Vaginal Microbicide Trials Research Articles

Hidden heterogeneity: Uncovering patterns of adherence in microbicide trials for HIV prevention.

BackgroundInterpretation of clinical trial results testing vaginal microbicide gels for HIV prevention depends on participant adherence. Prior to the era of antiretrovirals, microbicide trials collected adherence data via self-report, and trials typically reported trial population adherence as overall averages in primary results manuscripts. This study first sought to determine if different patterns of adherence from three trials of vaginal microbicide gels could be identified, using self-reported data and if so, how those patterns compare across trials. The second objective was to explore which individual-level factors were associated with different adherence patterns.MethodsData from the following three clinical trials of vaginal microbicides were used for this study: HIV Prevention Trials Network (HPTN) 035 testing PRO 2000 and Buffergel, the Microbicides Development Programme (MDP) 301 testing PRO 2000, and the Population Council’s Carraguard study, testing Carraguard gel. Latent Class Analysis (LCA) was used to identify longitudinal patterns of adherence using self-reported data about gel use. Multinomial multivariable logistic regression was used to estimate relative risk-ratios for factors which were independently associated with different latent adherence trajectories within each trial, and compared across trials.ResultsIncluded in this analysis are 2,282 women from HPTN 035 (age 17–56 years), 6238 women from MDP 301 (age 16–75 years), and 6039 women from Carraguard (age 16–73 years). Using LCA, 3–4 different patterns of gel adherence were identified in each trial; these patterns were similar across the trials. Factors associated with adherence patterns were identified in all trials. Older age was associated with the adherence trajectory that consistently reported gel use in three trials. Participant-reported negative reaction of partners to the gel was associated with trajectories that reported less consistent adherence in two trials. A greater number of baseline-reported sex partners or sex acts was associated with trajectories which reported less consistent adherence in some trials. Trial site location was associated with membership of trajectories in all trials.ConclusionLCA was able to identify patterns of microbicide gel adherence in clinical trials that used self-reported data. Key factors associated with patterns of adherence in this study were participant age, clinical trial site location, and partner reaction to the study gel. These findings, in particular, age and perceived partner reaction to the method, are consistent with results from other clinical trials and programmatic rollout of biomedical HIV prevention methods for women in Africa. This study contributes to the body of evidence that women need more support to navigate power dynamics within their relationships with men so that they can successfully use HIV prevention methods.

Topical microbicides for preventing sexually transmitted infections.

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

Women design their own vaginal microbicide trial: Suggestions on how to improve adherence from former participants of HIV prevention trials.

Low adherence in vaginal microbicide clinical trials for HIV prevention has impeded interpretation of trial results and hindered evaluation of potentially efficacious HIV prevention gels. Understanding the underlying reasons why women join trials and their barriers to product use can support identification of ways to improve adherence and its reporting. Eight focus group discussion workshops were conducted with 46 former microbicide trial participants in Durban, South Africa and Mwanza, Tanzania. Participants provided feedback on why women join trials, the barriers to using study gel and reporting adherence accurately, and how clinical trial design can be improved to support better adherence and its reporting. Women join microbicide trials for a number of important reasons such as healthcare and financial reimbursement. Fear of adverse effects from the investigational product was the most important reason why participants reported not using the gel. The key reason for inaccurate reporting of gel use was fear of removal from the trial. Participants made concrete suggestions for improving microbicide trial design such as applicator use testing and real time feedback, improving education to participants about how trials answer their research questions, and improving transparency and clarity about study procedures. Participants also gave feedback on an innovative trial design with a non-randomised arm. Identifying HIV prevention products for women requires better understanding of the lives of women asked to join these trials, and application of that understanding to microbicide trial design. This study has demonstrated that participants and research teams can work collaboratively to design clinical trials that meet needs of both the research and of participants.

Testing the waters: Ethical considerations for including PrEP in a phase IIb HIV vaccine efficacy trial.

The field of HIV prevention research has recently experienced some mixed results in efficacy trials of pre-exposure prophylaxis, vaginal microbicides, and HIV vaccines. While there have been positive trial results in some studies, in the near term, no single method will be sufficient to quell the epidemic. Improved HIV prevention methods, choices among methods, and coverage for all at-risk populations will be needed. The emergence of partially effective prevention methods that are not uniformly available raises complex ethical and scientific questions regarding the design of ongoing prevention trials. We present here an ethical analysis regarding inclusion of pre-exposure prophylaxis in an ongoing phase IIb vaccine efficacy trial, HVTN 505. This is the first large vaccine efficacy trial to address the issue of pre-exposure prophylaxis, and the decisions made by the protocol team were informed by extensive stakeholder consultations. The key ethical concerns are analyzed here, and the process of stakeholder engagement and decision-making described. This discussion and analysis will be useful as current and future research teams grapple with ethical and scientific study design questions emerging with the rapidly expanding evidence base for HIV prevention.

