Antiretrovirals

02/24/25 1
 ANTIRETROVIRAL DRUGS
• Life cycle of HIV-I
• Pathogenesis of HIV infection
• Mechanism of action of ARVs
• Classification
• Interactions
• Adverse Drug Reactions (Side Effects
and Toxicities)

02/24/25 2
 Lifecycle HIV-1
Entry

RNA RNA Viral protease

Proteins
Reverse RT
transcriptase
RNA
RNA
DNA
RT

DNA

DNA Provirus
Integrase

02/24/25 3
 Pathogenesis of HIV Infection(1)
• HIV & other retroviruses possesses an
enzyme called Reverse Transcriptase
• This virus consists of lipid bilayer
surrounding a capsid
• It has surface glycoprotein molecule which
has affinity for CD4 receptor protein found
on T helper lymphocytes
• However Monocytes & macrophages may
possess CD4 receptors in low quantities
02/24/25 4
 Pathogenesis of HIV infection (2)
• HIV virus can also attach to co-receptors
• There could be attachment to membrane
of the lymphocyte
• There is penetration after attachment to
host cell
• This is followed by shedding of outer coat
and release of genetic material
• Viral RNA add on nucleoside and
converted to Viral DNA by reverse
transcriptase enzyme

02/24/25 5
 Pathogenesis of HIV infection (3)
• The viral DNA is then integrated into the
host genome in the nucleus and direct the
host DNA to produce Viral DNA
• The resultant effects is the production of
new viral protein by transcription and
translation
• New viral particles are assembled and bud
out of the host cell, finally maturing into
infectious virions under the influence of
protease enzyme
02/24/25 6
 Mechanism of action of
(ARVs):Antiretroviral drugs (ARVs) act on the
HIV by interfering with its reproductive cycle.
The main stages of the cycle where these
drugs act to inhibit replication of the virus are:
NRTIs & NNRTIs
• Inhibit reverse transcriptase enzyme to
interrupt the production of proviral DNA.
• ARVs prevent formation of proviral DNA.
NRTI and NNRTI act here.
02/24/25 7
 Mechanism of action
Nucleoside reverse transcriptase inhibitors
(NRTIs)
• cause phosphorylation of reverse
transcriptase enzyme and act as a false
substrate
• lead to premature termination of the
production of the HIV DNA chain
• They are active against both HIV-1 and HIV-2
• resistance rapidly develops if given as single
drugs alone (monotherapy)

02/24/25 8
 Mechanism of action
Non-nucleoside reverse transcriptase
inhibitors (NNRTIs)
NNRTI bind to the active site of reverse
transcriptase enzyme and does not cause
phosphorylation.
Are active only against HIV-1
• Delavirdine and Nevirapine are antagonistic in
action on the HIV reverse transcriptase activity
and, therefore, should not be used together
• Have longer t1/2

02/24/25 9
 Mechanism of action cont.
Protease inhibitors, PIs
• Inhibit maturation of virion by interrupting
the protein processing by binding to active
site of HIV-1 protease enzyme, preventing
virus maturation of the newly produced
virions so that they remain non-infectious

02/24/25 10
• Entry & Fusion Inhibitor
- Interferes with the entry of HIV into cells
by inhibiting fusion of viral and host
cellular membranes.
- Entry of HIV into the target cell is
mediated by two viral envelope
glycoproteins, gp120 and gp41, which
form complexes that facilitate entry of the
virion into the host cell.

02/24/25 11
Integrase Inhibitor
• Integrase is an enzyme that HIV uses to
insert its DNA into the DNA genome of
human cells in the host nucleus.
• Integrase Inhibitor is an investigational
drug that inhibits the strand transfer stage
of the HIV integration process.

