Obiero J, Mwethera PG, Wiysonge CS. Topical microbicides for prevention of sexually transmitted infections. Cochrane Database Syst Rev. 2012 Jun 13;6:CD007961.
Systematic review of the literature on the use of topical microbicides for preventing sexually transmitted infections (STI), including HIV.
Randomized controlled trials (RCT).
Sexually active, HIV-uninfected women and men who have sex with men (MSM).
Topical microbicides for preventing STI acquisition. Interventions using nonoxynol-9 (N-9) were excluded from this review, as N-9 was addressed in previous Cochrane reviews.(1, 2) Interventions were compared to no treatment; use of cervical cap, condom, diaphragm, vaginal sponge or other barrier methods for STI prevention; or placebo.
Main Outcome Measures Primary
Incidence of any STI; Secondary: acceptability, safety, adverse events.
Standard Cochrane HIV/AIDS Group and Cochrane STI Group search strategies were used, along with a range of relevant keywords and medical subject heading (MeSH) terms . There were no limits to language or publication status. Databases searched included the Cochrane Central Register of Controlled Trials, EMBASE, Literatura Latino-Americana e do Caribe em Ciências da Sa�de (LILACS), PubMed and Web of Science, as well as online archives of major HIV/AIDS and STI conference abstracts. The date range for the searches of the peer-reviewed literature was from January 1980 to July 2011, apart from LILACS and Web of Science, which were searched up to May 2009. Archived conference abstracts were searched from 1985 to 2011. The World Health Organization (WHO)'s International Clinical Trials Registry Platform (ICTRP) and the National Institutes of Health's "ClinicalTrials.gov" were searched in July 2011 for ongoing trials. The reviewers checked reference lists of included trials and previous reviews, and contacted researchers in the field and relevant international organizations.
Searches, Screening and Data Extraction
Searches and update-searches were performed on three occasions. A total of 5,572 records were retrieved. Duplicate records were apparently not excluded. Standard Cochrane methods were used in the screening process and in data collection. Two reviewers working independently excluded 5,557 records (99.7%). Fifteen full-text articles were assessed for eligibility. Eight trials of six microbicides were included. Five studies did not meet inclusion criteria and were excluded; two were determined to be ongoing. Two reviewers working independently extracted data from included trials.
All eight included trials enrolled sexually active, HIV-uninfected women (total n=26,941), ranging in age from 16 to 72. No studies included MSM. All studies had HIV incidence as a primary endpoint. All trials tested topical microbicide gels vs. topical placebo gels. The six microbicide gels included BufferGel,(3) Carraguard,(4) cellulose sulphate (CS),(5, 6) PRO 2000,(3, 7) SAVVY(8, 9) and tenofovir (TDF).(10) Trials were conducted in Benin,(5) Ghana,(9) India,(6) Malawi,(3) Nigeria,(5, 8) South Africa,(3, 4, 7, 10) Tanzania,(7) Uganda,(7, 10) United States,(3) Zambia(3, 7, 8) and Zimbabwe.(3, 7, 10)
Primary outcomes: Of the six microbicides reviewed, only TDF gel significantly reduced the risk of HIV acquisition (relative risk [RR] 0.63; 95% confidence interval [CI] 0.43 to 0.93.).(10) Of three trials reporting on herpes simplex virus 2 (HSV-2) acquisition,(6, 7, 10) only TDF reduced the risk of acquiring HSV-2 (RR 0.55; 95% CI 0.37 to 0.83).(10) Combined results from two trials suggest that CS may reduce the risk of acquiring chlamydia infection (RR 0.70; 95% CI 0.49 to 0.99; I2 = 0%).(5, 6) None of the trials showed any significant evidence of effect in reducing acquisition of any other STI.
Adverse events: Each trial reported adverse events, some of which were deemed unrelated to the microbicide. Candidiasis and vaginal discharge were reported by all but one trial. The most common adverse events were bacterial vaginosis, erythema, laceration, menorrhagia, menstrual disorders, pruritus, ulceration, and vaginal hemorrhage. In the tenofovir trial, 838 of 889 women (94.3%) reported at least one adverse event, with a total of 4692 adverse events between intervention and control groups. Each group reported three severe adverse events.
Outcome: HIV incidence (measured as HIV acquisition):
|Abdool Karim 2011||BufferGel||1546||Malawi, South Africa, United States, Zambia, Zimbabwe||RR 1.05, 95% CI 0.73 to 1.52|
|Skoler-Karpoff 2008||Carraguard||6202||South Africa||RR 0.89, 95% CI 0.71 to 1.11|
|Halpern 2008, Van Damme 2008||CS||3069||Benin, India, Nigeria||RR 1.20, 95% CI 0.74 to 1.95|
|Abdool Karim 2011, McCormack 2010||PRO 2000||8191||Malawi, South Africa, Tanzania, Uganda, United States, Zambia, Zimbabwe||RR 0.93, 95% CI 0.77 to 1.14|
|Feldblum 2008, Peterson 2007||SAVVY (C31G)||4295||Ghana, Nigeria||RR 1.38, 95% CI 0.79 to 2.41|
|Abdool Karim 2010||TDF||889||South Africa, Uganda, Zimbabwe||RR 0.63, 95% CI 0.43 to 0.93|
The reviewers conclude that vaginal microbicides containing tenofovir may reduce HIV and HSV-2 acquisition in heterosexual women, and that there is no evidence that other kinds of vaginal microbicides have an effect in reducing acquisition of HIV, HSV-2, or any other STI.
