SAVVY (C31G) gel for prevention of HIV infection in women: a Phase 3, double-blind, randomized, placebo-controlled trial in Ghana.

OBJECTIVE: The objective of this trial was to determine the effectiveness of 1.0% C31G (SAVVY) in preventing male-to-female vaginal transmission of HIV infection among women at high risk. METHODOLOGY/PRINCIPAL FINDINGS: This was a Phase 3, double-blind, randomized, placebo-controlled trial. Participants made up to 12 monthly visits for HIV testing, adverse event reporting, and study product supply. The study was conducted between March 2004 and February 2006 in Accra and Kumasi, Ghana. We enrolled 2142 HIV-negative women at high risk of HIV infection, and randomized them to SAVVY or placebo gel. Main outcome measures were the incidence of HIV-1 and HIV-2 infection as determined by detection of HIV antibodies from oral mucosal transudate specimens and adverse events. We accrued 790 person-years of follow-up in the SAVVY group and 772 person-years in the placebo group. No clinically significant differences in the overall frequency of adverse events, abnormal pelvic examination findings, or abnormal laboratory results were seen between treatment groups. However, more participants in the SAVVY group reported reproductive tract adverse events than in the placebo group (13.0% versus 9.4%). Seventeen HIV seroconversions occurred; eight in participants randomized to SAVVY and nine in participants receiving placebo. The Kaplan-Meier estimates of the cumulative probability of HIV infection through 12 months were 0.010 in the SAVVY group and 0.011 in the placebo group (p = 0.731), with a hazard ratio (SAVVY versus placebo) of 0.88 (95% confidence interval 0.33, 2.27). Because of a lower-than-expected HIV incidence, we were unable to achieve the required number of HIV infections (66) to obtain the desired study power. CONCLUSIONS/SIGNIFICANCE: SAVVY was not associated with increased adverse events overall, but was associated with higher reporting of reproductive adverse events. Our data are insufficient to conclude whether SAVVY is effective at preventing HIV infection relative to placebo. TRIAL REGISTRATION: ClinicalTrials.gov NCT00129532.

Tenofovir disoproxil fumarate for prevention of HIV infection in women: a phase 2, double-blind, randomized, placebo-controlled trial.

OBJECTIVES: The objective of this trial was to investigate the safety and preliminary effectiveness of a daily dose of 300 mg of tenofovir disoproxil fumarate (TDF) versus placebo in preventing HIV infection in women. DESIGN: This was a phase 2, randomized, double-blind, placebo-controlled trial. SETTING: The study was conducted between June 2004 and March 2006 in Tema, Ghana; Douala, Cameroon; and Ibadan, Nigeria. PARTICIPANTS: We enrolled 936 HIV-negative women at high risk of HIV infection into this study. INTERVENTION: Participants were randomized 1:1 to once daily use of 300 mg of TDF or placebo. OUTCOME MEASURES: The primary safety endpoints were grade 2 or higher serum creatinine elevations (>2.0 mg/dl) for renal function, grade 3 or 4 aspartate aminotransferase or alanine aminotransferase elevations (>170 U/l) for hepatic function, and grade 3 or 4 phosphorus abnormalities (<1.5 mg/dl). The effectiveness endpoint was infection with HIV-1 or HIV-2. RESULTS: Study participants contributed 428 person-years of laboratory testing to the primary safety analysis. No significant differences emerged between treatment groups in clinical or laboratory safety outcomes. Study participants contributed 476 person-years of HIV testing to the primary effectiveness analysis, during which time eight seroconversions occurred. Two were diagnosed in participants randomized to TDF (0.86 per 100 person-years) and six in participants receiving placebo (2.48 per 100 person-years), yielding a rate ratio of 0.35 (95% confidence interval = 0.03-1.93), which did not achieve statistical significance. Owing to premature closures of the Cameroon and Nigeria study sites, the planned person-years of follow-up and study power could not be achieved. CONCLUSION: Daily oral use of TDF in HIV-uninfected women was not associated with increased clinical or laboratory adverse events. Effectiveness could not be conclusively evaluated because of the small number of HIV infections observed during the study.

Use of male condoms during and after randomized, controlled trial participation in Cameroon.

