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1.  Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis 
PLoS Medicine  2015;12(1):e1001778.
In a meta-analysis of individual participant data, Charles Morrison and colleagues explore the association between hormonal contraception use and risk of HIV infection in sub-Saharan Africa.
Background
Observational studies of a putative association between hormonal contraception (HC) and HIV acquisition have produced conflicting results. We conducted an individual participant data (IPD) meta-analysis of studies from sub-Saharan Africa to compare the incidence of HIV infection in women using combined oral contraceptives (COCs) or the injectable progestins depot-medroxyprogesterone acetate (DMPA) or norethisterone enanthate (NET-EN) with women not using HC.
Methods and Findings
Eligible studies measured HC exposure and incident HIV infection prospectively using standardized measures, enrolled women aged 15–49 y, recorded ≥15 incident HIV infections, and measured prespecified covariates. Our primary analysis estimated the adjusted hazard ratio (aHR) using two-stage random effects meta-analysis, controlling for region, marital status, age, number of sex partners, and condom use. We included 18 studies, including 37,124 women (43,613 woman-years) and 1,830 incident HIV infections. Relative to no HC use, the aHR for HIV acquisition was 1.50 (95% CI 1.24–1.83) for DMPA use, 1.24 (95% CI 0.84–1.82) for NET-EN use, and 1.03 (95% CI 0.88–1.20) for COC use. Between-study heterogeneity was mild (I2 < 50%). DMPA use was associated with increased HIV acquisition compared with COC use (aHR 1.43, 95% CI 1.23–1.67) and NET-EN use (aHR 1.32, 95% CI 1.08–1.61). Effect estimates were attenuated for studies at lower risk of methodological bias (compared with no HC use, aHR for DMPA use 1.22, 95% CI 0.99–1.50; for NET-EN use 0.67, 95% CI 0.47–0.96; and for COC use 0.91, 95% CI 0.73–1.41) compared to those at higher risk of bias (pinteraction = 0.003). Neither age nor herpes simplex virus type 2 infection status modified the HC–HIV relationship.
Conclusions
This IPD meta-analysis found no evidence that COC or NET-EN use increases women’s risk of HIV but adds to the evidence that DMPA may increase HIV risk, underscoring the need for additional safe and effective contraceptive options for women at high HIV risk. A randomized controlled trial would provide more definitive evidence about the effects of hormonal contraception, particularly DMPA, on HIV risk.
Editors’ Summary
Background
AIDS has killed about 36 million people since the first recorded case of the disease in 1981. About 35 million people (including 25 million living in sub-Saharan Africa) are currently infected with HIV, the virus that causes AIDS, and every year, another 2.3 million people become newly infected with HIV. At the beginning of the epidemic, more men than women were infected with HIV. Now, about half of all adults infected with HIV are women. In 2013, almost 60% of all new HIV infections among young people aged 15–24 years occurred among women, and it is estimated that, worldwide, 50 young women are newly infected with HIV every hour. Most women become infected with HIV through unprotected intercourse with an infected male partner—biologically, women are twice as likely to become infected through unprotected intercourse as men. A woman’s risk of becoming infected with HIV can be reduced by abstaining from sex, by having one or a few partners, and by always using condoms.
Why Was This Study Done?
Women and societies both benefit from effective contraception. When contraception is available, women can avoid unintended pregnancies, fewer women and babies die during pregnancy and childbirth, and maternal and infant health improves. However, some (but not all) observational studies (investigations that measure associations between the characteristics of participants and their subsequent development of specific diseases) have reported an association between hormonal contraceptive use and an increased risk of HIV acquisition by women. So, does hormonal contraception increase the risk of HIV acquisition among women or not? Here, to investigate this question, the researchers undertake an individual participant data meta-analysis of studies conducted in sub-Saharan Africa (a region where both HIV infection and unintended pregnancies are common) to compare the incidence of HIV infection (the number of new cases in a population during a given time period) among women using and not using hormonal contraception. Meta-analysis is a statistical method that combines the results of several studies; an individual participant data meta-analysis combines the data recorded for each individual involved in the studies rather than the aggregated results from each study.
What Did the Researchers Do and Find?
