Topical microbicides for preventing sexually transmitted infections

Jael Obiero; Paul Ogongo; Peter G Mwethera; Charles S Wiysonge

doi:10.1002/14651858.CD007961.pub3

. 2021 Mar 13;2021(3):CD007961. doi: 10.1002/14651858.CD007961.pub3

Topical microbicides for preventing sexually transmitted infections

Jael Obiero ^1,^✉, Paul Ogongo ², Peter G Mwethera ³, Charles S Wiysonge ⁴

Editor: Cochrane STI Group

PMCID: PMC8092571 PMID: 33719075

Abstract

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.

Plain language summary

Vaginal inserts for prevention of sexually transmitted infections

Review question

In this Cochrane Review we assessed the effects of topical microbicides (chemical substances that can be applied inside the vagina or rectum), compared to placebo (inactive substance), to prevent women who have sex with men and men who have sex with men from getting sexually‐transmitted infections (STIs), including HIV.

Background

This is an updated version of our Cochrane Review published in 2012. Both curable and incurable STIs continue to rise, despite the prevention strategies implemented to date. Women often have the highest rates of STIs and account for a disproportionate number of new infections. STIs are often without symptoms. Despite their greater vulnerability, current options to reduce the spread of STI remain limited for women. There is thus a clear need for new and effective strategies to prevent people from getting STIs, including HIV.

Trial characteristics

Cochrane researchers searched the available literature up to August 2020 and included 12 trials with 32,464 women who have sex with men. The trials included seven types of inserts (six vaginal gels and one vaginal ring) that were compared with placebo, all conducted among women aged over 16 years. All trials were conducted in sub‐Saharan Africa, with one having a study site in India and another having a site in the USA. The Cochrane researchers did not find any studies that were conducted among men who have sex with men.

Key results

Compared with placebo, the rate of HIV infection was lower in the group that took vaginal inserts containing the antiretroviral drug known as dapivirine, but other STIs occurred at similar rates in dapivirine and placebo groups. Tenofovir gel may also reduce the rates of herpes simplex virus infection, but not other STIs. In addition, the cellulose sulphate gel resulted in lower rates of chlamydia infection, compared to placebo. When other microbicide gels were compared with placebo, could be little or no difference in the rates of STI. None of the trials reported fungal STI as outcome.

Compared with placebo, the rate of HIV infection was lower in the group that took vaginal inserts containing the antiretroviral drug known as dapivirine, but other STIs occurred at similar rates in dapivirine and placebo groups. Tenofovir gel probably reduces the rates of herpes simplex virus infection, but not other STIs. Cellulose sulphate gel probably results in lower rates of chlamydia infection, compared to placebo. When other microbicide gels were compared with placebo, could be, there is little or no difference in the rates of STI. None of the trials reported fungal STI as outcome.

Certainty of evidence

The certainty of evidence was low for most outcomes reported in this review, due to heterogeneity and small number of studies and participants for certain microbicides. This led to imprecision of the findings (ranging from large clinical benefits to substantial harm).

How up‐to‐date is this review?

The review authors searched for studies that were published up to August 2020.

Summary of findings

Background

This is an updated version of the original Cochrane review published in Issue 6, 2012 (Obiero 2012a)

Description of the condition

Sexually‐transmitted infections (STIs) refer to a variety of clinical syndromes and infections caused by pathogens that can be acquired and transmitted through sexual activity (CDC 2015). STIs are common global causes of illness, long‐term disability, and death with serious medical and psychological consequences for millions of people (Newman 2015). They have far‐reaching health, social, and economic consequences in countries and communities where socio‐economic conditions are poor (Tsai 2012; Vogenthaler 2013).There are over 30 bacterial, viral, and parasitic pathogens that can be transmitted sexually. According to 2008 World Health Organization (WHO) estimates, 499 million new curable cases of the four most common curable infections, chlamydia, gonorrhoea, syphilis and trichomoniasis, occur annually throughout the world (WHO 2012). In addition, over 500 million people are estimated to have a viral STI such as herpes simplex virus type 2 (HSV‐2) or human papillomavirus (HPV) at any point in time (Gotlieb 2014). In the developed world, viral infections have become increasingly common and important, whereas bacterial STIs are more common in low‐ and middle‐income countries, but even this is changing with the increasing recognition of viral infections (Adler 2004).

The three most common presenting symptoms of an STI are urethral discharge, genital ulceration and vaginal discharge with or without vulval irritation (Sonkar 2017), Assymptomatic STIs (C. trachomatis, N. gonorrhoea and syphilis are more frequent in women than in men and in women the risk of complications and sequels are higher and also there is the risk of maternal to child transmission (Oakeshott 2010; Wasserheit 1989: WHO 2007:WHO 2016; Walker 2007). STIs also frequently result in stigma due to their sexual nature of transmission, stereotyping and vulnerability, and have been associated with gender‐based violence (Amin 2013). Often, screening and treatment are not given priority within public health services, nor do STIs receive the political, socio‐economic and cultural attention they warrant (Ortayli 2014). Clinical symptoms of STIs can be non‐specific, and where possible the diagnosis needs to be confirmed by laboratory testing (Gaitán‐Duarte 2013). Current STI control is hampered by several behavioural, biological and implementation challenges including a large proportion of asymptomatic infections, lack of feasible diagnostic tests, antimicrobial resistance, repeat infections and barriers to intervention access, availability and scale‐up (Ortayli 2014). In low and middle income countries, laboratory testing is not always available and women and men reporting symptoms suggestive of an STI are often treated according to algorithms without confirmatory tests (Trollope‐Kumar 2006). This approach is effective for certain infections such as male urethritis and genital ulcers, but with vaginal discharge the risk of misdiagnosis is high (Sonkar 2016). Syndromic management of STI can therefore lead to over‐treatment and adverse social consequences such as stigma and intimate partner violence (White 2008). In addition, it misses asymptomatic infections, which are by far the greatest burden of disease (WHO 2013a).

The rising trend and complications of the infections suggest limited impact of prevention approaches to date (UNAIDS 2010; WHO 2013b). Both male and female condoms have been considered one of the most effective biological mechanisms for reducing the transmission of STIs (Matson 2011). However, the positive impact of their use may be affected by inconsistent and incorrect use. In addition, several factors are known to be associated with low uptake of this method, including perception of reduced pleasure (Sarkar 2008), discomfort (Crosby 2005), partner trust (Abdullah 2002), religious beliefs (Thomsen 2004), availability and accessibility (Kumar 2006), existing inequalities in gender‐based norms and values (Mayaud 2001), cost (Essien 2005), women's lack of empowerment (Sarkar 2008), and negative community attitudes towards homosexuality combined with legal restrictions among MSM (Adimora 2010).

Description of the intervention

Microbicides are compounds that can be applied inside the vagina or rectum to protect against STIs including HIV (Smriti 2012; WHO 2000). They can be formulated as gels, creams, films, rings, sponges or suppositories (Lopez 2016; Singh 2014). Microbicides would greatly empower women and men who have sex with men (MSM) to protect themselves, as they are a potential preventive option that they can easily control and do not require the co‐operation, consent or even knowledge of the partner. Microbicides may or may not have spermicidal activity (contraceptive effect). An ideal microbicide would be safe and effective against a range of STI‐causing organisms, available in both spermicidal and non‐spermicidal formulations, effective over relatively long periods, acceptable to potential users, bio‐diffusible, bio‐adhesive, can be effective immediately, are stable at high temperatures and economically affordable in middle‐ and low‐income countries (Han 2009). Microbicides that have been developed include vaginal gels and rings. The microbicides are applied intravaginally or rectally before or before and after each sexual episode (Abdool Karim 2010; Feldblum 2008), The rings are slow‐release devices that are effective for a longer period of time (Baeten 2016).

How the intervention might work

The principal target of microbicides is to reduce male‐to‐female and male‐to‐male STI transmission, although they could also potentially prevent female‐to‐male transmission. Topical microbicides are grouped based on their mode and site of action (Cutler 2008); They include:

Surfactants: These are detergent‐like products that disrupt cell membranes or change membrane structure, which make it more porous and liable to disruption. These products are non‐specific and impact on all cells (host, commensal.and pathogen). Hence these products have a wide spectrum of activity against several microbes, spermatozoa and cell membranes, e.g. SAVVY and nonoxynol‐9 (Peterson 2007; Wilkinson 2002a; Wilkinson 2002b).

Vaginal defence enhancers: These are acid‐buffering agents that assist the natural immune defences of the vagina to deactivate the pathogen. They augment vaginal mucosal defence by increasing microbicidal activity of genital secretions. Lactic acid bacteria, notably lactobacilli, occur naturally in the vagina and release a variety of antimicrobial compounds such as lactic acid, hydrogen peroxide, bacteriocins and bio‐surfactants. A disruption of the natural balance of the vaginal ecosystem raises the risk of STI infection. The vagina is usually maintained at a low pH of about 4 to 5, which is achieved through secretion of lactic acid bacteria. These microbicides maintain the colonisation or re‐colonisation of the vagina with lactobacilli when these commensal organisms have been adversely affected, for example by use of antibiotics or reproductive tract infections. They also assist the vagina to maintain low pH in the presence of alkaline semen, the effect of which on the vaginal pH results in the loss of barrier to pathogens, e. g. Buffergel (Abdool Karim 2011; Keller 2012).

Entry inhibitors: This class of microbicide agents blocks the attachment of the pathogen to the host cell, fusion with the host‐cell membrane or entry into the host cells. They are polymers that act against viruses, predominantly by interfering with attachment to host cells. The envelope of HIV, particularly the gp41 component, which enables fusion with the cell membrane, is a critical target for a potentially successful microbicide. Polymers act by blocking viral entry into susceptible cells by blocking CD4 attachment or receptor attachment, or both, e.g. Carragurard and Pro2000 (Abdool Karim 2011; Skoler‐Karpoff 2008).

Agents that prevent replication of the pathogen after it has entered the cell: These are antiretroviral drugs developed as microbicides because of their capacity to inhibit the replication process of the pathogen. They act locally in the reproductive tract mucosa at specific steps in the replication cycle of the pathogen and therefore have a narrow spectrum against viruses, notably HIV, e.g. tenofovir (Abdool Karim 2010; Delany‐Moretlwe 2018) and dapivirine (Baeten 2016).

Why it is important to do this review

Despite the greater vulnerability of women and of men who have sex with men, current options to reduce acquisition of STI remain limited for women and men who are receptive partners during anal sex (Nunes 2014). There is a clear need for new and effective prevention strategies that women and MSM can use and control to reduce their risk of sexual acquisition of STIs. In the absence of a definitive cure or preventative vaccine, microbicides could offer an alternative or a complement to condoms as the most feasible method for primary prevention of STIs.

A registered vaginal or rectal microbicide is not yet available, despite the fact that over 60 candidate agents have been identified which have in vitro activity against STIs (Singh 2014). Some of the microbicides have already undergone large‐scale phase lll trials (Obiero 2012a). There is thus a need for a comprehensive and up‐to‐date synthesis of this evidence. This Cochrane Review is an update of one published in 2012 (Obiero 2012a).

Objectives

To determine the effectiveness and safety of topical microbicides for preventing acquisition of STIs, including HIV.

