Pharmacological markers of HIV prevention for oral pre-exposure prophylaxis in MSM

The human immunodeficiency virus (HIV) infected approximately 1.1 million individuals in 2024. Currently, there is no effective vaccine nor options to cure HIV. Moreover, resource-limited settings face massive cuts in funding for HIV treatment. To fight the global AIDS epidemic, cost-effective and widely-available HIV prevention, for example with oral emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (FTC/TDF-PrEP), are of utmost importance. Current PrEP guidelines differ between cisgender women and men who have sex with men (MSM). Mechanistically, the distinction is motivated by differences in tissue-level pharmacokinetics (PK) at vaginal vs. colo-rectal exposure sites. To test the validity of this mechanistic hypothesis, we utilized data from all major FTC/TDF-PrEP trials to establish 'PrEP efficacy when used' in MSM. We then independently predicted PrEP efficacy utilizing different PK-matrices (tissue vs. peripheral blood mononuclear cells, PBMCs) in a mechanistic model, simulated each clinical trial informed by adherence data and compared the predictions with clinical efficacy estimates to assess which pharmacological matrices predict efficacy. With this combined approach, two of the five trials (HPTN 083, DISCOVER) yielded sufficient statistical power to conclude (P<0.001) that pharmacokinetics in rectal tissue do not predict PrEP efficacy in MSM. In contrast, predictions utilizing drug concentrations in PBMCs agreed well with clinical PrEP efficacy and support previous findings regarding the suitability of on-demand use of oral PrEP in MSM. Moreover, when combining our findings with recent results on suitable pharmacokinetic markers in women, our work suggests that adherence requirements for cisgender women and MSM may not differ.