02/24/25 12
 Classification of ARVs
Nucleoside (nRTI) Protease Inhibitor (PI)
• AZT/ Zidovudine/ RETROVIR SQV/ Saquinavir/ INVIRASE, ORTOVASE
• DDI/ Didanosine/ VIDEX RTV/ Ritonavir/ NORVIR
• D4T/ Stavudine/ ZERIT IDV/ Indinavir/ CRIXIVAN
• ddC/ Zalcitabine/ HIVID NLF/ Nelfinavir/ VIRACEPT
• 3TC/ Lamivudine/ EPIVIR APV/ Amprenavir/ AGENERASE
• ABC/ Abacavir/ ZIAGEN LPV/r / Lopinavir+Ritonavir / KALETRA
ATZ / Atazanavir/ REYATAZ
• TDF/ Tenofovir/ VIREAD
fAPV / Fos-Amprenavir / LEXIVA
• FTC/ Emtricitabine/ EMTRIVA
Non-Nucleoside (nnRTI)
• DLV/ Delavirdine/ Combination Medications
RESCRIPTOR COMBIVIR (AZT+3TC)
• NVP/ Nevirapine/ VIRAMMUNE TRIZIVIR(AZT+3TC+ABC)
EPZICOM (ABC+3TC)
• EFV /Efavirenz/ SUSTIVA TRUVADA (TDF+FTC)
Fusion Inhibitors TRIOMMUNE (D4T+3TC+NVP) {outside U.S.}
• T-20/ enfuvirtide / FUZEON

02/24/25 13
 Nucleoside reverse transcriptase inhibitors
Generic name Brand name Unit Dose Daily Dose

AZT (ZDV) Zidovudine Retrovir 300 mg 2 x 1/d

DDI Videx 100 mg 4 /d

Didanosine Videx EC 250/400 mg 1 /d

DDC Zalcitabine Hivid 0.75 mg 3 x 1 /d

D4 T Stavudine Zerit 30/40 mg 2 x 1 /d

3TC Lamivudine Epivir 150 mg 2 x 1 /d

AZT + 3TC Zidovudine/ Combivir 2 x 1 /d

Lamivudine

ABC Abacavir Ziagen 300 mg 2 x 1 /d

AZT+3TC+ABC Trizivir 2 x 1 /d

02/24/25 14
 Non-nucleoside reverse
transcriptase inhibitors
Generic name Brand name Unit dose Daily Dose

Nevirapine Viramune 200 mg 14 d - 1 /d,

later 2 /d

Efavirenz 200 mg 3 /d
Stocrin

Delavirdine 200 mg 3 x 4 /d

Rescriptor

02/24/25 15
 Protease inhibitors
Generic name Brand name Unit dose Daily Dose

Indinavir Crixivan 200/400 mg 3 x 2/d

Ritonavir Norvir
100 mg 2 x 6/d
Nelfinavir Viracept
250 mg 2 x 5/d
or
3 x 3/d
Saquinavir HG 200 mg 3 x 6/d
Invirase
200 mg
Amprenavir 150 mg 2 x 8/d
Lopinavir 400/100 mg 2 x 3/d

Agenerase

Kaletra

02/24/25 16
 Drug Interactions in HIV
• Pharmacodynamics
• Pharmacokinetics
– Alterations in Absorption
– Alteration in Distribution
– Alterations of Drug Metabolism
– Alteration in elimination
• Pharmacogenomics
• Alterations in Pregnancy
• Issues with specific frequently-used medications
02/24/25 17
 Pharmacodynamic Interactions (1)

• The effects of a drug on physiologic

and biochemical processes
– Additive
– Synergistic
– Antagonism

02/24/25 18
 Pharmacodynamic Interactions
Examples:
• Additive toxicities of ARVs
– Atazanavir + Indinavir = hyperbilirubinemia
– Zidovudine + other NRTIs = bone marrow supression
– Stavudine + Didanosine = pancreatitis, neuropathy,
lactic acidosis
• Antagonism of ARVs:
– Example: Zidovudine + Stavudine
• Use same intracellular enzyme to phosphorylate (activate)

02/24/25 19
 Pharmacokinetics interactions

• Absorption
• Distribution
• metabolism
• Elimination

02/24/25 20
 Systemic
Circulation Oral
Medication
Hepatic
Vein Hepatic
Artery
Liver

Portal Intestinal
Vein Tract

Cytochrome P450 enzymes are found in GI Tract and

Liver
02/24/25 21
• Phamacokinetic interactions occur when one
drug alters the serum or tissue concentration of
another by changing its absorption, distribution,
metabolism, or elimination

• Such interactions can result in clinically

significant changes in drug concentration which
may require the dose of one or more drugs to be
modified or may necessitate the use of an
alternative drug or drugs

02/24/25 22
 Changes in Drug Absorption
• Alterations of gastric pH
– If a drug changes the gastric pH, it can affect the
absorption and thus concentration of other drugs that have
specific pH requirements for absorption.