Methods

Criteria for considering studies for this review

Types of studies

We included randomised controlled trials (RCTs), which followed up participants for at least 12 months. We exclude quasi‐randomised trials because these produce effect estimates that indicate more extreme benefits when they are compared with randomised trials (Higgins 2019). We exclude cross‐over and cluster trials, because of the nature of the condition and intervention (Higgins 2019). The unit of randomisation was the individual.

Types of participants

Eligible participants were sexually active non‐pregnant heterosexual women (i.e. WSM), and men who have sex with men (MSM), aged 16 years and above in any setting, who had no laboratory‐confirmed STIs at baseline.

Types of interventions

Eligible interventions were topical microbicides including detergent‐like products (surfactants) , vaginal defence enhancers, entry inhibitors, and agents that prevent replication of the pathogen after it has entered the host cell. We performed meta‐analyses separately for each STI, according to the assessed intervention based on its mechanism of action. We excluded nonoxynol‐9 because it is covered in other Cochrane Reviews (Wilkinson 2002a; Wilkinson 2002b). Eligible comparison interventions Included: placebo, no intervention, condom, diaphragm, vaginal sponge, and cervical cap. However, we did not find studies that compared microbicides with other active interventions.

Types of outcome measures

Primary outcomes

Laboratory confirmed incidence of STIs (viral, bacterial, fungal, protozoan). We reported the laboratory methods used for measurement of the outcomes included.
Serious adverse events, i.e. the proportion of participants who experience any adverse effect requiring hospitalisation or discontinuation of therapy, or both.

Secondary outcomes

Acceptability, i.e. proportion of participants that tolerated or allowed the intervention.
Minor adverse events, e.g. vaginal discharge, burning sensation, genital pain, rash, ulceration, erythema, vaginitis.

Search methods for identification of studies

We attempted to identify as many relevant randomised trials as possible of "topical microbicide", irrespective of language of publication or publication status (published or unpublished). We used both electronic searching in bibliographic databases and handsearching, as described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2019)

Electronic searches

With the assistance of the Information Specialist of the Cochrane Sexually Transmitted Infections Group, we implemented a comprehensive search strategy to identify as many relevant trials as possible in electronic databases. We used a combination of controlled vocabulary (MeSH, Emtree, DeCS, including exploded terms) and free‐text terms (considering spelling variants, synonyms, acronyms and truncation) for topical microbicides, with field labels, proximity operators, and boolean operators.

For the initial version of the review published in 2012 (Obiero 2012a), we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (1980 to 22 July 2011), MEDLINE (1980 to July 2011), Embase (1980 to July 2011), Web of Science (1980 to May 2009), LILACS (1980 to May 2009), NML Gateway (1980 to December 2009), WHO International Clinical Trials Registry Platform (ICTRP: www.who.int/ictrp/search/en/) (22 July 2011), and ClinicalTrials.gov (22 July 2011).

For this review update, we conducted searches between June 2015 and August 2020 (Appendix 1; Appendix 2; Appendix 3; Appendix 4: Appendix 5; Appendix 6) in MEDLINE, Embase, LILACS, Web of Science, ICTRP, ClinicalTrials.gov and CENTRAL for trials that were done after 2011.

Searching other resources

We conducted searches of conference proceedings and reference lists of relevant journal articles, and contacted organisations involved in microbicide research.

Conference proceedings

We searched proceedings of the following conferences from August 2011 to 22 August 2020 for relevant studies:

International Conference on AIDS and STDs in Africa (ICASA)
Biennial meeting of the International Society for Sexually Transmitted Diseases Research
International Congress of Sexually Transmitted Infections
Biannual International Microbicide Conference and Modern Mucosal Vaccines, Adjuvants and Microbicides
Annual Conference on Retroviruses and Opportunistic Infections (CROI)

Researchers, organisations and pharmaceutical companies

We contacted organisations involved in microbicide research, including the Alliance for Microbicide Development, International Partnership for Microbicides (IPM), the Joint United Nations Programme on HIV/AIDS (UNAIDS), and WHO. We also contacted microbicide and HIV prevention experts.

Reference lists

We checked the reference lists of relevant previous reviews (Buckheit 2010; Cutler 2008; Garg 2009; Klasse 2008; Nuttall 2010; Singh 2014; Wilkinson 2002a; Wilkinson 2002b) and full‐text articles reviewed for inclusion in this review.

Data collection and analysis

Selection of studies

For the original review (Obiero 2012a), Jael Obiero (JO) and Charles Shey Wiysonge (CSW) independently screened all citations and abstracts identified by the search strategy for potentially eligible studies. For this review update, JO and Paul Ogongo (PO) independently performed screening and study selection. The two review authors independently assessed the full‐text articles of potentially relevant studies using the prespecified trial inclusion criteria. We resolved any disagreements by discussion and consensus. When a disagreement could not be resolved, a third review author (Peter Gichuhi Mwethera (PGM) for the original review and CSW for this update) arbitrated. We excluded potentially eligible studies that did not meet our inclusion criteria and documented the reasons for exclusion in the table of Characteristics of excluded studies.

Data extraction and management

For the current update, JO and PO independently extracted data from included trials using a data extraction form. Extracted information included trial methods, participant characteristics, interventions, and outcomes. For all trials, we extracted the number of participants randomised, the number of participants with each outcome, and the number analysed. The authors resolved differences by discussion and consensus, with arbitration by PGM and CSW.

Assessment of risk of bias in included studies

Three review authors (JO, PO, and CSW) independently assessed the risks of bias in each included trial addressing seven specific domains: generation of allocation sequence, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting and 'other issues'. For each included trial, the three review authors independently described what the trial authors reported that they did for each domain and then made a decision relating to the risk of bias for that domain by assigning a judgement of 'low risk' of bias, 'high risk' of bias, or 'unclear risk' of bias. The review authors compared the results of their independent assessments of risks of bias and resolved any discrepancies by discussion and consensus (Higgins 2020). We assessed risk of bias using the Cochrane 'Risk of bias' tool. We provided justification for risk of bias (high, low, unclear) in the 'Risk of bias' table by direct reference to the relevant report.

Measures of treatment effect

Our outcomes were all dichotomous in nature, so we presented the trial results as risk ratios (RRs) with 95% confidence intervals (CIs). The RR is used as a relative effect measure that works well with a low or high rate of events, and is easy to interpret and use in clinical practice. We performed meta‐analyses separately for each STI, stratified by type of microbicide,compared to their respective placebos. This was because the microbicides in the trial belonged to different classes and their mechanisms of action differ.

Unit of analysis issues

The unit of analysis was the participant who received the preventive treatment.

Dealing with missing data

We identified the levels of attrition in the included trials and performed analyses for all outcomes as far as possible on an intention‐to‐treat basis, i.e. we analysed all participants in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial was the number randomised.

Assessment of heterogeneity

We assessed statistical heterogeneity in each meta‐analysis using the Tau², I² statistic, and Chi² test (Higgins 2019). We regarded heterogeneity as substantial if the I² statistic value was greater than 40% and if either the Tau² value was greater than zero or there was a P value less than 0.10 in the Chi² test.

We considered whether the clinical and methodological characteristics of the included studies were sufficiently similar for meta‐analysis to provide a clinically meaningful summary. We assessed statistical heterogeneity using the I² statistic as follows: not relevant (l² value below 40%), important (l² value 40% to 75%), or substantial (l² value above 75%) (Sutton 2008; Higgins 2020). We also assessed statistical heterogeneity in each meta‐analysis using the t² and Chi² statistics.

If we detected substantial heterogeneity, we explored possible explanations for it in subgroup analyses (see Subgroup analysis and investigation of heterogeneity). We took statistical heterogeneity into account if is not relevant we used fixed effects model, if heterogeneity is important we used a random‐effects analysis, and if heterogeneity is substantial and there is not explanation we did not pool data

Assessment of reporting biases

We planned to explore publication bias through assessment of funnel plot asymmetry and formal tests. For dichotomous outcomes we planned to use the test proposed by Harbord 2006. However, as we included fewer than 10 trials in the meta‐analyses we did not perform these analyses.

Data synthesis

We performed statistical analyses using Review Manager 5 (RevMan: RevMan 2014). For this version of the review, we used a fixed‐effect meta‐analysis, i.e. the trials examined the same intervention, and we judged the trials’ populations and methods to be sufficiently similar. We would have used a random‐effects model if there were clinical heterogeneity sufficient to expect that the underlying treatment effects differed between trials or if we detected substantial heterogeneity (I² = 40% or greater) to produce an overall summary if we considered an average treatment effect across trials to be clinically meaningful. In such circumstances, we would have treated the random‐effects summary as the average range of possible treatment effects and discussed the clinical implications of treatment effects differing between trials.

Subgroup analysis and investigation of heterogeneity

We planned to explore possible causes of any significant statistical heterogeneity of effects by using subgroup analyses, with subgroups defined by the sex of study participants (WSM or MSM), sexual route of transmission (vaginal or anal), population (high versus low risk), intervention type, and type of comparison group (placebo, condom, diaphragm, vaginal sponge, or cervical cap).

Sensitivity analysis

We conducted sensitivity analyses to investigate the effect of type of meta‐analysis (fixed‐effect versus random‐effects) on the robustness of the results.

Summary of findings and assessment of the certainty of the evidence

We graded our confidence in the evidence and summarised the findings in a 'Summary of findings' table using the approach recommended by the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) Working Group (GRADEpro GDT 2015). We compared the effectiveness of topical microbicides (surfactants, vaginal defence enhancers, entry inhibitors and agents that prevent replication of the pathogen after it has entered the cell) with placebo, no intervention, condom, diaphragm, vaginal sponge, and cervical cap for prevention of STI for each of the following important outcomes: laboratory confirmed incidence of STIs (viral, bacterial, fungal, protozoan), severe adverse events, acceptability and minor adverse events. We used the five GRADE considerations (study limitations, consistency of effect, imprecision, indirectness, and risk of bias) to assess the certainty of the evidence as it relates the outcomes (Balshem 2011; Guyatt 2011; Guyatt 2013) . We used methods and recommendations described in Section 8.5 and Chapter 12 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2020).

We plan to extract study data, format our comparisons in data tables and prepare a summary of findings table before writing the results and conclusions of our review.

Results

Description of studies

Results of the search

For the previous version of the review, we conducted searches up to July 2011 and included eight randomised trials (Obiero 2012a). For the current update, we conducted searches between June 2015 and August 2020 for trials conducted after 2011 and identified 1980 records (1834 without duplicates). From these records, we identified 16 potentially eligible studies (Figure 1). We included four of the studies, which met our inclusion criteria (Baeten 2016; Marrazzo 2015; Nel 2016; Delany‐Moretlwe 2018). Six of the 12 trials were stopped early due to safety concerns (Feldblum 2008: Halpern 2008; Marrazzo 2015; McCormack 2010; Peterson 2007; Van Damme 2008). We conducted sensitivity analyses and found that risk of bias (high versus moderate/low risk of bias) had no impact on the robustness of the findings.

PRISMA diagram showing the search and selection of studies

Combining data from the previous version of the review and the recent searches, gives 14 excluded and 12 included studies (Figure 1; Table 4). In this update, we do not have any studies awaiting assessment.

