Classification and Mechanisms of Action of Antiretroviral Drugs

Fig 34.15 — Drug targets in the HIV life cycle (Lippincott Illustrated Reviews: Pharmacology)

Fig 34.16 — Currently available antiretroviral drugs by class (Lippincott Illustrated Reviews: Pharmacology)

CLASS 1 — Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTIs)

Mechanism of Action

1. NRTIs enter host cells and are phosphorylated by cellular kinases to their active triphosphate form.
2. HIV reverse transcriptase (RT) preferentially incorporates the triphosphate NRTI analog into the growing viral DNA chain in place of the natural nucleotide.
3. Because the 3′-OH group is absent, the phosphodiester bond required to add the next nucleotide cannot form → obligate chain termination.
4. Viral DNA synthesis halts — preventing formation of double-stranded proviral DNA.

"Because the 3′-hydroxyl group is not present, a 3′,5′-phosphodiester bond between an incoming nucleoside triphosphate and the growing DNA chain cannot be formed, and DNA chain elongation is terminated." — Lippincott Illustrated Reviews: Pharmacology

• Class effect: lactic acidosis and hepatomegaly with steatosis (mitochondrial DNA polymerase γ inhibition)
• Abacavir: HLA-B*5701-associated hypersensitivity reaction (~5% of patients) — never rechallenge
• Zidovudine: bone marrow suppression, macrocytic anemia
• Didanosine (rarely used): peripheral neuropathy, pancreatitis, lipoatrophy
• TDF: nephrotoxicity, reduced bone mineral density

CLASS 2 — Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Mechanism of Action

1. NNRTIs bind directly to a hydrophobic pocket on the RT enzyme near (but distinct from) the active catalytic site — they do not require intracellular phosphorylation.
2. Binding causes a conformational change in the RT enzyme, reducing its catalytic activity.
3. The result is impaired synthesis of viral DNA from the RNA template.

• Do not need activation (not prodrugs)
• Do not compete with natural nucleotides
• Highly specific for HIV-1 RT (not active against HIV-2 — clinically important)
• Single mutations (e.g., K103N for efavirenz/nevirapine) can confer high-level resistance; etravirine and doravirine have a higher genetic barrier

• Efavirenz: CNS effects (vivid dreams, dizziness, depression), teratogenic (avoid in first trimester)
• Nevirapine: hepatotoxicity (especially in women with high CD4 counts), severe rash/Stevens-Johnson syndrome
• Rilpivirine: requires food and adequate gastric acid (avoid with PPIs); less CNS toxicity than efavirenz
• All NNRTIs: rash, CYP3A4 induction/inhibition (major drug interactions)

CLASS 3 — Protease Inhibitors (PIs)

Mechanism of Action

1. After the integrated provirus is transcribed and translated, HIV produces a long polyprotein precursor (Gag-Pol polyprotein).
2. The viral protease enzyme must cleave this polyprotein into individual functional proteins (structural proteins + enzymes) necessary for virion maturation.
3. PIs are peptidomimetic compounds that competitively bind the active site of HIV protease, blocking cleavage of the polyprotein.
4. The result is release of non-infectious, immature viral particles that cannot establish new infections.

"As the virion buds from the surface, the viral protease is activated and cleaves the polyproteins into their component proteins, which then assemble into the mature virion. Protease inhibitors prevent this essential step in virus maturation." — Lippincott Illustrated Reviews: Pharmacology

• Metabolic syndrome: dyslipidemia, insulin resistance, lipodystrophy (fat redistribution)
• Atazanavir: indirect hyperbilirubinemia (benign jaundice, inhibits UGT1A1), nephrolithiasis
• Indinavir: nephrolithiasis, requires high fluid intake
• Class effect: CYP3A4 inhibition → extensive drug interactions
• Tipranavir: hepatotoxicity, rare intracranial hemorrhage

CLASS 4 — Entry Inhibitors

4a. Fusion Inhibitors

• HIV envelope glycoprotein gp120 binds to CD4 on the host cell → conformational changes expose gp41 (transmembrane glycoprotein).
• gp41 undergoes a "hairpin" conformational change, bringing viral and host cell membranes together to fuse.
• Enfuvirtide is a synthetic 36-amino-acid peptide that binds to gp41, blocking the conformational change required for membrane fusion → viral RNA cannot enter the cell.
• Must be given subcutaneously (peptide, not orally bioavailable); injection-site reactions occur in nearly all patients.
• Reserved for treatment-experienced patients with virologic failure.

