10(8):e506-e517. Available at:
https://pubmed.ncbi.nlm.nih.gov/37541705.

42. 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://pubmed.ncbi.nlm.nih.gov/18097227.

43. 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://pubmed.ncbi.nlm.nih.gov/21297419.

44. 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://pubmed.ncbi.nlm.nih.gov/25222305.

45. 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://pubmed.ncbi.nlm.nih.gov/21610486.

46. 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://pubmed.ncbi.nlm.nih.gov/17417100.

47. 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://pubmed.ncbi.nlm.nih.gov/26582887.

48. Patel A, Jacobsen L, Jhaveri R, Bradford KK. Effectiveness of pediatric pill swallowing
interventions: a systematic review. Pediatrics. 2015;135(5):883-889. Available at:
https://pubmed.ncbi.nlm.nih.gov/25896843.

49. 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.

50. 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://pubmed.ncbi.nlm.nih.gov/34302760.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-35
51. Viani R, Alvero C, Fenton T, et al. Long-term safety and efficacy of dolutegravir in HIV
treatment-experienced adolescents. Presented at: Infectious Disease Week; 2015. San Diego, CA.
Available at.

52. 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.croiconference.org/abstract/impaact-
1093-dolutegravir-6-12-year-old-hiv-infected-children-48-week-results-0/.

53. 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://pubmed.ncbi.nlm.nih.gov/33446115.

54. Rungmaitree S, Aurpibul L, Best BM, et al. Efficacy, safety, and tolerability of
doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination tablets in
adolescents living with HIV: results through week 96 from IMPAACT 2014. J Pediatric Infect
Dis Soc. 2023;12(12):602-609. Available at: https://pubmed.ncbi.nlm.nih.gov/37815035.

55. Williams PL, Abzug MJ, Jacobson DL, et al. Pubertal onset in children with perinatal HIV
infection in the era of combination antiretroviral treatment. AIDS. 2013;27(12):1959-1970.
Available at: https://pubmed.ncbi.nlm.nih.gov/24145244.

56. 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://pubmed.ncbi.nlm.nih.gov/31274538.

57. 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://pubmed.ncbi.nlm.nih.gov/24845154.

58. Han WM, Law MG, Egger M, et al. Global estimates of viral suppression in children and
adolescents and adults on antiretroviral therapy adjusted for missing viral load measurements: a
multiregional, retrospective cohort study in 31 countries. Lancet HIV. 2021;8(12):e766-e775.
Available at: https://pubmed.ncbi.nlm.nih.gov/34856180.

59. Christopoulos KA, Grochowski J, Mayorga-Munoz F, et al. First demonstration project of long-
acting injectable antiretroviral therapy for persons with and without detectable human
immunodeficiency virus (HIV) viremia in an urban HIV clinic. Clin Infect Dis. 2023;76(3):e645-
e651. Available at: https://pubmed.ncbi.nlm.nih.gov/35913500.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-36
What Not to Start: Regimens Not Recommended for
Initial Antiretroviral Therapy in Infants and Children
Updated: June 27, 2024
Reviewed: June 27, 2024

This section describes antiretroviral (ARV) drugs and drug combinations that either are not
recommended for use in initial antiretroviral treatment (ART) regimens in infants and children or
lack sufficient data to recommend their use in children who have not received ART. Although many
ARV agents and combinations are available, some are not recommended for use as part of an initial
ART regimen, 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, 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 ART regimens in 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 drugs 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-37
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 PK 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 ARV drugs with minimal drug–drug
interactions seen with other ARV drugs and rifampin.2

Elvitegravir-Based Regimens
Elvitegravir (EVG) is a first-generation integrase strand transfer inhibitor (INSTI) that is available in
two FDC tablets: EVG/cobicistat (EVG/c)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF)
and EVG/c/FTC/tenofovir alafenamide (TAF). Cobicistat is a specific, potent CYP3A inhibitor that
has no activity against HIV. It is used as a PK enhancer that allows once-daily dosing of EVG.

The FDC regimens EVG/c/FTC/TDF and EVG/c/FTC/TAF are approved by the FDA for use in
ART-naive adults, children, and adolescents with HIV—EVG/c/FTC/TDF for those weighing ≥35 kg
and EVG/c/FTC/TAF for those weighing ≥25 kg. However, the Panel does not recommend EVG-
based regimens for initial ART in children or adolescents because EVG has a lower genetic barrier to
the development of resistance compared to second-generation INSTIs.3 The Panel recommends
initial ART with INSTI-based regimens that include dolutegravir (DTG) or bictegravir, according to
age and weight indications (see What to Start: Antiretroviral Treatment Regimens Recommended for
Initial Therapy in Infants and Children with HIV).

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 is now approved by the FDA for use in children
aged ≥2 years and weighing ≥10 kg.4-6 ETR is associated with multiple interactions with other ARV
drugs, including tipranavir/ritonavir, atazanavir/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.7 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.7 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-38
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.8 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 any infant or
child.

Cabotegravir with or without Rilpivirine for Oral or Intramuscular Injections

In 2021, the FDA approved long-acting injectable (LAI) formulations of cabotegravir (CAB), a novel
INSTI, and the NNRTI rilpivirine (RPV) for the treatment of HIV 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 (e.g., 3–6 months).
These two LAI ARV drugs 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 RPV and CAB may be considered to assess tolerability.9 The
LAI 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 (see the Cabotegravir section).
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.10,11 Data on the efficacy of triple-NRTI regimens for treatment
of ARV-naive children are limited to small observational studies.12,13 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.14 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 INSTI 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.15-19 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.20 There has been speculation that poor

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-39
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 36.21 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.

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 darunavir (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 study evaluating the safety, PK, and antiviral activity of FTR
in children and adolescents ≥20 kg who are experiencing virologic failure on their current ART
regimen and have dual or triple-class antiretroviral resistance (PENTA Foundation: NCT04648280)
is ongoing and will be completed by June 2028. At this time, the Panel does not recommend FTR as
part of an initial treatment regimen for HIV-1 infection in children.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-40
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.22 IBA is administered by intravenous infusion
every 2 weeks following a single loading dose. IBA was approved by the FDA 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 federal law. 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.

Lenacapavir-Containing Regimens
Lenacapavir (LEN) is a novel HIV-1 capsid inhibitor that interferes with three essential steps of
HIV-1 replication: viral nuclear transport, virus assembly and release, and capsid core formation.
Initiation of LEN requires the use of a combination of a subcutaneous (SQ) injection and an oral
tablet, and maintenance consists of SQ injections every 26 (±2) weeks.23 LEN was approved by the
FDA in 2022 for use in heavily treatment-experienced adults with multidrug-resistant HIV-1 in
whom current ARV regimens failed due to resistance, intolerance, or safety issues. LEN must be
used in combination with an optimized background regimen. The safety and efficacy of LEN in
children have not yet been established. This, together with the approval for use of LEN in ARV-
experienced individuals who are experiencing virologic failure on their current regimens, is the
reason why the Panel does not recommend LEN as initial treatment for HIV-1 in infants or children.

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
known susceptibility to the ARV drugs in the two-drug regimen have success after switching to these
regimens. Regimens that demonstrated efficacy in adult clinical trials include DTG plus RPV, DTG
plus 3TC or emtricitabine, 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-41
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 outweigh any benefit

Full-dose, dual-PI regimens Insufficient data to recommend; potential for added

toxicities

Oral regimens containing only two ARV drugs 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

EVG-based regimens First-generation INSTIs with lower barriers to resistance

than second-generation INSTIs (BIC and DTG) that are
now available for initial ARV regimens in children

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

LEN 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; BIC = bictegravir; CAB = cabotegravir; CYP = cytochrome P450; DRV = darunavir;
DRV/r = darunavir/ritonavir; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; FDA = U.S. Food and
Drug Administration; FTR = fostemsavir; IBA = ibalizumab; INSTI = integrase strand transfer inhibitor; LEN = lenacapavir;
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-42
Table 11. Antiretroviral Regimens or Components That Are Never Recommended for
Treating HIV in Children and Adolescents

ARV Regimen or Componenta 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 3TC Similar resistance profile and no No exceptions

Plus FTC additive benefit

Any Regimen Containing TDF and No data to support potential additive No exceptions
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-43
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11. van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to study first-line
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combination ZDV/3TC/abacavir (ABC) as initial therapy in HIV-infected children. Presented

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zidovudine in previously treated human immunodeficiency virus type 1-infected children.
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18. Wiznia A, Stanley K, Krogstad P, et al. Combination nucleoside analog reverse transcriptase
inhibitor(s) plus nevirapine, nelfinavir, or ritonavir in stable antiretroviral therapy-
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PACTG 377. Pediatric AIDS Clinical Trials Group 377 Study Team. AIDS Res Hum
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19. Krogstad P, Lee S, Johnson G, et al. Nucleoside-analogue reverse-transcriptase inhibitors

plus nevirapine, nelfinavir, or ritonavir for pretreated children infected with human
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20. Judd A, and EP, Paediatric HIV Cohort Collaboration study group in EuroCoord. Early
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21. Arrow Trial team, Kekitiinwa A, Cook A, et al. Routine versus clinically driven laboratory
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(ARROW): a 5-year open-label randomised factorial trial. Lancet. 2013;381(9875):1391-
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection F-46
Antiretroviral Management of Infants With In Utero,
Intrapartum, or Breastfeeding Exposure to HIV
Updated: December 19, 2024
Reviewed: December 19, 2024

Panel’s Recommendations
Antiretroviral Management for Infants With Exposure to HIV During the In Utero and Intrapartum Periods
• All newborns with in utero (antepartum) or intrapartum exposure to HIV should receive one or more antiretroviral (ARV)
drugs, dosed appropriately for the infant’s gestational age and weight and initiated as close to the time of birth as possible,
preferably within 6 hours (AII).
ARV regimen selection for infants with in utero or intrapartum exposure to HIV should be based on predicted risk for
transmission, determined by maternal HIV RNA levels (see Table 12, Table 13, Table 13.1, and Figure 1 below) (AII).
Infants at high risk of HIV infection from in utero or intrapartum exposure, defined as being perinatally exposed to viremia
(HIV RNA ≥50 copies/mL) in the 4 weeks prior to delivery, should be provided a three-drug ARV regimen, administered
from birth for 2–6 weeks, that serves as presumptive HIV therapy or enhanced prophylaxis. If the duration of the three-drug
regimen is shorter than 6 weeks, zidovudine (ZDV) should be continued alone to complete a total of 6 weeks of prophylaxis
(AII).
• Infants at low risk of in utero and intrapartum HIV acquisition, defined as being perinatally exposed to HIV RNA levels
<50 copies/mL from 20 weeks of gestation through delivery, should receive ZDV alone for a duration of 2 weeks (AII).
• Infants not meeting criteria for high or low risk should have ARV regimens and durations based on case-specific
factors related to the level and timing of viremia during the pregnancy (AII) (see Table 13).
• An HIV nucleic acid test (NAT) should generally be performed at birth for all infants (AII) but is not necessary for infants at
low risk who are not being breastfed (BIII). See Diagnosis of HIV Infection in Infants and Children and Table 3.
Recommended Virologic Testing Schedules for Infants With Perinatal and Breastfeeding Exposure to HIV for guidance
about infant testing.

Antiretroviral Management for Infants With Exposure to HIV During the Breastfeeding Period
• Recommendations about extended ARV prophylaxis are based on the current and anticipated maternal virologic status
during breastfeeding (see Table 14 and Table 14.1 below). Ideally, plans should be made during the antepartum period;
reassessment should take place both at delivery and regularly during the breastfeeding period (AII).
For infants at low risk of HIV acquisition during breastfeeding, some Panel members do not recommend extended ARV
prophylaxis; however, other Panel members do recommend extended ARV prophylaxis with either nevirapine (NVP) or
lamivudine (3TC) (CIII). 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) did not reach consensus.
Infants are considered at low risk of transmission during breastfeeding when (1) maternal antiretroviral therapy is being taken
while breastfeeding and sustained maternal virologic suppression (HIV RNA <50 copies/mL) was achieved for at least
3 months prior to delivery and (2) the provider and patient are confident that maternal ART adherence will be maintained
during breastfeeding (AII).
• For infants currently at low risk of HIV acquisition during breastfeeding but with concerns for future risk, the
Panels recommend extended ARV prophylaxis with either NVP or 3TC (BIII). Adherence support should always be
provided during breastfeeding (Table 14) (AIII).
• Extended ARV prophylaxis during breastfeeding, when used, should ensure continuous prophylaxis through the
postnatal period. Most experts recommend transitioning to NVP or 3TC after the completion of initial ZDV prophylaxis.
However, either NVP or 3TC can be given from birth, replacing ZDV and providing both initial postnatal prophylaxis and
extended prophylaxis during breastfeeding (BIII).

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-1
 • Extended ARV prophylaxis during breastfeeding, when used, should continue until either 6 weeks after the last
exposure to breast milk or 6 weeks after concerns about maternal virologic suppression have resolved—whichever occurs
first (BIII).

Recommendations for Infant Antiretroviral Management When the Infant is Exposed to New Viremia
• Breastfeeding should be stopped temporarily or discontinued and replacement feeding initiated (see Situations to Consider
Modifying or Stopping Breastfeeding in Preventing HIV Transmission During Infant Feeding) (AII). Most experts
recommend permanent discontinuation of breastfeeding when HIV RNA is ≥200 copies/mL (CIII).
• An infant HIV NAT should be performed (AII) (see Diagnosis of HIV Infection in Infants and Children and Table 3.
Recommended Virologic Testing Schedules for Infants With Perinatal and Breastfeeding Exposure to HIV for guidance
about infant testing).
• New viremia with HIV RNA ≥200 copies/mL: If a maternal HIV RNA level ≥200 copies/mL (viremia) develops or there is
presumed viremia (e.g., reports nonadherence to ARVs), the Panels recommend the initiation of a three-drug ARV regimen
for the infant for 4–6 weeks (AII) (see Table 14 and Table 14.1).
• New viremia with HIV RNA <200 copies/mL: When maternal viremia that is quantifiable but <200 copies/mL develops,
some Panel members recommend the initiation of a three-drug presumptive HIV therapy, other members recommend the
initiation of single-drug ARV prophylaxis (NVP or 3TC), and others recommend infant ARV management based on repeat
maternal HIV RNA testing (CII). The Panels did not reach consensus on management; consultation with an expert is
suggested (see Table 14).
Infant ARV Management When Perinatal HIV Exposure is Related to a New Diagnosis of HIV During Breastfeeding
• Infants exposed to newly diagnosed maternal HIV infection during breastfeeding should be managed like infants at high
risk of in utero or intrapartum HIV acquisition and receive a three-drug presumptive HIV therapy regimen for 2–6 weeks
(see Table 14) and replacement feeding. 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 (AII). See Diagnosis of HIV Infection in Infants and Children
and Table 3. Recommended Virologic Testing Schedules for Infants With Perinatal and Breastfeeding Exposure to HIV for
guidance about infant testing.
Providers with questions about ARV management of perinatal HIV exposure or exposure to HIV during breastfeeding
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

Risk of In Utero or Intrapartum HIV Transmission and Antiretroviral Management of

Infants
All infants with in utero or intrapartum exposure to HIV should receive antiretroviral (ARV) drugs
during the immediate neonatal period to reduce the risk of 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.

This section addresses ARV management of infants with exposure to HIV-1 recommended by the
Panel on the Treatment of HIV During Pregnancy and Prevention of Perinatal Transmission
(Perinatal Panel) and the Panel on Antiretroviral Therapy and Medical Management of Children
Living With HIV (Pediatric Panel). Information about ARV management for infants perinatally
exposed to HIV-2 infection is available in HIV-2 Infection and Pregnancy.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-2
The maternal viral load (HIV RNA level) is the most important risk factor for in utero and
intrapartum HIV transmission to the infant. Infants are at an increased risk for HIV acquisition when
antiretroviral therapy (ART) is not being taken during pregnancy and when antepartum treatment
does not result in antepartum viral suppression, particularly in the 4 weeks prior to delivery, but even
in the second half of pregnancy. Higher viral load correlates with higher risk of transmission. A
spectrum of transmission risk depends on these and other factors, including mode of delivery and
health status during pregnancy and delivery. Although current assays can detect very low levels of
HIV RNA, data from studies on transmission and viral load that were conducted prior to the
availability of highly sensitive tests indicate that an HIV RNA level <50 copies/mL sufficiently
predicts low risk of HIV transmission.1,2

Risk of HIV Transmission In Utero

The risk of in utero HIV transmission is believed to increase with gestational age, with the highest
rate of in utero infection occurring in the third trimester. However, methodological challenges in
assessing the timing of fetal infection limit the precision of risk estimates by gestational age. A
definitive diagnosis of in utero infection during pregnancy would require invasive sampling, carrying
risk that is not ethically or medically indicated. There are case reports of HIV being identified in fetal
tissue as early as 8-, 15-, and 20-weeks’ gestation, but whether they represented established infection
remains unclear.3-5 In a study of fetal thymuses in the second trimester, polymerase chain reaction
(PCR) testing revealed that 2 of 100 samples had HIV-1.6 For this reason, the Panels have a
20 week–gestational age as a conservative gestational age threshold below which in utero
transmission is unlikely to occur. A modeling study using profiles of viral culture positivity and
seroconversion from a cohort of 95 French infants suggests that the vast majority of in utero HIV
infection occurs in the third trimester.7 Another approach has been to examine how well ARVs
initiated at different gestational ages prevent in utero transmission. Among 34 women in a U.K./Irish
cohort who started ARVs during pregnancy, HIV transmission was more likely when ARVs were
started later in pregnancy (median gestational age at initiation of 30.1 weeks, interquartile
range [IQR] 27.4–32.6 weeks vs. 25.9 weeks, IQR 22.4–28.7 weeks, P < 0.001).8 Another model
made estimates of relative time of in utero or intrapartum transmission based on timing of ARV
initiation; they estimated 3% of transmissions occurred before 14 weeks’ gestation, 17% from 14 to
36 weeks, 50% from 36 weeks through onset of labor, and 30% from intrapartum exposure.9 In
summary, in utero HIV transmission in the context of maternal viremia is considered rare in the first
trimester, uncommon but possible in the second trimester, and most common in the third trimester.

Risk of HIV Transmission Intrapartum (During Labor and Delivery)

The highest risk of vertical HIV transmission is from exposure in the intrapartum period (i.e., during
labor and delivery). Risk increases with the level of maternal viremia.2 Recommended interventions
to reduce the risk of intrapartum transmission include ART for all pregnancies, intravenous
zidovudine (ZDV) during labor and delivery, and scheduled cesarean delivery when there is a
detectable HIV-1 viral load >1,000 copies/mL (see Intrapartum HIV Care).

Transmission Risk Assessment by HIV RNA Levels and Antenatal Time Period
Table 12 below summarizes in utero and intrapartum HIV transmission risk according to HIV RNA
levels at three antenatal time periods for the purpose of selecting infant ARV prophylaxis. Because
robust data are not available to define thresholds of risk across pregnancy, the Panels have defined
time points balancing available evidence with implications for clinical management. Transmission

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risk categories inform ARV choice and management of prophylaxis and presumptive HIV therapy for
infants with HIV exposure.

The assessment of transmission risk is generally but not exclusively dependent on HIV RNA levels
during the antepartum period. The Perinatal Panel recommends assessing maternal HIV RNA levels
at the initial antenatal visit with a review of prior levels, 2 to 4 weeks after initiating (or
changing) ART, and monthly until RNA levels are undetectable. Maternal HIV RNA levels
should also be assessed at least every 3 months during pregnancy and at approximately 36
weeks of gestation, or within 4 weeks of delivery (see Initial Evaluation and Continued Monitoring
of HIV During Pregnancy). However, discussion around transmission risk may not align exactly with
the recommended time frames, and clinicians must continue to utilize judgment to assess risk. For
example, viremia could be presumed based on reports of poor adherence for several weeks, even
without a documented test. Conversely, a missed HIV RNA test in a patient with years of virologic
control may not merit concern. Incident HIV infection during pregnancy and lack of receipt of ART
have been previously cited as risk factors for transmission; the current guidelines incorporate the
risks of those scenarios within the framework of documented or presumed viremia.

Table 12. Transmission Risk Assessment by HIV RNA Levels and Antenatal Time Period

Antenatal Time Period Transmission Risk

HIV RNA at HIV RNA ≥20 Weeks’

HIV RNA at ≤4 Weeks
<20 Weeks’ Gestation to 4 Weeks In Utero Intrapartum
Prior to Delivery
Gestation Prior to Delivery
N/Aa N/Aa ≥50 copies/mLb High High
N/Aa ≥50 copies/mLb <50 copies/mL Low to moderate Low
≥50 copies/mLb <50 copies/mL <50 copies/mL Low Low
<50 copies/mL <50 copies/mL <50 copies/mL Low Low
aHIV RNA levels in this time period do not change the transmission risk categorization because transmission risk is determined
by viremia later in gestation.
bHIV RNA values of ≥50 copies/mL can be documented or presumed (e.g., early [acute or recent] HIV, new diagnosis of HIV, or
known lapse in adherence).

Antiretroviral Management for Infants With In Utero or Intrapartum Exposure to HIV

Historically, the use of ARV drugs in the newborn period was referred to as ARV prophylaxis
because it primarily focused on protection against newborn acquisition of HIV. More recently,
clinicians have additionally sought to consider and optimize the management of newborns at elevated
risk for HIV acquisition in utero and initiate three-drug ARV regimens as presumptive HIV therapy.
In this section, the following terms will be used:

• ARV Prophylaxis: The administration of ARV drugs to a newborn without HIV infection to
reduce the risk of HIV acquisition.
• Presumptive HIV Therapy: The administration of a three-drug ARV regimen to newborns at
elevated risk of HIV acquisition. Presumptive HIV therapy is intended to be early treatment for a
newborn who has already acquired HIV but doesn’t have documentation of infection; it also

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 serves as enhanced ARV prophylaxis against HIV acquisition among infants at high risk but not
yet infected.
• ART: The administration of a three-drug ARV regimen to infants and children with documented
HIV infection (see Diagnosis of HIV Infection in Infants and Children and What to Start in the
Pediatric Antiretroviral Guidelines).

The terms ARV prophylaxis and presumptive HIV therapy describe the potential roles of ARV drugs
when the HIV status of an infant is unknown, and they often overlap in neonates at high risk. For
example, a presumptive HIV therapy regimen also provides drug exposure that would serve as
prophylaxis for a newborn. However, it is important to note that some two-drug and three-drug ARV
regimens used historically were designed and studied as prophylaxis, including some that used doses
of nevirapine (NVP) that target lower exposures than the doses used for treatment of HIV infection.

The Panels recommend initiating ARV prophylaxis or presumptive HIV therapy as soon as possible
after birth, preferably within 6 hours. Although the maximum interval during which newborn ARV
prophylaxis can be initiated and still be beneficial is unknown, most studies support providing ARV
drugs as early as possible after delivery.10-15

The guidance summarized in this section applies to infants perinatally exposed to HIV unless
otherwise noted. The algorithm in Figure 1 and Table 13 provide an overview of neonatal ARV
management recommendations according to the risk of HIV transmission from in utero and
intrapartum exposure based on HIV RNA levels at time points during pregnancy and other factors,
such as receipt of and adherence to ART. Table 13.1 summarizes the recommended ARV dosing for
prophylaxis or presumptive HIV therapy in newborns with in utero or intrapartum HIV exposure.
Additional information about dose selection for newborns, including preterm infants (<37 weeks
gestational age), can be found in Appendix A: Pediatric Antiretroviral Drug Information in the
Pediatric Antiretroviral Guidelines.

The National Perinatal HIV Hotline (1­888­448­8765) is a federally funded service that provides free
clinical consultation on difficult cases to providers who are providing HIV care during pregnancy
and for newborns after pregnancy, and consultants can provide referrals to local or regional pediatric
HIV specialists.

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Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
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Table 13. Antiretroviral Management for Infants With In Utero or Intrapartum Exposure
to HIV

Risk of Acquisition
Neonatal ARV
Clinical Setting Rationale
Managementa,b
In Utero Intrapartum
High Risk of Acquisition
HIV RNA ≥50 copies/mL High High Presumptive HIV therapy Viremia in the 4 weeks
in the 4 weeks prior to using a three-drug regimen of immediately prior to
delivery ZDV and 3TC plus either delivery confers very high
NVP (treatment dose) or RAL risk for in utero and
Viremia can be
intrapartum transmission.
documented by lab or Duration is from birth for
presumed by other 2–6 weeks; consensus not Plasma HIV RNA levels of
clinical factors (e.g., new reached by members of the 50–200 copies/mL could
diagnosis, ART Panel.c be expected to confer
adherence problems, lower risk than those
reports of having If the duration of a three-drug >200 copies/mL but could
stopped ART prior to regimen is <6 weeks, and the also be an indicator of poor
delivery). birth NAT is negative, ZDV adherence and raise
should be continued alone to concern for higher levels of
complete a total of 6 weeks viremia at other times.
of prophylaxis.

HIV NAT obtained before or

immediately after starting
presumptive therapy with
three drugsd,e

Low Risk of Acquisition

HIV RNA <50 copies/mL Low Low ZDV for 2 weeks Sustained virologic
from 20 weeks’ suppression from
gestation through 20 weeks’ gestation is
delivery associated with extremely
low risk of transmission in
Ideally documented by
utero or intrapartum.
at least two consecutive
tests at least four weeks Although in utero
apart with HIV RNA transmission events have
<50 copies/mL, but can been documented prior to
be based on clinical 20 weeks, the extremely
judgment of providers. low frequency of these
events does not merit the
presumptive HIV therapy
approach.

Other Clinical Scenarios

HIV RNA ≥50 copies/mL Low to Low HIV NAT at Birthd,e Viremia in the late second
at >20 weeks’ gestation, Moderate and third trimester elevates
Two Options for ARV
but HIV RNA risk of in utero
Management
<50 copies/mL in the transmission (increasing
4 weeks prior to delivery 1. Presumptive HIV therapy risk with higher HIV RNA
with a three-drug regimen, levels and longer duration

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Table 13. Antiretroviral Management for Infants With In Utero or Intrapartum Exposure
to HIV

Risk of Acquisition
Neonatal ARV
Clinical Setting Rationale
Managementa,b
In Utero Intrapartum
as described above for of viremia).
infants at high risk. If birth
the HIV NAT is negative, Option 1. Some Panel
de-escalate the members believe that the
prophylaxis regimen to potential benefit of early
ZDV alone to complete 2– treatment for an infant who
6 weeks total.c acquired the infection in
utero merits a presumptive
2. ZDV prophylaxis for HIV therapy approach.
2–6 weeks
Option 2. Other Panel
members believe that the
marginal potential benefit
and anticipated low
frequency of in utero
infection do not merit the
additional complexity of
and potential toxicity of
presumptive HIV therapy
and favor ZDV prophylaxis
only.

All infants should receive a

minimum of 2 weeks ZDV
prophylaxis, but up to
6 weeks may be used
when indicated based on
risk assessment.
Early (acute or recent) Moderate to High if HIV NAT at birthd,e Early or recent HIV
HIV at any point during High HIV RNA diagnosed at any time
pregnancy depending on ≥50 copies/m Manage infant ARVs during pregnancy is a
maternal HIV L in the last according to the level and unique situation because
RNA levels 4 weeks of timing of the maternal viremia very high HIV RNA levels
and weeks’ pregnancy as described in the rows place infants at high risk of
gestation above (just as for an infant HIV acquisition.
exposed to established
infection). For infants perinatally
exposed to known HIV
infection, risk of
transmission increases
when viremia occurs later
in pregnancy. Some Panel
members would manage
all cases with presumptive
therapy, whereas others
would only use it for
viremia after 20 weeks’
gestation.

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Table 13. Antiretroviral Management for Infants With In Utero or Intrapartum Exposure
to HIV

Risk of Acquisition
Neonatal ARV
Clinical Setting Rationale
Managementa,b
In Utero Intrapartum
Unconfirmed maternal High/ High/ HIV NAT at birthd,e Supplemental maternal
HIV status with at least Uncertain Uncertain HIV testing and/or NAT
one positive HIV test at Presumptive HIV therapy with testing of the infant is
delivery or postpartum a three-drug regimen as required to determine the
described above for level of risk and need to
or newborns with a high risk of continue infant
Newborn has a positive in utero or intrapartum HIV presumptive HIV therapy
HIV antibody test acquisition or initiate ART.e

If supplemental testing
confirms a negative maternal
HIV status, discontinue infant
ARV drugs immediately.
aInfant ARVs should be initiated in the first 6 hours after delivery, especially for infants with a high risk of acquisition. See
Table 13.1 for ARV dosing.
b See HIV-2 Infection and Pregnancy for ARV prophylaxis recommendations for infants perinatally exposed to HIV-2 mono-
infection. In the event of maternal HIV-2 infection or HIV-1 and HIV-2 coinfection, 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 using ARVs that are active against
HIV-2. Because HIV-2 is not susceptible to NVP, RAL should be used in presumptive HIV therapy regimens for infants at high
risk of HIV acquisition with exposure to HIV-2 or to both HIV-1 and HIV-2.
c The optimal duration of three-drug regimen 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 for 6 weeks. The other two ARVs, (3TC and NVP) or
(3TC and RAL), may be administered for 2 to 6 weeks; the recommended duration for treatment with three ARVs varies
depending on infant HIV NAT results, maternal viral load at the time of delivery, and the 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.
dNAT test at birth should be obtained before or immediately after starting ARVs. See Diagnosis of HIV Infection in Infants and
Children for additional information about HIV testing and NATs.
e When a newborn HIV NAT is positive, infant ART should be initiated without waiting for the results of confirmatory HIV NAT
testing, given the low likelihood of a false-positive HIV NAT (see When to Initiate Antiretroviral Treatment in Children with HIV
Infection and What to Start in the Pediatric Antiretroviral Guidelines). However, the specimen for confirmatory HIV testing should
be obtained prior to ART initiation.
Note: Providers with questions about ARV management of infants should consult an expert in pediatric HIV infection or the
National Perinatal HIV Hotline (1-888-448-8765).
Key: 3TC = lamivudine; ART = antiretroviral therapy; ARV = antiretroviral; NAT = nucleic acid test; 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; RAL = raltegravir; ZDV = zidovudine

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Table 13.1. Drug Dosing Recommendations for Antiretroviral Prophylaxis and
Presumptive HIV Therapy in Infants With In Utero or Intrapartum Exposure to HIVa

This table provides dosing for antiretroviral (ARV) prophylaxis and presumptive HIV therapy in
infants with in utero or intrapartum exposure to HIV. Dosing for additional ARV prophylaxis during
breastfeeding is provided in Table 14.1. Antiretroviral Prophylaxis Dosing for Infants Who Are
Breastfed.

For infants with HIV infection, recommendations for initial ARV therapy regimens and ARV dosing
are available in the Pediatric Antiretroviral Guidelines; see What to Start and Appendix A. Pediatric
Antiretroviral Drug Information.

ARV Drug Drug Doses by Gestational Age at Birth

ZDV ≥35 Weeks of Gestation at Birth

Note: For newborns who are Birth to Age ≤6 Weeks

unable to tolerate oral agents, the • ZDV 4 mg/kg per dose orally twice daily or alternative simplified weight-band dosing
IV dose is 75% of the oral dose (see table below)
while maintaining the same
dosing interval. Simplified Weight-Band Dosing for Newborns Aged ≥35 Weeks of Gestation From
Birth to 4 Weeks

Weight Band Volume of ZDV 10 mg/mL Oral Syrup Twice Daily

2 kg to <3 kg 1 mL
3 kg to <4 kg 1.5 mL
4 kg to <5 kg 2 mL

≥30 Weeks to <35 Weeks of Gestation at Birth

Birth to Age 2 Weeks
• ZDV 2 mg/kg per dose orally twice daily

Age 2 Weeks to ≤6 Weeks

• ZDV 3 mg/kg per dose orally twice daily

<30 Weeks of Gestation at Birth

Birth to Age 4 Weeks
• ZDV 2 mg/kg per dose orally twice daily

Age 4 Weeks to ≤6 Weeks

• ZDV 3 mg/kg per dose orally twice daily

3TC ≥32 Weeks of Gestation at Birth

Birth to Age <4 Weeks
• 3TC 2 mg/kg per dose orally twice daily

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to Reduce Perinatal HIV Transmission in the United States G-10
Table 13.1. Drug Dosing Recommendations for Antiretroviral Prophylaxis and
Presumptive HIV Therapy in Infants With In Utero or Intrapartum Exposure to HIVa

ARV Drug Drug Doses by Gestational Age at Birth

Age ≥4 Weeks to ≤6 weeks
• 3TC 4 mg/kg per dose orally twice daily

NVPb ≥37 Weeks of Gestation at Birth

Note: These are NVP treatment Birth to Age ≤6 Weeks

doses for a presumptive HIV • NVP 6 mg/kg per dose orally twice daily
therapy regimen. NVP dosing for
extended ARV prophylaxis during ≥34 Weeks to <37 Weeks of Gestation at Birth
breastfeeding is provided in Table
14.1. Birth to Age <1 Week
Note: Do not use NVP if HIV-2 • NVP 4 mg/kg per dose orally twice daily
infection (or HIV-2 co-infection
with HIV-1) is present or Age ≥1 Week to ≤6 Weeks
suspected; see HIV-2- Infection
• NVP 6 mg/kg per dose orally twice daily
and Pregnancy.
≥32 Weeks to <34 Weeks of Gestation at Birth
Birth to Age <2 Weeks
• NVP 2 mg/kg per dose orally twice daily
Age ≥2 Weeks to <4 Weeks
• NVP 4 mg/kg per dose orally twice daily

Age ≥4 Weeks to ≤6 Weeks

• NVP 6 mg/kg per dose orally twice daily

RAL ≥37 Weeks of Gestation at Birth and Weighing ≥2 kgc

Birth to Age 6 Weeks

Volume (Dose) of
Body Weight
RAL 10 mg/mL Suspension

Birth to 1 Week: Once-Daily

Approximately 1.5 mg/kg per dose
Dosing
2 kg to <3 kg 0.4 mL (4 mg) once daily

3 kg to <4 kg 0.5 mL (5 mg) once daily

4 kg to <5 kg 0.7 mL (7 mg) once daily

1 to 4 Weeks: Twice-Daily Dosing Approximately 3 mg/kg per dose

2 kg to <3 kg 0.8 mL (8 mg) twice daily

3 kg to <4 kg 1 mL (10 mg) twice daily

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Table 13.1. Drug Dosing Recommendations for Antiretroviral Prophylaxis and
Presumptive HIV Therapy in Infants With In Utero or Intrapartum Exposure to HIVa

ARV Drug Drug Doses by Gestational Age at Birth

4 kg to <5 kg 1.5 mL (15 mg) twice daily

4 to 6 Weeks: Twice-Daily Dosing Approximately 6 mg/kg per dose

3 kg to <4 kg 2.5 mL (25 mg) twice daily

4 kg to <6 kg 3 mL (30 mg) twice daily

6 kg to <8 kg 4 mL (40 mg) twice daily

ABCd ≥37 Weeks’ Gestation at Birth

Note: The Panels do not Birth to <1 Month

recommend ABC as part of three- • ABC 2 mg/kg per dose orally twice daily
drug regimen for newborns with
HIV exposure. However, in Age ≥1 Month to ≤6 Weeks
situations where ZDV is not
available or the infant has ZDV- • ABC 4 mg/kg per dose orally twice daily
associated toxicity, ABC could be
considered an alternative to ZDV.
a The optimal duration of three-drug regimens for newborns at high risk of HIV acquisition is unknown; all infants should receive
the ZDV component of the three-drug regimen for 6 weeks. The other two ARVs, (3TC and NVP) or (3TC and 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.
bThe 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.
cRAL 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. 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.
d 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-B*5701 allele should be confirmed prior to the administration of ABC.
Key: 3TC = lamivudine; ABC = abacavir; ARV = antiretroviral; 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

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Recommendations for Infant Antiretroviral Drugs in Specific Clinical Situations
In this section, Table 13. Antiretroviral Management for Infants With In Utero or Intrapartum
Exposure to HIV, and Figure 1. Antiretroviral Management Algorithm for Infants With In Utero or
Intrapartum HIV Exposure by Risk of Transmission, the Panels present available data and
recommendations for ARV management of newborns born with in utero and intrapartum exposure to
HIV.

Infants at High Risk of HIV Acquisition From In Utero or Intrapartum

Exposure
The Panels recommend that all newborns at high risk for HIV acquisition from in utero and
intrapartum exposure have an HIV nucleic acid test (NAT) at birth to determine in utero HIV
infection status and receive presumptive HIV therapy (see Table 13 and Figure 1).14,16-21 HIV
infection newly diagnosed during pregnancy is generally associated with high HIV RNA levels that
would confer an elevated high risk of transmission to the infant, especially in the case of recent (early
or acute) infection (see Table 13 and 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.22-31 Because of these potential benefits of
early ART the Panels recommend a three-drug presumptive HIV therapy regimen consisting of two
nucleoside reverse transcriptase inhibitors (ZDV plus lamivudine [3TC]) plus either a non-nucleoside
reverse transcriptase inhibitor (NNRTI) (NVP at treatment dose, see Table 13.1) or an integrase
strand transfer inhibitor (INSTI) (raltegravir [RAL]) for newborns at high risk of acquisition of HIV:

• ZDV plus 3TC plus NVP (at treatment dose, see Table 13.1) or
• ZDV plus 3TC plus RAL

In the event of maternal HIV-2 infection or concomitant HIV-1 and HIV-2 infection, the RAL-
containing regimen should be used for presumptive therapy because HIV-2 is not susceptible to
NVP.

Although no clinical trials have compared the safety and efficacy of presumptive HIV therapy with
single-drug or two-drug regimens, existing data suggest that presumptive HIV therapy in neonates
has not been associated with serious adverse events (see Antiretroviral Drug Safety of Infant
Prophylaxis below).

The pharmacokinetic (PK) and safety data of the three-drug regimens used for presumptive HIV
therapy have provided reassuring evidence for its use in the neonatal period. Although the use of
NVP to prevent 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 tenfold lower
than targeted therapeutic levels. However, studies of treatment doses of NVP and RAL have
established safe doses that achieve targeted PK parameters.21,32-37

At this time, the Panels do not recommend abacavir (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

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to Reduce Perinatal HIV Transmission in the United States G-14
circumstances where an increased risk of ZDV toxicity may exist, such as in infants with anemia or
neutropenia. Negative testing for HLA-B*5701 allele should be confirmed prior to the administration
of ABC. New dosing recommendations for ABC in neonates based on the IMPAACT P1106 trial and
two observational European and African cohorts are now available from the World Health
Organization (WHO).38 ABC is not approved by the U.S. Food and Drug Administration for use in
neonates and infants aged <3 months. However, 2 mg/kg per dose twice daily 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).39

The optimal duration of a three-drug regimen in newborns at high risk of HIV acquisition is
unknown. Consulting an expert in pediatric HIV is recommended when selecting a therapy duration
based on case-specific risk factors and interim HIV NAT results. HIV NAT diagnostic testing at birth
(prior to or immediately after starting ARVs) is recommended for infants at high risk for HIV
acquisition. A positive birth NAT test indicates in utero HIV infection. Panel members varied in their
recommendations for the duration of presumptive HIV therapy. Some Panel members would opt to
discontinue additional medications and complete 6 weeks ZDV prophylaxis alone if infant birth NAT
results are negative, whereas other Panel members would continue presumptive HIV therapy for 2 to
6 weeks, depending on the risk of HIV transmission. Panel members agreed that ZDV should be
continued for 6 weeks in all scenarios, regardless of the duration of the other two drugs. If the birth
NAT is positive, the infant should receive an ART regimen recommended for the treatment of HIV
infection (see What to Start: Antiretroviral Treatment Regimens Recommended for Initial Therapy in
Infants and Children With HIV and Appendix A: Pediatric Antiretroviral Drug Information in the
Pediatric Antiretroviral Guidelines).

Newborns at Low Risk of HIV Acquisition from In Utero or Intrapartum

Exposure
An infant perinatally exposed to HIV RNA levels <50 copies/mL and no HIV RNA levels
≥50 copies/mL after 20 weeks’ gestation is considered to have low risk of HIV acquisition and
should receive prophylaxis with ZDV alone for 2 weeks.

When ART is taken during pregnancy and labor and viral load is undetectable near or at the time of
delivery, the risk of HIV acquisition in newborns is <1%.2 In the Pediatric AIDS Clinical Trials
Group (PACTG) 076 study, ZDV alone reduced the incidence of HIV transmission by 66%, and
ZDV is recommended as prophylaxis for neonates when maternal ART resulted in consistent viral
suppression during pregnancy.40 Other studies have also compared NVP to ZDV infant
prophylaxis.41,42 The ANRS French Perinatal Cohort observed that NVP infant prophylaxis was
associated with less anemia than ZDV infant prophylaxis. 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 076.43 However, evidence supporting a reduced duration of ZDV prophylaxis in
infants born to mothers who were suppressed virologically during pregnancy and at the time of
delivery is mounting.44-46

No studies directly compare the efficacy of a 2-week versus 4-week duration of infant ZDV
prophylaxis. However, high-income countries have some experience with a 2-week duration of infant
prophylaxis. The United States, as well as the United Kingdom and other European countries,
recommends a 2-week neonatal ZDV prophylaxis regimen when the risk of HIV acquisition from
exposure is low and/or very low, with varying criteria across countries.47,48 Compared with the

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6-week ZDV regimen, a 2 to 4 week ZDV regimen has been reported to allow earlier recovery from
anemia in otherwise healthy newborns.49,50 In a cohort of 87 Swiss infants born to women with HIV
RNA levels <50 copies/mL in the last trimester who did not receive ARV prophylaxis, in accordance
with Swiss ARV guidance at that time, none acquired HIV infection.51

Other Clinical Scenarios

An infant perinatally exposed to HIV RNA levels ≥50 copies/mL after 20 weeks of gestation but
HIV RNA levels <50 copies/mL for the 4 weeks prior to delivery is considered to have low-to-
moderate risk for in utero and low risk for intrapartum acquisition of HIV (see Table 12). This
assessment takes into consideration that low-level viremia could reflect intermittent adherence
between laboratory tests. Low-level viremia (e.g., ≥50 copies/mL to 200 copies/mL) is not expected
to confer a high risk of in utero transmission of HIV but has been associated with elevated risk of
subsequent virologic failure.52,53 The Panels did not reach consensus on infant ARV management
(see Table 13) for this clinical scenario and consider factors such as the magnitude and duration of
elevated HIV RNA levels,2 maternal adherence to ART, and parental input in decision-making.

Some Panel members recommend that these infants receive presumptive HIV therapy until the results
of birth HIV NAT are available. If the birth HIV NAT is negative, excluding in utero HIV
acquisition, the Panels recommend de-escalation of presumptive HIV therapy to ZDV prophylaxis to
complete ZDV for a total of 6 weeks. This provides a balanced risk/benefit approach to quickly
identifying in utero HIV acquisition, limiting exposure to presumptive HIV therapy in the event HIV
transmission has not occurred in utero, and promptly administering very early presumptive therapy in
the event of in utero infection. Very early ART has been shown to provide durable virologic
suppression and reduce early viral reservoirs enabling HIV remission in some children with in utero
HIV acquisition.31,54 See When to Initiate Antiretroviral Therapy in Children With HIV Infection.
However, other Panel members argue that the data supporting the potential benefit of early ART has
not been demonstrated for this specific scenario, would likely apply to a small number of infants, and
carries risk of avoidable toxicity to infants without in utero infection; for these reasons, they
recommend 2 to 6 weeks of ZDV prophylaxis. Providers must decide which rationale aligns with
their own assessment and should consider involving parents in the decision.

When early (acute or recent) HIV is diagnosed during pregnancy, infant ARVs should be
managed according to the gestational timing of maternal viremia (see Table 13). Because HIV RNA
levels are generally very high in these situations, some Panel members would manage all infants with
a three-drug ARV regimen even with undetectable maternal viral load after 20 weeks. Other Panel
members would base decisions about infant ARVs on the timing of viremia.

When there is a positive maternal HIV test at delivery or postpartum or infants have a positive
HIV antibody test after birth, infants should receive a three-drug regimen as described above for
infants at high risk of HIV acquisition. If supplemental testing confirms a negative maternal HIV
status, infant ARV drugs should be discontinued immediately.

Newborns Exposed to Antiretroviral Drug-Resistant Virus

The optimal approach to selecting an ARV regimen for newborns exposed to ARV drug-resistant
virus is unknown. Some studies have suggested that ARV drug-resistant virus may have decreased
replicative capacity (reduced viral fitness) and transmissibility.55 The transmission of drug-resistant
virus to infants does occur.56-62 Whether resistant virus increases the risk of vertical HIV acquisition

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-16
by the infant remains unclear. A secondary analysis of data from the Eunice Kennedy Shriver
National Institute of Child Health and Human Development–HIV Prevention Trials Network (HPTN)
040/PACTG 1043 did not find that the presence of drug-resistance mutations in mothers who had not
received ARV drugs before the start of the study increased the risk of in utero or peripartum
transmission (adjusted odds ratio 0.8; 95% confidence interval [CI], 0.4–1.5).61 However, a case-
control study found that resistance to NNRTIs in the breastfeeding mother was an independent risk
factor for the vertical transmission of HIV during breastfeeding in the PROMISE trial.63

Although no trials have compared the efficacy of neonatal prophylaxis regimens customized to
address maternal drug resistance, the Panels recommend considering maternal drug resistance when
selecting the three-drug regimen for presumptive HIV therapy. For example, an infant at high risk of
infection perinatally exposed to HIV with NNRTI resistance could potentially benefit from a three-
drug regimen based on RAL rather than NVP. However, other factors must also be considered, such
as gestational age (limits the number of agents with available dosing) and feasibility for the caregiver
to administer the regimen (e.g., the preparation of RAL is more difficult than NVP).

Maraviroc (MVC) has been approved recently for infants ≥2 kg and may provide an additional ARV
option for newborns perinatally exposed to multidrug-resistant HIV-1 that remains CCR5-tropic.64
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.

For assistance in selecting a three-drug ARV regimen for newborns perinatally exposed to known or
suspected drug resistance, consultation with a pediatric HIV specialist or the National Perinatal HIV
hotline (1-888-448-8765) is recommended.

Antiretroviral Prophylaxis for Breastfeeding Infants

HIV care should include counseling about infant feeding options (e.g., formula feeding, banked
donor human milk, breastfeeding) throughout pregnancy. The conversation should include decision-
making about the risk and potential benefits of ARV prophylaxis. Recommendations and dosing for
infant ARV prophylaxis during breastfeeding are summarized in Table 14 and Table 14.1. In general,
infant ARV prophylaxis during breastfeeding should begin after initial ZDV prophylaxis is
completed. However, some experts recommend initiating ARV prophylaxis with NVP or 3TC in
place of ZDV from birth for simplicity. The duration of extended infant ARV prophylaxis can also
vary based on provider and parent preference. The most conservative course is to continue
prophylaxis until 6 weeks after the last exposure to breast milk. However, long-standing maternal
virologic suppression may be exhibited during breastfeeding, and with provider’s guidance, the
decision may be made to stop prophylaxis while continuing to breastfeed. The Panels recommend
patient-centered, evidence-based counseling to support shared decision-making about infant feeding.
See Preventing HIV Transmission During Infant Feeding for more information on counseling,
management, and monitoring.

Antiretroviral Prophylaxis for Breastfeeding Infants in the Setting of Sustained

Virologic Suppression (HIV RNA <50 Copies/mL)
The Panels could not reach consensus on recommendations regarding the use of extended infant
ARV prophylaxis during breastfeeding. For infants considered to be at low risk, Panel members
agreed on the provision of 2 weeks of ZDV to infants for standard prophylaxis for HIV exposure, but
some Panel members prefer to extend the duration of ZDV prophylaxis to 4 to 6 weeks when the

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-17
infant is being breastfed. For the period after initial postnatal prophylaxis, some Panel members
recommend no additional prophylaxis when virologic suppression is maintained throughout
breastfeeding, but other Panel members recommend extended ARV prophylaxis with NVP or 3TC
during breastfeeding. Both NVP and 3TC have been used effectively for extended prophylaxis during
breastfeeding.65,66 3TC has been studied through 12 months of age and requires twice-daily
administration. 66 NVP has been studied through 18 months of age and is given once daily. 65
Concerns related to the use of NVP include impaired efficacy in the context of maternal NNRTI and
the development of NNRTI resistance if an infant acquires HIV while receiving NVP during
breastfeeding (see Newborns Exposed to Antiretroviral Drug-Resistant Virus above).

When extended prophylaxis is used, most experts recommend transitioning to NVP or lamivudine
3TC after completion of the initial ZDV prophylaxis. However, NVP can be given from birth,
replacing ZDV and providing both initial postnatal prophylaxis and extended prophylaxis during
breastfeeding. ZDV should not be used for a period of more than 6 weeks.

Given the lack of consensus by the Panels for a recommendation about extended ARV prophylaxis
during breastfeeding, the Panels advise providers to involve the parent(s) in open discussion and
shared decision-making, weighing values about risk tolerance (for transmission and toxicity) and
other issues related to infant prophylaxis (e.g., prematurity). For additional information, see Safety of
Antiretroviral Drugs Used for Infant Prophylaxis below.

Most data to guide decisions about infant ARV prophylaxis during breastfeeding are from studies in
sub-Saharan Africa, where breastfeeding is recommended for all pregnancies impacted by HIV
infection and standard practice for prophylaxis also differs. The WHO recommends six weeks of
NVP for all infants who are breastfed when maternal ART is being received in resource-limited
countries.67 In the PROMISE study, among 1,219 infants of mothers on ART, there were seven HIV
transmissions reported. Among these, five mothers had documented detectable viral loads
immediately prior to the first report of the infant’s positive HIV NAT; the remaining two mothers
had elevated viral loads in subsequent testing.68 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 study, a sub-study of 31 infants with HIV and 232
infants who were uninfected and their mothers69 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.70 This meta-analysis was limited
by the heterogeneity in studies but reported an overall postnatal HIV transmission rate of 1.08%
(95% CI, 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 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.71

See ARV Prophylaxis for Infants When There Is a Concern About Risk of Future Viremia During
Breastfeeding, below, for additional data supporting the efficacy of NVP and 3TC as prophylaxis
during breastfeeding.

Taken together, existing data support the efficacy of maternal ART during breastfeeding with
documented sustained viral suppression to prevent postnatal transmission of HIV, suggesting

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-18
that the recommended management of 2 weeks of ZDV prophylaxis for infants at low risk of in
utero or intrapartum exposure is appropriate for breastfed infants when sustained maternal
HIV RNA levels of <50 copies/mL have been achieved. This approach is currently recommended
by the British HIV Association (BHIVA).47

Table 14. Antiretroviral Management of Infants With Exposure to HIV During

Breastfeeding

Maternal HIV RNA levels should be monitored periodically during breastfeeding because the status
of viral suppression can change over time (see Preventing HIV Transmission During Infant Feeding).
Decisions about infant antiretroviral (ARV) management during breastfeeding should be based on
clinical assessment and incorporate shared decision-making when indicated.

Providers with questions about ARV management of infants should consult an expert in pediatric
HIV infection or the National Perinatal HIV Hotline (1-888-448-8765).

Level of
Transmission Risk
Infant ARV Management During
During Breastfeeding Description
Breastfeedinga
by Maternal HIV RNA
Levels
Sustained Viral When sustained maternal virologic suppression • After completion of 2-week ZDV
Suppression (HIV RNA during pregnancy (at a minimum during the third prophylaxis in infants at low risk of in
<50 copies/mL) trimester has been achieved, documented by at utero or intrapartum transmission, some
least two HIV RNA measurements below the Panel members recommend no
limits of detection at least 1 month apart) and additional ARV prophylaxis, but others
breastfeeding and there are no concerns about recommend extended prophylaxis with
adherence NVP or 3TC during breastfeeding. The
Panels did not reach consensus about
the use of extended ARV prophylaxis
during breastfeeding (see Table 14.1).
• Most Panel members recommend that, if
used, extended ARV prophylaxis should
be continued until 6 weeks after last
exposure to breast milk. However, it may
be reasonable to discontinue prophylaxis
earlier when concern for maternal viremia
is low.