1. Summary table with the description of included studies.

Study	Participants	Intervention	Comparator	Outcome
Abdool Karim 2010	889 women	Tenofovir gel	Placebo gel	HIV, HSV‐2, HPV, Adverse events
Abdool Karim 2011	3101 women	Buffergel 0.5% PRO 2000 gel	Placebo gel	HIV, Chlamydia, Gonorrhoea, Trichomoniasis, HSV‐2 Adverse events
Baeten 2016	2629 women	Dapivirine ring	Placebo ring	HIV‐1, Gonorrhoea, Trichomoniasis, Chlamydia, Adverse events
Feldblum 2008	2153 women	SAVVY gel	Placebo gel	HIV, Adverse events
Halpern 2008	1644 women	Cellulose sulphate gel	Placebo gel	HIV, Gonorrhoea, Chlamydia, Adverse events
Marrazzo 2015	2010 women	Tenofovir gel	Placebo gel	HIV, HSV, Gonorrhoea, Chlamydia, Syphilis, Trichomoniasis, Adverse events
Nel 2016	1959 women	Dapivirine ring	Placebo ring	HIV, Gonorrhoea, Chlamydia, Syphilis, Trichomoniasis, Adverse events
McCormack 2010	9385 women	2% PRO 2000 gel 0.5% PRO 2000 gel	Placebo gel	HIV, HSV, Gonorrhoea, Chlamydia
Peterson 2007	2142 women	SAVVY gel	Placebo gel	HIV, Adverse events
Delany‐Moretlwe 2018	2059 women	Tenofovir gel	Placebo gel	HIV, HSV, Adverse events
Skoler‐Karpoff 2008	6202 women	Carraguard gel	Placebo gel	HIV, Gonorrhoea, Chlamydia, Syphilis, Trichomoniasis, Adverse events
Van Damme 2008	1428 women	Cellulose sulphate gel	Placebo gel	HIV, HSV, Gonorrhoea, Chlamydia, Syphilis, Condyloma, Trichomoniasis

Topical microbicides for preventing sexually transmitted infections
Population: heterosexual women Settings: Local clinics and community based locations in Malawi, South Africa, Uganda, and Zimbabwe (1 study) and South Africa and Uganda (1 study) Intervention: dapivirine vaginal microbicide rings Comparison: identical placebo rings
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)
Outcomes	Placebo	Dapivirine	Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)
HIV infection	78 per 1000	55 per 1000 (44 to 69)	RR 0.71 (0.57 to 0.89)	4588 (2 studies)	⊕⊕⊕⊝ Moderate¹
Herpes simplex virus	Data not reported				The dapivirine studies did not screen for herpes simplex virus
Gonorrhoea	153 per 1000	153 per 1000 (133 to 175)	RR 1.00  (0.87 to 1.15)	4588 (2 studies)	⊕⊕⊝⊝ low^1,2
Trichomoniasis	144 per 1000	153 per 1000 (133 to 177)	RR 1.06 (0.92 to 1.23)	4588 (2 studies)	⊕⊕⊝⊝ low³
Chlamydia	293 per 1000	285 per 1000 (261 to 314)	RR 0.97 (0.89 to 1.07)	4588 (2 studies)	⊕⊕⊝⊝ moderate²
Syphilis	8 per 1000	13 per 1000 (5 to 35)	RR 1.70 (0.63 to 4.59)	1956 (1 study)	⊕⊕⊝⊝ low³
Serious adverse events	110 per 1000	123 per 1000 (103 to 145)	RR 1.12 (0.94 to 1.32)	4588 (2 studies)	⊕⊕⊝⊝ low^1,2
Acceptability	No study reported this outcome in a form that could be put in a forest plot
Minor adverse events	No study reported this outcome in a form that could be put in a forest plot
The basis for the risk in the placebo group is the median risk across control groups of the included studies. The corresponding risk for dapivirine (and its 95% confidence interval) is based on the median risk in the dapivirine group and the risk ratio of the intervention (and its 95% CI). CI:* confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High certainty: Further research is very unlikely to change our confidence in the estimate of effect. Moderate certainty: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low certainty: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low certainty: We are very uncertain about the estimate.

Topical microbicide for preventing sexually transmitted infections
Patient or population: Heterosexual women Settings: Community clinics Nigeria (1 study), South Africa, Uganda, Benin and India (1 study) Intervention: Cellulose sulphate vaginal gel Comparison: Identical placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Certainty of the evidence (GRADE)
	Assumed risk	Corresponding risk
	Placebo	Cellulose sulphate
HIV Infection	19 per 1000	23 per 1000 (14 to 37)	RR 1.2 (0.74 to 1.95)	3069 (2 studies	⊕⊕⊝⊝ low¹
Herpes simplex	11 per 1000	11 per 1000 (4 to 30)	RR 0.99 (0.37 to 2.62)	1425 (1 study)	⊕⊕⊝⊝ low¹
Gonorrhoea	66 per 1000	59 per 1000 (44 to 77)	RR 0.89  (0.67 to 1.17)	3069 (2 studies)	⊕⊝⊝⊝ very low^1,2
Trichomoniasis	55 per 1000	53 per 1000 (34 to 82)	RR 0.96  (0.62 to 1.49)	1425 (1 study)	⊕⊕⊝⊝ low¹
Chlamydia	48 per 1000	34 per 1000 (24 to 48)	RR 0.70  (0.49 to 0.99)	3069 (2 studies)	⊕⊕⊝⊝ low¹
Syphilis	14 per 1000	10 per 1000 (4 to 26)	RR 0.69  (0.26 to 1.81)	1425 (1 study)	⊕⊕⊝⊝ low¹
Serious adverse events	33 per 1000	42 per 1000 (29 to 60)	RR 1.25 (0.87 to 1.79)	3069 (2 studies)	⊕⊕⊝⊝ low¹
Acceptability	No study reported this outcome in a form that could be put in a forest plot
Minor adverse events	No study reported this outcome in a form that could be put in a forest plot
The basis for the risk in the placebo group is the median risk across control groups of the included studies. The corresponding risk for cellulose sulphate (and its 95% confidence interval) is based on the median risk in the cellulose sulphate group and the risk ratio of the intervention (and its 95% CI). CI:* confidence interval; RR: risk ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

Date	Event	Description
22 August 2020	New citation required and conclusions have changed	We included four new studies (Baeten 2016; Delany‐Moretlwe 2018; Marrazzo 2015; Nel 2016)
22 August 2020	New search has been performed	Search updated in August 2020

Search electronic report #1
Search type	Update
Databases	§ MEDLINE § MEDLINE In‐Process & Other Non‐Indexed Citations § MEDLINE Daily Update
Platform	Ovid
Search date	06/06/2015
Update date	Undefined
Range of search date	2011‐Current
Language restrictions	None
Other limits	None
Search strategy (results)	1 microbicid$.tw. (5151) 2 antimicrobial.tw. (95662) 3 1 or 2 (100041) 4 vagin$.tw. (89605) 5 rectal$.tw. (67721) 6 rectum.tw. (30777) 7 anus.tw. (6110) 8 anal$.tw. (4313850) 9 topical$.tw. (79474) 10 local$.tw. (984656) 11 4 or 5 or 6 or 7 or 8 or 9 or 10 (5206760) 12 3 and 11 (30984) 13 exp Anti‐Infective Agents, Local/ (184098) 14 ((anti adj1 infective$) and topical).tw. (112) 15 ((anti adj1 infective$) and local).tw. (131) 16 (antiinfective$ adj5 topical).tw. (15) 17 (antiinfective$ adj5 local).tw. (3) 18 (mercurial adj5 antiseptic).tw. (4) 19 (antifung$ adj5 topical).tw. (934) 20 (antivir$ adj5 topical).tw. (235) 21 (antibacteri$ adj5 topical).tw. (327) 22 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 (185583) 23 12 or 22 (214580) 24 exp Sexually transmitted diseases/ or exp Sexually transmitted diseases, bacterial/ or exp Chancroid/ or exp Chlamydia infections/ or exp Lymphogranuloma venereum/ or exp Gonorrhea/ or exp Granuloma inguinale/ or exp Syphilis/ or exp Neurosyphilis/ or exp Tabes dorsalis/ or exp Syphilis, latent/ (296934) 25 exp Sexually transmitted diseases, viral/ or exp Condylomata acuminata/ or exp Herpes genitalis/ (236362) 26 (std or stds or sti or stis).tw. (17322) 27 ((sex$ adj5 transmitted) or (sex$ adj5 transmiss$)).tw. (29368) 28 ((venereal adj5 disease$) or (venereal adj5 infection$) or (venereal adj5 disorder$)).tw. (4219) 29 ((genital adj5 disease$) or (genital adj5 infection$) or (genital adj5 disorder$)).tw. (9327) 30 exp Chlamydia/ or exp Chlamydia trachomatis/ (12934) 31 chlamydia$.tw. (23287) 32 exp Treponema pallidum/ or treponema pallidum.tw. or condylom$.tw. or syphili$.tw. (28184) 33 (lymphogranuloma venereum or lymphogranuloma inguinale).tw. (980) 34 (granuloma inguinale or granuloma venereum or donovanosis or donovania).tw. (532) 35 exp Neisseria gonorrhoeae/ (8484) 36 (gonorrh$ or gonococc$).tw. (19345) 37 (nongonococcal urethritis or non‐gonococcal urethritis or ngu).tw. (1170) 38 exp Herpesvirus 1, human/ or exp Herpesvirus 2, human/ or (hsv1 or hsv‐1 or hsv2 or hsv‐2 or (herpes adj5 genital$)).tw. (19961) 39 (human cytomegalovirus or human herpesvirus‐5 or hhv‐5 or hcmv).tw. (8204) 40 exp Candidiasis/ or exp Candidiasis, vulvovaginal/ or exp Candidiasis, invasive/ or exp Candidemia/ or exp Candida albicans/ (41445) 41 (candidiasis or ((vagina$ adj5 candidosis) or ((vulvovagina$ adj5 candidosis) or (vagina$ adj5 mycoses)))).tw. (12498) 42 exp Vaginitis/ or exp Trichomonas vaginitis/ or exp Trichomonas vaginalis/ or exp Vulvovaginitis/ or (vaginitis or trichomoniasis or vaginalis).tw. (17816) 43 exp Vaginosis, bacterial/ or exp Gardnerella vaginalis/ or (vaginosis adj5 bacterial).tw. (4149) 44 exp Balanitis/ or balanitis.tw. (1040) 45 ((venereal adj5 ulcer$) or (venereal adj5 wart$)).tw. (113) 46 ((genital$ adj5 ulcer$) or (anogenital adj5 ulcer$) or (anorectal adj5 ulcer$) or (penile adj5 ulcer$) or (penis adj5 ulcer$)).tw. (2658) 47 ((genital$ adj5 wart$) or (anogenital adj5 wart$) or (anorectal adj5 wart$) or (penile adj5 wart$) or (penis adj5 wart$)).tw. (2510) 48 exp Alphapapillomavirus/ or exp Human papillomavirus 6/ or exp Human papillomavirus 11/ or exp Human papillomavirus 16/ or exp Human papillomavirus 18/ or exp Human papillomavirus 31/ or exp Betapapillomavirus/ or exp Gammapapillomavirus/ (5276) 49 (human papillomavirus$ or hpv or recurrent respiratory papillomatosis or condyloma$).tw. (36622) 50 exp Acquired Immunodeficiency Syndrome/ or exp HIV/ (148557) 51 ((human adj5 immun$ adj5 virus) or hiv or (acquired adj5 immun$ adj5 deficiency adj5 syndrome) or aids or (acquired adj5 immun$ adj5 syndrome)).tw. (329466) 52 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 (564437) 53 randomized controlled trial.pt. (397466) 54 controlled clinical trial.pt. (89683) 55 randomized.ab. (323220) 56 placebo.ab. (163406) 57 clinical trials as topic.sh. (173305) 58 randomly.ab. (232387) 59 trial.ti. (139792) 60 53 or 54 or 55 or 56 or 57 or 58 or 59 (966570) 61 exp animals/ not humans.sh. (4057817) 62 60 not 61 (891384) 63 23 and 52 and 62 (941) 64 limit 63 to yr="2011 ‐Current" (244)
# of records identified	244
# of records without duplicates	213