4b. CCR5 Antagonists (Co-receptor Antagonists)

• HIV uses either CCR5 (R5-tropic strains) or CXCR4 (X4-tropic strains) as a co-receptor alongside CD4 for entry.
• Maraviroc binds CCR5 on the host cell, causing an allosteric conformational change that prevents gp120 from binding the co-receptor → entry blocked.
• Requires tropism testing before use (Trofile assay) — effective only against R5-tropic virus; useless against X4-tropic or dual/mixed-tropic strains.
• Generally well tolerated; hepatotoxicity risk; possible cardiovascular effects.

4c. CD4-Directed Attachment Inhibitors

• Fostemsavir is an attachment inhibitor (prodrug of temsavir) that binds HIV gp120 directly, preventing it from attaching to CD4 — blocking the very first step of viral entry.
• Ibalizumab is a humanized monoclonal antibody that binds to domain 2 of CD4, blocking post-attachment conformational changes needed for co-receptor engagement — given IV every 2 weeks; reserved for heavily treatment-experienced patients with multi-drug resistant HIV.

CLASS 5 — Integrase Strand Transfer Inhibitors (INSTIs)

Mechanism of Action

1. Integrase first performs 3′-processing: removes two nucleotides from each end of the viral DNA, creating reactive 3′-OH ends.
2. Integrase then catalyzes strand transfer: the processed viral DNA ends attack the host chromosomal DNA, inserting the provirus.
3. INSTIs bind the active site of integrase by chelating the two divalent Mg²⁺ metal cations at the catalytic core — this occupies the active site and blocks the strand transfer step specifically.
4. Proviral integration is halted → no permanent infection of the cell.

"The active site of the integrase enzyme binds to the host cell DNA and includes two divalent metal cations that serve as chelation targets for the INSTIs." — Lippincott Illustrated Reviews: Pharmacology

PHARMACOKINETIC BOOSTERS (Not Antiretroviral Drugs per se)

Summary Classification Table

Standard Initial Regimen (per Harrison's 22e, 2025)

• Two NRTIs (tenofovir-based [TDF or TAF] + emtricitabine or lamivudine) PLUS
• An INSTI (dolutegravir or bictegravir preferred) OR
• A boosted PI (darunavir/r or /c) OR
• An NNRTI (rilpivirine or doravirine)

Note: KD Tripathi's Essentials of Medical Pharmacology is not available in this library's digital collection. The following answer is compiled from Katzung's Basic & Clinical Pharmacology (16th ed.) and Goodman & Gilman's Pharmacological Basis of Therapeutics — both cover antiretrovirals at exactly the same depth and format as KDT for MBBS 2nd year.

Antiretroviral Drugs — Classification & Mechanism of Action

As per Katzung / Goodman & Gilman (MBBS 2nd Year)

Fig 49-3: Life cycle of HIV showing sites of action of each antiretroviral class — Katzung's Basic & Clinical Pharmacology, 16th ed.

CLASSIFICATION

1. NUCLEOSIDE/NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)

Mechanism of Action

• NRTIs are structural analogs of natural nucleosides (building blocks of DNA) but with one critical difference: they lack the 3′-hydroxyl (–OH) group on the ribose sugar.
• After entering the cell, they are phosphorylated by host cell kinases to their active triphosphate form.
• HIV reverse transcriptase (RT) incorporates the triphosphate NRTI into the growing viral DNA chain in preference to the natural nucleotide.
• Because there is no 3′-OH group, the next nucleotide cannot be added → obligate chain termination → viral DNA synthesis stops.
• NRTIs have a lower affinity for host DNA polymerases than for HIV RT, giving selectivity. However, mitochondrial DNA polymerase γ is susceptible → basis of mitochondrial toxicities.

"Phosphorylated to active form to prevent infection of susceptible cells; do not eradicate virus from cells with integrated proviral DNA; active against HIV-1, HIV-2, and in some cases HBV." — Goodman & Gilman

• TDF (tenofovir disoproxil fumarate) — older, more renal/bone toxicity
• TAF (tenofovir alafenamide) — newer, achieves 5–7× higher intracellular levels at lower plasma concentrations → safer kidneys and bones

Key Toxicities

2. NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)

Mechanism of Action

• NNRTIs do NOT need intracellular phosphorylation (unlike NRTIs).
• They bind directly and non-competitively to a hydrophobic allosteric pocket on HIV-1 reverse transcriptase (near but distinct from the active catalytic site).
• This binding causes a conformational change in the enzyme → reduces RT's catalytic activity → viral RNA cannot be reverse-transcribed into DNA.
• Important distinction: NNRTIs are HIV-1 specific — they are NOT active against HIV-2 (which lacks the corresponding binding pocket). This is a key exam point.
• They do not compete with natural nucleotides.