The Need for Multi-product Technologies for Women Participating in Vaginal Microbicide Trials

AIDS Research and Human RetrovirusesVol. 30, No. S1 MPT DevelopmentThe Need for Multi-product Technologies for Women Participating in Vaginal Microbicide TrialsDuduzile E. Ndwandwe, Nathlee S. Abbai, Handan Wand, and Gita RamjeeDuduzile E. NdwandweSouth African Medical Research Council, HIV Prevention Research Unit, Durban, South AfricaSearch for more papers by this author, Nathlee S. AbbaiSouth African Medical Research Council, HIV Prevention Research Unit, Durban, South AfricaSearch for more papers by this author, Handan WandUniversity of New South Wales, The Kirby Institute, Sydney, AustraliaSearch for more papers by this author, and Gita RamjeeSouth African Medical Research Council, HIV Prevention Research Unit, Durban, South AfricaSearch for more papers by this authorPublished Online:30 Oct 2014https://doi.org/10.1089/aid.2014.5281.abstractAboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail View article"The Need for Multi-product Technologies for Women Participating in Vaginal Microbicide Trials." AIDS Research and Human Retroviruses, 30(S1), pp. A140–A141FiguresReferencesRelatedDetails Volume 30Issue S1Oct 2014 InformationCopyright 2014, Mary Ann Liebert, Inc.To cite this article:Duduzile E. Ndwandwe, Nathlee S. Abbai, Handan Wand, and Gita Ramjee.The Need for Multi-product Technologies for Women Participating in Vaginal Microbicide Trials.AIDS Research and Human Retroviruses.Oct 2014.A140-A141.http://doi.org/10.1089/aid.2014.5281.abstractPublished in Volume: 30 Issue S1: October 30, 2014PDF download

Contraceptive Preference among HIV High Risk Women Pre-screened for a Phase III Vaginal Microbicide Trial in South-Western Uganda

Background: Womens contraceptive choices vary according to the type of relationships they have and other aspects of their life. We describe the preference of modern contraceptive methods among HIV high risk women screened to participate in a Phase III vaginal microbicide trial. Methods: Medical Research Council/Uganda Virus Research Institute Uganda Research Unit on AIDS in collaboration with International Partnership for Microbicides (IPM) is evaluating safety and efficacy of a dapivirine vaginal ring among healthy HIV negative women in a multicentre Phase III trial (The Ring Study). One of the study eligibility criteria is being on a stable form of contraception in order to reduce the pregnancy rate. As part of the screening process women are identified from townships and fishing communities within 50 km from the centre. Data on use of modern contraception methods (Pills Injectables Implants IUCDs Surgical) are collected and confirmed by a contraceptive card or presence of an implant or IUCD strings. Women who are willing are provided by the research centre with contraception of choice (pills injectables) or referred to a provider (Implants IUCDs Surgical). The proportion of women per method used was determined. Results: A total of 489 women with a mean age of 28 years were pre-screened (age range 18 to 44 years). Most (306 63%) were already using contraception: 55% were on Injectables followed by Implants (28%) IUCDs (8%) Pills (7%) and only 2% had undergone a Surgical method. Of the women who were not on any method 106 (58%) accepted Injectables 40 (22%) preferred Implants 33 (18%) oral Pills and 4 (2%) chose IUCDs. Conclusions: There is high contraceptive use among HIV high risk women and the majority prefer Injectables. This is encouraging and will hopefully reduce discontinuation of volunteers from the trial due to pregnancy.

Sexually Transmitted Infections in Women Participating in a Biomedical Intervention Trial in Durban: Prevalence, Coinfections, and Risk Factors.