Search electronic report #2
Search type	Update
Database	EMBASE
Platform	EMBASE.com
Search date	06/06/2015
Update date	Undefined
Range of search date	2011‐Current
Language restrictions	None
Other limits	None
Search strategy (results)	1 1. 'microbicide'/exp 1,517 2. microbicid:ab,ti 5,691 3. antimicrobial:ab,ti 125,515 4. or/1‐3 130,714 5. vagin:ab,ti 118,442 6. rectal:ab,ti 94,192 7. rectum:ab,ti 42,697 8. anus:ab,ti 8,115 9. anal:ab,ti 5,404,464 10. topical:ab,ti 103,913 11. local:ab,ti 1,177,195 12. or/5‐11 6,465,683 13. 4 AND 12 42,322 14. 'topical antiinfective agent'/exp 278,026 15. (anti NEXT/1 infective):ab,ti AND topical:ab,ti 143 16. (anti NEXT/1 infective):ab,ti AND local:ab,ti 164 17. (antiinfective* NEAR/5 topical):ab,ti 17 18. (antiinfective* NEAR/5 local):ab,ti 12 19. (mercurial NEAR/5 antiseptic):ab,ti 4 20. (antifung* NEAR/5 topical):ab,ti 1,294 21. (antivir* NEAR/5 topical):ab,ti 265 22. (antibacteri* NEAR/5 topical):ab,ti 437 23. or/14‐22 279,950 24. 13 or 23 319,139 25. 'sexually transmitted disease'/exp OR 99,944 'chlamydiasis'/exp OR 'condyloma'/exp OR 'condyloma acuminatum'/exp OR 'condyloma latum'/exp OR 'genital herpes'/exp OR 'gonorrhea'/exp OR 'granuloma inguinale'/exp OR 'lymphogranuloma venereum'/exp OR 'syphilis'/exp OR 'secondary syphilis'/exp OR 'tabes dorsalis'/exp OR 'ulcus molle'/exp 26. std:ab,ti OR stds:ab,ti OR sti:ab,ti OR 22,872 stis:ab,ti 27. (sex* NEAR/5 transmitted):ab,ti OR (sex* NEAR/5 33,248 transmiss):ab,ti 28. (venereal NEAR/5 disease):ab,ti OR (venereal 4,349 NEAR/5 infection):ab,ti OR (venereal NEAR/5 disorder):ab,ti 29. (genital NEAR/5 disease):ab,ti OR (genital 11,299 NEAR/5 infection):ab,ti OR (genital NEAR/5 disorder):ab,ti 30. 'chlamydia'/exp OR 'chlamydia trachomatis'/exp 22,663 31. chlamydia:ab,ti 27,615 32. syphili:ab,ti OR chancre:ab,ti OR 30,274 condylom:ab,ti 33. 'lymphogranuloma venereum':ab,ti OR 1,102 'lymphogranuloma inguinale':ab,ti 34. 'granuloma inguinale':ab,ti OR 'granuloma 590 venereum':ab,ti OR donovanosis:ab,ti OR donovania:ab,ti 35. 'neisseria gonorrhoeae'/exp 13,702 36. gonorrh:ab,ti OR gonococc:ab,ti 22,251 37. 'nongonococcal urethritis'/exp OR 1,967 (nongonococcal:ab,ti AND urethritis:ab,ti OR 'non gonococcal':ab,ti AND urethritis:ab,ti) OR ngu:ab,ti 38. 'herpes simplex virus 1'/exp OR 'herpes simplex 28,336 virus 2'/exp OR hsv1:ab,ti OR 'hsv 1':ab,ti OR hsv2:ab,ti OR 'hsv 2':ab,ti OR (herpes NEAR/5 genital):ab,ti 39. human:ab,ti AND cytomegalovirus:ab,ti OR 5,528 human:ab,ti AND 'herpesvirus 5':ab,ti OR 'hhv 5':ab,ti OR hcmv:ab,ti 40. 'candidiasis'/exp OR 'vagina candidiasis'/exp OR 72,274 'genital candidiasis'/exp OR 'invasive candidiasis'/exp OR 'candidemia'/exp OR 'candida albicans'/exp 41. candidiasis:ab,ti OR (vagina* NEAR/5 16,572 candid):ab,ti OR (vulvovagina NEAR/5 candid):ab,ti OR (vagina NEAR/5 mycoses):ab,ti 42. 'gardnerella infection'/exp OR 'gardnerella 4,894 vaginalis'/exp OR (vaginosis NEAR/5 bacterial):ab,ti 43. 'vaginitis'/exp OR 'vulvovaginitis'/exp OR 25,299 'trichomoniasis'/exp OR 'trichomonas vaginalis'/exp OR vaginitis:ab,ti OR trichomoniasis:ab,ti OR vaginalis:ab,ti 44. 'balanitis'/exp OR balanitis:ab,ti 1,546 45. (genital* NEAR/5 wart):ab,ti OR (anogenital 3,185 NEAR/5 wart):ab,ti OR (anorectal NEAR/5 wart):ab,ti OR (penile NEAR/5 wart):ab,ti OR (penis NEAR/5 wart):ab,ti 46. (genital NEAR/5 ulcer):ab,ti OR (anogenital 3,440 NEAR/5 ulcer):ab,ti OR (anorectal NEAR/5 ulcer):ab,ti OR (penile NEAR/5 ulcer):ab,ti OR (penis NEAR/5 ulcer):ab,ti 47. (venereal NEAR/5 ulcer):ab,ti OR (venereal 131 NEAR/5 wart):ab,ti 48. 'human papillomavirus':ab,ti OR hpv:ab,ti 41,347 49. 'alphapapillomavirus'/exp OR 'human 9,441 papillomavirus type 11'/exp OR 'human papillomavirus type 16'/exp OR 'human papillomavirus type 18'/exp OR 'human papillomavirus type 31'/exp OR 'human papillomavirus type 6'/exp OR 'betapapillomavirus'/exp OR 'gammapapillomavirus'/exp 50. 'human immunodeficiency virus'/exp OR 'acquired 246,676 immune deficiency syndrome'/exp 51. (human NEAR/5 immun NEAR/5 virus):ab,ti OR 381,316 hiv:ab,ti OR (acquired NEAR/5 immun* NEAR/5 deficiency NEAR/5 syndrome):ab,ti OR aids:ab,ti OR (acquired NEAR/5 immun* NEAR/5 syndrome):ab,ti 52. or/25‐51 685,883 53. 'randomized controlled trial'/exp OR 'single 1,163,675 blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp OR random:ab,ti OR placebo:ab,ti OR allocat:ab,ti OR crossover:ab,ti OR 'cross over':ab,ti OR trial:ti OR (doubl* NEXT/1 blind*):ab,ti NOT ('animal'/de OR 'animal experiment'/de OR 'nonhuman'/de NOT ('animal'/de OR 'animal experiment'/de OR 'nonhuman'/de AND 'human'/de)) 54. 24 and 52 and 53 903 55. 54 and AND [2011‐2015]/py 329
# of records identified	329
# of records without duplicates	329

Search electronic report #3
Search type	Update
Database	The Cochrane Central Register of Controlled Trials (CENTRAL)
Platform	Ovid
Search date	06/06/2015
Update date	Undefined
Range of search date	2011‐Current
Language restrictions	None
Other limits	None
Search strategy (results)	1 microbicid$.tw. (231) 2 antimicrobial.tw. (3042) 3 1 or 2 (3262) 4 vagin$.tw. (7640) 5 rectal$.tw. (4982) 6 rectum.tw. (1016) 7 anus.tw. (131) 8 anal$.tw. (191113) 9 topical$.tw. (13692) 10 local$.tw. (30193) 11 4 or 5 or 6 or 7 or 8 or 9 or 10 (227088) 12 3 and 11 (1218) 13 exp Anti‐Infective Agents, Local/ (5912) 14 ((anti adj1 infective$) and topical).tw. (12) 15 ((anti adj1 infective$) and local).tw. (7) 16 (antiinfective$ adj5 topical).tw. (3) 17 (antiinfective$ adj5 local).tw. (0) 18 (mercurial adj5 antiseptic).tw. (0) 19 (antifung$ adj5 topical).tw. (112) 20 (antivir$ adj5 topical).tw. (21) 21 (antibacteri$ adj5 topical).tw. (43) 22 13 or 14 or 15 or 16 or 17 or 18 or 19 or 20 or 21 (6089) 23 12 or 22 (7102) 24 exp Sexually transmitted diseases/ or exp Sexually transmitted diseases, bacterial/ or exp Chancroid/ or exp Chlamydia infections/ or exp Lymphogranuloma venereum/ or exp Gonorrhea/ or exp Granuloma inguinale/ or exp Syphilis/ or exp Neurosyphilis/ or exp Tabes dorsalis/ or exp Syphilis, latent/ (8193) 25 exp Sexually transmitted diseases, viral/ or exp Condylomata acuminata/ or exp Herpes genitalis/ (7140) 26 (std or stds or sti or stis).tw. (1071) 27 ((sex$ adj5 transmitted) or (sex$ adj5 transmiss$)).tw. (987) 28 ((venereal adj5 disease$) or (venereal adj5 infection$) or (venereal adj5 disorder$)).tw. (29) 29 ((genital adj5 disease$) or (genital adj5 infection$) or (genital adj5 disorder$)).tw. (533) 30 exp Chlamydia/ or exp Chlamydia trachomatis/ (288) 31 chlamydia$.tw. (1000) 32 exp Treponema pallidum/ or treponema pallidum.tw. or condylom$.tw. or syphili$.tw. (561) 33 (lymphogranuloma venereum or lymphogranuloma inguinale).tw. (6) 34 (granuloma inguinale or granuloma venereum or donovanosis or donovania).tw. (6) 35 exp Neisseria gonorrhoeae/ (162) 36 (gonorrh$ or gonococc$).tw. (1062) 37 (nongonococcal urethritis or non‐gonococcal urethritis or ngu).tw. (145) 38 exp Herpesvirus 1, human/ or exp Herpesvirus 2, human/ or (hsv1 or hsv‐1 or hsv2 or hsv‐2 or (herpes adj5 genital$)).tw. (582) 39 (human cytomegalovirus or human herpesvirus‐5 or hhv‐5 or hcmv).tw. (49) 40 exp Candidiasis/ or exp Candidiasis, vulvovaginal/ or exp Candidiasis, invasive/ or exp Candidemia/ or exp Candida albicans/ (807) 41 (candidiasis or ((vagina$ adj5 candidosis) or ((vulvovagina$ adj5 candidosis) or (vagina$ adj5 mycoses)))).tw. (807) 42 exp Vaginitis/ or exp Trichomonas vaginitis/ or exp Trichomonas vaginalis/ or exp Vulvovaginitis/ or (vaginitis or trichomoniasis or vaginalis).tw. (1026) 43 exp Vaginosis, bacterial/ or exp Gardnerella vaginalis/ or (vaginosis adj5 bacterial).tw. (450) 44 exp Balanitis/ or balanitis.tw. (25) 45 ((venereal adj5 ulcer$) or (venereal adj5 wart$)).tw. (2) 46 ((genital$ adj5 ulcer$) or (anogenital adj5 ulcer$) or (anorectal adj5 ulcer$) or (penile adj5 ulcer$) or (penis adj5 ulcer$)).tw. (102) 47 ((genital$ adj5 wart$) or (anogenital adj5 wart$) or (anorectal adj5 wart$) or (penile adj5 wart$) or (penis adj5 wart$)).tw. (219) 48 exp Alphapapillomavirus/ or exp Human papillomavirus 6/ or exp Human papillomavirus 11/ or exp Human papillomavirus 16/ or exp Human papillomavirus 18/ or exp Human papillomavirus 31/ or exp Betapapillomavirus/ or exp Gammapapillomavirus/ (139) 49 (human papillomavirus$ or hpv or recurrent respiratory papillomatosis or condyloma$).tw. (1204) 50 exp Acquired Immunodeficiency Syndrome/ or exp HIV/ (3294) 51 ((human adj5 immun$ adj5 virus) or hiv or (acquired adj5 immun$ adj5 deficiency adj5 syndrome) or aids or (acquired adj5 immun$ adj5 syndrome)).tw. (11859) 52 24 or 25 or 26 or 27 or 28 or 29 or 30 or 31 or 32 or 33 or 34 or 35 or 36 or 37 or 38 or 39 or 40 or 41 or 42 or 43 or 44 or 45 or 46 or 47 or 48 or 49 or 50 or 51 (18532) 53 23 and 52 (533) 54 limit 53 to yr="2011 ‐Current" (122)
# of records identified	122
# of records without duplicates	122

