HIV reverse transcriptase inhibitors

RTIs - The Viral Copy Jam

Reverse Transcriptase Inhibitors (RTIs) prevent HIV RNA from being converted into DNA, halting replication.

• NRTIs (Nucleoside/tide RTIs): Act as chain terminators.

  • 📌 Zidovudine, Abacavir, Lamivudine, Emtricitabine, Stavudine, Tenofovir.
  • ⚠️ Class effect: Mitochondrial toxicity → lactic acidosis, pancreatitis.

• NNRTIs (Non-Nucleoside RTIs): Allosterically inhibit reverse transcriptase.

  • Efavirenz, Nevirapine, Rilpivirine.
  • ⚠️ Class effect: Rash (incl. SJS), hepatotoxicity.

⭐ Test for HLA-B*5701 allele before starting Abacavir to predict potentially fatal hypersensitivity reactions.

NRTIs - Faulty Building Blocks

• Mechanism: Nucleos(t)ide analogs that competitively inhibit HIV reverse transcriptase. Incorporation into the growing viral DNA strand results in chain termination as they lack a 3'-OH group.
• Activation: All NRTIs (except Tenofovir, a nucleotide) require phosphorylation by cellular kinases to their active triphosphate form.
• Drugs (📌 Z-LATE):
  • Zidovudine (AZT)
  • Lamivudine (3TC)
  • Abacavir (ABC)
  • Tenofovir (TDF/TAF)
  • Emtricitabine (FTC)
• Class Adverse Effects:
  • Mitochondrial toxicity → Lactic acidosis, pancreatitis, peripheral neuropathy.
• Key Individual Toxicities:
  • Abacavir: Hypersensitivity reaction; screen for HLA-B*57:01 allele.
  • Tenofovir disoproxil fumarate (TDF): Nephrotoxicity (Fanconi-like syndrome), ↓ bone mineral density.
  • Zidovudine: Myelosuppression (anemia, neutropenia).

⭐ Zidovudine is a key agent used in the peripartum period to prevent vertical (mother-to-child) transmission of HIV.

NNRTIs - Allosteric Wrecking Crew

• Mechanism: Allosteric inhibitors of HIV-1 reverse transcriptase. Bind directly to a hydrophobic pocket near the catalytic site, inducing a conformational change that inactivates the enzyme.
  • Do NOT require phosphorylation to be active.
  • Effective only against HIV-1.
• Agents: 📌 NEvada DrivER
  • Nevirapine, Efavirenz, Delavirdine, Etravirine, Rilpivirine
• Adverse Effects & Pearls:
  • Class: Rash (incl. SJS), hepatotoxicity (↑ Nevirapine), many drug interactions (CYP450 metabolism).
  • Efavirenz: CNS toxicity (vivid dreams, confusion), teratogenic.
  • Rilpivirine: Needs acid gut for absorption (avoid PPIs).
• Resistance: Low genetic barrier; a single mutation (e.g., K103N) can cause class resistance.

⭐ Efavirenz is notorious for causing significant CNS side effects, including vivid dreams, dizziness, and depression, often appearing shortly after starting therapy.

Resistance Patterns - The Great Escape

• Core Issue: HIV's reverse transcriptase lacks proofreading, leading to high mutation rates (≈1 error per replication cycle) and rapid selection of drug-resistant variants.

• NRTIs (Nucleoside/tide Reverse Transcriptase Inhibitors):

  • M184V Mutation: Key mutation for Lamivudine (3TC) & Emtricitabine (FTC) resistance.
    • 💡 Paradoxically, it can ↑ susceptibility to Zidovudine (AZT) & Tenofovir (TDF).
  • Thymidine Analog Mutations (TAMs): Cause broad cross-resistance to multiple NRTIs.

• NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors):

  • Low Genetic Barrier: A single mutation (e.g., K103N) can confer high-level, class-wide resistance.

⭐ The M184V mutation, while conferring resistance to 3TC/FTC, reduces the virus's replicative capacity ("fitness cost"), a key principle in salvage therapy.

High‑Yield Points - ⚡ Biggest Takeaways

• NRTIs are competitive inhibitors requiring phosphorylation; NNRTIs are allosteric, non-competitive, and do not.
• The major class toxicity for NRTIs is mitochondrial toxicity, leading to lactic acidosis.
• Test for HLA-B*57:01 before starting Abacavir to prevent hypersensitivity reaction.
• Key toxicities: Zidovudine (anemia), Didanosine (pancreatitis), Tenofovir (nephrotoxicity).
• NNRTIs are noted for rash (SJS) and hepatotoxicity.
• Efavirenz is teratogenic and causes prominent CNS/psychiatric side effects.