alafenamide

Alafenamide refers to a class of phosphoramidate prodrugs designed to deliver nucleotide analogs more efficiently into target cells. The most widely used member is tenofovir alafenamide (TAF), a prodrug of tenofovir developed to replace tenofovir disoproxil fumarate (TDF) in many antiretroviral regimens. Alafenamide prodrugs are activated intracellularly to release the active nucleotide.

Mechanism and pharmacology: after administration, alafenamide prodrugs are taken up by cells and cleaved by intracellular enzymes such as cathepsin A to release tenofovir, which is then phosphorylated to the active tenofovir diphosphate (TFV-DP). This process yields high intracellular TFV-DP concentrations while maintaining substantially lower plasma tenofovir levels compared with TDF, contributing to a more favorable safety profile.

Clinical use: in HIV therapy, tenofovir alafenamide is used in several fixed-dose combinations, including bictegravir/emtricitabine/TAF (Biktarvy) and elvitegravir/cobicistat/emtricitabine/TAF (Genvoya). Descovy (emtricitabine/TAF) is used for HIV treatment and, in certain populations, for pre-exposure prophylaxis. For hepatitis B, Vemlidy (tenofovir alafenamide) is approved as a therapy option.

Safety and considerations: compared with TDF, TAF generally provides improved renal and bone safety due to lower systemic exposure to tenofovir. Nevertheless, adverse effects can occur and vary by regimen. Long-term safety continues to be monitored in clinical use.

Development and significance: the alafenamide prodrug technology was developed to improve safety and tolerability while maintaining antiviral efficacy at lower doses. It underpins several modern HIV and HBV regimens and represents a key evolution in nucleotide-based antiviral therapy.