Current HIV RNA Levels When maternal virologic suppression has been • Consider extended ARV prophylaxis with
<50 copies/mL But achieved during pregnancy but there is concern NVP or 3TC (see Table 14.1).
Concerns About Future about future risk (e.g., ART adherence or loss of
Risk virologic suppression for other reasons) during • Recommended duration is until 6 weeks
breastfeeding after last exposure to breast milk.
Providers and parents may consider
cessation earlier if concerns about future
risk for viremia have resolved.
• Provide added adherence support as
indicated.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-19
Table 14. Antiretroviral Management of Infants With Exposure to HIV During
Breastfeeding

Level of
Transmission Risk
Infant ARV Management During
During Breastfeeding Description
Breastfeedinga
by Maternal HIV RNA
Levels
New Viremia During When maternal viremia with HIV RNA • Breastfeeding should be stopped
Breastfeeding (HIV RNA ≥200 copies/mL develops or presumed viremia temporarily or discontinued and
≥200 copies/mL) (e.g., nonadherence, interrupted access to replacement feeding initiated (see
ARVs) Situations to Consider Modifying or
Stopping Breastfeeding in Preventing HIV
Transmission During Infant Feeding).
Most experts recommend permanent
discontinuation of breastfeeding if HIV
RNA ≥200 copies/mL, but some support
resuming breastfeeding once re-
suppressed.
• Perform infant HIV NAT.a
• Initiate presumptive HIV therapy using
three-drug regimen of ZDV, 3TC, and
DTG.b For infants aged <4 weeks, ZDV
and 3TC plus NVP (treatment dose) or
RAL should be used. See Table 14.1 for
dosing information.
• Duration of 2–6 weeks; consensus was
not reached by Panel members.
• If the duration of the three-drug regimen
is <6 weeks, and the NAT is negative,
continue ZDV alone to complete a total of
6 weeks of prophylaxis.

New Viremia During The Panels did not reach consensus about • Breastfeeding should be stopped
Breastfeeding (HIV RNA neonatal management when maternal viremia temporarily or discontinued and
<200 copies/mL) develops that is quantifiable but <200 copies/mL. replacement feeding initiated (see
Situations to Consider Modifying or
Stopping Breastfeeding in Preventing HIV
Transmission During Infant Feeding).
• Perform infant HIV NAT.a
• Some Panel members recommend
initiation of presumptive ARV therapy
(as described for new viremia
≥200 copies/mL, above); other Panel
members recommend initiation of single-
drug ARV prophylaxis (see Table 14.1).
• Some Panel members recommend
management based on repeat HIV RNA
testing.
• Consultation with an expert is suggested.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-20
Table 14. Antiretroviral Management of Infants With Exposure to HIV During
Breastfeeding

Level of
Transmission Risk
Infant ARV Management During
During Breastfeeding Description
Breastfeedinga
by Maternal HIV RNA
Levels
New Diagnosis of HIV Newly diagnosed maternal HIV while • Stop breastfeeding and initiate
When Breastfeeding breastfeeding infant replacement feeding.
• Perform infant HIV NAT.a
• Initiate presumptive HIV therapy using
three-drug regimen of ZDV, 3TC, and
DTG.b For infants aged <4 weeks, ZDV
and 3TC plus NVP (treatment dose) or
RAL should be used. See Table 14.1 for
dosing information.
• Duration of 2 to 6 weeks; consensus was
not reached by Panel members.
• If the duration of three-drug regimen is
<6 weeks and the NAT is negative,
continue ZDV alone to complete a total of
6 weeks of prophylaxis.
aAn HIV NAT at birth is recommended for all breastfeeding infants. A NAT should be obtained before or immediately after
starting ARVs. See Diagnosis of HIV Infection in Infants and Children for additional information about infant NATs during
breastfeeding and follow-up testing after maternal viremia.
b DTG, a second-generation integrase strand transfer inhibitor with a higher barrier to resistance than RAL, can be used in
infants aged ≥4 weeks and weighing ≥3 kg.
Note: Given limited data, decisions about infant ARV prophylaxis during breastfeeding should be based on shared decision-
making with the infant’s parents.
Key: 3TC = lamivudine; ART = antiretroviral therapy; ARV = antiretroviral; DTG = dolutegravir; NAT = nucleic acid test;
NVP = nevirapine; the Panels = 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

Table 14.1. Antiretroviral Prophylaxis Dosing for Infants Who Are Breastfed

ARV Prophylaxis for Infants When Maternal Sustained Viral Suppression is Achieved

Recommended Regimen Recommended Duration and Dosing

ZDV ZDV administered for 2 weeks after birth (see Table 13.1 for dosing)

Options for Extended Postnatal Prophylaxisa

Recommended Regimen Recommended Duration and Dosing

ZDV ZDV administration continued for 4–6 weeks after birth (See Table 13.1
for dosing; note that ZDV is not recommended for prophylaxis beyond
this initial postnatal period.)

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-21
Table 14.1. Antiretroviral Prophylaxis Dosing for Infants Who Are Breastfed

NVPb,c NVP administered starting at birth or after completion of initial

prophylaxis ZDV, through 6 weeks after cessation of breastfeeding
Simplified Age-Based NVP Dosing for Newborns ≥32 Weeks’
Gestation Receiving Extended NVP Prophylaxis During
Breastfeedingb,c

Dose and Volume of

Age NVP 10 mg/mL Oral Syrup
Administered Once Daily
Birth to 6 weeks 2.0 to < 3.0 kg: 10 mg (1.0 mL)
≥ 3.0 kg: 15 mg (1.5 mL)
6 weeks to 6 months 20 mg (2.0 mL)
6 months to 30 mg (3.0 mL)
9 months
9 months to 18 40 mg 4.0 mL
months

3TC 3TC administered starting after completion of initial prophylaxis ZDV,

through 6 weeks after cessation of breastfeeding

Age 2 Weeks to <4 Weeks

• 3TC 2 mg/kg per dose orally twice daily

Age ≥4 Weeks to 12 months

• Use simplified weight-band dosing outlined in the table below.
Simplified Weight-Band Dosing for 3TC (10 mg/ml Solution) When
Used as Prophylaxis During Breastfeedingd

Dose and Volume of 3TC 10 mg/mL Oral

Weight Band
Solution Administered Twice Daily
2 to < 3 kg 10 mg (1 mL)
3 kg to <4 kg 15 mg (1.5 mL)
4 kg to <8 kg 25 mg (2.5 mL)
≥8 kg 50 mg (5 mL)

Recommended Infant ARV Management When Maternal Viremia Develops or HIV is Diagnosed During
Breastfeedinga

Presumptive HIV Therapy Regimens Recommended Duration and Dosing

ZDV plus 3TC plus DTGe Three-drug presumptive HIV therapy regimen. ZDV and 3TC plus NVP
or RAL should be used in place of DTG for infants aged <4 weeks
and/or weighing <3 kg.e,f See Table 13.1 for dosing of ZDV and 3TC in
infants aged <6 weeks. Refer to drug sections in Appendix A: Pediatric
Antiretroviral Drug Information for appropriate age-based dosing of DTG
and for dosing of ZDV, 3TC, NVP, or RAL in infants aged >6 weeks.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-22
Table 14.1. Antiretroviral Prophylaxis Dosing for Infants Who Are Breastfed

Presumptive HIV therapy is recommended for a duration of 2–6 weeks

(see Table 14).
a Consultation and referrals to local or regional Pediatric HIV specialists are available through the National Perinatal HIV Hotline
(1­888­448­8765).
b NVP dosing is adapted from the Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service Delivery and
Monitoring: Recommendations for a Public Health Approach. For infants at low risk of transmission, these doses can be given
from birth. (Simplified Age-Based Dosing for Newborns ≥32 Weeks’ Gestation Receiving Extended NVP Prophylaxis During
Breastfeeding in the World Health Organization’s Consolidated Guidelines on HIV Prevention, Testing, Treatment, Service
Delivery and Monitoring: Recommendations for a Public Health Approach, July 2021)
c3TC should be used as extended ARV prophylaxis during breastfeeding when there is evidence or concern for maternal NVP
resistant virus (including HIV-2 infection or HIV-1/HIV-2 co-infection) or when an infant cannot tolerate NVP. Dosing
recommendations for 3TC are included in the table.
dDosing for extended 3TC prophylaxis during breastfeeding, based on established 3TC dosing for treatment and weight-band
dosing used in PROMISE-EPI Source: Mennecier A, Kankasa C, et al. Optimised prevention of postnatal HIV transmission in
Zambia and Burkina Faso (PROMISE-EPI): a phase 3, open-label, randomised controlled trial. Lancet. 2024;403(10434):1362-
1371. https://pubmed.ncbi.nlm.nih.gov/38484756.
eDTG, a second-generation integrase strand transfer inhibitor with a higher barrier to resistance than RAL, is preferred in infants
aged ≥4 weeks and weighing ≥3 kg.

fWhen maternal HIV infection is diagnosed while breastfeeding, a three-drug presumptive HIV therapy regimen is recommended
for the infant, with a duration of 2–6 weeks (see Table 14.1). The same regimen is recommended for infants at high risk of HIV
acquisition after in utero or intrapartum exposure (see Table 13 and Table 13.1). No trials have evaluated the use of multidrug
regimens to prevent transmission after cessation of breastfeeding with early (acute or recent) HIV infection. Some Panel
members recommend 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.

Key: 3TC = lamivudine; ARV = antiretroviral; NVP = nevirapine; RAL = raltegravir; ZDV = zidovudine

Antiretroviral Prophylaxis for Infants When There Is Concern About the Risk of
Future Viremia During Breastfeeding
When there is an interest in breastfeeding and the criteria for the lowest anticipated risk of breast
milk transmission is met, with current and recent HIV RNA levels of <50 copies/mL, there may be
concern about future adherence in the postpartum period or factors that may impact virologic
suppression (e.g., postpartum depression, interrupted access to ARVs).72 Lapses in adherence in the
postpartum period are common, with increased risk among women of younger age and more recent
ART initiation.73 Providers may consider additional adherence history and postpartum adherence
challenges following prior pregnancies when making recommendations about infant prophylaxis
during breastfeeding. There may be anticipated changes in social structure, such as moving to a new
home, in the postpartum period that may generate new challenges to adherence. It is also important
for providers to elicit parents’ concerns, regardless of the provider’s assessment. If there are concerns
about ARV adherence during breastfeeding, the Panels recommend extended infant ARV
prophylaxis during breastfeeding with either NVP or 3TC and the addition of maternal adherence
support (see Table 14 and Table 14.1).

Data suggest that infant prophylaxis can be very effective in preventing breast milk transmission in
the context of maternal viremia. In the PROMISE trial, only 7 of the 1,211 (0.58%) analyzed infants
in the infant NVP prophylaxis arm acquired HIV infection.68 A randomized controlled trial in
Burkina Faso and Zambia found that initiation of same day infant 3TC prophylaxis in women with a

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-23
viral load of >1,000 copies/mL during breastfeeding resulted in a reduction in postnatal HIV
transmission compared to local standard of care.66 Although findings did not reach statistical
significance because the study was underpowered, the findings suggest that early infant diagnosis, in
conjunction with on-demand HIV RNA testing in the breastfeeding mother and extended infant
prophylaxis, could be a valuable approach in eliminating postnatal HIV transmission risk. A pooled
analysis of these trials reported that mothers with a viral load of 40 to 1,000 copies/mL in the initial 6
to 8 weeks postpartum were at high risk for having a viral load >1,000 copies/mL at 6 or 12 months
postpartum.74 Given the efficacy demonstrated in the trials, the Panels believe that extended ARV
prophylaxis should be considered for breastfeeding infants when there is concern about future risk of
HIV exposure during episodes of maternal viremia.

Antiretroviral Prophylaxis for Infants Exposed to Detectable HIV RNA During

Breastfeeding
Parents should receive counseling and be involved in decision-making about infant ARV prophylaxis
and management of infant feeding. In situations where there is increased risk of postnatal
transmission due to the development/occurrence of viremia during breastfeeding, the Panels advise
initiation of additional infant ARV prophylaxis to prevent breastfeeding-associated HIV
transmission. When detectable maternal HIV RNA levels develop during breastfeeding, the infant
should be tested for HIV infection (using a NAT) prior to or immediately after initiating ARVs, as
well as at specified time points after cessation of breastfeeding and completion of presumptive HIV
therapy (see Diagnosis of HIV Infection in Infants and Children and Table 3. Recommended
Virologic Testing Schedule for Infants With Perinatal and Breastfeeding Exposure to HIV). If infant
HIV testing returns a positive HIV NAT result, see Infants with HIV Infection below and What to
Start in the Pediatric Antiretroviral Guidelines).

When new maternal viremia develops, the Panels recommend that breastfeeding be stopped
temporarily or discontinued and replacement feeding initiated (see Situations to Consider
Modifying or Stopping Breastfeeding in Preventing HIV Transmission During Infant Feeding). Most
experts recommend permanent discontinuation of breastfeeding when HIV RNA is ≥200 copies/mL.
This guidance is more directive than counseling when suppressive ART is being taken. In situations
where viremia is lower and an addressable cause has been identified, the added risk of short term
continued breastfeeding would be less.

Management of New Maternal Viremia With HIV RNA ≥200 Copies/mL While
Breastfeeding

In cases where new maternal viremia with an HIV RNA level ≥200 copies/mL occurs while
breastfeeding, the Panels recommend immediate initiation of infant presumptive HIV therapy using a
three-drug regimen of ZDV plus 3TC plus DTG (NVP or RAL in place of DTG, if infant age < 4
weeks) (see Table 14 and Table 14.1 above). The drugs should be administered together for 2 to
6 weeks, with duration based on timing of results of infant NAT. As for management of high risk
around the time of birth, if 3TC plus (DTG or NVP or RAL) are discontinued, ZDV should be
continued alone to complete a total of 6 weeks prophylaxis.

As noted above, in cases where new maternal viremia with an HIV RNA level ≥200 copies/mL
develops while breastfeeding, the Panels recommend permanent cessation of breastfeeding.
However, the decision may be made to continue to breastfeed in which case longer durations of

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-24
ARVs for infants may be indicated. Discussion with parents and consultation with the National
Perinatal HIV Hotline (1­888­448­8765) or consultation with another expert is suggested.

Management of New Maternal Viremia With HIV RNA <200 Copies/mL While
Breastfeeding

In cases where new maternal viremia that is quantifiable but with HIV RNA <200 copies/mL occurs
while breastfeeding, some Panel members recommend initiation of presumptive HIV therapy for the
infant, other Panel members recommend initiation of single-drug ARV prophylaxis (with NVP or
3TC), and other Panel members recommend infant ARV management based on repeat maternal HIV
RNA testing. The rationale for the cutoff of 200 copies/mL is that low-level viremia <200 copies/mL
has been shown to predict future virologic failure with HIV RNA >200 copies/mL.75 The Panels did
not reach consensus about infant ARV prophylaxis or presumptive HIV therapy in this situation (see
Table 14). Discussion with parents and consultation with the National Perinatal HIV Hotline
(1­888­448­8765) or consultation with another expert is suggested.

Special Situations in Breastfeeding Infants

Initiation or Continuation of Breastfeeding With Viremia

The Panels strongly advise against initiating or continuing breastfeeding infants at high risk of HIV
acquisition from in utero, intrapartum, and/or postnatal exposure. 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 Preventing HIV Transmission During
Infant Feeding). Discussion with parents and consultation with the National Perinatal HIV Hotline
(1­888­448­8765) or consultation with another expert is recommended.

Infants Exposed to Newly Diagnosed Maternal HIV While Breastfeeding

When maternal HIV is suspected (e.g., a positive initial screening test), breastfeeding should be
discontinued immediately, until HIV is ruled out. Pumping and temporarily discarding or freezing
breast milk can be recommended when maternal HIV while breastfeeding is suspected but HIV
serostatus is not yet confirmed and continuation of breastfeeding is desired. 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 maternal HIV infection is
confirmed while breastfeeding.76 See New HIV Diagnosis While Breastfeeding in Diagnosis of HIV
Infection in Infants and Children for guidance about infant testing.

Breastfed infants exposed to newly diagnosed maternal HIV diagnosis during breastfeeding are
considered to be at high risk of HIV acquisition and treated accordingly with a three-drug
presumptive HIV therapy regimen for 2 to 6 weeks (see Table 14 and Table 14.1). No trials have
evaluated the use of multidrug regimens to prevent transmission after cessation of breastfeeding by a
parent with early (acute or recent) HIV infection. Given the higher risk of postnatal transmission
from early (acute or recent) HIV infection while 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. The National Perinatal HIV Hotline (1-888-448-8765) can provide

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-25
referrals to local or regional pediatric HIV specialists.

Safety of Antiretroviral Drugs Used for Infant Prophylaxis

This section is intended to provide the information needed for clinical management and counseling
parents on decision-making around infant prophylaxis. When used alone for prophylaxis in low-risk
scenarios during the neonatal period and breastfeeding, ARVs appear highly safe. The most
prominent toxicity in the neonatal period is anemia from ZDV given alone or in combination
regimens; anemia occurs after 2–4 weeks but recovers with the cessation of treatment to levels
similar to controls (see Initial Postnatal Management of the Neonate Exposed to HIV). During the
breastfeeding period, 3TC has been shown to be safe through at least 41 weeks. NVP has been shown
to be safe for infants from birth through 18 months of life; one trial identified cases with concerns of
a hypersensitivity reaction, but larger subsequent trials did not report hypersensitivity reactions.
Three-drug combinations appear safe within the durations currently recommended (i.e., 2–6 weeks).

Based on existing safety data, longitudinal laboratory monitoring for adverse events is not
needed in otherwise healthy infants receiving currently recommended ARVs used for
prophylaxis in the first 6 weeks of life. The American Academy of Pediatrics recommends
periodic monitoring of hematologic and liver toxicity in breastfeeding infants receiving ARV
prophylaxis beyond this period and for extended durations.77

Zidovudine
ZDV was the first agent studied for prophylaxis against HIV transmission to infants and
remains the standard of care for prophylaxis in low-risk situations. The major side effect from
short-term (6 weeks or less) use of ZDV appears to be transient anemia.

• In the landmark PACTG 076 trial, 415 infants were randomized and received ZDV or placebo;
hemoglobin levels in the ZDV arm were lower at the end of the 6-week treatment course but
recovered and were equivalent between arms by 12 weeks.43 No other toxicities were
significantly different between arms, and no new toxicities were identified through 18 months of
follow up.78
• Subsequent trials of 6-week regimens of ZDV alone did not identify other significant toxicities.20
• A 4-week ZDV regimen, compared with the 6-week ZDV regimen, has been reported to result in
earlier recovery from anemia in infants who are HIV-exposed but otherwise healthy.49 Severe
cases of anemia can be treated with erythropoietin79; substitution of ZDV with 3TC and/or NVP41
can also be considered.

Lamivudine
3TC has been extensively studied in combination with ZDV, but data primarily from two trials
support the safety of 3TC used alone as prophylaxis during breastfeeding through at least
41 weeks of life.

• The Mitra Study was an open-label single-arm prospective cohort trial in which 398 infants were
treated with ZDV + 3TC from birth to 1 week of age, and then with 3TC alone for the duration of
breastfeeding (maximum of 6 months) plus 2 weeks after stopping breastfeeding.80 No serious
adverse events were attributed to the study drug.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-26
• In ANRS 12174, 1,273 infants were randomized at 7 days to receive either
lopinavir/ritonavir (LPV/r) or 3TC through the completion of breastfeeding (median duration
41 weeks)81; there were no differences in adverse events rates between the arms.
• In ANRS 12397 PROMISE-EPI, in infants breastfed by mothers with HIV who were viremic
during pregnancy, 3TC was initiated as prophylaxis at 6 weeks and 6 months, and continued
through 12 months of age; the initial report noted no safety concerns, but the full results have not
yet been published.82,83

Nevirapine
Several trials support the safety of once-daily NVP in the first 6 weeks of life and through
breastfeeding. Although reactions concerning hypersensitivity were reported in the
Breastfeeding, Antiretrovirals, and Nutrition (BAN) trial, no cases have been identified in
subsequent large trials or from clinical programs. Strong data also support the safety of twice-
daily NVP used in a three-drug presumptive HIV therapy regimen.

• In the SWEN trial, infants were randomized to either single dose (n = 1,047) or 6-week courses
(n = 977) of once-daily NVP; adverse events were common overall (~40%) but without
significant differences by arm.81
• In the BAN trial, 2,369 mother-infant dyads were randomized to infant prophylaxis with once-
daily NVP, maternal ARV treatment, or enhanced control until the cessation of breastfeeding but
no longer than 28 weeks.84 A hypersensitivity reaction (rash, with eosinophilia in 10 infants, with
or without fever) developed in 16 (1.9%) infants within 4 weeks after the initiation of NVP
therapy; reactions resolved after NVP was replaced with 3TC. Hypersensitivity was the only
adverse event significantly different between arms.
• In HPTN 046, 1,519 breastfeeding infants were randomized to 6 months of once-daily NVP or
placebo (after 6 weeks of NVP from birth); no differences in adverse event rates were noted by
arm through 12 months of follow up.81
• In the PEPI-Malawi trial, 3,016 infants were randomized to receive NVP with 1 week of ZDV
(control), once daily NVP extended through 14 weeks, or NVP + ZDV extended through
14 weeks.85 Among the three arms, no significant differences were seen in serious adverse event
rates overall, nor among adverse events deemed probably associated with study drugs. However,
the extended NVP + ZDV arm had significantly more serious adverse events deemed possibly
related to NVP or ZDV, the most common of which was neutropenia.
• In IMPAACT 1077BF, the breastfeeding component of the PROMISE trial, 2,431 mother-infant
dyads were randomized to either maternal ART or infant NVP prophylaxis (once daily)
continued until 18 months after delivery or breastfeeding cessation65; the median duration of
breastfeeding was 16 months in both arms. No differences were seen between study arms in
Grade 3 or 4 adverse event rates or liver or skin toxicity. Of the 1,204 infants in the NVP arm
who started on the study-recommended regimen, only 20 (2%) stopped the recommended
regimen because of concerns of toxicity, and no cases of hypersensitivity were reported.
• The French Perinatal Cohort observed less frequent Grade 2 or higher anemia in 830 infants
receiving once-daily NVP versus ZDV prophylaxis in a high-resource setting.41
• In IMPAACT P1115, infants at high risk of HIV acquisition were given NVP twice daily as part
of a three-drug presumptive HIV therapy approach; NVP was dosed as 6 mg/kg twice daily for

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-27
 term neonates (≥37 weeks gestational age) or 4 mg/kg twice daily for 1 week and 6 mg/kg twice
daily thereafter for preterm neonates (34 to <37 weeks gestational age).21 Among 438 neonates
enrolled, 389 (89%) were born at term; 36 were subsequently found to have in utero HIV
infection. Division of AIDS (DAIDS) Grade 3 or 4 adverse events that were classified as at least
possibly related to ARVs were reported in 30 infants (7%; 95% CI, 5–10) but did not lead to
cessation of NVP in any cases; neutropenia (25 neonates [6%]) and anemia (six neonates [1%])
were the most commonly reported toxicities.

Abacavir
Data on the use of ABC in HIV-exposed neonates are limited, but suggest it is well tolerated. In
a metanalysis and population PK model that included data from three separate PK trials with a total
of 45 infants aged <3 months and born to women with HIV, no adverse events of Grade 3 or greater
were attributed to ABC.86 At this time, the Panels suggest using ABC in neonates as an alternative to
ZDV in rare situations and only after negative HLA-B*5701 allele testing.

Raltegravir
The primary toxicity of concern with the use of RAL in the neonatal period has been the
potential increase in bilirubin levels, but at recommended dosing, RAL appears safe. 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, RAL binds to albumin, raising concern that the
displacement of bilirubin could lead to hyperbilirubinemia. However, in vitro studies suggested RAL
would be safe at the drug exposures achieved for treatment.87 IMPAACT P1110, the single-arm
regulatory Phase 1/2 trial that established dosing for RAL, evaluated safety in 52 infants of 34 weeks
gestational age and older; no adverse events were attributed to RAL, and no bilirubin levels exceeded
16 mg/dL.88

Combination ARV Regimens

Combination ARV regimens are associated with elevated risk of toxicity compared to single
agents, but the three-drug regimens currently recommended for presumptive HIV therapy in
neonates (e.g., NVP/ZDV/3TC or RAL/ZDV/3TC) appear very safe when used for 6 or fewer
weeks. Early studies of two and three-drug regimens used as prophylaxis suggested that hematologic
and mitochondrial toxicity is more common than with exposure to a single NRTI.89-93 However, more
recent studies provide data about the safety of the ARV regimen that is currently recommended for
presumptive HIV therapy, suggesting it is generally well tolerated, but does confer an increased risk
of anemia.

• In IMPAACT P1115, 438 infants of at least 34 weeks gestational age at high risk of HIV
acquisition initiated NVP plus 2 NRTIs (ZDV + 3TC in 96%) within 48 hours of life and
continued until in utero infection was excluded by HIV DNA testing at birth (a median of
13 days).21 Grade 3 or 4 adverse events at least possibly related to ARVs occurred in 30 (7%) of
438 infants, with neutropenia (25 [6%]) and anemia (6 [1%]) being the most common. Toxicity
led to the permanent discontinuation of ZDV in nine (2%) of 438 participants (four found to have
in utero HIV, and five without) with neutropenia and anemia being the primary reasons for
discontinuation; no other ARVs were permanently discontinued because of toxicity.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-28
• A prospective cohort study in Thailand reported a greater proportion of infants receiving
ZDV/3TC/NVP for 6 weeks experienced Grade 2 anemia (38%) at 1 month compared to infants
receiving ZDV alone (21%, P = 0.007).94 However, the risk of Grade 3 anemia was lower and
similar between arms at 9.2% versus 10.2%, respectively (P = 0.81). Hemoglobin levels
recovered by 2 months, at which time there was no difference between the arms. No differences
in neutropenia or hepatotoxicity between the groups were observed.
• A retrospective study described outcomes of 148 Canadian infants at high risk of HIV
transmission treated with three drugs for 6 weeks including ARV based on NVP (40%),
nelfinavir (50%), and LPV/r (5%); all together, infants receiving combination regimens had
lower hemoglobin levels than infants who received ZDV alone over 6 months, but no difference
was seen between the subgroup receiving NVP-based treatment compared to ZDV alone.32

Generalizability of Available Safety Data

A number of considerations affect the generalizability of the safety data reviewed here to current
patient populations.

• The majority of trials included were completed at a time when mothers of infants receiving
prophylaxis were not receiving ART. It is possible that ARVs passed through breast milk could
add to toxicity in infants also receiving prophylaxis during breastfeeding. Current data suggest
that only clinically insignificant, small amounts of approved ARVs enter the breast milk, but this
hypothetical possibility must be considered for new agents. See Safety of Antiretroviral Drugs
During Breastfeeding in Preventing HIV Transmission During Infant Feeding for more details.
• This section focused on the risk of severe (Grade 3 or 4) adverse events; most trials did not report
the frequencies of lower-grade toxicities. Please see the DAIDS reference tables for more
information.95
• The overall rate of adverse events was high in many of the trials. For example, in IMPAACT
1077BF, approximately 35% of infants in both arms experienced Grade 3 adverse events or
death, a rate much higher than experienced in settings with more health care resources.65 The
high rate of events unrelated to study drugs overall may reflect the limited health care resources
in the settings in sub-Saharan Africa. However, some data suggest that the normal value ranges
developed in the United States may not be applicable in other settings or countries.96,97 As a
result, it is difficult to extrapolate the individual risk of events for an infant in settings that differ
from the trials. However, the possibility of an added risk of adverse events from agents can still
be evaluated by comparing arms in randomized trials.
• This section focuses on agents and approaches that are currently recommended. Safety data about
approaches that are no longer recommended (e.g., NVP plus ZDV) can be found in archived
guidelines.
• Additional information about ARV toxicity can be found in the Pediatric Antiretroviral
Guidelines (see Appendix A: Pediatric Antiretroviral Drug Information); however, data
summarized there are generally from clinical trials and other studies of children with HIV, in
whom the coadministration of other ARVs and comorbidities may also have contributed to
toxicity.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-29
Infants With HIV Infection
When infant HIV testing returns a positive HIV NAT result, the Pediatric Antiretroviral Guidelines
recommend rapid initiation of ART (defined as initiating ART immediately or within days of HIV
diagnosis) without waiting for a confirmatory test, given the low likelihood of a false-positive HIV
NAT (see When to Initiate Antiretroviral Treatment in Children with HIV Infection and Diagnosis of
HIV Infection in Infants and Children). ART should be discontinued if subsequent negative NAT
testing excludes the presence of HIV infection. What to Start in the Pediatric Antiretroviral
Guidelines provides recommendations about initial ART for infants and children with HIV, including
those who are receiving presumptive HIV therapy or other ARV prophylaxis at the time of diagnosis.

Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-30
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65. Flynn PM, Taha TE, Cababasay M, et al. Prevention of HIV-1 transmission through
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69. Davis NL, Miller WC, Hudgens MG, et al. Maternal and breastmilk viral load: impacts of
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71. Coovadia H, Brown E, Maldonado Y, et al. Efficacy of extended daily infant nevirapine
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72. Momplaisir F, Hussein M, Kacanek D, et al. Perinatal depressive symptoms, human

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73. Hoffman RM, Warshaw MG, Amico KR, et al. Predictors of viremia in postpartum women
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74. Kania D, Moles JP, Rutagwera D, et al. Understanding vertical transmission: from molecules
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75. Aldredge A, Mehta CC, Lahiri CD, et al. Consequences of low-level viremia among women
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76. Van de Perre P, Lepage P, Homsy J, et al. Mother-to-infant transmission of human

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78. Gray GE, Urban M, Chersich MF, et al. A randomized trial of two postexposure prophylaxis
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79. Ascensao JL, Bilgrami S, and Zanjani ED. Erythropoietin. Biology and clinical applications.
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80. 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
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81. Nagot N, Kankasa C, Tumwine JK, et al. Extended pre-exposure prophylaxis with lopinavir-
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weeks in infants in Africa (ANRS 12174): a randomised controlled trial. Lancet.
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82. Mennecier A, Kankasa C, Fao P, et al. Design and challenges of a large HIV prevention
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and Burkina Faso. Contemp Clin Trials. 2021;105106402. Available at:
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83. Kankasa C, Mennecier A, Tassembedo S, et al. Improved strategy to prevent HIV postnatal
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84. 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):2271-81. Available at:
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85. 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):119-29. Available at:
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86. 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.
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87. Clarke DF, Wong RJ, Wenning L, et al. Raltegravir in vitro effect on bilirubin binding.
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88. 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

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 (IMPAACT P1110). J Acquir Immune Defic Syndr. 2020;84(1):70-77. Available at:
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89. Mandelbrot L, Landreau-Mascaro A, Rekacewicz C, et al. Lamivudine-zidovudine

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90. 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-
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91. Le Chenadec J, Mayaux MJ, Guihenneuc-Jouyaux C, et al. Perinatal antiretroviral treatment

and hematopoiesis in HIV-uninfected infants. AIDS. 2003;17(14):2053-61. Available at:
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92. 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
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93. Feiterna-Sperling C, Weizsaecker K, Buhrer C, et al. Hematologic effects of maternal

antiretroviral therapy and transmission prophylaxis in HIV-1-exposed uninfected newborn
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94. Anugulruengkitt S, Suntarattiwong P, Ounchanum P, et al. Safety of 6-week neonatal triple-

combination antiretroviral postexposure prophylaxis in high-risk HIV-exposed infants.
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96. Lubega IR, Fowler MG, Musoke PM, et al. Considerations in using US-based laboratory
toxicity tables to evaluate laboratory toxicities among healthy Malawian and Ugandan
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97. Kourtis AP, Bramson B, van der Horst C, et al. Low absolute neutrophil counts in African
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Recommendations for the Use of Antiretroviral Drugs During Pregnancy and Interventions
to Reduce Perinatal HIV Transmission in the United States G-39
Special Considerations for Antiretroviral Therapy
Use in Adolescents with HIV
Updated: June 27, 2024
Reviewed: June 27, 2024

Panel’s Recommendations
• All adolescents with HIV should receive maximally suppressive antiretroviral 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: Antiretroviral Treatment Regimens Recommended for Initial Therapy in Infants and Children with HIV and
Management of Children Receiving Antiretroviral Therapy for more information.
• All adolescents with HIV should be screened for mental health 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 antiretroviral
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 (PHIV) 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 (NPHIV).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 postpubertal 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
(SMR) between 1 and 3 can be found in What to Start: Antiretroviral Treatment Regimens
Recommended For Initial Therapy in Infants and Children with HIV and Appendix A. Pediatric
Antiretroviral Drug Information. ART recommendations for adolescents and young adults with
SMRs of 4 or 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 (PK) 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 ARV 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 nonadherence 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
PHIV 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
Adherence to Antiretroviral Therapy in Children and Adolescents with HIV, Adolescents and Young

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-2
Adults with HIV in the Adult and Adolescent Antiretroviral Guidelines, and a 2013 review by Agwu
and Fairlie.3

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 approved in 2022 for use in adolescents aged ≥12 years
and weighing ≥35 kg who are virally suppressed; however, data on use in adolescents are limited (see
Cabotegravir and Rilpivirine),16-18 and data are not yet available on its potential use in those with
adherence concerns. Alternatives to changing the ARV regimen include, but are not limited to, using
cellphone alerts and other mobile health, or mHealth, approaches to remind patients to take their
medication and attend clinic visits19; 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. Even small
and short-term improvements in virologic suppression may have longer-term clinical value for
adolescents with HIV.20

Mental Health and Substance Use Concerns in Adolescents

Adolescent mental distress is a growing concern. Between 2009 and 2019, national youth surveys
showed increases in the proportion of youth reporting persistent feelings of sadness or hopelessness,
increases in the proportion of youth seriously considering suicide, and a concurrent rise in suicide
rates in youth ages 10 to 24 years.8,21 During the same period, adolescent use of social media
increased exponentially, and potential harmful impacts on youth mental health emerged (see
Protecting Youth Mental Health: The U.S. Surgeon General’s Advisory 2021 and Social Media and
Youth Mental Health: The U.S. Surgeon General’s Advisory 2023).

Many factors can increase the risk of adverse mental health outcomes among adolescents with PHIV,
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 PHIV is high, with
nearly 70% of these adolescents meeting the criteria for a psychiatric disorder at some point in their
lives.7,22-24 The most common conditions include anxiety, behavioral disorders, mood disorders
(including depression), and attention deficit hyperactivity disorder. Trauma experience is also high
among people with HIV generally and among youth with PHIV.25-27 Additionally, although data are
sparse, the prevalence of attempted suicide has been notably higher in adolescents with HIV than in
those who have been exposed to HIV but are uninfected.28 The risk of psychosis and severe chronic
mental health disorders has been shown to be higher in adolescents with PHIV than expected in the
general young adult population.29 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).13,30-32

Interventions that address mental health in youth with PHIV 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.33 Current evidence suggests that a combination of tailored

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-3
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.34,35 One recent study
randomized adolescents with HIV with depressive symptoms across 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. After 6 months, sites using the COMB-R intervention showed 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.36
Interest in the adoption of trauma-informed care (TIC) practices for people with HIV is emerging;
however, research evaluating TIC interventions is limited, and efficacy is mixed.37 Providers may
consider utilizing TIC principles for youth with PHIV who have experienced trauma.

Evidence exists that adolescents with PHIV are more likely to have substance use disorders than the
general population38; however, available studies on substance use among adolescents with PHIV
show age of initiation and rates of substance use similar to age-matched peers without HIV.39 In a
comparison of 390 youth with perinatal exposure to HIV versus 211 youth with PHIV, 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 participants who used marijuana reporting at least daily use.40 In another study, there was
no difference in substance use between adolescents exposed to HIV and adolescents with HIV. While
rates of substance use may not be higher in adolescents with PHIV, the impact on health outcomes—
including interference with medication adherence, 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.41,42

Providers who are caring for adolescents with HIV should incorporate screening for psychiatric
disorders (including suicidality), trauma exposure and experiences, 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.43 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.44 Although adolescents with either NPHIV or
PHIV had elevated rates of STIs, those with NPHIV had higher rates than those with PHIV. 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.45 Furthermore, a
negative assay at a single site does not preclude the possibility of infection at another site.46 For a

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-4
more detailed discussion of STIs, see the Centers for Disease Control and Prevention STI Treatment
Guidelines,47 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.

Contraception, Pregnancy, and Antiretroviral Therapy

Adolescents with HIV may initiate sexual activity before or after puberty, but adolescents with PHIV
do not appear to initiate sexual activity earlier than adolescents without HIV.48 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.49,50 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),51,52 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 offer complete guidance, providers
must be familiar with local laws and regulations. For additional information, refer to Prepregnancy
Counseling and Care and Reproductive Options When One or Both Partners Have HIV in the
Perinatal Guidelines. The American Academy of Pediatrics Committee on Adolescence offers
guidance about the integration of sexual and reproductive health care in pediatric clinical settings.53

Interactions Between Contraceptives and Antiretroviral Drugs

People with HIV can use all available contraceptive methods, including hormonal contraceptives,
implantable devices, intrauterine devices, transdermal patches, and vaginal rings.54

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 effects.55-57 Integrase strand transfer
inhibitors appear to have no interaction with estrogen-based contraceptives.58,59 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.

HIV and Pregnancy During Adolescence

Childbearing potential and the possibility of planned and unplanned pregnancy should be considered
when selecting an ARV regimen for an adolescent. 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 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. See Table 7 in the Recommendations for

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-5
Use of Antiretroviral Drugs During Pregnancy section of the Perinatal Guidelines for more details
about choosing an ARV regimen for use during pregnancy , including among adolescents with HIV.
Pregnancies occur as people with PHIV enter adolescence and young adulthood.60,61 Some studies
suggest higher rates of adverse pregnancy outcomes—such as small-for-gestational-age infants—
among those with PHIV than among those with NPHIV. Unplanned pregnancy is not uncommon in
youth with PHIV.61-63 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 than in adults with HIV.64 Adolescents with
PHIV also may be more likely to have complex ARV histories, virologic failure, and drug resistance
at the time of pregnancy.64-66 However, the rate of perinatal transmission among people with PHIV
who are receiving ART appears to be similar to the rate among people on ART with NPHIV.67-71

Other Considerations for Adolescents with HIV

Adolescence is a period of emerging recognition of sexual orientation and self-expression.
Adolescents with HIV who are lesbian, gay, bisexual, or nonbinary require both culturally competent
providers and tailored medical care. Health care providers should ask patients nonjudgmental
questions about their sexuality to determine whether they require specific medical and support
services and whether those services are available locally. It is important to consider the possibility of
drug–drug interactions in adolescents who are receiving both ART and medications such as
testosterone or estrogen. Additional resources for the care of these adolescents can be found in
Adolescents and Young Adults with HIV in 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.”72 Facilitating a successful transition for
adolescents with HIV from their pediatric/adolescent care clinic to adult care is important but
challenging.73-76 Many adolescents disengage from care during the transition to adult care, putting
them at risk for HIV progression and transmission to partners.77-79 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 PHIV 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. Qualitative research has demonstrated that established patient–
provider relationships among adolescents with HIV and their providers are integral to HIV care
engagement and that collaborative approaches to build trusted, new patient–provider relationships are
necessary to support successful transition.80,81 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-6
care (e.g., making appointments, requesting prescriptions, arranging transportation to appointments)
were more likely to be engaged in adult care.82 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.83,84 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.76,85 Recent studies have shown potential for successful
transition and ongoing retention using models that include an individualized transition plan and a
multidisciplinary approach that 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.86-88

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. Some 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.77,78,89 Other U.S. sites have reported initial success in transitioning adolescents but with
declining post-transition retention over time.90 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.76,79 Furthermore, some reports from the United Kingdom suggest that the mortality rate of
adolescents with HIV increases after transition,31,79,91 underscoring the need to critically examine
transition and determine the best mechanisms to optimize the long-term outcomes for youth with
PHIV.77

Some general guidelines, based on emerging evidence and consensus expert opinion, are available
about transition plans and who might benefit most from them.74,88,92-99 To maximize the likelihood of
success, providers should prepare adolescents for transition long before it occurs. 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;

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-7
• 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
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45. Loerinc L, Scheel A, Jordan-Thompson S, et al. Incidence, reinfection, and discrepancy

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46. Sultan B, White JA, Fish R, et al. The “3 in 1” study: pooling self-taken pharyngeal, urethral
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47. Workowski KA, Bolan GA, Centers for Disease Control and Prevention. Sexually
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48. Ter Haar AM, Fieten A, Van den Hof M, et al. Sexual development in perinatally HIV-
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50. Sutton MY, Patel R, Frazier EL. Unplanned pregnancies among HIV-infected women in
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51. Cohen MS, Chen YQ, McCauley M, et al. Antiretroviral therapy for the prevention of HIV-1
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55. Sevinsky H, Eley T, Persson A, et al. The effect of efavirenz on the pharmacokinetics of an
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56. Zhang J, Chung E, Yones C, et al. The effect of atazanavir/ritonavir on the pharmacokinetics
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57. El-Ibiary SY, Cocohoba JM. Effects of HIV antiretrovirals on the pharmacokinetics of
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58. Song IH, Borland J, Chen S, et al. Dolutegravir has no effect on the pharmacokinetics of oral
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59. Patel R, Stalter R, Onono M, et al. Dolutegravir-containing art does not reduce etonogestrel
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etonogestrel-implant-concentrations.

60. Kenny J, Williams B, Prime K, et al. Pregnancy outcomes in adolescents in the UK and
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61. Byrne L, Thorne C, Foster C, Tookey P. Pregnancy outcomes in women growing up with
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62. Jao J, Agwu A, Mhango G, et al. Growth patterns in the first year of life differ in infants born
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63. 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:
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64. Murphy E, Keller J, Argani C, et al. Pregnancy in an urban cohort of adolescents living with
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65. Lazenby GB, Mmeje O, Fisher BM, et al. Antiretroviral resistance and pregnancy
characteristics of women with perinatal and nonperinatal HIV infection. Infect Dis Obstet
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66. 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://pubmed.ncbi.nlm.nih.gov/27338425.

67. 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://pubmed.ncbi.nlm.nih.gov/19806493.

68. Williams SF, Keane-Tarchichi MH, Bettica L, et al. 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://pubmed.ncbi.nlm.nih.gov/18973871.

69. 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://pubmed.ncbi.nlm.nih.gov/20827164.

70. 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://pubmed.ncbi.nlm.nih.gov/20807252.

71. 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://pubmed.ncbi.nlm.nih.gov/24885649.

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72. Reiss JG, Gibson RW, Walker LR. Health care transition: youth, family, and provider
perspectives. Pediatrics. 2005;115(1):112-120. Available at:
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73. 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:
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74. 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://pubmed.ncbi.nlm.nih.gov/29528851.

75. Foster C, Fidler S. Optimizing HIV transition services for young adults. Curr Opin Infect
Dis. 2018;31(1):33-38. Available at: https://pubmed.ncbi.nlm.nih.gov/29210712.

76. 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://pubmed.ncbi.nlm.nih.gov/32746881.

77. Ryscavage P, Macharia T, Patel D, et al. Linkage to and retention in care following
healthcare transition from pediatric to adult HIV care. AIDS Care. 2016;28(5):561-565.
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78. 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://pubmed.ncbi.nlm.nih.gov/29887488.

79. 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):21848. Available at:
https://pubmed.ncbi.nlm.nih.gov/28872281.

80. Barr EA, Raybin JL, Dunlevy H, et al. 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://pubmed.ncbi.nlm.nih.gov/33654006.

81. Momplaisir F, McGlonn K, Grabill M, et al. Strategies to improve outcomes of youth

experiencing healthcare transition from pediatric to adult HIV care in a large U.S. city. Arch
Public Health. 2023;81(1):49. Available at: https://pubmed.ncbi.nlm.nih.gov/37004125.

82. 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://pubmed.ncbi.nlm.nih.gov/31584617.

83. 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://pubmed.ncbi.nlm.nih.gov/34235876.

84. Harris LR, Hoffman HJ, Griffith CJ, et al. Factors associated with transition of HIV care
readiness among adolescents and youth from a specialty pediatric HIV clinic in the United

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 States. AIDS Patient Care STDS. 2021;35(12):495-502. Available at:
https://pubmed.ncbi.nlm.nih.gov/34851725.

85. Barr EA, Raybin JL, Dunlevy H, et al. 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. Available at: https://pubmed.ncbi.nlm.nih.gov/33654006.

86. Griffith D, Jin L, Childs J, et al. 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://pubmed.ncbi.nlm.nih.gov/30985513.

87. Griffith D, Snyder J, Dell S, et al. 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://pubmed.ncbi.nlm.nih.gov/30422910.

88. Jegede OE, van Wyk B. Transition interventions for adolescents on antiretroviral therapy on
transfer from pediatric to adult healthcare: a systematic review. Int J Environ Res Public
Health. 2022;19(22). Available at: https://pubmed.ncbi.nlm.nih.gov/36429633.

89. 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://pubmed.ncbi.nlm.nih.gov/26908490.

90. Hussen SA, Doraivelu K, Goldstein MH, et al. Human immunodeficiency virus (HIV) care
continuum outcomes after transition to adult care among a prospective cohort of youth with
HIV in Atlanta, Georgia. Clin Infect Dis. 2023;76(7):1218-1224. Available at:
https://pubmed.ncbi.nlm.nih.gov/36409586.

91. 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://pubmed.ncbi.nlm.nih.gov/31651427.

92. Gilliam PP, Ellen JM, Leonard L, et al. 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://pubmed.ncbi.nlm.nih.gov/20541443.

93. 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.

94. 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://pubmed.ncbi.nlm.nih.gov/21868035.

95. Dowshen N, D’Angelo L. Health care transition for youth living with HIV/AIDS. Pediatrics.
2011;128(4):762-771. Available at: https://pubmed.ncbi.nlm.nih.gov/21930548.

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

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97. Sharer M, Fullem A. Transitioning of care and other services for adolescents living with HIV
in sub-Saharan Africa. USAID’s AIDS Support and Technical Assistance Resources,
AIDSTAR-One, Task Order 1. 2012. Available at:
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adolescents-living-hiv-sub-saharan-africa.

98. Hussen SA, Chahroudi A, Boylan A, et al. Transition of youth living with HIV from pediatric
to adult-oriented healthcare: a review of the literature. Future Virol. 2015;9(10):921-929.
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99. Njuguna IN, Beima-Sofie K, Mburu CW, et al. Transition to independent care for youth
living with HIV: a cluster randomised clinical trial. Lancet HIV. 2022;9(12):e828-e837.
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection H-17
Adherence to Antiretroviral Therapy in Children and
Adolescents with HIV
Updated: June 27, 2024
Reviewed: June 27, 2024

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 ART 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).
• To facilitate adherence, simplified oral ART regimens (e.g., once daily, low pill burden) should be prescribed whenever
feasible (AII*).
• The option of long-acting injectable ART to facilitate and support adherence should be discussed with eligible patients and
their caregivers (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
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. 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.1-3 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. Chronic nonadherence and
persistent viremia can lead to immune dysfunction and clinical complications (see Recognizing and
Managing Antiretroviral Treatment Failure).

With modern ART, the level of adherence needed to achieve viral suppression may be as low as 80%
to 85%.4,5 However, emerging data indicate that less than 100% ARV adherence is associated with
negative immunologic and clinical effects, even if the level of adherence is sufficient to achieve and
sustain viral suppression.6-9 A recent modeling analysis of data from studies in adults found that
increasing adherence in persons with viral suppression could reduce the risk of severe non-AIDS

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-1
events and death.9 These data point out the need to prioritize addressing and maximizing adherence
at visits for all children and adolescents, even those with viral suppression.

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.10-12 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 (PHIV), 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 preadolescence and late adolescence/young adulthood.13 Similarly, in a report
from the Early Pediatric Initiation Canada Cure Cohort, only 73% of the children with PHIV initiated
on ART maintained viral suppression 3 years after it was first achieved.14 Furthermore, several
studies have demonstrated that adherence is not static and can vary with time on treatment.15 In
particular, adolescents often struggle to sustain adherence over time. In a study of 933 adolescents in
South Africa aged 10 to 19 years who were 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. Only
37% of participants reported consistent 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 assessments.16 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.17,18 Despite improvements over the last several years,
the availability of once-daily, 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.19,20 Caregivers also
may be inadequately prepared to support their child’s adherence. In a study of communication
strategies among caretakers of children with PHIV in rural South Africa, many caregivers used
coercion and threats of grave consequences of nonadherence as a communication strategy to enforce
adherence.21 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.22

Adherence also may be jeopardized by social and health issues within a family (e.g., substance use,
poor physical or mental health, death of a family member or friend, unstable housing, poverty,
violence, involvement with the criminal justice system, limited social support).23-26 Because stressful
life events can disrupt adherence,13 additional monitoring and adherence supports should be
implemented at these times. Furthermore, children with PHIV 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-2
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 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 children and adolescents about their
experiences with taking medications, as well as concerns and expectations about treatment, or
address these issues with caregivers if the child is too young to engage in the conversation. Prior to
treatment, it is important that the child/adolescent and/or caregiver explicitly agree to the treatment
plan, which should include strategies to support adherence. It is also important to alert
children/adolescents 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.

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.27-29 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.30 With the introduction of long-
acting injectable ART, adherence is related to receiving scheduled injections on time. Therefore,
barriers to long-acting injectable ART adherence have shifted from home management to retention
barriers. Optimizing adherence requires assessment of such factors as transportation, appointment
scheduling, and school or work absences. In addition to viral load monitoring, providers should use
at least one other method to assess adherence, such as self-report of missed doses.28 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.31

Strategies to Improve and Support Adherence

When concerns about adherence emerge, the child/adolescent and/or caregiver should be seen and/or
contacted frequently to assess adherence. Strategies to improve and support adherence should be
individualized to the child/adolescent 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), optimizing
the use of social and community support services, and addressing barriers to attending long-acting
injectable ART administration appointments, if applicable. 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.32

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-3
Regimen-Related Strategies
Oral 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.33-37 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 fixed-
dose combination tablets in children.

Long-acting injectable cabotegravir (CAB) and rilpivirine (RPV) is an additional formulation option
for adolescents ≥12 years of age and who weigh at least 35 kg and who have sustained viral
suppression but struggle with daily adherence (see the Cabotegravir and Rilpivirine sections for
eligibility criteria). This formulation is not currently U.S. Food and Drug Administration approved
for use in people who have not achieved sustained viral suppression. Using long-acting injectable
CAB and RPV in people who are not virally suppressed and are nonadherent is currently being
studied in adults in the Long-Acting Therapy to Improve Treatment Success in Daily
LifE (LATITUDE) trial.38 A program in San Francisco demonstrated promising findings: adults with
such barriers to ART adherence as housing instability, mental illness, and substance use who were
treated with long-acting injectable CAB and RPV despite not achieving viral suppression prior to
initiation of therapy were able to attend injection appointments and achieve viral suppression with
appropriate support and outreach.39

Drugs in the regimen should be chosen to minimize drug interactions and AEs (see Management of
Medication Toxicity or Intolerance).40 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
amount of flavoring syrup or food if simultaneous administration of food is not contraindicated
(see Appendix A. Pediatric Antiretroviral Drug Information).41 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.42 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.43

Family-Related Adherence Strategies

Education is an essential component of establishing good medication adherence. 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-4
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.44

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.45,46 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 systematic review of adolescents living in sub-Saharan Africa, 12 studies with
4,422 participants found that knowledge of HIV status was associated with adherence to ART (odds
ratio [OR] 1.88; 95% confidence interval [CI], 1.21–2.94; P = <0.001).47 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) had 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.21 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.

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 people.48-50 Among 50 adolescents on atazanavir-based second-line therapy
participating in a study of modified directly administered ART (mDAART), mDAART was
significantly associated with reduced risk of nonadherence (relative risk [RR] 0.1; 95% 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.51 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
Adherence)—for viremic youth in the United States demonstrated improved adherence but not viral
suppression compared with the standard of care.25

Other strategies to support adherence include using mobile applications (apps) that remind people to
take medications; setting cell phone 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. An 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.52

However, several systematic reviews evaluating the use of mobile phone technologies to improve
ART adherence (mHealth) have been published and results continue to be inconclusive on the
effectiveness of digital interventions to improve adherence in adolescents. A recent systematic
review of digital interventions to improve adherence in youth with HIV who live in sub-Saharan
Africa provided mixed evidence, with two of six trials finding significant improvement in viral
suppression and the remaining four trials showing no significant improvement in adherence-related
measures.53 In another 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-5
middle-income countries.54 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.55

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.56

Two studies provided evidence of the efficacy of peer-based interventions to improve ART
adherence and viral suppression among adolescents and young people 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 60.3% to 59.4% in the comparison arm (interaction term OR, 4.66; 95% CI, 1.84–11.78).57
Another RCT 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.58

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,59-61
many children and youth with HIV report attendance to camp programs to be empowering and
helpful to learn about adherence to daily ART.

Further evidence of the efficacy of peer-support interventions for people 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.62

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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-6
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.31

Provider characteristics that have been associated with improved 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 child/adolescent 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-7
Table 15. Approaches for Monitoring Medication Adherence

Routine Assessment of Medication

Description
Adherence in 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 child/adolescent 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 child/adolescent 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 child/adolescent and/or 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 Telemedicine visits allow remote and often face-to-face contact and
medication administration. 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 Approaches include asking people to bring medications to the clinic,
counts. conducting home visits, or providing referrals to community health
nursing.

Monitor attendance for ART injection For individuals on long-acting injectable ART, adherence is related to
appointments among adolescents on long-acting receiving scheduled injections on time. Therefore, reducing barriers to
injectable regimens. adherence should focus on scheduling convenient appointments,
minimizing school and work absences, and ensuring transportation to
appointments.

