Antiretroviral Drugs Protect Against HIV-1 Infection in Heterosexuals

BackgroundAntiretroviral preexposure prophylaxis is a promising approach for preventing human immunodeficiency virus type 1 (HIV-1) infection in heterosexual populations.MethodsWe conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services.ResultsWe enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group (incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study.ConclusionsOral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women. (Funded by the Bill and Melinda Gates Foundation; Partners PrEP ClinicalTrials.gov number, NCT00557245.)

Comparing pharmacologic measures of tenofovir exposure in a U.S. pre-exposure prophylaxis randomized trial

<div><p>It is critical to assess adherence to pre-exposure prophylaxis (PrEP) in clinical trials. The relationship between pharmacokinetic measures of PrEP adherence and other adherence measures used in PrEP trials requires further characterization. Plasma, peripheral blood mononuclear cells (PBMCs), and hair samples were collected from 88 HIV-uninfected men who have sex with men in a placebo-controlled randomized PrEP trial; announced pill counts, medication electronic monitoring (MEMS), and self-report using visual analog scale (VAS) were also collected. Tenofovir (TFV or TFV-DP) in plasma, hair, and PBMCs were quantified. Proportions with drug detection, Spearman correlation coefficients, and univariate and multivariable regression models were used. Drug detection in plasma, PBMC, and hair samples was highly concordant with treatment arm assignment. TFV or TFV-DP levels were detected in most active-arm participants: 44/47 (94%) in plasma, 46/47 (98%) in hair, and 44/47 (94%) in PBMCs and in only 1/41 placebo arm participant. Correlation coefficients were r = 0.59 for plasma and PBMC, r = 0.34 for PBMC and hair and r = 0.36 for plasma and hair. MEMS and announced pill-counts were moderately correlated (r = 0.52) but less so with pharmacologic measures (range of r = 0.12 to 0.38). Self-reported adherence by visual analog scale demonstrated essentially no correlation with drug levels (r = 0.06 for hair, PBMC or plasma) and was a poor indicator of exposure to study product. Indices of drug exposure are important indicators in assessing adherence to PrEP; accounting for variability between measures may improve interpretation and use of adherence measures in future PrEP studies.</p><p>Clinical trial registration</p><p>Clinical Trials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT00131677" target="_blank">NCT00131677</a></p></div