Prodrugs phosphorylated intracellularly to active triphosphate forms. Incorporated into viral DNA by RT in place of natural nucleotides. Lack 3′-OH group → chain stops. Plasma levels do NOT reflect intracellular active drug — intracellular half-lives govern dosing interval.
Bind a hydrophobic pocket adjacent to (not at) the RT active site. No phosphorylation required. Induce conformational change that slows RT catalysis. Active only against HIV-1 — this pocket is absent in HIV-2 RT and human DNA polymerases.
Tenofovir prodrugs. TDF: high plasma exposure → renal/bone toxicity (OAT1-mediated tubular accumulation → Fanconi syndrome). TAF: lymphocyte-targeted delivery → ~10× lower plasma tenofovir → far less renal/bone toxicity. Both active against HBV.
Emtricitabine and lamivudine. Cytidine analogues. Well tolerated. FTC intracellular half-life ~39 h. Both active against HBV → discontinuation in HIV/HBV co-infected patients can cause fatal HBV flare. Screen for HBsAg before ART.
No renal dose adjustment (hepatic metabolism). Fatal HSR in HLA-B*57:01 carriers (~5–8%). Screen before prescribing — eliminates most clinical HSR. Rechallenge after confirmed HSR is absolutely contraindicated.
Always include TDF or TAF plus FTC or 3TC in ART for HIV/HBV co-infected patients. Never discontinue without a plan to maintain HBV suppression — abrupt stop risks fatal hepatic decompensation from HBV flare.
Risk: ZDV > ABC >> TDF / FTC / 3TC / TAF. Manifestations: lactic acidosis (most severe), hepatic steatosis, peripheral neuropathy, lipoatrophy. ZDV also causes anemia and neutropenia (bone marrow suppression). Stavudine and didanosine had highest risk — no longer used.
OAT1 transporter concentrates TDF in proximal tubular cells → mitochondrial injury → Fanconi syndrome: glucosuria (without hyperglycemia), phosphaturia, proteinuria. Risk increased by concurrent ritonavir/cobicistat (inhibit tubular efflux). TAF avoids this: plasma tenofovir ~10× lower.
M184V (selected by 3TC/FTC): high-level resistance to both, but increases susceptibility to ZDV and TDF. K65R (selected by TDF/ABC): resistance to TDF, TAF, ABC; preserves ZDV susceptibility. M184V and K65R are mutually antagonistic — K65R suppresses TAM pathway.
Selected by ZDV. Enhance RT pyrophosphorolysis → remove incorporated chain-terminating NRTI → chain elongation resumes. Six canonical TAMs (M41L, D67N, K70R, L210W, T215F/Y, K219Q/E). Multiple TAMs = broad NRTI cross-resistance. TAM and K65R pathways are largely mutually exclusive.
CYP3A4/2B6 inducer. CNS toxicity (vivid dreams, dizziness, depression). Reduces methadone 50–60% → opioid withdrawal. Lowers oral contraceptive levels. K103N → high-level resistance. Avoid in psychiatric illness and methadone patients.
CYP3A4 substrate only (no induction). Must take with substantial meal. PPIs contraindicated (suppress gastric acid all day → poor absorption regardless of timing). K103N does NOT cause resistance. Contraindicated: VL >100,000 or CD4 <200.
CYP3A4 substrate only. Active against K103N and E138K. No food requirement. Excellent CNS tolerability. Rifampin contraindicated (reduces AUC ~88%). Good option when efavirenz CNS toxicity or interactions are a concern.
Efavirenz reduces methadone by 50–60% via CYP3A4/CYP2B6 induction. Opioid withdrawal begins within 1–2 weeks. Coordinate with the methadone prescriber before starting efavirenz. An INSTI-based regimen is strongly preferred in all patients on methadone maintenance.
PPIs are absolutely contraindicated with rilpivirine — they suppress gastric acid throughout the day and prevent adequate absorption regardless of timing. H2 blockers may be used if taken at least 12 hours before or at least 4 hours after rilpivirine. Antacids: separate by at least 2 hours before or 4 hours after.
K103N is present in ~2–8% of newly diagnosed treatment-naive patients in the U.S. K103N causes high-level resistance to efavirenz and nevirapine, but NOT to rilpivirine or doravirine. Baseline genotypic resistance testing is required before selecting any NNRTI.