Targeted Approaches to Monitoring

Description
Adherence in 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

Description
Adherence 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.27,63,64

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-8
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 the 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 child/adolescent 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 child/adolescent and family together, develop a treatment plan that they believe is achievable.
• Work with the child/adolescent 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). Consider long-acting injectable regimens (e.g., long-
acting injectable CAB and RPV) for eligible patients.
• When choosing a regimen, consider the child/adolescent’s routines and potential variations in individual 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 or check if the pill can be crushed. Consider dispersible formulations if possible. See drug sections in
Appendix A: Pediatric Antiretroviral Drug Information for information about available formulations and administration of
individual drugs.
• Choose ARV regimens with high genetic barriers to resistance, when available, if there are concerns about adherence.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-9
Table 16. Strategies to Improve Adherence to Antiretroviral Medications

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.
• Provide education and counseling that explain the meaning and significance of viral load results.
• Use education aids, including pictures, calendars, and stickers.
• Encourage the use of pill boxes, reminders, mobile apps, and alarms.
• 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
individuals.
• 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: app = application; AE = adverse effect; ARV = antiretroviral; CAB = cabotegravir; CDC = Centers for Disease Control and
Prevention; DOT = directly observed therapy; RPV = rilpivirine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-10
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35. Pantuzza LL, Ceccato M, Silveira MR, et al. Association between medication regimen
complexity and pharmacotherapy adherence: a systematic review. Eur J Clin Pharmacol.
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36. 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

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37. Altice F, Evuarherhe O, Shina S, et al. Adherence to HIV treatment regimens: systematic
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38. National Institute of Allergy and Infectious Diseases. The LATITUDE Study: Long-Acting
Therapy to Improve Treatment SUccess in Daily LifE. 2019. Available at:
https://www.clinicaltrials.gov/study/NCT03635788?id=NCT03635788&rank=1.

39. M Gandhi, J Salazar, M Hickey, et al. High virologic suppression rates on long-acting ART
in a safety-net clinical population. Presented at: Conference on Retroviruses and
Opportunistic Infections. 2023. Seattle, WA. Available at:
https://www.croiconference.org/abstract/high-virologic-suppression-rates-on-long-acting-art-
in-a-safety-net-clinic-population.

40. 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://pubmed.ncbi.nlm.nih.gov/19795999.

41. 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.

42. 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.
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43. Shingadia D, Viani RM, Yogev R, et al. Gastrostomy tube insertion for improvement of
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immunodeficiency virus. Pediatrics. 2000;105(6):E80. Available at:
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44. Foster C, McDonald S, Frize G, et al. “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://pubmed.ncbi.nlm.nih.gov/24428797.

45. Sin NL, DiMatteo MR. Depression treatment enhances adherence to antiretroviral therapy: a
meta-analysis. Ann Behav Med. 2014;47(3):259-269. Available at:
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46. 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://pubmed.ncbi.nlm.nih.gov/29227462.

47. Mengesha MM, Teshome A, Ajema D, et al. The association between HIV diagnosis
disclosure and adherence to anti-retroviral therapy among adolescents living with HIV in
Sub-Saharan Africa: a systematic review and meta-analysis. PLoS One.
2023;18(5):e0285571. Available at: https://www.ncbi.nlm.nih.gov/pubmed/37167342.

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48. 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://pubmed.ncbi.nlm.nih.gov/22161452.

49. 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://pubmed.ncbi.nlm.nih.gov/20707731.

50. 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://pubmed.ncbi.nlm.nih.gov/20375848.

51. Chawana TD, Katzenstein D, Nathoo K, et al. 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://pubmed.ncbi.nlm.nih.gov/31649827.

52. 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://pubmed.ncbi.nlm.nih.gov/33547993.

53. Griffee K, Martin R, Chory A, Vreeman R. A systematic review of digital interventions to

improve ART adherence among youth living with HIV in sub-Saharan Africa. AIDS Res
Treat. 2022;2022:9886306. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36199816.

54. Demena BA, Artavia-Mora L, Ouedraogo D, et al. 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://pubmed.ncbi.nlm.nih.gov/32049555.

55. Amankwaa I, Boateng D, Quansah DY, et al. 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://pubmed.ncbi.nlm.nih.gov/30240417.

56. 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://pubmed.ncbi.nlm.nih.gov/32754779.

57. 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:
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58. 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
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59. Ness TE, Agrawal V, Guffey D, et al. Impact of using creative arts programming to support
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60. Gillard A, Witt PA, Watts CE. Outcomes and processes at a camp for youth with HIV/AIDS.
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61. 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
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https://pubmed.ncbi.nlm.nih.gov/30045639.

62. 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://pubmed.ncbi.nlm.nih.gov/34138897.

63. 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. AIDS Care.
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64. 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://pubmed.ncbi.nlm.nih.gov/28520618.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection I-16
Management of Medication Toxicity or Intolerance
Updated: June 27, 2024
Reviewed: June 27, 2024

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 due to effective antiretroviral
therapy (ART) far outweigh the risks associated with the adverse effects (AEs) of some antiretroviral
(ARV) drugs. AEs have been reported with the use of all ARV drugs, however. 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 and
real-world observational studies, however, few ARV-treated patients had treatment-limiting AEs.4-13

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.14-16 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 or
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.17 For selected children aged <3 years who require treatment with efavirenz (EFV), an
additional pharmacogenetic marker, cytochrome P450 2B6 genotype, should be assessed in an attempt to
prevent toxicity17-21 (see Efavirenz in Appendix A: Pediatric Antiretroviral Drug Information). For such
agents 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.22 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,23 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 replace the drug with another effective agent as soon as possible.5,24 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-3
• 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
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
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https://pubmed.ncbi.nlm.nih.gov/35113365.

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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
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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: June 27, 2024
Reviewed: June 27, 2024

Associated Onset/ Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Clinical Manifestations Frequency Monitoring
Global CNS LPV/r oral Onset Unknown; rare case Prematurity Avoid use of LPV/r until Discontinue LPV/r;
Depression solution that reports have been a postmenstrual age of symptoms should resolve
contains both • 1–6 days after starting LPV/r published. Low birth weight 42 weeks and a in 1–5 days.
ethanol postnatal age of ≥14
Presentation Aged <14 days (whether If needed, reintroducing
(42.4% v/v) and days unless no other
propylene glycol Neonates/Premature Infants birth was premature or alternatives are LPV/r can be considered
(15.3% w/v) as term) available. See when the patient is
• Global CNS depression outside the vulnerable
excipients Lopinavir/Ritonavir.
(e.g., abnormal EEG, altered period
state of consciousness, (i.e., a postmenstrual age
somnolence) of 42 weeks and a
postnatal age ≥14 days).
Neuropsychiatric EFV Onset Variable, depending Insomnia is associated Avoid use of EFV for If symptoms are
Symptoms and on age, symptoms, with elevated EFV trough initial ART in children excessive or persistent,
Other CNS • For many symptoms, onset and assessment concentration and adolescents to obtain EFV trough
Manifestations is 1–2 days after starting method (≥4 mcg/mL). prevent EFV-associated concentration. If EFV
EFV. CNS side effects. See trough concentration is >4
• Many symptoms subside or Children CYP2B6 polymorphisms What to Start: mcg/mL and/or symptoms
diminish by 2–4 weeks, but that decrease EFV Antiretroviral Treatment are severe, strongly
• 24% of patients metabolism and cause
symptoms may persist in a Regimens consider drug substitution
experienced increased EFV serum
significant proportion of Recommended for if a suitable alternative
any EFV-related concentrations (CYP2B6
patients. Initial Therapy in Infants exists.
CNS manifestation 516 T/T genotype or and Children with HIV.
in one case series, co-carriage of CYP2B6 Alternatively, consider
Presentation (May Include with 18% of
One or More of the 516 G/T and 983 T/C dose reduction with
participants variants) repeat TDM and dose
Following) requiring drug adjustment (with input
Neuropsychiatric Symptoms discontinuation. from an expert
• Abnormal dreams pharmacologist).

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

Associated Onset/ Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Clinical Manifestations Frequency Monitoring
• Psychosis • Five of History of psychiatric In situations where EFV
45 participants illness or use of treatment may be
• Suicidal ideation or (11%) experienced psychoactive drugs indicated, consider the
attempted/completed suicide new-onset following:
seizures in one
Other CNS Manifestations • Administer EFV on
study of children
an empty stomach,
• Dizziness aged <36 months;
preferably at bedtime.
two of these
• Somnolence participants had • Prescreen for
• Insomnia or poor sleep alternative causes psychiatric illness;
quality for seizures. avoid use in the
presence of
• Impaired concentration • Cases of
psychiatric illness,
cerebellar
• Seizures (including absence including depression
dysfunction have
seizures) or suicidal thoughts.
been reported in
Avoid concomitant
• Cerebellar dysfunction children with very
use of psychoactive
(e.g., tremor, dysmetria, high EFV plasma
drugs.
ataxia) levels.
• Consider using TDM
Note: CNS side effects Adults in children with mild
(e.g., impaired concentration, • 30% incidence for or moderate EFV-
abnormal dreams, sleep any CNS associated toxicities.
disturbances) may be more manifestations of
difficult to assess in children. any severity
• 6% incidence for
EFV-related,
severe CNS
manifestations,
including
suicidality.
However, evidence
is conflicting about
whether EFV use
increases the

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

Associated Onset/ Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Clinical Manifestations Frequency Monitoring
incidence of
suicidality.
• Two case series
reported late-onset
ataxia with or
without
encephalopathy
associated with
high EFV levels.
RPV Onset Children History of Monitor carefully for Consider drug substitution
neuropsychiatric illness depressive disorders in cases of severe
• Most symptoms occur in the • Depressive and other CNS symptoms.
first 4–8 weeks of treatment. disorders of all symptoms.
severity grades
Presentation were reported in
Neuropsychiatric Symptoms 19.4% of pediatric
patients aged
• Depressive disorders 12–17 years.
Severe depressive
• Suicidal ideation
disorders were
• Abnormal reported in 5.6% of
dreams/nightmares patients, including
one suicide
Other CNS Manifestations attempt.
• Headache • Somnolence was
reported in 5 of
• Dizziness 36 children (14%).
• Insomnia
• Somnolence

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

Associated Onset/ Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Clinical Manifestations Frequency Monitoring
Adults
• CNS/neuropsychia
tric adverse events
of all severity
grades were
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.
RAL Onset Children Elevated RAL Prescreen for Consider drug substitution
concentrations psychiatric symptoms. (RAL or coadministered
• As early as 3–4 days after • Increased drug) in cases of severe
starting RAL psychomotor Co-treatment with TDF, a Monitor carefully for insomnia or other
activity was PPI, or inhibitors of CNS symptoms. neuropsychiatric
Presentation reported in one UGT1A1 symptoms.
child. Use with caution in the
• Increased psychomotor
activity Prior history of insomnia presence of drugs that
Adults or depression increase RAL
• Headaches • Headache concentration.

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

Associated Onset/ Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Clinical Manifestations Frequency Monitoring
• Insomnia • Insomnia (<5% in
adult trials)
• Depression
• Rare case reports
• Cerebellar dysfunction of cerebellar
(e.g., tremor, dysarthria, dysfunction in
ataxia) adults
DTG Onset Children Preexisting depression Use with caution in the For persistent or severe
or other psychiatric presence of psychiatric neuropsychiatric
• 7–30 days after starting DTG • In a retrospective illness illness, especially in symptoms, consider
cohort analysis, patients with discontinuing DTG if a
Presentation neuropsychiatric History of ARV-related depression or a history suitable alternative exists.
Neuropsychiatric Symptoms events that neuropsychiatric of ARV-related
resulted in symptoms neuropsychiatric For mild symptoms,
• Depression or exacerbation discontinuation continue DTG and
symptoms.
of preexisting depression occurred in 2 of 29 Higher frequency of counsel patient that
(6.8%) children overall neuropsychiatric Consider morning symptoms likely will
• Anxiety
who initiated DTG. symptoms reported when dosing of DTG. resolve with time.
• Self-harm thoughts, suicidal DTG is coadministered
• Significantly higher
ideation, or attempted/ with ABC, and of
frequency of self-
completed suicide depression and dizziness
harm or suicidal
thoughts reported when DTG is
• Drowsiness
in children in the coadministered with
• Neurocognitive deficits ODYSSEY trial RPV. However, evidence
(lower total competence and receiving DTG is conflicting for ABC
school performance) (23%) compared to association.
SOC ARVs (5%).
Other CNS Manifestations They were
(Generally Mild) transient, self-
• Sleep disturbances resolved, and did
not lead to
• Dizziness treatment changes.
• Headache

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-12
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous
System Toxicity

Associated Onset/ Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Clinical Manifestations Frequency Monitoring
Adults
• 2.7% of the
neuropsychiatric
AEs reported in a
large prospective
cohort resulted in
treatment
discontinuation.
• Higher frequency
of neuropsychiatric
symptoms reported
with DTG than with
other INSTIs. A
class effect has
been suggested.
BIC Onset Children Preexisting depression Use with caution in the For persistent or severe
or other psychiatric presence of psychiatric neuropsychiatric
• 1–63 days after starting BIC • One child (1%) had conditions conditions or in patients symptoms, consider
(as late as 233 days for Grade 2 insomnia with a history of ARV- discontinuing BIC if a
schizoaffective disorders) and anxiety that History of ARV-related related neuropsychiatric suitable alternative exists.
led to drug neuropsychiatric symptoms.
Presentation discontinuation in symptoms For mild symptoms,
Neuropsychiatric Symptoms clinical trials. continue BIC and counsel
patient that symptoms
• Depression or exacerbation Adults likely will resolve with
of preexisting depression time.
• Overall, the
• Suicidal ideation or frequency of
attempted suicide neuropsychiatric
events in BIC and
• Schizoaffective disorders DTG comparator
• Anxiety arms appeared
similar in adult
clinical trials.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-13
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous
System Toxicity

Associated Onset/ Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Clinical Manifestations Frequency Monitoring
Other CNS Manifestations • Abnormal dreams,
(Generally Mild) dizziness, and
insomnia occurred
• Sleep disturbances
in 1% to 5% of
• Dizziness adults.
• Insomnia • Suicidal ideation,
suicide attempts,
schizoaffective
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 depression Monitor individuals for Promptly evaluate severe
or other psychiatric depressive symptoms depressive symptoms,
Neuropsychiatric Symptoms • Insomnia was conditions could be or self-injurious self-injurious behavior, or
(Generally Mild or Moderate, reported in 1 of 8 contributing factors, but thoughts or behavior, other CNS symptoms for
Occasionally Serious) adolescents in causal links have not especially if prior history a possible relationship
the ongoing clearly been identified. of such. with CAB, and assess
• Mood disorders, including
MOCHA trial. risks and benefits of
depression and suicidal
ideation or attempt continued CAB treatment.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-14
Table 17a. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Central Nervous
System Toxicity

Associated Onset/ Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Clinical Manifestations Frequency Monitoring
• Anxiety disorders Adults CAB exposure did not If CAB is discontinued—
differ between study
Other CNS Manifestations • 2–4% pooled participants with and • Counsel the individual
(Generally Mild or Moderate) incidence was those without CNS or about prolonged
reported in Phase neuropsychiatric residual CAB levels in
• Sleep disorders 3 trials for CNS the blood for 52 weeks
manifestations.
AEs, including or longer, and monitor
• Dizziness
sleep disorders, frequently for symptom
• Headache dizziness, and resolution.
headache.
• Somnolence • Ensure that a new
• Less than 2% suppressive regimen is
incidence was started within 30 days
reported for of last injection.
depressive
disorders,
including suicidal
ideation, in
Phase 3 trials, with
comparable
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-glucuronosyltransferase family 1 member A complex; % v = volume; w = weight

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-15
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38. Rizzardini G, Overton ET, Okrin C, et al. Long-acting cabotegravir+rilpivirine for HIV maintenance therapy: week 48 pooled analysis of
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40. Shubber Z, Calmy A, Andrieux-Meyer I, et al. Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral
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50. Walmsley S, Baumgarten A, Berenguer J, et al. Brief report: dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in
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51. Waters L, Fisher M, Winston A, et al. A Phase IV, double-blind, multicentre, randomized, placebo-controlled, pilot study to assess the
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-20
Table 17b. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Dyslipidemia
Updated: April 11, 2022
Reviewed: June 27, 2024

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
frequency varies HIV disease additional ASCVD risk factors.
• All PIs, • As early as with specific ARV • Low-fat diet Patients with HIV are
especially 2 weeks to months regimen, duration High-fat, considered to be at moderate
RTV-boosted after beginning • Exercise
of ART, and the high-cholesterol diet risk for ASCVD.b
PIs; lower therapy specific laboratory • Smoking-prevention
incidence parameters used Sedentary lifestyle counseling ARV regimen changes should
reported with Presentation be considered, especially when
to diagnose lipid • Use of ARV drugs, such as
DRV/r and PIs abnormalities. Obesity the patient is receiving older PIs
ATV, with or INSTIs, and to a lesser
(e.g., LPV/r) and/or RTV
without RTV • ↑ LDL-C, TC, and Hypertension extent, newer PIs (e.g., ATV,
10% to 20% of boosting. Switching to a PI-
TG DRV), is associated with a
young children sparing regimen, a PI-based
NRTIs Smoking lower prevalence of
receiving LPV/r will regimen with a more favorable
NRTIs dyslipidemia.
• Lower have lipid Family history of lipid profile, or COBI boosting
incidence • ↑ LDL-C, TC, and abnormalities. dyslipidemia or • When considering a TDF- causes a decline in LDL-C or
reported with TG. Significant premature ASCVD based or TAF-based TG values. The lipid-lowering
TDF than with increase in plasma 40% to 75% of regimen, the lipid-lowering effect of an ARV regimen switch
TAF lipid values was older children and Metabolic syndrome beneficial effect of TDF on LDL-C is less pronounced
observed in adults adolescents with should be weighed against than with statin therapy but may
NNRTIs switching from prolonged ART Fat maldistribution its potential for increased be enough to re-establish a
TDF to TAF, history will have renal and bone toxicities. healthy lipid profile.
• Lower lipid abnormalities.
regardless of third
incidence Refer patients to a lipid
agent or presence
reported with specialist early if LDL-C is
of a boosting
NVP, RPV, ≥250 mg/dL or TG is
agent.
and ETR than ≥500 mg/dL.
with EFV NNRTIs
INSTIs • ↑ LDL-C, TC, and
HDL-C
• EVG/c

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-21
Table 17b. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Dyslipidemia

Pooled Monitoringa If LDL-C is ≥130 mg/dL but

dyslipidemia <250 mg or TG is ≥150 mg/dL
prevalence of • Obtain fasting (or but <500 mg/dL, the following
39.5% and an non-fasting) lipid profile (TC, staged treatment approach is
incidence of 32% HDL-C, non-HDL-C, LDL-C, recommended by the NHLBI
(191 per 1,000 and TG) twice (>2 weeks but guidelinesb:
person-years) ≤3 months apart) and
reported in a average these results. • Implement diet, nutrition, and
recent meta- Monitor every 6 months (for lifestyle management for
analysis and a abnormal results) or every 6–9 months. Consult with a
recent review of a 12 months (for normal dietician if one is available.
large consortium of results).
• If a 6- to 9-month trial of
prospective • If TG or LDL-C is elevated or lifestyle modification fails and
observational if a patient has additional risk the patient is aged ≥10 years,
cohorts, factors, obtain FLP. consider implementing lipid-
respectively. lowering therapy after
Children with Lipid consulting a lipid specialist.
Abnormalities and/or Additional
Risk Factors • Statin therapy should be
considered for patients with
• Obtain 12-hour FLP before elevated LDL-C levels.
initiating or changing therapy NHLBI guidelines provide
and every 6 months recommendations for statin
thereafter (more often if therapy in patients with
indicated). specific LDL-C levels and risk
factors.b Concurrent
Children Receiving Lipid- substitution—preferably to
Lowering Therapy with Statins ARV drugs with no inhibitory
or Fibrates or inducing effect on CYP3A4
• Obtain 12-hour FLP, LFT, or OATP1B1 (e.g., INSTI)—
and CK at 4 weeks, 8 weeks, also should be considered as
and 3 months after starting appropriate to limit drug–drug
lipid therapy. interaction potential.

• If minimal alterations in AST, • Drug therapy can be

ALT, and CK are indicated, considered in cases of
monitor every 3–4 months severe hypertriglyceridemia
during the first year and (TG ≥500 mg/dL). Fibrates
every 6 months thereafter (or (gemfibrozil and fenofibrate)
as clinically indicated). may be used.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-22
Table 17b. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Dyslipidemia

• Repeat FLP 4 weeks after The long-term risks of lipid

increasing doses of abnormalities in children who
antihyperlipidemic agents. are receiving ART are unclear.
However, persistent
dyslipidemia in children may
lead to premature ASCVD.
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; 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-23
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-27
Table 17c. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—
Gastrointestinal Effects
Updated: June 27, 2024
Reviewed: June 27, 2024

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 emesis, Consider switching to ARV
both of which may drugs with smaller tablet sizes
be associated with (see Appendix A, Table 2.
anorexia and/or Antiretroviral Fixed-Dose
abdominal pain Combination Tablets and Co-
packaged Formulations:
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 and
stools that are
generally soft

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-28
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
Reassure patient that this
adverse effect generally
improves over time (usually in
6–8 weeks). Consider
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,
ribavirin)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-29
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
Presentation Hypertriglyceridemia If pancreatitis is associated
with hypertriglyceridemia,
• Emesis, abdominal Advanced HIV consider using interventions to
pain, and elevated infection lower TG levels.
amylase and
lipase levels Previous episode of
(asymptomatic pancreatitis
hyperamylasemia or
elevated lipase do Alcohol use
not in and of
themselves indicate
pancreatitis)

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-30
References
1. Basile FW, Fedele MC, Lo Vecchio A. Gastrointestinal diseases in children living with HIV. Microorganisms. 2021;9(8). Available
at: https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/26712880.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-31
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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/22544446.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-32
Table 17d. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—
Hematologic Effects
Updated: June 27, 2024
Reviewed: June 27, 2024

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
to months after • Severe anemia is • Premature birth is the • Obtain CBC at birth. intervention unless it is
starting therapy uncommon but most common risk symptomatic or
might be factor. • Consider repeating Hgb <7.0 g/dL.
Presentation coincident with CBC at 4 weeks for
physiologic Hgb • In utero exposure to neonates who are at • ZDV administration can be
More Common ZDV-containing higher risk (e.g., those limited to 4 weeks in low-risk
nadir.
• Asymptomatic regimens born prematurely or neonates (see Antiretroviral
Children with HIV who are known to Management of Infants With
• Mild fatigue • Advanced maternal HIV have low birth Hgb) In Utero, Intrapartum, or
Who Are Taking
ARV Drugs • Neonatal blood loss and for neonates who Breastfeeding Exposure to
• Pallor receive ZDV beyond HIV).
• Tachypnea • Anemia is two to • Combination ARV 4 weeks.
three times more prophylaxis or Children with HIV Who Are
Rare common with presumptive HIV Children with HIV Who Taking ARV Drugs
ZDV-containing therapy, although no Are Taking ARV Drugs
• Congestive heart regimens than particular regimen has • Discontinue non-ARV,
failure with all other been identified as being • Avoid using ZDV in marrow-toxic drugs, if
regimens. worse than others. children with severe feasible.
anemia when
alternative agents are • Treat coexisting iron
Children with HIV Who deficiency, OIs, and
Are Taking ARV Drugs available.
malignancies.
• Underlying • Obtain CBC as part of
routine care (see • For persistent, severe
hemoglobinopathy anemia that is thought to be
(e.g., sickle cell disease, Clinical and
Laboratory Monitoring associated with ARV drugs
G6PD deficiency) (typically macrocytic
of Pediatric HIV
Infection).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-33
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 anemia), switch to a regimen
(e.g., TMP-SMX, that does not contain ZDV.
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 No management required.
ages required—macrocytosis
• Within days or can be detected if CBC
weeks of starting is 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
or may progress
to anemia

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-34
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
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
• Rare • In utero exposure to • Obtain CBC as part of intervention; some experts
Presentation ARV drugs routine care. would consider using an
Children with HIV alternative NRTI for
• Asymptomatic Who Are Taking • Combination ARV prophylaxis if ANC reaches
ARV Drugs prophylaxis, particularly <500 cells/mm3. ZDV
ZDV plus 3TC and NVP administration can be limited
• 2% to 4% of
to 4 weeks in low-risk
children on ARV Children with HIV Who
neonates (see Antiretroviral
drugs Are Taking ARV Drugs
Management of Infants With
• Highest rates • Advanced or poorly In Utero, Intrapartum, or
occur in children controlled HIV infection Breastfeeding Exposure to
on ZDV-containing HIV).
regimens • Myelosuppressive drugs
(e.g., TMP-SMX, Children with HIV Who Are
ganciclovir, hydroxyurea, Taking ARV Drugs
rifabutin)
• Discontinue non-ARV,
marrow-toxic drugs, if
feasible.
• Treat coexisting OIs and
malignancies.
• In cases of persistent,
severe 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-35
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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/26279668.

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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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/26481928.

15. Nanthatanti N, Charoenphak S, Sungkanuparph S. Progression of non-anemic macrocytosis to anemia in HIV-positie persons
receiving zidovudine-containing regimens in resource-limited setting. Int J STD AIDS. 2022;33(14):1193-1198. Available at:
https://pubmed.ncbi.nlm.nih.gov/36254724.

16. 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://pubmed.ncbi.nlm.nih.gov/31033907.

17. 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://pubmed.ncbi.nlm.nih.gov/22716975.

18. 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://pubmed.ncbi.nlm.nih.gov/23114115.

19. 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://pubmed.ncbi.nlm.nih.gov/24047928.

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20. 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://pubmed.ncbi.nlm.nih.gov/26482352.

21. 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://pubmed.ncbi.nlm.nih.gov/26000984.

22. 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://pubmed.ncbi.nlm.nih.gov/27127401.

23. 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://pubmed.ncbi.nlm.nih.gov/34082441.

24. 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.

25. 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://pubmed.ncbi.nlm.nih.gov/19000014.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-38
Table 17e. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Hepatic Events
Updated: April 11, 2022
Reviewed: June 27, 2024

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 supplements elevated levels of
use of NVP and occur later. (e.g., St. John’s wort Asymptomatic
hepatic enzymes
EFV. • Steatosis presents [Hypericum perforatum], (>5 times to Hepatitis
after months or years chaparral [Larrea 10 times ULN) or
NVP, EFV, ABC, tridentata], germander • Potentially offending
of therapy. chronic liver disease, ARV drugs should
RAL, DTG, and [Teucrium chamaedrys]) most clinicians would
MVC have been • Patients with HBV be discontinued if
avoid NVP. ALT or AST level is
associated with coinfection can Alcohol use
hepatitis in the experience a hepatitis >5 times ULN.
Monitoring
context of HSRs. flare with the initiation Pregnancy
or withdrawal of 3TC, For ARV Drugs Other Symptomatic
NRTIs, especially FTC, TDF, or TAF. A Obesity than NVP Hepatitis
ZDV, have been flare also can occur • Obtain AST and ALT • Discontinue all ARV
Higher drug
associated with with the emergence of levels at baseline drugs and other
concentrations of PIs
lactic acidosis and resistance to 3TC or and at least every potentially
hepatic steatosis. 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-39
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-40
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 is stop ATV.
at least one total needed.
Presentation Psychological impact
bilirubin level • After an initial rise
• Can be asymptomatic >5 times ULN, and over the first few of jaundice should be
or associated with 1.4% of children months of therapy, evaluated, and
jaundice experienced unconjugated alternative agents
jaundice. bilirubin levels should be considered.
• Levels of direct
generally stabilize;
bilirubin can be Jaundice can result in
levels can improve
normal or slightly nonadherence,
over time.
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.
bLess 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-41
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23. Pokorska-Spiewak M, Stanska-Perka A, Popielska J, et al. Prevalence and predictors of liver disease in HIV-infected children and
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24. Rutstein RM, Samson P, Fenton T, et al. Long-term safety and efficacy of atazanavir-based therapy in HIV-infected infants, children
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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.
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27. Sohrab SS, Suhail M, Ali A, Qadri I, Harakeh S, Azhar EI. Consequence of HIV and HCV co-infection on host immune response,
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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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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:
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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:
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-44
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:
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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.
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34. The National Institute of Diabetes and Digestive and Kidney Diseases. Clinical and research information on drug-induced liver
Injury. 2019. Available at: https://pubmed.ncbi.nlm.nih.gov/31643176/

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.
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-45
Table 17f. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Insulin Resistance,
Asymptomatic Hyperglycemia, and Diabetes Mellitus
Updated: April 11, 2022
Reviewed: June 27, 2024

Associated Onset/Clinical Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Manifestations Frequency Monitoring
Insulin ZDV, LPV/r, and Onset Children Risk Factors for Prevention Counsel patient on lifestyle
Resistance, possibly other Type 2 DM modification
Asymptomatic PIs and INSTIs • Weeks to months after • IR, 6% to 12% • Lifestyle modification (e.g., implementing a diet
Hyperglycemia, beginning therapy (incidence is • Lipodystrophy low in saturated fat,
higher during Monitoring
and Diabetes • Metabolic syndrome cholesterol, trans fat, and
Presentation puberty, 20% to
Mellitusa • Monitor for signs of refined sugars; increasing
30%) • Family history of DM physical activity; ceasing
• Asymptomatic fasting DM, change in body
hyperglycemia (which • IFPG, 0% to 7% • High BMI (obesity) habitus, and smoking).
sometimes occurs in acanthosis nigricans.
the setting of • IGT, 3% to 4% Recommend that the patient
lipodystrophy), • Obtain RPG levels at consult with a dietician.
• DM, 0.2 per initiation of ART,
metabolic syndrome, 100 child-years
or growth delay 3–6 months after If the patient is receiving
ART initiation, and ZDV, switch to TAF, TDF, or
• Symptomatic DM yearly thereafter. ABC.
(rare)
• In patients with an For Patients with Either an
RPG ≥140 mg/dL, RPG ≥200 mg/dL plus
obtain FPG after an Symptoms of DM or an
8-hour fast and FPG ≥126 mg/dL
consider referring the
patient to an • These patients meet
endocrinologist. diagnostic criteria for DM;
consult an endocrinologist.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-46
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
of 100–125 mg/dL
• Impaired FPG suggests
insulin resistance; consult
an endocrinologist.

For Patients with an FPG

of <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-47
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11. Hadigan C, Kattakuzhy S. Diabetes mellitus type 2 and abnormal glucose metabolism in the setting of human immunodeficiency
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20. Rebeiro PF, Jenkins CA, Bian A, et al. Risk of incident diabetes mellitus, weight gain, and their relationships with integrase
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-50
Table 17g. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lactic Acidosis
Updated: June 27, 2024
Reviewed: June 27, 2024

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, • A few cases have been significant
mitochondrial • Chronic HCV infection should not be used in ARV drugs temporarily while
ABC, TAF, and reported shortly after preterm neonates or any conducting additional
TDF initiation in people with dysfunction than • African-American race
ZDV. neonate who has not diagnostic work-up.
underlying liver disease. attained a postmenstrual
Other Drugs • Coadministration of TDF
age of 42 weeks and a For Patients with Lactate
Presentation with metformin
• See the Risk postnatal age of >5.0 mmol/L (Confirmed with
Factors and • Lactic acidosis may be • Overdose of propylene ≥14 days. a Second Test)b or
Prevention/ clinically asymptomatic. glycol >10.0 mmol/L (Any One Test)
• Monitor for clinical
Monitoring • Discontinue all ARV drugs.
Lactic Acidosis May Also • CD4 count manifestations of lactic
columns for
Present with Insidious <350 cells/mm3 acidosis and promptly
information • Provide supportive therapy
Onset of a Combination of adjust therapy.
regarding the • Acquired riboflavin or (e.g., IV fluids; some
toxicity of Signs and Symptoms thiamine deficiency patients may require
Monitoring
propylene glycol sedation and respiratory
• Generalized fatigue, • Possible pregnancy
when LPV/r oral Asymptomatic Patients support to reduce oxygen
weakness, and myalgias
solution is used • Overdose in setting of demand and ensure
• Routine measurement of
in neonates. • Vague abdominal pain, renal insufficiency adequate oxygenation of
serum lactate is not
weight loss, unexplained (e.g., 3TC) tissues).
recommended.
nausea, or vomiting
Anecdotal (Unproven)
• Dyspnea Supportive Therapies
• Peripheral neuropathy • Administer bicarbonate
infusions, THAM, high doses
Note: Patients may present of thiamine and riboflavin,
with acute multiorgan and oral antioxidants
failure (e.g., fulminant (e.g., L-carnitine, co-enzyme
hepatic failure, pancreatic Q10, vitamin C).
failure, respiratory failure).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-51
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
Preterm Infants or Any Patients with Clinical Signs Following the resolution of
Neonates Who Have Not or Symptoms Consistent clinical and laboratory
Attained a Postmenstrual with Lactic Acidosis abnormalities, resume therapy
Age of 42 Weeks and a either with an NRTI-sparing
Postnatal Age of • Obtain blood lactate regimen or a revised NRTI-
≥14 Days level.a containing regimen. Institute a
• Additional diagnostic revised NRTI-containing
• Exposure to propylene regimen with caution, using
glycol, which is used as a evaluations should include
serum bicarbonate, anion NRTIs that are less likely to
diluent in LPV/r oral induce mitochondrial
solution, because these gap, and/or arterial blood
gas; amylase and lipase; dysfunction (i.e., ABC, TAF,
newborns have a TDF, FTC, or 3TC). Lactate
diminished ability to serum albumin; and
hepatic transaminases. should be monitored monthly
metabolize propylene for ≥3 months.
glycol may lead to
accumulation, increasing
the risk of adverse
events.
aBlood 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-52
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Asia. Pediatr Infect Dis J. 2019;38(3):287-292. Available at: https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/31361914.

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://pubmed.ncbi.nlm.nih.gov/21288314.

8. Konala VM, Adapa KP, Dinesh KP. et al. Lamivudine-associated lactic acidosis. Am J Ther. 2022;29(4):449-451. Available at:
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trial. HIV Clin Trials. 2015;16(3):89-99. Available at: https://pubmed.ncbi.nlm.nih.gov/25979186.

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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/25762872.

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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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/24428886.

15. Matthews LT, Giddy J, Ghebremichael M, et al. A risk-factor guided approach to reducing lactic acidosis and hyperlactatemia in patients on
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16. Moren C, Noguera-Julian A, Garrabou G, et al. Mitochondrial evolution in HIV-infected children receiving first- or second-generation
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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:
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18. Wester CW, Eden SK, Shepherd BE, et al. Risk factors for symptomatic hyperlactatemia and lactic acidosis among combination
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19. Arnouk S, Whitsett M, Papadopoulos Z, et al. Successful treatment of tenofovir alafenamide-induced lactic acidosis: a case report. J Pharm
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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://pubmed.ncbi.nlm.nih.gov/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:
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22. Kraut JA, Madias NE. Lactic acidosis. N Engl J Med. 2014;371(24):2309-2319. Available at: https://pubmed.ncbi.nlm.nih.gov/25494270.

23. Marfo K, Garala M, Kvetan V, Gasperino J. Use of tris-hydroxymethyl aminomethane in severe lactic acidosis due to highly active
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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://pubmed.ncbi.nlm.nih.gov/31418093.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-54
Table 17h. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lipodystrophies
and Weight Gain
Updated: June 27, 2024
Reviewed: June 27, 2024

Associated Onset/Clinical Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Manifestations Frequency Monitoring
Lipodystrophy (Fat See below for Onset Frequency is low • Genetic Prevention • Physicians should perform a
Maldistribution) specific (<5%) with predisposition regimen review and
associations. • Increase in trunk current regimens. • Initiate a calorically
consider changing the
General Information and limb fat is the • Puberty appropriate low-fat
regimen when lipodystrophy
first sign; peripheral diet and an exercise
• HIV-associated occurs.
fat wasting may not regimen.
appear for inflammation • Improvement in fat
12–24 months after • Older age Monitoring maldistribution can vary
ART initiation. following a regimen change.
• Longer duration of • BMI measurement
Improvement may occur
ART • Waist circumference after several months or
• Body habitus and waist-hip ratio years, or it may not occur at
all.
Central Can occur in the Presentation Frequency is low • Obesity before Prevention • Counsel patient on lifestyle
Lipohypertrophy absence of ART, (<5%) with initiation of therapy modification and dietary
or but these • Central fat current regimens. • Initiate a calorically
interventions
Lipo-accumulation conditions most accumulation with • Sedentary lifestyle appropriate low-fat
(e.g., maintaining a
often are increased diet and an exercise
calorically appropriate diet
associated with abdominal girth, regimen.
that is low in saturated fats
the use of PIs which may include a
Monitoring and simple carbohydrates
and EFV. dorsocervical fat
and starting an exercise
pad (buffalo hump).
• BMI measurement regimen, especially strength
Gynecomastia may
training).
occur in males, or • Waist circumference
breast hypertrophy and waist-hip ratio • Recommend smoking
may occur in measurements cessation (if applicable) to
females, particularly decrease future CVD risk.
with the use of EFV.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-55
Table 17h. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lipodystrophies and
Weight Gain

Associated Onset/Clinical Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Manifestations Frequency Monitoring
• 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-56
Table 17h. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lipodystrophies and
Weight Gain

Associated Onset/Clinical Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Manifestations Frequency Monitoring
Facial/Peripheral Most cases are Presentation Frequency is low Underweight before Prevention • Replace ZDV with another
Lipoatrophy associated with (<5%) with ART initiation NRTI when possible.
the use of ZDV, a • Thinning of current regimens. • Limit the use of ZDV.
thymidine subcutaneous fat in Data Are Insufficient to
the face, buttocks, Monitoring
analogue NRTI. Allow the Panel to Safely
and extremities, Recommend Use of Any of
• Patient self-report
measured as a the Following Modalities in
and physical
decrease in Children
examination are the
trunk/limb fat by
most sensitive
DXA or triceps • Injections of poly-L-lactic
methods of
skinfold thickness. acid
monitoring
Preservation of lean
lipoatrophy. • Recombinant human leptin
body mass
distinguishes • Autologous fat
lipoatrophy from transplantation
HIV-associated
wasting. • Thiazolidinediones

Weight Gain Significant weight Onset Rate of In Infants and Prevention Counsel patient on lifestyle
gain may occur development of Children modifications and dietary
with all ARV • Gradual weight gain obesity is • Initiate a calorically interventions
regimens, but it after initiating ARV unclear. • Limited evaluation appropriate low-fat (e.g., maintaining a calorically
appears to be drugs is common has demonstrated diet and an exercise appropriate healthy diet that is
more pronounced with all currently weight gain, but regimen. low in saturated fats and
with INSTIs used regimens. The such observations simple carbohydrates and
mechanism for have not been Monitoring
(DTG, BIC, EVG, starting an exercise regimen,
RAL) and TAF. weight gain is consistently especially strength training).
• BMI measurement
unclear and under attributable to
investigation. specific ARVs • Waist circumference Children with HIV and
and waist-hip ratio significant weight gain should
In Adolescents measurements be managed according to
• Female sex standard AAP
recommendations for weight
• Pre-treatment management.
obesity

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-57
Table 17h. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Lipodystrophies and
Weight Gain

Associated Onset/Clinical Estimated Prevention/

Adverse Effects Risk Factors Management
ARVs Manifestations Frequency Monitoring
In Adults
• Low pre-treatment
BMI
• Older age
• Female sex
• Black race
• Possible genetic
polymorphisms

Key: AAP = American Academy of Pediatrics; ART = antiretroviral therapy; ARV = antiretroviral; BIC = bictegravir; BMI = body mass index; CVD = cardiovascular disease;
DTG = dolutegravir; DXA = dual energy X-ray absorptiometry; EFV = efavirenz; EVG = elvitegravir; INSTI = integrase strand transfer inhibitor; NRTI = nucleoside reverse
transcriptase inhibitor; PI = protease inhibitor; RAL = raltegravir; 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-58
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-63
Table 17i. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—
Nephrotoxic Effects
Updated: June 27, 2024
Reviewed: June 27, 2024

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 urine pH (>5.7) hydration and pain
DRV causes • Weeks to months after starting in <10% of patients • Maintain adequate control. Consider
crystalluria, but it is therapy and has been reported The risk factors in hydration. using another ARV
not associated with after stopping ATV. children are drug in place of
nephrolithiasis. Clinical Findings unknown. Monitoring
ATV.
• 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 urine glucose, and cause, consider
• Variable; in adults, renal • Approximately 2% the Following serum creatinine at using an alternative
dysfunction may occur weeks to of adults experience Characteristics 3- to 6-month ARV drug. TAF has
months after initiating therapy. increased serum intervals. Some significantly less
creatinine levels. • Aged >6 years Panel members toxicity than TDF.
• Hypophosphatemia appears at a
median of 18 months. • Approximately 0.5% • Black race, routinely monitor Changing from TDF
of adults experience Hispanic/Latino serum phosphate to TAF may improve
• Glucosuria may occur after severe renal ethnicity levels in patients who renal function.
1 year of therapy. complications. are taking TDF.
• Advanced HIV
• Abnormal urine infection
protein/osmolality ratio may be
an early indicator.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-64
Table 17i. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Nephrotoxic Effects

Presentation Children • Hypertension Measure serum

phosphate if the
More Common • Approximately 4% • Diabetes patient experiences
of children
• Increased serum creatinine
experience • Concurrent use of persistent proteinuria
levels, proteinuria, and PIs (especially or glucosuria or has
hypophosphatemia symptoms of bone
normoglycemic glucosuria LPV/r) and
or proximal
tubulopathy; preexisting renal pain, muscle pain, or
• Increased urinary weakness.
frequency increases dysfunction
protein/creatinine ratio and
albumin/creatinine ratio with prolonged TDF • Longer duration Because toxicity risk
therapy and of TDF treatment increases with the
• Hypophosphatemia, usually advanced HIV duration of TDF
asymptomatic; may present with infection. • The presence of treatment, do not
bone and muscle pain or muscle the apolipoprotein decrease the
weakness L1 variants G1 frequency of
and G2 appears monitoring over time.
Less Common to increase the
• Renal failure, acute tubular risk of renal
necrosis, Fanconi syndrome, abnormality in
proximal renal tubulopathy, children with HIV.
interstitial nephritis, and These alleles are
nephrogenic diabetes insipidus more common in
with polyuria people of Black
descent.

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
increases by patient about the
Presentation benign nature of the
>0.4 mg/dL or if
• Asymptomatic. These drugs increases continue laboratory
decrease renal tubular secretion over time. abnormality.
of creatinine, leading to an
increase in serum creatinine
levels without a true change in
eGFR.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-65
Table 17i. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Nephrotoxic Effects

• Clinicians need to distinguish

between a true 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-66
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12. Gupta SK, Post FA, Arribas JR, et al. Renal safety of tenofovir alafenamide vs. tenofovir disoproxil fumarate: a pooled analysis of
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13. Judd A, Boyd KL, Stöhr W, et al. Effect of tenofovir disoproxil fumarate on risk of renal abnormality in HIV-1-infected children on
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23. Seo JW, Kim K, Jun KI, et al. Recovery of tenofovir-induced nephrotoxicity following switch from tenofovir disoproxil fumarate to
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-69
Table 17j. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Osteopenia and
Osteoporosis
Updated: April 11, 2023
Reviewed: June 27, 2024

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 prevention
and than −2.0 greater severity of HIV
Osteoporosis Specific Agents • Any age; decrease disease • Ensure that the patient Consider changing the ARV
of Concern in BMD is usually • <10% in U.S. has sufficient intake and regimen (e.g., switching from
seen soon after cohorts Detectable viral load levels of both calcium and TDF to TAF and/or from LPV/r
• TDF, initiating ART. vitamin D. to RPV or an unboosted INSTI
especially • Approximately
10% to 20% in Vitamin D • Encourage weight-bearing whenever possible).
when used in Presentation insufficiency/deficiency
a regimen that international exercise.
• Usually cohorts Supplement with vitamin D3 to
includes a Delayed growth or • Minimize modifiable risk raise serum 25-OH-vitamin D
boosting agent asymptomatic
pubertal delay factors (e.g., smoking, low concentrations to >30 ng/mL.
(i.e., RTV, • Rarely presents as BMI, use of steroids or There is no clear benefit to
COBI) osteoporosis, a Low BMI medroxyprogesterone). administering daily
• PIs (LPV, clinical diagnosis supplemental vitamin D3 doses
defined by Lipodystrophy • Use TAF instead of TDF that are >4,000 IU. If patients
ATV>DRV) whenever possible.
evidence of bone are receiving a daily dose of
• EFV fragility (e.g., a Smoking
• Use TDF with RPV or an vitamin D3 that is >4,000 IU,
fracture with unboosted INSTI. consider monitoring levels of
Prolonged systemic
minimal trauma). 25-OH-vitamin D.
corticosteroid use • When using TDF or EFV
in a regimen, consider An increase in BMD was seen
Medroxyprogesterone
measuring vitamin D in one trial that evaluated the
use
levels and supplementing use of alendronate in youth with
Lack of weight-bearing with vitamin D3 if HIV and low BMD. However, the
exercise deficiency is identified. role of bisphosphonates in
managing osteopenia and
osteoporosis in children with
HIV has not been established.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-70
Table 17j. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Osteopenia and
Osteoporosis

Monitoring
• Assess nutritional intake
(i.e., 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
aDrugs of 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.
bDXA 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-71
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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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/26355674.

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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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/21917867.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-76
Table 17k. Antiretroviral Therapy–Associated Adverse Effects and Management Recommendations—Rash and
Hypersensitivity Reactions
Updated: June 27, 2024
Reviewed: June 27, 2024

Adverse Associated Onset/Clinical Estimated Prevention/

Risk Factors Management
Effects ARVs Manifestations Frequency Monitoring
Rash Any ARV Onset Common • Sulfonamide allergy When Starting NVP or Mild-to-Moderate
drug can (>10%) is a risk factor for Restarting NVP After Maculopapular Rash without
cause rash. • First few days to weeks Interruptions of >14 Days Systemic or Mucosal
rash in patients who
after starting new ARV • EFV Involvement
are taking PIs that
drug(s) • Utilize once-daily lead-in
• ETR contain a
dosing.a This may not be • Most rashes will resolve without
Presentation sulfonamide moiety
• FTC necessary in children intervention; ARV drugs can be
(i.e., DRV).
ages <2 years.b continued while monitoring.a
• Most rashes are mild-to- • NVP
moderate diffuse • Polymorphisms in
• Avoid the use of • Antihistamines may provide
maculopapular CYP2B6 and multiple
Less Common systemic corticosteroids some relief.
eruptions HLA loci are
(5% to 10%) during NVP dose
associated with an Severe Rash and/or Rash
escalation.
Note: A rash can be the • ABC increased risk of rash Accompanied by Systemic
initial manifestation of in patients who are • Assess the patient for Symptoms
• ATV taking NVP. rash severity, mucosal
systemic hypersensitivity
(see the SJS/TEN/EM • DRV involvement, and other • Manage as SJS/TEN/EM major,
major and HSR sections signs of systemic DRESS, or HSR, as applicable
below). • TDF reaction. (see below).

Unusual Rash in Patients Receiving NVP

(2% to 4%)
• Given the elevated risk of HSR,
• BIC measure hepatic
transaminases.
• LPV/r
• If hepatic transaminases are
• MVC
elevated, NVP should be
• RAL discontinued and not
restarted (see the HSR section
• RPV below).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-77
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
SJS/TEN/EM Many ARV Onset Infrequent Adults When Starting NVP or • Discontinue all ARV drugs and
Major drugs, Restarting NVP After other possible causative agents
especially • First few days to weeks • NVP (0.3%) • Female sex Interruptions of >14 Days (e.g., TMP-SMX).
NNRTIs (see after starting new ARV
drug(s) • EFV (0.1%) Patients who are Black, • Utilize once-daily lead-in
the • Provide intensive supportive
• ETR (<0.1%) Asian, or Hispanic are dosing.a This may not be care, including IV hydration,
Estimated
Presentation at higher risk. necessary in children aggressive wound care, eye
Frequency
column) Case Reports aged <2 years.b care, labial adhesion preventive
• Initial rash may be mild,
but it often becomes care, pain management, and
• ABC • Counsel families to
painful, evolving to antipyretics. Parenteral nutrition
report symptoms as
blister/bulla formation • ATV and antibiotics may also be
soon as they appear.
with necrosis in severe necessary.
• DRV
cases. Usually involves • Corticosteroids and/or IVIG are
mucous membrane • LPV/r sometimes used, but the use of
ulceration and/or these interventions is
• RAL
conjunctivitis. controversial.
• ZDV
• Systemic symptoms • Do not reintroduce the
may also include fever, offending medication.
tachycardia, malaise,
myalgia, and arthralgia. • In cases where a patient
experiences SJS/TEN/EM
major while taking an NNRTI,
many experts would avoid using
other NNRTIs when restarting
ART.

DRESS DRV, DTG, Onset Rare • Unknown Obtain a CBC and AST, • Discontinue all ARV drugs and
EFV, ETR, ALT, and creatinine levels other possible causative agents
NVP, RAL, • 1–8 weeks after starting • Potential association from patients who present (e.g., TMP-SMX).
RPV, BIC new ARV drug(s) with HLA-B*53:01 with suggestive symptoms.
and RAL-induced • The role of systemic steroids or
Presentation DRESS IVIG in treatment is unclear;
• Fever consultation with a specialist is
recommended.
• Lymphadenopathy

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-78
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
• Facial swelling • Provide supportive care for end-
organ disease.
• Morbilliform to
polymorphous rash • Do not reintroduce the
offending medication.
• Peripheral eosinophilia
• Atypical circulating
lymphocytes
• Internal organ
involvement (particularly
the liver and/or kidneys)

HSR ABC Onset <1% to 9% • HLA-B*5701 (HSR is • Screen for HLA-B*5701. • Discontinue all ARV drugs and
(varies by very uncommon in ABC should not be investigate other causes of the
With or With First Use
ethnicity) people who are HLA- prescribed if symptoms (e.g., a concurrent
without skin
• Within first 6 weeks of B*5701 negative.) HLA-B*5701 is present. viral illness).
involvement
initiating ABC The medical record
and excluding • The prevalence of • Provide symptomatic treatment.
should clearly indicate
SJS/TEN HLA-B*5701 is
With Reintroduction that ABC is • Most symptoms resolve within
generally lower in contraindicated in
• Within hours of initiating people from Africa 48 hours after discontinuing
these patients. ABC.
ABC and East Asia.
• When starting ABC,
Presentation • Do not rechallenge with ABC
counsel patients and
even if the patient is HLA-
• Symptoms include high families about the signs
B*5701 negative.
fever, diffuse skin rash, and symptoms of HSR to
malaise, nausea, ensure prompt reporting
headache, myalgia, of reactions.
arthralgia, diarrhea,
vomiting, abdominal
pain, pharyngitis, and
respiratory symptoms
(e.g., dyspnea).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-79
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
• 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 Restarting NVP After
• Occurs most frequently average, with a • ARV-naive with a Interruptions of >14 Days • Consider other causes of
in the first few weeks of range of 2.5% to higher CD4 count hepatitis and discontinue all
therapy but can occur (>250 cells/mm3 • A 2-week lead-in period hepatotoxic medications.
11%.
through 18 weeks. in women; with once-daily dosing,
>400 cells/mm3 in followed by dose • Provide supportive care as
Presentation men) escalation to twice daily indicated and monitor the
as recommended, may patient closely.
• Flu-like symptoms • Female sex (risk is reduce the risk of • Do not reintroduce NVP. It is
(including nausea, threefold higher in reaction.a This may not unclear whether it is safe to use
vomiting, myalgia, females than in be necessary in children other NNRTIs after a patient
fatigue, fever, males). aged <2 years.b experiences symptomatic
abdominal pain, and
jaundice) with or without Children • Counsel families about hepatitis due to NVP, and many
skin rash that may signs and symptoms of experts would avoid the NNRTI
progress to hepatic • NVP hepatotoxicity drug class when restarting
HSR to ensure prompt
failure with and HSR are less treatment.
reporting of reactions.
encephalopathy common in
prepubertal children
than in adults, and
both are uncommon
in infants.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-80
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
• High CD4 • Obtain AST and ALT
percentage is levels in patients with
associated with an rash. Obtain AST and
increased risk of ALT levels at baseline,
NVP toxicity. In the before dose escalation,
PREDICT Study, the 2 weeks after dose
risk of NVP toxicity escalation, and
(rash, hepatotoxicity, thereafter at 3-month
and hypersensitivity) intervals.
was 2.65 times
greater in children • Avoid NVP use in
who had CD4 women with CD4 counts
percentages ≥15% >250 cells/mm3 and in
than in children who men with CD4 counts
had CD4 >400 cells/mm3, unless
percentages <15%. benefits outweigh risks.
• Do not use NVP as post-
exposure prophylaxis
outside of the neonatal
period.

