Antiretroviral Drugs

Overview
• Used in management of HIV infection.

• Classes:
– Nucleoside/nucleotide Reverse Transcriptase
Inhibitors (NRTIs)
– Non nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)
– Protease Inhibitors (PIs)
– Entry Inhibitors
– Fusion Inhibitors
– Integrase Inhibitors.
ARVs and the HIV Lifecycle

Nucleoside/-tide Reverse Transcriptase Inhibitors(NRTIs)

Mechanism of Action
• Undergo intracellular phosphorylation to active
triphosphates.
• Incorporated into viral DNA by Reverse
Transcriptase (RT).
• Terminate DNA chain elongation.
• Human mitochondrial DNA polymerase γ is also inhibited.
Pharmacokinetics
• Renally excreted (require dose adjustment).
• Except abacavir
Adverse Effects
• Inhibition of mitochondrial DNA polymerase
– Peripheral neuropathy
– Pancreatitis
– Lipoatrophy
– Lactic acidosis
– Hepatomegaly
1. Zidovudine (AZT)
• Excellent CNS penetration
• Glucuronylated by liver.
• Adverse Effects:
– Bone marrow toxicity: macrocytic anemia
– Headaches

2. Stavudine (d4T)
• Thymidine analog.
• Strong inhibitor of mitochondrial DNA polymerase (toxicity).
• Adverse Effects:
– Peripheral neuropathy (major, most common)
– Lipoatrophy
– Hyperlipidemia.
3. Didanosine (ddI)
• Adverse Effects:
– Pancreatitis
– Peripheral neuropathy

4. Tenofovir (TDF)
• Nucleotide analog.
• Converted to diphosphate (inhibits HIV RT)
• Taken with meal to increase bioavailability.
• Long half life (OD).
• Adverse Effects:
– Nausea, diarrhea, vomiting – Nephrotoxicity.
– TAF- Tenofovir Alafenamide-

5. Lamivudine (3TC)
• Cytosine analog.
• Inhibits RT of both HIV and HBV.
• No effect on mitochondrial DNA

6. Emtricitabine (FTC)
• Fluoro-derivative of lamivudine
• Inhibits HIV and HBV RT.
• Adverse Effects:
– Hyperpigmentation of soles and palms
– Withdrawal in HBV exacerbates hepatitis.

7. Abacavir (ABC)
• Guanosine analog.
• Adverse Effects:
– GIT disturbance, headache, dizziness
 – Hypersensitivity reaction

Non Nucleoside Reverse Transcriptase Inhibitors(NNRTIs)

Overview
• Highly selective, non-competitive inhibitors of HIV RT.
• Bind at a site adjacent to the active site → inducing a conformational change → results in
enzyme inhibition.

NRTIs vs NNRTIs….

Overview
• No cross resistance with NRTIs.
• Common characteristics:
– Cross resistance within NNRTIs.
– Hypersensitivity reactions (rash).

1. Nevirapine (NVP)
• Wide tissue distribution (fetus, breast milk, CNS – lipophillic)
• CYP3A4 inducer: Increases metabolism of
– Protease inhibitors
– Oral contraceptives – Metronidazole – Warfarin.
• Adverse Effects:
– Rash, Fever – Hepatotoxicity – SJS, TEN.
• 2 week titration to reduce risk of A/E.

2. Delavirdine (DLV)
• Extensively metabolized
• Fecal and urinary excretion
• Cytochrome P450 inhibitor

3. Efavirenz (EFV)
• Preferred NNRTI
• Bioavailability enhanced by fatty meal.
• Well distributed incl. CNS
• Bound to albumin (99%)
• Potent CYP P450 inducer
Adverse effects:
– CNS manifestations:
Dizziness, headache, vivid dreams, loss of concentration • Resolve within
weeks • Avoid in pregnancy.

4. Etravirine
• 2nd generation NNRTI.
• Active against strains resistant to 1st generation NNRTI.
• Pharmacology similar to EFV except:
– Given BD – No
CNS side effects –
Use in pregnancy.

Protease Inhibitors(PIs)

Examples
• Lopinavir
• Ritonavir
• Saquinavir
• Indinavir
• Nelfinavir
• Atazanavir
• Fosamprenavir
Mechanism of Action
• Reversible inhibitors of HIV protease
– Inhibit cleavage of viral polyprotein into enzymes and structural proteins.
• Inhibition of viral maturation and production of non-infectious virions.
Pharmacokinetics
• Poor oral bioavailability.
• Extensive metabolism by CYP3A4.
• Poor CNS penetration.
• Plasma protein bound (α1 acid glycoprotein)
Adverse Effects
• Paresthesias
• Nausea, vomiting, diarrhea
• Disturbances in glucose, lipid metabolism:
– Diabetes
– Hypertriglyceridemia, hypercholesterolemia.
– Fat redistribution ( loss from extremities, accumulation in abdomen) – Breast
enlargement.
Drug Interactions
• Common problem
• Potent inhibitors of CYP P450:
– Ritonavir (most potent) – Saquinavir (least
potent)
• C/I:
– Simvastatin, lovastatin (rhabdomyolysis)
– Midazolam, triazolam (excess sedation)
– Fentanyl (respiratory depression)

Ritonavir
• Used as a pharmacokinetic booster of other
PIs
– Potent CYP3A inhibitor
– Increase bioavailability of 2nd PI
– Longer dosing intervals, prevent resistance

Entry Inhibitor

Maraviroc
• Blocks CCR5 co-receptor
• Given orally
• Well tolerated.

Fusion Inhibitor

Enfurvitide
• Fusion inhibitor:
– Binds to gp41, preventing HIV fusion with cell membrane.
• Given subcutaneously.

Integrase Inhibitors

Raltegravir, Dolutegravir, Cabotegravir, Elvitegravir

Dolutegravir
• Inhibits integration of viral DNA into host cell
DNA.
• Avoid in 1st trimester of pregnancy- risk of fetal malformations