Ritonavir and cobicistat block CYP3A4 → raise concentrations of all CYP3A4 substrates co-administered. Critical interactions: simvastatin/lovastatin (contraindicated — 50-fold rise); tacrolimus/cyclosporine (dramatic rise — transplant patients); DOACs rivaroxaban and apixaban (contraindicated); rifabutin (reduce dose to 150 mg every other day).
Lower concentrations of CYP3A4 substrates. Rifampin: reduces PI AUC 75–90% (contraindicated with all boosted PIs); reduces dolutegravir AUC 54% (double dose to 50 mg BID); reduces efavirenz AUC ~26% (acceptable — use efavirenz with rifampin). Efavirenz/nevirapine: lower methadone 50–60%; lower oral contraceptives 40–55%.
Rifampin: contraindicated with all boosted PIs. Use efavirenz or dolutegravir 50 mg BID. Rifabutin (weaker inducer): usable with PIs (reduce rifabutin dose), INSTIs (standard dose), NNRTIs (standard dose). Preferred rifamycin in resource-rich settings.
PPIs: contraindicated with rilpivirine (throughout day — can't overcome with timing). Contraindicated with unboosted atazanavir. H2 blockers: OK with rilpivirine (separate by 12 h before or 4 h after). DTG and BIC: no acid-dependent absorption — use in PPI-dependent patients.
Efavirenz reduces methadone 50–60% via CYP3A4/2B6 induction → opioid withdrawal within days. Nevirapine: similar reduction (~46%). Coordinate with methadone prescriber before starting these ARVs. Dolutegravir and bictegravir: no significant methadone interaction — preferred in all patients on methadone maintenance.
OAT1 transporter concentrates TDF in proximal tubules → mitochondrial injury → Fanconi syndrome (glucosuria without hyperglycemia, phosphaturia, proteinuria). Risk increased by cobicistat/ritonavir (block MRP2 tubular efflux). Bone mineral density loss greater with TDF than TAF or abacavir. Switch to TAF when eGFR <60 or osteoporosis risk.
Nevirapine: immune-mediated; risk highest in women with CD4 >250 and men with CD4 >400 at initiation. Atazanavir: unconjugated hyperbilirubinemia (UGT1A1 inhibition) — benign, not hepatotoxicity. Abacavir: associated with increased MI risk (1.7–1.9-fold) — avoid in high cardiovascular risk patients. Monitor liver function in HBV/HCV co-infected patients starting ART.
Occurs in 10–25% of patients starting ART with CD4 <100 cells/mm³ — typically within 4–8 weeks. Two forms: unmasking IRIS (subclinical infection becomes apparent) and paradoxical IRIS (treated infection worsens). Most common precipitants: TB, MAC, Cryptococcus, CMV. Cryptococcal IRIS carries highest mortality — manage raised ICP with therapeutic lumbar puncture. Continue ART; add corticosteroids for severe non-cryptococcal IRIS.
Dolutegravir: now recommended throughout pregnancy including at conception (NTD signal largely resolved). Raltegravir: preferred INSTI alternative (most pregnancy safety data). NRTI backbone: TDF/FTC preferred (most data; dual HBV activity). Intrapartum IV ZDV: give if VL >1,000 copies/mL or unknown VL at delivery regardless of oral regimen.
Cabotegravir-rilpivirine long-acting injectable: contraindicated (no safety data; prolonged PK tail if must stop). Atazanavir near term: neonatal hyperbilirubinemia risk — monitor neonatal bilirubin. Efavirenz: non-preferred but acceptable when no alternative available. Lopinavir/ritonavir oral solution: contraindicated in neonates (propylene glycol/ethanol).
TDF: avoid if eGFR <60 mL/min. TAF: safe to eGFR ≥15 mL/min. Abacavir: no renal adjustment (hepatic metabolism). INSTIs (DTG, BIC, RAL): no dose adjustment at any eGFR including dialysis. Biktarvy: not recommended below eGFR 15. Genvoya: not recommended below eGFR 30 (cobicistat component). Cobicistat/dolutegravir creatinine artifact: use cystatin C eGFR for true GFR assessment.
Darunavir and lopinavir: contraindicated in Child-Pugh C. Raltegravir: preferred INSTI in Child-Pugh C (pharmacokinetics minimally affected). Dolutegravir: AUC increases 1.5-fold in Child-Pugh B — not recommended in Child-Pugh C. Abacavir: contraindicated in moderate-severe hepatic impairment (hepatic metabolism via alcohol dehydrogenase and UGT). Tipranavir: contraindicated in any clinically significant hepatic impairment.
Start TB treatment first. Start ART within 2 weeks if CD4 <50 cells/mm³; within 8–12 weeks if CD4 ≥50 cells/mm³. Use dolutegravir 50 mg BID with rifampin, OR switch rifampin to rifabutin 150 mg three times weekly to allow standard-dose dolutegravir. Monitor liver function every 2–4 weeks during intensive TB treatment phase. Paradoxical TB-IRIS: occurs in 15–20% — NSAIDs for mild, corticosteroids for severe cases.