Predicting PrEP efficacy in women with partial adherence to tenofovir disoproxil fumarate/emtricitabine


BACKGROUND: Pre-exposure prophylaxis (PrEP) with daily oral Tenofovir disoproxil fumarate and emtricitabine (TDF-FTC) has been proven safe and effective for HIV prevention. Measures of adherence using intracellular tenofovir diphosphate (TFV-DP) in men suggest that partial adherence leads to reduction in HIV incidence of 76%, 96%, and 99% with two, four and seven pills per week. Randomized placebo-controlled trials (RCTs) in women have had conflicting results, although substantial reduction in HIV risk is associated with increasing proportions of women with detectable Tenofovir in plasma. We aimed to estimate percent HIV risk reduction in sub-Saharan African women as a function of TFV-DP concentration, which was used as a biomarker of adherence.
METHODS: We assume an exponential relationship between efficacy and TFV-DP, which has provided a good fit to HIV risk reduction by TDF-DP in men. We use observed efficacy in three RCTs of TDF-FTC in women: VOICE, FEM-PrEP and Partners PrEP (N=520) in which plasma tenofovir concentrations were measured, but TFV-DP was not. TFV-DP concentrations were inferred by bootstrap re-sampling from concurrent plasma tenofovir and TFV-DP measurements in HPTN 082, an open label study of TDF-FTC PrEP in women. Samples were drawn from the HPTN 082 dataset by dichotomizing the data with the same criteria for detectability used in each RCT. The exponential parameter was fit using Markov chain Monte Carlo. TFV-DP concentrations associated with 2, 4 and 7 pills per week was inferred from directly observed dosing studies.
RESULTS: Our model showed good agreement with the available data: the observed efficacy associated with the proportion of women with detectable plasma tenofovir in each RCT fell within the predicted 99% credible interval. We predict that a TFV-DP associated with taking 2, 4, and 7 pills per week reduces HIV risk by 62% (99% Credible Interval 32-92), 87% (55-100), and 97% (76-100), respectively.
CONCLUSIONS: Our analysis suggests that partial adherence to PrEP may provide similar or only slightly lower protection in women as in men. Our derived curve can be used to estimate TDF-FTC PrEP effectiveness in future prevention studies in women and predict the impact of interventions in mathematical models.