Search electronic report #4
Search type	Update
Database	LILACS http://lilacs.bvsalud.org/es/
Platform	Biblioteca Virtual en Salud (BVS), interfaz iAHx
Search date	06/06/2015
Update date	Undefined
Range of search date	None
Language restrictions	None
Other limits	None
Search strategy	(ab:(microbicide)) OR (ti:(microbicid)) AND (ab:(topical)) OR (ti:(topical)) AND db:("LILACS") RCTs filter: ((PT:"ensayo clinico controlado aleatorio" OR PT:"ensayo clinico controlado" OR PT:"estudio multicéntrico" OR MH:"ensayos clinicos controlados aleatorios como asunto" OR MH:"ensayos clinicos controlados como asunto" OR MH:"estudio multicéntricos como asunto" OR MH:"distribución aleatoria" OR MH:"método doble ciego" OR MH:"metodo simple‐ciego") OR ((ensaio$ OR ensayo$ OR trial$) AND (azar OR acaso OR placebo OR control$ OR aleat$ OR random$ OR enmascarado$ OR simpleciego OR ((simple$ OR single OR duplo$ OR doble$ OR double$) AND (cego OR ciego OR blind OR mask))) AND clinic$)) AND NOT (MH:animales OR MH:conejos OR MH:ratones OR MH:ratas OR MH:primates OR MH:perros OR MH:gatos OR MH:porcinos OR PT:"in vitro")
# of records identified	1
# of records without duplicates	1

Search electronic report #5
Search type	Update
Database	Web of Science webofscience.com/
Platform	Thomson Reuters
Search date	06/06/2015
Update date	Undefined
Range of search date	2009‐current
Language restrictions	None
Other limits	None
Search strategy	TS=(topical) AND TS=(microbicid) AND TI=(trial) Refinado por: Años de publicación: ( 2010 OR 2009 OR 2014 OR 2011 OR 2012 )
# of records identified	22
# of records without duplicates	22
Search electronic report #6
Search type	New
Database	International Clinical Trials Registry Platform www.who.int/ictrp/
Platform	ICTRP Portal
Search date	06/06/2015
Update date	Undefined
Range of search date	None
Language restrictions	None
Other limits	None
Search strategy	topical microbicid*
# of records identified	1
# of records without duplicates	1

Search electronic report #7
Search type	New
Database	Clinicaltrials.gov
Platform	Clinicaltrials.gov
Search date	06/06/2015
Update date	Undefined
Range of search date	None
Language restrictions	None
Other limits	None
Search strategy	"topical microbicide"
# of records identified	11
# of records without duplicates	11

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1.1 HIV	12		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only
1.2 Herpes simplex	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.2.1 Tenofovir	2	2439	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.82, 0.99]
1.2.2 Cellulose sulphate	1	1425	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.37, 2.62]
1.2.3 PRO 2000	1	6651	Risk Ratio (M‐H, Fixed, 95% CI)	0.95 [0.73, 1.23]
1.3 Condyloma acuminatum	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.3.1 Cellulose sulphate	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.4 High‐risk HPV	1		Risk Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.5 Gonorrhoea	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.5.1 Carraguard	1	6202	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.88, 1.27]
1.5.2 Cellulose sulphate	2	3069	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.67, 1.17]
1.5.3 PRO 2000	2	8191	Risk Ratio (M‐H, Fixed, 95% CI)	1.15 [0.87, 1.52]
1.5.4 BufferGel	1	1546	Risk Ratio (M‐H, Fixed, 95% CI)	0.99 [0.51, 1.93]
1.5.5 Tenofovir	1	2010	Risk Ratio (M‐H, Fixed, 95% CI)	0.66 [0.40, 1.10]
1.5.6 Dapivirine	2	4586	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.87, 1.15]
1.6 Chlamydia	8		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.6.1 Cellulose sulphate	2	3069	Risk Ratio (M‐H, Fixed, 95% CI)	0.70 [0.49, 0.99]
1.6.2 BufferGel	1	1546	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.65, 1.45]
1.6.3 Carraguard	1	6202	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.83, 1.12]
1.6.4 Dapirivine	2	4586	Risk Ratio (M‐H, Fixed, 95% CI)	0.97 [0.89, 1.07]
1.6.5 PRO 2000	2	8191	Risk Ratio (M‐H, Fixed, 95% CI)	1.01 [0.84, 1.22]
1.6.6 Tenofovir	1	2010	Risk Ratio (M‐H, Fixed, 95% CI)	0.90 [0.71, 1.13]
1.7 Syphilis	4		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.7.1 Carraguard	1	6202	Risk Ratio (M‐H, Fixed, 95% CI)	1.07 [0.75, 1.52]
1.7.2 Cellulose sulphate	1	1425	Risk Ratio (M‐H, Fixed, 95% CI)	0.69 [0.26, 1.81]
1.7.3 Dapivirine	1	1956	Risk Ratio (M‐H, Fixed, 95% CI)	1.70 [0.63, 4.59]
1.7.4 Tenofovir	1	2010	Risk Ratio (M‐H, Fixed, 95% CI)	1.27 [0.58, 2.78]
1.8 Trichomoniasis	6		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.8.1 Dapivirine	2	4588	Risk Ratio (M‐H, Fixed, 95% CI)	1.06 [0.92, 1.23]
1.8.2 BufferGel	1	1546	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.80, 1.15]
1.8.3 Carraguard	1	6202	Risk Ratio (M‐H, Fixed, 95% CI)	0.85 [0.72, 1.01]
1.8.4 Cellulose sulphate	1	1425	Risk Ratio (M‐H, Fixed, 95% CI)	0.96 [0.62, 1.49]
1.8.5 PRO 2000	1	1546	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.99, 1.39]
1.8.6 Tenofovir	1	2010	Risk Ratio (M‐H, Fixed, 95% CI)	1.21 [0.84, 1.74]
1.9 Serious Adverse Events	12		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only
1.9.1 Dapivirine	2	4588	Risk Ratio (M‐H, Fixed, 95% CI)	1.12 [0.94, 1.32]
1.9.2 Tenofovir	3	4958	Risk Ratio (M‐H, Fixed, 95% CI)	1.00 [0.81, 1.24]
1.9.3 BufferGel	1	1546	Risk Ratio (M‐H, Fixed, 95% CI)	1.29 [0.81, 2.06]
1.9.4 Carraguard	1	6202	Risk Ratio (M‐H, Fixed, 95% CI)	0.92 [0.67, 1.27]
1.9.5 Cellulose sulphate	2	3069	Risk Ratio (M‐H, Fixed, 95% CI)	1.25 [0.87, 1.79]
1.9.6 PRO 2000	2	8191	Risk Ratio (M‐H, Fixed, 95% CI)	1.18 [0.96, 1.46]
1.9.7 SAVVY	2	4295	Risk Ratio (M‐H, Fixed, 95% CI)	1.36 [0.79, 2.35]

*Study characteristics*
Methods	Setting: urban and rural clinics in South Africa Trial design: 2‐arm double‐blind, randomised placebo‐controlled trial; allocation sequential identification number corresponded to a unique envelope (accessible to each site pharmacist) and randomly allocated using permuted block randomisation of various sizes Duration of enrolment: May 2007 to January 2009 Loss to follow‐up: 5% both groups Follow‐up duration: 2.5 years Analyses were performed on an ITT basis
Participants	Number enrolled: 1085 (445 allocated to tenofovir and 444 to placebo) Mean age: tenofovir 23.6 years; placebo 24.2 years Inclusion criteria: 18 to 40 years, sexually active, not pregnant and using a non‐barrier form of contraceptive Exclusion criteria: history of adverse reactions to latex, planning to either travel away from the study site for more than 30 consecutive days, relocate away from the study site, becoming pregnant, or enrol in any other behavioural or investigational product study,creatinine clearance < 50 mL/minute,evidence of genital deep epithelial disruption, participation in any research related to any vaginally‐applied product(s) or had an untreated STI or reproductive tract infection in the past year
Interventions	Intervention arm: 1% tenofovir gel and condom Control arm: placebo gel and condom 1 dose of each gel inserted within 12 hours before sex and a second as soon as possible after sex and no more than 2 doses in a 24‐hour period. Both gels appeared identical and were dispensed in the same pre‐filled vaginal applicators with identical packaging.
Outcomes	Primary: HIV incidence, safety Secondary: incidence of deep epithelial irritation, viral load, resistance, pregnancy rates and outcomes, product hold at study exit on HIV infection and tenofovir resistance Tertiary: impact of tenofovir gel in preventing STIs, including HSV‐2 and HPV infections
Notes	The study was approved by the University of KwaZulu‐Natal's Biomedical Research Ethics Committee (E111/06), Family Health International's Protection of Human Subjects Committee (#9946) and the South African Medicines Control Council (#20060835). Participants signed informed written consent. Funding sources: The trial was supported by National Institutes of Health ClinicalTrials.gov number NCT00441298
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation in blocks of 12 and 18 assumed to have been done by computer
Allocation concealment (selection bias)	Low risk	Central randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Study gels Identical in appearance and packaging
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were not aware of the assignments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was 5% in both arms
Selective reporting (reporting bias)	Low risk	Reported all primary and secondary outcomes as stated in protocol
Other bias	Low risk	No other potential sources of bias identified