BACKGROUND AND OBJECTIVE: This study evaluated patterns of long-term use of male condoms among partners of 966 Cameroonian women who received eight intensive, monthly counseling sessions about condoms and sexually transmitted infection testing and treatment. METHOD: An interrupted time-series design was used with study participants reporting condom use and other covariates at enrollment, monthly for 6 months during the randomized, controlled trial, and at approximately 14 months after the trial. RESULTS: Consistent condom use began decreasing while women were still receiving monthly condom use counseling, with every month in the trial associated with an odds ratio of 0.96 (95% confidence interval [CI], 0.94-0.99) of consistent condom use and dropped substantively after the trial with a 0.39 (95% CI, 0.26-0.59) odds ratio in a logistic regression analysis. The incidence of unprotected coital acts as each month passed increased by 3% (95% CI, 1-4%) with no statistically significant change during the condom use follow-up survey as indicated in a zero-inflated Poisson regression model for unprotected coital acts. Condom use in a coital act was 0.84 (95% CI, 0.78-0.92) less likely during the follow-up survey than during the trial. CONCLUSION: Only a few women sustained consistent condom use throughout the study period and for more than 1 year after. It is important to continue documenting the impact of condom promotion in a rigorous manner and to identify content and delivery of counseling that will lead to sustained condom use beyond the intervention period.

Evaluating factors associated with STD infection in a study with interval-censored event times and an unknown proportion of participants not at risk for disease.

Sexually transmitted diseases (STD) are a major cause of morbidity and mortality world-wide. Because of their association with an increased risk of infection with human immunodeficiency virus, the prevention and control of STD are particularly important. Studies designed to evaluate factors associated with the transmission of STD can pose a number of statistical challenges, however. Two such concerns are the interval-censored event times that result from spacing between follow-up test visits, and an unknown proportion of study participants who are not at risk for infection. Researchers in various fields of study have used parametric mixture models to account for individuals not at risk. Owing to non-identifiability concerns within the mixture model framework, however, it is not always possible to distinguish between effects of explanatory variables on the distribution of event times for at-risk individuals and their effects on the probability of being at risk. We address these issues using data from a clinical trial designed to investigate the effectiveness of an intravaginal microbicide in preventing male-to-female transmission of STD. Factors associated with time to infection among at-risk women are initially identified by fitting right-truncated models to the interval-censored event times of participants who tested positive for STD, and hence are known to have been at risk. Subsequently, factors associated with the probability of being at risk are evaluated using mixture models that incorporate information contributed by the right-censored event-free times of uninfected study participants.

Effect of nonoxynol-9 gel on urogenital gonorrhea and chlamydial infection: a randomized controlled trial.

CONTEXT: Nonoxynol-9 has been suggested as a vaginal microbicide to protect against common sexually transmitted infections. OBJECTIVE: To compare nonoxynol-9 gel and condom use (gel group) vs condom use alone (condom group) for the prevention of male-to-female transmission of urogenital gonococcal and chlamydial infection. DESIGN AND SETTING: Randomized controlled trial conducted at 10 community clinics and 10 pharmacies in Yaoundé, Cameroon, between October 1998 and September 2000, with 6 months of follow-up. PARTICIPANTS: High-risk population of 1251 women (excluding sex workers) being treated for or who had symptoms of sexually transmitted infections. Three were excluded from the gel group (0.5%) and 7 from the condom group (1%) because of no follow-up data. INTERVENTIONS: Nonoxynol-9 gel (100 mg) and condoms or condoms only. MAIN OUTCOME MEASURE: A positive test result for gonococcal or chlamydial infection by the ligase chain reaction assay; secondary outcome measure was a positive test result for human immunodeficiency virus (HIV). RESULTS: The rate ratio (RR) for new urogenital infections was 1.2 for the gel group vs condom group (95% confidence interval [CI], 0.9-1.6; P =.21). The gel group had 116 diagnosed gonococcal infections, chlamydial infections, or both for a rate of 43.6 per 100 person-years, and the condom group had 100 infections for a rate of 36.6 per 100 person-years. The RR for gonococcal infection in the gel group vs the condom group was 1.5 (95% CI, 1.0-2.3) and for chlamydial infection was 1.0 (95% CI, 0.7-1.4). There were 5 new cases of HIV infections in the gel group and 4 in the condom group. Three women in each group became pregnant during the study. CONCLUSION: Nonoxynol-9 gel did not protect against urogenital gonococcal or chlamydial infection.