ETR Onset Rare Unknown Evaluate for • Discontinue all ARV drugs.
hypersensitivity if the
• Any time during therapy patient is symptomatic. • Rechallenge with ETR is not
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-81
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.
bLead-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 13.1. Drug Dosing Recommendations for Antiretroviral Prophylaxis and Presumptive HIV Therapy in Infants
With In Utero or Intrapartum Exposure to HIV in Antiretroviral Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to HIV.
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*53:01 = human leucocyte antigen gene variant; 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; 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-82
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12. Prasertvit P, Chareonyingwattana A, Wattanakrai P. Nevirapine patch testing in Thai human immunodeficiency virus infected
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection J-85
Management of Children Receiving Antiretroviral
Therapy
Updated: June 27, 2024
Reviewed: June 27, 2024

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 (PK),
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 and

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-1
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,
and offer simplified dosing using coformulated drugs and/or once-daily regimens when appropriate
(see Table 18 below). Clinicians also should consider a child’s ART history, drug-resistance test
results, and ability to swallow tablets. Efforts to increase the availability of coformulated complete
ARV regimens have yielded several once-daily options for children that should be considered. The
International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) 2019 study
demonstrated safety, efficacy, and appropriate dosing of a fixed-dose combination (FDC) tablet
containing abacavir, dolutegravir, and lamivudine (ABC/DTG/3TC) in children aged <12 years, with
use of dispersible tablets (Triumeq PD) or an immediate-release tablet (Triumeq) to be swallowed
depending on the child’s weight.3 For children weighing ≥14 kg who can swallow pills, additional
options include coformulated bictegravir, emtricitabine, and tenofovir alafenamide (BIC/FTC/TAF;
Biktarvy) or FTC/TAF (Descovy) plus DTG, which is a two-pill, once-daily regimen. Additional
coformulated options are available when children reach 25 kg to 35 kg in weight. See Table 18 below
for more information on once-daily options and other coformulated complete ARV regimens. 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 suppression4; emerging evidence also supports the
safety, efficacy, and tolerability of STRs in younger children.5-7 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.

If using an FDC once-daily regimen is not possible, clinicians should determine whether the child’s
ARV regimen could be simplified in other ways. For example, small studies have shown that
children who achieve virologic suppression using twice-daily dosing for certain ARV drugs
(e.g., 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 FDCs 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: 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.8-11

Long-acting injectable (LAI) 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 kg and aged ≥12 years, with viral
suppression (defined as <50 copies/mL), on a stable ARV regimen, without a history of treatment

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-2
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 with adults who stayed on a daily three-drug oral regimen.12,13
Similarly, in the ATLAS-2M and SOLAR trials, injections of CAB and RPV every 2 months were
found to be non-inferior to monthly injections and once-daily ART, respectively.14,15 The IMPAACT
2017 study is currently evaluating CAB and RPV in children aged 12 to 18 years. At 24 weeks of
follow-up, injections of CAB and RPV every 2 months maintained viral suppression, showed
acceptable PK, and demonstrated an acceptable safety profile in 144 adolescents.16 Additionally,
participating youth and their caregivers reported high acceptability of the treatment and a strong
preference for LAI ART over daily oral ART.17 The Panel on Antiretroviral Therapy and Medical
Management of Children Living with HIV (the Panel) notes that questions remain, including whether
there are additional adverse effects specific to the pediatric population, whether a two-drug
nucleoside-sparing regimen for children with significant ARV treatment history18 will be effective,
and what potential implementation challenges will emerge. A single site in the United States has
reported on three adolescents and young adults who experienced viremia while on bimonthly
injections which resolved with monthly injections. Two of the individuals also experienced
postinjection adverse events that self-resolved.19 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 the
Cabotegravir and Rilpivirine sections for additional information about these drugs and the 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 have some data supporting efficacy in pediatric and adult populations. A
two-drug FDC tablet containing 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.20-
22
No equivalent data exist for this drug combination in pediatric patients, although a clinical trial is
underway in children aged 6 to 12 years. 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, 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 to the standard of care in
maintaining virologic suppression at 48 weeks in participants without INSTI or protease inhibitor
(PI) resistance.23 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.
DTG/3TC (Dovato) also has demonstrated non-inferiority to continuation of three- or four-drug
regimens in treatment-experienced adults and those without a history of treatment failure in the
TANGO and SALSA studies, respectively.24,25 In the ongoing DANCE study, DTG/3TC is being
evaluated as an initial regimen in ART-naive adolescents aged 12 to <18 years and weighing ≥25 kg

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-3
and with HIV RNA of 1,000 copies/mL to ≤500,000 copies/mL. Safety and efficacy of DTG/3TC
were comparable to adults, and 22 of 32 participants achieved viral suppression at 96 weeks.26 Based
on these findings, the FDA has approved DTG/3TC in adolescents aged ≥12 years and weighing
≥25 kg as an initial regimen or for those on a stable ART regimen with no history of treatment failure
and no known drug resistance to the individual drugs. The Panel notes that adolescents may have
difficulties adhering to therapy and recommends close monitoring with viral load testing in anyone
on oral two-drug regimens. The Panel does not recommend two-drug regimens for initial ART in
children (see What to Start).

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 to an efavirenz (EFV)-based regimen (NEVEREST 3).27-29
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 BIC), based on studies in adults and emerging evidence of non-inferiority or superiority in
children.30,31 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.32 Results from the younger ODYSSEY cohort of children weighing between 3 kg
and 14 kg also showed superiority of DTG-based ART compared with other regimens, more than
70% of which were PI-based regimens.33 Additionally, several observational studies in sub-Saharan
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.34-36 Similarly, a
retrospective study from six African countries reporting on 7,898 children and adolescents aged 0 to
≤19 years demonstrated that 93% remained virologically suppressed after switching from NNRTI-
and PI-based regimens to DTG-based regimens, and nearly 80% of those previously unsuppressed
achieved viral suppression while on DTG.37 The INSTI-based FDC regimen BIC/FTC/TAF also has
shown efficacy and high rates of long-term viral suppression in adolescents and children >2 years
and weighing 14 kg to <25 kg.38,39 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 RPV40 and doravirine41—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 (TDF), TAF, zidovudine, or ABC; replacing PIs with NNRTIs), including improved lipid

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-4
profiles.42-46 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.40 Additionally, studies in adults have shown improved tolerability, lipid profiles, and
insulin sensitivity in patients who were switched from PIs to INSTIs,47-51 and adults who were
switched from EFV to an INSTI have shown improvement in neuropsychiatric symptoms. One study
in South Africa showed that prevalence of hepatic steatosis decreased from 17% to 3% among
30 adolescents who switched to a DTG-containing regimen but increased from 8% to 16% among
38 adolescents who continued a non-DTG-containing regimen. Additionally, cholesterol and
triglycerides were lower in those who switched to DTG and in whom no excess weight gain was
observed.52 In other studies, 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.53-57
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 with those who continued on TDF.58 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%).20

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, atazanavir/ritonavir)59,60 and monotherapy regimens of
DTG61,62 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.60,63-66

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.). 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.67-71 The evidence that
supports many of these ARV changes is indirect (i.e., 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.

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

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 drug 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 for more information.

3TC Twice Daily Aged ≥3 years 3TC once daily See the Lamivudine section for more information.

Any age (starting FTC once daily See the Emtricitabine section for more information.
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.

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
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 the
Cabotegravir section for more information.

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
Weighing ≥35 kg
because DTG was approved for younger ages/lower
weights), 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.

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 infants and
children aged ≥3 months and weighing ≥6 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). 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 ABC/DTG/3TC Once-daily dosing. Dispersible tablets with dosage for use in
(Triumeq PD) children based on weight. Aligns a child’s regimen with an
Weighing ≥6 kg to
efficacious regimen that is used in adults. See the
<25 kg
Dolutegravir section for more information.

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 ≥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 kg 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 the Cabotegravir section for more information.

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.

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
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
infants and children aged ≥3 months and weighing ≥6 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 months ABC/DTG/3TC Once-daily dosing. Dispersible tablets with dosage for use in
(Triumeq PD) children based on weight. Aligns a child’s regimen with an
Weighing ≥6 kg to
efficacious regimen that is used in adults. See the
<25 kg
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
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 kg 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.

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
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 the Cabotegravir section for more information.

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 dispersible FDC for
Weighing >14 kg
children weighing ≥6 kg to 25 kg; in a single-drug film-
coated tablet for children weighing ≥14 kg; or as an FDC
tablet. 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 infants and children aged ≥3 months and
weighing ≥6 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). 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 kg 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 the Cabotegravir section for more information.

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
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 dispersible FDC for
children weighing ≥6 kg to 25 kg; in a single-drug film-
coated tablet for children weighing ≥14 kg; or as an FDC
tablet. 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 infants and children aged ≥3 months and
weighing ≥6 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), 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 kg 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 the Cabotegravir section for more information.

Other
Any Multi-Pill Aged ≥3 months ABC/DTG/3TC Once-daily dosing. Dispersible tablets with dosage for use in
and/or Twice- (Triumeq PD) children based on weight. Aligns a child’s regimen with an
Weighing ≥6 kg to
Daily Regimen efficacious regimen that is used in adults. See the
<25 kg
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 kg to <25 kg and another
for those ≥25 kg.

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
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 the Cabotegravir section for more information.

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.

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 because
Weighing ≥35 kg
DTG is approved for younger ages/lower weights), 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-12
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 DTG/3TC Once-daily, two-drug complete regimen approved in
(Dovato) adolescents and adults with no known mutations associated
Weighing ≥25 kg
with resistance to the individual components who are either
ART-naive or who are virologically suppressed on a stable
ART regimen with no history of treatment failure. Because
adolescents may have difficulties adhering to therapy, close
monitoring with viral load testing is recommended.
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 and their caregivers, it is important to consider childbearing potential and 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 During Pregnancy and When Trying to Conceive, and Appendix C.
Antiretroviral Counseling Guide for Health Care Providers).
bFor 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 in those aged ≥3 months. ABC is not
approved by the U.S. Food and Drug Administration for use in neonates and infants aged <3 months. 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 twice daily ABC in infants aged ≥1 month to <3 months, in consultation with a
pediatric HIV specialist (see the Abacavir section for more information).
cFor 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, NNRTI, or 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-13
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week results of a randomised, open-label, phase 3b, non-inferiority trial. Lancet Infect Dis.
2014;14(7):581-589. Available at: https://pubmed.ncbi.nlm.nih.gov/24908551.

48. 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://pubmed.ncbi.nlm.nih.gov/20467288.

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49. 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://pubmed.ncbi.nlm.nih.gov/22112606.

50. 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://pubmed.ncbi.nlm.nih.gov/31213857.

51. 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-diabetic HIV-infected patients. J Antimicrob Chemother. 2019;74(3):731-738. Available
at: https://pubmed.ncbi.nlm.nih.gov/30541118.

52. Rose PC, De la Rey Nel E, Cotton MF, et al. Decreased hepatic steatosis in South African
adolescents with perinatal HIV switching to dolutegravir-containing regimens. Pediatr Infect
Dis J. 2023;42(7):564-572. Available at: https://pubmed.ncbi.nlm.nih.gov/36917035.

53. Eckard AR, McComsey GA. Weight gain and integrase inhibitors. Curr Opin Infect Dis.
2020;33(1):10-19. Available at: https://pubmed.ncbi.nlm.nih.gov/31789693.

54. Sokhela S, Venter WDF, Bosch B, et al. Final 192-week efficacy and safety results of the
ADVANCE trial, comparing 3 first-line antiretroviral regimens. Open Forum Infect Dis.
2024;11(3):ofae007. Available at: https://pubmed.ncbi.nlm.nih.gov/38529213.

55. Dirajlal-Fargo S, Koay WLA, Levy ME, et al. 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.

56. 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://pubmed.ncbi.nlm.nih.gov/33847305.

57. 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://pubmed.ncbi.nlm.nih.gov/33838004.

58. 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://pubmed.ncbi.nlm.nih.gov/29239893.

59. 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://pubmed.ncbi.nlm.nih.gov/28621159.

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60. 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://pubmed.ncbi.nlm.nih.gov/26709605.

61. 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://pubmed.ncbi.nlm.nih.gov/27029845.

62. 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://pubmed.ncbi.nlm.nih.gov/31891143.

63. 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://pubmed.ncbi.nlm.nih.gov/26888910.

64. 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://pubmed.ncbi.nlm.nih.gov/25397553.

65. 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://pubmed.ncbi.nlm.nih.gov/26781004.

66. 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://pubmed.ncbi.nlm.nih.gov/23190774.

67. 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://pubmed.ncbi.nlm.nih.gov/23782477.

68. 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://pubmed.ncbi.nlm.nih.gov/26713503.

69. Dehority W, Deville JG, Lujan-Zilbermann J, et al. 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://pubmed.ncbi.nlm.nih.gov/23970770.

70. 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://pubmed.ncbi.nlm.nih.gov/16014925.

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71. Kuritzkes DR. Preventing and managing antiretroviral drug resistance. AIDS Patient Care
STDS. 2004;18(5):259-273. Available at: https://pubmed.ncbi.nlm.nih.gov/15186710.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-21
Recognizing and Managing Antiretroviral Treatment
Failure
Updated: June 27, 2024
Reviewed: June 27, 2024

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 (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

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-22
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)–
or raltegravir (RAL)-based regimens—increases the risk of drug resistance.2,3 RAL, a first-generation
integrase strand transfer inhibitor (INSTI), has a low barrier to resistance and requires twice-daily
dosing in children and adolescents; it is the only INSTI approved for use in infants <30 days of age.
For very young infants started on an antiretroviral therapy (ART) regimen with RAL or the NNRTI
nevirapine (NVP), a change to dolutegravir (DTG), a second-generation INSTI, is recommended
after 30 days of age for effective and durable viral suppression (see What to Start: Antiretroviral
Treatment Regimens Recommended for Initial Therapy in Infants and Children with HIV).

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 virologic 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

Poor Immunologic Response Despite Virologic Suppression

Poor immunologic response despite virologic suppression is uncommon in children.16 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. Centers for Disease Control and
Prevention Pediatric HIV CD4 Cell Count/Percentage and HIV-Related Diseases Categorization).
Patients who have very low baseline CD4 T lymphocyte (CD4) cell counts 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.17-19 During the early

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-23
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).20 Among
those with a poor immunologic response at 1 year after 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 [CI], 1.83–8.92). Poor immunologic response dropped to 7% at 2 years and 3% at
3 years in those with continued viral suppression.20 Studies in adults with HIV note that CD4 count
recovery at 1 year and 2 years after initiation of initial therapy is independent of the drug class used
(i.e., boosted protease inhibitor [PI], INSTI, or NNRTI).21

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, tuberculosis [TB], malnutrition, Sjogren’s syndrome,
sarcoidosis, syphilis, cirrhosis, acute viral infections) are independently associated with low CD4
values.22

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. These circumstances, including IRIS, do
not represent ART treatment failure and do not generally require discontinuation or change in
ART.23,24 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.25 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 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-24
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.16 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.26,27

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 (e.g., cardiomyopathy), renal (e.g., 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: AE = adverse effect; ART = antiretroviral therapy; CD4 = CD4 T lymphocyte; HCV = hepatitis C virus;
IRIS = immune reconstitution inflammatory syndrome; TB = tuberculosis; TMP-SMX = trimethoprim-sulfamethoxazole;
ZDV = zidovudine

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-25
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 Management of Medication Toxicity or Intolerance, Appendix A. Pediatric Antiretroviral Drug
Information, and Drug-Resistance Testing in the Adult and Adolescent Antiretroviral Guidelines).
Although many 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.

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 (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 in Appendix A. Pediatric Antiretroviral Drug Information). 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 FDCs 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 address barriers to 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 child’s past and recent drug-resistance
test results, the child’s prior exposure to ARV drugs, whether the child and caregiver is likely to

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-26
adhere to the regimen, and whether the child and caregiver find a particular regimen acceptable.28-32
This process often requires using agents from one or more drug classes that are new to the child.
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 child 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 durable virologic suppression and will likely result in additional drug resistance.
When reviewing results of drug-resistance assays, clinicians should review 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. 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 experienced treatment failure.

The process of switching a patient to a new regimen must include a discussion of treatment
adherence and potential toxicity with the child and the child’s caregivers. This discussion should be
appropriate for the childs’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.33

Therapeutic Options to Achieve Complete Virologic Suppression After Virologic

Failure
ARV regimens should be chosen based on a child’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 child may be constructed.

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).

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.34,35 Second-
generation INSTIs DTG and bictegravir have the advantage of once-daily dosing, small pill size or
dispersible formulations, 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
the Dolutegravir and Bictegravir sections for the latest age and weight indications).36 Caution should
be exercised when considering regimens that include first-generation INSTIs with a lower barrier to

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-27
resistance (e.g., RAL, elvitegravir) in children who are highly treatment experienced as they are less
likely to achieve viral suppression.37

Data from pediatric and adult studies support the efficacy of a regimen that contains a second-
generation INSTI (DTG) plus two nucleoside reverse transcriptase inhibitors (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)38 and Nucleosides And
Darunavir/Dolutegravir in Africa (NADIA)39 trials indicate that DTG is non-inferior to a boosted-PI
regimen when transitioning from a failing NNRTI-based regimen.

In ODYSSEY, 707 children weighing at least 14 kg, with a median age of 12.2 years, were
randomized to DTG-based ART versus standard care for either first-line or second-line treatment.
Fifty-six percent (n = 396) of participants were in the second-line therapy group (ODYSSEY B
cohort), with an enrollment HIV-1 RNA viral load of at least 500 copies/mL. Participants were
randomized 1:1 to either DTG and two NRTIs or second-line standard care (a third new agent and
two NRTIs with at least one NRTI with preserved activity); 98% of those in the standard-care group
received a boosted PI–based regimen. Boosted-PI regimens were 72% boosted lopinavir, 24%
boosted atazanvir, and 1% boosted darunavir. NRTI backbone therapies included abacavir and
lamivudine (3TC) in 65% of participants, tenofovir disoproxil fumarate (TDF) and 3TC or TDF and
emtricitabine (FTC) in 23% of participants, and zidovudine (ZDV) and 3TC in 11% of participants,
and 1% of participants received a different combination. The NRTIs were balanced across the
groups. Across both cohorts, the risk of treatment failure was approximately 40% lower (hazard ratio
0.60; 95% CI, 0.42–0.86) in the DTG-based treatment group than in the standard-care group. Within
the ODYSSEY B cohort at 96 weeks, 32 of 196 participants (16%) in the DTG group had treatment
failures, and 41 of 200 participants (20%) in the standard-care group had treatment failures. Twenty-
nine of the 32 participants in the DTG group with treatment failure had a post-treatment resistance
test available, with 23 of 29 having at least one major mutation after treatment. In the standard-care
cohort, 36 of 40 participants with virologic failure had a major mutation after treatment. In the DTG
group, four participants had an INSTI-related mutation, and three of the four were receiving ZDV
and 3TC. In the standard-care group, two participants had a new PI-related mutation.

In the NADIA trial, adults experiencing virologic failure on a NNRTI plus 3TC or FTC and TDF
regimen were randomized to DTG or darunavir/ritonavir (DRV/r) plus 3TC and secondarily
randomized to either TDF or 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, and the DTG
regimen was non-inferior to the DRV/r regimen. At 96 weeks, 9 of 235 (4%) participants on the DTG
regimen developed DTG resistance, with the majority (6 of 9) also assigned to ZDV. No PI
resistance was developed in the DRV/r group.

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.40,41 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 these are typically better tolerated than PI-based
regimens.34,35,42-44

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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-28
(184V) that can partially reverse the effects of other mutations that confer resistance to ZDV and
TDF.45-47

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.48,49 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.49 There are no studies of NRTI-sparing regimens in children
with virologic failure and multidrug resistance, but an NRTI-sparing regimen may be a reasonable
option for children with extensive NRTI resistance.

Additional Therapeutic Options to Achieve Virologic Suppression When

Multidrug-Resistant Virus Is Present
The NNRTIs etravirine (ETR) and rilpivirine 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.28,50 For this reason, the Panel recommends using
ETR as part of a regimen that includes a boosted PI (see the Etravirine section). Doravirine is a once-
daily NNRTI that retains activity against EFV/NVP-resistant virus and is approved by the U.S. Food
and Drug Administration (FDA) for use in children and adolescents weighing ≥35 kg. Studies have
been completed in adolescents aged 12 to <18 years demonstrating safety and tolerability51,52 (see the
Doravirine section).

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.53,54
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.55-58

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.59 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.60

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 uses, and referral to suitable clinical trials are recommended.

Two agents that inhibit the attachment of the glycoprotein 120 (gp120) 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-29
monoclonal antibody that targets the gp120 attachment area on the CD4 molecule.61,62 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 multidrug-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 163 of 272 (60%) of participants.63 It should be noted
that resistance can develop with incomplete adherence to these new agents, especially when added to
a failing regimen. Although FTR is only approved for adults, research is ongoing to assess safety in
the pediatric population.64

Lenacapavir (LEN) is a capsid inhibitor that is newly FDA approved for heavily treatment-
experienced adults who have limited ARV options due to resistance, safety, or intolerance (see the
Lenacapavir section). A randomized, placebo-controlled, double-blind, multicenter trial (CAPELLA)
evaluated LEN in combination with an optimized background ART regimen in 72 patients with
virologic failure who had multidrug-resistant HIV-1 (resistance to at least two antiretroviral
medications from at least three main drug classes).65 Although open to patients age ≥12 years, the
youngest patient enrolled was 23 years. The results showed that in cohort one, 21 of 24 (88%)
patients in the LEN group had a decrease of at least 0·5 log10 copies/mL in viral load by Day 15, as
compared to 2 of 12 patients (17%) in the placebo group (P < 0.001); 81% of patients in the LEN
group achieved durable viral suppression through 26 weeks of LEN plus an optimized background
ART regimen. None of the patients developed serious adverse events related to LEN. Those
receiving LEN had a greater reduction from baseline in viral load than those who received placebo.
Eight participants of 72 enrolled developed LEN resistance.66

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
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.67 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 FTC) monotherapy-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-30
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.68

Complete treatment interruption also has been associated with immunologic declines and poor
clinical outcomes69,70; 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 child’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
NNRTIs 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 emtricitabine and lamivudine is present, these
medications should be continued if the new regimen contains tenofovir disoproxil fumarate, tenofovir
alafenamide, or zidovudine. 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). When modifying ARV regimens in children with chronic hepatitis B/HIV coinfection,
the new regimen must contain agents active against hepatitis B. 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.

Prior Failed Regimen New Regimen Optionsa,b

Two NRTIs Plus an NNRTI Preferred Regimen
• Two NRTIs plus a second-generation INSTI (BIC or DTG)c

Alternative Regimen(s)
• Two NRTIs plus a boosted PI

Two NRTIs Plus a PI Preferred Regimen

• Two NRTIs plus a second-generation INSTI (BIC or DTG)c

Alternative Regimen(s)
• DTG plus a different boosted PI and with or without NRTI(s)
Two NRTIs Plus an INSTI • Two NRTIs plus a boosted PI
• Second-generation INSTI (DTGc or BICc if not used in the prior regimen) with
a boosted PI with or without NRTI(s). DTG may need to be given twice daily
if a patient has certain documented INSTI mutations, or if there is concern
about certain mutations (see the Dolutegravir section for dosing instructions).
• Two NRTIs plus an NNRTId

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-31
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
Failed Regimen(s) That Included If NRTIs Are Fully Active
NRTI(s), NNRTI(s), and PI(s)
• Second-generation INSTI (DTG or BIC)c plus two NRTIs

If NRTIs Are Not Fully Activeb

• Second-generation INSTI plus TAF/FTC or TDF/XTC if able to take TAF or
TDF
• Second-generation INSTI plus two NRTIs with a boosted PI
• Second-generation INSTI with a boosted PI (based on resistance results).
Consider ETR or RPV based on resistance results, age, and weight.
• Consider MVC if additional active drug(s) are needed.
• Consider off-label use of approved agents or enrollment in clinical trials for
novel antiretroviral treatments.
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 and their caregivers, it is important to consider childbearing potential and 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 During Pregnancy and When Trying to Conceive, and Appendix C.
Antiretroviral Counseling Guide for Health Care Providers).
bWhen modifying ARV regimens in children with chronic hepatitis B/HIV coinfection, the new regimen must contain agents
active against hepatitis B.
c RAL, a first-generation INSTI, has a low barrier to resistance and requires twice-daily dosing in children and adolescents; the
second-generation INSTIs BIC and DTG have a higher barrier to resistance and only require once-daily dosing. Many Panel
members would use BIC/FTC/TAF (Biktarvy) in patients with prior treatment failure who have virus with the M184 mutation (see
the Bictegravir section).
dNNRTIs could be an option in younger patients with no exposure to NNRTIs and with taste aversion to boosted PIs, if NRTIs
have preserved activity.
Key: ART = antiretroviral therapy; ARV = antiretroviral; BIC = bictegravir; DTG = dolutegravir; FTC = emtricitabine;
ETR = etravirine; INSTI = integrase strand transfer inhibitor; MVC = maraviroc; NNRTI = non-nucleoside reverse transcriptase
inhibitor; NRTI = nucleoside reverse transcriptase inhibitor; PI = protease inhibitor; RAL = raltegravir; RPV = rilpivirine;
TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate; XTC = 3TC (lamivudine) or FTC

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-32
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42. Viani RM, Alvero C, Fenton T, et al. Safety, pharmacokinetics and efficacy of dolutegravir
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43. Patten G, Puthanakit T, McGowan CC, et al. Raltegravir use and outcomes among children
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44. 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:
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45. 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.
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46. 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://pubmed.ncbi.nlm.nih.gov/9237704.

47. 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://pubmed.ncbi.nlm.nih.gov/15280780.

48. 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://pubmed.ncbi.nlm.nih.gov/21172789.

49. 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://pubmed.ncbi.nlm.nih.gov/26595748.

50. 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://pubmed.ncbi.nlm.nih.gov/33831904.

51. 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://pubmed.ncbi.nlm.nih.gov/36215957.

52. Rungmaitree S, Aurpibul L, Best BM, et al. Efficacy, safety, and tolerability of
doravirine/lamivudine/tenofovir disoproxil fumarate fixed-dose combination tablets in
adolescents living with HIV: results through week 96 from IMPAACT 2014. J Pediatric
Infect Dis Soc. 2023;12(12):602-609. Available at:
https://pubmed.ncbi.nlm.nih.gov/37815035.

53. 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://pubmed.ncbi.nlm.nih.gov/27078121.

54. 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://pubmed.ncbi.nlm.nih.gov/31981458.

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55. Huerta-Garcia G, Vazquez-Rosales JG, Mata-Marin JA, et al. Genotype-guided antiretroviral
regimens in children with multidrug-resistant HIV-1 infection. Pediatr Res. 2016;80(1):54-
59. Available at: https://pubmed.ncbi.nlm.nih.gov/26999770.

56. 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://pubmed.ncbi.nlm.nih.gov/23315674.

57. 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:
https://pubmed.ncbi.nlm.nih.gov/19823069.

58. 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://pubmed.ncbi.nlm.nih.gov/27661787.

59. Kearns GL, Abdel-Rahman SM, Alander SW, et al. Developmental pharmacology-drug
disposition, action, and therapy in infants and children. N Engl J Med. 2003;349(12):1157-
1167. Available at: https://pubmed.ncbi.nlm.nih.gov/13679531.

60. 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://pubmed.ncbi.nlm.nih.gov/17609682.

61. 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://pubmed.ncbi.nlm.nih.gov/30110589.

62. 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://pubmed.ncbi.nlm.nih.gov/32212519.

63. 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://pubmed.ncbi.nlm.nih.gov/33128903.

64. Clinicaltrials.gov. Safety and pharmacokinetics evaluation of fostemsavir + (OBT) in HIV-1

Infected children and adolescents who are failing their cART and have dual- or triple-class
antiretroviral resistance. 2024. Available at:
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65. Margot NA, Naik V, VanderVeen L, et al. Resistance analyses in highly treatment-
experienced people with human immunodeficiency virus (HIV) treated with the novel capsid
HIV inhibitor lenacapavir. J Infect Dis. 2022;226(11):1985-1991. Available at:
https://pubmed.ncbi.nlm.nih.gov/36082606.

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66. Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid inhibition with lenacapavir in
multidrug-resistant HIV-1 infection. N Engl J Med. 2022;386(19):1793-1803. Available at:
https://pubmed.ncbi.nlm.nih.gov/35544387.

67. Wong FL, Hsu AJ, Pham PA, et al. Antiretroviral treatment strategies in highly treatment
experienced perinatally HIV-infected youth. Pediatr Infect Dis J. 2012;31(12):1279-1283.
Available at: https://pubmed.ncbi.nlm.nih.gov/22926213.

68. 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://pubmed.ncbi.nlm.nih.gov/28604824.

69. 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://pubmed.ncbi.nlm.nih.gov/18310171.

70. 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://pubmed.ncbi.nlm.nih.gov/26182197.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-39
Antiretroviral Treatment Interruption in Children
with HIV
Updated: June 27, 2024
Reviewed: June 27, 2024

Panel’s Recommendations
• Outside the context of clinical trials, treatment interruptions of antiretroviral therapy (ART) are not recommended for
children.
• Treatment interruption is not recommended as a strategy in clinical settings to confirm diagnosis or to assess remission
or cure (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). See Adherence to Antiretroviral Therapy in Children and Adolescents with HIV (BIII).
• At times, ART may need to be interrupted or changed due to drug-related side effects or toxicity. See Management of
Medication Toxicity or Intolerance for guidance (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

Unplanned Treatment Interruptions

Temporary discontinuation of antiretroviral therapy (ART) may be unavoidable in some situations
that preclude oral intake, such as serious treatment-related toxicity, acute gastrointestinal illnesses, or
planned surgeries. Children might experience interruptions due to antiretroviral (ARV) drugs being
out of stock locally or if they run out of ARV drugs during travel or immigration to the United States.
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, 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-40
RNA levels than participants who had continuous treatment.6 A study from the International
epidemiology Databases to Evaluate AIDS Southern Africa, which includes 53,674 children aged
<16 years, 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% confidence interval [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

The risk of unplanned ART interruptions can be mitigated by clinicians working closely with
families. Providers should provide anticipatory guidance about potential short-term interruptions
(e.g., sleepovers). If a child will be away from home for an extended period of time (e.g., tourism,
education, summer camp), clinicians should help families plan to ensure continuous access to
medications. Some pharmacies are able to dispense up to 90 days of treatment, depending on the
insurance plan. Pharmacies also are often able to dispense additional doses specifically justified
because of travel. Clinicians should review the duration of current prescriptions and anticipate any
dose changes that might be needed due to growth of the child and to determine when the prescribed
refills will terminate. For prolonged travel within the United States, providers either can proactively
order refills at pharmacies close to their travel destinations to ensure they will be in stock or have
medications mailed directly to families at other convenient locations. Alternatively, changing the
ART regimen to incorporate ARV drugs available in the locations where families will be traveling
would make it easier to address cases of lost medications or unanticipated prolonged travel. For
additional information, refer to the Centers for Disease Control and Prevention (CDC) webpage on
Traveling Abroad with Medicine | CDC, as well as the guideline section on Adherence to
Antiretroviral Therapy in Children and Adolescents with HIV.

Unforeseeable events, such as natural disasters or political instability, may occur and displace
children from their primary HIV care programs. See Guidance for Non-HIV-Specialized Providers
Caring for People With HIV Who Have Been Displaced by Disasters (Such as a Hurricane) for
information about how to care for children with HIV who are in these situations.

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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-41
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
Antiretroviral Management of Infants With In Utero, Intrapartum, or Breastfeeding Exposure to
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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-42
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% CI, −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 vs. 8 in the CT arm, with the primary difference being rate of
hospitalizations); however, the arms experienced comparable rates of the CDC 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 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-43
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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:
https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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.

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: Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25742088

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://pubmed.ncbi.nlm.nih.gov/31764816.

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://pubmed.ncbi.nlm.nih.gov/30679439.

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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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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:
https://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: https://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://pubmed.ncbi.nlm.nih.gov/27562743.

29. Bernays S, Paparini S, Seeley J, et al. 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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/29684092.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection K-46
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
Capsid Inhibitors
Lenacapavir

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: June 27, 2024
Reviewed: June 27, 2024

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 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 (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 infants aged <3 months. appetite, and respiratory symptoms (e.g., cough,
shortness of breath).
• However, the Panel on Antiretroviral Therapy and Medical
Management of Children Living with HIV (the Panel) recommends
Special Instructions
ABC 2 mg/kg twice daily for full-term infants from birth through <1
month of age. This recommendation is based on data from • To predict the risk of HSRs, test patients for the
pharmacokinetic (PK) modeling of neonatal ABC dosing to target HLA-B*5701 allele before starting therapy.
adult plasma ABC exposures, and observational data supporting Patients who test positive for the HLA-
safety of ABC in neonates. The World Health Organization B*5701 allele should not be given ABC. Patients
Consolidated Guidelines on HIV Prevention, Testing, Treatment, with no prior HLA-B*5701 testing who are
Service Delivery, and Monitoring Annex 1: Dosages for ARV tolerating ABC do not need to be tested.
Drugs provides weight-band dosing recommendations for full-term
neonates based on the same data. See the 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.
Infant (Aged ≥1 Month to <3 Months) Dose
• ABC and coformulated tablets can be given with
Oral Solution or without food. The oral solution does not require
refrigeration.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-4
 • ABC is not approved by the FDA for use in infants aged • For ABC/DTG/3TC dispersible tablets, fully
<3 months. disperse them in 20 mL of drinking water in the
supplied cup and swirl the suspension so that no
• The Panel recommends ABC 4 mg/kg twice daily in full-term lumps remain. After full dispersion and within 30
infants aged ≥1 month to <3 months. This recommendation is minutes of mixing, administer the oral suspension.
based on modeling data of the ABC 4 mg/kg twice-daily dose Rinse the dosing cup with a small amount of
using PK simulation for full-term infants aged ≥1 month to water and give this additional water to the child to
<3 months. The International Maternal Pediatric Adolescent AIDS ensure that the child takes the full dose and that
Clinical Trials (IMPAACT) P1106 study and two observational no medication remains in the dosing cup.
cohorts provide reassuring data on the safety of ABC in infants ABC/DTG/3TC dispersible tablets should not be
with HIV aged <3 months. See the Approval, Pharmacokinetics in swallowed whole, chewed, cut, or crushed.
Neonates and Infants, and Safety in Neonates and Infants
sections below. • Screen patients for hepatitis B virus (HBV)
infection before using ABC FDC tablets that
Infant and Child (Aged ≥3 Months) Dose contain 3TC. Severe acute exacerbation of HBV
infection can occur when 3TC is discontinued
Oral Solution
(see Lamivudine).
• ABC 8 mg/kg twice daily (maximum 300 mg per dose) or ABC
16 mg/kg once daily (maximum 600 mg per dose)
Metabolism/Elimination
• In infants and young children who are being treated with liquid
formulations of ABC, initiation with once-daily ABC is not generally • ABC is systemically metabolized by alcohol
recommended. The ABC dose can be changed from twice daily to dehydrogenase and glucuronyl transferase.
once daily with the liquid formulation to harmonize with other • The majority of ABC is excreted as metabolites in
antiretroviral drugs administered once daily. urine.
Weight-Band Dosing of ABC Tablets for Children and Abacavir Dosing in Patients with Hepatic
Adolescents Weighing ≥14 kg and <25 kg Impairment
Scored 300-mg ABC Tablet • ABC requires a dose adjustment in patients with
mild hepatic insufficiency and is contraindicated
Weight Twice-Daily Twice-Daily Once-Daily with moderate or severe hepatic insufficiency.
Dose, AM Dose, PM Dose
• Do not use Epzicom, Triumeq PD, or Triumeq (or
14 kg to ½ tablet ½ tablet 1 tablet the generic equivalents of these FDC tablets) in
<20 kg (150 mg) (150 mg) (300 mg) patients with impaired hepatic function because
≥20 kg to ½ tablet 1 tablet 1½ tablets the dose of ABC cannot be adjusted.
<25 kg (150 mg) (300 mg) (450 mg)
Abacavir Dosing in Patients with Renal
Impairment
Child and Adolescent (Weighing ≥ 25 kg) and Adult Dose
• ABC does not require dose adjustment in patients
• ABC 300 mg twice daily or ABC 600 mg once daily with renal impairment.
[Epzicom] Abacavir/Lamivudine • Do not use FDC tablets containing 3TC
(Epzicom, Triumeq PD, Triumeq, or the generic
Child and Adolescent (Weighing ≥ 25 kg) and Adult Dose
equivalents of these FDC tablets) in patients with
• One tablet once daily creatinine clearance (CrCl) <30 mL/min or
patients on dialysis, because the doses of 3TC
[Triumeq PD] Abacavir/Dolutegravir (DTG)/Lamivudine (3TC) cannot be adjusted. Data from FDC DTG/3TC
(Dovato) suggest that patients with a sustained
Child Weighing ≥6 kg to <25 kg and Aged ≥3 Months CrCl of 30–49 mL/min may experience a higher
• Dispersible Triumeq PD tablets are FDA approved for children 3TC exposure and should be monitored for
aged ≥3 months and weighing ≥6 to <25 kg. Triumeq PD is not hematologic toxicities and potential FDC
recommended for children weighing ≥25 kg who are eligible for discontinuation and subsequent adjustment of the
adult Triumeq dosing. treatment regimen. See package inserts for
additional information.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-5
 • Administer the appropriate number of tablets once daily dispersed
in 15-20 mL of water. See Special Instructions below. Triumeq PD
tablets should not be swallowed whole, chewed, cut, or crushed.

Weight-Band Dosing of Triumeq PD Tablets for Children

Weighing ≥6 kg and <25 kg

Number of
Recommended
Weight Triumeq PD
Daily Dose
Tablets

6 kg to <10 kga ABC 180 mg 3a

DTG 15 mg
3TC 90 mg

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

aIn infants weighing 6 to <10 kg dosing only requires 15 mL water.

• 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 (CYP) 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 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 CYP3A 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, such as protease
inhibitors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), that are
metabolized through these pathways.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-6
• 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 (PK) of ABC showed that children on boosted PI LPV/r or NNRTI efavirenz
(EFV) had similar ABC exposures, while concomitant tuberculosis treatment and use of super-
boosting with LPV 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 The clinical significance of
this interaction is unknown.

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 (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
information on 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.

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
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.7-11 In
an observational study of nine cohorts from the International Epidemiology Databases to Evaluate
AIDS (IeDEA) Southern Africa collaboration, 6- and 12-month viral suppression (<400 copies/mL)
rates were evaluated among infants who initiated ART at age <3 months, and were compared with
infants aged <28 and ≥28 days and weighing <3 and ≥3 kg at the time of ART initiation. Viral
suppression at 12 months did not differ by age or weight at the time of ART initiation and it was
slightly lower in infants on ABC (174/329 [53%]) versus in those on ZDV (77/138 [56%]) (adjusted
odds ratio 1.8; 95% confidence interval (CI) 1.0–3.2).12

Pharmacokinetics
Pharmacokinetics in Neonates and Infants
The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) P1106 trial
reported PK data in 25 infants aged <3 months with HIV who were initiated on a median ABC dose
of 10 mg/kg (range, 6–13 mg/kg) twice daily in combination with 3TC and LPV/r after 1 month of

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-8
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 before 15 days of life had substantially
higher exposures than in infants and children and no reported adverse events.14 Higher ABC
exposures in neonates than in infants and children are likely due to slower drug clearance through
immature enzyme pathways.

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).14 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 (area
under the curve from time zero to 12 hours after drug administration; AUC0–12) 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 AUC0–12; however, data in LBW infants are
lacking.14 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.15 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 10–20 mg/kg/dose). 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 studies 14 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.16

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]).5,17-20 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.17-21 Both the 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
A total daily dose of ABC 600 mg can be used safely in a person weighing 25 kg.5 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.22

In the three ABC dosing pediatric trials described above,17-20 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.11 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
formulation could be considered when harmonizing with other antiretroviral drugs administered once
daily, such as 3TC and dolutegravir (DTG).

Recent data from the IMPAACT 2019 clinical trial of dispersible and immediate-release
ABC/DTG/3TC tablets in children with HIV has validated the FDA-approved dosing in infants and
children weighing 10 to <25 kg and established newly proposed dosing of this fixed-dose
combination (FDC) (3 tablets once daily of ABC 60 mg, DTG 5 mg, and 3TC 30 mg dispersed in
15–20 mL of water) in infants aged ≥3 months weighing 6 to <10 kg.(Food and Drug Administration
2023) ABC/DTG/3TC dispersible FDC dosing was developed based on PK and safety data in each
weight band at the originally selected dosing, which aligned with WHO weight band dosing for the
individual ARV agents. Follow-up through 24 weeks confirmed the safety, tolerability, and
virological efficacy of both formulations.23

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.12,13,24 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 multi-dose
treatment.13 In two cohorts of neonates (<1 month 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.14,25 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 IeDEA Southern Africa

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-11
collaboration compared safety outcomes (measured as ABC discontinuations and their reasons)
between infants who started ABC aged <28 days (n = 232) and those aged ≥28 days (n = 605), and
between infants who started ABC with weight <3 kg (n = 53) and those with weight ≥3 kg (n = 784)
at the time of ABC initiation.12ABC discontinuations at 6 and 12 months were not significantly
different in infants who started ART aged <28 days versus ≥28 days or in infants who weighed <3 kg
versus ≥3 kg. ABC discontinuations were less frequent than ZDV discontinuations (adjusted hazard
ratio 0.14, 95% CI 0.10–0.20).12

Safety in Children and Adolescents

ABC has less of an effect on mitochondrial function than the NRTI ZDV7,8 and less bone and renal
toxicity than tenofovir disoproxil fumarate.26,27

Systematic 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.28

Several observational cohort studies, including contemporary cohort analyses, suggest that an
increased risk of cardiovascular disease (CVD) events—such as myocardial infarction, stroke, and
invasive cardiovascular procedure—exists in adults who are currently using ABC or who have
recently used ABC (see Cardiovascular Risk in Nucleoside Reverse Transcriptase Inhibitor Options
as Part of Initial Therapy in the Adult and Adolescent Guidelines); however, other studies have not
substantiated this finding. Limited data are available on the CVD risks associated with ABC use in
children. One cohort study of South African adolescents (385 participants with HIV and 63
participants as 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 suggested that the use of ABC may be a CVD risk factor for young people with
perinatally acquired HIV.29 In a recent prospective study of 101 virally suppressed (≤400 copies/mL)
youth aged 10 to 18 years with HIV and 97 uninfected controls from Uganda, the baseline common
carotid artery intima-media thickness (IMT) was slightly higher in participants with HIV than in
controls (P < 0.01), and pulse wave velocity (PWV) did not differ between groups. In longitudinal
analyses, the longer ART duration was associated with lower PWV in youth with HIV (β =.008 [95%
CI, -.008 to .003]), while ABC use was associated with greater IMT in youth with HIV (β =.043
[95% CI, .012–.074]). These findings suggest that in adolescents with HIV, early prolonged ART
may prevent progression of subclinical vascular disease, while prolonged ABC use may increase it. 30

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-12
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paediatric tablets for African HIV-infected children (CHAPAS-3): an open-label,
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11. Musiime V, Kasirye P, Naidoo-James B, et al. Once vs. twice-daily abacavir and
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12. de Waal R, Rabie H, Technau KG, et al. Abacavir safety and effectiveness in young
infants with HIV in South African observational cohorts. Antivir Ther.
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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, 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://pubmed.ncbi.nlm.nih.gov/34883066.

15. 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

16. Sleasman JW, Robbins BL, Cross SJ, et al. Abacavir pharmacokinetics during chronic
therapy in HIV-1-infected adolescents and young adults. Clin Pharmacol Ther.
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17. 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://pubmed.ncbi.nlm.nih.gov/16732152.

18. 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://pubmed.ncbi.nlm.nih.gov/15865218.

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19. 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://pubmed.ncbi.nlm.nih.gov/20516550.

20. 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://pubmed.ncbi.nlm.nih.gov/21149918.

21. Zhao W, Piana C, Danhof M, et al. Population pharmacokinetics of abacavir in infants,

toddlers and children. Br J Clin Pharmacol. 2013;75(6):1525-1535. Available at:
https://pubmed.ncbi.nlm.nih.gov/23126277.

22. 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.

23. Brooks KM, Kiser JJ, Ziemba L, et al. Pharmacokinetics, safety, and tolerability of
dispersible and immediate-release abacavir, dolutegravir, and lamivudine tablets in
children with HIV (IMPAACT 2019): week 24 results of an open-label, multicentre,
phase 1-2 dose-confirmation study. Lancet HIV. 2023;10(8):e506-e517. Available at:
https://pubmed.ncbi.nlm.nih.gov/37541705.

24. Crichton S, Collins IJ, Turkova A, et al. Abacavir dosing, effectiveness, 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. Bekker A, Decloedt EH, Slade G, et al. 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://pubmed.ncbi.nlm.nih.gov/32697327.

26. 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://pubmed.ncbi.nlm.nih.gov/20431394.

27. 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://pubmed.ncbi.nlm.nih.gov/21606537.

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28. 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-
analysis. Lancet Child Adolesc Health. 2022;6(10):692-704. Available at:
https://pubmed.ncbi.nlm.nih.gov/36058225.

29. 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://pubmed.ncbi.nlm.nih.gov/30156434.

30. Dirajlal-Fargo S, Zhao C, Labbato D, et al. Longitudinal changes in subclinical vascular

disease in Ugandan Youth with human immunodeficiency virus. Clin Infect Dis.
2023;76(3):e599-e606. Available at: https://www.ncbi.nlm.nih.gov/pubmed/36004575.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-16
Emtricitabine (FTC, Emtriva)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 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

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 regard to
• FTC 6 mg/kg once daily (maximum 240 mg per dose). The
food, some FDC tablet formulations that contain FTC
maximum dose of oral solution is higher than the capsule dose
have food requirements.
because a pediatric pharmacokinetic analysis reported that the
plasma exposure for FTC was 20% lower in patients who • FTC oral solution can be kept at room temperature,
received the oral solution than in patients who received the up to 77°F (25°C), if used within 3 months;
capsule formulation. refrigerate oral solution for long-term storage.

Capsules (for Patients Weighing >33 kg) • Screen patients for hepatitis B virus (HBV) infection
before using FTC or FDC tablets that contain FTC.
• FTC 200 mg once daily Severe acute exacerbation of HBV infection can
occur when FTC is discontinued; therefore, hepatic
Adult Dose function and hepatitis B viral load should be
Oral Solution for Patients Who Are Unable to Swallow Capsules monitored for several months after patients with HBV
infection stop taking FTC.
• FTC 240 mg (24 mL) once daily

Capsules Metabolism/Elimination
• FTC 200 mg once daily • No CYP interactions

[Atripla and Generic] Efavirenz/FTC/Tenofovir Disoproxil • Eighty-six percent of FTC is excreted in urine. FTC
Fumarate (TDF) may compete with other compounds that undergo
renal elimination.
Child and Adolescent (Weighing ≥40 kg) and Adult Dose
FTC Dosing in Patients with Hepatic Impairment
• One tablet once daily
• Atripla should be used with caution in patients with
• Take on an empty stomach.
hepatic impairment.
[Biktarvy] Bictegravir/FTC/Tenofovir Alafenamide (TAF) • Biktarvy, Genvoya, Stribild, and Symtuza are not
Neonate or Child (Aged <2 Years and Weighing <14 kg) Dose recommended for use in patients with severe hepatic
impairment.
• No data are available on the appropriate dose of Biktarvy in
children aged <2 years and weighing <14 kg. Studies are • Complera, Descovy, and Odefsey do not require
currently being conducted to identify the appropriate dose for this dose adjustment in mild or moderate hepatic
age and weight group. impairment but should not be used in patients with
severe hepatic impairment because they have not
Child, Adolescent, and Adult Dose been studied in this group.
• One tablet once daily, with or without food. FTC Dosing in Patients with Renal Impairment

Body Weight Dose • Decrease the dose of FTC in patients with impaired
renal function. Consult the manufacturer’s
≥14 kg to <25 kg Bictegravir 30 mg/emtricitabine 120 mg/ prescribing information for recommended dose
tenofovir alafenamide 15 mg adjustments.
≥25 kg Bictegravir 50 mg/emtricitabine 200 mg/ • Do not use the FDC tablets Atripla or Complera in
tenofovir alafenamide 25 mg patients with creatinine clearance (CrCl) <50 mL/min
or in patients who require dialysis.
• Do not use the FDC tablets Truvada or Biktarvy in
patients with CrCl <30 mL/min. Do not use Truvada
in patients who require dialysis.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-18
 • Stribild should not be initiated in patients with
• The U.S. Food and Drug Administration approved Biktarvy for
estimated CrCl <70 mL/min and should be
use only in antiretroviral therapy (ART)–naive patients or to
discontinued in patients with estimated
replace the current antiretroviral (ARV) regimen in patients who
CrCl <50 mL/min.
have been virologically suppressed (HIV RNA <50 copies/mL) on
a stable ARV regimen with no history of treatment failure and no • TAF-containing formulations are not recommended
known mutations associated with resistance to the individual for use in patients with estimated CrCl <30 mL/min.
components of Biktarvy. Some members of the Panel on
Antiretroviral Therapy and Medical Management of Children
Living with HIV recommend the use of Biktarvy in patients with
prior treatment failure and who have virus containing the M184V
mutation.
• See the Bictegravir section for additional information.

[Complera] FTC/Rilpivirine (RPV)/TDF

Child and Adolescent (Aged ≥12 Years and Weighing ≥35 kg) and
Adult Dose
• 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] FTC/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 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-19
 [Genvoya] Elvitegravir/Cobicistat (COBI)/FTC/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] FTC/RPV/TAF
Child and Adolescent (Aged ≥12 Years and Weighing ≥35 kg) and
Adult Dose
• One tablet once daily 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) 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/COBI/FTC/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 (DRV)/COBI/FTC/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 DRV or tenofovir.

[Truvada] 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-20
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 or as a Co-packaged Formulation, by Drug Class, and refer to other sections
of the Drug Appendix for drug interaction information for each individual component of an FDC
tablet.
• 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, 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-21
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. A Swiss cohort study 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.

Efficacy
Following a dose-finding study (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 PK 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 dose of FTC 200 mg once daily. 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-22
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.

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, et al. 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: https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/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.

