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antiretroviral therapy HIV treatment
I now have comprehensive material from Katzung's pharmacology textbook. Let me compile the complete answer.
Antiretroviral Agents
— Katzung's Basic and Clinical Pharmacology, 16th Edition; Goodman & Gilman's Pharmacological Basis of Therapeutics
HIV Life Cycle & Sites of Drug Action
Each class of antiretroviral agent blocks a distinct step in the HIV replication cycle:
- gp120 attachment inhibitors → block initial attachment to CD4
- CCR5 antagonists → block co-receptor binding
- CD4 post-attachment inhibitors → block post-binding entry
- Fusion inhibitors → block membrane fusion via gp41
- NRTIs / NNRTIs → inhibit reverse transcription (RNA → DNA)
- INSTIs → block viral DNA integration into host chromosome
- Protease inhibitors (PIs) → block virion maturation (budding step)
- Capsid inhibitors → block capsid assembly/disassembly
Class 1: Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)
Mechanism: Analogues of natural nucleosides → phosphorylated intracellularly to active triphosphates → competitively inhibit HIV reverse transcriptase → cause chain termination.
Class toxicity: Mitochondrial toxicity (via inhibition of mitochondrial DNA polymerase γ) → lactic acidosis, hepatic steatosis, lipoatrophy, peripheral neuropathy.
| Drug | Key Features | Toxicities |
|---|---|---|
| Zidovudine (ZDV/AZT) | First ARV (1987); thymidine analog; CSF penetration good | Bone marrow suppression (anemia, neutropenia), myopathy, macrocytosis |
| Abacavir (ABC) | Test HLA-B*5701 before use; avoid alcohol | Fatal hypersensitivity reaction (rash, fever, GI); possible ↑ MI risk |
| Emtricitabine (FTC) | Fluorinated lamivudine analog; intracellular t½ ≥24 h; only FDA-approved PrEP backbone (with TDF) | Headache, rash, hyperpigmentation of palms/soles (up to 13% in African Americans) |
| Lamivudine (3TC) | Active vs. HIV-1 & HBV; oral bioavailability >80% | Headache, GI discomfort; pancreatitis rare |
| Tenofovir DF (TDF) | Nucleotide prodrug; requires only 2 phosphorylation steps; active vs. HIV + HBV | Nephrotoxicity (proximal tubular dysfunction, Fanconi syndrome), ↓ bone density |
| Tenofovir AF (TAF) | Newer prodrug; better intracellular delivery → lower plasma levels → less renal/bone toxicity | Weight gain; lipid changes |
| Stavudine (d4T) | No longer preferred; thymidine analog | High mitochondrial toxicity, lipoatrophy, peripheral neuropathy |
| Didanosine (ddI) | Must fast (give on empty stomach) | Peripheral neuropathy, pancreatitis, retinal changes |
Note: Emtricitabine + lamivudine must not be combined — they compete for intracellular phosphorylation and both select for the M184V/I resistance mutation.
HBV co-infection: Stopping drugs active against HBV (3TC, FTC, TDF, TAF) can precipitate severe HBV flares.
Class 2: Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)
Mechanism: Bind allosterically to a hydrophobic pocket near the active site of reverse transcriptase → conformational change → inhibit catalytic activity. Not phosphorylated; active against HIV-1 only (not HIV-2).
| Drug | Key Features | Toxicities / Drug Interactions |
|---|---|---|
| Efavirenz (EFV) | Once daily; CNS penetration excellent; teratogenic (avoid in 1st trimester) | Vivid dreams, dizziness, CNS disturbances, rash; CYP3A4 inducer |
| Nevirapine (NVP) | CYP3A4 inducer; risk of severe hepatotoxicity especially in women with CD4 >250 | Severe rash (Steven–Johnson syndrome), hepatotoxicity; must lead-in with low dose for 14 days |
| Rilpivirine (RPV) | Must be taken with a ≥500 kcal meal; contraindicated with PPIs; also available as LA injection (monthly) | Depression, insomnia, rash; lower barrier to resistance than EFV |
| Etravirine (ETR) | Active against some NNRTI-resistant strains; twice daily | Rash, nausea; multiple drug interactions (CYP3A4, CYP2C9 inhibitor/inducer) |
| Doravirine (DOR) | Once daily; no food restriction; minimal drug interactions | Dizziness, nausea, abnormal dreams |
Class 3: Protease Inhibitors (PIs)
Mechanism: Inhibit HIV aspartyl protease → prevent cleavage of the Gag-Pol polyprotein → virions remain immature and non-infectious.
Class toxicities: GI intolerance, hyperlipidemia (↑ triglycerides, ↑ LDL), insulin resistance, lipodystrophy, elevated liver enzymes.
Boosting: All modern PIs require co-administration with ritonavir (100 mg) or cobicistat (150 mg) as pharmacokinetic boosters. Ritonavir itself is a potent CYP3A4 inhibitor.
| Drug | Key Features | Toxicities |
|---|---|---|
| Atazanavir (ATV) | Once daily; no insulin resistance or ↑ CV risk; needs acid for absorption — separate from antacids/PPIs | Indirect hyperbilirubinemia/jaundice (~10%), PR prolongation, renal stones, rash |
| Darunavir (DRV) | High genetic barrier to resistance; sulfonamide moiety → sulfa allergy risk; monitor LFTs | Diarrhea, rash, hepatotoxicity |
| Lopinavir/ritonavir (LPV/r) | Fixed-dose; no additional booster needed | GI toxicity, QTc prolongation, lipid effects |
Class 4: Integrase Strand Transfer Inhibitors (INSTIs)
Mechanism: Inhibit HIV integrase → block insertion of viral dsDNA into host genome. Highest barrier to resistance among all ARV classes (especially dolutegravir, bictegravir).
