HIV reverse transcriptase inhibitors

HIV reverse transcriptase inhibitors

HIV reverse transcriptase inhibitors

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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.

NNRTI mechanism: blocking reverse transcriptase

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.

Zidovudine phosphorylation, metabolism, and HIV inhibition

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.

HIV RT with Nevirapine and AZTTP binding sites

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.

Practice Questions: HIV reverse transcriptase inhibitors

Test your understanding with these related questions

A 32-year-old man comes to the physician for a follow-up examination 1 week after being admitted to the hospital for oral candidiasis and esophagitis. His CD4+ T lymphocyte count is 180 cells/μL. An HIV antibody test is positive. Genotypic resistance assay shows the virus to be susceptible to all antiretroviral therapy regimens and therapy with dolutegravir, tenofovir, and emtricitabine is initiated. Which of the following sets of laboratory findings would be most likely on follow-up evaluation 3 months later? $$$ CD4 +/CD8 ratio %%% HIV RNA %%% HIV antibody test $$$

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Flashcards: HIV reverse transcriptase inhibitors

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Non-nucleoside RTIs (NNRTIs) directly inhibit _____ by binding to a different site from NRTIs

TAP TO REVEAL ANSWER

Non-nucleoside RTIs (NNRTIs) directly inhibit _____ by binding to a different site from NRTIs

HIV reverse transcriptase

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