Background. Sexually transmitted infections (STIs) continue to be a significant public health problem especially among women of reproductive age in Africa. Methods. A total of 2236 women that had enrolled in the MDP301 vaginal microbicide trial were tested for the presence of Chlamydia trachomatis (CT), Neisseria gonorrhea (NG), Treponema pallidum, and Trichomonas vaginalis (TV). Results. CT was identified as the most prevalent STI (11%) followed by TV (10%), NG, and Syphilis (3%). The highest prevalence of coinfection was reported between T. pallidum and TV (19.67%, P = 0.004), followed by CT and TV (13.52%, P ≤ 0.001). Risk factors that were significantly associated with STI acquisition were women of 23 years of age or younger (HR: 1.50, 95% CI 1.17, 1.93), baseline STI with CT (HR: 1.77, 95% CI 1.32, 2.35), TV (HR: 1.58, 95% CI, 1.20, 2.10), and T. pallidum (HR: 5.13, 95% CI 3.65, 7.22), and a low education level (HR: 1.30, 95% CI 1.02, 1.66). Conclusion. Young women with lower education and a history of STIs are at high risk of multiple STIs. Prevention programs should consider target approach to STI prevention among young women. This trial is registered with ISRCTN64716212.

Pregnancy Incidence and Risk Factors among Women Participating in Vaginal Microbicide Trials for HIV Prevention: Systematic Review and Meta-Analysis

IntroductionPregnancy is contraindicated in vaginal microbicide trials for the prevention of HIV infection in women due to the unknown maternal and fetal safety of the microbicides. Women who become pregnant are taken off the microbicide during pregnancy period but this result in reduction of the power of the trials. Strategies to reduce the pregnancy rates require an understanding of the incidence and associated risk factors of pregnancy in microbicide trials. This systematic review estimates the overall incidence rate of pregnancy in microbicide trials and describes the associated risk factors.MethodsA comprehensive literature search was carried out to identify eligible studies from electronic databases and other sources. Two review authors independently selected studies and extracted relevant data from included studies. Meta-analysis of incidence rates of pregnancy was carried out and risk factors of pregnancy were reported narratively.ResultsFifteen studies reporting data from 10 microbicide trials (N=27,384 participants) were included. A total of 4,107 participants (15.0%) fell pregnant and a meta-analysis of incidence rates of pregnancy from 8 microbicide trials (N=25,551) yielded an overall incidence rate of 23.37 (95%CI: 17.78 to 28.96) pregnancies per 100 woman-years. However, significant heterogeneity was detected. Hormonal injectable, intra-uterine device (IUD) or implants or sterilization, older age, more years of education and condom use were associated with lower pregnancy. On the other hand, living with a man, history of pregnancy, self and partner desire for future baby, oral contraceptive use, increased number of unprotected sexual acts and inconsistent use of condoms were associated with higher pregnancy.ConclusionsThe incidence rate of pregnancy in microbicide trials is high and strategies for its reduction are urgently required in order to improve the sample size and power of these trials.

Methodological Lessons from Clinical Trials and the Future of Microbicide Research

Interpretation of microbicide trial results has been compromised by challenges to accurate measurement of product adherence and sexual risk behaviors. This article provides an evaluation of the methods used to measure adherence and other sensitive behaviors relevant to assessment of product safety and effectiveness in recently completed trials of vaginal and rectal microbicides. We review the strengths and limitations of existing and novel behavioral measurement strategies and provide recommendations for future trial design with the goal of facilitating the development and identification of safe and effective microbicides for HIV prevention.

Sexual Behavior Before and After Pregnancy Detection in Four Microbicide Trials

Vaginal microbicide gel trials for HIV prevention may require withdrawal of study product when a woman becomes pregnant. We assessed the potential impact of withdrawals in four trials by comparing self-reported sexual behavior pre- and post-pregnancy detection: (1) behavior in the month prior to positive pregnancy test versus behavior reported at the subsequent monthly visit; (2) behavior changes according to pregnancy status at the subsequent visit (continuing pregnancy versus not); (3) average sexual behaviors reported for all months prior to pregnancy detection versus all months after pregnancy was no longer detected; and (4) behavior changes among participants never testing positive for pregnancy. Pregnancy detection was associated with immediate reductions in self-reported numbers of partners and sex acts. The proportion of acts in which study gel was used following a negative pregnancy test did not return to pre-pregnancy levels. Pregnancies complicate the conduct and interpretation of vaginal microbicide trials when product must be withdrawn.

