Feldblum PJ, Adeiga A, Bakare R, Wevill S, Lendvay A, Obadaki F, et al. SAVVY vaginal gel (C31G) for prevention of HIV infection: a randomized controlled trial in Nigeria. PLoS ONE. 2008 Jan; 3(1):e1474.
To investigate the safety and effectiveness of 1.0% C31G (SAVVY) gel in preventing male-to-female transmission of HIV in a population of young, sexually active Nigerian women at high risk for HIV infection
This is a Phase III, double-blind, randomized placebo-controlled trial conducted between September 2004 and December 2006.
Central clinics and peripheral outreach offices in Lagos and Ibadan, Nigeria
HIV-negative, non-pregnant women aged 18-35 years who reported having more than two coital acts per average week and more than one sex partner in the past three months. Participants were recruited from local market areas, bars, hostels, military barracks and colleges. Brothels were not used for recruitment.
Women who consented to participate in the study underwent eligibility confirmation, which included pregnancy testing; rapid HIV testing; physical and pelvic exams; tests for Chlamydia, gonorrhea, and syphilis; and microscopic examination of vaginal specimens for trichomoniasis, candidiasis, and bacterial vaginosis. Pregnant and HIV-positive women were not enrolled in the study. Women who were deemed eligible after the screening were asked to return within 42 days to be enrolled in the study, when they again received pregnancy and HIV testing as well as family planning counseling and referral to services, if requested. Participants were randomized to receive SAVVY or placebo gel. Randomization was done using a 1:1 allocation with computer-generated random numbers. Gels were packaged into six-colored labeled packages. Sequentially numbered, sealed, opaque envelopes were used to assign participants to one of six groups (three SAAVY and three placebo groups). The randomization envelopes were kept in a secure office and were not available to staff until immediately prior to randomization. Once randomized, participants were given a supply of 60 condoms and 60 study (SAVVY or placebo) gels (to last a period of one month). Participants, field study staff, monitors, statisticians, and other staff involved in the trial were not aware of which gels were associated with SAVVY or placebo. Participants also were scheduled for 12 monthly return visits. Participants were instructed in the proper use of a condom and the study gel, and they were told to return to the clinic if they needed more supplies. Study staff also counseled participants to use condoms at every coital act; that the gel effectiveness was unknown; and that they may have received a placebo gel that does not protect against HIV.
At each monthly follow-up visit, participants were administered structured questionnaires, which collected information on sexual behavior, condom and gel use, and medical problems or medication use since last visit. At each visit, participants underwent pregnancy and HIV testing and STI risk-reduction counseling. They also received one month's supply of condoms and gel. At the 6-month visit, participants were given pelvic examinations for STIs and saline wet mount examinations for vaginal specimens. Participants who were found to be pregnant were discontinued from the intervention but remained in the study for monitoring purposes. Participants who were confirmed to be HIV positive were discontinued and referred to the PEPFAR care and treatment program. If a participant missed a scheduled visit, an outreach worker would make three attempts to contact the participant and reschedule the visit. If the participant did not return to the study by the end of the study period, she was considered lost to follow-up at closeout.
Of the 3334 women who were screened, 2153 were enrolled; 1076 were randomized to receive active gel and 1077 received placebo. Among the women in the SAVVY group, 657 completed the study, 136 stopped before the study ended, 251 were lost to follow-up and 32 discontinued early. The results were similar in the placebo group: 643 completed, 150 stopped before the study was terminated, 251 were lost to follow-up, and 33 stopped early.
Demographic and risk characteristics of the SAVVY and placebo groups were similar. The most commonly reported contraceptive used was male condoms. At follow-up, the number of sex partners reported in the previous 30 days decreased for both groups: from 13 to 9 for the SAVVY group and from 12.5 to 8.3 for the placebo group. The frequency of sex also decreased among women in both groups, The frequency of gel use was similar for both groups: 78% of coital acts in the SAVVY group and 79% in the placebo group. Both groups reported using condoms for 87% of coital acts. Gel and condom use decreased over time for both groups.
Thirteen HIV infections occurred in Lagos and 20 in Ibadan. The overall HIV incidence rate was 1.87 per 100 person-years (95% confidence interval [CI], 1.29-2.63). Most seroconversions occurred in younger people aged 18-25 years. Of the 33 seroconversions, 21 occurred in the SAVVY group and 12 in the placebo group.
