MTN-003

Primary Objectives

• Estimate the effectiveness of daily tenofovir 1% gel compared to a vaginal placebo gel, and the effectiveness of oral TDF and oral FTC/TDF compared to an oral placebo in preventing HIV infection among women at risk for sexually transmitted infection (STI)
• Evaluate the extended safety of daily tenofovir 1% gel, oral TDF, and oral FTC/TDF in women at risk for sexually transmitted HIV infection

Study Summary
VOICE was a Phase 2B, multi-site, five-arm, randomized, controlled trial. A total of 5029 women were randomized to five study arms in a 1:1:1: 1:1 ratio. Secondary objectives focused on adherence/behavioral factors, HIV-1 drug resistance (among those who become HIV-infected during the study), pharmacokinetic parameters, and the potential for delayed seroconversion during an off-product period scheduled at the end of study participation. Additional objectives included exploring the impact of study products on vaginal microenvironment and assessing potential relationships between method of contraception and HIV seroconversion, product adherence, and adverse events. The VOICE trial was unique in the HIV prevention field as it was designed to provide parallel comparisons of oral and topically (vaginal) applied antiretroviral strategies for prevention of HIV infection in women. Following the Data and Safety Monitoring Board (DSMB) reviews in September 2011 and November 2011, the oral tenofovir tablet study arms and the vaginal tenofovir gel and corresponding placebo arms were stopped due to futility.

MTN-003 completed follow-up on February 22, 2013. Primary results were presented at the annual Conference on Retroviruses and Opportunistic Infections (CROI) held on March 3-6, 2013, in Atlanta, GA. The primary results were published in the New England Journal of Medicine in February 2015. A total of 25 papers have been published from this study as of the date of this report. Secondary manuscripts development is ongoing.

Primary 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.