The researchers included 18 studies that measured hormonal contraceptive use and incident HIV infection among women aged 15–49 years living in sub-Saharan Africa in their meta-analysis. More than 37,000 women took part in these studies, and 1,830 became newly infected with HIV. Half of the women were not using hormonal contraception, a quarter were using depot-medroxyprogesterone acetate (DMPA; an injectable hormonal contraceptive), and the remainder were using combined oral contraceptives (COCs) or norethisterone enanthate (NET-EN, another injectable contraceptive). After adjustment for other factors likely to influence HIV acquisition (for example, condom use), women using DMPA had a 1.5-fold increased risk of HIV acquisition compared to women not using hormonal contraception. There was a slightly increased risk of HIV acquisition among women using NET-EN compared to women not using hormonal contraception, but this increase was not statistically significant (it may have happened by chance alone). There was no increased risk of HIV acquisition associated with COC use. DMPA use was associated with a 1.43-fold and 1.32-fold increased risk of HIV acquisition compared with COC and NET-EN use, respectively. Finally, neither age nor herpes simplex virus 2 infection status modified the effect of hormonal contraceptive use on HIV acquisition.
What Do These Findings Mean?
The findings of this individual patient data meta-analysis provide no evidence that COC or NET-EN use increases a woman’s risk of acquiring HIV, but add to the evidence suggesting that DMPA use increases the risk of HIV acquisition. These findings are likely to be more accurate than those of previous meta-analyses that used aggregated data but are likely to be limited by the quality, design, and representativeness of the studies included in the analysis. These findings nevertheless highlight the need to develop additional safe and effective contraceptive options for women at risk of HIV, particularly those living in sub-Saharan Africa, where although contraceptive use is generally low, DMPA is the most widely used hormonal contraceptive. In addition, these findings highlight the need to initiate randomized controlled trials to provide more definitive evidence of the effects of hormonal contraception, particularly DMPA, on HIV risk.
Additional Information.
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001778.
Information is available from the US National Institute of Allergy and Infectious Diseases on HIV infection and AIDS
NAM/aidsmap provides basic information about HIV/AIDS, and summaries of recent research findings on HIV care and treatment, including personal stories about living with HIV/AIDS and a news report on this meta-analysis
Information is available from Avert, an international AIDS charity, on many aspects of HIV/AIDS, including detailed information on women, HIV, and AIDS, and on HIV and AIDS in South Africa (in English and Spanish); personal stories of women living with HIV are available
The World Health Organization provides information on all aspects of HIV/AIDS (in several languages); information about a 2012 WHO technical consultation about hormonal contraception and HIV
The 2013 UNAIDS World AIDS Day report provides up-to-date information about the AIDS epidemic and efforts to halt it; UNAIDS also provides information about HIV and hormonal contraception
doi:10.1371/journal.pmed.1001778
PMCID: PMC4303292  PMID: 25612136
2.  Evaluation of Three Approaches for Assessing Adherence to Vaginal Gel Application in Clinical Trials 
Sexually transmitted diseases  2013;40(12):950-956.
Background:
Accurate measurement of adherence to product use is an ongoing challenge in microbicide trials.
Methods:
We compared adherence estimates using two applicator tests (a dye stain assay [DSA] and an ultraviolet light assay [UVA]), the Wisebag (an applicator container that electronically tracks container openings), and self-reported adherence (ability, frequency, and percent missed doses). Healthy, HIV-negative, non-pregnant US women aged 23 to 45 received a Wisebag and 32 applicators filled with placebo gel, were instructed to insert one applicator daily for 30 days, returned the Wisebag and all applicators, and completed an exit interview. Emptied applicators were tested by UVA and then DSA, and scored by two blinded readers. Positive and negative controls were randomly included in applicator batches.
Results:
Among 42 women enrolled, 39 completed the study. DSA and UVA yielded similar sensitivity (97% and 95%) and specificity (79% and 79%). Two participants had fully inoperable Wisebags and nine had partially inoperable Wisebags. The proportion of participants considered to have high adherence (≥80%) varied: 43% (Wisebag), 46% (UVA), 49% (DSA), and 62% to 82% (self-reports). For estimating high adherence, Wisebag had a sensitivity of 76% (95% CI, 50% to 93%) and a specificity of 85% (95% CI, 62% to 97%) compared with DSA. Although 28% of participants reported forgetting to open the Wisebag daily, 59% said it helped them remember gel use.
