Nondaily preexposure prophylaxis for HIV prevention

To discuss nondaily preexposure prophylaxis (PrEP) modalities that may provide advantages compared with daily PrEP in cost and cumulative toxicity, but may have lower adherence forgiveness.

Animal models have informed our understanding of early viral transmission events, which help guide event-driven PrEP dosing strategies. These models indicate early establishment of viral replication in rectal or cervicovaginal tissues, so event-driven PrEP should rapidly deliver high mucosal drug concentrations within hours of the potential exposure event. Macaque models have demonstrated the high biological efficacy for event-driven dosing of oral tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) against both vaginal and rectal virus transmission. In humans, the IPERGAY study demonstrated 86% efficacy for event-driven oral TDF/FTC dosing among men who have sex with men (MSM), while no similar efficacy data are available on women or heterosexual men. The HPTN 067 study showed that certain MSM populations adhere well to nondaily PrEP, whereas other populations of women adhere more poorly to nondaily versus daily regimens. Pharmacokinetic studies following oral TDF/FTC dosing in humans indicate that TFV-diphosphate (the active form of TFV) accumulates to higher concentrations in rectal versus cervicovaginal tissue, but nonadherence in trials complicates the interpretation of differential mucosal drug concentrations.

Event-driven dosing for TFV-based PrEP has promise for HIV prevention in MSM. Future research of event-driven PrEP in women and heterosexual men should be guided by a better understanding of the importance of mucosal drug concentrations for PrEP efficacy and its sensitivity to adherence.