| Drug | Key Features | Toxicities |
|---|---|---|
| Raltegravir (RAL) | First INSTI approved; twice daily; no CYP3A4 interactions (glucuronidated via UGT1A1) | Well tolerated; creatine kinase elevation, myopathy rare |
| Elvitegravir (EVG) | Requires cobicistat boosting; once daily; part of single-tablet regimens (Stribild, Genvoya) | GI effects; multiple drug interactions via cobicistat |
| Dolutegravir (DTG) | No boosting needed; high barrier to resistance; minimal drug interactions; preferred in pregnancy | Weight gain, insomnia, headache; neural tube defect signal with periconceptional use (controversial but label caution maintained) |
| Bictegravir (BIC) | Only available in fixed-dose tablet (BIC/TAF/FTC = Biktarvy); once daily; high genetic barrier | Nausea, diarrhea; separate from antacids by ≥2 h |
| Cabotegravir (CAB) | Available as LA IM injection (monthly or every 2 months) with rilpivirine; also oral for PrEP | Injection-site reactions; tail pharmacokinetics — drug detectable >1 year after last injection |
Class 5: Entry/Fusion Inhibitors
Fusion Inhibitor
- Enfuvirtide (T-20): Peptide that mimics the HR2 domain of gp41 → prevents membrane fusion. Subcutaneous injection twice daily. Major drawback: injection-site reactions in nearly 100% of patients. Reserved for salvage therapy in multidrug-resistant HIV.
CCR5 Co-receptor Antagonist
- Maraviroc: Binds host CCR5 → prevents HIV-CCR5 interaction. Requires tropism testing first — only active against CCR5-tropic virus (R5), NOT against CXCR4- or dual/mixed-tropic virus. Substrate for CYP3A4 and P-glycoprotein (dose must be adjusted with CYP3A4 inhibitors/inducers). Adverse effects: hepatotoxicity (preceded by allergic reaction), myocardial ischemia, postural hypotension.
CD4 Post-Attachment Inhibitor
- Ibalizumab: Monoclonal antibody binding CD4 domain 2 → blocks post-attachment conformational changes needed for HIV entry. Given as IV infusion every 2 weeks. Indicated for heavily treatment-experienced adults with multidrug-resistant HIV-1.
gp120 Attachment Inhibitor
- Fostemsavir: Prodrug converted to temsavir → binds HIV-1 gp120 directly, preventing interaction with CD4. For multidrug-resistant HIV. Adverse effects: nausea, diarrhea, elevated LFTs.
Capsid Inhibitor
- Lenacapavir: Binds HIV-1 capsid protein → interferes with multiple stages (nuclear import, capsid assembly, uncoating). Given as subcutaneous injection every 6 months — the longest-acting ARV available. For treatment-experienced adults with multidrug-resistant HIV.
Pharmacokinetic Boosters
| Drug | Role | Mechanism |
|---|---|---|
| Ritonavir | Booster for PIs (and nirmatrelvir in COVID-19 Paxlovid) | Potent CYP3A4 inhibitor → raises trough levels of co-administered drug |
| Cobicistat | Booster for PIs, TAF, elvitegravir | Selective CYP3A4 inhibitor; no anti-HIV activity itself |
Long-Acting (LA) Formulations
A major advance aimed at improving adherence:
| Regimen | Route | Frequency | Indication |
|---|---|---|---|
| Cabotegravir + Rilpivirine (Cabenuva) | IM injection | Monthly or every 2 months | HIV treatment (virologically suppressed) |
| Cabotegravir (Apretude) | IM injection | Every 8 weeks | HIV PrEP |
| Lenacapavir | SC injection | Every 6 months | Multidrug-resistant HIV |
LA cabotegravir for PrEP was shown to reduce HIV infection by 68% in men and 89% in women compared to daily oral TDF/FTC in large phase III trials.
Preferred First-Line Regimens (Current Guidelines)
A complete ART regimen typically contains 2 NRTIs + 1 "third agent" (INSTI preferred). Preferred initial regimens include:
- Bictegravir/TAF/FTC (Biktarvy) — single tablet, once daily
- Dolutegravir + TAF/FTC or Dolutegravir/abacavir/3TC (Triumeq, if HLA-B*5701 negative)
- Dolutegravir + 3TC (two-drug regimen, Dovato) — for treatment-naive patients with no HBV co-infection
Drug Interactions — Key Points
- CYP3A4 inducers (rifampin, efavirenz, etravirine, carbamazepine, St. John's Wort): ↓ levels of PIs, NNRTIs, INSTIs → treatment failure
- CYP3A4 inhibitors (ritonavir, cobicistat, azole antifungals, macrolides): ↑ levels of PIs → toxicity
- Antacids/PPIs: ↓ absorption of atazanavir and rilpivirine (chelation/pH effect)
- Metformin: cobicistat inhibits organic cation transporters → ↑ metformin levels
Special Populations
| Situation | Preferred Agents |
|---|---|
| Pregnancy | Dolutegravir (preferred), boosted atazanavir or darunavir; emtricitabine + TDF (backbone) |
| HBV co-infection | Must include TDF or TAF (dual HIV/HBV activity); stopping these can cause severe HBV flare |
| Renal impairment | TAF preferred over TDF (less nephrotoxic); avoid TDF if GFR <30 |
| Multidrug-resistant HIV | Lenacapavir, fostemsavir, ibalizumab (salvage agents) |
Sources: Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 49; Goodman & Gilman's Pharmacological Basis of Therapeutics, 14th Edition.
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