HIV Prevalence and Incidence among Sexually Active Females in Two Districts of South Africa to Determine Microbicide Trial Feasibility

BackgroundThe suitability of populations of sexually active women in Madibeng (North-West Province) and Mbekweni (Western Cape), South Africa, for a Phase III vaginal microbicide trial was evaluated.MethodsSexually active women 18–35 years not known to be HIV-positive or pregnant were tested cross-sectionally to determine HIV and pregnancy prevalence (798 in Madibeng and 800 in Mbekweni). Out of these, 299 non-pregnant, HIV-negative women were subsequently enrolled at each clinical research center in a 12-month cohort study with quarterly study visits.ResultsHIV prevalence was 24% in Madibeng and 22% in Mbekweni. HIV incidence rates based on seroconversions over 12 months were 6.0/100 person-years (PY) (95% CI 3.0, 9.0) in Madibeng and 4.5/100 PY (95% CI 1.8, 7.1) in Mbekweni and those estimated by cross-sectional BED testing were 7.1/100 PY (95% CI 2.8, 11.3) in Madibeng and 5.8/100 PY (95% CI 2.0, 9.6) in Mbekweni. The 12-month pregnancy incidence rates were 4.8/100 PY (95% CI 2.2, 7.5) in Madibeng and 7.0/100 PY (95% CI 3.7, 10.3) in Mbekweni; rates decreased over time in both districts. Genital symptoms were reported very frequently, with an incidence of 46.8/100 PY (95% CI 38.5, 55.2) in Madibeng and 21.5/100 PY (95% CI 15.8, 27.3) in Mbekweni. Almost all (>99%) participants said that they would be willing to participate in a microbicide trial.ConclusionThese populations might be suitable for Phase III microbicide trials provided that HIV incidence rates over time remain sufficiently high to support endpoint-driven trials.

HPV Vaccination to Prevent HIV Infection: Time for Randomized Controlled Trials

Despite many years of rigorous evaluation of a variety of interventions, HIV incidence rates in parts of Africa remain unacceptably high. A recent review identified 37 randomized controlled trials testing interventions to reduce HIV incidence.1 Except for 3 randomized controlled trials of male circumcision2‐4 and 1 trial of syndromic treatment of sexually transmitted diseases,5 and, recently, 1 trial of a vaginal microbicide,6 no significant reductions in HIV incidence were observed. In some trials of vaginal microbicides, trial participants in the active treatment arm actually had increased HIV incidence rates.7 Trials with candidate vaccines have been equally disappointing.8 A recently completed trial of a prime-boost strategy conducted in Thailand showed statistically significant, but limited, protection against HIV.9 Nevertheless, even vaccine optimists think that a preventive HIV vaccine is many years away. Sexually transmitted infections (STIs) were identified as important cofactors for HIV transmission early in the epidemic.10,11 Many prospective observational studies showed that the presence of ulcerative and nonulcerative STIs increased the likelihood of HIV transmission.10,11 Several interventions were based on this observation including mass treatment with antibiotics,12 improved syndromic management of STIs,5,13 and herpes simplex virus (HSV)-2 suppressive treatment.14 Null findings of these interventions should be interpreted with caution. Failure to show an effect does not necessarily mean that the STI is not causally associated with HIV. As Barnabas and Wasserheit highlight,15 the stage of the HIV epidemic in which an intervention trial is conducted may significantly influence observed efficacy. Another possible reason for the failure of these trials to demonstrate efficacy is that the intervention may not have adequately controlled the STI or its biologic effects.

Predictors of pregnancy in microbicide trials

Background High pregnancy rates undermine the conduct and interpretation of HIV prevention trials. We performed this analysis to identify baseline participant characteristics associated with increased risk of pregnancy in recent vaginal microbicide trials. Study Design We analyzed the data from four recently completed Phase III trials of candidate microbicides for prevention of HIV infection. Cox proportional hazard models, stratified by site nested within study, were used to determine the baseline factors that predict pregnancy. Six thousand seven hundred forty-eight women contributed data for this analysis. Results Pregnancies were detected in a total of 1826 (27.1%) women. The hazard of pregnancy was higher for women who had a history of pregnancy, were living with a man or reported more sexual acts not protected by condoms in the week prior to enrollment. The risk of pregnancy was lower in older participants; in women with more years of education; in women who reported more sexual partners at baseline interview; in women who reported using intrauterine contraception, implants, sterilization or injectables and in women who reported use of a condom during their last act of vaginal intercourse. Conclusions Our data suggest that current use or acceptance of intrauterine contraception, implants, sterilization or injectables is the most effective approach to reduce pregnancy rates and might be a useful eligibility criterion in future HIV prevention trials.

