Topical microbicides for preventing sexually transmitted infections.

BACKGROUND: This is a updated version of our Cochrane Review published in Issue 6, 2012. Sexually-transmitted infections (STIs) continue to rise worldwide, imposing an enormous morbidity and mortality burden. Effective prevention strategies, including microbicides, are needed to achieve the goals of the World Heath Organization (WHO) global strategy for the prevention and control of these infections. OBJECTIVES: To determine the effectiveness and safety of topical microbicides for preventing acquisition of STIs, including HIV. SEARCH METHODS: We undertook a comprehensive search of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, LILACS, CLIB, Web of Science, ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and reference lists of relevant articles up to August 2020. In addition, we contacted relevant organisations and experts. SELECTION CRITERIA: We included randomised controlled trials of vaginal microbicides compared to placebo (except for nonoxynol-9 because it is covered in related Cochrane Reviews). Eligible participants were sexually-active non-pregnant, WSM and MSM, who had no laboratory confirmed STIs. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected studies, extracted data, and assessed risks of bias in duplicate, resolving differences by consensus. We conducted a fixed-effect meta-analysis, stratified by type of microbicide, and assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: We included eight trials from the earlier version of the review and four new trials, i.e. a total of 12 trials with 32,464 participants (all WSM). We did not find any eligible study that enrolled MSM or reported fungal STI as an outcome. We have no study awaiting assessment. All 12 trials were conducted in sub-Saharan Africa, with one having a study site in the USA, and another having a site in India. Vaginal microbicides tested were BufferGel and PRO 2000 (1 trial, 3101 women), Carraguard (1 trial, 6202 women), cellulose sulphate (2 trials, 3069 women), dapivirine (2 trials, 4588 women), PRO 2000 (1 trial, 9385 women), C31G (SAVVY) (2 trials, 4295 women), and tenofovir (3 trials, 4958 women). All microbicides were compared to placebo and all trials had low risk of bias. Dapivirine probably reduces the risk of acquiring HIV infection: risk ratio (RR) 0.71, (95% confidence interval (CI) 0.57 to 0.89, I2 = 0%, 2 trials, 4588 women; moderate-certainty evidence). The other microbicides may result in little to no difference in the risk of acquiring HIV (low-certainty evidence); including tenofovir (RR 0.83, 95% CI 0.68 to 1.02, cellulose sulphate (RR 1.20, 95% CI 0.74 to 1.95, BufferGel (RR 1.05, 95% CI 0.73 to 1.52), Carraguard (RR 0.89, 95% CI 0.71 to 1.11), PRO 2000 (RR 0.93, 95% CI 0.77 to 1.14), and SAVVY (RR 1.38, 95% CI 0.79 to 2.41). Existing evidence suggests that cellulose sulphate (RR 0.99, 95% CI 0.37 to 2.62, 1 trial, 1425 women), and PRO 2000 (RR 0.95, 95% CI 0.73 to 1.23) may result in little to no difference in the risk of getting herpes simplex virus type 2 infection (low-certainty evidence). Two studies reported data on tenofovir's effect on this virus. One suggested that tenofovir may reduce the risk (RR 0.55, 95% CI 0.36 to 0.82; 224 participants) while the other did not find evidence of an effect (RR 0.94, 95% CI 0.85 to 1.03; 1003 participants). We have not reported the pooled result because of substantial heterogeneity of effect between the two studies (l2 = 85%). The evidence also suggests that dapivirine (RR 1.70, 95% CI 0.63 to 4.59), tenofovir (RR 1.27, 95% CI 0.58 to 2.78), cellulose sulphate (RR 0.69, 95% CI 0.26 to 1.81), and (Carraguard (RR 1.07, 95% CI 0.75 to 1.52) may have little or no effect on the risk of acquiring syphilis (low-certainty evidence). In addition, dapivirine (RR 0.97, 95% CI 0.89 to 1.07), tenofovir (RR 0.90, 95% CI 0.71 to 1.13), cellulose sulphate (RR 0.70, 95% CI 0.49 to 0.99), BufferGel (RR 0.97, 95% CI 0.65 to 1.45), Carraguard (RR 0.96, 95% CI 0.83 to 1.12), and PRO 2000 (RR 1.01, 95% CI 0.84 to 1.22) may result in little to no difference in the risk of acquiring chlamydia infection (low-certainty evidence). The evidence also suggests that current topical microbicides may not have an effect on the risk of acquiring gonorrhoea, condyloma acuminatum, trichomoniasis, or human papillomavirus infection (low-certainty evidence). Microbicide use in the 12 trials, compared to placebo, did not lead to any difference in adverse event rates. No study reported on acceptability of the intervention.  AUTHORS' CONCLUSIONS: Current evidence shows that vaginal dapivirine microbicide probably reduces HIV acquisition in women who have sex with men. Other types of vaginal microbicides have not shown evidence of an effect on acquisition of STIs, including HIV. Further research should continue on the development and testing of new microbicides.