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:
https://pubmed.ncbi.nlm.nih.gov/21896911.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-24
Lamivudine (3TC, Epivir)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-25
 Dosing Recommendations Selected Adverse Events
Note: See Antiretroviral Management of Infants With In Utero, • Headache
Intrapartum, or Breastfeeding Exposure to HIV and Table 13.1. Drug
Dosing Recommendations for Antiretroviral Prophylaxis and
Special Instructions
Presumptive HIV Therapy in Infants With In Utero or Intrapartum
Exposure to HIV for information about using lamivudine (3TC) to • 3TC and coformulated tablets can be given with
prevent perinatal HIV transmission. and without food.
Neonate (≥32 Weeks Gestation at Birth) and Infant (Birth to • Store 3TC oral solution at room temperature.
<4 Weeks) Dose
• For abacavir (ABC)/dolutegravir (DTG)/3TC
Oral Solution dispersible tablets, fully disperse them in 20 mL
• 3TC 2 mg/kg twice daily of drinking water in the supplied cup and swirl
the suspension so that no lumps remain. After
Infant and Child Dose full dispersion and within 30 minutes of mixing,
administer the oral suspension. Rinse the dosing
• Once-daily dosing of the 3TC oral solution is not recommended cup with a small amount of water and give this
when initiating 3TC oral solution in infants and young children. additional water to the child to ensure that the
Patients can be transitioned to once-daily treatment with the oral child takes the full dose and no medication
solution when they have been stable on twice-daily treatment for remains in the dosing cup. ABC/DTG/3TC
36 weeks and are aged ≥3 years. Please see the note below and dispersible tablets should not be swallowed
refer to the text for more detail. whole, chewed, cut, or 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 3TC.
Aged ≥3 Months to <3 Years Hepatic function and HBV viral load should be
• 3TC 5 mg/kg twice daily of the oral solution (maximum 150 mg monitored for several months after patients with
per dose) HBV infection stop taking 3TC. Patients with
HBV/HIV coinfection who receive Dovato will
Aged ≥3 Years 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 ABC, test patients
for the HLA-B*5701 allele before starting therapy
• 3TC 10 mg/kg once daily of the oral solution (maximum 300 mg to predict the risk of hypersensitivity reactions.
per dose) Patients who test positive for the HLA-
B*5701 allele should not be given an ABC-
Weight-Band Dosing for the 10-mg/mL 3TC Oral Solution in
containing FDC. Patients with no prior HLA-
Children Weighing ≥3 kg
B*5701 testing who are tolerating an ABC-
containing regimen do not need to be tested.
Twice-Daily Dose, Twice-Daily Dose, 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 3TC 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 ZDV should not
be used in patients who have impaired hepatic
• Weight-band dosing (see table below; dose is approximately 3TC
function.
5 mg/kg per day twice daily or 3TC 10 mg/kg once daily)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-26
 • 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
Weight-Band Dosing for the Scored, 150-mg 3TC Tablet in moderate or severe hepatic impairment.
Children Weighing ≥14 kg
• Delstrigo and Dovato do not require dose
Twice-Daily Twice-Daily Once-Daily adjustment in mild or moderate hepatic
Weight impairment but have not been studied in patients
Dose, AM Dose, PM Dose
and so are not recommended with severe
14 kg to <20 kg ½ tablet ½ tablet 1 tablet hepatic impairment.
(75 mg) (75 mg) (150 mg)
3TC Dosing in Patients with Renal Impairment
≥20 kg to <25 kg ½ tablet 1 tablet 1½ tablets
(75 mg) (150 mg) (225 mg) • Dose adjustment of 3TC is required for patients
with renal insufficiency.
≥25 kg 1 tablet 1 tablet 2 tablets
(150 mg) (150 mg) (300 mg) • Do not use FDC tablets containing 3TC in
patients with creatinine clearance <30 mL/min or
Note: The Panel on Antiretroviral Therapy and Medical Management of patients on dialysis, because the doses of 3TC
Children Living with HIV (the Panel) supports switching from twice-daily cannot be adjusted. Data from the FDC
dosing to once-daily dosing of 3TC (using the oral solution or tablets) in DTG/3TC (Dovato) suggest that patients with a
children aged ≥3 years who have been clinically stable for 36 weeks sustained creatinine clearance 30–49 mL/min
with undetectable viral loads and stable CD4 T lymphocyte cell counts. may experience a higher 3TC exposure and
Clinicians should choose a once-daily regimen using the once-daily should be monitored for hematologic toxicities
dose of 3TC indicated above (approximately 3TC 10 mg/kg, with a and potential FDC discontinuation and
maximum of 3TC 300 mg once daily). subsequent adjustment of the treatment
regimen. See package inserts for additional
Child and Adolescent (Weighing ≥25 kg) and Adult Dose information.
• 3TC 150 mg twice daily; or
• 3TC 300 mg once daily

[Cimduo] 3TC/Tenofovir Disoproxil Fumarate (TDF)

Child and Adolescent (Weighing >35 kg) and Adult Dose
• One tablet once daily

[Combivir and Generic] 3TC/Zidovudine (ZDV)

Child and Adolescent (Weighing ≥30 kg) and Adult Dose
• One tablet twice daily

[Delstrigo] Doravirine/3TC/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] DTG/3TC
Adult Dose
• One tablet once daily with or without food as a complete ARV
regimen in antiretroviral therapy (ART)–naive adults with no known

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-27
 mutations associated with resistance to the individual components of
Dovato
• 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] ABC/3TC
Child and Adolescent (Weighing ≥25 kg) and Adult Dose
• One tablet once daily

[Symfi] Efavirenz (EFV) 600 mg/3TC/TDF

Child and Adolescent (Weighing ≥40 kg) and Adult Dose
• One tablet once daily on an empty stomach

[Symfi Lo] EFV 400 mg/3TC/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 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] 3TC/TDF
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• One tablet once daily

[Triumeq PD] ABC/DTG/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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-28
 Weight-Band Dosing of Triumeq PD Tablets for Children Weighing
≥6 kg

Recommended Daily Number of Triumeq

Weight
Dose PD Tablets
6 kg to <10 kg* ABC 180 mg 3
DTG 15 mg
3TC 90 mg
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
≥25 kg Use Triumeq (see below)
* Investigational dose (see above).
• For use in children who are ARV-naive or ARV-experienced (but
integrase strand transfer inhibitor [INSTI]-naive) and who are not
being treated with uridine diphosphate glucuronosyltransferase 1A1
(UGT1A1) or cytochrome P450 (CYP) 3A inducers

[Triumeq] ABC/DTG/3TC
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 INSTI-naive) and who are not being treated with
UGT1A1 or CYP3A inducers.

[Trizivir and Generic] ABC/3TC/ZDV

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).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-29
• 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 or as a Co-packaged
Formulation, by Drug Class 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
• 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-30
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

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 PK 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 compared with 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 PK 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-31
when used with liquid ABC. The Panel does not recommend using a once-daily dose of 3TC until a
child is aged ≥3 years. After 3 years of age, switching to once-daily dosing with the liquid
formulation could be considered when harmonizing with other ARV drugs administered once daily,
such as ABC and dolutegravir (DTG).

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 (AUC0–24h) values that are similar to those seen
in patients taking 3TC 4 mg/kg twice daily, but minimum blood plasma concentration (Cmin) values
are significantly lower and maximum blood plasma concentration (Cmax) values are significantly
higher in children aged 1 year to 18 years.19 Intensive PK 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
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. AUC0–24h 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 AUC0–24h 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 non-inferior to) those of twice-daily
3TC.22

All four of the studies discussed above enrolled patients who had 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-32
Recent data from the IMPAACT 2019 clinical trial of dispersible and immediate-release
ABC/DTG/3TC tablets in children with HIV has confirmed the FDA-approved dosing in infants and
children weighing 10 to <25 kg and confirmed newly proposed dosing of this FDC (three tablets
once daily of ABC 60 mg, DTG 5 mg, and 3TC 30 mg dispersed in 15–20 mL of water) in infants
weighing 6 to <10 kg. ABC/DTG/3TC dispersible FDC dosing was confirmed based on PK and
safety data in each weight band at the originally selected dosing, which aligned with WHO
weight-band dosing for the individual ARV agents. Follow-up through 24 weeks confirmed the
safety, tolerability, and virological efficacy of both formulations. The dosing guidance for infants
weighing 6 to <10 kg is awaiting regulatory approval.29

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-33
References
1. Anderson PL, Lamba J, Aquilante CL, et al. 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: https://pubmed.ncbi.nlm.nih.gov/16791115.

2. Rokx C, Gras L, van de Vijver D, et al. 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: https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/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. J
Acquir Immune Defic Syndr. 2005;39(2):189-194. Available at:
https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/9835513.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-34
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: https://pubmed.ncbi.nlm.nih.gov/10659875.

12. Scherpbier HJ, Bekker V, van Leth F, et al. 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: https://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/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/DevelopmentResources
/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://pubmed.ncbi.nlm.nih.gov/29150845.

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: https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/21149918.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-35
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:
https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/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;jsessionid=3
1285037F69DEBBDEE7C08D16ADD48F7?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: https://pubmed.ncbi.nlm.nih.gov/18316996.

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

29. Brooks KM, Kiser JJ, Ziemba L, et al. Pharmacokinetics, safety, and tolerability of
dispersible and immediate-release abacavir, dolutegravir, and lamivudine tablets in children
with HIV (IMPAACT 2019): week 24 results of an open-label, multicentre, phase 1-2 dose-
confirmation study. Lancet HIV. 2023;10(8):e506-e517. Available at:
https://pubmed.ncbi.nlm.nih.gov/37541705.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-36
Tenofovir Alafenamide (TAF, Vemlidy)
Updated: June 27, 2024
Reviewed: June 27, 2024

Formulations
Tablet: 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. • Measure serum creatinine before starting a TAF-
Studies are currently being conducted to identify the containing regimen.
appropriate dose for this age and weight group.
• Screen patients for hepatitis B virus (HBV) infection
Child (Aged ≥2 years), Adolescent, and Adult Dose before initiating TAF. Severe acute exacerbation of
HBV infection can occur when TAF is discontinued;
• One tablet once daily, with or without food.
therefore, hepatic function should be monitored for
several months after patients with HBV infection stop
Body Weight Dose taking TAF.
≥14 kg to <25 kg BIC 30 mg/FTC 120 mg/TAF 15 mg • 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-36
 • 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
the virus with the M184V mutation. See the Bictegravir section TAF Dosing in Patients with Hepatic Impairment
for 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-37
 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, increased both TAF and TFV exposures. Coadministration of TAF with
darunavir/ritonavir (DRV/r) resulted in unchanged TAF area under the curve (AUC) and doubled

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-38
 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
OATP1B1 and OATP1B3. 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-39
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 200 mg, RPV 25 mg, and TAF 25 mg
(FTC/RPV/TAF), is approved by the FDA7 for use in children who weigh ≥35 kg. Genvoya, an FDC
tablet that contains EVG 150 mg, COBI 150 mg, FTC 200 mg, and TAF 10 mg (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.10,11-13 Symtuza, an FDC tablet that contains DRV 800 mg, COBI 150 mg, FTC
200 mg, and TAF 10 mg (DRV/c/FTC/TAF) is approved by the FDA10 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 people 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). FTC/TAF available formulations
contain either TAF 15 mg (for children weighing 14 to <25 kg) or TAF 25 mg (for weight ≥25 kg),
but neither formulation should be used in children weighing <35 kg in combination with PIs that
require boosting with RTV or COBI. Both EVG/c/FTC/TAF and DRV/c/FTC/TAF contain TAF 10
mg, whereas FTC/RPV/TAF contains 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 people weighing ≥25 kg. COBI boosts TAF blood concentrations and tenofovir
diphosphate (TFV-DP) intracellular exposure after TAF administration. Therefore, in people
weighing ≥25 kg, administration of EVG/c/FTC/TAF, which contains TAF 10 mg and COBI,

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-40
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
absorbed12,13 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).14 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.15,16 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.17 Once inside the
cell, TAF is hydrolyzed to TFV,18,19 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.15 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). In a combined analysis of two
randomized crossover directly observed therapy studies of FTC/TAF (200 mg/25 mg) versus
FTC/TDF (200 mg/300 mg) in adults without HIV, FTC/TAF produced 6.7- to 7.3-fold higher

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-42
TFV-DP in peripheral blood mononuclear cells (PBMCs) compared to FTC/TDF across adherence
levels (33%, 67%, or 100%). Additionally, the half-life of TFV-DP in PBMCs appeared numerically
but not significantly 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). These data support a conclusion of increased potency and
pharmacological forgiveness with FTC/TAF over FTC/TDF in the PBMC compartment.20

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.17,21 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).22 High plasma TFV concentration also has been closely associated with both
glomerular22-24 and proximal tubular25 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 AUCtau (ng·h/mL) 267.7 (26.7) 1,918.0 (39.4)

Plasma TFV Cmax (ng/mL) 15.7 (22.1) 252.1 (36.6)

Plasma TFV Ctau (ng/mL) 9.2 (26.1) 38.7 (44.7)

PBMC TFV-DP AUCtau (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:
https://pubmed.ncbi.nlm.nih.gov/23807155.
Key: AUCtau = area under the curve for the dosing interval (i.e., 24 hours); Cmax = peak concentration; Ctau = 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 non-inferior to TDF in its ability to control viral load over 48 to 96 weeks when
used in combination with EVG, COBI, and FTC26-29; with FTC and RPV30; with DRV, COBI, and
FTC31-33; and when TAF and FTC are administered in combination with other ARV drugs.34 In a
switch study of adults who were virologically suppressed on a three-drug regimen that included
abacavir (ABC), FTC/TAF was non-inferior 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
levels35 (−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.36-38

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-43
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 years39 and those
weighing ≥25 kg and aged ≥6 years40 (see the Elvitegravir section for details). In a switch study,
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). Initial evidence in a systematic review suggests good viral
suppression and no obvious safety concerns in children and adolescents on TAF-containing regimens
for more than 24 to 48 weeks.41

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 twofold21 to sevenfold higher than those generated with TDF at clinically
meaningful doses.17,20,26 Higher TFV-DP concentrations result in a stronger antiviral potency17 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.39

Drug Exposure and Safety: All Age Groups

FTC/TAF can be safely combined with DTG or raltegravir without concern for drug interactions (see
Table C below). FTC and TAF also have been safely combined with BIC in the FDC tablet Biktarvy.

Table C. Changes in Tenofovir Alafenamide Pharmacokinetic Parameters in the Presence

of Co-administered Antiretroviral Drugs in Adult Healthy Volunteers

Dosage TAF Dosage Mean Ratio Mean Ratio

Co-administered ARV (Once Daily) (Once Daily) N of TAF Cmax of TAF AUC
(mg) (mg) (90% CI)a (90% CI)a
300 (+100 ritonavir) 10 10 1.77 1.91
Atazanavir
(1.28, 2.44) (1.55, 2.35)

150 8 12 2.83 2.65

Cobicistat
(2.20, 3.65) (2.29, 3.07)

800 (+150 cobicistat) 25b 11 0.93 0.98

(0.72, 1.21) (0.80, 1.19)
Darunavir
800 (+100 ritonavir) 10 10 1.42 1.06
(0.96, 2.09) (0.84, 1.35)

50 10 10 1.24 1.19
Dolutegravir
(0.88, 1.74) (0.96, 1.48)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-44
 Dosage TAF Dosage Mean Ratio Mean Ratio
Co-administered ARV (Once Daily) (Once Daily) N of TAF Cmax of TAF AUC
(mg) (mg) (90% CI)a (90% CI)a
600 40b 11 0.78 0.86
Efavirenz
(0.58, 1.05) (0.72, 1.02)

800 (+200 ritonavir) 10 10 2.19 1.47

Lopinavir
(1.72, 2.79) (1.17, 1.85)

25 25 17 1.01 1.01
Rilpivirine
(0.84, 1.22) (0.94, 1.09)
a Ratio represents concentrations of TAF plus the concomitant drug(s) divided by concentrations of TAF alone.
b Study was conducted with Descovy (emtricitabine [FTC]/TAF).
Source: Table was modified from the U.S. Food and Drug Administration Descovy product label.
Key: ARV = antiretroviral drug; AUC = area under the curve; CI = confidence interval; Cmax = maximum concentration;
TAF = tenofovir alafenamide.
When FTC/TAF, which contains TAF 25 mg, is combined with boosted atazanavir (ATV), DRV, or
lopinavir (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 D below).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-45
Table D. 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 AUC of TFV AUC of
TAF TFV
Regimen TAF-Containing TAF-Containing
AUCa AUCa
Regimen/TAF AUC of 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

TAF is available in FDA-approved adult FDC tablets at dosages of either 10 mg or 25 mg. The initial
clinical trials in adults showing the safety of FTC/TAF with ATV/r or DRV/r used FTC 200 mg/TAF
10 mg.44 However, 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 initially recommended for approval instead of FTC/TAF
10 mg.45 The FDA label 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 either observed or are
expected.”2 The combination of FTC 200 mg/TAF 25 mg was 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 but some FDC tablets for adults (i.e., EVG/c/FTC/TAF and
DRV/c/FTC/TAF) have subsequently been FDA approved with a 10-mg TAF component.8,46

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-46
Drug Exposure and Safety: Aged 12 to 18 Years and Weighing ≥35 kg
A study of FTC/TAF in 18 children and adolescents (aged 12–18 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%).47

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 D above), and that the drug
combination was well tolerated and efficacious over 48 weeks of study.39 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 D above), but
the drug combination was well tolerated and efficacious over 24 weeks of study.40,48 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.49

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 safety and PK studies are ongoing on the use
of these combinations 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.50Therefore, 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-47
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 weeks51 (see the Bictegravir section for details). Safety and PK studies in
children using TAF and FTC with atazanavir/cobicistat or DRV/c are ongoing.50

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.52 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.53 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.54
Based on an adult bioequivalence study, crushed BIC/FTC/TAF may lead to suboptimal FTC and
TAF exposures.55 Thus, crushed BIC/FTC/TAF is not recommended (see the Bictegravir section
for details).

Toxicity
Bone
TAF causes bone toxicity less frequently than TDF.26-28,31-34,56,57 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.26 These differences were
maintained until 96 weeks.29 The clinical importance of these changes in BMD is unclear.

Renal
Studies in adolescents aged 12 to 17 years39 and adults26-28,31,32,34 show that TAF is less frequently
associated with glomerular and renal tubular damage than TDF.58 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.26 These differences persisted until
96 weeks of follow-up.29 Safety of EVG/c/FTC/TAF has been demonstrated in adults with estimated
creatinine clearances between 30 mL/min and 69 mL/min.59 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-48
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
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.60 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.32 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 TDF61-68 (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 TDF62,63; increases in weight
and body mass index (BMI) have been observed in ARV switch studies, as well.64,67,69 In adults, the
effect may be greatest in Black females,63,67 especially if administered in combination with
INSTIs.63,65 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 people with BMI <30 kg/m2 at baseline.61

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-49
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58. Gupta SK, Post FA, Arribas JR, et al. Renal safety of tenofovir alafenamide vs. tenofovir
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59. Pozniak A, Arribas JR, Gathe J, et al. Switching to tenofovir alafenamide, coformulated
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impairment: 48-week results from a single-arm, multicenter, open-label phase 3 study. J
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-57
Tenofovir Disoproxil Fumarate (TDF, Viread)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 or
recommended for use in neonates or infants aged • Decreased bone mineral densitya
<2 years.
Special Instructions
Child (Aged ≥2 Years to <12 Years) and Weighing
≥10 kg Dosea • TDF oral powder formulation is available for patients who are
unable to swallow tablets.
• TDF 8 mg/kg per dose once daily
• TDF oral powder should be measured only with the supplied
dosing scoop: one level scoop = 1 g powder = TDF 40 mg.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-58
 TDF Oral Powder Dosing Table • Mix TDF oral powder with 2–4 oz of soft food that does not
require chewing (e.g., applesauce, yogurt). Administer
TDF Oral Powder immediately after mixing to avoid the bitter taste.
Body Weight
Once-Daily Scoops of Powder
• Do not try to mix the TDF oral powder with liquid. The
10 kg to <12 kg 2 scoops (80 mg) powder may float on the top even after vigorous stirring.
12 kg to <14 kg 2.5 scoops (100 mg) • Although TDF can be administered without food, food
14 kg to <17 kg 3 scoops (120 mg) requirements vary depending on the other ARV drugs
contained in an FDC tablet. Food requirements are listed
17 kg to <19 kg 3.5 scoops (140 mg) with dosing recommendations in Appendix A, Table 2.
19 kg to <22 kg 4 scoops (160 mg) Antiretroviral Fixed-Dose Combination Tablets and
Co-packaged Formulations: Minimum Body Weights and
22 kg to <24 kg 4.5 scoops (180 mg) Considerations for Use in Children and Adolescents.
24 kg to <27 kg 5 scoops (200 mg) • Measure serum creatinine and perform a urine dipstick test
for protein and glucose before starting a TDF-containing
27 kg to <29 kg 5.5 scoops (220 mg)
regimen. Serum creatinine should be monitored, and urine
29 kg to <32 kg 6 scoops (240 mg) should be tested for protein and glucose at intervals during
continued therapy (see Table 17i. Nephrotoxic Effects).
32 kg to <34 kg 6.5 scoops (260 mg) Measure serum phosphate if there is clinical suspicion of
34 kg to <35 kg 7 scoops (280 mg) hypophosphatemia.

≥35 kg 7.5 scoops (300 mg) • Screen patients for hepatitis B virus (HBV) infection before
using TDF. Severe acute exacerbation of HBV infection can
occur when TDF is discontinued; therefore, hepatic function
TDF Tablet Dosing Table should be monitored for several months after patients with
HBV infection stop taking TDF.
TDF Tablet
Body Weight • Tenofovir alafenamide (TAF) is associated with less bone
Once Daily
and renal toxicity than TDF, but it has equal antiviral efficacy.
17 kg to <22 kg 150 mg Do not use TAF and TDF together. Consider switching
22 kg to <28 kg 200 mg from TDF to TAF in appropriate clinical settings.

28 kg to <35 kg 250 mg Metabolism/Elimination

≥35 kg 300 mg TDF Dosing in Patients with Hepatic Impairment
Child and Adolescent (Weighing ≥35 kg)a and Adult • No change in TDF dosing is required for patients with hepatic
Dose impairment.
• TDF 300 mg once daily • Stribild should not be used in patients with severe hepatic
impairment.
[Atripla and Generic] Efavirenz/Emtricitabine/TDF
• Atripla, Symfi, and Symfi Lo should be used with caution in
Child and Adolescent (Weighing ≥40 kg) and Adult Dose patients with hepatic impairment; Symfi and Symfi Lo are not
recommended for use in moderate or severe hepatic
• One tablet once daily
impairment.
• Take on an empty stomach.
TDF Dosing in Patients with Renal Insufficiency
[Cimduo] Lamivudine/TDF
• The tenofovir metabolite of TDF is renally excreted.
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• The dose of TDF should be decreased in patients with
• One tablet once daily impaired renal function (creatinine clearance [CrCl]
<50 mL/min). Consult the manufacturer’s prescribing
information for directions on how to adjust the dose in
accordance with CrCl.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-59
 [Complera] Emtricitabine/Rilpivirine/TDF • The FDCs Atripla, Cimduo, Complera, Delstrigo, Symfi,
Symfi Lo, or Temixys should not be used in patients with
Child and Adolescent (Aged ≥12 Years and Weighing
CrCl <50 mL/min or in patients who require dialysis.
≥35 kg) and Adult Dose
• The FDC Truvada should not be used in patients with CrCl
• One tablet once daily in antiretroviral therapy (ART)–
<30 mL/min or in patients who require dialysis.
naive adults with baseline HIV RNA
≤100,000 copies/mL. This dose of Complera also can • The FDC Stribild should not be initiated in patients with
be used in virologically suppressed (HIV RNA estimated CrCl <70 mL/min and should be discontinued in
<50 copies/mL) adults who are currently on their first or patients with estimated CrCl <50 mL/min.
second regimen and have no history of virologic failure
or resistance to rilpivirine and other antiretroviral (ARV) • FTC and TDF require dosage adjustments in patients with
drugs. these levels of renal impairment, and such adjustments
cannot be achieved with an FDC tablet.
• Administer with a meal of ≥500 calories.

[Delstrigo] Doravirine/Lamivudine/TDF
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• One tablet once daily in ART-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 with no
known mutations associated with resistance to the
individual components of Delstrigo

[Stribild] Elvitegravir/Cobicistat/Emtricitabine/TDF
Adolescent (Weighing >35 kg with a Sexual Maturity
Rating [SMR] of 4 or 5) and Adult Dose
• One tablet once daily in ART-naive adults. 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) on a stable ARV
regimen, with no history of treatment failure, and with no
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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-60
 • 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
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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-61
• Other nucleoside reverse transcriptase inhibitors (NRTIs): 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 should not be coadministered
with TDF, because TDF decreases ATV plasma concentrations. The combination of
atazanavir/ritonavir, darunavir/ritonavir (DRV/r), and lopinavir/ritonavir 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.
Similarly, dolutegravir (DTG) should be taken 2 hours before or 6 hours after taking cation-
containing antacids or laxatives, sucralfate, oral iron supplements, oral calcium supplements, or
buffered medications.3 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 calcinuria 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-62
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.4

In adults, the recommended once-daily dose of TDF 300 mg is highly effective when used in
combination with other antiretroviral (ARV) drugs.5-12 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.6,13 FDA approval of
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.14 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 DTG or
DRV/r.15-17

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 non-inferior to
twice-daily zidovudine-containing ART or stavudine-containing ART over 48 weeks of randomized
treatment.18,19 Virologic success is lower in treatment-experienced patients with extensive multiclass
drug resistance.20-22 In an analysis of genotypic resistance testing performed on 650 unique patients at
a single laboratory in the Republic of South Africa, predicted intermediate or high-level resistance to
TDF was lower for children experiencing virologic failure while on abacavir (ABC)-containing
(8.5%) and zidovudine-containing (9.4%) regimens than those experiencing virologic failure while
on a TDF-containing regimen (24.6%). Clinical data are lacking in children on the efficacy of
switching from a failing regimen containing these NRTIs to a regimen containing TDF.23

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.24 A
modeling study suggests that children and adolescents who are treated with TDF may have higher
intracellular TFV-DP concentrations than adults,25 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.4,26,27

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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-63
Toxicity
Bone Toxicity
TDF administration is associated with decreased BMD in both adults28,29 and children.19,30-32
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).26 Discontinuation of TDF results in partial or complete recovery of BMD.30,33

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.20

TDF administration disrupts vitamin D metabolism,34,35 and the decrease in BMD associated with
TDF initiation was attenuated in adults with coadministration of high doses of vitamin D3 (4,000 IU
daily) and calcium carbonate (1,000 mg daily) for the first 48 weeks of TDF treatment.36 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 D3.34,37 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.38 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.39 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 levels40 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 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,41,42 the Panel favors the use of ABC or TAF over TDF in children with
SMRs 1 to 3.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-64
Renal Toxicity
New-onset renal impairment and worsening renal impairment have been reported in adults43 and
children44,45 receiving TDF. In one study, renal toxicity led to the discontinuation of TDF in 6 of
159 (3.7%) children with HIV who were treated with TDF.22 Although TDF is clearly associated
with a decline in glomerular filtration rate, the effect is generally small, and severe glomerular
toxicity is rare.43,44 Irreversible renal failure is quite rare, but cases have been reported.46

The main target of TDF nephrotoxicity is the renal proximal tubule.44 Case reports highlight the
infrequent but most severe manifestations of renal Fanconi syndrome, hypophosphatemia,
hypocalcemia, diabetes insipidus, myalgias, bone pain, and fractures.47,48

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.49 The risks of TDF-
associated proteinuria and chronic kidney disease increase with the duration of treatment.50,51 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
tubular dysfunction, with the discontinuations occurring between 84 and 156 weeks on TDF
therapy.18 In adults, renal dysfunction is more common when TDF is used in patients with older age
or a pre-existing renal disease52; in children, renal dysfunction may be more common when TDF is
used with boosted PIs than with non-nucleoside reverse transcriptase inhibitors.53

Plasma TFV is the TDF metabolite most closely associated with both glomerular39,54 and proximal
tubular55 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 TDF56 (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.57,58 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-65
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virus infection being treated with tenofovir disoproxil fumarate: a randomized, placebo-
controlled trial. Clin Infect Dis. 2018;66(2):220-228. Available at:
https://pubmed.ncbi.nlm.nih.gov/29020329.

35. 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://pubmed.ncbi.nlm.nih.gov/30260797.

36. 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://pubmed.ncbi.nlm.nih.gov/26075752.

37. 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://pubmed.ncbi.nlm.nih.gov/22267714.

38. 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://pubmed.ncbi.nlm.nih.gov/28902705.

39. 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://pubmed.ncbi.nlm.nih.gov/24002093.

40. Van Welzen BJ, Thielen MAJ, Mudrikova T, et al. 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://pubmed.ncbi.nlm.nih.gov/31021851.

41. 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://pubmed.ncbi.nlm.nih.gov/23032412.

42. 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://pubmed.ncbi.nlm.nih.gov/24072196.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-69
43. Cooper RD, Wiebe N, Smith N, et al. 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://pubmed.ncbi.nlm.nih.gov/20673002.

44. Hall AM. Update on tenofovir toxicity in the kidney. Pediatr Nephrol. 2013;28(7):1011-
1023. Available at: https://pubmed.ncbi.nlm.nih.gov/22878694.

45. 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://pubmed.ncbi.nlm.nih.gov/19561425.

46. Wood SM, Shah SS, Steenhoff AP, et al. Tenofovir-associated nephrotoxicity in two HIV-
infected adolescent males. AIDS Patient Care STDS. 2009;23(1):1-4. Available at:
https://pubmed.ncbi.nlm.nih.gov/19183077.

47. 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://pubmed.ncbi.nlm.nih.gov/16773419.

48. 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://pubmed.ncbi.nlm.nih.gov/23843401.

49. 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://pubmed.ncbi.nlm.nih.gov/17901802.

50. 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: https://pubmed.ncbi.nlm.nih.gov/21076275.

51. 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://pubmed.ncbi.nlm.nih.gov/23249917.

52. 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://pubmed.ncbi.nlm.nih.gov/25826420.

53. 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://pubmed.ncbi.nlm.nih.gov/32634168.

54. 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://pubmed.ncbi.nlm.nih.gov/23196828.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-70
55. 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://pubmed.ncbi.nlm.nih.gov/20299966.

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://pubmed.ncbi.nlm.nih.gov/30932951.

57. Sise ME, Hirsch JS, Canetta PA, et al. Nonalbumin proteinuria predominates in biopsy-
proven tenofovir nephrotoxicity. AIDS. 2015;29(8):941-946. Available at:
https://pubmed.ncbi.nlm.nih.gov/25784440.

58. 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://pubmed.ncbi.nlm.nih.gov/22413854.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-71
Zidovudine (ZDV, Retrovir)
Updated: June 27, 2024
Reviewed: June 27, 2024

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

• [Generic] Lamivudine 150 mg/zidovudine 300 mg (scored)
• [Generic] Abacavir 300 mg/lamivudine 150 mg/zidovudine 300 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

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
Infants With In Utero, Intrapartum, or Breastfeeding Exposure to HIV
and Table 13 for information about using ZDV to prevent • Nausea, vomiting, headache, insomnia, asthenia
perinatal transmission. • Lactic acidosis/severe hepatomegaly with hepatic
steatosis
Recommended Neonatal Dose for Treatment of HIV by
Gestational Age at Birtha • Lipodystrophy and lipoatrophy
• Myopathy (associated with prolonged use of
Gestational ZDV) and myositis
Oral ZDV Dose
Age at Birth
Special Instructions
≥35 Weeks Birth to Age 4 Weeks
• Give ZDV without regard to food.
• ZDV 4 mg/kg twice daily; or
• If substantial granulocytopenia or anemia
• Alternative simplified weight-band dosing develops in patients who are receiving ZDV, it
may be necessary to discontinue therapy until
bone marrow recovery is observed. In this
setting, some patients may require erythropoietin
or filgrastim injections or transfusions of red
blood cells.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-72
 Simplified Weight-Band Dosing for Infants • Screen patients for hepatitis B virus (HBV)
with a Gestational Age ≥35 Weeks at Birth infection before using FDC products that contain
lamivudine (3TC). Severe acute exacerbation of
Note: The doses in this table provide
HBV infection can occur when 3TC is
approximately ZDV 4 mg/kg twice daily from
discontinued; therefore, hepatic function should
birth to age 4 weeks.
be monitored for several months after patients
with HBV infection stop taking 3TC.
Twice-Daily Volume of
Weight Band ZDV 10 mg/mL Syrup
Metabolism/Elimination
2 kg to <3 kg 1 mL • ZDV is eliminated primarily by hepatic
3 kg to <4 kg metabolism. The major metabolite is ZDV
1.5 mL
glucuronide, which is renally excreted.
4 kg to <5 kg 2 mL
• ZDV is phosphorylated intracellularly to active
ZDV triphosphate.
Aged >4 Weeks
• ZDV 12 mg/kg twice daily ZDV Dosing in Patients with Hepatic Impairment

≥30 Weeks to Birth to Age 2 Weeks • The dose of ZDV may need to be reduced in
<35 Weeks patients with hepatic impairment.
• ZDV 2 mg/kg twice daily
• Do not use FDC products in patients who have
Aged 2 Weeks to 6 Weeks impaired hepatic function.
• ZDV 3 mg/kg twice daily ZDV Dosing in Patients with Renal Impairment

Aged >6 Weeks • A dose adjustment is required for ZDV in patients

with renal insufficiency.
• ZDV 12 mg/kg twice daily
• Do not use FDC products in patients with
<30 Weeks Birth to Age 4 Weeks creatinine clearance <50 mL/min and patients
who are on hemodialysis.
• ZDV 2 mg/kg twice daily

Aged 4 Weeks to 8 Weeks

• ZDV 3 mg/kg twice daily

Aged >8 Weeks

• ZDV 12 mg/kg twice daily
Note: For infants who are unable to tolerate oral agents, the
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 ZDV

Weight Twice-Daily Dosing

4 kg to <9 kg 12 mg/kg
9 kg to <30 kg 9 mg/kg
≥30 kg 300 mg

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-73
 Alternative Body Surface Area Dosing
Oral
• ZDV 180–240 mg per m2 of body surface area every 12 hours

Child and Adolescent (Weighing ≥30 kg) and Adult Dose

• ZDV 300 mg twice daily

Lamivudine (3TC)/ZDV
Child and Adolescent (Weighing ≥30 kg) and Adult Dose
• One tablet twice daily

Abacavir/3TC/ZDV
Child and Adolescent (Weighing ≥30 kg) and Adult Dose
• One tablet twice daily
aFor premature infants who receive an HIV diagnosis, the time to change to the continuation dose varies with postgestational
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
(ARV) medications.
• Rare: Possible increased risk of cardiomyopathy.2-4

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-74
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
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
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 (NVP) 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-NRTI 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 Infants With In Utero, Intrapartum,
or Breastfeeding Exposure to HIV 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 are uninfected should continue on the
prophylactic dose for 2 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 postdelivery Day 1 and Day 28, whereas ZDV diphosphate and
ZDV triphosphate remained low throughout the sampling period.14 ZDV dose is poorly correlated

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-75
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 ZDV 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.

Infants with HIV Infection

The Early Infant Treatment Study in Botswana evaluated the safety and efficacy of initiation of ART
in the first week of life. Forty infants who tested positive for HIV within 96 hours of birth were
started on ZDV, 3TC, and 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 postgestational 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 postgestational age of 6 to 8 weeks.
• For infants born at <30 weeks, switch to ZDV 12 mg/kg twice daily at a postgestational age of 8
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 PK 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-76
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 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 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

The PK of intravenous ZDV in a premature neonate with gestational age of 32 weeks on extra
corporal membrane oxygenation (ECMO) has been reported in a single case report. Based on
measurements of ZDV plasma concentrations during and after ECMO, the authors concluded that
ECMO did not have an impact on ZDV PK and that standard intravenous dosing of ZDV can be used
in preterm neonates.19

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.5,6,20 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.21 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 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).21 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 ARV neonatal presumptive therapy with ZDV/3TC/NVP
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 ARV 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 from 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-77
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
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-78
References

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to prevent intrapartum HIV infection. N Engl J Med. 2012;366(25):2368-2379. Available
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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.
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3. Williams PL, Correia K, Karalius B, et al. Cardiac status of perinatally HIV-infected

children: assessing combination antiretroviral regimens in observational studies. AIDS.
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4. McCrary AW, Nyandiko WM, Ellis AM, et al. Early cardiac dysfunction in children and
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5. Balis FM, Pizzo PA, Murphy RF, et al. The pharmacokinetics of zidovudine administered
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https://pubmed.ncbi.nlm.nih.gov/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
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9. Mulenga V, Musiime V, Kekitiinwa A, et al. Abacavir, zidovudine, or stavudine as

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parallel-group, randomised controlled trial. Lancet Infect Dis. 2016;16(2):169-179.
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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://pubmed.ncbi.nlm.nih.gov/11888583.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-79
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:
https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/33464021.

19. Emonts M, Waalewijn H, Colbers A, et al. First reported use of zidovudine for prevention
of perinatal HIV transmission in a premature neonate on extra corporal membrane
oxygenation. AIDS. 2018;32(14):2084-2085. Available at:
https://pubmed.ncbi.nlm.nih.gov/30157085.

20. 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:
https://pubmed.ncbi.nlm.nih.gov/24736440.

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21. 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://pubmed.ncbi.nlm.nih.gov/31033907.

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://pubmed.ncbi.nlm.nih.gov/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 2014. Boston, MA. Available
at: https://www.croiconference.org/wp-content/uploads/sites/2/posters/2014/919.pdf.

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://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/12095385.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-81
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-82
Doravirine (DOR, Pifeltro)
Updated: June 27, 2024
Reviewed: June 27, 2024

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
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

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] DOR/Lamivudine (3TC)/Tenofovir Disoproxil Special Instructions

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.)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-83
 DOR Dosing in Patients with Hepatic Impairment
• Dose adjustment is not required in patients with mild or
moderate hepatic impairment. DOR has not been studied
in patients with severe hepatic impairment.

DOR 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
• 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.5,6
• 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.2,5,6

Major Toxicities
• More common: Nausea, headache, fatigue, diarrhea, abdominal pain, abnormal dreams.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-84
• 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 non-nucleoside reverse transcriptase
inhibitor (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.5,6 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 (FDA) for use in children and
adolescents weighing ≥35 kg.5,6 IMPAACT 2014, a Phase 1/2 study (described below under Efficacy
in Clinical Trials) evaluated the PK, safety, and tolerability of DOR and DOR/3TC/TDF in children
and adolescents with HIV.4

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.7 The efficacy trials included two randomized, multicenter, double-blind, active-controlled
Phase 3 trials (DRIVE-FORWARD and DRIVE-AHEAD) in treatment-naive adults8-11 and one
open-label, active-controlled, randomized noninferiority trial that enrolled virologically suppressed
adults on antiretroviral therapy (DRIVE-SHIFT).12

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.7

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.8 In the DRIVE-AHEAD trial, adult subjects received either coformulated
DOR/3TC/TDF (n = 364) or EFV/FTC/TDF (n = 364) once daily.9 An integrated efficacy analysis

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-85
from both trials (DRIVE-FORWARD and DRIVE-AHEAD) at Week 48 demonstrated that 84.1% of
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.9 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 96.11 At
Week 96 in the DRIVE-FORWARD trial, 277 (95%) of 292 participants who remained on DOR
maintained viral suppression (i.e., 73% of the overall 383 participants), whereas 248 (91%) of 273
participants who remained on DRV/r maintained viral suppression (i.e., 66% of the overall 383
participants).10

In the DRIVE-SHIFT study, adult subjects with HIV who were virologically suppressed for
≥6 months on two nucleoside reverse transcriptase inhibitors 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 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]).12
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 of 438) and 83.7% of
DSG (175 of 209) in FDA snapshot (intent-to-treat) analysis.13

IMPAACT 2014 study data in antiretroviral (ARV)-naive or ARV-experienced virologically

suppressed adolescents suggest favorable antiviral effect comparable to adult data.4 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 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 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.4

Pharmacokinetics
The PK 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.9

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 24.7 In the integrated safety analysis from
the DRIVE-FORWARD and DRIVE-AHEAD trials, 25.5% of patients on DOR-based regimens

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-86
experienced CNS AEs at Week 48, compared with 55.9% of patients on EFV-based regimes.9,14
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 (LDL-C) and non–high density
lipoprotein cholesterol (HDL-C) 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).12 The
reduction in fasting lipids was maintained through Week 144 in the extension arm of the DRIVE-
SHIFT study.13 Similarly, the 96 weeks of data from the DRIVE-FORWARD trial supported greater
mean reductions in LDL-C (−14.6 mg/dL [95% CI, −18.2 to −11.0]) and non–HDL-C (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.10
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 arms11 (−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 3 or 4 AEs, serious AEs, or premature
study drug discontinuation due to AEs.4

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-87
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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/30783000.

3. Greaves W, Wan H, Yee KL, et al. 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://pubmed.ncbi.nlm.nih.gov/31548188.

4. 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://pubmed.ncbi.nlm.nih.gov/36215957.

5. 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.

6. Doravirine [package insert]. Food and Drug Administration. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210806s007lbl.pdf.

7. 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://pubmed.ncbi.nlm.nih.gov/31355775.

8. 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://pubmed.ncbi.nlm.nih.gov/29592840.

9. 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://pubmed.ncbi.nlm.nih.gov/30184165.

10. 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.
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11. Orkin C, Squires KE, Molina JM, et al. Doravirine/lamivudine/tenofovir disoproxil fumarate
(TDF) versus efavirenz/emtricitabine/TDF in treatment-naive adults with human

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 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://pubmed.ncbi.nlm.nih.gov/33336698.

12. 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://pubmed.ncbi.nlm.nih.gov/30985556.

13. 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://pubmed.ncbi.nlm.nih.gov/33633036.

14. 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
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Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-89
Efavirenz (EFV, Sustiva)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 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

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, impaired
Pediatric Dose concentration, agitation, seizures, depression, suicidal
• EFV capsules can be opened and the contents used as ideation, late-onset ataxia, and encephalopathy
a sprinkle preparation for infants and children who are • Gynecomastia
unable to swallow capsules.
• Hepatotoxicity
Infants and Children Aged 3 Months to <3 Years and
• Corrected QT prolongation
Weighing ≥3.5 kg
• Use of EFV may produce false-positive results with some
• The Panel on Antiretroviral Therapy and Medical
cannabinoid and benzodiazepine tests.
Management of Children Living with HIV (the Panel)
does not recommend the use of EFV in children aged
3 months to <3 years due to highly variable Special Instructions
pharmacokinetics in this age group. • EFV capsules and tablets can be swallowed whole, or EFV
capsules can be administered by sprinkling the contents of
an opened capsule on food, as described below.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-90
 Children Aged ≥3 Years and Weighing ≥10 kg • Bedtime dosing is recommended, particularly during the first
2 to 4 weeks of therapy, to improve tolerability of CNS side
Once-Daily Doses of EFV by Weight
effects.

Weight EFV Dosea,b • Administer EFV, Atripla, Symfi, or Symfi Lo on an empty

stomach. Avoid administration with a high-fat meal because
10 kg to <15 kg 200 mg this has the potential to increase absorption.

15 kg to <20 kg 250 mg Instructions for Using the EFV Capsule as a Sprinkle

Preparation with Food or Formula
20 kg to <25 kg 300 mg
• Hold capsule horizontally over a small container and
25 kg to <32.5 kg 350 mg carefully twist open to avoid spillage.
32.5 kg to <40 kg 400 mg • Gently mix capsule contents with 1 to 2 teaspoons of an
600 mg age-appropriate soft food (e.g., applesauce, grape jelly,
≥40 kg
yogurt) or reconstituted infant formula at room temperature.
aThe dose in mg can be dispensed in any combination of
capsule strengths. Capsules may be administered by • Administer within 30 minutes of mixing, and do not consume
sprinkling the contents onto an age-appropriate food (see additional food or formula for 2 hours after administration.
Special Instructions below).
Metabolism/Elimination
bSome experts recommend a dose of EFV 367 mg per m2
of body surface area (maximum dose 600 mg) due to • Cytochrome P450 (CYP) 2B6 is the primary enzyme for EFV
concerns about underdosing at the upper end of each metabolism. CYP2A6, CYP3A4, CYP3A5, and uridine
weight band (see the Pediatric Use section below for diphosphate glucuronosyltransferases also contribute to
details). Weight bands approximate a dose of EFV metabolism.
367 mg per m2 of body surface area, with a maximum
• CYP3A and CYP2B6 inducer in vivo
dose of 600 mg.
• Interpatient variability in EFV exposure can be explained in
Child and Adolescent (Weighing ≥40 kg) and Adult Dose part by polymorphisms in CYP, particularly in CYP2B6.
• EFV 600 mg once daily Slower metabolizers are at higher risk of toxicity. See the
Therapeutic Drug Monitoring section below for information
[Atripla] EFV 600 mg/Emtricitabine/Tenofovir about the management of mild or moderate toxicity.
Disoproxil Fumarate (TDF)
EFV Dosing in Patients with Hepatic Impairment
Child and Adolescent (Weighing ≥40 kg) and Adult Dose
• EFV is not recommended for patients with moderate or
• One tablet once daily severe hepatic impairment.
• Take on an empty stomach. Atripla, Symfi, and Symfi Lo Dosing in Patients with Renal
Impairment
[Symfi] EFV 600 mg/Lamivudine (3TC)/TDF
Child and Adolescent (Weighing ≥40 kg) and Adult Dose • Because Atripla, Symfi, and Symfi Lo are FDC products
containing TDF, lamivudine, and/or emtricitabine that require
• One tablet once daily dose adjustments based on renal function, they should not
be used in patients with creatinine clearance <50 mL/min or
• Take on an empty stomach. in patients on dialysis.
[Symfi Lo] EFV 400 mg/3TC/TDF
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
• One tablet once daily
• Take on an empty stomach.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-91
 Note: Symfi Lo has not been studied in children (sexual
maturity ratings [SMRs] 1–3), and major interindividual
variability in 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. Therapeutic drug
monitoring is suggested by some Panel members when
Symfi Lo is used in pediatric patients weighing ≥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 use) 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-92
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 also has
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 non-inferior 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 that 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
non-inferior 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 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 participants, 31.3% among Black participants, and 34.9% among Hispanic
participants.22 A retrospective study of pediatric patients in a multiethnic, high-income setting

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-93
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 Maternal 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 exposure occurred in those with
the T/T genotype.21,24 Optimal dosing may require pre-treatment CYP2B6 genotyping in children
aged <3 years (see Pharmacokinetics and Dosing: Infants and Children Aged <3 Years 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 (Ctrough) 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 PK 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-94
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. Evaluation of the 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.
Source: 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.
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 participants 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 PK, safety, and efficacy of using capsule sprinkles in children
aged 3 months to 6 years (see Table A above). 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.

In another study, PK data modeling was used to determine the impact of the CYP2B6 genotype in
infants and children, as well as mothers and breastfeeding infants.31 These data were derived from
studies of African populations and included data from IMPAACT P1070. In these models, the FDA-
approved doses of EFV were approximated by the models for dosing in children aged 3 months to <3
years who were EMs. The investigational doses from IMPAACT P1070 were approximated by the
models for dosing in children aged 3 months to <3 years who were SMs.

The Panel does not recommend use of EFV in children aged 3 months to <3 years due to highly
variable PK in this age group.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-95
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, and 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 EFV
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. Antiretroviral Therapy-
Associated Adverse Effects and Management Recommendations—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 non-inferior 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).

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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-96
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 preexisting 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 at 12

hours postdose (C12h) of >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 C12h >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
concentration at 24 hours (C24h) threshold for increased risk of unsuppressed viral load is C24h 0.65
mg/L.60

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-97
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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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/23080225.

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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.

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://pubmed.ncbi.nlm.nih.gov/31241542.

31. Pan X, Rowland Yeo K. Physiologically based pharmacokinetic modeling to determine

the impact of CYP2B6 genotype on efavirenz exposure in children, mothers and
breastfeeding Infants. Clin Pharmacol Ther. 2023;114(1):182-191. Available at:
https://pubmed.ncbi.nlm.nih.gov/37078251.

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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/19635964.

34. Viljoen M, Gous H, Kruger HS, et al. 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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/25937791.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-101
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://pubmed.ncbi.nlm.nih.gov/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
darunavir/ritonavir monotherapy: a randomized, controlled trial (MIDAS). Antivir Ther.
2016;21(4):287-296. Available at: https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/24430534.

42. Dave JA, Cohen K, Micklesfield LK, et al. 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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/16267739.

45. Marzolini C, Telenti A, Decosterd LA, et al. 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://pubmed.ncbi.nlm.nih.gov/11192870.

46. Treisman GJ, Kaplin AI. Neurologic and psychiatric complications of antiretroviral
agents. AIDS. 2002;16(9):1201-1215. Available at:
https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/24522178.

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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://pubmed.ncbi.nlm.nih.gov/30770324.

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://pubmed.ncbi.nlm.nih.gov/23343913.

51. Puthanakit T, Tanpaiboon P, Aurpibul L, et al. 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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/25394021.

55. Napoli AA, Wood JJ, Coumbis JJ, et al. 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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/26715213.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-103
59. Orrell C, Bienczak A, Cohen K, et al. Effect of mid-dose efavirenz concentrations and
CYP2B6 genotype on viral suppression in patients on first-line antiretroviral therapy. Int
J Antimicrob Agents. 2016;47(6):466-472. Available at:
https://pubmed.ncbi.nlm.nih.gov/27211824.

60. 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://pubmed.ncbi.nlm.nih.gov/27116047.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-104
Etravirine (ETR, Intelence)
Updated: June 27, 2024
Reviewed: June 27, 2024

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,
ETR 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-105
 ETR 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.

ETR 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 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-106
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 (FDA) 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 children and adolescents with multi-drug resistant HIV receiving ETR-
based therapy in Spain, 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 of 124 patients) with follow-up data
through 12 months achieved HIV RNA <50 copies/mL, and 80% (99 of 124 patients) 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 through 12 hours postdose (AUC0–12h) and minimum plasma concentration—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 AUC0–12h) remained lower

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-107
in older adolescents than in adults and younger children, and exposures were lower in Asian
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 [C0h]
<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.3

Table A. Pharmacokinetic Parameters in Children, Adolescents, and Adults Receiving

Etravirine Twice Daily with an Optimized Background Regimen, Including a Ritonavir-
Boosted Protease Inhibitor

Mean ETR AUC0–12h Mean ETR C0h

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: AUC0–12h = area under the curve from time zero to 12 hours postdose; C0h = pre-dose concentration; ETR = etravirine

Source: 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://pubmed.ncbi.nlm.nih.gov/27060341.

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 an 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 AUC0–12h 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
AUC0–12h 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 AUC0–12h value seen in adults). However, considerable
intersubject variability was observed, with 5 (33.3%) of 15 participants having AUC0–12h values that
were below the 10th percentile for the adult AUC0–12h range (<2,350 ng·hr/mL). The ETR AUC0–12h
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 who were aged 1 year to <2 years also were enrolled in IMPAACT P1090.
Although the ETR exposures satisfied protocol-defined PK targets (AUC0–12h 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 AUC0–12h 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-108
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.

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) deemed possibly related to
ETR occurred in 13% of pediatric participants and emerged at a median of 10 days, lasting a median
of 7 days. The occurrence of any rash was observed more frequently in female patients (17 of 64
patients; 26.6%) than in male patients (6 of 37 patients; 16.2%).3 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 participant 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-109
References

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etravirine alone and co-administered in HIV-infected patients. J Antimicrob Chemother.
2018;73(3):732-737. Available at: https://pubmed.ncbi.nlm.nih.gov/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:
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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:
https://pubmed.ncbi.nlm.nih.gov/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:
https://pubmed.ncbi.nlm.nih.gov/21395964.

5. European Pregnancy and Paediatric Infections Cohort Collaboration E, Lyons A,

Thompson L, 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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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: https://pubmed.ncbi.nlm.nih.gov/22156961.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-110
Nevirapine (NVP, Viramune)
Updated: June 27, 2024
Reviewed: June 27, 2024

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-111
 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 NVP Dosing in Patients with Hepatic
this dose increase for infants with confirmed HIV infection. 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 NVP Dosing in Patients with Renal Failure
• NVP 200 mg/m2 of BSA per dose twice daily after lead-in dosing.a In 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 absolute dose need not
be decreased as the child reaches age 8 years; rather, the absolute dose
can be left static to achieve the appropriate mg-per-m2 dose as the child
grows, assuming 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 NVP 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-112
 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

NVP Used in Combination with Lopinavir/Ritonavir (LPV/r)

• A higher dose of LPV/r 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.
bSevere life-threatening and, in rare cases, fatal hepatotoxicity—including fulminant and cholestatic hepatitis, hepatic necrosis,
and hepatic failure—has 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-113
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-114
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 log10 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 (PK) 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-115
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-116
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 ng/mL) for 50% of
2-week measurements, 37 of 40 infants (92.5%) had an HIV RNA decline.31 Among this cohort, 38
of 40 participants survived to 96 weeks with a preserved CD4 count and low reservoir, which was
predicted by a low pre-ART reservoir size.32 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-117
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2/3 trial. Lancet Infect Dis. 2011;11(4):273-283. Available at:
https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/20942667.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-119
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://pubmed.ncbi.nlm.nih.gov/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-
infected children. JAMA. 2013;309(17):1803-1809. Available at:
https://pubmed.ncbi.nlm.nih.gov/23632724.

22. Kekitiinwa A, Spyer M, et al. Virologic response to first-line efavirenz- or nevirapine-

based antiretrovial therapy in HIV-infected African children. Pediatr Infect Dis J.
2017;36(6):588-594. Available at: https://pubmed.ncbi.nlm.nih.gov/28505015/

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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/23595153.

28. Magnusson MO, Dahl ML, Cederberg J, et al. 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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/33242457.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-120
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.