Conclusions:
DSA and UVA performed similarly. Compared with these tests, self-reports overestimated and Wisebag underestimated adherence. Although Wisebag may encourage gel use, the applicator tests currently appear more useful for measuring use in clinical trials.
doi:10.1097/OLQ.0000000000000053
PMCID: PMC4130378  PMID: 24220357
Wisebag; electronic adherence monitor; microbicide; applicator test; adherence
3.  Perspectives on use of oral and vaginal antiretrovirals for HIV prevention: the VOICE-C qualitative study in Johannesburg, South Africa 
Journal of the International AIDS Society  2014;17(3Suppl 2):19146.
Introduction
Antiretroviral (ARV)-based pre-exposure prophylaxis (PrEP) is a promising new HIV prevention strategy. However, variable levels of adherence have yielded mixed results across several PrEP trials and populations. It is not clear how taking ARV – traditionally used for HIV treatment – is perceived and how that perception may affect the use of these products as preventives. We explored the views and experiences of VOICE participants, their male partners and community members regarding the use of ARV as PrEP in the VOICE trial and the implications of these shared meanings for adherence.
Methods
VOICE-C was a qualitative ancillary study conducted at the Johannesburg site of VOICE, a multisite, double-blind, placebo-controlled randomised trial testing tenofovir gel, oral tenofovir and oral Truvada® for HIV PrEP. We interviewed 102 randomly selected female VOICE participants, 22 male partners and 40 community members through in-depth interviews, serial ethnography, or focus group discussions. All interviews were audiotaped, transcribed, translated and coded thematically for analysis.
Results
The concept of ARV for prevention was understood to varying degrees across all study groups. A majority of VOICE participants understood that the products contained ARV, more so for the tablets than for the gel. Although participants knew they were HIV negative, ARV was associated with illness. Male partners and community members echoed these sentiments, highlighting confusion between treatment and prevention. Concerned that they would be mistakenly identified as HIV positive, VOICE participants often concealed use of or hid their study products. This occasionally led to relationship conflicts or early trial termination. HIV stigma and its association with ARV, especially the tablets, was articulated in rumour and gossip in the community, the workplace and the household. Although ARV were recognised as potent and beneficial medications, transforming the AIDS body from sickness to health, they were regarded as potentially harmful for those uninfected.
Conclusions
VOICE participants and others in the trial community struggled to conceptualise the idea of using ARV for prevention. This possibly influenced willingness to adopt ARV-based prevention in the VOICE clinical trial. Greater investments should be made to increase community understanding of ARV for prevention and to mitigate pervasive HIV stigma.
doi:10.7448/IAS.17.3.19146
PMCID: PMC4163995  PMID: 25224610
HIV prevention; antiretroviral; pre-exposure prophylaxis; microbicides; adherence; South Africa; qualitative methods; HIV stigma
4.  Influences on visit retention in clinical trials: Insights from qualitative research during the VOICE trial in Johannesburg, South Africa 
BMC Women's Health  2014;14:88.
Background
Although significant progress has been made in clinical trials of women-controlled methods of HIV prevention such as microbicides and Pre-exposure Prophylaxis (PrEP), low adherence to experimental study products remains a major obstacle to being able to establish their efficacy in preventing HIV infection. One factor that influences adherence is the ability of trial participants to attend regular clinic visits at which trial products are dispensed, adherence counseling is administered, and participant safety is monitored. We conducted a qualitative study of the social contextual factors that influenced adherence in the VOICE (MTN-003) trial in Johannesburg, South Africa, focusing on study participation in general, and study visits in particular.
Methods
The research used qualitative methodologies, including in-depth interviews (IDI), serial ethnographic interviews (EI), and focus group discussions (FGD) among a random sub-sample of 102 female trial participants, 18 to 40 years of age. A socio-ecological framework that explored those factors that shaped trial participation and adherence to study products, guided the analysis. Key codes were developed to standardize subsequent coding and a node search was used to identify texts relating to obstacles to visit adherence. Our analysis includes coded transcripts from seven FGD (N = 40), 41 IDI, and 64 serial EI (N = 21 women).
Results
Women’s kinship, social, and economic roles shaped their ability to participate in the clinical trial. Although participants expressed strong commitments to attend study visits, clinic visit schedules and lengthy waiting times interfered with their multiple obligations as care givers, wage earners, housekeepers, and students.
