Preexposure chemoprophylaxis for HIV prevention in men who have sex with men

Abstract

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

Methods: We randomly assigned 2499 HIV-seronegative men or transgender women who have sex with men to receive a combination of two oral antiretroviral drugs, emtricitabine and tenofovir disoproxil fumarate (FTC-TDF), or placebo once daily. All subjects received HIV testing, risk-reduction counseling, condoms, and management of sexually transmitted infections.

Results: The study subjects were followed for 3324 person-years (median, 1.2 years; maximum, 2.8 years). Of these subjects, 10 were found to have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in the FTC-TDF group and 64 in the placebo group), indicating a 44% reduction in the incidence of HIV (95% confidence interval, 15 to 63; P=0.005). In the FTC-TDF group, the study drug was detected in 22 of 43 of seronegative subjects (51%) and in 3 of 34 HIV-infected subjects (9%) (P<0.001). Nausea was reported more frequently during the first 4 weeks in the FTC-TDF group than in the placebo group (P<0.001). The two groups had similar rates of serious adverse events (P=0.57).

Conclusions: Oral FTC-TDF provided protection against the acquisition of HIV infection among the subjects. Detectable blood levels strongly correlated with the prophylactic effect. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT00458393.).

Figure 1. Enrollment and Outcomes

The most common laboratory abnormalities that led to exclusion were elevations in hepatic aminotransferase levels, hyperbilirubinemia, and renal insufficiency. A total of 18 enrollees (0.7%) did not meet all eligibility criteria, including 2 subjects with preexisting diabetes mellitus, who were instructed to stop taking a study drug when the history was discovered. All enrolled subjects, including those who were subsequently found to be ineligible, were followed for HIV infection and safety. Quarterly-visit attendance is shown. Visits were considered to have been completed if they occurred before the subsequent visit window, with completion rates of 75 to 94% for all visits. The completion rate was more than 86% for all visits before week 132. Visits occurred within the protocol-defined window of ±5 days in 62 to 86% of visits.

Figure 2. Kaplan–Meier Estimates of Time to HIV Infection (Modified Intention-to-Treat Population)

The cumulative probability of HIV acquisition is shown for the two study groups. The efficacy of preexposure prophylaxis with emtricitabine and tenofovir disoproxil fumarate (FTC–TDF) was 44%, as compared with placebo (P = 0.005). The inset graph shows a more detailed version of the overall graph up to a probability of 0.10.

Figure 3. HIV Incidence among Subjects Receiving FTC–TDF, According to Subgroup

The efficacy of emtricitabine and tenofovir disoproxil fumarate (FTC–TDF) is 1 minus the hazard ratio. Hazard ratios of less than 1 indicate efficacy, and 95% confidence intervals (shown by horizontal lines) that do not cross 1 indicate significant evidence of efficacy. All subgroup analyses were prespecified except for testing for herpes simplex virus type 2 (HSV-2) at screening and pill use at the rate of 90%. P values for the intention-to-treat analysis and the modified intention-to-treat analysis apply to the hypothesis of any evidence of efficacy; P values for other comparisons refer to the hypothesis that efficacy differed between the two strata. NA denotes not applicable, and URAI unprotected receptive anal intercourse.

Figure 4. Levels of Study-Drug Components in Blood of Subjects Receiving FTC–TDF, According to HIV Status

Shown are intracellular levels (Panels A and B) and plasma levels (Panels C and D) of components of emtricitabine and tenofovir disoproxil fumarate (FTC–TDF), quantified in specimens obtained from subjects in the FTC–TDF group. FTC-TP denotes emtricitabine triphosphate, and TFV-DP tenofovir diphosphate. The horizontal lines in each panel indicate medians.