HIV prevention – where now? Background and introduction

HIV prevention – where now? Background and introduction

How informed is consent in vulnerable populations? Experience using a continuous consent process during the MDP301 vaginal microbicide trial in Mwanza, Tanzania

BackgroundHIV prevention trials conducted among disadvantaged vulnerable at-risk populations in developing countries present unique ethical dilemmas. A key concern in bioethics is the validity of informed consent for trial participation obtained from research subjects in such settings. The purpose of this study was to investigate the effectiveness of a continuous informed consent process adopted during the MDP301 phase III vaginal microbicide trial in Mwanza, Tanzania.MethodsA total of 1146 women at increased risk of HIV acquisition working as alcohol and food vendors or in bars, restaurants, hotels and guesthouses have been recruited into the MDP301 phase III efficacy and safety trial in Mwanza. During preparations for the trial, participatory community research methods were used to develop a locally-appropriate pictorial flipchart in order to convey key messages about the trial to potential participants. Pre-recorded audio tapes were also developed to facilitate understanding and compliance with gel-use instructions. A comprehension checklist is administered by clinical staff to all participants at screening, enrolment, 12, 24, 40 and 50 week follow-up visits during the trial. To investigate women's perceptions and experiences of the trial, including how well participants internalize and retain key messages provided through a continuous informed consent process, a random sub-sample of 102 women were invited to participate in in-depth interviews (IDIs) conducted immediately after their 4, 24 and 52 week follow-up visits.Results99 women completed interviews at 4-weeks, 83 at 24-weeks, and 74 at 52 weeks (a total of 256 interviews). In all interviews there was evidence of good comprehension and retention of key trial messages including that the gel is not currently know to be effective against HIV; that this is the key reason for conducting the trial; and that women should stop using gel in the event of pregnancy.ConclusionsProviding information to trial participants in a focussed, locally-appropriate manner, using methods developed in consultation with the community, and within a continuous informed-consent framework resulted in high levels of comprehension and message retention in this setting. This approach may represent a model for researchers conducting HIV prevention trials among other vulnerable populations in resource-poor settings.Trial registrationCurrent Controlled Trials ISRCTN64716212

Heterosexual Anal Intercourse Has the Potential to Cause a Significant Loss of Power in Vaginal Microbicide Effectiveness Studies

Vaginal microbicides are topical products being studied for their potential to reduce the risk of penile-vaginal human immunodeficiency virus (HIV) transmission. Because the sexual acts that lead to infection in effectiveness trials are unobserved, identification of an effective vaginal product may be unwittingly circumvented if adherence to product is poor or if participants acquire infection through nonvaginal routes of exposure. To model the impact of receptive anal intercourse (RAI) on the measured effectiveness of vaginal microbicides and the power of clinical trials. A mathematical model is proposed for assessing effectiveness and power as a function of microbicide efficacy, the probability that the microbicide is used for vaginal acts of intercourse with exposure to HIV, the probability that an act of intercourse with exposure to HIV is rectal, and the ratio of transmission probabilities for rectal versus vaginal intercourse. The model demonstrated that a moderate frequency of RAI among vaginal microbicide trial participants is expected to substantially reduce study power; if 1 in 50 acts are rectal, and if the rectal transmission probability is 20-fold greater than that of vaginal intercourse, then power to detect an otherwise 40% effective product with a 160 endpoint trial is reduced from 90% to 56%. If 1 in 25 acts are rectal then power is only 34%. Accurate reports of adherence and rates of RAI are difficult to obtain, and precise HIV transmission probabilities are unknown. Hence the true impact of unprotected RAI on vaginal microbicide trials cannot be quantified with certainty. Counseling against RAI should be provided to all vaginal microbicide trial participants irrespective of sexual history. Collection of accurate behavioral data on RAI during trials is essential to understand whether failure to demonstrate an effect might be attributed to RAI.

Are women who work in bars, guesthouses and similar facilities a suitable study population for vaginal microbicide trials in Africa?

BackgroundA feasibility study was conducted to investigate whether an occupational at-risk cohort of women in Mwanza, Tanzania are a suitable study population for future phase III vaginal microbicide trials.Methodology/Principal Findings1573 women aged 16–54 y working in traditional and modern bars, restaurants, hotels, guesthouses or as local food-handlers were enrolled at community-based reproductive health clinics, provided specimens for HIV/STI and pregnancy testing, and asked to attend three-monthly clinical follow-up visits for 12-months. HIV positive and negative women were eligible to enter the feasibility study and to receive free reproductive health services at any time. HIV prevalence at baseline was 26.5% (417/1573). HIV incidence among 1156 sero-negative women attending at baseline was 2.9/100PYs. Among 1020 HIV sero-negative, non-pregnant women, HIV incidence was 2.0/100PYs, HSV-2 incidence 12.7/100PYs and pregnancy rate 17.8/100PYs. Retention at three-months was 76.3% (778/1020). Among 771 HIV sero-negative, non-pregnant women attending at three-months, subsequent follow-up at 6, 9 and 12-months was 83.7%, 79.6%, and 72.1% respectively. Older women, those who had not moved home or changed their place of work in the last year, and women working in traditional bars or as local food handlers had the highest re-attendance.Conclusions/SignificanceWomen working in food outlets and recreational facilities in Tanzania and other parts of Africa may be a suitable study population for microbicide and other HIV prevention trials. Effective locally-appropriate strategies to address high pregnancy rates and early losses to follow-up are essential to minimise risk to clinical trials in these settings.

