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.

Summary Background Oral emtricitabine-tenofovir disoproxil fumarate (FTC/TDF) pre-exposure prophylaxis (PrEP) is used to prevent the sexual acquisition of HIV. Transgender women (TGW) have unique characteristics that may relate to PrEP use, effectiveness, and safety. Methods The iPrEx trial was a randomized controlled trial (RCT) of oral FTC/TDF PrEP versus placebo among men who have sex with men (MSM) and TGW, followed by an open label extension (OLE). Drug concentrations were measured in blood by liquid chromatography and tandem mass spectroscopy. Findings Of the 2499 participants enrolled in the RCT, 29 (1%) identified as women, 296 (12%) identified as “trans”, 14 (1%) identified as men but reported use of feminizing hormones, such that 339 (14%) reported one or more of these characteristics (TGW). Compared with MSM, TGW more frequently reported transactional sex, receptive anal intercourse without a condom, or more than 5 partners in the past 3 months. Among TGW, there were 11 HIV infections in the active arm and 10 in the placebo arm, representing a hazard ratio of 1.1 (95% CI: 0.5 to 2.7). Among active arm participants, drug was detected in none of the TGW at the seroconversion visit, 18% (6/37) of seronegative TGW (P=0.31), and 52% (58/111) of seronegative MSM (P < 0.0001). PrEP use was not linked to behavioral indicators of HIV risk among TGW, while MSM at highest risk were more adherent. Interpretation There were no HIV infections among TGW having drug concentrations commensurate with use of 4 or more FTC/TDF tablets per week. TGW receiving PrEP had low drug concentrations, especially at times of potential HIV exposure, leading to no PrEP effectiveness among this subgroup. Funding U.S. National Institutes of Health and the Bill and Melinda Gates Foundation; study medication was donated by Gilead Sciences.

Objective:Tenofovir disoproxil fumarate (TDF) pre-exposure prophylaxis decreases sexual acquisition of HIV infection. We sought to evaluate the renal safety of TDF in HIV-uninfected persons.Design and methods:The Iniciativa Profilaxis Pre-Exposición (iPrEx) study randomly assigned 2499 HIV-seronegative men and transgender women who have sex with men (MSM) to receive oral daily TDF coformulated with emtricitabine (FTC/TDF) or placebo. Serum creatinine and phosphorus during randomized treatment and after discontinuation were measured, and creatinine clearance (CrCl) was estimated by the Cockcroft–Gault equation. Indicators of proximal renal tubulopathy (fractional excretion of phosphorus and uric acid, urine protein, and glucose) were measured in a substudy.Results:There was a small but statistically significant decrease in CrCl from baseline in the active arm, compared to placebo, which was first observed at week 4 (mean change: −2.4 vs. −1.1 ml/min; P = 0.02), persisted through the last on-treatment visit (mean change: +0.3 vs. +1.8 ml/min; P = 0.02), and resolved after stopping pre-exposure prophylaxis (mean change: −0.1 vs. 0.0 ml/min; P = 0.83). The effect was confirmed when stratifying by drug detection. The effect of FTC/TDF on CrCl did not vary by race, age, or history of hypertension. There was no difference in serum phosphate trends between the treatment arms. In the substudy, two participants receiving placebo had indicators of tubulopathy.Conclusions:In HIV-seronegative MSM, randomization to FTC/TDF was associated with a very mild nonprogressive decrease in CrCl that was reversible and managed with routine serum creatinine monitoring.