Conclusions
The research findings highlight the importance of the social context in shaping participation in HIV prevention trials, beyond focusing solely on individual characteristics. This points to the need to focus interventions to improve visit attendance by promoting a culture of active and engaged participation.
doi:10.1186/1472-6874-14-88
PMCID: PMC4115485  PMID: 25065834
HIV prevention; PrEP; Microbicides; Visit retention; South Africa
5.  Acceptability in Microbicide and PrEP Trials: Current Status and a Reconceptualization 
Current opinion in HIV and AIDS  2012;7(6):534-541.
Purpose of Review
Assessment of acceptability is a central component of most oral PrEP and microbicide trials. In this paper we review current definitions and frameworks employed in acceptability research, discuss findings from recent studies of product acceptability and summarize trends in acceptability research. We conclude by offering a new framework for investigating product acceptability within clinical trials, one which considers product acceptability to be conceptually distinct from adherence.
Recent Findings
While numerous studies have investigated product acceptability, a consensus is lacking regarding the definition and operationalization of the concept. In addition fewer than half of the studies reviewed investigated actual candidate products. To the extent that an overall measure of acceptability is considered, the consensus is that most participants find the products acceptable. However, it is the rare study that investigates whether product adherence is associated with acceptability.
Summary
Given the critical role of adherence to the success of clinical trials, it is important to identify the extent to which acceptability is a factor in product usage and to ascertain which dimensions of acceptability — product attributes, dosing regimen, delivery mechanism, use attributes, partner's attitudes, effect of product on the sexual encounter, product-related norms — if any, affect adherence.
doi:10.1097/COH.0b013e3283590632
PMCID: PMC4026162  PMID: 23032737
Acceptability; microbicide; PrEP; adherence
6.  Women’s Experiences with Oral and Vaginal Pre-Exposure Prophylaxis: The VOICE-C Qualitative Study in Johannesburg, South Africa 
PLoS ONE  2014;9(2):e89118.
Background
In VOICE, a multisite HIV pre-exposure prophylaxis (PrEP) trial, plasma drug levels pointed to widespread product nonuse, despite high adherence estimated by self-reports and clinic product counts. Using a socio-ecological framework (SEF), we explored socio-cultural and contextual factors that influenced participants’ experience of daily vaginal gel and oral tablet regimens in VOICE.
Methods
In Johannesburg, a qualitative ancillary study was concurrently conducted among randomly selected VOICE participants assigned to in-depth interviews (n = 41), serial ethnographic interviews (n = 21), or focus group discussions (n = 40). Audiotaped interviews were transcribed, translated, and coded thematically for analysis.
Results
Of the 102 participants, the mean age was 27 years, and 96% had a primary sex partner with whom 43% cohabitated. Few women reported lasting nonuse, which they typically attributed to missed visits, lack of product replenishments, and family-related travel or work. Women acknowledged occasionally skipping or mistiming doses because they forgot, were busy, felt lazy or bored, feared or experienced side effects. However, nearly all knew or heard of other study participants who did not use products daily. Three overarching themes emerged from further analyses: ambivalence toward research, preserving a healthy status, and managing social relationships. These themes highlighted the profound and complex meanings associated with participating in a blinded HIV PrEP trial and taking antiretroviral-based products. The unknown efficacy of products, their connection with HIV infection, challenges with daily regimen given social risks, lack of support–from partners and significant others–and the relationship tradeoffs entailed by using the products appear to discourage adequate product use.
Conclusions
Personal acknowledgment of product nonuse was challenging. This qualitative inquiry highlighted key influences at all SEF levels that shaped women’s perceptions of trial participation and experiences with investigational products. Whether these impacted women’s behaviors and may have contributed to ineffective trial results warrants further investigation.
doi:10.1371/journal.pone.0089118
PMCID: PMC3931679  PMID: 24586534
7.  Feasibility, performance, and acceptability of the Wisebag™ for potential monitoring of daily gel applicator use in Durban, South Africa 
AIDS and behavior  2013;17(2):640-648.