Efficacy dilution in randomized placebo-controlled vaginal microbicide trials.

BackgroundTo date different vaginal gel microbicides have been evaluated in phase 2b/3 trials, but none have demonstrated effectiveness for preventing HIV infection. Failure to demonstrate effectiveness however does not necessarily indicate that a product is truly inefficacious, as several sources of efficacy dilution may compromise our ability to identify products that may have been truly efficacious.MethodsFor four individual sources of dilution, we describe the dilution mechanisms and quantify the expected effectiveness. An overall expected effectiveness that combines all sources of dilution in a trial is derived as well.ResultsUnder conditions that have been observed in recent microbicide trials, the overall expected effectiveness assuming an active gel with true efficacy of 50% and 75% are in the range of [16%; 33%] and [28%; 50%], respectively, when considering the four major sources of dilution. In contrast the diluting effect due to adherence alone (assuming an adherence of 80%) leads to higher expected effectiveness, 40% and 60% assuming an active gel with true efficacy of 50% and 75%, respectively. Individual sources of dilution may demonstrate a small effect when evaluated independently, but the overall dilution effect in a trial with several sources of dilution can be quite substantial.ConclusionCurrently planned phase 2b/3 microbicide trials of new candidate vaginal microbicides are not immune from these shortcomings. A good understanding of dilution effects is necessary to properly interpret microbicide trial results and to identify products worthy of further development and evaluation. Greater attention should be devoted to reducing and assessing the impact of efficacy dilution and to carefully selecting the effect size in the design of future trials.

The safety of candidate vaginal microbicides since nonoxynol-9: a systematic review of published studies

To gain a greater understanding of published safety data for candidate vaginal microbicides. A systematic review of human safety trials of candidate vaginal microbicides - agents designed to protect women against HIV and other sexually transmitted infections. Trials were published in peer-reviewed journals, and publication cut-off was August week 4, 2008. Trials of nonoxynol-9 were excluded, as were trials without a control group, trials that enrolled only male participants or reported on the investigation of a product for the treatment of a genital infection. Twenty-one trials of 11 products, involving 1465 women, satisfied review criteria. Most trials reported on genital epithelial findings and urogenital symptoms and a number reported a range of other local and systemic toxicity endpoints. Trials were generally of short duration (2 weeks or less) with small sample sizes. There were few findings of significant difference between women in active and control arms. Among the products assessed in more than one study, there were significantly more genital findings with intact epithelium in recipients of PRO2000 [relative risk (RR) 1.68, 95% confidence interval (CI) 1.08-2.60] and a lower incidence of bacterial vaginosis in dextrin sulphate recipients (RR 0.61, 95% CI 0.42-0.88). CIs were generally very wide, and most studies were unable to exclude differences of a substantial magnitude between treated and control women. Larger and longer safety studies are necessary to detect clinically important toxicities, including those that indicate a potential increase in HIV risk, and provide assurance that agents are ready for large-scale effectiveness trials.

In global health research, is it legitimate to stop clinical trials early on account of their opportunity costs?

After the failure of three large clinical trials of vaginal microbicides, a Nature editorial stated that the microbicide field "requires a mechanism to help it make rational choices about the best candidates to move through trials" [1]. In this month's debate, James Lavery and colleagues propose a new mechanism, based on stopping trials early for "opportunity costs." They argue that microbicide trial sites could have been saturated with trials of scientifically less advanced products, while newer, and potentially more promising, products were being developed. They propose a mechanism to reallocate resources invested in existing trials of older products that might be better invested in more scientifically advanced products that are awaiting clinical testing. But David Buchanan argues that the early stopping of trials for such opportunity costs would face insurmountable practical barriers, and would risk causing harm to the participants in the trial that was stopped.