*Study characteristics*
Methods	Setting: urban, peri‐urban, and rural clinics in South Africa Trial design: multicentre double‐blind, 2‐arm, randomised, placebo‐controlled Trial duration: October 2011 to August 2014
Participants	Number enrolled: 2059 women (1032 allocated to tenofovir gel, 1027 to placebo gel) Mean age: tenofovir 23 years, placebo 23 years Inclusion criteria:age 18 to 30 years,HIV‐negative, willing to provide written informed consent and adequate locater information, sexually active, no evidence of glycosuria and proteinuria greater than trace, no history of pathological bone fractures, non‐pregnant, not breast‐feeding, agreed to use a study‐approved effective non‐barrier form of contraception, adherent to study visits and procedures, willing to use study gel as advised and not using or taking any of the following groups of medication; nephrotic agents, drugs that slow renal excretion, immune system modulators or other antiretrovirals Exclusion criteria: history of adverse reaction to latex, planning to travel away from the study site for more than 30 consecutive days, relocate away from the study site, becoming pregnant, enrolment in another study of an investigational product or behaviour modification related to HIV prevention, those with inadequate renal function, Grade 3 ALT or AST at screening or any of liver disease, abnormal serum phosphate levels (Grade 3 and above, clinically‐apparent finding on speculum pelvic examination, previously or receiving an experimental HIV vaccine, participating in another HIV prevention study or in other clinical trial with a biomedical intervention in the last 6 months, current STI symptoms or other reproductive tract infection requiring treatment and those with evidence of untreated cervical abnormalities
Interventions	Intervention arm: tenofovir 1% gel, pH 4 ‐ 5, supplied in a single‐use applicator containing approximately 4 grams of gel equivalent to approximately 40 mg of tenofovir Control arm: universal placebo gel, an inert gel containing HEC as the gelling agent with each applicator containing approximately 4 ml placebo gel Participants were requested to insert a single dose of assigned gel intravaginally up to 12 hours before coitus and the second dose within 12 hours after coitus. but no more than 2 applicators within a 24‐hour period
Outcomes	Primary: 1. Incidence of HIV‐1 infection: determined by detection of HIV antibodies using 2 HIV rapid tests, 1 detecting both HIV‐1 and HIV‐2 and the other specific for HIV‐1 2. Safety: Grade 2, 3 and 4 clinical and laboratory adverse events as defined by the DAIDS toxicity table Secondary: Incidence of HSV‐2 infection: determined by HSV western blot
Notes	Funding source: USAID, the Bill & Melinda Gates Foundation and the South African Department of Science and Technology and Department of Health ClinicalTrials.gov number NCT01386294
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Randomisation in block sizes of 8 and 16 within each study site assumed to have been done by computer
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All staff and participants were blinded to study group allocation. sequentially numbered sealed tamper‐proof envelopes were used
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were not aware of the assignments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was less than 8% in both treatment arms
Selective reporting (reporting bias)	Unclear risk	All the potential outcomes were not reported
Other bias	Low risk	No other potential source of bias suspected

*Study characteristics*
Methods	Setting: community clinics in Malawi, South Africa, Zambia, Zimbabwe, and USA Trial design: multicentre randomised, placebo‐controlled trial with 3 double‐blinded gel arms and 1 open‐label no‐gel arm. Randomisation was stratified by site in blocks of size 12 or 24, distributed randomly. Each random sequence was determined through generation of uniform random variates in a computer programme Trial duration: 2005 to 2009 Loss to follow‐up: about 5% in each group Mean duration of follow‐up: 20.4 months Analyses performed on the ITT basis
Participants	Number enrolled: 3087 (775 allocated to BufferGel, 769 to 0.5% PRO 2000, 771 to placebo gel, 722 to no gel). Mean age: Buffergel 26.2 years, PRO 2000 26.3 years, placebo gel 26.5 years, no gel 26.3 years Inclusion criteria: HIV‐negative non‐pregnant women, 18 years and older, sexually active, able to provide adequate contact information to study officials for purposes of follow‐up Exclusion criteria: history of adverse reactions to latex, use of non‐therapeutic injection drugs in the past 12 months and a history of vaginal intercourse more than an average of twice per day in the past 2 weeks, planned to become pregnant in the 30 months after study entry, to travel away from the study site for more than 3 consecutive months in the 30 months after study entry, to relocate away from the study site in the 30 months after study entry, participation in another clinical trial of a vaginal product, pregnant within 42 days of study entry, had an STI or other reproductive tract infection abnormal pelvic examination, condition that in the opinion of the investigator may interfere with the study, liver or kidney function abnormality of grade 3 or higher, blood or blood‐clotting abnormality of grade 4 or higher
Interventions	Intervention arm: 1. BufferGel 2. 5% PRO 2000 Control arm: 1. Placebo gel 2. No gel One single‐use, prefilled applicator of both gels inserted intravaginally up to 1 hour before each episode of vaginal intercourse. Study gels were similar in appearance and packaging
Outcomes	Primary: 1. Safety: deep epithelial disruption, other genital symptoms or other systemic symptoms, adverse genital signs and symptoms, as well as haematological hepatic and renal abnormalities of grade 3 or higher severity based on the Division of AIDS Table for Grading Adult and Paediatric Adverse Events, 2004 2. HIV infection (laboratory tests) Secondary: Incidence of STIs: Chlamydia, genital ulcer disease, gonorrhoea, syphilis, trichomoniasis, HSV‐2; bacterial vaginosis; pregnancy; acceptability of study product; number of behavioural risk assessment questions not answered in self‐reported interviews, rates of condom use versus gel use, establishment of repository of vaginal swab specimens for long‐term storage and future research testing on biomarkers
Notes	The study was approved by 11 institutional review boards that oversee research conducted at 8 study sites, as well as regulatory authorities in the USA, South Africa and Zimbabwe. All participants provided written informed consent Funding sources: National Institutes of Health ClinicalTrials.gov number NCT00074425
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation sequence
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	All the study gels were similar in appearance and packaging. Blinding was not possible in the open‐label arm, but the outcomes were unlikely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were not aware of the assignments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was about 5% in both treatment arms
Selective reporting (reporting bias)	Low risk	All prespecified secondary outcomes have been reported
Other bias	Low risk	No other potential sources of bias suspected

*Study characteristics*
Methods	Setting: sexually‐transmitted disease clinics, family planning clinics, and community‐based locations in Malawi, South Africa, Uganda, and Zimbabwe Trial design: randomised, double‐blind placebo‐controlled trial with the use of fixed‐block size block randomisation, stratified according to site either to the treatment or placebo vaginal ring. Trial duration: August 2012 to June 2015 Median follow‐up 1.6 years; maximum follow‐up 2.6 years Loss to follow‐up: less than 1% in both groups Follow‐up: monthly The median follow‐up was 1.6 years and the maximum follow‐up was 2.6 years
Participants	Number enrolled: 2629 (1313 allocated to dapivirine, 1316 allocated to placebo) Mean age (SD): dapivirine 27.2 (6.1) years, placebo 27.3 (6.3) years Inclusion criteria: healthy women aged 18 through 45 years, sexually active, able and willing to provide adequate locator information and written informed consent, HIV‐1‐seronegative, using an effective method of contraception except contraceptive rings, intrauterine device and sterilisation, agree not participate in other research studies involving drugs, medical devices, vaginal products or vaccines during study participation Exclusion criteria: pregnant or intending to become pregnant, planning to relocate or planning to travel away from the study site for more than 8 consecutive weeks during study participation, breast‐feeding, infection with urinary tract or pelvic inflammatory disease, an STI or reproductive tract infection, having clinical apparent Grade 2 or higher pelvic finding, clinical evidence of adverse study products or condom, or participation in any HIV prevention study using systemic or topical antiretroviral medications within 12 months of enrolment
Interventions	Intervention arm: silicone elastomer vaginal matrix ring containing 25 mg of dapivirine Control arm: placebo vaginal ring, a flexible platinum‐catalysed‐cured silicone matrix ring which contains no active drug. The rings were indistinguishable and were used for 4 weeks and then replaced with another. Women were taught how to insert and remove the vaginal ring and counselled to wear it for the entire month
Outcomes	Primary: 1. Incidence of HIV‐1 infection; indicated by presence of HIV‐1 RNA PCR assay 2. Safety: indicated by a composite of any serious adverse event, any grade 3 or 4 adverse event, and any grade 2 adverse event that was assessed by the trial clinicians as being related to dapivirine Secondary: 1. Adherence: detected by use of validated ultra‐performance liquid chromatography assay of collected plasma samples. Women were defined as being adherent if the returned ring contained less the 23.5 mg of dapivirine 2. Drug concentration: determined by measuring drug concentration in blood plasma
Notes	The trial protocol was approved by the ethics review committee at each site. All participants signed written informed consent. The ring was manufactured by QPharma, which had no role in design or implementation of the trial Funding: National Institutes of Health ClinicalTrials.gov number NCT01617096
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	The randomisation scheme was computer‐generated
Allocation concealment (selection bias)	Low risk	There was central randomisation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The rings were indistinguishable With the exception of staff members at the CDSC, investigators and participants were unaware of randomisation assignments until completion of trial
Blinding of outcome assessment (detection bias) All outcomes	Low risk	The intervention and control rings were indistinguishable
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was less than 1% in each treatment arm
Selective reporting (reporting bias)	Low risk	All outcomes in the protocol have now been reported
Other bias	Low risk	None identified

*Study characteristics*
Methods	Setting: community clinics and colleges in Nigeria Trial design: double‐blind, randomised, placebo‐controlled. Allocation sequence developed using a computer random‐number generator and randomly varied blocks of different sizes stratified by site. Sequentially‐numbered, sealed opaque envelopes used to assign participants to a group Trial duration: September 2004 to December 2006 Loss to follow‐up: 23% in both groups Follow‐up: Monthly for 12 months ITT analyses
Participants	Number enrolled: 2153 (1076 allocated to SAVVY, 1077 to placebo) Mean age (SD): SAVVY 23.5 (3.7) years, placebo 23.6 (3.8) years Inclusion criteria: women aged 18 to 35 years, non‐pregnant, HIV‐negative, sexually active, willing to use vaginal gel and condom for 12 months Exclusion criteria: HIV‐positive, pregnant
Interventions	Inervention arm: 1.0% C31G (SAVVY) gel and condom Control arm: HEC (placebo) as the gelling agent and sorbic acid as preservative Both gels were similar in appearance (clear viscous) dispensed in 3.5 mL doses with applicator and had pH 4.4. The gels were Inserted before intercourse (and a second time if more than 1 hour had elapsed between the first application and sexual intercourse), and condoms used at every at every coital act
Outcomes	Incidence of HIV infection
Notes	The study was approved by the University of Ibadan, the Nigerian Institute of Medical Research, and the Protection of Human Subjects Committee, FHI (US). Participants signed written informed consent. Investigational products donated by Cellegy Pharmaceuticals. Funding source: USAID Study was prematurely terminated in August 2006. The DSMB recommended that the study be stopped because the HIV incidence was less than half the expected rate. It was estimated that the study needed to enrol approximately 1980 additional participants to identify the number of HIV infections that would offer the desired study power ClinicalTrials.gov number NCT00130078
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation sequence
Allocation concealment (selection bias)	Low risk	Sequentially‐numbered, sealed opaque envelopes were used to assign participants to a group
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both study gels were similar in appearance and packaging and trial staff (participants, field staff, monitors, statisticians, other staff) not aware of colours used to differentiate identical packed gels
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were not aware of the assignments
Incomplete outcome data (attrition bias) All outcomes	High risk	Follow‐up data were not available for more than 20% of women in both groups, because the trial was stopped early. Although the loss to follow‐up was not linked to treatment allocation, we judged the risk of attrition bias as high.
Selective reporting (reporting bias)	Low risk	HIV incidence was the outcome stated in the protocol and it has been reported
Other bias	Low risk	Trial stopped early for data‐dependent processes, but we do not think that this could have introduced bias to the study

