The clinical pharmacology of antiretrovirals for HIV prevention

Pre-exposure prophylaxis (PrEP) clinical trial results using antiretrovirals can seem confusing, if not conflicting. We review recent antiretroviral pharmacokinetic studies to help explain PrEP trial results.

Pharmacokinetic studies indicate that topical dosing, compared with oral dosing, achieves far higher colon and vaginal tissue drug concentrations, and far lower drug concentrations in blood. After oral dosing, higher tenofovir diphosphate concentrations are found in colon tissue than cervico-vaginal tissue, but the reverse is the case for emtricitabine triphosphate, although it does not persist as long. Vaginal dosing achieves measurable tenofovir concentrations in the rectum and vice versa. Within and among oral PrEP trials, increased drug concentration is associated with increased HIV protection, with drug concentration differences best explained by adherence, rather than pharmacokinetics. The poor level of protection in topical studies is not consistent with concentration-response in oral studies indicating unknown variables in need of further investigation.

Sparse pharmacokinetic sampling in large trials combined with more intensive sampling in smaller pharmacokinetic-focused studies help explain trial outcome differences due largely to differences in adherence, tissue pharmacokinetics, and type of HIV exposure. Pharmacokinetic analysis can identify protective drug concentration targets, guide dose optimization, and inform future trials.