Tenofovir-based preexposure prophylaxis for HIV infection among African women

Abstract

Background: Reproductive-age women need effective interventions to prevent the acquisition of human immunodeficiency virus type 1 (HIV-1) infection.

Methods: We conducted a randomized, placebo-controlled trial to assess daily treatment with oral tenofovir disoproxil fumarate (TDF), oral tenofovir-emtricitabine (TDF-FTC), or 1% tenofovir (TFV) vaginal gel as preexposure prophylaxis against HIV-1 infection in women in South Africa, Uganda, and Zimbabwe. HIV-1 testing was performed monthly, and plasma TFV levels were assessed quarterly.

Results: Of 12,320 women who were screened, 5029 were enrolled in the study. The rate of retention in the study was 91% during 5509 person-years of follow-up. A total of 312 HIV-1 infections occurred; the incidence of HIV-1 infection was 5.7 per 100 person-years. In the modified intention-to-treat analysis, the effectiveness was -49.0% with TDF (hazard ratio for infection, 1.49; 95% confidence interval [CI], 0.97 to 2.29), -4.4% with TDF-FTC (hazard ratio, 1.04; 95% CI, 0.73 to 1.49), and 14.5% with TFV gel (hazard ratio, 0.85; 95% CI, 0.61 to 1.21). In a random sample, TFV was detected in 30%, 29%, and 25% of available plasma samples from participants randomly assigned to receive TDF, TDF-FTC, and TFV gel, respectively. Independent predictors of TFV detection included being married, being older than 25 years of age, and being multiparous. Detection of TFV in plasma was negatively associated with characteristics predictive of HIV-1 acquisition. Elevations of serum creatinine levels were seen more frequently among participants randomly assigned to receive oral TDF-FTC than among those assigned to receive oral placebo (1.3% vs. 0.2%, P=0.004). We observed no significant differences in the frequencies of other adverse events.

Conclusions: None of the drug regimens we evaluated reduced the rates of HIV-1 acquisition in an intention-to-treat analysis. Adherence to study drugs was low. (Funded by the National Institutes of Health; VOICE ClinicalTrials.gov number, NCT00705679.).

Figure 1. Study Cohort

The most common reason for exclusion from participation was prevalent HIV infection (33% of excluded participants). Failure to complete screening and enrollment within the 56-day window resulted in the exclusion of 21% of potential participants. Collectively, abnormal laboratory results accounted for 16% (range, 5 to 23) of all exclusions; the most common results were positivity for the hepatitis B surface antigen (3.4%), anemia (2.9%), abnormal (grade 2 or higher) Papanicolaou smear (2.7%), and a urine-dipstick result of 2+ or higher for protein (2.5%). Conditions related to reproductive outcomes resulted in the exclusion of 9% of the women: 5.9% were pregnant at the time of screening, with the remainder reporting current breast-feeding or the intention to become pregnant in the next 2 years. A total of 22 participants who were found to have HIV-1 RNA, as assessed by means of a polymerase-chain-reaction assay, at the time of enrollment were classified as having acute HIV-1 infection and were excluded from the analysis. FTC denotes emtricitabine, TDF tenofovir disoproxil fumarate, and TFV tenofovir.

Figure 2. Cumulative Probability of HIV-1 Infection, According to Study Group

The numbers shown below the graph are the numbers of participants who were at risk at the start of each quarterly interval. The inset shows the same data on an enlarged y axis.