Fig. 1: General approach of combining data-driven, ‘top-down’ and hypotheses-driven, ‘bottom-up’ modeling to investigate FTC/TDF-based PrEP efficacy in cis women.

In the ‘top-down’ approach, we solely used clinical data to infer PrEP efficacy in cis women with detectable plasma TFV (cis women who took some product). Based on pharmacokinetic models, we could dichotomize PrEP intervention arms. When the drug was undetectable, incidences corresponded to placebo incidences, so efficacy was assumed to be 0%. By simulating this placebo-like subcohort of the PrEP intervention arm, we could estimate drug efficacy in individuals with detectable drug. In the ‘bottom-up’ approach we implemented all previously proposed hypotheses (exposure, drug potency and drug pharmacokinetics) that aim at mechanistically explaining distinct efficacy and adherence–efficacy requirements in cis women (in comparison to MSM) using advanced multiscale modeling and simulation. In a final step, we assessed whether proposed hypotheses hold up against clinically observed outcomes.