Tenofovir

Tenofovir is available in two prodrug forms: tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). Mechanism: After intracellular phosphorylation to tenofovir diphosphate, it competes with endogenous deoxyadenosine triphosphate for incorporation into viral DNA by HIV reverse transcriptase or HBV polymerase, causing premature chain termination due to lack of a 3'-OH group. It is typically combined with emtricitabine or other antiretrovirals (e.g., in Truvada, Atripla, Biktarvy) for HIV treatment and pre-exposure prophylaxis (PrEP). It is also a first-line agent for chronic hepatitis B due to its potent suppression of viral replication and high barrier to resistance.

Pharmacokinetics: TDF results in higher plasma tenofovir levels and more systemic exposure (greater renal/bone toxicity), whereas TAF achieves higher intracellular concentrations in lymphoid cells with lower plasma levels, resulting in improved renal and bone safety profiles.

Adverse effects: Nephrotoxicity (proximal renal tubulopathy, Fanconi syndrome, acute kidney injury) is more common with TDF due to renal tubular accumulation via organic anion transporters. Decreased bone mineral density (osteomalacia, increased fracture risk) can occur, again more with TDF. Other effects include GI upset. Dose adjustment needed in renal impairment. Caution advised with concurrent nephrotoxic drugs.

Resistance: High genetic barrier; K65R mutation in HIV reverse transcriptase confers reduced susceptibility.

Clinical use highlights: Part of standard first-line ART regimens combined with an integrase strand transfer inhibitor (e.g., dolutegravir) or NNRTI. Used in PrEP for HIV-negative individuals at high risk. Effective against HBV due to overlapping polymerase inhibition, important in HIV/HBV coinfected patients to avoid HBV flare if discontinued.