32. Ajibola G, Maswabi K, Hughes MD, et al. Brief Report: Long-Term Clinical,
Immunologic, and Virologic Outcomes Among Early-Treated Children With HIV in
Botswana: A Nonrandomized Controlled Clinical Trial. J Acquir Immune Defic Syndr.
2023;92(5):393-398. Available at: https://pubmed.ncbi.nlm.nih.gov/36729692.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-121
Rilpivirine (RPV, Edurant)
Updated: June 27, 2024
Reviewed: June 27, 2024

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-122
 [Complera] Emtricitabine (FTC)/Rilpivirine (RPV)/
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 DTG/RPV is administered with a
regimen in patients who are currently on their first or moderate- or high-fat meal.1 Patients must be able to
second regimen and who have been virologically 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 (DTG)/RPV • 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] FTC/RPV/Tenofovir Alafenamide (TAF)
• Screen patients for hepatitis B virus (HBV) infection
Child and Adolescent (Aged ≥12 Years and Weighing before using FDC tablets that contain TDF or TAF.
≥35 kg) and Adult Dose Severe acute exacerbation of HBV infection can occur
• One tablet once daily with a meal in ART-naive patients when TDF or TAF are discontinued (see the Tenofovir
with HIV RNA ≤100,000 copies/mL. One tablet once daily Disoproxil Fumarate and Tenofovir Alafenamide
also can be used to replace a stable ARV regimen in sections). Therefore, hepatic function and hepatitis B
patients who have been virologically suppressed (HIV RNA viral load should be monitored for several months after
<50 copies/mL) for at least 6 months with no history of therapy with TDF or TAF is discontinued in patients with
treatment failure and no known mutations associated with HBV.
resistance to the individual components of Odefsey. • Refer to the Cabotegravir section for special instructions
when using CAB and RPV for IM injection.
[Cabenuva] Cabotegravir (CAB) and RPV Kit
Child and Adolescent (Aged ≥12 Years and Weighing Metabolism/Elimination
≥35 kg) and Adult Dose
• Cytochrome P450 3A substrate
• Cabenuva is a two-drug co-packaged product for
intramuscular (IM) injection that is approved by the • Refer to the Cabotegravir section for information about
U.S. Food and Drug Administration as a complete regimen the IM CAB and RPV regimen.
for the treatment of HIV-1 in patients with HIV RNA levels
<50 copies/mL on a stable ARV regimen with no history of RPV Dosing in Patients with Hepatic Impairment
treatment failure and no known or suspected resistance to • No dose adjustment is necessary in patients with mild or
CAB or RPV. moderate hepatic impairment.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-123
 • Oral lead-in dosing for at least 28 days can be used to RPV Dosing in Patients with Renal Impairment
assess tolerability prior to initiating IM CAB and RPV
• RPV decreases tubular secretion of creatinine and
injections or patients can proceed directly to IM CAB and
slightly increases measured serum creatinine, but it does
RPV on the last day of their current ARV regimen.
not affect glomerular filtration.
• Refer to the Cabotegravir section for dosing information.
• No dose adjustment is necessary in patients with mild or
• Long-acting CAB and RPV for IM injection are not moderate renal impairment. However, RPV should be
approved for children aged <12 years. used with caution in patients with severe renal
impairment or end-stage renal disease. These patients
should be monitored more frequently for adverse events;
renal dysfunction may alter drug absorption, distribution,
and metabolism, leading to increased RPV
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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-124
Major Toxicities
• More common: Insomnia, headache, rash
• 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 (mcg) adrenocorticotropic hormone
(ACTH) stimulation test (peak cortisol level <18.1 mcg/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 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 people 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 17 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 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-125
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 or want to switch from
a multi-pill regimen and who do not have any drug-resistance mutations associated with 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, maintained and achieved
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-based therapy 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 (PK), 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 adolescents aged >12 years to ≤15 years and 12 adolescents aged >15 years to ≤18 years
underwent intensive PK assessment after they took an observed dose of RPV with a meal. PK were
comparable to those in adults; results are listed in the table below.12

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-126
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

Number of Participants Studied 679 34

AUC24h (ng·h/mL)
Mean ± SD 2,235 ± 851 2,424 ± 1,024

Median (Range) 2,096 (198–7,307) 2,269 (417–5,166)

C0h (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: AUC24h = area under the curve after 24 hours; C0h = plasma concentration just prior to next dose; RPV = rilpivirine;
SD = standard deviation

In a PK study of adolescents and young adults 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 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-127
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
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-other-month IM 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 people initiating treatment.22 IMPAACT study 2017, More Options for Children
and Adolescents (MOCHA), is currently evaluating the safety, tolerability, acceptability, and PK
profile of IM CAB and RPV in adolescents weighing ≥35 kg 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 evaluation of 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-128
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-129
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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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, et al. A case of rilpivirine drug-induced liver injury. Sex
Transm Infect. 2020;96(8):618-619. Available at:
https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/27310962.

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://pubmed.ncbi.nlm.nih.gov/35001501.

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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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/29239893.

17. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release

injectable suspension), co-packaged for intramuscular use [package insert]. Food and Drug
Administration. 2023. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212888s011lbl.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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/33794181.

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://pubmed.ncbi.nlm.nih.gov/33308425.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-131
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://pubmed.ncbi.nlm.nih.gov/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. Available at:
https://www.natap.org/2022/CROI/croi_154.htm.

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. 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://pubmed.ncbi.nlm.nih.gov/28198203.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-132
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-133
Atazanavir (ATV, Reyataz)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 ATVa
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.
ATV Powder Dosing Table for Infants and Children Aged • Because ATV can prolong the PR interval of the
≥3 Months and Weighing ≥15 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,
15 kg to <25 kgb ATV 250 mg (five packets) plus RTV verapamil).
100 mg (powder or tablet) with food
• ATV absorption is dependent on low gastric pH;
therefore, when ATV is administered with medications
Capsule Formulation of ATVa that increase gastric pH, dosing adjustments may be
• ATV capsules are not approved for use in children aged indicated (see the Drug Interactions section in the ATV
<6 years or weighing <15 kg. package insert).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-134
 Atazanavir/Ritonavir (ATV/r) Capsule Dosing Table for • The plasma concentration and, therefore, the therapeutic
Children and Adolescents Aged ≥6 Years and Weighing effect of ATV can be expected to decrease substantially
≥15 kg when ATV is coadministered with proton-pump
inhibitors (PPIs). Antiretroviral therapy (ART)–naive
Weight Once-Daily Dose patients who are receiving any PPI should receive a
dose of that PPI that is equivalent to no more than a
<15 kg Capsules not recommended 20-mg dose of omeprazole. PPIs should be taken
15 kg to <35 kg ATV/r 200 mg/100 mg, both with foodc approximately 12 hours before taking boosted ATV.
Coadministration of ATV with PPIs is not recommended
≥35 kg ATV/r 300 mg/100 mg, both with foodc in ART-experienced patients.
• Patients with hepatitis B or C virus infections and
ART-Naive Patients Who Are Unable to Tolerate RTV patients who have marked elevations in transaminase
Child and Adolescent (Aged ≥13 Years and Weighing levels before treatment may have an increased risk of
≥40 kg) and Adult Dose further elevations in transaminase levels or hepatic
decompensation.
• ATV 400 mg (capsule formulation only) once daily with food
Powder Administration
• ATV powder is not an option because it must be
administered with RTV. • ATV oral powder contains phenylalanine, which can be
harmful to patients with phenylketonuria. Each packet of
• For the capsule formulation, the U.S. Food and Drug oral powder contains 35 mg of phenylalanine.
Administration (FDA) and the Panel on Antiretroviral
Therapy and Medical Management of Children Living with • Mix ATV oral powder with at least 1 tablespoon of soft
HIV (the Panel) do not recommend the use of unboosted food (e.g., applesauce, yogurt). Oral powder mixed with
ATV in children aged <13 years. a beverage (at least 30 mL of milk or water) may be used
for older infants who can drink from a cup. For young
• Although the FDA does allow for unboosted ATV in
infants (aged <6 months) who cannot eat solid food or
adolescents aged ≥13 years and weighing ≥40 kg if they
drink from a cup, oral powder should be mixed with at
are not concurrently taking tenofovir disoproxil
least 10 mL of infant formula and administered using an
fumarate (TDF) or tenofovir alafenamide (TAF), the Panel
oral dosing syringe.
does not recommend the use of unboosted ATV in this
population. Unboosted ATV is not recommended • Administer RTV immediately following powder
because adolescents may require doses of ATV that are administration.
higher than those recommended for use in adults to
achieve target drug concentrations (see Pediatric Use • Administer the entire dose of oral powder within 1 hour of
below). preparation.

ART-Naive and ART-Experienced Patients Metabolism/Elimination

Child and Adolescent (Weighing ≥35 kg) and Adult Dose • ATV is a substrate and inhibitor of cytochrome
• ATV/r 300 mg/100 mg once daily with foodd P450 (CYP) 3A4 and an inhibitor of CYP1A2, CYP2C9,
and uridine diphosphate glucuronosyl transferase 1A1.
• Atazanavir/cobicistat (ATV/c) 300 mg/150 mg once daily
with food, administered as single agents simultaneously or ATV Dosing in Patients with Hepatic Impairment
as the coformulated drug Evotaze
• ATV should be used with caution in patients with mild or
• Both ATV/r and ATV/c must be used in combination with moderate hepatic impairment. Consult the
other antiretroviral drugs. manufacturer’s prescribing information for the dose
adjustment in patients with moderate impairment.
[Evotaz] ATV/c
• ATV should not be used in patients with severe hepatic
Child and Adolescent (Weighing ≥35 kg) and Adult Dose impairment.
• One tablet once daily with food
ATV Dosing in Patients with Renal Impairment
• No dose adjustment is required for patients with renal
impairment.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-135
 • 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, and the effect of tenofovir alafenamide (TAF) on
unboosted ATV is unknown. Thus, only atazanavir/ritonavir (ATV/r) or
atazanavir/cobicistat (ATV/c) should be used in combination with TDF or 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 increase 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 increase gastric pH.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-136
• 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. Because RTV oral solution is no longer
commercially available, use of ATV/r is limited to children weighing ≥15 kg who can use the RTV
100 mg powder packet or 100 mg tablet. ATV coformulated with COBI (as Evotaz) has been
approved by the FDA for use in pediatric patients weighing ≥35 kg.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-137
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 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(Kiser, Fletcher et al. 2008, Kiser, Rutstein et al. 2011)

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 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 (Cmax) was higher and the
minimum plasma concentration (Cmin) was lower in the unboosted arms. Median doses of ATV, both
with and without RTV boosting, from IMPAACT/PACTG 1020A are outlined in Table A 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 PK in ART-
experienced children, concluded that once-daily ATV 400 mg provided suboptimal exposure and that

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-138
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-139
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 to <18 years:

• Weighing 15 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-140
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)
AUCtau μg∙h/mL 49.48 (49.1) 39.96 (52.1) 12.11 (44.7) 9.65 (41.8)
Geometric mean (CV%)
Cmax μg/mL 4.32 (49.9) 3.54 (45.8) 1.28 (31.7) 1.28 (35.6)
Geometric mean (CV%)
Ctau 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; AUCtau = area under the concentration-time curve over the dosing interval; Cmax = maximum serum
concentration; Ctau = 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 PK, 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 years9

• PRINCE-2, which enrolled pediatric patients aged 3 months to <11 years10

In total, 134 treated patients (weighing 5 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 to <10 kg: ATV 150 mg or ATV 200 mg and RTV 80 mg

• Weighing 10 to <15 kg: ATV 200 mg and RTV 80 mg
• Weighing 15 to <25 kg: ATV 250 mg and RTV 80 mg
• Weighing 25 to <35 kg: ATV 300 mg and RTV 100 mg

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-141
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)
C24h 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.
Note: RTV oral solution is no longer available. Use of ATV/r is now limited to children weighing ≥15 mg who can receive 100 mg
RTV using powder or tablets.
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 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-142
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
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-143
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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/26066346.

10. Reyataz (Atazanavir) [package insert]. Food and Drug Administration. 2023. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021567s048,206352s010lbl.pdf

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-144
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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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_Atazanav
ir_Ctrough_is_associated_with_efficacy_and_safety_definition_of_therapeutic_range/links/5
60106c808ae07629e52b5e1/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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. Available at:
https://www.croiconference.org/abstract/pharmacokinetics-safety-and-efficacy-atv-or-drv-
cobi-adolescents.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-145
Darunavir (DRV, Prezista)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 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

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 • Once-daily DRV is not generally recommended for use
≤10 kg. In juvenile rats, DRV caused convulsions and death; in children aged <12 years or weighing <40 kg. Dosing
these events have been attributed to immaturity of the estimates for these patients were based on limited
blood–brain barrier and liver metabolic pathways. data, and limited clinical experience exists with this
dosing schedule in this age group.
Aged ≥3 to <12 Years
• Once-daily DRV should not be used if any one of the
• Dosing recommendations in the table below are for children
following resistance-associated mutations is present:
aged ≥3 to <12 years and weighing ≥20 kg who are
V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V,
antiretroviral therapy–naive or treatment-experienced and
I84V, or L89V.
with or without resistance testing results that demonstrate
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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-146
 Twice-Daily DRV and RTV Doses for Children Aged 3 to <12 • Pediatric dosing requires coadministration of tablets of
Years and Weighing ≥20 kg different strengths to achieve the recommended dose
for each weight band. It is important to provide careful
Dose instructions to caregivers when recommending a
Weight combination of different-strength tablets.
(Twice Daily with Food)a
20 kg to <30 kgb DRV 375 mg (combination of tablets • Store DRV tablets and oral suspension at room
or 3.8 mL)d plus RTV 100 mg (tablet temperature (25º C or 77º F). The suspension must be
or powder)c shaken well before dosing.
30 kg to <40 kgb DRV 450 mg (combination of tablets • Screen patients for hepatitis B virus (HBV) infection
or 4.6 mL)c,d plus RTV 100 mg (tablet before using FDC tablets that contain FTC or TAF.
or powder) Severe acute exacerbation of HBV infection can occur
when FTC or TAF are discontinued; therefore, liver
≥40 kgb DRV 600 mg (tablet or 6 mL) plus function should be monitored for several months after
RTV 100 mg (tablet or powder) patients with HBV infection stop taking FTC or TAF.

Child and Adolescent (Aged ≥12 Years and Weighing Metabolism/Elimination

≥30 to <40 kg) Dose for Treatment-Naive or Treatment-
Experienced Patients with or without at Least One • Cytochrome P450 3A4 substrate and inhibitor
Mutation Associated with DRV Resistance
DRV Dosing in Patients with Hepatic Impairment
• DRV 450 mg (using a combination of tablets) plus RTV
100 mg, both twice daily with food • DRV is primarily metabolized by the liver. Caution
should be used when administering DRV to patients
Child and Adolescent (Aged ≥12 years and Weighing with hepatic impairment. DRV is not recommended in
≥40 kg)d and Adult Dose for Treatment-Naive or Treatment- patients with severe hepatic impairment.
Experienced Patients with No Mutations Associated with
DRV Resistance DRV Dosing in Patients with Renal Impairment

• DRV 800 mg (using a tablet or combination of tablets) plus • No DRV dose adjustment is required in patients with
RTV 100 mg, both once daily with food moderate renal impairment (creatinine clearance [CrCl]
30–60 mL/min).
Child and Adolescent (Weighing ≥40 kg) and Adult Dose • The FDC Symtuza is not recommended for use in
for Treatment-Naive or Treatment-Experienced Patients patients with an estimated CrCl <30 mL/min.
with No Mutations Associated with DRV Resistance
• DRV 800 mg (tablet) plus COBIe 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 DRV Resistance
• DRV 600 mg plus RTV 100 mg, both twice daily with food
• The use of COBI is not recommended with DRV 600 mg
twice daily.

[Prezcobix] DRV/COBI
Child and Adolescent (Weighing ≥40 kg) and Adult Dose for
Treatment-Naive or Treatment-Experienced Patients with No
Mutations Associated with DRV Resistance
• One tablet once daily with food

[Symtuza] DRV/COBI/Emtricitabine (FTC)/ Tenofovir

Alafenamide (TAF)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-147
 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.

aOnce-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).
bRTV oral solution is no longer available. Use of DRV boosted with ritonavir (DRV/r) is now limited to children weighing ≥20 kg
who can receive 100 mg RTV using powder or tablets.
c The volumes for the 375-mg and 450-mg DRV doses are rounded for dosing convenience of suspension.
dSome Panel 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 to <40 kg (see Table B below).
e See Cobicistat 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 aged 13 to 16 years with HIV, both TDF and DRV exposures were lower than
those 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.3 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 to <24 years did not have a significant effect on DRV plasma concentrations.4
When DRV/r was coadministered with ETR twice daily in pediatric patients, target
concentrations for both DRV and ETR were achieved.5 DRV PKs were not affected when
DRV was coadministered with rilpivirine (RPV) in a study of adolescents and young adults.6
DRV/r coadministration increased RPV exposure twofold to threefold; close monitoring for
RPV-related adverse events is advisable.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-148
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, spontaneous bleeding in people with hemophilia, and 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. .
Because RTV oral solution is no longer commercially available, use of DRV/r is limited to children
weighing ≥20 kg who can use the RTV 100 mg powder packet or 100 mg tablet.

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
DRV/c/emtricitabine/tenofovir alafenamide (Symtuza) 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 to <6 years, 17 (81%) of 21 children who received DRV/r twice daily
had viral loads <50 copies/mL at Week 48.7-9

A randomized, open-label, multicenter pediatric trial9 that evaluated twice-daily DRV/r among
80 treatment-experienced children aged 6 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.

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.10 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-149
In one study, 12 participants aged 12 to 17 years received DRV/r once daily.11 After 48 weeks, all but
one participant had viral loads <50 copies/mL.

Pharmacokinetics and Dosing

Pharmacokinetics in Children Aged 3 to <6 Years
Twenty-one children aged 3 to <6 years and weighing 10 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.7,8,12 The DRV area
under the curve from 0-12 hours (AUC0–12h), measured as a percent of the adult AUC value,7,8,13 was
126% overall, 143% in children weighing 10 to <15 kg, and 121% in children weighing 15 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 to <18 years and weighing ≥20 kg.14 Part 1 of the trial used a weight-adjusted
dose of DRV (9–15 mg/kg) and RTV (1.5–2.5 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 (AUC0–24h) that was 81% of
the AUC0–24h observed in adults and a predose concentration (C0h) that was 91% of the C0h 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 to 19 mg/kg and RTV 1.5 to 2.5 mg/kg twice daily. This dose resulted in a DRV AUC0–24h of
123.3 mcg•h/mL (range 71.9–201.5 mcg•h/mL) and a C0h 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 to <30 kg and 30 to <40 kg. The
current weight-band doses of twice-daily DRV/r for treatment-experienced pediatric patients
weighing >20 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 PK
and efficacy of DRV/r once daily administered in combination with abacavir and lamivudine.10 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 study15: 600 mg/100 mg for patients weighing 15 to 30 kg, 675 mg/100 mg for patients
weighing 30 to 40 kg, and 800 mg/100 mg for patients weighing >40 kg. The geometric mean
AUC0–24h 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
dose exceeded the trough plasma concentration recommended for treatment-experienced adults
(0.55 mg/L).16 One child developed neuropsychiatric symptoms (anxiety and hallucinations) and was
removed from study. This child did not have an excessive exposure to DRV; the AUC0–24h was
47.8 mg•h/L.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-150
Table A. Darunavir Pharmacokinetics with Twice-Daily Administration with Ritonavir
and Optimized Background Therapy in Children, Adolescents, and Adults

AUC12h
C0h (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 to <12 Yearsb Determined by weight

24 56.4 3,354
bandsb

Adolescents Aged 12 to <18 Yearsb Determined by weight

50 66.4 4,059
bandsb

Adults Aged >18 Yearsc 285/278/119 600 mg/100 mg 54.7–61.7 3,197–3,539

(Three Studies)
aSource: 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.
bDRV/r was administered at doses of 375 mg/50 mg twice daily for patients weighing 20 to <30 kg, 450 mg/60 mg twice daily for
patients weighing 30 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.
cSource: Darunavir [package insert]. Food and Drug Administration. 2016. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/021976s043,202895s017lbledt.pdf.
Note: RTV oral solution is no longer available. Use of DRV/r is now limited to children weighing ≥20 kg who can receive 100
mg RTV using powder or tablets.
Key: AUC12h = 12-hour area under the curve; C0h = predose 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 to <30 kg), 450 mg (in children weighing 30–
40 kg), and 600 mg (in children weighing ≥40 kg).17 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.14,17
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. No data are available on the
safety and tolerability of using DRV with the RTV 100-mg tablet or powder formulation in children
weighing <20 kg.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-151
Data on the dosing of DRV/c are available primarily for adult patients.18 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.16

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 (area under the curve for the dosing interval
[AUCtau]) that were similar to those observed in adults, except for a lower trough concentration at the
end of the dosing interval (Ctau). The median DRV Ctau (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 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.19

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 to <12 years and weighing 10 to <40 kg.8,20 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 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-152
Table B. U.S. Food and Drug Administration–Approved Once-Daily 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 to
<12 years.

Weight Dose (Once Daily with Food)

15 kg to <30 kg DRV 600 mg (tablet, combination of tablets, or 6 mL) plus RTV 100 mg (tablet or powder)a
30 kg to <40 kg DRV 675 mg (combination of tablets or 6.8 mL)b,c plus RTV 100 mg (tablet or powder)a
≥40 kg DRV 800 mg (tablet, combination of tablets, or 8 mL)c plus RTV 100 mg (tablet or powder)a
a RTV oral solution is no longer available. Use of DRV/r is now limited to children weighing ≥20 kg who can receive 100 mg

RTV using powder or tablets.

b DRV 100 mg/mL oral suspension; the 675-mg once daily DRV dose is rounded for dosing convenience of suspension.
c 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; DRV/r = darunavir/ritonavir; 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 PK were evaluated in treatment-experienced children aged 3 to <12 years as part of a substudy.
After the conclusion of the substudy, the participants switched back to a twice-daily regimen.16,20 The
DRV/r dose for once-daily use, which was based on PK simulation and 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.20,21
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 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,10 the geometric mean AUC0–24h 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 to
<12 years. The Panel makes this recommendation because of the small data set used for 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-153
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)a (n = 335)
DRV AUC0–24h geometric mean, ng•h/mL (SD) 115 (40.6) 89.7 (27.0)
DRV C0h geometric mean, ng/mL (SD) 3,029 (1,715) 2,027 (1,168)
a Source:Kakuda TN, Brochot A, van de Casteele T, et al. 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.

Key: AUC0–24h = 24-hour area under the curve; C0h = predose 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).11 After 48 weeks, 83.3% of patients had
viral loads <50 copies/mL and 91.7% had viral loads <400 copies/mL.11 Interestingly, no relationship
was observed between DRV AUC0–24h and C0h 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/r 800 mg/100 mg was administered to 24
subjects with a median age of 19.5 years (range 14–23 years).22 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

AUC0–24ha C0h (ng/mL)

Population n Dose of DRV/r (mcg•h/L) Median
Median
Adolescents Aged 12–17 Years
(Mean Age 14.6 years)b 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)c
Adults Aged >18 Years
335/280 800 mg/100 mg 87.8–87.9 1,896–2,041
(Two Studies)a
a Source: Darunavir [package insert]. Food and Drug Administration. 2020. Available at:

https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/021976Orig1s063lbl.pdf.
bSource: Kakuda TN, Brochot A, van de Casteele T, et al. 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-154
cSource: 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.

Key: AUC0–24h = 24-hour area under the curve; C0h = predose 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.11,23

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-155
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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/21670182.

3. Mujuru A, Strehalu R, Rakhmanina N, et al. Six-month outcome of F/TAF Cobicistat-

boosted Darunavir in children 14 to <25kg. Presented at: Conference on Retroviruses and
Opportunistic Infections; 2023. Seattle, Washington. Available at:
https://www.croiconference.org/abstract/six-month-outcome-of-f-taf-cobicistat-boosted-
darunavir-in-children-14-to-25kg.

4. 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://pubmed.ncbi.nlm.nih.gov/27199469.

5. 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://pubmed.ncbi.nlm.nih.gov/27103489.

6. 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.
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7. 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://pubmed.ncbi.nlm.nih.gov/25719453.

8. Darunavir (Prezista) [package insert]. Food and Drug Administration. 2023. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/021976s06s068,202895s036l
bl.pdf

9. Darunavir/cobicistat (Prezcobix) [package insert]. Food and Drug Administration. 2023.

Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/205395s025lbl.pdf

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10. 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://pubmed.ncbi.nlm.nih.gov/29474261.

11. 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://pubmed.ncbi.nlm.nih.gov/25361024.

12. Clinical pharmacology review of darunavir [package insert]. Food and Drug
Administration. 2011. Available at:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResou
rces/UCM287674.pdf

13. Food and Drug Administration. Clinical pharmacology review of darunavir. 2011.
Available at:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResou
rces/UCM287674.pdf

14. 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://pubmed.ncbi.nlm.nih.gov/19724191.

15. 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://pubmed.ncbi.nlm.nih.gov/26312164.

16. Kakuda TN, Brochot A, Tomaka FL, et al. Pharmacokinetics and pharmacodynamics of
boosted once-daily darunavir. J Antimicrob Chemother. 2014;69(10):2591-2605.
Available at: https://pubmed.ncbi.nlm.nih.gov/24951533.

17. 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://pubmed.ncbi.nlm.nih.gov/22954687.

18. Cobicistat (Tybost) [package insert]. Food and Drug Administration. 2021. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2021/203094s016lbl.pdf.

19. 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:
http://www.croiconference.org/sessions/pharmacokinetics-safety-and-efficacy-atv-or-drv-
cobi-adolescents.

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20. Prezista drug label. Clinical review of darunavir [package insert]. Food and Drug
Administration. 2012. Available at:
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DevelopmentResou
rces/UCM346671.pdf.

21. Kakuda TN, Brochot A, van de Casteele T, et al. 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: http://www.natap.org/2013/Pharm/Pharm_19.htm.

22. 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. Available at.

23. 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://pubmed.ncbi.nlm.nih.gov/25138061.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-158
Lopinavir/Ritonavir (LPV/r, Kaletra)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 (NVP), Efavirenz (EFV), Fosamprenavir (FPV), or • PR interval prolongation
Nelfinavir (NFV)
• QT interval prolongation and Torsades de Pointes
Infant (Aged 14 Days to 12 Months) Dose
• Risk of toxicity—including life-threatening
• Once-daily dosing is not recommended. cardiotoxicity—is increased in premature infants
(see Major Toxicities below).
• LPV/r 300 mg/75 mg per m2 of body surface area per dose twice
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 Special Instructions
is associated with lower lopinavir (LPV) trough levels than those
found in adults; LPV dosing should be adjusted for growth at • LPV/r tablets can be administered without regard to
frequent intervals (see Pharmacokinetics and Dosing below). food; administration with or after meals may
enhance GI tolerability.
Child and Adolescent (Aged >12 Months to 18 Years) Dose
• LPV/r tablets must be swallowed whole. Do not
• Once-daily dosing is not recommended. crush or split tablets.
• LPV/r 300 mg/75 mg per m2 of body surface area per dose twice • LPV/r oral solution should be administered with food
daily (maximum dose LPV/r 400 mg/100 mg twice daily, except because a high-fat meal increases absorption.
as noted below). For patients weighing <15 kg, this dose

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-159
 approximates LPV/r 13 mg/3.25 mg (both per kg body weight) • The poor palatability of LPV/r oral solution is difficult
twice daily. For patients weighing ≥15 kg to 45 kg, this dose to mask with flavorings or foods (see Formulations
approximates LPV/r 11 mg/2.75 mg (both per kg body weight) below).
twice daily. This dose is routinely used by many clinicians and is
the preferred dose for antiretroviral therapy (ART)–experienced • LPV/r oral solution can be kept at room temperature
patients who could harbor virus with decreased LPV (up to 77ºF or 25ºC) if used within 2 months. If kept
susceptibility (see Pharmacokinetics and Dosing below). refrigerated (36ºF to 46ºF or 2ºC to 8ºC), LPV/r oral
solution remains stable until the expiration date
• LPV/r 230 mg/57.5 mg per m2 of body surface area per dose printed on the label.
twice daily can be used in antiretroviral (ARV)-naive patients
aged >1 year. For patients weighing <15 kg, this dose • Children aged <18 years who receive once-daily
approximates LPV/r 12 mg/3 mg per kg body weight given twice dosing of LPV/r have shown considerable variability
daily. For patients weighing ≥15 kg to 40 kg, this dose in plasma concentrations and have a higher
approximates LPV/r 10 mg/2.5 mg per kg body weight given incidence of diarrhea. Therefore, once-daily dosing
twice daily. This lower dose should not be used in treatment- is not recommended for this age group.
experienced patients who could harbor virus with decreased • Use of LPV/r once daily is contraindicated if three
LPV susceptibility. or more of the following LPV resistance–associated
substitutions are present: L10F/I/R/V, K20M/N/R,
Weight-Band Dosing for LPV/r 100-mg/25-mg Pediatric Tablets L24I, L33F, M36I, I47V, G48V, I54L/T/V,
in Children and Adolescents V82A/C/F/S/T, and I84V. This is because higher
LPV trough concentrations may be required to
Recommended Number of LPV/r 100-mg/25-mg Tablets suppress resistant virus.
Given Twice Daily
Dosing target 300 mg/m2 per 230 mg/m2 per Metabolism/Elimination
dose given twice dose given twice
daily daily • Cytochrome P450 3A4 substrate and inhibitor.

Body Weight LPV/r Dosing in Patients with Hepatic Impairment

15 kg to 20 kg 2 2 • LPV/r is eliminated primarily by hepatic metabolism.
Use caution when administering LPV to patients
>20 kg to 25 kg 3 2
with hepatic impairment. No dosing information is
>25 kg to 30 kg 3 3 currently available for children or adults with hepatic
insufficiency.
>30 kg to 35 kg 4a 3
• In the coformulation of LPV/r, ritonavir acts as a
>35 kg to 45 kg 4a 4a
pharmacokinetic enhancer, not as an ARV agent.
>45 kg 4a or 5b 4a Ritonavir inhibits the metabolism of LPV and
increases LPV plasma concentrations.
aTwo tablets that each contain LPV/r 200 mg/50 mg can be
substituted for the four LPV/r 100-mg/25-mg tablets in children who
are capable of swallowing a larger tablet.
bIn patients who weigh >45 kg and who are receiving concomitant
NVP, EFV, FPV, or NFV, the FDA-approved adult 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.

Adult (Aged ≥18 Years) Dose

• LPV/r 800 mg/200 mg once daily; or
• LPV/r 400 mg/100 mg twice daily

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-160
 • Do not use once-daily dosing in children; adolescents; patients
receiving concomitant therapy with NVP, EFV, FPV, or NFV; or
patients with three or more LPV-associated mutations (see
Special Instructions for a list of mutations below).

Dosing for Individuals with Three or More LPV-Associated

Mutations (See Special Instructions for List)
• LPV/r 400 mg/100 mg twice daily

Dosing for Individuals Receiving Concomitant NVP or EFV

• 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.

LPV/r 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. Fluticasone is a
CYP3A substrate and LPV/r significantly increases fluticasone exposures, potentially resulting in
adverse systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.1
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.2-4

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-161
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.

Major Toxicities
• More common: Diarrhea, headache, asthenia, nausea and vomiting, rash, insulin resistance,5 and
hyperlipidemia, especially hypercholesterolemia and hypertriglyceridemia,6-8 which may be more
pronounced in girls than in boys.9 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 occur10.
• Special populations—neonates: An increased risk of toxicity in premature infants has been
reported, including cases of transient symptomatic adrenal insufficiency,11,12 life-threatening
bradyarrhythmias and cardiac dysfunction (including complete atrioventricular block,
bradycardia, and cardiomyopathy),13-15 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,15 which include propylene glycol (15.3%) and
ethanol (42.4%). Transient asymptomatic elevation in 17-hydroxyprogesterone levels also has
been reported11 in term newborns treated at birth with LPV/r. The pharmacokinetics (PK) and
safety of LPV/r were studied in IMPAACT P1106, a Phase 4 prospective study evaluating the
safety and PK of antiretroviral medications in low and normal birthweight infants <3 months old,
in which one group received LPV/r as clinical care16. A total of 28 neonates with HIV were
enrolled, with a median birth weight of 2,288 g (interquartile range [IQR] 1,360–3,320 g) and a
median gestational age of 36 weeks (IQR 27–39 weeks). In 25 infants with available PK data, the
median LPV dose was 418mg/m2 twice daily (23.6 mg/kg). The median trough LPV levels was
5.14 (IQR 2.95–8.51) µg/mL, above the minimal effective target concentration of 1 µg/mL.
Nearly half of infants initiated therapy prior to 42 weeks postmenstrual age with no observed
safety or PK differences compared with infants who initiated LPV/r at or after 42 weeks
postmenstrual age. No adverse events Grade 3 or higher were considered related to LPV/r
treatment.16

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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-162
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.17

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
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.18-26

LPV/r has been studied in both ART-naive and ART-experienced children and has demonstrated
durable virologic activity and acceptable toxicity.27-35

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 (Ctrough) 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 infants17,29,34 are compared to those in older children27 and adults36 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)36 (n = 12)27 (n = 15)27 6 Months <6 Weeks
(n = 20)34
(n = 18)29 (n = 9)17
LPV Dose 400 mg 230 mg/m2 300 mg/m2 300 mg/m2 300 mg/m2 300 mg/m2

AUC0–12 92.6 72.6 116.0 101.0 74.5 43.4

(mcg·hr/mL)
Cmax (mcg/mL) 9.8 8.2 12.5 12.1 9.4 5.2

Ctrough (mcg/mL) 7.1 4.7 7.9 4.9 2.7 2.5

Cmin (mcg/mL) 5.5 3.4 6.5 3.8 2.0 1.4

aThis 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-163
Key: AUC0–12h = area under the curve from time zero to 12 hours after drug administration; Cmax = maximum plasma
concentration; Cmin = minimum plasma concentration; Ctrough = trough concentration; LPV = lopinavir; m = meter; 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 life37 and clearance slowing by
age 2.3 years.38 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
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.39

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 weeks17 and infants aged 6 weeks to 6 months.29
Even at this higher dose, Ctrough levels were highly variable, but they were lower in infants than in
children aged >6 months. Ctrough 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.34 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,30 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 Ctrough 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).26 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-164
Pharmacokinetics and Dosing with Concurrent Nevirapine, Efavirenz, Fosamprenavir,
or Nelfinavir
In both children and adults, the LPV Ctrough 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,27 the mean LPV Ctrough 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.27,40 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
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 Ctrough values. Five of 15 children (33%) had LPV 12-hour Ctrough
values that were <1.0 mcg/mL, the plasma concentration needed to inhibit wild-type HIV.41 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 Ctrough values,42 perhaps because the trial used an EFV dose that
was approximately 11 mg/kg body weight42 instead of the 14 mg/kg body weight dose used in the trial
discussed above.41

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.43 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.44-47 The currently available tablet formulation of LPV/r has lower variability in trough
levels than the previously used soft-gel formulation.47,48 An international, randomized, open-label trial
attempted to demonstrate that once-daily LPV/r dosing was non-inferior 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.49

Dosing and Its Relation to Efficacy

LPV/r is effective in treatment-experienced patients with severe immune suppression,50,51 although
heavily pretreated patients may be slower to reach undetectable viral loads51,52 and may have less
robust CD4 T lymphocyte cell (CD4) count percentage responses.53

The relationship between LPV exposure and the susceptibility of the HIV-1 isolate is a key
component of successful treatment. The ratio of Ctrough to half maximal effective concentration (EC50)
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 Ctrough or EC50 alone.54-56 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-165
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.30 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.57 An LPV plasma concentration of
≥1 mcg/mL is cited as a minimum target Ctrough,58-60 but this Ctrough may not adequately control
viremia in patients with multiple LPV resistance mutations.61,62

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.63-65

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 (Cmax), and Ctrough compared with
swallowing the whole tablet. The variability of the reduced exposure with the crushed tablets (5% to
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.66 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 Ctrough measurements.48

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.32,67-71 However, one study did not
observe this difference in the effect of LPV/r on CD4 count,72 and another study found that the
difference did not persist after a year of therapy.35 Some studies found no differences between the
weight gain of children treated with LPV/r and those treated with EFV.70,73 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).70,71 Bone mineral density improved
when children were treated with EFV-containing regimens instead of regimens that contained
LPV/r.74 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 and procollagen type I N-terminal propeptide did not differ between
the two groups.75 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.76

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-166
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44. 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
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45. 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-
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46. la Porte C, van Heeswijk R, Mitchell CD, et al. 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://pubmed.ncbi.nlm.nih.gov/19578247.

47. 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.
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48. 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://pubmed.ncbi.nlm.nih.gov/19858772.

49. 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://pubmed.ncbi.nlm.nih.gov/26558544.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-171
50. 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://pubmed.ncbi.nlm.nih.gov/15602192.

51. 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://pubmed.ncbi.nlm.nih.gov/16446377.

52. 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://pubmed.ncbi.nlm.nih.gov/15929702.

53. 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://pubmed.ncbi.nlm.nih.gov/18025025.

54. 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://pubmed.ncbi.nlm.nih.gov/12545089.

55. 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://pubmed.ncbi.nlm.nih.gov/15385734.

56. 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://pubmed.ncbi.nlm.nih.gov/12499212.

57. Rakhmanina N, van den Anker J, Baghdassarian A, et al. 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://pubmed.ncbi.nlm.nih.gov/19258274.

58. 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://pubmed.ncbi.nlm.nih.gov/24518130.

59. Moholisa RR, Schomaker M, Kuhn L, et al. Effect of lopinavir and nevirapine
concentrations on viral outcomes in protease inhibitor-experienced HIV-infected

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 children. Pediatr Infect Dis J. 2016;35(12):e378-e383. Available at:
https://pubmed.ncbi.nlm.nih.gov/27583591.

60. 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://pubmed.ncbi.nlm.nih.gov/27749514.

61. 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
setting. J Acquir Immune Defic Syndr. 2011;56(4):333-339. Available at:
https://pubmed.ncbi.nlm.nih.gov/21239995.

62. 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://pubmed.ncbi.nlm.nih.gov/27345268.

63. Food and Drug Administration. NDA 205425 tentative approval 2015. 2015. Available
at:
https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2015/205425Orig1s000TAltr.
pdf.

64. 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://pubmed.ncbi.nlm.nih.gov/27128199.

65. Rotsaert A, Ogara C, Mwanga-Amumpaire J, et al. Acceptability of a new 4-in-1

abacavir/lamivudine/lopinavir/ritonavir paediatric fixed-dose combination: the caregiver-
child dyads' perspective. Ther Adv Infect Dis. 2023;10:20499361231159993. Available
at: https://pubmed.ncbi.nlm.nih.gov/36968554.

66. 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://pubmed.ncbi.nlm.nih.gov/21876444.

67. 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://pubmed.ncbi.nlm.nih.gov/20823434.

68. 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://pubmed.ncbi.nlm.nih.gov/22716976.

69. 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

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 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://pubmed.ncbi.nlm.nih.gov/25222305.

70. 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://pubmed.ncbi.nlm.nih.gov/28419200.

71. 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://pubmed.ncbi.nlm.nih.gov/26529159.

72. 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
randomised trial. BMC Med. 2017;15(1):85. Available at:
https://pubmed.ncbi.nlm.nih.gov/28434406.

73. 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://pubmed.ncbi.nlm.nih.gov/27580060.

74. 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://pubmed.ncbi.nlm.nih.gov/27427876.

75. 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://pubmed.ncbi.nlm.nih.gov/32590137.

76. 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://pubmed.ncbi.nlm.nih.gov/34127577.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-174
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-175
Fostemsavir (FTR, Rukobia)
Updated: June 27, 2024
Reviewed: June 27, 2024

Formulations
Extended-release tablet: 600 mg

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Child and Adolescent (Aged • QT corrected (QTc) interval prolongation with higher than recommended dosages
<18 Years) 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 glycoprotein 120 (gp-
120)–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 (<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.

FTR Dosing in Patients with Hepatic Impairment

• No dose adjustment is required in patients with mild-to-severe hepatic impairment.

FTR 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-176
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 QT corrected for heart rate (QTc) interval of the echocardiogram.
• Oral contraceptives and gender-affirming hormonal therapy: TMR may increase ethinyl
estradiol concentrations and risk of thrombosis. Do not exceed 30 mcg ethinyl estradiol daily
when fostemsavir is co-administered with estrogen-based therapies. For gender-affirming
hormonal therapy, estrogen concentrations can be monitored with dose adjustments as needed.1
• 3-hydroxy-3-methylglutaryl coenzyme A (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 (ARV) agents: Drug interaction studies of fostemsavir (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.2,3

Major Toxicities
• More common: Nausea, fatigue, diarrhea (reported in ≥5% of patients)
• Less common: QTc prolongation with higher-than-recommended doses4; 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 predominant subtype found in
Southeast Asia but not commonly found elsewhere in the world). Treatment-emergent
glycoprotein 120 (gp120) genotypic substitutions at four key sites—S375, M434, M426, and
M475—have been found in evaluable participants 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.5

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-177
Pediatric Use
FTR is an 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 adults in
combination with other ARV drugs, with approval limited to heavily treatment-experienced adults
with multidrug-resistant HIV who are experiencing virologic failure on their current regimen due to
resistance, intolerance, or safety considerations.6 A pharmacokinetic, safety, acceptability, and
swallowability study of FTR in children and adolescents weighing ≥20 kg is open to enrollment
(PENTA Foundation: NCT04648280). The dose selection of FTR for children and adolescents
weighing ≥20 kg utilized a population pharmacokinetic model–based approach to achieve similar
adult TMR exposures following FTR 600 mg twice daily dosing that was demonstrated to be safe
and effective in the BRIGHTE study in heavily treatment-experienced patients.7

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 vs. 0.17 log10 copies, respectively).8 After Day 8, all participants received
FTR as part of an optimized regimen. In results reported through 48 weeks,8 54% of participants had
an HIV viral load of <40 copies/mL. At Week 96, 60% of participants6,9 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 participants 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.10 Patients with the lowest CD4 counts at baseline were more likely to experience
serious adverse events or death.10

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.8 For this cohort, at 96 weeks,6 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.11

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.5

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-178
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 half-life is approximately 11 hours.12

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-179
References

1. Nwokolo N, Post E, Mageau AS, et al. Fostemsavir and ethinyl estradiol drug interaction:
Clinical recommendations for co-administration. HIV Med. 2023;24(5):580-587.
Available at: https://pubmed.ncbi.nlm.nih.gov/36372442.

2. 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://pubmed.ncbi.nlm.nih.gov/35315687.

3. Wire MB, Magee M, Ackerman P, et al. 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://pubmed.ncbi.nlm.nih.gov/35285786.

4. Lagishetty C, Moore K, Ackerman P, et al. 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://pubmed.ncbi.nlm.nih.gov/32027457.

5. 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://pubmed.ncbi.nlm.nih.gov/34297843.

6. Fostemsavir (Rukobia) [package insert]. Food and Drug Administration. 2024. Available
at:
https://gskpro.com/content/dam/global/hcpportal/en_US/Prescribing_Information/Rukobi
a/pdf/RUKOBIA-PI-PIL.PDF.

7. Thakkar N, Magee M, Goyal N, et al. Model-based dose selection of fostemsavir for

pediatric populations with multidrug-resistant HIV-1 and relative bioavailability
assessment in healthy adults. Clin Pharmacol Drug Dev. 2023;12(10):991-1000.
Available at: https://pubmed.ncbi.nlm.nih.gov/37329260.

8. 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://pubmed.ncbi.nlm.nih.gov/32212519.

9. 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://pubmed.ncbi.nlm.nih.gov/35502922.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-180
10. 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://pubmed.ncbi.nlm.nih.gov/33946085.

11. 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. Patient. 2021;15:131-143. Available at:
https://pubmed.ncbi.nlm.nih.gov/34180035.

12. Magee M, Slater J, Mannino F, et al. 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://pubmed.ncbi.nlm.nih.gov/33368327.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-181
Ibalizumab (IBA, Trogarzo)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 in utero.
• A single-loading dose infusion of IBA, 2,000 mg of Whether this association exists for infants with potential in utero or
diluted solution, is administered intravenously (IV) intrapartum exposure to IBA is unknown.
over 30 minutes.
• The maintenance dose of IBA is 800 mg given Special Instructions
every 2 weeks. The maintenance dose can be
• For administration by IV infusion, the appropriate number of vials
given as 800 mg of diluted solution administered IV
must be diluted in 250 mL of 0.9% sodium chloride injection.
over 15 minutes or as 800 mg of undiluted solution
given by IV push over 30 seconds. • Using aseptic technique, withdraw 1.33 mL from each vial and
transfer into a 250-mL bag of 0.9% sodium chloride for IV injection.
• U.S. Food and Drug Administration approval of IBA
Other IV diluents must not be used.
is limited to heavily treatment-experienced adults
with multidrug-resistant HIV infection who are • Once diluted, the solution should be administered immediately. If not
experiencing treatment failure on their current used immediately, the solution can be stored at room temperature
regimen. 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
• IBA is used in combination with other antiretroviral
30 minutes but no more than 4 hours prior to administration.
drugs.
• Diluted solution is administered as an IV infusion, not as a bolus or
IV push.
• Undiluted solution may be given by IV push over 30 seconds to
administer the maintenance dose.

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 immunoglobulin G4 monoclonal antibody that blocks HIV

entry into CD4 T lymphocyte (CD4) cells. Based on IBA’s mechanism of action and target-

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-182
 mediated drug 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, 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 federal law. The FDA requested that the company (i.e., Theratechnologies) 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. Health care providers are encouraged to report these adverse events to Theratechnologies by
calling 1-833-23-THERA (1-833-23-4372).

Efficacy in Clinical Trials

A TaiMed Biologics trial, 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-183
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 prenatal and postnatal 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 with potential in utero or intrapartum exposure to IBA. 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-184
References

1. Ibalizumab-uiyk (Trogarzo) [package insert]. Food and Drug Administration. 2022.

Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/761065s013lbl.pdf.

2. Iacob SA, Iacob DG. Ibalizumab targeting CD4 receptors, an emerging molecule in HIV
therapy. Front Microbiol. 2017;8:2323. Available at:
https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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, MA. Available at:
http://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://pubmed.ncbi.nlm.nih.gov/29689540.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-185
Maraviroc (MVC, Selzentry)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 (ARV) agents, for the treatment of CCR5-tropic • Abdominal pain, diarrhea
HIV-1 infection in infants born full term and weighing ≥2 kg, • Cough
children, adolescents, and adults.
• Upper respiratory tract infections
Recommended MVC 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
Twice- Oral
Weight rash and/or other signs of systemic allergic reaction)
Daily Solution Tablets
Band
Dosing (20 mg/mL) • Postural hypotension (generally seen in patients with
severe renal insufficiency)
Recommended doses when MVC is given with noninteracting
drugs, such as nucleoside reverse transcriptase • Dizziness
inhibitors (NRTIs), nevirapine (NVP), enfuvirtide (T-20), and
raltegravir (RAL) Special Instructions
2 kg to 30 mg 1.5 mL N/A • MVC is recommended for use in patients who have
<4 kg only CCR5-tropic HIV-1. Before using MVC, conduct
testing with an HIV tropism assay (see Drug-
4 kg to 40 mg 2 mL N/A Resistance Testing in the Adult and Adolescent
<6 kg Antiretroviral Guidelines) to exclude the presence of
6 kg to 100 mg 5 mL One 25-mg tablet CXCR4-tropic or mixed/dual-tropic HIV. Do not use
<10 kg and one 75-mg MVC if CXCR4-tropic or mixed/dual-tropic HIV is
tablet present.

10 kg to 150 mg 7.5 mL One 150-mg tablet • MVC can be given without regard to food.
14 kg • Instruct patients on how to recognize symptoms of
allergic reactions or hepatitis.
14 kg to 200 mg 10 mL One 150-mg tablet
<30 kg and two 25-mg • Use caution when administering MVC to patients with
tablets underlying cardiac disease.
30 kg to 300 mg 15 mL One 300-mg tablet
<40 kg
≥40 kg 300 mg 15 mL One 300-mg tablet

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-186
 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 ARV agents or other medications that act
2 kg to Not recommended. Data are insufficient to as CYP3A inducers or inhibitors, the dose of MVC
<10 kg make dosing recommendations for infants should be adjusted accordingly.
weighing <10 kg and receiving a potent P450
CYP3A inhibitor. MVC 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 mg 4 mL One 75-mg tablet
<30 kg MVC 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
<40 kg and one 75-mg pediatric patients with mild or moderate renal
tablet impairment. MVC is contraindicated for pediatric
≥40 kg 150 mg 7.5 mL One 150-mg tablet patients with severe renal impairment or end-stage
renal disease who are on regular hemodialysis and
Recommended doses when MVC is given with potent CYP3A who are receiving potent CYP3A inhibitors.
inducers (without a potent CYP3A inhibitor), including • Refer to the manufacturer’s prescribing information
efavirenz (EFV) and etravirine (ETR) for the appropriate doses to use in adolescent and
Infants and Not recommended. Data are insufficient to adult patients with renal impairment.
children and make dosing recommendations.
adolescents
in all weight
bands

Recommended MVC Dose for Adults: Tablets

When Coadministered with Dose

Noninteracting concomitant medications, 300 mg twice
including NRTIs, T-20, NVP, and RAL daily

Potent CYP3A inhibitors (with or without a 150 mg twice

potent CYP3A inducer), including all PIs daily

Potent CYP3A inducers (without a potent 600 mg twice

CYP3A inhibitor), including EFV and ETR 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-187
• 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 glycoprotein 120 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 of CCR5-tropic
HIV virus, when used in conjunction with other antiretroviral drugs, in full-term infants weighing ≥2
kg, children, adolescents, and adults.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
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 (Cavg) ≥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-188
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 Cavg ≥75 ng/mL at
Week 1, whereas 77% of the EFV-unexposed infants had a Cavg ≥75 ng/mL. At Week 4, the
proportion of infants achieving a Cavg ≥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. A population PK model, which included assessment of age and
maturational changes, was developed from IMPAACT 2007 data to describe MVC disposition within
the first 6 weeks of life.3 Simulations with FDA-approved weight-band dosing resulted in the
majority of simulated patients (84.3%) achieving an average concentration of ≥75 ng/mL. 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, and 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 Cavg >100 ng/mL) was achieved with
both the tablet and oral solution formulation of MVC.4

From a mean baseline plasma HIV RNA concentration of 4.4 log10 copies/mL, a decrease of
≥1.5 log10 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.4 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-189
References

1. Maraviroc (Selezentry) [package insert]. Food and Drug Administration. 2020. Available
at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/022128Orig1s019,208984Or
ig1s002lbl.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://pubmed.ncbi.nlm.nih.gov/33252481.

3. Liyanage M, Nikanjam M, McFadyen L, et al. Maraviroc population pharmacokinetics

within the first 6 weeks of life. Pediatr Infect Dis J. 2022;41(11):885-890. Available at:
https://pubmed.ncbi.nlm.nih.gov/35980827.

4. 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://pubmed.ncbi.nlm.nih.gov/29023357.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-190
Appendix A: Pediatric Antiretroviral Drug Information
Capsid Inhibitors
Lenacapavir (LEN, Sunlenca)

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-191
Lenacapavir (LEN, Sunlenca)
Updated: June 27, 2024
Reviewed: June 27, 2024

Formulations
Tablet: 300 mg
Single-Use Vial for Subcutaneous Injection: 463.5 mg/1.5 mL suspension

For additional information, see Drugs@FDA or DailyMed.

Dosing Recommendations Selected Adverse Events

Child and Adolescent Dose • Injection site reaction
• The safety and efficacy of using lenacapavir (LEN) in children and • Nausea
adolescents has not been established.
• Headache
Adult Dose
Special Instructions
• Approved for use in heavily treatment-experienced adults with
multidrug resistant HIV-1 infection who are experiencing virologic • If LEN is discontinued, initiate an alternative, fully
failure on their current antiretroviral (ARV) regimen due to suppressive ARV regimen ≤28 weeks after the final
resistance, intolerance, or safety considerations. LEN is used in injection of LEN to avoid virologic resistance.
combination with an optimized background regimen.
Metabolism/Elimination
Initiation Option 1
• Minor metabolism by cytochrome P450 3A4 and
• Day 1: 927 mg by subcutaneous injection (two 1.5 mL uridine diphosphate glucuronosyltransferase 1A1
subcutaneous injections in the abdomen) and 600 mg orally (two
300-mg tablets) • Major route of elimination is unchanged drug in feces.

• Day 2: 600 mg orally (two 300-mg tablets) Dosing in Patients with Hepatic Impairment

Initiation Option 2 • No dosage adjustment reported. Data on use in

patients with severe hepatic impairment are
• Day 1: 600 mg orally (two 300-mg tablets) insufficient.
• Day 2: 600 mg orally (two 300-mg tablets) Dosing in Patients with Renal Impairment
• Day 8: 300 mg orally (one 300-mg tablet) • Creatinine clearance (CrCl) ≥15 mL/minute: No
• Day 15: 927 mg by subcutaneous injection (two 1.5 mL dosage adjustment is required.
subcutaneous injections in the abdomen) • CrCl <15 mL/minute: No dosage adjustments are
provided in the manufacturer’s prescribing information
Maintenance
(i.e., not studied).
• 927 mg by subcutaneous injection (two 1.5 mL subcutaneous
• Dialysis: No dosage adjustments are required. Not
injections in the abdomen) every 26 weeks +/- 2 weeks from date
expected to be significantly removed by dialysis due to
of last injection
high protein binding.

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-192
• Metabolism: Concomitant administration of lenacapavir (LEN) (a moderate cytochrome
P450 [CYP] 3A inhibitor) with moderate or strong CYP3A inducers may significantly decrease
LEN plasma concentrations, which may result in the loss of therapeutic effect and development
of resistance to LEN. Concomitant administration with strong inducers is contraindicated and
with moderate inducers is not recommended.
• Combined P-glycoprotein, uridine diphosphate glucuronosyltransferase 1A1, and strong CYP3A
inhibitors may significantly increase plasma concentrations of LEN. Concomitant administration
of LEN with these inhibitors is not recommended.
• LEN is a moderate inhibitor of CYP3A. Due to the long half-life of LEN following
subcutaneous (SQ) administration, LEN may increase the exposure of drugs primarily
metabolized by CYP3A.
• Drug interactions may occur up to 9 months after the last SQ dose of LEN.

