HIV Protease Inhibitors
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Direct answer
HIV protease inhibitors block the viral aspartyl protease that cleaves the gag-pol polyprotein, so virions assemble but remain immature and non-infectious. Members include atazanavir, darunavir, lopinavir and the boosting agent ritonavir, whose ferocious CYP3A4 inhibition raises levels of partner drugs. Their burden is metabolic — lipodystrophy, hyperlipidaemia and insulin resistance — together with a web of drug interactions that disqualify simvastatin and rifampicin.
What you must remember
- Mechanism: transition-state analogues occupy the protease active site, preventing post-translational cleavage of viral precursors; the result is structurally defective, non-infectious particles.
- Ritonavir boosting: even low-dose ritonavir inhibits CYP3A4 so profoundly that it pharmacokinetically boosts atazanavir, darunavir or lopinavir, allowing lower doses and longer intervals — lopinavir-ritonavir was the fixed-dose mainstay of Indian programmes.
- Darunavir boosted with ritonavir or cobicistat is the preferred protease inhibitor for treatment-naive and experienced patients, owing to its high genetic barrier.
- Signature toxicities: indinavir — crystalluria, nephrolithiasis and unconjugated hyperbilirubinaemia; atazanavir — benign indirect hyperbilirubinaemia with jaundice and cholelithiasis; darunavir — rash and hepatotoxicity.
- Class metabolic syndrome: peripheral fat wasting with central accumulation, hypertriglyceridaemia, insulin resistance and new-onset diabetes, plus transaminase elevation.
- Interactions dominate prescribing: simvastatin and lovastatin are contraindicated; rifampicin is avoided with protease inhibitors, using rifabutin instead in tuberculosis coinfection; doses of warfarin, steroids and antiarrhythmics spiral unpredictably.
- All are heavily protein-bound, and boiled down to exam essence: protease inhibitors are inhibitors of cytochrome P450 that act as victims and perpetrators of interactions in both directions.
Common confusion
Ritonavir's role confuses students most: at boosting doses it contributes little antiviral activity and exists purely to inhibit CYP3A4 and raise companion drug levels. The second muddle is treating atazanavir jaundice as hepatotoxicity — it is benign unconjugated hyperbilirubinaemia from bilirubin glucuronidation inhibition that mimics Gilbert syndrome, not liver injury.
Exam-focused takeaway
Theory answers should explain gag-pol cleavage blockade, ritonavir-boosting logic, the metabolic toxicity cluster and interaction rules. Viva examiners ask why rifampicin and protease inhibitors clash and how tuberculosis-HIV coinfection is handled. MCQs test mechanism, indinavir stones, atazanavir jaundice, contraindicated statins and lipodystrophy.
Frequently asked questions
How do protease inhibitors render HIV non-infectious?
By inhibiting the viral protease that cleaves gag-pol polyproteins, so progeny virions are produced with immature cores unable to complete the replication cycle.
Why is ritonavir given in small doses with other protease inhibitors?
It inhibits CYP3A4-mediated metabolism so strongly that partner drug exposure rises, allowing lower doses, longer dosing intervals and a higher genetic barrier to resistance.
Which protease inhibitor causes renal stones?
Indinavir, through crystalluria and stone formation — one reason it has disappeared from routine use.
Why does atazanavir cause jaundice?
It inhibits hepatic glucuronidation of bilirubin, producing reversible unconjugated hyperbilirubinaemia and clinical jaundice without liver damage.
Which drugs are contraindicated with protease inhibitors?
Simvastatin and lovastatin, risking rhabdomyolysis, and rifampicin, which collapses protease inhibitor levels — alternatives like pravastatin and rifabutin are used instead.