*Study characteristics*
Methods	Setting: community clinics in Nigeria Trial design: double‐blind, randomised, placebo‐controlled trial. Sequentially‐numbered sealed opaque envelopes were used to assign participants to 1 of the 6 colour groups Trial duration: November 2004 to March 2007 Loss to follow‐up: 30% in both treatment groups Analysis performed based on ITT.
Participants	Number enrolled: 1644 women (820 allocated to CS, 824 to placebo) Mean age (SD): cellulose sulphate 23.4 (3.7) years, placebo 23.3 (3.5) years Inclusion criteria: Age 18 to 35 years HIV‐antibody negative, sexually active, no STI, not pregnant Exclusion criteria: Pregnant, HIV‐positive, participation in another microbicide trial, less than 3 months since their last pregnancy or desire to become pregnant in the next 12 months, and drug injection use
Interventions	Intervention arm: cellulose sulphate and condom. Each 3.5 mL application of 6% cellulose sulphate gel contained 231 mg of the active ingredient, sodium, and had a pH of 7.5 Control arm: placebo gel and condom. The gel contained HEC as gelling agent, no cell toxicity or anti‐HIV properties, and had a pH of 4.4 Both cellulose sulphate and placebo were administered in a 3.5 mL dose via a plastic single‐use applicator. The contents of the assigned gels of 1 full applicator were inserted into the vagina immediately prior to each act of sexual intercourse and re‐applied if intercourse did not take place throughout the 12 months Participants were instructed to use condoms for all acts of sexual intercourse regardless of gel use, not to douche after sex, not to use any other vaginal products and not to use the study gel in anal intercourse. Follow‐up visits were held every month for 12 months
Outcomes	Primary: incidence of HIV‐1 and HIV‐2 infections Secondary: incidence of STI (gonorrhoea or chlamydial infection)
Notes	The trial received ethical approval from the College of Medicine, University of Lagos; the University of Port Harcourt Teaching Hospital and FHI. Written informed consent was required and measures were put in place to ensure the process was adequate for illiterate participants. Informed consent was obtained Funding source: USAID Premature stoppage: an unplanned interim safety analysis was conducted in January 2007 after an apparent increased risk of HIV in the cellulose sulphate arm was found in a parallel trial (Van Damme 2008). The DSMB found no increased HIV risk in the CS arm of this study but recommended that the trial be stopped due to safety concerns arising from the results of the parallel trial (Van Damme 2008). Last follow‐up visit was in March 2007 ClinicalTrials.gov number NCT00120770
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Assumed to be computer‐generated (block randomisation with varying block sizes)
Allocation concealment (selection bias)	Low risk	Sequentially‐numbered sealed opaque envelopes were used to assign participants to 1 of the 6 colour groups
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Both gels were identical in packaging and labelling. 6 product label colours (3 for CS and 3 for placebo) were used to improve blinding. There was no indication that any unblinding occurred during the study. Both CS and placebo gels were identical in packaging and labelling
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were not aware of the assignments.
Incomplete outcome data (attrition bias) All outcomes	High risk	Loss to follow‐up was 30% due to early stopping of the trial. Although the loss to follow‐up was not linked to treatment allocation, we judged the risk of attrition bias as high.
Selective reporting (reporting bias)	Low risk	All outcomes were reported as stated in the protocol
Other bias	Low risk	Trial stopped early for data‐dependent processes, but we do not think that this could have introduced bias to the study other than attrition bias as indicated above

*Study characteristics*
Methods	Setting: urban and rural clinics South Africa, Uganda, Zimbabwe Trial design: a 5‐arm randomised placebo‐controlled trial Trial duration: September 200 to June 2011 Loss to follow‐up: intervention arm 7.8%, control arm 6.8%
Participants	Number enrolled: 5029 women (3 arms composed of 3019 allocated to oral interventions, 2010 allocated to gel use (1007 to 1% tenofovir, 1003 to placebo gel)) Mean age (SD): tenofovir gel 25.3 (5.2) years, placebo gel 25.3 (5.1) years Inclusion criteria: women aged 18 to 45 years, sexually active, HIV‐negative, not pregnant or breast‐feeding, using effective contraception and willing to use effective method for the next 24 months, able and willing to provide written informed consent and locator information, having normal haematologic and hepatic function,agreed not to join studies of drugs, medical devices or vaginal products for the next 24 months Exclusion criteria: women who reported any of the following: adverse reaction to any of the study product or latex, pathologic bone fracture not related to trauma, non‐therapeutic infection drug use in past 12 months, post‐exposure prophylaxis for HIV exposure in the past 6 months, being pregnant or had gynaecologic or genital procedures in past 42 days, participation in any other study of drugs, medical devices or vaginal products in past 30 days, breast‐feeding, using spermicide, interferon or interleukin therapy, medication with nephrotoxic potential,, significant uncontrolled active or chronic cardiovascular, renal, liver, haematologic, neurologic, immunologic disorders or infectious disease, laboratory abnormalities, intending to become pregnant in the next 24 months, planned to relocate away from site for more than 8 consecutive weeks, urinary tract infections, pelvic inflammatory diseases, STIs, grade 2 or higher exam pelvic finding
Interventions	Intervention arm: 1% tenofovir gel Control arm: placebo gel Participants were counselled to use products daily. 1 single‐use, prefilled applicator of both gels inserted intravaginally up to 1 hour before each episode of vaginal intercourse. Study gels were similar in appearance and were packaged in identical vaginal applicators
Outcomes	Primary: 1. Incidence of HIV‐1 infection, determined by any rapid HIV assay and confirmed by means on an enzyme‐linked immunosorbent assay and subsequent Western blotting 2. Safety (Grades 2, 3, and 4 clinical and laboratory adverse events) Secondary: 1. Adherence/behavioural 2. HIV‐1 drug resistance 3. Pharmacokinetic 4. Delayed seroconversion
Notes	This was a 5‐arm study that enrolled 5020 women and 2 study arms were assigned to receive vaginal 1% tenofovir gel and placebo gel. In November 2011, the DSMB recommended that the treatment with 1% tenofovir gel be discontinued for futility Funding source: National Institutes of Health The study was approved annually by the institutional review boards and ethics committees at all participating institutions. ClinicalTrials.gov number: NCT00705679
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer‐generated randomisation sequence
Allocation concealment (selection bias)	Low risk	Central allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Identical placebo
Blinding of outcome assessment (detection bias) All outcomes	Low risk	All end points were reviewed by an HIV end point adjudication committee, the members of which were unaware of the study group assignments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow ‐up was less than 10% with similar reasons for missing outcome data in both treatment groups
Selective reporting (reporting bias)	Low risk	All outcomes listed in protocol reported
Other bias	Low risk	None

*Study characteristics*
Methods	Setting: clinics in South Africa, Uganda, Zambia, and Tanzania Trial design: randomised, double‐blind parallel‐group trial, 3‐arm. Trial duration: September 2005 to August 2008 Loss to follow‐up: 2% PRO2000 1.7%, 0.5% PRO 2000 8.7%, placebo 10.6% ITT analyses
Participants	Number enrolled: 9385 women (2734 assigned to 2% PRO2000, 3326 to 0.5% PRO2000, 3325 to placebo) Age: ‐2% PRO 2000: 15 to 24 years (37%), 25 to 34 years (35%), 34 t0 44 years (19%), ≥ 45 years (8%) ‐0.5% PRO 2000: 15 to 24 years (38%), 25 to 34 years (32%), 35 to 44 years (19%), ≥ 45 years 8% ‐Placebo: 15 to 24 years (38%), 25 t0 34 years (33%) 35 to 44 years (21%), ≥ 45 years (8%) Inclusion criteria: 18 years or older, (> 16 years in Tanzania and Uganda), HIV‐1‐negative, willing to have regular speculum examinations and urinary pregnancy tests, willing to use gel as instructed, ,sexually active, willing to receive health education about condoms, able to give informed consent Exclusion criteria: unable or unwilling to provide a reliable method of contact, were likely to move out of the area within 12 months, were likely to have sex more than 14 times a week on a regular basis ( a regulatory requirement was that no more than 60 applicators were to be dispensed at every 4‐weekly visit), used spermicides regularly, were pregnant or within 6 weeks' post partum, had a severe clinical or laboratory abnormality, needed referral for assessment of a suspicious cervical lesion, had received treatment to the cervix or other gynaecological procedure within 30 days of enrolment, were allergic to latex, or were participating or had participated in another clinical trial that was likely to affect the primary efficacy end point within 30 days before enrolment
Interventions	Intervention arm: 1. 2% PRO 2000 and condom 2. 0.5% PRO 2000 gels and condom Control arm: HEC placebo gel and condom Gel was dispensed in identical applicators, in packs of 10 prefilled single‐dose applicators (maximum of 60 applicators in 10 packs per visit). Women were instructed to apply gel within 1 hour before sexual intercourse. They were counselled to use condoms during all sex acts and received unrestricted supplies of free condoms at the research clinics. Follow‐up at every 4‐week visit
Outcomes	Primary: 1. HIV‐1 infection 2. Safety Seconday: STIs (HSV N. gonorrhoea, C trachomatis)
Notes	The protocol was approved by local and national ethics committees, in all participating countries and in the UK. Authorisation was obtained from the national regulatory authority in all participating countries and the US Food and Drug Administration. Participants provided written informed consent or witnessed thumbprint. Enrolment on protocol; 9404 Funding source: UK Department for International Development, UK Medical Research Council, European and Developing Countries Clinical Trials Partnership, IPM and Endo Pharmaceuticals Solutions The 2% PRO 2000 gel was discontinued early (14 February 2008) after a review by the DSMB, which advised there was little chance of the 2% gel showing benefit, given the planned sample size and postulated effect size. However, the conditional power for significant benefit from the 0.5% PRO 2000 dose (based on the original sample size assumptions) was sufficiently high to warrant trial continuation ClinicalTrials.gov number, NCT00153777
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence generated with a computerised random‐number generator
Allocation concealment (selection bias)	Low risk	Central allocation (pharmacy controlled)
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Investigators and participants were masked to group assignment. Site pharmacists dispensed gel in identical applicators on the basis of the trial number and the assigned study product codes on the clinic randomisation list. Only statisticians responsible for the preparation of the DSMB reports and essential manufacturing and distribution staff had access to the list matching study product codes to gel. No other site personnel had access to the list
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were not aware of the assignments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Less that 20% with similar reasons for missing date in each treatment group
Selective reporting (reporting bias)	Low risk	All outcomes listed in the protocol are reported
Other bias	Low risk	Funding by a pharmaceutical company (Endo Pharmaceuticals Solutions). Trial stopped early for data‐dependent processes, but we do not think that this could have introduced bias to the study

