Pharmacological markers of HIV prevention for oral pre-exposure prophylaxis in men who have sex with men

Abstract The human immunodeficiency virus (HIV) infected approximately 1.1 million individuals in 2024. There is no effective vaccine or cure, and funding cuts in resource-limited settings threaten treatment access. Cost-effective and widely available prevention strategies, such as oral emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (FTC/TDF-PrEP), are therefore essential. Current PrEP guidelines differ between cisgender women and men who have sex with men (MSM), based on mechanistic differences in tissue-level pharmacokinetics (PK) at vaginal vs. colorectal exposure sites. To test these mechanistic hypothesis, we use data from major FTC/TDF-PrEP trials to establish PrEP efficacy when used in MSM. We independently predict efficacy utilizing different PK-matrices in a mechanistic model, simulate each clinical trial informed by adherence data and compare the predictions with clinical efficacy estimates. With this combined approach, two of the five trials (HPTN 083, DISCOVER) yield sufficient statistical power to conclude that rectal tissue pharmacokinetics do not predict PrEP efficacy in MSM. In contrast, PBMC-based predictions agree with clinical PrEP efficacy and support the suitability of on-demand use of oral PrEP in MSM. 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.