Major Toxicities
• More common (incidence >10%): Injection site reactions (62% to 65%)—including pain (19% to
31%), swelling (23% to 36%), erythema (25% to 31%), induration (15%), or the development of
a nodule (14% to 25%)—were reported. Most injection site reactions resolve within days;
however, nodules may persist for long periods of time consistent with their depot formulation.1-3
Nausea (12% to 14%), headache (8% to 13%),2,3 constipation (11% to 13%),1,2 and diarrhea (8%
to 14%)1-3 have been reported. No Grade 3 or 4 laboratory abnormalities were deemed clinically
significant; the most frequent was abnormal creatinine clearance (CrCl) (13%). Low levels of
CrCl or estimated glomerular filtration rate or high creatinine levels were transient or
unconfirmed abnormalities.2
• Less common (more severe): Immune reconstitution syndrome has been reported in patients
treated with combination antiretroviral therapy (ART).

Resistance
Resistance to LEN was noted in 8 of 72 patients in the CAPELLA trial (mainly in those with M66I
mutations). Resistance largely occurred early in the trial, and half of these patients had low adherence
to their optimized background therapy as indicated by plasma drug concentrations.2 After 26 weeks,
only one patient developed LEN resistance.1

The reported prevalence of LEN-resistance mutations is low (0.14%) among drug-naive individuals.4

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
LEN is not approved by the U.S. Food and Drug Administration (FDA) for use in pediatric patients.
LEN was approved by the FDA in 2022 in combination with other antiretroviral(s) (ARVs) and is
indicated for the treatment of HIV-1 infection in heavily treatment-experienced adults with multidrug

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-193
resistant HIV-1 infection who are experiencing virologic failure on their current ARV regimen due to
resistance, intolerance, or safety considerations. LEN is given alongside two other fully active agents
in the treatment of HIV if at least one agent has a high barrier to resistance; otherwise, three fully
active agents are recommended in addition to LEN.5

There are limited data on the efficacy and safety of LEN in people with HIV who are initiating ART.

LEN is in Phase 3 development for HIV prevention in adults and adolescents.6

LEN has not been studied in pregnancy, and it is unknown if LEN is excreted in breast milk.7

Efficacy and Pharmacokinetics in Clinical Trials

Clinical Trials in Adults

A randomized, placebo-controlled, double-blind, multicenter trial (CAPELLA) evaluated LEN in

combination with an optimized background ART regimen in 72 patients with multidrug resistant
HIV-1.2 Because CAPELLA was a clinical trial, the optimized background ART regimen did not
include experimental agents. CAPELLA enrolled participants 23 to 78 years of age (enrollment
criteria included those ≥12 years of age) who were experiencing virologic failure on their current
regimen and with documented resistance to at least two ARV medications from at least three of the
four main classes (nucleoside reverse transcriptase inhibitors, non–nucleoside reverse transcriptase
inhibitors, protease inhibitors, and integrase strand transfer inhibitors) and to no more than two fully
active ARV drugs from the four main classes that could be effectively combined. Patients were
enrolled in two cohorts according to change in plasma HIV-1 RNA level between the screening and
cohort-selection visits. In cohort 1, patients were first randomly assigned in a 2:1 ratio to receive oral
LEN or placebo in addition to their failing therapy for 14 days. During the maintenance period,
starting on Day 15, patients in the LEN group received SQ LEN once every 6 months, and those in
the placebo group received oral LEN, followed by SQ LEN. Both groups also received optimized
background therapy. In cohort 2, all the patients received open-label oral LEN with optimized
background therapy on Days 1 through 14, and then SQ LEN was administered once every 6 months
starting on Day 15. The primary endpoint was defined by the percentage of patients in the first cohort
who had a decrease of at least 0.5 log10 copies/mL viral load from baseline to Day 15. The secondary
endpoint was a viral load of <50 copies/mL at Week 26. The results showed that 21 of 24 (88%)
patients in the LEN group met the primary endpoint, as compared to 2 of 12 (17%) patients in the
placebo group (P < 0.001); 81% of patients met the secondary endpoint.8 None of the patients
developed serious adverse events that were considered related to LEN. At 52-week follow-up in
CAPELLA, nine participants had emergent LEN resistance, four of whom resuppressed to
<50 copies/mL. A high rate of virological suppression was achieved in this treatment-experienced
cohort, with 83% (95% confidence interval [CI], 67% to 94%) achieving suppression to
<50 copies/mL and 86% (95% CI, 71% to 95%) achieving suppression to <200 copies/mL.1 LEN
added to an optimized background regimen led to high efficacy in highly treatment-experienced
participants with multidrug resistance but could select for resistance when used unintentionally as
functional monotherapy (e.g., when patients have poor adherence to a self-administered optimized
background regimen).8

CALIBRATE is a Phase 2, ongoing, randomized, open-label trial that enrolled 183 treatment-naive
patients with HIV ≥18 years of age to evaluate the efficacy of LEN in various combinations versus
bictegravir (BIC)/tenofovir alafenamide/emtricitabine combination pill. At Week 54, virologic

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-194
suppression was greater for the BIC-containing combination pill group (92%) compared to various
combinations with LEN (85% to 90%). This ongoing study will follow participants through 80 weeks
of therapy.3

Pharmacokinetics
The elimination half-life of LEN is about 10 to 12 days (oral formulation) and 8 to 12 weeks (SQ
formulation). Residual concentrations of LEN long-acting injection may remain in the systemic
circulation of patients for ≥12 months. To minimize the potential risk of resistance development, an
alternative, fully suppressive ARV regimen should be initiated no later than 28 weeks after the final
LEN injection when possible.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-195
References
1. Ogbuagu O, Segal-Maurer S, Ratanasuwan W, et al. Efficacy and safety of the novel capsid
inhibitor lenacapavir to treat multidrug-resistant HIV: week 52 results of a Phase 2/3 trial.
Lancet HIV. 2023;10(8):e497-e505. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/37451297.

2. Segal-Maurer S, DeJesus E, Stellbrink HJ, et al. Capsid inhibition with lenacapavir in

multidrug-resistant HIV-1 infection. N Engl J Med. 2022;386(19):1793-1803. Available at:
https://pubmed.ncbi.nlm.nih.gov/35544387.

3. Gupta SK, Berhe M, Crofoot G, et al. Lenacapavir administered every 26 weeks or daily in
combination with oral daily antiretroviral therapy for initial treatment of HIV: a randomised,
open-label, active-controlled, Phase 2 trial. Lancet HIV. 2023;10(1):e15-e23. Available at:
https://pubmed.ncbi.nlm.nih.gov/36566079.

4. Nka AD, Bouba Y, Teto G, et al. Evaluation of HIV-1 capsid genetic variability and
lenacapavir (GS-6207) drug resistance-associated mutations according to viral clades among
drug-naive individuals. J Antimicrob Chemother. 2022;78(1):272-275. Available at:
https://pubmed.ncbi.nlm.nih.gov/36411257.

5. Mushtaq A, Kazi F. Lenacapavir: a new treatment of resistant HIV-1 infections. Lancet Infect
Dis. 2023;23(3):286. Available at: https://pubmed.ncbi.nlm.nih.gov/36841248.

6. ClinicalInfo Drug Database. Drug database: lenacapavir (HIV prevention). 2023. Available
at: https://clinicalinfo.hiv.gov/en/drugs/lenacapavir-hiv-prevention/health-
professional#:~:text=Metabolism%2FElimination,of%20the%20total%20radioactive%20dos
e.

7. Tuan J, Ogbuagu O. Lenacapavir: a twice-yearly treatment for adults with multidrug-resistant

HIV infection and limited treatment options. Expert Rev Anti Infect Ther. 2023;21(6):565-
570. Available at: https://pubmed.ncbi.nlm.nih.gov/37067160.

8. Margot NA, Naik V, VanderVeen L, et al. Resistance analyses in highly treatment-

experienced people with human immunodeficiency virus (HIV) treated with the novel capsid
HIV inhibitor lenacapavir. J Infect Dis. 2022;226(11):1985-1991. Available at:
https://pubmed.ncbi.nlm.nih.gov/36082606.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-196
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-197
Bictegravir (BIC)
Updated: June 27, 2024
Reviewed: June 27, 2024

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. Studies Drug Interactions section below for guidance when
are being conducted to develop an age-appropriate formulation administering Biktarvy with antacids or iron or
and identify the appropriate dose for this age and weight group. calcium supplements.
• For children who are unable to swallow a whole
Child (Aged ≥2 Years), Adolescent, and Adult Dose
tablet, the tablet can be split and each part taken
• One tablet once daily with or without food separately, as long as all parts are swallowed within
approximately 10 minutes. Dissolving tablets may
Body Weight Dose be an alternative, but crushing tablets is not
recommended.
≥14 to <25 kg BIC 30 mg/FTC 120 mg/TAF 15 mg
• Screen patients for hepatitis B virus (HBV) infection
≥25 kg BIC 50 mg/FTC 200 mg/TAF 25 mg before using FTC or TAF. Severe acute
exacerbation of HBV can occur when discontinuing
• The U.S. Food and Drug Administration approved Biktarvy for FTC or TAF; therefore, monitor hepatic function for
use in only antiretroviral therapy–naive patients or to replace the several months after halting therapy with FTC or
current antiretroviral (ARV) regimen in patients who have been TAF.
virologically suppressed (HIV RNA <50 copies/mL) on a stable
ARV regimen and who have no history of treatment failure and Metabolism/Elimination
no known mutations associated with resistance to the individual
components of Biktarvy. Some members on the Panel on • BIC is metabolized by cytochrome P450 3A4 and
Antiretroviral Therapy and Medical Management of Children uridine diphosphate glucuronosyltransferase 1A1.
Living with HIV 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 the
Efficacy in Clinical Trials in Adults section below).

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-198
 Biktarvy Dosing in Patients with Hepatic
Impairment
• Biktarvy is not recommended for use in patients
with severe hepatic impairment.

Biktarvy Dosing in Patients with Renal Impairment

• Biktarvy is not recommended for use in pediatric
patients with estimated creatinine clearance
<30 mL/min. See the Biktarvy product label for use
in adult 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 3A4 and uridine diphosphate
glucuronosyltransferase (UGT) 1A1. Tenofovir alafenamide (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 emtricitabine (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 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
postmarketing observational study in adults experienced thrombocytopenia,4 and 1 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,6,7 with an associated
increased risk of cardiometabolic complications,8 but preliminary pediatric data regarding weight

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-199
 gain appear to be inconsistent9,10 (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. Drug reaction with
eosinophilia and systemic symptoms, or DRESS, syndrome has been reported in an adult starting
a BIC-containing regimen.11 Additionally, two cases of drug-induced liver injury—one leading to
death—have been reported in adult women with HIV who were switched to a BIC-containing
regimen.12,13

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, which contains 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 <25 kg. 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 the Efficacy in Clinical Trials in Adults
section below).

Clinical Efficacy 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.14 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-200
did occur in 1% of participants who received ABC/DTG/3TC.2,15 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
discontinuation occurred in 1% of participants in both groups.2 In an open-label extension following
two randomized trials, 98.6% (426 of 432) (95% confidence interval [CI], 97.0% to 99.5%) of
participants with available viral load data at week 240 maintained HIV RNA <50 copies/mL; in an
analysis counting missing viral loads as failures, 67.2% (426 of 634) (95% CI, 63.4% to 70.8%) met
viral suppression criteria. No treatment-emergent resistance to BIC/FTC/TAF was detected, and
adverse events led to drug discontinuation in 1.6% of participants.6 Similar BIC/FTC/TAF efficacy
has been demonstrated in historically underrepresented populations, including Black and female
populations with HIV.16,17

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.2,18,19 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.20 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.21,22 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.21 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.21 In
an analysis of participant data pooled from six clinical trials switching virologically suppressed
adults with HIV to BIC/FTC/TAF, 98% (179 of 182) of participants with pre-existing M184V/I and
99% (2,012 of 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.21,23-25 In a retrospective review at a single center in Spain involving 506 treatment-
experienced adults with HIV who started BIC/FTC/TAF with a viral load <50 copies/mL, 69 (13.6%)
had documented preexisting NRTI resistance mutations (11.2% M184V/I and 5.9% tenofovir
mutations). In the intention-to-treat analysis, the proportion with a viral load <50 copies/mL was
88.4% (61/69) in those with NRTI resistance mutations versus 82.2% (359 of 437) in those without
NRTI resistance mutations. In the per-protocol analysis, the proportions were 93.8% (61 of 65) in
those with NRTI resistance mutations versus 94.4% (359 of 380) in those without NRTI mutations.26
In another analysis from an HIV program in Canada using electronic health records from 50 adults
with major NRTI resistance mutations prior to starting BIC/FTC/TAF, 49 had a viral load

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-201
<100 copies/mL at a mean of 18.6 months after starting the regimen, with the remaining patient
having questionable adherence.27 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.28

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.29 These studies show a higher BIC
maximum serum concentration (Cmax) 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 (Ctau) and higher Cmax in the younger age/lower body weight cohorts suggest
more rapid clearance in children and adolescents than in adults. In the cohorts with body weight29
≥14 to <25 kg and body weight5 ≥35 kg, there is a lower geometric mean ratio when Ctau is compared
to adult values, and the lower 90% CI 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 people with lower adherence (see Table B below).30

Table A. Bictegravir Pharmacokinetics in Children, Adolescents, and Adults with HIV

Children Children Adolescents

Aged ≥2 Years and Aged 6 Years to Aged 12 Years to
PK Parameters Adults
Weighing ≥14 to <12 Years and <18 Years and
<25 kg Weighing ≥25 kg Weighing ≥35 kg
Dose (mg) 30 50 50 50
Dose for Lowest Weight 2.14 2 1.43 1.25a
in the Cohort (mg/kg)
AUCtau ng•h/mL 109,000 (24) 128,000 (28) 89,100 (31) 102,000 (26.9)
Mean (CV%)
Cmax ng/mL 10,100 (21) 9,460 (24) 6,240 (27) 6,150 (22.9)
Mean (CV%)
Ctau ng/mL 2,000 (78) 2,360 (39) 1,780 (44) 2,610 (35.2)
Mean (CV%)
a This dose was calculated using 40 kg as the lowest weight for adults.

Key: AUCtau = area under the concentration time curve over the dosing interval; Cmax = maximum serum concentration;
Ctau = trough serum concentration at the end of the dosing interval; CV = coefficient of variation; PK = pharmacokinetic
Sources: 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
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://pubmed.ncbi.nlm.nih.gov/34302760.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-202
Food and Drug Administration. Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide) [package insert]. 2022. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/210251s015lbl.pdf.
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) AUCtau Cmax Ctau
Aged ≥2 Years and 30 2.14 109 (96.7–122) 166 (149–184) 67.7 (49.6–92.4)
Weighing ≥14 to <25 kg29
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 with 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: AUCtau = area under the concentration time curve over the dosing interval; Cmax = maximum serum concentration;
Ctau = trough serum concentration at the end of the dosing interval; CI = confidence interval; GMR = geometric mean ratio

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 maintained 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 to <25 kg) and adolescents
(body weight ≥35 kg) with adult cohorts, the geometric mean ratio of Ctau 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 Cmax (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 Ctau
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 Cmax, similar to those in patients aged 6 years to <12 years who
weighed ≥25 kg, a similarly low Ctau (see Table A above), and a lower geometric mean ratio when
Ctau was compared with adult values (see Table B above).29 In general, the low-dose tablet was well
tolerated over 55 weeks in the 22 children studied.31 Adverse events considered related to the study

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-203
drug included transient neutropenia (n = 2) and abdominal pain (n = 3).31 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.31

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 Dissolving BIC/FTC/TAF tablets may be an alternative method of administration, but
crushing tablets is not recommended.

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 ARV
components. Although the dissolved tablet Cmax was considered bioequivalent for BIC and FTC, the
TAF Cmax 90% lower confidence limit was not (dissolved vs. solid ratio, 96% [90% CI, 74% to
124%]). For crushed tablets mixed with applesauce, the BIC component was considered
bioequivalent for AUC and Cmax. However, crushed FTC and TAF AUC and Cmax were lower than
that of solid tablets, with FTC Cmax (crushed vs. solid ratio, 70% [90% CI, 63% to 78%]), TAF
AUC (84% [90% CI, 69% to 103%]), and TAF Cmax (66% [90% CI, 51% to 85%]) failing to meet
bioequivalence criteria. Crushing Biktarvy tablets may lead to suboptimal FTC and TAF exposures.32

In the clinical literature, case reports in adults with HIV receiving crushed BIC/FTC/TAF describe
inconsistent virological and resistance outcomes.24,33-36 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-204
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. Food and Drug Administration. Biktarvy (bictegravir/emtricitabine/tenofovir alafenamide)

[package insert]. 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.
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with BIC/FTC/TAF: postmarketing study. Open Forum Infect Dis. 2020;7(9):ofaa285.
Available at: https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/34302760.

6. Sax PE, Arribas JR, Orkin C, et al. Bictegravir/emtricitabine/tenofovir alafenamide as initial

treatment for HIV-1: five-year follow-up from two randomized trials. EClinicalMedicine.
2023;59:101991. Available at: https://pubmed.ncbi.nlm.nih.gov/37200995.

7. Emond B, Rossi C, Cote-Sergent A, et al. Body mass index increase and weight gain among
people living with HIV-1 initiated on single-tablet
darunavir/cobicistat/emtricitabine/tenofovir alafenamide or
bictegravir/emtricitabine/tenofovir alafenamide in the United States. Curr Med Res Opin.
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10. Patel K, Karalius B, Yao T, et al. Weight changes after initiation of an integrase strand
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States: a descriptive cohort study. Presented at: International Workshop on HIV and

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11. DiLorenzo MA, Medrano N, Chen JN, et al. Bictegravir-induced drug reaction with
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Open Forum Infect Dis. 2023;10(3):ofad066. Available at:
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14. 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://pubmed.ncbi.nlm.nih.gov/28196003.

15. 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://pubmed.ncbi.nlm.nih.gov/28867497.

16. 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://pubmed.ncbi.nlm.nih.gov/34397746.

17. 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://pubmed.ncbi.nlm.nih.gov/34506342.

18. Daar ES. Virology and immunology of acute HIV type 1 infection. AIDS Res Hum
Retroviruses. 1998;14 Suppl 3:S229-234. Available at:
https://pubmed.ncbi.nlm.nih.gov/9814948.

19. 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://pubmed.ncbi.nlm.nih.gov/29925489.

20. 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://pubmed.ncbi.nlm.nih.gov/31430369.

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21. 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://pubmed.ncbi.nlm.nih.gov/32668455.

22. 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://pubmed.ncbi.nlm.nih.gov/32701823.

23. 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://pubmed.ncbi.nlm.nih.gov/34189182.

24. 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://pubmed.ncbi.nlm.nih.gov/35511892.

25. Sax PE, Andreatta K, Molina JM, et al. High efficacy of switching to
bictegravir/emtricitabine/tenofovir alafenamide in people with suppressed HIV and
preexisting M184V/I. AIDS. 2022;36(11):1511-1520. Available at:
https://pubmed.ncbi.nlm.nih.gov/35466963.

26. Mican R, de Gea Grela A, Cadinanos J, et al. Impact of preexisting nucleos(t)ide reverse
transcriptase inhibitor resistance on the effectiveness of bictegravir/emtricitabine/tenofovir
alafenamide in treatment experience patients. AIDS. 2022;36(14):1941-1947. Available at:
https://pubmed.ncbi.nlm.nih.gov/35848506.

27. Shafran SD, Hughes CA. Bictegravir/emtricitabine/tenofovir alafenamide in patients with

genotypic NRTI resistance. HIV Med. 2023;24(3):361-365. Available at:
https://pubmed.ncbi.nlm.nih.gov/35973753.

28. 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://pubmed.ncbi.nlm.nih.gov/32176183.

29. 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

30. Shuter J. Forgiveness of non-adherence to HIV-1 antiretroviral therapy. J Antimicrob

Chemother. 2008;61(4):769-773. Available at: https://pubmed.ncbi.nlm.nih.gov/18256112.

31. 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.
https://www.natap.org/2021/IAS/IAS_80.htm.

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32. 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://pubmed.ncbi.nlm.nih.gov/36322475.

33. 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://pubmed.ncbi.nlm.nih.gov/32862660.

34. 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://pubmed.ncbi.nlm.nih.gov/32207818.

35. 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://pubmed.ncbi.nlm.nih.gov/31982483.

36. 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://pubmed.ncbi.nlm.nih.gov/34787026.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-208
Cabotegravir
Updated: June 27, 2024
Reviewed: June 27, 2024

Cabotegravir (CAB, Vocabria)

Cabotegravir for Intramuscular Injection (CAB, Apretude)
Cabotegravir and Rilpivirine for Intramuscular Injections (Long-Acting
Injectable CAB and RPV, Cabenuva)

Formulations
Tablet
• [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 Formulations
• [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 (CAB) for Intramuscular Injection • Depression
• CAB 600 mg/3 mL for intramuscular (IM) injection is approved by • Insomnia
the U.S. Food and Drug Administration (FDA) for use as HIV pre-
exposure prophylaxis (PrEP) in adults and adolescents weighing • Headache
≥35 kg; an oral dosing lead-in period of approximately 1 month is • Rash (can be severe and include drug reaction with
optional. See package insert for additional information about eosinophilia and systemic symptoms) or
dosing and administration of CAB as PrEP; this indication is not hypersensitivity
addressed in the Pediatric Antiretroviral Guidelines.
• Hepatotoxicity
[Cabenuva] CAB and Rilpivirine (RPV) for IM Injection (Long-
• Altered adrenocorticotropic hormone stimulation test of
Acting Injectable CAB and RPV)
uncertain clinical significance
Pediatric Dose
• Injection site reactions
• CAB tablets and co-packaged long-acting injectable CAB and
RPV are not FDA approved for the treatment of HIV in children • Creatine phosphokinase elevation following IM
aged <12 years. injection
• Weight gain

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-209
 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 long-acting injectable than 7 days and oral therapy has not been taken,
CAB and RPV injections, or patients can proceed directly to long- clinically reassess the patient to determine if
acting injectable CAB and RPV on the last day of their current resumption of injection dosing remains appropriate.
ARV regimen. Refer to the package insert for information about
managing planned and unplanned missed doses.
• Refer to the package insert for instructions about changing the • Long-acting injectable CAB and RPV is a complete
frequency of IM injections, i.e., from monthly to every-2-month regimen. Coadministration with other ARV drugs is not
dosing or from every-2-month to monthly dosing. recommended.
Oral Lead-in Dosing • When long-acting injectable CAB and RPV injections
are stopped, residual concentrations may remain
o CAB 30 mg orally and RPV 25 mg orally once daily with a
measurable for up to 12 months or longer. It is
meal for at least 28 days.
essential to initiate an alternative, fully suppressive
Dosing for Monthly Administration of Long-Acting Injectable ARV regimen no later than 1 month after the final
CAB and RPV injections of long-acting injectable CAB and RPV.

o On the last day of oral lead-in therapy or the current oral ARV • Use CAB and RPV with caution when coadministering
regimen, a loading dose of CAB 600 mg (3 mL) and RPV with a drug that has a known risk of prolonging the QT
900 mg (3 mL) should be given as two separate IM injections corrected for heart rate interval or causing Torsades
in separate ventrogluteal sites. de Pointes (for more information, see CredibleMeds).

o Continuation therapy of CAB 400 mg (2 mL) and RPV 600 mg

Metabolism/Elimination
(2 mL) IM is given 1 month after the loading dose and once a
month thereafter, with allowance for a ±7-day administration
• CAB is metabolized by uridine diphosphate-
window.
glucuronosyl transferase 1A1.
Dosing for Every-2-Month Administration of Long-Acting • RPV is a cytochrome P450 3A substrate.
Injectable CAB and RPV
Dosing in Patients with Hepatic Impairment
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 • No dose adjustment of CAB or long-acting injectable
injections in separate ventrogluteal sites on the last day of oral CAB and RPV is necessary in patients with mild or
lead-in or the current oral ARV regimen and 1 month after the moderate hepatic impairment.
initial injections.
Dosing in Patients with Renal Impairment
o After these two initiation injections 1 month apart for 2 months,
continuation therapy with IM CAB 600 mg (3 mL) and RPV • RPV decreases tubular secretion of creatinine and
900 mg (3 mL) is administered every 2 months, with allowance slightly increases measured serum creatinine, but it
for a ±7-day administration window. does not affect glomerular filtration.

Patients should be monitored for approximately 10 minutes for post- • No dose adjustment of CAB or long-acting injectable
injection reactions. A 23-gauge, 1.5-inch IM needle is CAB and RPV is necessary in patients with mild or
recommended for the injection and is provided in the packaging. moderate renal impairment. However, long-acting
Longer, 2-inch needles (not included with packaging) should be injectable CAB and RPV should be used with caution
used in patients with a body mass index >30 kg/m2. The Panel on in patients with severe renal impairment or end-stage
Antiretroviral Therapy and Medical Management of Children Living renal disease. These patients should be monitored
with HIV recommends that providers review instructions available more frequently for adverse events.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-210
 with the package insert prior to beginning IM administration of long-
acting injectable CAB and RPV. Additional clinical resources,
including injection education, are available from the manufacturer,
ViiV.

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

glucuronosyltransferase 1A1 (UGT1A1). CAB is contraindicated in patients receiving strong
inducers of UGT1A1 because such inducers decrease CAB plasma concentrations which may
result in a loss of virologic response.
• 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 2 hours before or 4 hours after oral RPV.
o H2 receptor antagonists should not be administered 12 hours before or 4 hours after oral
RPV.
o Oral RPV is contraindicated 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 long-acting injectable 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-211
• Rare: Hepatotoxicity and 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

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 long-acting injectable CAB and RPV (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 long-acting injectable 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
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 did not lead to treatment discontinuations. Two adolescents
experienced Grade 3 adverse events, one due to insomnia (CAB arm) and one due to hypersensitivity

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-212
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
clinical experience with this product remains limited. Intermittent viremias have been reported in
young adults transitioned to long-acting injectable CAB and RPV with oral lead-in.7 The Panel on
Antiretroviral Therapy and Medical Management of Children Living with HIV notes that significant
questions remain regarding the use of long-acting injectable 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 long-acting injectable 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.8 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—was similar across treatment arms. Of those failing the
every-2-month injection regimen, a majority had NNRTI resistance–associated mutations.9

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 long-acting injectable 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 long-acting injectable CAB and RPV group, and
lasted a median of 3 days.10 The FLAIR study was extended to include an assessment of switching
those participants remaining in the oral ARV arm after 120 weeks to long-acting injectable 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.11

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-213
These studies demonstrated noninferiority of switching to monthly long-acting injectable CAB and
RPV compared to continuing oral ART. In all studies, adult patients expressed a high degree of
treatment satisfaction and preference for the long-acting injectable CAB and RPV regimen. Although
documented virologic failure with the long-acting injectable 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 long-acting injectable CAB and RPV Phase 3 trials, presence of at
least two baseline factors of RPV resistance–associated mutations, HIV-1 subtype A6/A1, and body
mass index >30 kg/m2 was associated with increased risk of virologic failure at 48 weeks.12

Pharmacokinetics
The pharmacokinetics (PK) of IM CAB are driven by slow absorption from the injection site. 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 long-acting injectable CAB and RPV
in the ATLAS and FLAIR studies described above.5

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-214
 References

1. Cabenuva (cabotegravir extended-release injectable suspension; rilpivirine extended-release

injectable suspension), co-packaged for intramuscular use [package insert]. Food and Drug
Administration. 2023. Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/212888s011lbl.pdf.

2. Lee MJ, Berry P, D'Errico F, et al. A case of rilpivirine drug-induced liver injury. Sex Transm
Infect. 2020;96(8):618-619. Available at: https://pubmed.ncbi.nlm.nih.gov/31974214.

3. Vocabria (cabotegravir) tablets,for oral use [package insert]. Food and Drug Administration.
2023. Available at:
https://gskpro.com/content/dam/global/hcpportal/en_us/prescribing_information/vocabria/pdf/vo
cabria-pi-pil.pdf

4. Apretude (cabotegravir extended-release injectable suspension), for intramuscular use [package

insert]. Food and Drug Administration. 2023. Available at:
https://gskpro.com/content/dam/global/hcpportal/en_us/prescribing_information/apretude/pdf/ap
retude-pi-pil-ifu.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. 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. Available at: https://www.natap.org/2022/CROI/croi_154.htm.

7. 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://pubmed.ncbi.nlm.nih.gov/36480701.

8. 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.

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://pubmed.ncbi.nlm.nih.gov/34648734.

10. 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-215
 study. Lancet HIV. 2021;8(4):e185-e196. Available at:
https://pubmed.ncbi.nlm.nih.gov/33794181.

11. 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://pubmed.ncbi.nlm.nih.gov/34656207.

12. 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://pubmed.ncbi.nlm.nih.gov/33730748.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-216
Dolutegravir (DTG, Tivicay, Tivicay PD)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 FDCs of dolutegravir (DTG) are U.S. Food • Insomnia
and Drug Administration (FDA)–approved for use in treatment-
naive or treatment-experienced pediatric, adolescent, and adult • Headache
patients naive to the integrase strand transfer inhibitor (INSTI) • Neuropsychiatric symptoms (i.e., depression and/or
drug class. The Panel on Antiretroviral Therapy and Medical suicidal thoughts or actions), especially in patients
Management of Children Living with HIV endorses the use of DTG with a history of psychiatric illness
as appropriate for some children with prior INSTI use (see
Modifying Antiretroviral Regimens in Children with Sustained • Rare cases of hypersensitivity reactions (HSRs),
Virologic Suppression on Antiretroviral Therapy and Recognizing including rash and DRESS (drug reaction [or rash]
and Managing Antiretroviral Treatment Failure in Management of with eosinophilia and systemic symptoms),
Children Receiving Antiretroviral Therapy). constitutional symptoms, and organ dysfunction
(including liver injury)
Neonate Dose
• DTG is not approved by the FDA for use in neonates. Special Instructions
• DTG may be taken with or without food.
• DTG should be taken 2 hours before or 6 hours after
taking cation-containing antacids or laxatives,
sucralfate, oral iron supplements, oral calcium
supplements, or buffered medications.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-217
 [Tivicay PD] DTG Dispersible Tablets • For DTG dispersible tablets, fully disperse the
dispersible tablets in 5 mL of drinking water (if using
Infant (Aged ≥4 Weeks and Weighing ≥3 kg), Child, and
one or three tablets) or in 10 mL of drinking water (if
Adolescent Dose
using four, five, or six tablets) in the supplied cup;
swirl the suspension so that no lumps remain. After
Recommended Dosea of
Pediatric Number of full dispersion and within 30 minutes of mixing,
Dolutegravir Dispersible
Body Weight 5-mg Tablets administer the oral suspension. Rinse the dosing cup
Tablets
with a small amount of water and give this additional
3 kg to <6 kg 5 mg once daily 1 water to the child to ensure the child takes the full
dose and no medication remains in the dosing cup.
6 kg to <10 kg 15 mg once daily 3
• DTG dispersible tablets may be swallowed whole. If
10 kg to <14 kg 20 mg once daily 4 more than one tablet is required, swallow one tablet at
a time to reduce the risk of choking. DTG dispersible
14 kg to <20 kg 25 mg once daily 5 tablets should not be chewed or crushed.

≥20 kg 30 mg once daily 6 • For ABC/DTG/3TC dispersible tablets, tablets should

be fully dispersed in the appropriate volume of
a If certain drugs that induce uridine diphosphate glucuronyl drinking water in the supplied cup and the suspension
transferase (UGT) 1A or cytochrome P450 (CYP) 3A are should be swirled so that no lumps remain. After full
coadministered, administer DTG dispersible tablets twice daily dispersion and within 30 minutes of mixing, administer
(see the Drug Interactions section below). the oral suspension. Rinse the dosing cup with a
small amount of water and give this additional water
[Tivicay] DTG Film-Coated Tablets to the child to ensure the child takes the full dose and
Child and Adolescent (Weighing ≥14 kg) Dose no medication remains in the dosing cup.
ABC/DTG/3TC dispersible tablets should not be
• DTG film-coated tablets and DTG dispersible tablets are not swallowed whole, chewed, or crushed.
bioequivalent and are not interchangeable on a milligram-per-
milligram basis. Each formulation has different doses. • No data exist regarding dispersion in breast milk or
any vehicles other than water.
Dosing of Film-Coated Tablets for Pediatric Patients Weighing • In patients who have difficulty swallowing the film-
≥14 kg Who Can Swallow Tablets coated tablets whole, 50-mg tablets may be either
split into halves followed by immediate ingestion of
Recommended Dosea both halves of the tablet or crushed and added to a
Pediatric Number of
of DTG Film­Coated small amount of semisolid food or liquid, all of which
Body Weight Tablets
Tablets should be consumed immediately.1
14 kg to <20 kg 40 mg once daily 4 x 10 mg • The efficacy of DTG is reduced in patients with certain
≥20 kg 50 mg once daily 1 x 50 mg combinations of INSTI-resistance mutations. DTG
dosing strategies in pediatric patients with first-
a If certain drugs that induce UGT1A or CYP3A are generation INSTI mutations differ from those in adults
coadministered, administer DTG tablets twice daily (see the Drug (see Table A and the Resistance section below).
Interactions section below). Screen patients for hepatitis B virus (HBV)
infection before using FDC tablets that contain 3TC.
Some infants may have received raltegravir as presumptive HIV Severe acute exacerbations of HBV can occur after
therapy prior to diagnosis. These infants and other infants and discontinuation of 3TC. Patients with HBV/HIV
children with HIV who have received INSTIs are candidates to coinfection who receive Dovato will require additional
switch to once-daily DTG if they are virologically suppressed or treatment for chronic HBV infection.
have no mutations associated with resistance to INSTIs.
• For any FDC tablets containing ABC, test patients for
Adult Dose the HLA-B*5701 allele before starting therapy to
predict the risk of HSRs. Patients who test positive for
• One 50-mg DTG film-coated tablet once daily the HLA-B*5701 allele should not be given an ABC-
• If certain drugs that induce UGT1A or CYP3A are containing FDC. Patients with no prior HLA-B*5701
coadministered, administer DTG 50 mg twice daily (see the testing who are tolerating an ABC- containing regimen
Drug Interactions section below). do not need to be tested. See the Abacavir section.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-218
 • Adults who are INSTI-experienced with certain INSTI-
associated resistance mutations or clinically suspected INSTI Metabolism/Elimination
resistance should receive 50 mg DTG twice daily. • Substrate for UGT1A1 and CYP3A. Also, a substrate
of UGT1A3, UGT1A9, breast cancer resistance
[Dovato] DTG/Lamivudine (3TC) protein (BCRP), and P-glycoprotein (P-gp) in vitro.
Adolescents Aged ≥12 Years and Weighing ≥25 kg and Adult Drugs that induce these enzymes and transporters
Dose may decrease plasma concentrations of DTG. Drugs
that inhibit these enzymes or transporters may
• One tablet once daily with or without food as a complete
increase DTG plasma concentrations.
regimen in antiretroviral (ARV)-naive adolescents with no
known mutations associated with resistance to the individual DTG Dosing in Patients with Hepatic Impairment
components of Dovato
• No dose adjustment is necessary in patients with mild
[Juluca] DTG/Rilpivirine or moderate hepatic impairment. Due to the lack of
Adult Dose data, DTG is not recommended for use in patients
with severe hepatic impairment.
• One tablet once daily with a meal as a complete regimen to
replace the current ARV regimen in patients who have been • FDC tablets containing ABC or 3TC should not be
virologically suppressed (HIV RNA <50 copies/mL) on a stable used in patients with impaired hepatic function.
ARV regimen for at least 6 months, with no history of treatment
failure, and no known mutations associated with resistance to DTG Dosing in Patients with Renal Impairment
the individual components of Juluca • DTG decreases tubular secretion of creatinine and
increases measured serum creatinine without
[Triumeq PD] Abacavir (ABC)/DTG/3TC affecting glomerular filtration.
Children Aged ≥3 Months and Weighing ≥6 kg to <25 kg
• No dose adjustment is required in INSTI-naive
• Dispersible Triumeq PD tablets are FDA approved for children patients with mild, moderate, or severe renal
weighing ≥6 to <25 kg. They are not recommended for children impairment, or in INSTI-experienced patients with
weighing ≥25 kg. mild or moderate renal impairment.
• Administer the appropriate number of tablets for a child’s weight • Use DTG with caution in INSTI-experienced patients
once daily. Tablets should be dispersed in 15 mL of water if with severe renal impairment (creatinine
using three tablets or 20 mL of water if using four to six tablets, clearance [CrCl] <30 mL/min), because DTG
see Special Instructions. Triumeq PD tablets should not be concentrations will be decreased. The cause of this
swallowed whole, chewed, cut, or crushed. decrease is unknown.

Weight-Band Dosing of Triumeq PD Tablets for Children • FDC tablets containing 3TC (Dovato, Triumeq PD,
Aged ≥3 Months and Weighing ≥6 kg and Triumeq) should not be used in patients who
have CrCl <30 mL/min or patients who are on dialysis
because the doses of 3TC cannot be adjusted. Data
Number of
Recommended about the FDC DTG/3TC (Dovato) suggest that
Weight Triumeq PD
Daily Dose patients with a sustained creatinine clearance
Tablets
30–49 mL/min may experience a higher 3TC
6 kg to <10 kg ABC 180 mg, DTG 15 mg, 3 exposure and should be monitored for hematologic
3TC 90 mg toxicities and potential FDC discontinuation and
subsequent adjustment of the treatment regimen. See
10 kg to <14 kg ABC 240 mg, DTG 20 mg, 4 package inserts for additional information.
3TC 120 mg
14 kg to <20 kg ABC 300 mg, DTG 25 mg, 5
3TC 150 mg
20 kg to <25 kg ABC 360 mg, DTG 30 mg, 6
3TC 180 mg
≥25 kg Use Triumeq. See below.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-219
 • 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.

[Triumeq] ABC/DTG/3TC
Child and Adolescent (Weighing ≥25 kg) and Adult Dose
• One tablet once daily with or without food
• 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.

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.2-4 Because etravirine (ETR) significantly reduces plasma concentrations of DTG, DTG
should not be administered with ETR without coadministration of atazanavir/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.
• Atazanavir (ATV) is an inhibitor of UGT1A1. In a 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.5
• 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).6-9
• 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 postmarketing reports note that neuropsychiatric
adverse events (AEs) have occurred following the initiation of DTG-based therapy in adults.10,11

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-220
• 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.12,13 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.14,15
• Rare: A single case of drug reaction (or rash) with eosinophilia and systemic
symptoms (DRESS) has been reported.16

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 is reduced in patients with the INSTI-resistance Q148 substitution plus two or
more additional INSTI-resistance mutations, and this reduced efficacy cannot be completely
overcome with increasing DTG dosing.17,18

For adults with first-generation INSTI-resistance mutations, the package insert recommends doubling
the DTG dose and give the standard dose twice daily rather than once daily. However, modeling and
simulation of this strategy with the dispersible tablet formulation of DTG in children suggested
elevated maximum plasma concentrations (Cmax) in comparison to historical data in adults,
adolescents, and children would result. Thus, a different dosing strategy was needed for children with
first-generation INSTI-resistance mutations. The proposed dosing schedule in Table A below was
based on simulations with the goal of achieving geometric mean concentration at 12 hours postdose
>1.97 µg/mL and area under the curve (AUC) through 12 hours postdose >32.2 µg∙h/mL while
avoiding elevated Cmax values.19 Additionally, the coformulated dispersible tablet containing
abacavir (ABC)/DTG/lamivudine (3TC) cannot be used in combination with a separate dose of
single-agent dispersible release DTG because the dosing of the separate formulation is not double the
regular dose and the modified dosing strategy would result in underdosing the ABC and 3TC
components.

Table A. Weight-Band Dosing of Dolutegravir Dispersible Tablets for Pediatric Patients

Weighing ≥3 kg and Aged ≥3 Months with First-Generation INSTI-Resistance Mutations

Recommended Number of
Weight
Twice Daily Dose Tablets per Dose
3 kg to <6 kg 5 mg 1
6 kg to <10 kg 10 mg 2
10 kg to <14 kg 15 mg 3
14 kg to <20 kg 15 mg 3
20 kg to <30 kg 20 mg 4
30 kg to <40 kg 20 mg 4

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-221
Pediatric Use
Approval
DTG is approved by the FDA for use, in combination with other ARV drugs, in pediatric patients
aged at least 4 weeks and weighing ≥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). DTG dispersible tablets and film-coated tablets in either the single-entity or fixed-dose
combination (FDC) form can be administered with or without food.20,21 Pediatric patients weighing
≥20 kg may take the DTG 50-mg film-coated tablets if they are able to swallow tablets. The
combination tablet 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 tablet DTG/3TC (Dovato) is
approved by the FDA for adolescents weighing ≥25 kg and aged ≥12 years but is not approved for
use in children aged <12 years. The combination tablet DTG/rilpivirine (RPV) (Juluca) is 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,22 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 Aged 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.23-25 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
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 cell (CD4) 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-222
both formulations were well tolerated by pediatric patients. The effectiveness observed in the trial
was comparable to that of treatment-experienced adult participants.26

Sixteen adolescents in Cohort 1 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.27

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 AEs attributed to
DTG. Of 68 participants with HIV RNA data at 48 weeks, 91% and 68% achieved HIV RNA
<400 copies/mL and <50 copies/mL, respectively.25

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.28 As
assessed by 96 weeks, DTG-based ART as both first-line therapy and second-line therapy in children
was superior to standard care.29 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.29-31

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 AUC and maximum plasma concentration (Cmax) values that were higher than
adult PK reference values but still acceptable. Both doses achieved trough plasma concentration
values that were slightly lower than adult reference values and exhibited greater variability but were
determined to be acceptable.32 Later-enrolling ODYSSEY cohorts included children weighing 3 kg to
<20 kg.33 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 AUC through 24 hours post-dose 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 weighing <20 kg experienced Grade 3 or higher AEs, including two deaths (one
kwashiorkor and one accidental trauma) assessed as unrelated to the study drug. Eleven participants
experienced serious AEs, 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 B 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-223
Separate PK studies have continued to support adequate DTG exposures among children and
adolescents at the currently recommended doses.20,34,35 Dosing in neonates is under investigation.

Table B: Summary of Pharmacokinetic Parameters in Pediatric Participants with HIV-1

(Pooled Analyses for IMPAACT P1093 and ODYSSEY Trials)

Pharmacokinetic Parameter
Geometric Mean (% CV)
Doseb of DTG FCT
Weight Banda n
or DTG DT
Cmax AUC0–24h C24h
(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.26
Key: AUC0–24h = 24-hour area under the curve; C24h = concentration at 24 hours postdose; Cmax = maximum plasma
concentration; CV = coefficient of variation; DT = dispersible tablets; DTG = dolutegravir; FCT = 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 integrase inhibitor naive (90.3%) and had virologic suppression at baseline (63.4%).36 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.36 Retrospective analyses of children and adolescents aged ≤19 years and
weighing ≥20 kg have also been performed from DTG rollout programs across Botswana, Eswatini,
Lesotho, Malawi, Tanzania, and Uganda.37 Of the 9,419 children and adolescents who initiated DTG
between 2017 and 2020, 73% received tenofovir disoproxil fumarate (TDF)/3TC/DTG, 24% received
ABC/DTG/3TC, and 3% received zidovudine/3TC/DTG. Only 0.7% reported a toxicity that resulted

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-224
in DTG discontinuation. Virologic suppression was documented in 92.7% (8,273 of 8,921) before
switching to DTG. Following the switch, 93.4% (7,378 of 7,898) on DTG had documented virologic
suppression, including 79.8% (426 of 534) of those not previously suppressed on their original
regimen. However, the analysis did not include data for comparison among participants who were
not suppressed and did not switch to a DTG-containing regimen. Factors associated with increased
odds of virologic suppression included being virologically suppressed prior to ART switch (odds
ratio [OR] 3.87; 95% confidence interval [CI], 3.03–4.95) and use of once-daily TDF/3TC/DTG as a
single-tablet regimen (OR 1.78; 95% CI, 1.43–2.22), whereas age increases were associated with
slightly reduced odds of virologic suppression (OR 0.94 for each 1-year increase; 95% CI,
0.91–0.97). A separate report among 3,347 children aged <14 years receiving DTG as part of a
national rollout program in southern Mozambique revealed virologic suppression rates of 79.7% (63
of 79) in children newly initiating DTG and 85.8% (1,775 of 2,068) in those switching to DTG.38
However, more than one-third experienced at least two regimen changes during the follow-up period
from 2019 to 2021, some of which involved switching from DTG to either a PI or non-nucleoside
reverse transcriptase inhibitor (NNRTI). These changes were attributable, in part, to drug shortage,
illustrating the importance of continued access and supply of DTG to support rollout initiatives.

Although observational studies have shown high virologic suppression rates, emerging INSTI
mutations specific to DTG have been reported among children being monitored in national treatment
programs, as opposed to observational studies. Thus, continued assessments of virologic suppression
longer term and the development of resistance will be important.39,40

The PK, safety, tolerability, and efficacy of dispersible and immediate-release FDC tablet
formulations of ABC/DTG/3TC were investigated in children weighing 6 kg to <40 kg and aged <12
years among 57 children enrolled in the IMPAACT 2019 study.41 Children were dosed across five
weight bands in alignment with the WHO ARV dosing recommendations for each component.
Children weighing 6 kg to <25 kg received the dispersible FDC formulation containing ABC 60
mg/DTG 5 mg/3TC 30 mg (Triumeq PD), and those weighing 25 to <40 kg received the immediate-
release FDC formulation containing ABC 600 mg/DTG 50 mg/3TC 300 mg (Triumeq). Drug
exposures for all three components were comparable to previous studies in children and adults with
HIV, including DTG exposures from IMPAACT P1093 and ODYSSEY. Dosing was confirmed
based on PK and safety criteria across all weight bands in alignment with WHO weight-band dosing
recommendations. Data available through 24 weeks of treatment showed there were no Grade 3 or 4
AEs related to the drug components, and no participant discontinued the study drug because of AEs.
At Week 24, 54 of 57 (95%) of participants were suppressed to <200 copies/mL, and all treatment-
experienced patients who switched to ABC/DTG/3TC maintained suppression. Both formulations
were also well tolerated, and 10 of 11 participants in the highest weight band were able to swallow
the larger immediate-release tablet whole and intact (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). Analyses of safety and efficacy data through
48 weeks are ongoing.

A separate cohort of adolescents in Barcelona, Spain, received the immediate-release FDC ABC
600 mg/DTG 50 mg/3TC 300 mg (Triumeq). Of the 12 patients described, 1 was treatment naive,
6 were undergoing treatment simplification, and 5 had previously experienced virologic failure on a
different ART regimen. Nine of the 12 patients achieved or maintained viral suppression after
switching to Triumeq; three patients did not 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, in contrast to tolerability findings in IMPAACT 2019.42

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-225
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.30 A
separate systematic review of INSTI use in children with perinatal HIV infection identified rates of
neuropsychiatric effects from 1% to 16% among those receiving DTG (n=3,448 children).43

In a subset of ODYSSEY participants aged 6 to <18 years, no differences were identified in vitamin
B12 levels across study arms, although plasma and RBC folate levels were lower among participants
receiving standard care.44

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
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.7
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 participants with baseline BMI ≥50th
percentile, whose rate of BMI z-score change was lower post-DTG (difference: −0.23; P = 0.04).45
Another group measured multiple body fat parameters and cholesterol/lipid profiles in Italian
adolescents switched from a PI- or NNRTI-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.6 A small, single-center cohort in Australia identified similar increases in BMI
among adolescents switched to either DTG- or tenofovir alafenamide–containing regimens.8 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.9 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.31 A separate study in South
Africa showed no significant change in BMI z-score, reduced hepatic steatosis, and lower total
cholesterol and triglycerides among 30 adolescents switched to DTG in comparison to those who
remained on their original ART regimen, the majority of which were PI-based (84%).46 Another
retrospective study in a Swiss cohort of 60 children with HIV did not identify any significant changes
in BMI or BMI standard deviation scores associated with DTG when comparing at 1 year post-DTG
switch.47

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-226
Based on these collective 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. See the What to Start section for
additional considerations.

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.48 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.49
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.50

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 naive
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 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%).51 The
combination of DTG/3TC was evaluated as initial ART in adolescents weighing ≥25 kg and aged
≥12 years to <18 years with baseline HIV-1 RNA between 100 copies/mL and ≤500,000 copies/mL
through the DANCE study. A total of 32 participants were enrolled, of which 81% and 69% achieved
HIV RNA levels <50 copies/mL at Weeks 48 and 96, respectively.52 These results included
individuals with missing data due to site closures; thus, sensitivity analyses were performed with the
participants excluded. Virologic suppression rates in the sensitivity analyses were 87% (26 of 30) at
Week 48 and 88% (22 of 25) at Week 96. Drug exposures for both components were also
comparable to historical data in adults and the combination was overall safe and well tolerated.

Although Juluca is not approved by the FDA for use in adolescents, the doses of the component
drugs that make up this FDC tablet is 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-227
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).

The combination of once-daily darunavir/ritonavir (DRV/r) with an INSTI is being investigated in a

randomized non-inferiority trial among virologically suppressed children aged 6 years to <18 years
through the SMILE Penta-17-ANRS 152 clinical trial.53 Participants were randomized to either once-
daily DRV/r with an INSTI or continuing their standard-of-care regimen consisting of a boosted PI or
NNRTI with a nucleoside reverse transcriptase inhibitor backbone. A total of 318 participants were
enrolled between 2016 and 2019, of which 158 were randomized to DRV/r with an INSTI (97%
DTG, 3% elvitegravir). DRV/r with an INSTI was non-inferior to standard of care at Week 48 (HIV
viral load ≥50 copies/mL in 5% for DRV/r with an INSTI vs. 7.6% in the standard-of-care arm;
difference −2.5% [95% CI, −7.6% and 2.5%]). Secondary analyses comparing DRV/r with an INSTI
versus standard of care revealed decreases in CD4 counts (−48.3 cells/mm3 [95% CI, −93.4 and −3.2;
P = 0.036] and mean high-density lipoprotein change from baseline (−4.1 mg/dL [95% CI, −6.7
and −1.4; P = 0.003]), and increases in weight and BMI (+1.97 kg [95% CI, 1.1 and 2.9; P < 0.001]
and +0.66 kg/m2 [95% CI, 0.3 and 1.0; P < 0.001], respectively). A nested PK substudy in
153 adolescents aged ≥12 years to <18 years from SMILE also demonstrated that total and unbound
DTG concentrations were adequate and well above the protein-adjusted 90% inhibitory concentration
for DTG.54 DTG trough concentrations were also comparable to those measured in adults receiving
50 mg once daily. Apparent clearance of the unbound drug was influenced by total bilirubin
concentrations and Asian ethnicity.

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 must be consumed immediately.1 In healthy adults, the use of
crushed tablets resulted in slightly higher exposures than the use of whole tablets.55 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 tube56 or nasogastric tube.57 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-228
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2023;39(6):263-284. Available at: https://pubmed.ncbi.nlm.nih.gov/36352827.

44. Barlow-Mosha LN, Ahimbisibwe GM, Chappell E, et al. Effect of dolutegravir on folate,
vitamin B12 and mean corpuscular volume levels among children and adolescents with
HIV: a sub-study of the ODYSSEY randomized controlled trial. J Int AIDS Soc.
2023;26(9):e26174. Available at: https://pubmed.ncbi.nlm.nih.gov/37766505.

45. 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://pubmed.ncbi.nlm.nih.gov/35306718.

46. Rose PC, De la Rey Nel E, Cotton MF, et al. Decreased hepatic steatosis in South African
adolescents With perinatal HIV switching to dolutegravir-containing regimens. Pediatr
Infect Dis J. 2023;42(7):564-572. Available at:
https://pubmed.ncbi.nlm.nih.gov/36917035.

47. Belfrage E, Soeria-Atmadja S, Naver L. Growth, weight gain and BMI in virally
suppressed children on antiretroviral therapy with specific reference to dolutegravir.
BMC Pediatr. 2023;23(1):339. Available at: https://pubmed.ncbi.nlm.nih.gov/37403042.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-233
48. 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, Washington. Available at:
https://www.natap.org/2017/CROI/croi_11.htm.

49. 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://pubmed.ncbi.nlm.nih.gov/32675772.

50. 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://pubmed.ncbi.nlm.nih.gov/29239893.

51. 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://pubmed.ncbi.nlm.nih.gov/31834000.

52. Puthanakit T, Aurpibul L, Lopez M, et al. Efficacy and safety of dolutegravir /

lamivudine (DTG/3TC) in antiretroviral therapy (ART)- naive adolescents living With
HIV-1: DANCE study week 96 Results. Presented at: International AIDS Conference,
2023; 2023. Available at: https://www.natap.org/2023/IAS/IAS_75.htm.

