Block HIV-1 aspartyl protease, which cleaves Gag and Gag-Pol polyproteins into mature structural proteins after virion budding. PIs produce release of non-infectious immature particles. All PIs require pharmacokinetic boosting (ritonavir or cobicistat) to achieve therapeutic plasma concentrations via CYP3A4 and P-gp inhibition.
Ritonavir (100–200 mg): inhibits CYP3A4, CYP2D6, CYP2C9. Broader interaction profile. Cobicistat (150 mg): inhibits CYP3A4 only (cleaner profile) but blocks MATE1 → serum creatinine rises 0.1–0.2 mg/dL without true nephrotoxicity. Neither booster has antiviral activity at boosting doses. Both contraindicated with rifampin.
Very high resistance barrier — requires ≥3 simultaneous major mutations. Extensive hydrogen bond contacts with protease backbone. Rash (sulfonamide moiety). Rifampin contraindicated. Reduce statins.
UGT1A1 inhibition → unconjugated hyperbilirubinemia, scleral icterus (benign, reversible). Nephrolithiasis (~1–3%). Unboosted ATV: PPIs contraindicated. Moderate resistance barrier.
Simvastatin and lovastatin are absolutely contraindicated — CYP3A4 inhibition raises levels up to 50-fold → rhabdomyolysis. Use rosuvastatin or pravastatin. Atorvastatin: lowest effective dose only with monitoring.
Twice daily. Eliminated by UGT1A1 — no CYP involvement. Low resistance barrier (single mutation: Y143, Q148, or N155). Preferred in pregnancy (most safety data) and severe hepatic impairment.
Once daily. Very high resistance barrier — single mutations produce minimal resistance. Metabolized by UGT1A1/CYP3A4. Creatinine artifact (OCT2 inhibition). NTD signal largely resolved — acceptable in pregnancy. Weight gain.
Available only as Biktarvy (BIC/TAF/FTC). Equivalent resistance barrier to dolutegravir. No treatment-emergent resistance in phase 3. Creatinine artifact (OCT2/MATE1). Rifampin contraindicated — no dose doubling option.
Ca2+, Mg2+, Al3+, Fe2+/3+ in supplements and antacids chelate INSTI diketo pharmacophore in GI tract → dramatically reduce absorption. Dolutegravir/raltegravir: separate by 2 h before or 6 h after. Bictegravir: may take with Ca/Fe if taken with food. Affects all INSTIs — counsel every patient on calcium and iron supplements.
1st gen (RAL/EVG): Y143C/R, Q148H/R/K, N155H. Q148 pathway with G140S is highest concern — reduces dolutegravir susceptibility 8–25-fold. 2nd gen (DTG/BIC): no consistent single-mutation pathway in treatment-naive patients. Never use 2nd-gen INSTI after 1st-gen failure without resistance testing.
Rifampin induces UGT1A1/CYP3A4. Reduces dolutegravir AUC ~54% → dose double to 50 mg BID. Reduces bictegravir AUC ~75% → contraindicated (no dose doubling in fixed-dose combo). Rifabutin: weaker inducer, use standard INSTI doses.
Blocks CCR5 co-receptor conformational change required for gp41-mediated fusion. Targets host protein → resistance = tropism shift (R5 to X4), not drug-binding site mutation. Requires validated tropism assay confirming exclusively R5 virus before prescribing. CYP3A4 substrate: dose adjusts with boosted PIs (150 mg BID) or inducers (600 mg BID).
Enfuvirtide (T-20): HR2 peptide mimetic, prevents gp41 six-helix bundle. Subcutaneous injection BID — salvage only. Universal injection site reactions. Ibalizumab: anti-CD4 domain 2 mAb, IV q2 weeks — MDR HIV. Fostemsavir: gp120 attachment inhibitor, oral — heavily treatment-experienced MDR HIV.
Bictegravir/TAF/FTC (Biktarvy) — single tablet once daily, no food requirement, no significant CYP interactions, highest-barrier INSTI.
Dolutegravir + TAF/FTC — two pills once daily, component-level flexibility. Both achieve ~90% virologic suppression by week 48 with no resistance at failure.
Cabotegravir + rilpivirine IM monthly or every 2 months. After stopping injections: cabotegravir detectable up to 12 months, rilpivirine up to 4 years → functional monotherapy window as levels fall. Must transition to oral ART the day after last injection. Contraindications: NNRTI/INSTI resistance mutations, rifamycins, VL >100,000, CD4 <200, pregnancy.