Eg. Methadone can slow the gut, thereby slowing absorption

of other medications
Atazanavir requires acidic environment
– Avoid concomitant antacid use
– Avoid Proton Pump Inhibitors
• Omeprazole etc
– Avoid H2 Blockers
• Or, space at least 12 hours away from them

02/24/25 23
 Changes in Drug Absorption
• Presence or absence of food
– Food can enhance or decrease the
bioavailability of a drug--often because of
gastric acidity
– Some drugs, such as didanosine and
Indinavir, must be administered one hour
before or two hours after eating
• Chelation
– Binding of two drugs/compounds to form
insoluble complexes that cannot be absorbed
—this changes absorption of a drug
02/24/25 24
 Food – Drug Interactions
Didanosine 55%  AUC with Food Administer 30 min before or
2 hours after meal
Indinavir 77%  AUC with high Administer on empty stomach or
fat-protein caloric meal with low-fat, light meal
Nelfinavir 2-3 Fold  AUC with Administer with meal or light snack
food
Saquinavir Marked  AUC with Administer within 2 hrs of meal
food
Atazanavir Administer with food

Atovaquone 3-fold  AUC wih Administer with high fat meal

high-fat meal
Itraconazole Increased AUC with Administer with food
food

02/24/25 25
 Changes in Drug Distribution
• Protein-binding
– Things that alter the protein-binding of a drug affect
the amount of free drug that is available to produce
the necessary therapeutic effect

• Hypoalbuminemia
– Patients with low albumin levels can experience an
increased therapeutic effect and/or risk for toxicity
– This occurs with drugs that are highly protein-bound,
such as warfarin or phenytoin

02/24/25 26
 Changes in Metabolism
Metabolism in the liver cytochrome P450 system
• The induction or inhibition of various P450 enzymes by
one drug can significantly alter the serum concentration
of another drug that is metabolized by the same P450
enzyme

• PIs and NNRTIs are primarily metabolized by the same

P450 CYP3A4 isoenzyme and can inhibit or induce this
isoenzyme. This result in increases or decreases in the
concentration of concomitantly administered drugs

• Other drugs that inhibit or induce this isoenzyme can

bring about increases and decreases in the
concentration of concomitantly administered PIs and/or
NNRTIs
02/24/25 27
 Changes in Metabolism, continued
• Each PI and NNRTI has a different drug interaction
profile, depending primarily on its potency as an inducer
or inhibitor of CYP3A4 and/or other P450 enzymes
– Ritonavir is the most potent CYP3A4 inhibitor and
consequently has the most drug interactions and
contraindications
– Nevirapine is a CYP3A4 inducer.
– Efavirenz is both an inducer and inhibitor of CYP3A4
– Rifampicin is a potent inducer of hepatic metabolism
and significantly decreases the concentration of PIs to
subtherapeutic levels

02/24/25 28
 Changes in Metabolism, continued

• Nelfinavir, Ritonavir, and the NNRTIs can significantly

decrease the estrogen levels in contraceptives.
– Women taking these drugs cannot rely on oral
contraceptives and should use another or an
additional method of contraception.

• PIs and EFZ can raise the serum concentration of

cisapride and non-sedating antihistamines (astemizole,
terfenadine), which can lead to cardiotoxicity.
• They can also increase the serum concentration of
benzodiazapines, and this can result in prolonged
sedation.