53. Compagnucci A, Chan MK, Saidi Y, et al. Nucleoside/nucleotide reverse transcriptase

inhibitor sparing regimen with once daily integrase inhibitor plus boosted darunavir is
non-inferior to standard of care in virologically-suppressed children and adolescents
living with HIV –week 48 results of the DA SMILE Penta-17-ANRS 152 clinical trial.
EClinicalMedicine. 2023;60:102025. Available at:
https://pubmed.ncbi.nlm.nih.gov/37304494.

54. Abdalla S, Compagnucci A, Zheng Y, et al. Population pharmacokinetics of unbound and

total dolutegravir concentrations in children aged 12 years and older: a PK substudy of
the SMILE trial. J Antimicrob Chemother. 2023;78(4):1041-1049. Available at:
https://pubmed.ncbi.nlm.nih.gov/36869720.

55. Roskam-Kwint M, Bollen P, Colbers A, et al. Crushing of dolutegravir fixed-dose

combination tablets increases dolutegravir exposure. J Antimicrob Chemother.
2018;73(9):2430-2434. Available at: https://pubmed.ncbi.nlm.nih.gov/29796595.

56. 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://pubmed.ncbi.nlm.nih.gov/28198203.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-234
57. Chrdle A, Jerhotova Z, Vacik M, et al. 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://pubmed.ncbi.nlm.nih.gov/30231834.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-235
Elvitegravir (EVG)
Updated: June 27, 2024
Reviewed: June 27, 2024

Formulations
Tablet: 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 to <25 kg) • Diarrhea

• Limited data are available on the dose of Genvoya in • Fatigue

children with weight ≥14 kg to <25 kg. A study is being • Headache
conducted to assess the safety and efficacy of an
investigational low-dose tablet with EVG 90 mg/cobicistat TAF-Specific Adverse Events
(COBI) 90 mg/FTC 120 mg/TAF 6 mg.
• Increased levels of low-density lipoprotein cholesterol, high-
Child and Adolescent (Weighing ≥25 kg) and Adult Dose density lipoprotein cholesterol, triglycerides, and total
cholesterol
• One tablet once daily with food in antiretroviral therapy
(ART)–naive or treatment-experienced patients who • Glomerular and proximal renal tubular dysfunction (less
have been virologically suppressed (HIV RNA common when compared to TDF)
<50 copies/mL) on a stable ART regimen for at least
6 months with no history of treatment failure and no TDF-Specific Adverse Events
known mutations associated with resistance to the • Glomerular and proximal renal tubular dysfunction
individual components of Genvoya.
• Decreased bone mineral density
[Stribild] Elvitegravir/Cobicistat/Emtricitabine/Tenofovir
• Flatulence
Disoproxil Fumarate (EVG/c/FTC/TDF)
Child and Adolescent (Weighing ≥35 kg) and Adult Dose COBI-Specific Adverse Events
• One tablet once daily with food in ART-naive or • Benign increases in serum creatinine levels (reductions in
treatment-experienced patients who have been estimated glomerular filtration) due to inhibition of tubular
virologically suppressed (HIV RNA <50 copies/mL) on a secretion of creatinine
stable ART 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-236
 Special Instructions
• Administer both Genvoya and Stribild with food.
• Genvoya and Stribild should be administered at least
4 hours before or after antacids and supplements or
multivitamins that contain iron, calcium, aluminum, and/or
magnesium.
• When using Genvoya or Stribild, monitor estimated
creatinine clearance (CrCl), urine glucose, and urine
protein at baseline and every 3 to 6 months while on
therapy. In patients who are at risk of renal impairment,
also monitor serum phosphate. Patients with an increase in
serum creatinine levels >0.4 mg/dL should be closely
monitored for renal safety.
• Screen patients for hepatitis B virus (HBV) infection before
initiating FTC, TDF, or TAF. Severe acute exacerbation of
HBV can occur when FTC, TDF, or TAF are discontinued.
In patients with HBV, 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 COBI, TDF, and TAF
sections for further details on the metabolism of these
drugs.

EVG Dosing in Patients with Hepatic Impairment

• Stribild and Genvoya should not be used in patients with
severe hepatic impairment.

EVG 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-237
Drug Interactions
Additional information about drug interactions is available in the Adult and Adolescent
Antiretroviral Guidelines and the HIV Drug Interaction Checker.

• 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). COBI itself does not
have antiretroviral (ARV) activity, but it is a cytochrome P450 (CYP) 3A4 inhibitor that acts as a
pharmacokinetic (PK) enhancer, similar to ritonavir (RTV).2 EVG is metabolized predominantly
by CYP3A4, secondarily by uridine diphosphate glucuronosyltransferase 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 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.3 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.4

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,

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-238
 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
pronounced in patients with preexisting renal disease.4 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.5,6
However, Genvoya is associated with greater increases in lipid levels than Stribild, according to
findings from large-scale clinical trials in adults.

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 (RAL).7

Pediatric Use
Approval
Genvoya (EVG/c/FTC/TAF) is approved by the U.S. Food and Drug Administration (FDA) for use
in ARV-naive children and adolescents with HIV weighing ≥25 kg. 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.

Stribild (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. 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
EVG/c/FTC/TDF was found to be non-inferior to efavirenz/emtricitabine/TDF (EFV/FTC/TDF)9-11
and atazanavir/ritonavir plus FTC/TDF in adults through 144 weeks of treatment.12-14

Studies of EVG/c/FTC/TDF and EVG/c/FTC/TAF in children with HIV aged ≥12 years and
weighing ≥35 kg have demonstrated 90% efficacy (as measured by virological suppression) similar
to that seen in adults through 24 weeks and 48 weeks of study, respectively.15,16

EVG/c/FTC/TAF is FDA approved to treat children weighing ≥25 kg based on 24 weeks of data in
23 children.17 In this study, all 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
and all participants maintained virological suppression (HIV-1 RNA <50 copies/mL) at Week 24.

A retrospective analysis of integrase strand transfer inhibitor (INSTI) use in children and adolescents
showed that 83.7% (61/73) of patients on an elvitegravir/cobicistat (EVG/c)-containing therapy

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-239
continued their prescribed regimen through the end of the study follow-up period (median
[interquartile range (IQR)] 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.18

In a PK, safety, and efficacy study with a low-dose tablet in children aged ≥2 years and weighing
≥14 kg to <25 kg, children had to be virologically suppressed (HIV RNA <50 copies/mL) for at least
6 months prior to entry.19 In the most recent analysis, virologic suppression was maintained20 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
the criteria for resistance analyses through Week 48. 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 24.19

Pharmacokinetics
EVG/c/FTC/TDF (Stribild)

The PK of EVG 150 mg/c 150 mg/FTC 200 mg/TDF 300 mg tablet were evaluated in 14 treatment-
naive adolescents with HIV who were between 12 and <18 years of age and weighing ≥35 kg. EVG
area under the plasma concentration versus time curve over the dosing interval (AUCtau) and peak
concentrations (Cmax) were 30% higher (90% confidence interval [CI], 105% to 162%) and 42%
higher (90% CI, 116% to 173%), respectively, in comparison to historical data in adults. EVG
concentrations at the end of the dosing interval (Ctau) were 6% higher (90% CI, 70% to 160%) than
in adults, and approximately ninefold higher than the protein-adjusted 95% inhibitory
concentration (PA-IC95) of 44.5 ng/mL for EVG. COBI, FTC, and TFV exposures were comparable
to those measured in adults.16

EVG/c/FTC/TAF (Genvoya)

The PK of EVG 150 mg/c 150 mg/FTC 200 mg/TAF 10 mg tablet have been evaluated in
adolescents 12 to <18 years of age weighing ≥35 kg and children 6 to <12 years of age weighing
≥25 kg.17 AUCtau, Cmax, and Ctau for EVG, COBI, FTC, TAF, and TFV were comparable to or higher
than those measured in adults with HIV in both cohorts (see Tables A and B below).

The PK of a low-dose FDC tablet containing EVG 90 mg/c 90 mg/FTC 120 mg/TAF 6 mg were
evaluated in 27 children with HIV weighing ≥14 kg and <25 kg.19 EVG and TAF AUCtau were higher
in comparison to historical data in adults receiving full-strength Genvoya (see Tables A and B
below). EVG Ctau was 21% lower (90% CI [53.1% to 117%]) in children versus adults but was
approximately 4.4-fold higher and ninefold higher than the PA-IC95 and protein-adjusted 50%
inhibitory concentration (PA-IC50) for wild-type virus, respectively. However, EVG Ctau measured in
this cohort was lower than those previously measured in children and adolescents weighing ≥25 kg
on EVG at the 150-mg dose. COBI, FTC, and TFV exposures were all comparable to or higher than
historical data in adults.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-240
Table A. 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 kg19 Weighing ≥25 kg17 Weighing ≥35 kg15

Mean Mean Mean

n GLSM n n n
(%CV) (%CV) (%CV)
EVG AUCtau (ng∙h/mL) 27 29,900 22 33,814 (58%) 24 23,840 (26%) 19 22,800 (35%)
Cmax (ng/mL) 27 2,850 23 3,055 (39%) 24 2,230 (19%) 19 2,100 (34%)
Ctau (ng/mL) 27 195 23 370 (119%) 24 301 (81%) 19 290 (62%)
COBI AUCtau (ng∙h/mL) 27 12,300 20 15,891 (52%) 23 8,241 (36%) 19 9,500 (34%)
Cmax (ng/mL) 27 1,270 23 2,079 (47%) 24 1,202 (35%) 19 1,500 (28%)
Ctau (ng/mL) 27 16.6 23 96 (169%) 15 25 (180%) 19 20 (85%)
FTC AUCtau (ng∙h/mL) 27 18,600 22 20,629 (19%) 24 14,424 (24%) 19 11,714 (17%)
Cmax (ng/mL) 27 2,810 23 3,397 (27%) 24 2,265 (23%) 19 2,056 (20%)
Ctau (ng/mL) 27 77.4 23 115 (24%) 23 102 (39%) 19 95 (47%)
TAF AUCtau (ng∙h/mL) 27 344 23 333 (45%) 24 189 (56%) 539 206 (72%)
Cmax (ng/mL) 27 218 23 313 (61%) 24 167 (64%) 539 162 (51%)
TFV AUCtau (ng∙h/mL) 27 327 23 440 (21%) 23 288 (19%) 841 293 (27%)
Cmax (ng/mL) 27 19.1 23 26 (21%) 23 18 (24%) 841 15 (26%)
Ctau (ng/mL) 27 11.1 23 15 (25%) 23 10 (21%) 841 11 (29%)
TFV-DP in
C0h (fmol/106 cells) — — — — 12 222 (94%) 21 121 (91%)
PBMC
a Adult pharmacokinetic parameters for elvitegravir, cobicistat, and emtricitabine were derived from intensive pharmacokinetic

analysis from a Phase 2 study GS 102; data for tenofovir alafenamide and tenofovir were from population pharmacokinetic
analyses in Phase 3 GS studies 104 and 111.
Key: AUCtau = area under the plasma concentration versus time curve over the dosing interval; C0h = concentration at
time 0 (pre-dose); Cmax = maximum observed plasma concentration of drug; Ctau = 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; PBMC = peripheral blood mononuclear
cell; TAF = tenofovir alafenamide; TFV = tenofovir; TFV-DP = tenofovir-diphosphate

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-241
Table B. 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

Component Parameter Children Aged ≥2 Years Children Aged 6 to

Dose and Weighing ≥14 to Dose <12 Years and
(mg) <25 kg17 (mg) Weighing ≥25 kg19
EVG AUCtau (ng∙h/mL) 139 (112,172) 134 (104,173)
Cmax (ng/mL) 90 143 (113,180) 150 141 (115,173)
Ctau (ng/mL) 79 (53,117) 86 (55,133)
COBI AUCtau (ng∙h/mL) — 158 (126,198)
Cmax (ng/mL) 90 — 150 127 (98,165)
Ctau (ng/mL) — 171 (95,310)
FTC AUCtau (ng∙h/mL) — 175 (160,192)
Cmax (ng/mL) 120 — 200 164 (145,184)
Ctau (ng/mL) — 125 (107,146)
TAF AUCtau (ng∙h/mL) 193 (166,224) 171 (147,199)
Cmax (ng/mL) 150 (116,195) 182 (146,225)
TFV AUCtau (ng∙h/mL) 6 — 10 152 (142,163)
Cmax (ng/mL) — 173 (161,186)
Ctau (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: AUCtau = area under the plasma concentration versus time curve over the dosing interval; Cmax = maximum observed
plasma concentration of drug; COBI = cobicistat; Ctau = 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

Coadministration of Elvitegravir, Cobicistat, and Darunavir

The combination of Stribild or Genvoya plus DRV may provide a low-pill-burden regimen for
treatment-experienced individuals. However, an unfavorable drug interaction between EVG/c and
DRV is possible, and the available data on the significance of the interaction and efficacy are
conflicting.21-24 The most rigorous drug interaction study in HIV-seronegative adults found 21%
lower DRV trough concentrations (Ctrough) and 52% lower EVG Ctrough in combination with DRV
800 mg plus EVG/c 150 mg/150 mg once daily compared to the administration of either DRV/c
800 mg/150 mg once daily or EVG/c 150 mg/150 mg once daily alone.25 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 on 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.23 Given

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-242
the uncertainty around the true magnitude of the drug interaction and the absence of pediatric data,
viral load should be closely monitored in children taking this combination.

Toxicity
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).6 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.

In children and adolescents, EVG/c/FTC/TAF is generally preferred over EVG/c/FTC/TDF because

of the lower risk of renal and bone toxicity with EVG/c/FTC/TAF compared to EVG/c/FTC/TDF
(see the Tenofovir Alafenamide section). Long-term bone safety data through 96 weeks with
EVG/c/FTC/TAF in adolescents weighing ≥35 kg revealed no concerns for toxicity26 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.27

In the approval study of EVG/c/FTC/TAF in children weighing ≥25 kg, no study discontinuations
occurred due to medication toxicity. 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.20 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.17 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),28 the median
CD4 count decline at 48 weeks was 25 cells/mm3 and at 96 weeks was 45 cells/mm3. Additionally,
the CD4 percentage did not significantly change across Weeks 24, 48, and 96.20 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.29

In an ongoing PK, safety, and efficacy study with a low-dose EVG/c/FTC/TAF tablet in children
aged ≥2 years and weighing ≥14 kg to <25 kg,19 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.27 CD4 counts decreased20 by a mean
of 187 cells/mm3 between baseline and Week 48, although the CD4 percentage did not differ (mean
[standard deviation] change of 0.0 [<5.0]). In a cumulative analysis of two pediatric cohorts (Cohort
2 aged 6 to <12 years and weighing ≥25 kg and Cohort 3 aged ≥2 years and weighing ≥14 kg to
<25 kg) on EVG/c/FTC/TAF once daily for at least 48 weeks, the absolute lymphocyte counts and
absolute CD4 counts decreased from baseline to Week 48 in both cohorts, with larger decreases in the
younger cohort.30 Median (IQR) absolute lymphocyte counts (×103 per µL) at baseline in Cohort 2

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-243
and Cohort 3 were 2.31 (range, 1.92–2.78) and 2.96 (range, 2.39–3.82), respectively. The absolute
lymphocyte counts decreased during treatment (particularly in Cohort 3), with changes of −0.04
(range, −0.67 to 0.29) and −0.52 (range, −1.16 to 0.05) in Cohorts 2 and 3, respectively, at Week 48.
Small decreases were seen in median (IQR) absolute CD4 counts (cells/µL), with changes of −33
(−194 to 80) and −187 (−370 to 44) in Cohorts 2 and 3, respectively, at Week 48. However, the
relative proportion of CD4 cells and the CD4:CD8 ratio remained stable during treatment. Overall,
the decline in absolute CD4 counts mirrored known physiological fluctuations in young children and
was mainly observed in those aged <6 years.30

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-244
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and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial
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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://pubmed.ncbi.nlm.nih.gov/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.
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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.
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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.
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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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/27765666.

16. Gaur A, Fourle J, et al. Pharmacokinetics, efficacy and safety of an integrase inhibitor
STR in HIV-infected adoelscents. Presented at: 21st Conference on Retroviruses and
Opportunistic Infections; 2014. Boston, MA. Available at:
https://www.natap.org/2014/CROI/croi_176.htm.

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
Child Adolescent Health. 2017;1(1):27-34. Available at:
http://www.sciencedirect.com/science/article/pii/S2352464217300093?via%3Dihub.

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18. 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-
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19. 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.

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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 2021. Virtual Meeting.
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21. Gutierrez-Valencia A, Benmarzouk-Hidalgo OJ, Llaves S, et al. Pharmacokinetic

interactions between cobicistat-boosted elvitegravir and darunavir in HIV-infected
patients. J Antimicrob Chemother. 2017;72(3):816-819. Available at:
https://pubmed.ncbi.nlm.nih.gov/27999051.

22. Harris M, Ganase B, Watson B, et al. 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://pubmed.ncbi.nlm.nih.gov/29096670.

23. 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://pubmed.ncbi.nlm.nih.gov/27753684.

24. Naccarato MJ, Yoong DM, Fong IW, et al. 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://pubmed.ncbi.nlm.nih.gov/29385867.

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: http://www.natap.org/2012/pharm/Pharm_28.htm.

26. 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-247
27. Rakhmanina N, Gordon CN, E., Kosalaraksa PA, S. Shao, Y., 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; 2021.
Virtual Meeting. Available at:
https://academicmedicaleducation.com/meeting/international-workshop-hiv-pediatrics-
2021/abstract.

28. Rakhmanina N, Natukunda E, Kosalaraksa P, 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.
Available at: https://academicmedicaleducation.com/meeting/international-workshop-
hiv-pediatrics-2019/abstract/safety-and-efficacy-ecftaf.

29. 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/.

30. Rakhmanina N, Natukunda E, Strehalu R, et al. Longitudinal lymphocyte dynamics in

virologically suppressed children with HIV initiating single-tablet elvitegravir, cobicistat,
emtricitabine and tenofovir alafenamide Presented at: IAS Conference on HIV Science;
2023. Brisbane, Australia. Available at: https://www.natap.org/2023/IAS/IAS_93.htm.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-248
Raltegravir (RAL, Isentress)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 13.1. Drug Dosing hypersensitivity reaction, and toxic epidermal
Recommendations for Antiretroviral Prophylaxis and necrolysis
Presumptive HIV Therapy in Infants With In Utero or
Intrapartum Exposure to HIV for information about using • Nausea, diarrhea
raltegravir (RAL) for the prevention of perinatal HIV • Headache, dizziness, fatigue
transmission.
• Insomnia
Neonate (Weighing ≥2 kg) Dosea,b
• Fever
RAL Oral Suspension Dosing Table for Full-Term Neonates
from Birth to Age 4 Weeks • Creatine phosphokinase elevation, muscle weakness,
and rhabdomyolysis
Neonates Aged ≥37 Weeks and Weighing ≥2 kg
Special Instructions
Volume (Dose) of
Weight • RAL can be given without regard to food.
Suspensionb
• Coadministration or staggered administration of
Birth to 1 Week of Age: Approximately aluminum-containing and magnesium-containing
Once-Daily Dosing 1.5 mg/kg per Dose antacids is not recommended with any RAL
2 kg to <3 kg 0.4 mL (4 mg) once daily formulations.

3 kg to <4 kg 0.5 mL (5 mg) once daily • Significant drug interactions are more likely to occur
when the RAL HD formulation is used once daily. The
4 kg to <5 kg 0.7 mL (7 mg) once daily following drugs should not be coadministered with
once-daily RAL HD dosing: calcium carbonate
1–4 Weeks of Age: Approximately antacids, rifampin, tipranavir/ritonavir, and etravirine.
Twice-Daily Dosing 3 mg/kg per Dose
• Chewable tablets can be chewed, crushed (before
2 kg to <3 kg 0.8 mL (8 mg) twice daily administration), or swallowed whole.
3 kg to <4 kg 1 mL (10 mg) twice daily • Film-coated tablets, including HD tablets, must be
swallowed whole.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-249
 4 kg to <5 kg 1.5 mL (15 mg) twice daily • The chewable tablets and oral suspension have better
bioavailability than the film-coated tablets. Because the
a RAL is metabolized by uridine diphosphate glucuronyl
formulations are not interchangeable, do not
transferase (UGT) 1A1, and enzyme activity is low at birth;
substitute chewable tablets or oral suspension for
enzyme activity increases rapidly during the next 4 to 6 weeks
film-coated tablets. See specific recommendations for
of life.
proper dosing of different formulations.
b For neonates, most of the prepared oral suspension will be
• The chewable tablets should be stored in the original
discarded. The volume for the required dose is much smaller
package with a desiccant to protect them from
than the 10 mL suspension that is prepared.
moisture.
Note: If the birthing parent has taken RAL 2 to 24 hours prior to • Instructions for preparing and administering the
delivery, the neonate’s first dose may be delayed until 24 to 48 chewable tablet as a crushed tablet are as follows:
hours after birth. Place the tablet(s) in a small, clean cup. For each
tablet, add a teaspoon (~5 mL) of liquid (e.g., water,
Infant >4 Weeks of Age and Child (Weighing ≥3 kg to juice, or breast milk). Within 2 minutes, the tablet(s) will
<20 kg) Dose absorb the liquid and fall apart. Using a spoon, crush
• For children weighing 3 to 20 kg, either oral suspension or any remaining pieces of the tablet(s). Immediately
chewable tablets can be used. administer the entire dose orally. If any portion of the
dose is left in the cup, add another teaspoon (~5 mL)
RAL Oral Suspension Dosing Table for Patients Aged >4 of liquid, swirl, and administer immediately.
Weeksa
• The chewable tablets contain phenylalanine, a
Note: The maximum dose of oral suspension is 10 mL component of aspartame. Phenylalanine can be
(RAL 100 mg) twice daily. harmful to patients with phenylketonuria, and the
necessary dietary adjustments should be made in
Twice-Daily Volume (Dose) consultation with a metabolic specialist.
Weight
of Suspensionb
• The oral suspension comes in a kit that includes
3 kg to <4 kg 2.5 mL (25 mg) twice daily instructions for use, mixing cups, oral dosing syringes,
and 60 foil packets. Detailed instructions for
4 kg to <6 kg 3 mL (30 mg) twice daily preparation are provided in the Instructions for Use
6 kg to <8 kg 4 mL (40 mg) twice daily document.1 Each single-use foil packet contains
100 mg of RAL, which will be suspended in 10 mL of
8 kg to <10 kg 6 mL (60 mg) twice daily water for a final concentration of RAL 10 mg/mL.
10 kg to <14 kg 8 mL (80 mg) twice daily Gently swirl the mixing cup for 45 seconds in a circular
motion to mix the powder into a uniform suspension.
14 kg to <20 kg 10 mL (100 mg) twice daily
• Do not shake the oral suspension. Dose should be
aThe weight-based dose recommendation for the oral administered within 30 minutes of mixing; unused
suspension is based on a dose of approximately RAL 6 mg/kg solution should be discarded as directed in the
per dose twice daily. Instructions for Use document. For neonates, most of
the prepared oral suspension will be discarded,
bFor neonates, most of the prepared oral suspension will be because the volume for the required dose is much
discarded, because the volume for the required dose is much smaller than 10 mL.
smaller than 10 mL.

Child and Adolescent Dose for Chewable Tablets, Film- Metabolism/Elimination

Coated Tablets, and HD Tablets
• UGT1A1-mediated glucuronidation
Children Weighing ≥3 kg
RAL Dosing in Patients with Hepatic Impairment
• Weighing <25 kg
• No dose adjustment is necessary for patients with
o Chewable tablets twice daily. See the table below for mild-to-moderate hepatic insufficiency who are
chewable tablet doses. receiving RAL twice daily.
• Weighing ≥25 kg

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-250
 o RAL 400-mg, film-coated tablets twice daily or chewable • No studies have been conducted on the use of RAL
tablets twice daily. See the table below for chewable HD in patients with hepatic impairment. Therefore,
tablet doses. administering RAL HD is not recommended in
patients with hepatic impairment.
Children and Adolescents Weighing ≥40 kg
• The effect of severe hepatic impairment on RAL
• Two RAL 600-mg HD tablets (1,200 mg) once daily
pharmacokinetics has not been studied.
• This dose is for antiretroviral therapy–naive or virologically
suppressed patients who are on an initial dose of RAL RAL Dosing in Patients with Renal Impairment
400 mg twice daily.
• No dose adjustment is necessary in patients with any
Chewable Tablet Dosing Tablea degree of renal impairment.

Note: The maximum dose of chewable tablets is RAL 300 mg

twice daily.

Twice-Daily Number of
Weight
Dose Chewable 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— 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-251
 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
rifampicin for TB prophylaxis, three to four times the currently recommended dose of 12 mg/kg
twice daily was needed4 to achieve target trough concentrations (Ctrough) >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. Ctrough in
adults is approximately 30% lower with RAL HD 1,200 mg once daily than with RAL 400 mg
twice daily. A lower Ctrough increases the potential for clinically significant drug interactions with
interfering drugs that decrease RAL exposure and further lower Ctrough. 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, alanine
aminotransferase, 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, DRESS (drug reaction with
eosinophilia and systemic symptoms),5,6 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-252
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 P1110.7

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
non-inferior 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.8-10
Results from the SPRING-2 study in treatment-naive adults showed that RAL and dolutegravir (DTG)
were equally effective and had similar safety profiles.11 ACTG A5257 compared RAL to ATV/r and
darunavir/ritonavir; all regimens had equivalent virologic efficacy, but RAL had better tolerability.12
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. Once-daily dosing with RAL 1,200 mg (taken
as two 600-mg HD tablets) was found to be as effective as dosing with RAL 400 mg twice daily.
Discontinuation rates due to AEs were not different between the two groups.13 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 PK, 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 log10 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 loads14-16 <400 copies/mL.

A systematic review of observational and clinical trials published on the effectiveness and safety of
RAL and DTG for treating children and adolescents with HIV was conducted by the World Health
Organization. The authors concluded that both medications are safe and effective as preferred
regimens.17

Efficacy and Pharmacokinetics of Once-Daily Dosing in Children and Adults

RAL PK exhibit considerable intrasubject and intersubject variability.18,19 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
Ctrough concentrations <45 nM (20 ng/mL) were at greater risk of experiencing treatment failure.18,19
Overall drug exposures were similar in both groups, but the association between higher risk of
treatment failure and lower Ctrough concentrations suggests that maintaining RAL trough plasma
concentrations >45 nM (20 ng/mL) is important for efficacy.18,19

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-253
The highest concentration (Cmax) 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.7

Efficacy and Pharmacokinetics in Children

IMPAACT P1066 evaluated the PK, 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.15,16

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)
AUC0–12h (μM·h)c,d C12h (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: AUC0–12h 14–25 µM·h (6–11 mg·h/L);
C12h nM ≥33 nM (14.7 ng/mL)
d Pharmacokinetic targets for oral suspension: AUC0–12h 14–45 µM·h (6–20 mg·h/L); C12h nM ≥75 nM (33.3 ng/mL)
e To approximate 6 mg/kg twice daily
Key: AUC = area under the curve; AUC0–12h = AUC from time zero to 12 hours after drug administration; C12h = concentration at
12 hours (trough); CV = coefficient of variation

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.16,20 Participants 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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-254
adults: PK targets were a geometric mean (GM) AUC from time zero to 12 hours after drug
administration (AUC0–12h) of 14 µM·h to 25 µM·h and a GM 12-hour concentration (C12h) >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) cell count increase16 of 156 cells/mm3 (4.6%). Among 36 participants 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.16 Overall, RAL was well
tolerated when administered as a film-coated tablet twice daily in participants aged 6 years to <19
years and as chewable tablets at a dose of approximately 6 mg/kg twice daily in participants aged 2
years to <12 years, with favorable virologic and immunologic responses.21

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 participants 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 AUC0–12h of
14 µM·h to 45 µM·h and a GM C12h ≥75 nM (33.3 ng/mL). These targets were modified so that an
estimated >90% of patients would have C12h above the 45 nM threshold. By Week 48, two
participants 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 log10 decline in HIV RNA or <400 copies/mL at 48 weeks, was achieved in >87% of participants.
At 48 weeks of follow up, 45.5% of participants had HIV RNA <50 copies/mL and mean CD4 count
increases of 527.6 cells/mm3 (7.3%). Four participants 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.15

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.22 Eligible participants were

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-255
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.22

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.22

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
P1097.23 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).24

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.25 Protocol exposure targets for each participant were
AUC from time zero to 24 hours after drug administration (AUC0–24hr) 12 mg·h/L to 40 mg·h/L,
AUC0–12hr 6 mg·h/L to 20 mg·h/L, and C12h or C24h >33 ng/mL. Safety was assessed using clinical and
laboratory evaluations.23,26,27

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.27

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-256
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%)

AUC0–24h (mg·h/L)a 38.2 (42.0%) 42.9 (25.3%) — —
AUC0–12h (mg·h/L) — — 14.3 (49.5%) 18.3 (62.8%)
Ctrough (ng/mL)b 948 (84.0%) 946 (74.0%) 176 (162.1%) 274 (176.4%)
Cmax (ng/mL)c 2,350 (36.5%) 2,565 (23.1%) 2,849 (47.5%) 3,667 (46.3%)
Tmax (hours) 5.4 (71.5%) 3.8 (88.8%) 2.3 (77.1%) 1.9 (52.3%)
T1/2 (hours) 15.8 (101.4%) 14.4 (69.5%) 2.5 (34.1%) 2.9 (20.7%)
a AUC targets: AUC0–24h 12–40 mg·h/L and AUC0–12h 6–20 mg·h/L.
b Ctrough
concentration >33 ng/mL. For initial dose, the last measurable plasma concentration collected at 24 hours was used. For
Days 15–18, C12h 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 postdose).
c Cmax <8,724 ng/mL
d AUC0–24h could not be estimated for one infant.
e AUC0–12h and Ctrough could not be estimated for one infant with delayed absorption.
f AUC0–12h and Cmax could not be estimated for one infant with incomplete sample collection.
Key: AUC = area under the curve; AUC0–12h = AUC from time zero to 12 hours after drug administration; AUC0–24h = AUC from
time zero to 24 hours after drug administration; Cmax = maximum concentration; Ctrough = trough concentration; CV = coefficient
of variation; GM = geometric mean; PK = pharmacokinetic; RAL = raltegravir; T1/2 = half-life; Tmax = 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, AUC0–24h 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.7 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-257
should have their first dose of RAL delayed until 24 to 48 hours after birth.26,27 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.28 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
P1097.29 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.29

Two case reports of preterm infants who received RAL to prevent perinatal transmission have been
published.30,31 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.30,31 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 PK 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.32 In adult volunteers, the PK of RAL 800 mg taken once
daily by chewing was compared with the PK 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.33 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.34 Compared with the
RAL 400-mg tablet formulation, the RAL 600-mg tablet has higher relative bioavailability.7,35
Interpatient and intrapatient variability for PK parameters of RAL are considerable, especially with
the film-coated tablets.7,36 Because of differences in the bioavailability of various formulations, the

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-258
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.2,37 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.38 An in vitro evaluation demonstrated that the chewable tablets are stable in various liquids,
including water, apple juice, and breast milk.38 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.15,16 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.39,40

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-259
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17. Townsend CL, O’Rourke J, Milanzi E, et al. Effectiveness and safety of dolutegravir and
raltegravir for treating children and adolescents living with HIV: a systematic review. J Int
AIDS Soc. 2022;25(11):e25970. Available at: https://pubmed.ncbi.nlm.nih.gov/36377082.

18. 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://pubmed.ncbi.nlm.nih.gov/22430964.

19. 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://pubmed.ncbi.nlm.nih.gov/25753401.

20. 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://pubmed.ncbi.nlm.nih.gov/24600298.

21. 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://pubmed.ncbi.nlm.nih.gov/27615375.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-261
22. 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://pubmed.ncbi.nlm.nih.gov/30527329.

23. 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://pubmed.ncbi.nlm.nih.gov/25162819.

24. Clarke DF, Wong RJ, Wenning L, et al. Raltegravir in vitro effect on bilirubin binding.
Pediatr Infect Dis J. 2013;32(9):978-980. Available at:
https://pubmed.ncbi.nlm.nih.gov/23470680.

25. 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
neonatal dosing regimens: IMPAACT P1110. J Acquir Immune Defic Syndr. 2019;82(4):392-
398. Available at: https://pubmed.ncbi.nlm.nih.gov/31658182.

26. 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://pubmed.ncbi.nlm.nih.gov/31215170.

27. 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://pubmed.ncbi.nlm.nih.gov/31913995.

28. 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://pubmed.ncbi.nlm.nih.gov/35863363.

29. 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://pubmed.ncbi.nlm.nih.gov/32925360.

30. 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://pubmed.ncbi.nlm.nih.gov/30882734.

31. 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://pubmed.ncbi.nlm.nih.gov/28198351.

32. 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://pubmed.ncbi.nlm.nih.gov/22964253.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-262
33. 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://pubmed.ncbi.nlm.nih.gov/24988438.

34. 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. 2010. San Francisco, CA. Available at:
https://www.natap.org/2010/CROI/croi_118.htm

35. Krishna R, Rizk ML, Larson P, et al. Single- and multiple-dose pharmacokinetics of once-
daily formulations of raltegravir. Clin Pharmacol Drug Dev. 2018;7(2):196-206. Available
at: https://pubmed.ncbi.nlm.nih.gov/28419778.

36. 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://pubmed.ncbi.nlm.nih.gov/22406652.

37. 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.

38. Teppler H, Thompson K, Chain A, et al. Crushing of raltegravir (RAL) chewable tablets for
adminstration in infants and young children. Presented at: International Workshop on HIV
Pediatrics. 2017. Paris, France.

39. Archary M, Zanoni BC, Lallemant M, et al. 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://pubmed.ncbi.nlm.nih.gov/31815839.

40. 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://pubmed.ncbi.nlm.nih.gov/36053612.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-263
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-264
 Cobicistat (COBI, Tybost)
Updated: June 27, 2024
Reviewed: June 27, 2024

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 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

Cobicistat (COBI) Is a Pharmacokinetic Enhancer • COBI is an inhibitor of renal tubular transporters of
creatinine. This increases serum creatinine and
• The only use of COBI is as a pharmacokinetic (PK) enhancer
reduces the estimated glomerular filtration rate, with no
(boosting agent) for certain protease inhibitors (PIs) and
change in glomerular function.
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
Child and Adolescent (Weighing ≥35 kg) and Adult Dose
has a PK-boosting effect that is comparable to RTV
• COBI 150 mg with atazanavir (ATV) 300 mg administered at 100 mg.
the same time with food
• Drug interactions may differ between RTV and COBI,
Child and Adolescent (Weighing ≥40 kg) and Adult Dose because COBI is a stronger P-glycoprotein inhibitor
and lacks some of the induction effects of RTV.
• COBI 150 mg with darunavir (DRV) 800 mg administered at
the same time with food • Do not administer COBI with RTV or with FDC tablets
that contain COBI.
[Evotaz] ATV/COBI • COBI is not recommended for use with more than
Child and Adolescent (Weighing ≥35 kg) and Adult Dose one ARV drug that requires PK enhancement
(e.g., EVG used in combination with a PI).
• One tablet once daily with food
• Using COBI with PIs other than once-daily ATV
• Use in combination with other antiretroviral (ARV) drugs. 300 mg or DRV 800 mg is not recommended.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-265
 [Genvoya] Elvitegravir (EVG)/COBI/Emtricitabine (FTC)/ • Patients with a confirmed increase in serum creatinine
Tenofovir Alafenamide (TAF) >0.4 mg/dL from baseline should be closely monitored
for renal safety.
Child (Weighing ≥14 to <25 kg)
• When using COBI in combination with TDF, monitor
• Limited data currently exist on the appropriate dose of
serum creatinine, urine protein, and urine glucose at
Genvoya in children weighing ≥14 kg to <25 kg. Studies are
baseline and every 3 to 6 months while the patient is
currently being conducted to assess the safety and efficacy of
receiving therapy (see Table 17i. Nephrotoxic Effects).
a low-dose tablet with EVG 90 mg/COBI 90 mg/
In patients who are at risk of renal impairment, serum
FTC 120 mg/TAF 6 mg.
phosphate also should be monitored.
Child and Adolescent (Weighing ≥25 kg) and Adult Dose • For information on crushing and cutting tablets,
• One tablet once daily with food see Information on Crushing and Liquid Drug
Formulations from Toronto General Hospital.
[Prezcobix] DRV/COBI
Metabolism/Elimination
Child and Adolescent (Weighing ≥40 kg) and Adult Dose
• COBI is a strong inhibitor of cytochrome P450 (CYP)
• One tablet once daily with food
3A4 and a weak inhibitor of CYP2D6.
• Use in combination with other ARV drugs.
COBI Dosing in Patients with Hepatic Impairment
[Stribild] EVG/COBI/FTC/Tenofovir Disoproxil
• COBI does not require dose adjustment in patients
Fumarate (TDF)
with mild-to-moderate hepatic impairment. No data are
Child and Adolescent (Weighing ≥35 kg) and Adult Dose available in patients with severe hepatic impairment.
Dosing recommendations for medications that are
• One tablet once daily with food
coadministered with COBI should be followed.
• The Panel on Antiretroviral Therapy and Medical Management
• Genvoya, Prezcobix, Stribild, and Symtuza are not
of Children Living with HIV recommends using Stribild only in
recommended in patients with severe hepatic
patients with sexual maturity ratings of 4 or 5.
impairment.
[Symtuza] DRV/COBI/FTC/TAF • Evotaz is not recommended in patients with any
Child and Adolescent (Weighing ≥40 kg) and Adult Dose degree of hepatic impairment.

• One tablet once daily with food COBI Dosing in Patients with Renal Impairment
• COBI does not require a dose adjustment in patients
with renal impairment, including those with severe
renal impairment. Dosing recommendations for
medications that 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.
• 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-266
 • Stribild 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 FTC
and TDF in these patients cannot be achieved with an
FDC tablet.
• Symtuza is not recommended in patients with
estimated CrCl <30 mL/min.

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 (ARV) 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.2 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.1,3
• 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 (Ctrough) of EVG was 50% lower than the Ctrough seen in people who
received elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate
(EVG/c/FTC/TDF) without DRV.4 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.5
• Integrase inhibitors: In one small study, dolutegravir (DTG) Ctrough was 107% higher when
DTG was administered with darunavir/cobicistat (DRV/c) than when it was administered
with darunavir/ritonavir.6 Bictegravir (BIC) area under the curve increases 74% when BIC is
administered with DRV/c.7

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-267
 • 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.8,9

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 ARV 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.10 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.11 The FDA has not approved COBI as a component
of Genvoya for use in children weighing <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),12 is approved by the FDA at
the adult dose for use in children and adolescents weighing ≥35 kg. COBI, coformulated with DRV
(as Prezcobix)13 and as a component of Symtuza,14 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-268
 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. 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: http://www.natap.org/2012/pharm/Pharm_24.htm.

3. 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. Available at:
https://www.natap.org/2013/Pharm/Pharm_15.htm.

4. 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: http://www.natap.org/2012/pharm/Pharm_28.htm.

5. Gutierrez-Valencia A, Trujillo-Rodriguez M, Fernandez-Magdaleno T, et al.

Darunavir/cobicistat showing similar effectiveness as darunavir/ritonavir monotherapy
despite lower trough concentrations. J Int AIDS Soc. 2018;21(2). Available at:
https://pubmed.ncbi.nlm.nih.gov/29430854.

6. 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://pubmed.ncbi.nlm.nih.gov/28333266.

7. Zhang H, Custudio J, Wei X, et al. Clinical pharmacology of the HIV integrase strand
transfer inhibitor bictegravir. Presented at: Conference on Retrovirsues and Opportunistic
Infections; 2017. Seattle, WA. Available at:
http://www.croiconference.org/sessions/clinical-pharmacology-hiv-integrase-strand-
transfer-inhibitor-bictegravir.

8. 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://pubmed.ncbi.nlm.nih.gov/23590676.

9. 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://pubmed.ncbi.nlm.nih.gov/23535292.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-269
 10. 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.

11. 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.

12. Evotaz (atazanavir/cobicistat ) [package insert]. Food and drug Administration. 2020.
Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/206353s007lbl.pdf.

13. Prezcobix (darunavir/cobicistat) [package insert]. Food and Drug Administration. 2022.
Available at:
https://www.accessdata.fda.gov/drugsatfda_docs/label/2022/205395s024lbl.pdf.

14. 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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-270
Ritonavir (RTV, Norvir)
Updated: June 27, 2024
Reviewed: June 27, 2024

Formulations
Oral Powder: 100 mg per packet

Tablet: 100 mg

Generic Formulation
• 100-mg tablet

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 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

Ritonavir (RTV) as a Pharmacokinetic Enhancer • Gastrointestinal (GI) intolerance, nausea, vomiting,
diarrhea
• RTV is used as a pharmacokinetic (PK) enhancer of other
protease inhibitors (PIs). The recommended dose of RTV varies • Hyperlipidemia, especially hypertriglyceridemia
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
• RTV oral powder should be used only for dosing increments of
100 mg and cannot be used for doses <100 mg. • Administer RTV with food to increase absorption
and reduce the likelihood and severity of GI
[Kaletra] Lopinavir/Ritonavir adverse events.
Infant, Child, Adolescent, and Adult Dose • Do not administer RTV with cobicistat (COBI) or
drugs that contain COBI (e.g., Stribild, Genvoya,
• See the Lopinavir/Ritonavir section of Appendix A. Pediatric Prezcobix, Evotaz).
Antiretroviral Drug Information for information.
• RTV oral powder should be mixed with a soft
food (e.g., applesauce, vanilla pudding) or a liquid
(e.g., water, chocolate milk, infant formula) to help

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-271
 mitigate the bitter taste. Administer or discard the
mixture within 2 hours of mixing.

To Increase Tolerability of RTV Oral Powder in

Children
• Mix the powder with milk, chocolate milk, ice
cream, or vanilla or chocolate pudding.
• Before administering RTV, give a child ice chips,
an ice pop, 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.

RTV 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.
• Before RTV is administered, a patient’s medication profile should be reviewed carefully for
potential interactions with RTV and overlapping toxicities with other drugs.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-272
• 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 Table 24a. 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.

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.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-273
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 the Lopinavir/Ritonavir section).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-274
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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/29749880.

9. Changes to Norvir labeling. AIDS Patient Care STDS. 2008;22(10):834-835. Available at:
https://pubmed.ncbi.nlm.nih.gov/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://pubmed.ncbi.nlm.nih.gov/18025905.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-275
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://pubmed.ncbi.nlm.nih.gov/19820426.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-276
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-277
Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or as a Co-packaged Formulation,
by Drug Class
Updated: June 27, 2024
Reviewed: June 27, 2024

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-278
Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or as a Co-packaged Formulation, by
Drug Class

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-279
Appendix A, Table 1. Antiretrovirals Available in Fixed-Dose Combination Tablets or as a Co-packaged Formulation, by
Drug Class
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-280
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: June 27, 2024
Reviewed: June 27, 2024

General Considerations When Using Fixed-Dose Combination Products

Please see the individual drug sections under Appendix A. 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

• Bictegravir (BIC) and dolutegravir (DTG), second-generation integrase strand transfer inhibitors (INSTIs), have a higher barrier to resistance
than the first-generation INSTIs, elvitegravir (EVG) and raltegravir (RAL).
• For children weighing ≥6 kg and aged ≥3 months, DTG is available in once-daily FDC formulations of abacavir (ABC)/ DTG/lamivudine
(3TC). If ABC/DTG/3TC is not an option, then single-entity DTG can be used in combination with other FDC tablets. Refer to Dolutegravir for
dosing information.
o ABC/DTG/3TC is available in two different formulations, with the appropriate formulation depending on weight. For children weighing ≥6
kg to <25 kg and aged ≥3 months, 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.

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 and Adolescents

• For children weighing ≥14 kg, BIC is available as the single-tablet, once-daily regimen BIC/emtricitabine (FTC)/tenofovir alafenamide (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. Refer to Bictegravir for dosing information.
• For children weighing ≥25 kg, EVG is available as the single-tablet, once-daily regimen EVG/cobicistat (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).
Refer to Elvitegravir for dosing information.
• The two-drug, co-packaged regimen of long-acting injectable cabotegravir (CAB) and rilpivirine (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 and Rilpivirine for
instructions about dosing and administration.

Nucleoside/Nucleotide Reverse Transcriptase Inhibitors

• ABC or TAF in combination with 3TC or FTC are favored over zidovudine (ZDV)/3TC because of the lower risk of nucleoside/nucleotide
reverse transcriptase inhibitor (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 non-nucleoside reverse
transcriptase inhibitor (NNRTI), but not with a protease inhibitor; this restriction does not apply to regimens containing ZDV or ABC.

Non-Nucleoside Reverse Transcriptase Inhibitors

• The FDC tablet doravirine (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 and Adolescents

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 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
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 25 kg 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 6 to <25 kg and aged N/A (dispersible) Take with or without food.
≥3 monthsg

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.

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 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/PI/COBI
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
Tablets ≥14 Days

• LPV 200 mg/RTV 50 mg • No minimum weight

• LPV 100 mg/RTV 25 mg

aThe 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 and their caregivers, it is important to consider childbearing potential and 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 During Pregnancy and When 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).
f The Panel does not currently recommend using DTG/RPV (Juluca) as a complete two-drug 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.

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 and Adolescents
g ABC/DTG/3TC is available in dispersible tablets (Triumeq PD) for children weighing ≥6 kg to <25 kg and aged ≥3 months 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.
hLong-acting injectable CAB and RPV for intramuscular administration 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-287
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-288
 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-289
 associated with a 5.5-fold (95% CI, 2.1–14.4) increased risk of cancer with first-trimester
exposure.2 During adolescence, disanosine use while pregnant or at risk of becoming pregnant
should prompt health care professionals to caution about this cancer 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-290
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-291
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-292
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-293
 • 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-294
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 >1.0log 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 (>1.0log 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 log10 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-295
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-296
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-297
 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-298
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-288
Table A. Fosamprenavir Dose and Amprenavir Exposure by Age Group

AUC0-24h
(mcg*hr/mL) Cmin
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 AUC0-12 (mcg*hr/mL)
Key: AUC0-24h = area under the curve for 24 hours post-dose; Cmin = 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 Cmin are not
available.

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection L-300
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/archive/AdultandAdolescentGL0034
12.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-301
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-302
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-303
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-304
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-305
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-306
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-307
• 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-308
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
(Cmin) <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 Ctrough <0.8 mcg/mL were
younger than the children in the group with Ctrough >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-309
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-310
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-311
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-312
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-313
 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-314
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-315
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-316
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-317
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-318
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-319
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-320
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-321
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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-325
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-326
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-327
 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-328
• 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-329
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-330
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-331
Appendix B. Acronyms
Updated: June 27, 2024
Reviewed: June 27, 2024

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
LEN lenacapavir
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
 SQV saquinavir
T-20 enfuvirtide
TAF tenofovir alafenamide
TDF tenofovir disoproxil fumarate
TFV tenofovir
TFV-DP tenofovir diphosphate
THAM tris (hydroxymethyl) aminomethane
TMP-SMX trimethoprim sulfamethoxazole
TMR temsavir
TPV tipranavir
XTC 3TC (lamivudine) or FTC (emtricitabine)
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
AAP American Academy of Pediatrics
ACTH adrenocorticotropic hormone
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
AUC0–12h area under the curve from time 0 to 12 hours postdose
AUC12h 12-hour area under the curve
AUC24h 24-hour area under the curve
AUCtau 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
C0h pre-dose concentration
C12h concentration at 12 hours
C24h concentration at 24 hours
CAR chimeric antigen receptor
Cavg average plasma concentration
CBC complete blood count
CD4 CD4 T lymphocyte
CD8 CD8 T lymphocyte

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-3
CDC Centers for Disease Control and Prevention
CEPAC Cost-Effectiveness of Preventing AIDS Complications, a model
CI confidence interval
CK creatine kinase
Cmax maximum plasma concentration
Cmin minimum plasma concentration
CMV cytomegalovirus
CNS central nervous system
COMB-R cognitive behavioral therapy and medication management algorithm
Cr creatinine
CRAFFT Car, Relax, Alone, Forget, Friends, and Trouble
CrCl creatinine clearance
CT continuous therapy
Ctau concentration at the end of a dosing interval
Ctrough trough concentration
CTx C-telopeptide of type 1 collagen
CV coefficient of variation
CVD cardiovascular disease
CYP cytochrome P450
CYP2B6 cytochrome P450 family 2 subfamily B member 6
DAIDS Division of AIDS (NIAID)
DBS dried blood spot
DM diabetes mellitus
DOT directly observed therapy
DRESS drug reaction (or rash) with eosinophilia and systemic symptoms
DSG delayed switch group
DT dispersible tablet
DXA dual energy X-ray absorptiometry
EBV Epstein-Barr virus
EC enteric-coated
EC50 half maximal effective concentration
ECG electrocardiogram
ECMO extracorporeal membrane oxygenation
EEG electroencephalogram
eGFR estimated glomerular filtration rate
EM erythema multiforme or extensive metabolizer
FCT film-coated tablet

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-4
FDA U.S. Food and Drug Administration
FDC fixed-dose combination
FLP fasting lipid profile
FPG fasting plasma glucose
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
gp120 glycoprotein 120
HA height age
HAV hepatitis A virus
HBcAB HBV core antibody
HBsAb HBV surface antibody
HBsAg HBV surface antigen
HBV hepatitis B virus
HCV hepatitis C virus
HD high dose
HDL high-density lipoprotein
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
HLA human leukocyte antigen
HMG-CoA 3-hydroxy-3-methylglutaryl coenzyme A
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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-5
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
L liter
LAI long-acting injectable
LBW low birth weight
LDL low-density lipoprotein
LDL-C low-density lipoprotein cholesterol
LFT liver function test
log10 the logarithm to the base 10
LS lipodystrophy syndrome
LVH left ventricular hypertrophy
MCV mean cell volume
mDAART modified directly administered ART
MEMS medication event monitoring system
N/A not available or not applicable
NASBA nucleic acid sequence–based amplification
NAT nucleic acid test
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
OR odds ratio

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-6
 PA-IC95 protein-adjusted IC95
The Panel the Panel on Antiretroviral Therapy and Medical Management of Children Living with
HIV
PBMC peripheral blood mononuclear cell
PCP Pneumocystis jirovecii pneumonia
PEPFAR President’s Emergency Plan for AIDS Relief
PCR polymerase chain reaction
PEP post-exposure prophylaxis
PG plasma glucose
P-gp P-glycoprotein
PHIV perinatally acquired HIV
PK pharmacokinetic
PI protease inhibitor
POC point of care
PPI proton pump inhibitor
PrEP pre-exposure prophylaxis
QTc heart rate–corrected QT
RCT randomized controlled trial
RPG random plasma glucose
RR relative risk
RT-PCR reverse transcription polymerase chain reaction
SAM severe acute malnutrition
SBIRT Screening, Brief Intervention, and Referral to Treatment
SCT short-cycle therapy
SD standard deviation
SJS Stevens-Johnson syndrome
SM slow metabolizer
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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-7
 TDM therapeutic drug monitoring
TEN toxic epidermal necrolysis
TG triglyceride
TIC trauma-informed care
TMA transcription-mediated amplification
Tmax time to reach maximum concentration
U=U Undetectable = Untransmittable
UGT uridine diphosphate glucuronosyltransferase
UGT1A and UGT1A1 uridine diphosphate (UDP)-glucuronosyltransferase family 1 member A complex or
uridine diphosphate (UDP)-glucuronosyltransferase family 1 member A complex 1
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-8
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
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
DolPHIN-2 Dolutegravir in Pregnant HIV Mothers and Their Neonates
ECHO Evidence for Contraceptive Options and HIV Outcomes
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
HPTN HIV Prevention Trials Network
IeDEA International Epidemiology Databases to Evaluate AIDS
IMPAACT International Maternal Pediatric Adolescent AIDS Clinical Trials
LATTITUDE Long-Acting Therapy to Improve Treatment Success in Daily LifE
MOCHA More Options for Children and Adolescents
NADIA Nucleosides And Darunavir/Dolutegravir in Africa
NEVEREST Nevirapine Resistance Study
ODYSSEY Once-daily DTG based ART in Young people vS Standard thErapY
PACTG Pediatric AIDS Clinical Trials Group
PAINT Pediatric Study in Adolescents Investigating a New NNRTI TMC278
PENPACT Trial run in collaboration between PENTA and PACTG/IMPAACT
PENTA Paediatric European Network for Treatment of AIDS
PHACS Pediatric HIV/AIDS Cohort Study
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

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-9
 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
SWORD-1 and SWORD-2 Regimen Switch to Dolutegravir + Rilpivirine from Current Antiretroviral Regimen in
Human Immunodeficiency Virus Type 1 Infected and Virologically Suppressed Adults
THRIVE TMC278 against HIV, in a once-daily Regimen Versus Efavirenz

Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection M-10
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 Log10 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