Analysis of efficacy was done using a subpopulation of all participants who had been randomized, which included the 1041 SAVVY and 1041 placebo participants who had HIV testing after enrollment. Of the 33 seroconversions, 21 occurred in the SAVVY group compared to 12 in the placebo group. The Kaplan-Meier probability estimate of HIV infection at 12 months in the SAVVY group was 0.028 and 0.015 in the placebo group. The log-rank test for effectiveness of treatment did not detect a statistically significant effect (P=0.121) and the relative hazard for SAVVY versus placebo was 1.7 (95% confidence limits 0.9, 3.5). There were no significant differences in frequency of adverse events between treatment groups.
Interim analyses by the data monitoring committee determined that the unexpected low incidence would require an additional 1,980 participants. This was deemed unfeasible and the study was discontinued.
The findings from this study are inconclusive because of low power and early discontinuation of the study. The relative hazard associated with SAVVY is higher when compared to placebo but is not statistically significant, leaving open the question of whether SAVVY increases the risk of HIV. More powerful Phase III studies in populations with higher incidence need to be done to determine the effectiveness, safety and feasibility of using microbicides for prevention of HIV infection in women.
Based on Cochrane guidelines for assessing quality of randomized controlled trials, this study is of good quality. It was a randomized, double-blinded, placebo-controlled trial. The authors describe the sequence of participants as having been generated using a computer random number generator and randomly varied permuted-blocks. The authors also discussed allocation concealment, implementation of the random allocation sequence, and blinding. The study had some limitations, one of which is the possible over-reporting of adherence in this trial, because low adherence compromises the power of a prevention trial. Additionally, condoms were used more than gel, and participants were more likely to use gel if a condom was also used, making it difficult to detect a difference in HIV incidence as that difference could arise only from a small proportion of potential exposures.
Other studies examining the effectiveness of vaginal microbicides have not been promising, either because of evidence that they increase the risk of infection(1) or because they were not found to be effective.(2,3,4,5) Several factors are likely to have contributed to the failure of these trials to demonstrate effectiveness, including 1) low HIV incidence resulting in insufficient power, 2) low adherence, 3) condom use with and without gel, 4) effective risk reduction counseling. Results from this study provide no evidence for either the effectiveness of SAAVY gel or its potential to increase risk of HIV transmission.
Although the authors conclude that Phase III trials with larger samples of women and in areas with higher HIV incidence are needed, the situations needed for such trials to succeed appear difficult to find; and in one of the successful trials, microbicides were found to increase the risk of HIV transmission. The known benefits of other methods to reduce the risk of HIV transmission, including male circumcision, HIV counseling and testing, condom use, and risk reduction counseling should be promoted widely until newer methods have been found to be safe and effective. Given the lack of evidence for benefits of using SAVVY, this product should not be used as a method of preventing HIV transmission.
- Van Damm L, Ramjee G, Alary M, Vulsteke B, Chandeying V, et al, Effectiveness of COL-1492, a nonoxynol-9 vaginal gel on HIV-1 transmission in female sex workers: a randomized controlled trial. Lancet 2002;360:971-77.
- Roddy RE, Zekeng L, Ryan KA, Tamoufe U, Weir SS, et al, A controlled trial of nonoxynol-9 film to reduce male-to-female transmission of sexually transmitted diseases, N Engl J Med 339:504-10.
- Peterson L, Nanda K, Opoku BK, Ampofo WK, Owusu-Amoako M, Boakye AY, Rountree W, Troxler A, Dominik R, Roddy R, Dorflinger L. SAVVY (C31G) gel for prevention of HIV infection in women: a Phase 3, double-blind, randomized, placebo-controlled trial in Ghana. PLoS ONE. 2007 Dec 19;2(12):e1312.
- Halpern V, Wang L, Obunge O, Ogunsola F, Mehta N, et al. Effectiveness of cellulose sulfate gel for prevention of HIV: results of the phase III trial in Nigeria. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, Sydney, Australia, July 22-25, 2007. Abstract WESS302.
- Van Damm L, Govinden R, Mirembe F, Guedou F, Solomon S, et al, Phase III trial of 6% cellulose sulfate (CS) gel for the prevention of HIV transmission, 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, Sydney, Australia, July 22-25, 2007. Abstract WESS301.