02/24/25 29
 ARV-ARV Combinations
-Protease Inhibitors-
• All approved protease inhibitors are
substrates for Cytochrome P450 drug
metabolizing enzymes.
• All approved PI’s are inhibitors of CYP450
3A4 (RTV>NFV=IDV=APV>>SQV).
• RTV and NFV are inducers of CYP450
drug metabolizing enzymes.
• APV may also act as an inducer for some
drugs.
02/24/25 30
 ARV-ARV Combinations
-NNRTIs-
• All approved NNRTI’s are substrates for
Cytochrome P450 drug metabolizing
enzymes.
• Delavirdine is an inhibitor of CYP450 3A4.
• Nevirapine is an inducer of CYP450
enzymes.
• Efavirenz is both a P450 inhibitor and a
P450 inducer.
02/24/25 31
 Adverse drug reactions:
(Side effects and Toxicities)
Drug Side effects and Toxicity
Name
Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)

ZDV, GI intolerance, asthenia, headache, anemia,

AZT leukopenia
ddI GI intolerance: pancreatitis, peripheral
neuropathy, lactic acidosis
d4T peripheral neuropathy, pancreatitis,
02/24/25
lactic acidosis 32
Common Side Effects and Toxicities
Toxicity (toxicities italicized)
Nucleoside Reverse Transcriptase
Inhibitors (NRTIs)
3TC- Generally well tolerated: lactic acidosis
ABC - Hypersensitivity reaction (HSR)—
symptoms of fever, rash, GI, respiratory
problems, lactic acidosis

02/24/25 33
 Common Side Effects and
Toxicities
Drug Side effects and Toxicity
(toxicities italicized)

Non-Nucleotide Reverse Transcriptase

Inhibitors (NNRTIs)
NVP- Extensive rash, hepatitis
EFZ - CNS, Rash. Avoid in pregnancy

02/24/25 34
 Protease Inhibitors (PIs)
Invirase (INV) - GI intolerance, paresthesias,
hepatitis, lipodystrophy
Indinavir (IDV) - GI intolerance, nephrolithiasis,
benign increase in bilirubin, lipodystrophy
Saquinavir (SQV) - GI intolerance, lipodystrophy
Fortovase (FTV) - GI intolerance, lipodystrophy
Invirase (INV) - GI intolerance, lipodystrophy
NLF - Diarrhea, lipodystrophy
LPV/r - GI intolerance (esp. diarrhea), asthenia,
lipodystrophy
02/24/25 35
 Summary Overview of ARV Adverse Effects
Class specific ARV specific
NRTI Mitochondrial toxicity Nail pigmentation
(lactic acidosis, lipoatrophy) (ZDV)
Hypersensitivity
(abacavir)
NNRTI Rash CNS dysfunction
(efavirenz)
Severe hepatitis
(nevirapine
PI Metabolic abnormalities Nephrolithiasis
Lipodystrophy (indinavir)
Bleeding in hemophliliacs Diarrhoea (nelfinavir,
ritonavir, lopinavir)
02/24/25 Rash (amprenavir) 36
 Review of side effects
• Zidovudine: Nausea, myalgia, anaemia
• Lamivudine: Nausea, Pancreatitis
• Stavudine: Peripheral neuropathy,
Pancreatitis
• Nevirapine: Rash, hepatitis
• Efavirenz: Rash, Sleep abnormalities
• Nelfinavir: Diarrhoea
• Indinavir: Renal stones, diarrhoea

02/24/25 37
 Administration and Storage of ARVs
• Take on an empty stomach–1 hr before or 2hrs
after meal
– Didanosine
– Indinavir (except if given with ritonavir)
• Take with food
– Nelfinavir, ritonavir, lopinavir, saquinavir
– Tenofovir
– ddI when given with tenofovir
• Take with or without food
– ZDV, D4T, 3TC, COMBIVIR
– Nevirapine
– Efavirenz: with low fat foods
02/24/25 38
 Administration and storage of ARVs, continued

• Indinavir (Crixivan) should be administered with

liquids with or without a light meal one hour before or
two hours after a regular meal.
• Storage of ARVs in the refrigerator
– Ritonavir
– ddI suspension
– d4T solution
– Lopinavir/ritonavir (Kaletra) capsules and solution
• Storage of ARVs in glass jars
– ZDV syrup
– d4T syrup
02/24/25 39
 References
• www.hiv-druginteractions.org
• www.hivpharmacology.com
• http://hivinsight.ucsf.edu

LOVE LIFE AND STOP HIV/AIDS

02/24/25 40