Characterizing HIV-Preventive, Plasma Tenofovir Concentrations-A Pooled Participant-level Data Analysis From Human Immunodeficiency Virus Preexposure Prophylaxis (PrEP) Clinical Trials

Background Daily dosing of tenofovir disoproxil fumarate, with or without emtricitabine, has high efficacy in preventing human immunodeficiency virus (HIV) infection when individuals are adherent. The target protective plasma concentration of tenofovir (TFV), however, is not fully understood. The aim of this study is to estimate the protective TFV plasma concentration. Methods Participant data from TFV-based daily oral and topical active arms of phase 3 trials (iPrEx, VOICE, and Partners PrEP) were pooled (n = 2950). Individual specific risk scores (low and high risk) of acquiring HIV, based on an earlier placebo analysis, were created. Longitudinal TFV pharmacokinetics (PK), HIV outcome, individual risk scores and the effect of sex at birth data were integrated and analyzed using non-linear mixed effects models. Results Around 50% of the individuals were estimated to be adherent, which differed from self-reported adherence (similar to 90%) and large variation between longitudinal adherence patterns were identified. Following oral administration, the estimated protective TFV trough concentration was substantially higher in high-risk females (45.8 ng/mL) compared with high-risk males (16.1 ng/mL) and to low-risk individuals (similar to 7.5 ng/mL). Dosing simulations indicated that high-risk women require full adherence to maintain protective levels. Conclusions Using the largest PK-HIV outcome database to date, we developed a population adherence-PK-risk-outcome model. Our results indicate that high-risk females need higher levels of plasma TFV to achieve HIV protection compared with males. HIV protection exceeds 90% in all populations if daily adherence is achieved. We estimated human immunodeficiency virus (HIV)-protective, plasma tenofovir concentration using pharmacokinetic-HIV outcome modeling. Women at high risk of infection need higher plasma tenofovir levels to prevent HIV acquisition compared with men. HIV protection exceeds 90% in all populations if daily adherence is achieved.