Key Toxicities

3. PROTEASE INHIBITORS (PIs)

Mechanism of Action

• PIs act at a late post-transcriptional stage of the HIV life cycle.
• HIV first transcribes and translates its genome into a long Gag-Pol polyprotein precursor — a non-functional, immature protein chain.
• The viral protease enzyme must cleave this polyprotein into individual structural proteins and enzymes (e.g., reverse transcriptase, integrase, capsid) → required for virion maturation.
• PIs are peptidomimetic compounds that competitively bind the active site of HIV protease → block polyprotein cleavage → immature, non-infectious viral particles are released.
• Result: virions bud but cannot infect new cells.

Pharmacokinetic Boosting

• Most PIs are metabolized by CYP3A4.
• Ritonavir (at low/booster dose) and cobicistat are potent CYP3A4 inhibitors used to raise plasma levels of co-administered PIs → less frequent dosing, more sustained levels.
• e.g., Lopinavir is always given as LPV/r (+ ritonavir 100 mg); Darunavir + ritonavir (DRV/r) or darunavir + cobicistat.

Key Toxicities

4. INTEGRASE STRAND TRANSFER INHIBITORS (INSTIs)

Mechanism of Action

• After reverse transcription, HIV double-stranded DNA must be inserted into the host cell's chromosomal DNA — a step catalyzed by viral integrase.
• Integrase carries two Mg²⁺ metal ions at its active site, essential for catalytic activity.
• INSTIs chelate these divalent metal cations at the integrase active site → block the strand transfer step (insertion of viral DNA into host DNA) → no provirus formation → no permanent infection.
• The cell is not permanently infected, and viral gene expression cannot occur.

• Cabotegravir IM + rilpivirine IM = first long-acting complete ART regimen (given monthly or every 2 months)
• Cabotegravir IM alone = approved for PrEP (pre-exposure prophylaxis)

Key Toxicities

• Generally well tolerated — nausea, diarrhea most common
• Chelation interaction with antacids, iron, calcium, magnesium supplements (reduce oral INSTI absorption significantly — separate doses)
• Dolutegravir: mild creatinine elevation (inhibits tubular secretion, not true nephrotoxicity); neural tube defect risk around conception
• Elvitegravir: requires cobicistat boosting; cross-resistance with raltegravir

5. ENTRY INHIBITORS

5a. Fusion Inhibitor

• HIV surface glycoprotein gp120 binds to CD4 on the host cell → exposes gp41 (transmembrane protein).
• gp41 undergoes a hairpin conformational change that brings the viral and host cell membranes close together → membrane fusion → viral RNA enters the cell.
• Enfuvirtide is a 36-amino-acid synthetic peptide that binds to gp41, preventing its conformational change → fusion blocked.
• Must be given subcutaneously (is a peptide, not orally bioavailable).
• Used only in treatment-experienced patients with multidrug-resistant HIV.
• ADR: injection-site reactions (pain, erythema, nodules) — nearly universal.

5b. CCR5 Antagonist (Co-receptor Antagonist)

• HIV requires a co-receptor (CCR5 or CXCR4) in addition to CD4 for entry.
• Maraviroc binds CCR5 on the host cell → allosteric conformational change → gp120 cannot bind CCR5 → viral entry blocked.
• Tropism testing is mandatory before use (effective only against R5-tropic virus, not X4-tropic).
• ADR: hepatotoxicity (with allergic reaction), possible cardiovascular risk, upper respiratory tract infections.

5c. gp120 Attachment Inhibitor

• Prodrug of temsavir; binds gp120 directly → prevents attachment to CD4.
• Used in heavily treatment-experienced adults with multidrug-resistant HIV.

5d. CD4 Post-attachment Inhibitor

• Humanized monoclonal antibody that binds domain 2 of CD4 → blocks post-attachment conformational changes needed for co-receptor engagement → entry inhibited.
• Given IV every 2 weeks; reserved for multidrug-resistant HIV.

6. CAPSID INHIBITOR (Newest Class)

• Binds HIV-1 capsid protein → disrupts multiple stages of the viral life cycle (nuclear import, assembly, uncoating).
• Given twice-yearly subcutaneous injection — longest-acting antiretroviral available.
• Used for multidrug-resistant HIV in combination with other agents; also under investigation for PrEP.

PHARMACOKINETIC BOOSTERS

STANDARD FIRST-LINE ART REGIMEN (Preferred)

2 NRTIs  +  1 INSTI (preferred)
              OR 1 NNRTI
              OR 1 boosted PI

HIGH-YIELD EXAM POINTS (MBBS 2nd Year)