NRTI, NNRTI, PI, INSTI, and entry inhibitors

NRTIs - Backbone Blockers

• Mechanism: Competitive inhibitors of reverse transcriptase → chain termination. All require phosphorylation except Tenofovir.
• Class Adverse Effects: Lactic acidosis, Hepatic steatosis (Mitochondrial toxicity).
• Key Drugs & Unique Side Effects:

📌 Mnemonic: 'Have you dined (Didanosine) with my nuclear (NRTI) family?'

NNRTIs - Allosteric Antagonists

• Mechanism: Bind directly to an allosteric site on reverse transcriptase, inducing a conformational change that inactivates the enzyme. Do NOT require phosphorylation.
• Class Adverse Effects:
  • Rash, which can progress to Stevens-Johnson Syndrome (SJS).
  • Hepatotoxicity (monitor LFTs).
  • Significant drug-drug interactions as many are CYP450 inducers/inhibitors.
• Key Drugs & Unique Effects:
  • Efavirenz: Vivid dreams and CNS disturbances.
  • Nevirapine: Higher risk of severe hepatotoxicity.
  • Rilpivirine: Requires an acidic gut for absorption (take with food, avoid PPIs).

⭐ Efavirenz is well-known for causing significant neuropsychiatric side effects, a frequently tested clinical association.

Protease Inhibitors - Cutting Class

• Mechanism: Inhibit HIV protease, preventing cleavage of viral gag-pol polyproteins into mature, functional proteins. This results in immature, non-infectious virions.
• 📌 Mnemonic: Suffix -navir (Never cleave).
• Class Adverse Effects:
  • Metabolic syndrome: Hyperglycemia, hyperlipidemia, and lipodystrophy (fat redistribution).
  • GI intolerance.
  • ⚠️ All are CYP450 inhibitors.
• Key Drugs & Unique Effects:
  • Atazanavir: Jaundice/hyperbilirubinemia.
  • Darunavir: Use with caution in sulfa allergy.

⭐ Ritonavir is a potent CYP3A4 inhibitor, used less as an antiviral and more as a pharmacokinetic 'booster' to increase the levels of other PI drugs.

INSTIs - Integration Inhibitors

• Mechanism: Inhibit HIV integrase, preventing proviral DNA from integrating into the host cell genome.
• 📌 Suffix: -tegravir
• Key Drugs:
  • Dolutegravir, Bictegravir: Common in initial regimens.
  • Raltegravir: Can cause ↑ creatine kinase.
  • Elvitegravir: Requires a pharmacokinetic booster.
• Class Adverse Effects:
  • Generally well-tolerated.
  • Potential for weight gain, headache, insomnia.

  ⭐ Chelation: INSTIs bind polyvalent cations. Separate doses from Ca, Fe, Mg, or Al supplements by 2 hours before or 6 hours after.

Entry Inhibitors - Denied Access

Mechanism: Prevent HIV from entering CD4+ cells by targeting various surface proteins on either the virus or the host cell, effectively blocking attachment, co-receptor binding, or fusion.

High‑Yield Points - ⚡ Biggest Takeaways

• NRTIs are notorious for mitochondrial toxicity (e.g., lactic acidosis); Abacavir requires HLA-B*57:01 screening due to hypersensitivity risk.
• NNRTIs do not require phosphorylation and are associated with rash (SJS) and hepatotoxicity.
• Protease Inhibitors (-navir suffix) commonly cause metabolic syndrome, including hyperglycemia and lipodystrophy.
• Integrase Inhibitors (-tegravir suffix) are generally well-tolerated and prevent integration of viral DNA.
• Maraviroc (an entry inhibitor) is only effective against CCR5-tropic HIV strains.