Topical microbicides for prevention of sexually transmitted infections.

BACKGROUND: Two decades of research on topical microbicides for prevention of sexually transmitted infections (STIs) have had limited success. However, new microbicide randomised controlled trial (RCT) data have recently been published; but these have not yet been the subject of a systematic review. OBJECTIVES: To determine the effects of topical microbicides for prevention of the acquisition of STIs, including human immunodeficiency virus (HIV) infection, by women from men and by men who have sex with men (MSM). SEARCH METHODS: In July 2011 we searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, Web of Science, NLM Gateway, CLIB, AIDS Education Global Information System, ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform; handsearched reference lists of relevant articles and contacted relevant organisations and experts. SELECTION CRITERIA: RCTs of topical microbicides (except Nonoxynol-9) in sexually active, HIV-negative women or MSM. We excluded Nonoxynol-9 because previous systematic reviews showed that it does not have a significant effect on HIV or STIs. DATA COLLECTION AND ANALYSIS: We assessed study eligibility, extracted data and assessed risk of bias in duplicate; resolving differences by discussion and consensus. We then conducted fixed-effect meta-analysis, stratified by type of microbicide. MAIN RESULTS: We found that by the end of 2011, nine microbicide RCTs had either been conducted to term (one BufferGel and 0.5% PRO 2000, one Carraguard and one tenofovir trial) or stopped early due to safety concerns (two cellulose sulphate trials) or insufficient rate of HIV infection and low likelihood of showing a protective effect (one 2% PRO 2000, one tenofovir and two SAVVY trials). The nine RCTs enrolled 31,941 sexually active women between 2004 and 2011; in Benin, Ghana, Malawi, Nigeria, South Africa, Tanzania, Uganda, Zambia, Zimbabwe, India, and the US. A small proof-of-concept RCT found that tenofovir (a nucleotide reverse transcriptase inhibitor) reduced the risk of HIV acquisition (one trial, 889 women; risk ratio (RR) 0.63; 95% CI 0.43 to 0.93). Effectiveness data are not yet available from the second tenofovir RCT that enrolled 5000 women and was stopped early due to low likelihood of showing a protective effect. We found no evidence of an effect on HIV acquisition for cellulose sulphate (2 trials, n = 3069; RR 1.20; 95% CI 0.74 to 1.95), SAVVY (two trials, n = 4295; RR 1.38; 95% CI 0.79 to 2.41), Carraguard (one trial, n = 6202; RR 0.89; 95% CI 0.71 to 1.11), PRO 2000 (two trials, n = 12,486; RR 0.93, 95% CI 0.77 to 1.14) and BufferGel (one trial, n = 1546; RR 1.05; 95% CI 0.73 to 1.52). Tenofovir reduced the incidence of herpes simplex virus type 2 (HSV-2) infection (one trial, 426 women; RR 0.55; 95% CI 0.37 to 0.83) and cellulose sulphate reduced the risk of chlamydia infection (two trials, n = 3069; RR 0.70, 95% CI 0.49 to 0.99). However, there was no evidence of an effect of any microbicide on the acquisition of gonorrhoea, syphilis, condyloma acuminatum, trichomoniasis, or human papillomavirus (HPV) infection. A substudy of the Carraguard trial found the prevalence of high-risk HPV infection (HR-HPV) to be 23.5% in women on Carraguard and 23.0% on placebo (n = 1718; RR 1.02; 95% CI 0.86 to 1.21). After controlling for HR-HPV risk factors, the authors found that compliant Carraguard users were 0.62 (95% CI 0.41 to 0.94) times as likely to be HR-HPV positive as compliant placebo users. Overall, there was no significant difference in the incidence of adverse events between microbicide and placebo groups. AUTHORS' CONCLUSIONS: Limited evidence suggests that vaginal tenofovir microbicides may reduce the risk of acquisition of HIV and HSV-2 infections in women; but other types of topical microbicides have not shown evidence of an effect on HIV or STI acquisition. Therefore, there is not enough evidence to recommend topical microbicides for HIV or STI prevention at present. Further studies are needed to confirm the beneficial effects of tenofovir microbicide gel in vaginal sex. In addition, further research should continue on the development and testing of new microbicides. If the effectiveness of the tenofovir and/or other microbicides is confirmed in further studies, there will need to be a clear pathway to rapid regulatory approval. Successful launch of the effective gel would depend on having in place appropriate mechanisms for distribution to the women who need it, along with a strategy for ensuring that they use it correctly.