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Model-based predictions of protective HIV pre-exposure prophylaxis adherence levels in cisgender women
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Nov 2023 Nature Medicine
Most human immunodeficiency virus (HIV) infections occur in cisgender women in resource-limited settings. In women, self-protection with emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (FTC/TDF-PrEP) constitutes a major pillar of HIV prevention. However, clinical trials in women had inconsistent outcomes, sparking uncertainty about adherence requirements and reluctance in evaluating on-demand regimens. We analyzed data from published FTC/TDF-PrEP trials to establish efficacy ranges in cisgender women. In a ‘bottom-up’ approach, we modeled hypotheses in the context of risk-group-specific, adherence–efficacy profiles and challenged those hypotheses with clinical data. We found that different clinical outcomes were related to the proportion of women taking the product, allowing coherent interpretation of the data. Our analysis showed that 90% protection was achieved when women took some product. We found that hypotheses of putative male/female differences were either not impactful or statistically inconsistent with clinical data. We propose that differing clinical outcomes could arise from pill-taking behavior rather than biological factors driving specific adherence requirements in cisgender women.
Through comprehensive analysis of available clinical data, combined with computational modeling of FTC/TDF-based PrEP: (1) we assessed whether apparent discrepancy among clinical trial outcomes3,9,11,12,23,37 in women has a statistical foundation; (2) we challenged various mechanisms that were proposed in the context of risk-group-specific efficacy; and (3) we analyzed adherence requirements that provide sufficient PrEP protection.
Our population-pharmacokinetic (Pop-PK) modeling indicated that individuals with undetectable TFV levels (clinical adherence marker) must have taken FTC/TDF less than once a week, if at all (Supplementary Figs. 1 and 2). As TFV detectability has been reported in a random subset of the PrEP intervention arm of PrEP trials in cisgender women, we were able to dichotomize the intervention arms into subcohorts ‘undetectable drug’ (≤1 dose per week) and ‘detectable drug’ (≥1 dose per week). It is interesting that identical dichotomization of MSM trials concluded that FTC/TDF-based PrEP is ∼92% efficient in individuals who take some product, in contrast to un-dichotomized estimates of 44% in MSM38.

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