Abstract
Background
Daily dosing of tenofovir disoproxil fumarate (TDF), with or without emtricitabine (FTC), has high efficacy in preventing 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 III trials (iPrEx, VOICE and Partners PrEP) were pooled (n = 2,950). 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 (NONMEM).
Results
Around 50% of the individuals were estimated to be adherent, which differed from self-reported adherenc e (∼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 to high risk males (16.1 ng/mL) and to low risk individuals (∼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 to males. HIV protection exceeds 90% in all populations if daily adherence is achieved.
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