BACKGROUND-Antiretroviral chemoprophylaxis before exposure is a promising approach for the prevention of human immunodeficiency virus (HIV) acquisition.

Background The impact of HIV pre-exposure prophylaxis (PrEP) depends on uptake, adherence, and sexual practices. Methods Men and transgender women who have sex with men (MSM/TGW) previously enrolled in PrEP trials were enrolled in a 72 week open label extension (iPrEx OLE). Drug concentrations were measured in plasma and dried blood spots (DBS) in seroconverters and a random sample of seronegatives. Findings 1603 HIV uninfected persons were enrolled, of whom 76% received PrEP. PrEP uptake was higher among those reporting condomless receptive anal intercourse (ncRAI; P=0.003) and having serological evidence of herpes (P=0.03). Among those receiving PrEP, HIV incidence was 1.8/100PY, which was 49% (95% CI: −1 to 74%) lower than among those who concurrently did not choose PrEP after adjusting for sexual behavior, and 53% (95% CI: 26 to 70%) lower than in the placebo arm of the prior randomized phase (3.9/100PY). Among those receiving PrEP, HIV incidence was 4.7/100PY if drug was not detected in DBS, 2.3/100PY if drug concentrations indicated use of less than 2 tablets per week, 0.6/100PY for use of 2 to 3 tablets per week, and 0/100PY for use of 4 or more tablets per week (P<0.0001). PrEP drug concentrations were higher among people with older age, more schooling, ncRAI, more sexual partners, trans-identification, and a history of syphilis or herpes. Interpretation PrEP uptake was high when made available free of charge by experienced providers. PrEP impact is increased by greater uptake and adherence during periods of higher risk; disengagement after initial use is common. DBS drug concentrations are strongly correlated with PrEP’s protective benefit.

Drug concentrations associated with protection from HIV-1 acquisition have not been determined. This study evaluated drug concentrations among men who have sex with men in a substudy of the iPrEx trial,(1) a randomized placebo controlled trial of daily oral emtricitabine/tenofovir disoproxil fumarate pre-exposure prophylaxis (PrEP). Any detectable drug in blood plasma and viably cryopreserved peripheral blood mononuclear cells (vPBMCs) was less frequent in HIV-infected cases at the visit when HIV was first discovered compared with controls at the matched time point of the study (8% vs 44%, P<0.001) and in the 90 days prior to that visit (11% vs 51%, P<0.001). An intracellular tenofovir-diphosphate (TFV-DP) concentration of 16 fmol per million vPBMCs was associated with a 90% reduction in HIV acquisition relative to the placebo arm. Directly observed dosing in a separate study, STRAND, yielded TFV-DP concentrations that, when analyzed with this iPrEx model, corresponded with HIV-1 risk reduction of 76% for 2 doses per week, 96% for 4 doses per week, 99% for 7 doses per week. Prophylactic benefits were observed over a range of doses and drug concentrations, suggesting ways to optimize PrEP regimens for this population.

Tenofovir (TFV) disoproxil fumarate (TDF) -emtricitabine (FTC) are widely used for HIV treatment and chemoprophylaxis, but variable adherence may lead to suboptimal responses. Methods that quantify adherence would allow for interventions to improve treatment and prevention outcomes. Our objective was to characterize the pharmacokinetics of TFV-diphosphate (TFV-DP) and FTC-triphosphate (FTC-TP) in red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs); to extend the RBC analysis to dried blood spots (DBSs); and to model how RBC/DBS monitoring could inform recent and cumulative drug exposure/adherence. Blood samples were collected from 17 HIV-negative adults at 5 visits over a 30-day pharmacokinetics study of daily oral TDF/FTC. Dosing was discontinued on day 30 and blood was collected on days 35, 45, and 60 during the washout period. Plasma/RBCs/PBMCs/DBSs were all quantified by liquid chromatography/tandem mass spectrometry. DBSs were paired with RBCs and plasma for comparisons. The median (interquartile range) RBC TFV-DP half-life was 17.1 (15.7-20.2) versus 4.2 (3.7-5.2) days in PBMCs. At steady state, TFV-DP was 130 fmol/ 10 6 RBCs versus 98 fmol/10 6 PBMCs. FTC-TP was not quantifiable in most RBC samples. TFV-DP in RBCs versus DBSs yielded an r 2 = 0.83. TFV-DP in DBSs was stable at -20°C. Simulations of TFV-DP in RBCs/DBSs, when dosed from one to seven times per week, demonstrated that each dose per week resulted in an average change of approximately 19 fmol/10 6 RBCs and 230 fmol/punch. TFV and FTC in plasma versus DBSs was defined by y = 1.4x; r 2 = 0.96 and y = 0.8x; r 2 = 0.99, respectively. We conclude that DBSs offer a convenient measure of recent (TFV/FTC) and cumulative (TFV-DP in RBCs) drug exposure with potential application to adherence monitoring.