The reviewers used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology11 to assess evidence quality. GRADE ranks the quality of evidence on four levels: "high," "moderate," "low" and "very low." Evidence from randomized controlled trials starts at "high," but can be downgraded based on study limitations, inconsistency of results, indirectness of evidence, imprecision or for reporting bias. Evidence from observational studies starts at "low," but can be upgraded if the magnitude of treatment effect is very large, if there is a significant dose-response relation, or if all possible confounders would decrease the magnitude of an apparent treatment effect. Evidence from observational studies can also be downgraded. The reviewers found that there was low quality evidence of vaginal tenofovir gel's efficacy in preventing HIV. However, they may been too severe in their assessment of the single tenofovir trial. In GRADE, a single trial can provide high quality evidence.(12) While it is true that the trial was fairly small (n=889) and that the number of events in the treatment arm was very low (n=38), the treatment effect was large. The reviewers found the trial to be at low risk of bias in every category (e.g. allocation concealment, randomization process, blinding, etc.). It may not have been necessary to grade the evidence down for potential inconsistency with future trials. The quality of evidence should probably be rated as moderate.
This is a high quality systematic review. It meets every relevant criterion of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines.(13)
Microbicides could be an important means of preventing HIV, especially for women whose partners refuse to use condoms.
Vaginal microbicides that contain TDF may be useful in circumstances where uninfected women are at risk for sexually acquiring HIV. As such, it is one of an emerging suite of antir�troviral preventive measures, including oral pre-exposure prophylaxis (PrEP)(14) and early treatment, (15) that will become increasingly central to HIV prevention efforts. As with any biomedical intervention, however, understanding who is and who is not infected is key to prescribing the correct options, and, hence, HIV counseling and testing programs need to diagnose and refer infected and at-risk uninfected individuals at greater numbers than are currently occurring.
- Wilkinson D, Ramjee G, Tholandi M, Rutherford G. Nonoxynol-9 for preventing vaginal acquisition of sexually transmitted infections by women from men. Cochrane Database Syst Rev. 2002;(4):CD003939. Review. PubMed PMID: 12519623.
- Wilkinson D, Ramjee G, Tholandi M, Rutherford G. Nonoxynol-9 for preventing vaginal acquisition of HIV infection by women from men. Cochrane Database Syst Rev. 2002;(4):CD003936. Review. PubMed PMID: 12519622.
- Abdool Karim SS, Richardson BA, Ramjee G, Hoffman IF, Chirenje ZM, Taha T, et al. Safety and effectiveness of BufferGel and 0.5% PRO2000 gel for the prevention of HIV infection in women. AIDS 2011;25:957-66.
- Skoler-Karpoff S, Ramjee G, Ahmed K, Altini L, Plagianos MG, Friedland B, et al . Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial. The Lancet 2008;372:1977-87.
- Halpern V, Ogunsola F, Obunge O, Wang CH, Onyejepu N, Oduyebo O, et al . Effectiveness of cellulose sulfate vaginal gel for the prevention of HIV infection: results of a phase III trial in Nigeria. PLoS One 2008;3(11):e3784.
- Van Damme L, Govinden R, Mirembe FM, Gu�dou F, Solomon S, Becker ML, et al . Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. New England Journal of Medicine 2008;359:463-73.
- McCormack S, Ramjee G, Kamali A, Rees H, Crook AM, Gafos M, et al . PRO2000 vaginal gel for prevention of HIV-1 infection (Microbicides Development Programme 301): a phase 3, randomised, double-blind, parallel-group trial. Lancet 2010;376:1329-37.
- 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;3(1):e1474.
- Peterson L, Nanda K, Opoku BK, Ampofo WK, Owusu-Amoako M, Boakye AY, et al . SAVVY (C31G) gel for prevention of HIV infection in women: a phase 3, double-blind, randomized, placebo-controlled trial in Ghana. PLoS One 2007;2(12):e1312.
- Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor EL, et al. Effectiveness and safety of tenofovir Gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 2010;329:1168-74.
- Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ. 2008;336:924-926
- Guyatt GH, Oxman AD, Vist G, Kunz R, Brozek J, Alonso-Coello P, et al. GRADE guidelines: 4. Rating the quality of evidence-study limitations (risk of bias). J Clin Epidemiol. 2011 Apr;64(4):407-15.
- Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009) Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed.1000097
- Okwundu CI, Uthman OA, Okoromah CA. Antiretroviral pre-exposure prophylaxis (PrEP) for preventing HIV in high-risk individuals. Cochrane Database Syst Rev. 2012 Jul 11;7:CD007189.
- Anglemyer A, Rutherford GW, Baggaley RC, Egger M, Siegfried N. Antiretroviral therapy for prevention of HIV transmission in HIV-discordant couples. Cochrane Database Syst Rev. 2011 Aug 10;(8):CD009153.