*Study characteristics*
Methods	Setting: Community clinics Ghana Trial design: double‐blind, randomised, placebo‐controlled trial. Trial duration: March 2004 to February 2006 Loss to follow‐up: SAVVY arm 13.3%, placebo arm 15.6% ITT analyses performed
Participants	Number enrolled: 2142 women (1073 allocated to SAVVY, 1069 to placebo) Mean age (SD): SAVVY 22.7 (3.6), placebo 22.7 (3.6) Inclusion criteria: Aged 18 to 35 years, HIV‐antibody‐negative, non‐pregnant, agreed to use the study gel as directed and follow study participation and report self‐medication with antibiotics during study procedures, avoided use of spermicides or other vaginal contraceptives or lubricants during the study Exclusion criteria: Intended to become pregnant, had a history of latex allergy, were injecting drug users or had gynaecological conditions that could affect the safety or effectiveness of the study gel
Interventions	Intervention arm: 1% C31G (SAVVY) and condom Control arm: HEC (placebo) as the gelling agent and sorbic acid as preservative and condom Both gels were similar in appearance (clear, viscous), dispensed in 3.5 mL doses with applicator and had a pH of 4.4. The gels were inserted vaginally before each act of sexual intercourse (a second dose was inserted if more than 1 hour had elapsed between the first application and sexual intercourse) and condom use was advised for all sexual contacts with all partners Follow‐up visits took place monthly for 12 months
Outcomes	Incidence of HIV‐1 and HIV‐2, measured by detecting antibodies in ORT (Rapid HIV‐1/2 test) and confirmed by ELISA, Western blot or both
Notes	The study protocol was approved by the Committee on Human Research, Publications and Ethics, School of Medical Sciences, University of Science and Technology, Kumasi, Ghana; Noguchi Memorial Institute for Medical Research IRB, University of Ghana, Legon, Ghana; and the Protection of Human Subjects Committee FHI, US. Written informed consent was required. Investigational products donated by Cellegy Pharmaceuticals Funding source: USAID The study was stopped prematurely (November 2005) following recommendations of DSMB because the HIV incidence among enrolled participants was substantially lower than expected. The study statistician estimated that approximately 3500 additional participants (beyond the 2124 planned sample size) would be needed to achieve the required number of HIV infections ClinicalTrials.gov number NCT00129532
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Sequence generated using a computer random‐number generator
Allocation concealment (selection bias)	Low risk	Sequentially‐numbered sealed opaque envelopes were used
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The gels were similar in appearance
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were not aware of the assignments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was less than 20%, but was not linked to treatment allocation
Selective reporting (reporting bias)	Low risk	Incidence of HIV‐1 or HIV‐2 infection were the main outcomes stated in the protocol. The reported outcome is HIV without specifying the type, but we do not regard this as selective reporting
Other bias	Low risk	Trial stopped early for data‐dependent processes, but we do not think that this could have introduced bias to the study other than attrition bias mentioned above

*Study characteristics*
Methods	Setting: local health clinics, malls, churches, taxi ranks, and other community venues in South Africa Trial design: randomised, 2‐arm, double‐blind, placebo‐controlled trial Trial duration: March 2004 to March 2007 Loss to follow‐up: Carraguard 7.1%, placebo 6.7% Follow‐up duration: every 3 months for up to 2 years (a minimum of 9 months and maximum of 24 months) A sub‐study assessed the association of HR‐HPV in women at study end and Carraguard use. Participants entered the HR‐HPV study in October 2006, 6 months before the study end
Participants	Number enrolled: 6202 women (3103 allocated to Carraguard gel, 3099 to placebo) Inclusion criteria: aged 16 years and older, sexually active, HIV‐negative, sexually active, willing to give informed consent and provide locator information to study staff, comply with all aspects of the study protocol, citizen or permanent resident of South Africa, no use of any vaginal products except those prescribed or approved by the study clinician Exclusion criteria: pregnant or a desire to become pregnant in the next 2 years at the time of screening, within 4 weeks of last pregnancy outcome at time of enrolment, Pap smear at screening grades as carcinoma, injected illicit drugs in the 12 months before screening or were participating in any other clinical trial or HIV prevention study
Interventions	Intervention arm: Carraguard gel and condom Control arm: methylcellulose (placebo) gel and condom Both gels were packaged in single‐use microlax‐type applicators, each filled with 7 mL of gel to dispense approximately 4 mL. Appearance and frequency of administration of the gels were similar. Participants were instructed to vaginally insert the study gel up to 1 hour before every act of vaginal intercourse, use condoms together with the gel and not to insert any other vaginal products (apart from the medication prescribed by study clinicians)
Outcomes	Primary: HIV infection Secondary: 1. Safety 2. Incidence of STIs
Notes	The study was reviewed and approved by the Population Council Institutional Review Board, NY, USA, the University of KwaZulu‐Natal Biomedical Research Ethics Committee for the Medical Research Council; the University of Limpopo, Medunsa Campus, Research, Ethics and Publications Committee; the University of Cape Town Research Ethics Committee; and the South African Medicines Control Council, and was undertaken in accordance with the declaration of Helsinki. Participants gave written informed consent Funding source: US Agency for International Development, Bill and Melinda Gates Foundation ClinicalTrials.gov number NCT00213083
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	A computer pseudo‐random‐number generator was used
Allocation concealment (selection bias)	Low risk	There was central allocation
Blinding of participants and personnel (performance bias) All outcomes	Low risk	The gels were similar in appearance and packaging. To maintain blinding, only 2 non‐clinical staff members at the Population Council, who were not involved in daily procedures, data cleaning or analysis, had access to records showing which barcodes corresponded to Carraguard or placebo
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Outcome assessors were not aware of the assignments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up was 7.1% in the intervention group and 6.7% in the control group
Selective reporting (reporting bias)	Low risk	All outcomes reported as per protocol
Other bias	Low risk	No other potential sources of bias

*Study characteristics*
Methods	Setting: community clinics in South Africa, Uganda, Benin, and India Trial design: randomised, 2‐arm, double‐blind, placebo‐controlled trial Trial duration: July 2005 to March 2007 Loss to follow‐up: cellulose sulphate 10.7%, placebo 9.0% Follow‐up: 12 monthly follow‐up visits
Participants	Number enrolled: 1428 women (717 allocated to cellulose sulphate, 708 to placebo) Median age: cellulose sulphate 28 years, placebo 29 years Inclusion criteria: aged at least 18 years, negative HIV‐antibody test, sexually active, agreed to come to the clinic for 12 monthly follow‐up visits Exclusion criteria: allergy to latex or spermicides, pregnancy or wanted to become pregnant in the next year, intravenous drug users, participation in another trial, had already been screened for this trial, or had any condition that made participation unsafe or that the investigator believed could complicate interpretation of the data
Interventions	Intervention arm: 6% cellulose sulphate gel and condom. CS had a pH of 7.5 Control arm: placebo gel and condom. The placebo gel had a pH of 4.4 The gels were identical in appearance, delivered in 3.5 mL single‐use opaque applicators and frequency of administration was similar. The gels were to be inserted vaginally within 1 hour before each act of vaginal intercourse, during a period of 1 year
Outcomes	incidence of HIV‐1 and HIV‐2
Notes	The study was approved by the Institutional Review Board of the Eastern Virginia Medical School and by local ethical committees at the sites where women were recruited. Written informed consent was required Funding source: USAID and the Bill & Melinda Gates Foundation The trial was stopped prematurely after the Independent Data Monitoring Committee determined that CS gel may have increased the risk of HIV infection as compared with placebo. In January 2007, sites were instructed to withdraw the product as soon as possible. Last follow‐up visit was in March 2007 ClinicalTrials.gov number NCT00153777 3 participants had positive PCR test for RNA at enrolment and were excluded (1 in South Africa 1 in Uganda1 in Benin)
*Risk of bias*
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Computer random‐number generator was used
Allocation concealment (selection bias)	Low risk	Sequentially‐numbered, sealed opaque envelopes were used, that were kept in a secure office at each site
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Participants and personnel blinded
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blind outcome assessment. Outcome assessors were not aware of the assignments
Incomplete outcome data (attrition bias) All outcomes	Low risk	Loss to follow‐up comprised 10.7% in the intervention group and 9.0% in the control group
Selective reporting (reporting bias)	Low risk	HIV‐1 and HIV‐2 are listed as primary outcomes and, although the results reported do not specify the type of HIV, we do not think there is selective reporting
Other bias	Low risk	Trial stopped early for data‐dependent processes, but we do not think that this could have introduced bias to the study

Study	Reason for exclusion
Artz 2005	The microbicide used in the study was nonoxynol‐9, which is not included in this review. This microbicide has been covered in other Cochrane Reviews. See Wilkinson 2002a and Wilkinson 2002b
Barbone 1990	The microbicide used in the study was nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Cutler 1997	The microbicide used in the study was nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Ettiègne‐Traoré 1997	The microbicide used in the study was nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Kreiss 1992	The microbicide used in the study was nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Louv 1998	The microbicide used in the study was nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Niruthisard 1992	The microbicide used in the study was nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Rendon 1980	The microbicide used in the study was nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Roddy 1988	The microbicide used in the study was Nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Rosenberg 1987a	The microbicide used in the study was nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Rosenberg 1987b	The microbicide used in the study was nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Sacks 1990	The microbicide used in the study was nonoxynol‐9, which is not included in this review. See Wilkinson 2002a and Wilkinson 2002b
Van der Straten 2007	The study included HIV‐positive women.
Zaneveld 2002	This is an in vitro and animal study

PERMALINK

Topical microbicides for preventing sexually transmitted infections

Jael Obiero

Paul Ogongo

Peter G Mwethera

Charles S Wiysonge

Abstract

Background

Objectives

Search methods

Selection criteria

Data collection and analysis

Main results

Authors' conclusions

Plain language summary

Summary of findings

Background

Description of the condition

Description of the intervention

How the intervention might work

Why it is important to do this review

Objectives

Methods

Criteria for considering studies for this review

Types of studies

Types of participants

Types of interventions

Types of outcome measures

Primary outcomes

Secondary outcomes

Search methods for identification of studies

Electronic searches

Searching other resources

Conference proceedings

Researchers, organisations and pharmaceutical companies

Reference lists

Data collection and analysis

Selection of studies

Data extraction and management

Assessment of risk of bias in included studies

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Assessment of heterogeneity

Assessment of reporting biases

Data synthesis

Subgroup analysis and investigation of heterogeneity

Sensitivity analysis

Summary of findings and assessment of the certainty of the evidence

Results

Description of studies

Results of the search

1.

1. Summary table with the description of included studies.

Included studies

Study design

Population

Intervention

Comparators

Outcomes

Length of follow up

Excluded studies

Risk of bias in included studies

Allocation

Blinding

Incomplete outcome data

Selective reporting

Other potential sources of bias

Summary of risk of bias

2.

3.

Effects of interventions

Summary of findings 1. Dapivirine vaginal microbicide for preventing sexually transmitted infections.

Summary of findings 2. Tenofovir vaginal microbicide for preventing sexually transmitted infections.

Summary of findings 3. Cellulose sulphate vaginal microbicide for preventing sexually transmitted infections.

Overall quality of the body of evidence: Summary of findings table

1. Primary outcomes

1.1.1. HIV infection

1.1. Analysis.

1.1.2. Herpes simplex virus infection