The Wisebag™, a lunchbag-style container with an electronic events-monitoring system, was designed as a real-time indirect objective measure of microbicide gel use. Due to cost, alternative functionalities (i.e. use of offline and dummy versions) were explored. We conducted a three-arm, double-blinded pilot study among fifty HIV-negative women in Durban, South Africa to assess participant adherence and Wisebag acceptability and performance. Participants were randomized 2:2:1 to Wisebag with online (events transmitted via cellular signal in real-time), offline (events stored in device memory) or inactive “dummy” devices. Participants were instructed to open the Wisebag daily for two weeks, retrieve a study sticker and affix it on a diary card. All participants completed the study. At exit, 94% did not know which device they had received, nor could they differentiate the Wisebag types when presented with the three options. Five offline devices failed (no data recorded). Per Wisebag events, 26% of women were perfectly adherent compared to 48% by self-report and 46% per diary card. Of reported non-adherence, 92% did not open the Wisebag (travelling or forgot) and 22% opened Wisebag >1x/day (curiosity). Participants liked and were comfortable carrying Wisebag. Successful blinding will allow inclusion of offline and/or dummy Wisebags in future study designs. Perfect adherence by opening events was significantly lower than by self-report, highlighting the importance of objective measures of adherence in clinical trials. Additional studies to validate Wisebag data with actual products, with and without SMS and online functionality, in different populations and settings, and in comparison to biomarkers are warranted.
doi:10.1007/s10461-012-0330-y
PMCID: PMC3562379  PMID: 23054042
Microbicide gel; adherence; electronic monitoring; Africa
8.  Adherence Support Approaches in Biomedical HIV Prevention Trials: Experiences, Insights and Future Directions from Four Multisite Prevention Trials 
AIDS and Behavior  2013;17(6):2143-2155.
Adherence is a critical component of the success of antiretroviral-based pre-exposure prophylaxis (PrEP) in averting new HIV-infections. Ensuring drug availability at the time of potential HIV exposure relies on self-directed product use. A deeper understanding of how to best support sustained PrEP adherence remains critical to current and future PrEP efforts. This paper provides a succinct synthesis of the adherence support experiences from four pivotal PrEP trials—Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004, FEM-PrEP, Iniciativa Prophylaxis (iPrEx), and Vaginal and Oral Interventions to Control the Epidemic (VOICE). Notwithstanding variability in the design, population/cohort, formulation, drug, dosing strategy, and operationalization of adherence approaches utilized in each trial, the theoretical basis and experiences in implementation and monitoring of the approaches used by these trials provide key lessons for optimizing adherence in future research and programmatic scale-up of PrEP. Recommendations from across these trials include participant-centered approaches, separating measurement of adherence from adherence counseling, incorporating tailored strategies that go beyond education, fostering motivation, and addressing the specific context in which an individual incorporates and negotiates PrEP use.
doi:10.1007/s10461-013-0429-9
PMCID: PMC3672509  PMID: 23435697
PrEP; Microbicides; Adherence; Intervention; Counseling; Clinical trials; HIV prevention
9.  Diaphragm Used with Replens Gel and Risk of Bacterial Vaginosis: Results from a Randomized Controlled Trial 
Background. Bacterial vaginosis (BV) has been linked to female HIV acquisition and transmission. We investigated the effect of providing a latex diaphragm with Replens and condoms compared to condom only on BV prevalence among participants enrolled in an HIV prevention trial. Methods. We enrolled HIV-seronegative women and obtained a vaginal swab for diagnosis of BV using Nugent's criteria; women with BV (score 7–10) were compared to those with intermediate (score 4–6) and normal flora (score 0–3). During quarterly follow-up visits over 12–24 months a vaginal Gram stain was obtained. The primary outcome was serial point prevalence of BV during followup. Results. 528 participants were enrolled; 213 (40%) had BV at enrollment. Overall, BV prevalence declined after enrollment in women with BV at baseline (OR = 0.4, 95% CI 0.29–.56) but did not differ by intervention group. In the intention-to-treat analysis BV prevalence did not differ between the intervention and control groups for women who had BV (OR = 1.01, 95% CI 0.52–1.94) or for those who did not have BV (OR = 1.21, 95% CI 0.65–2.27) at enrollment. Only 2.1% of participants were treated for symptomatic BV and few women (5–16%) were reported using anything else but water to cleanse the vagina over the course of the trial. Conclusions. Provision of the diaphragm, Replens, and condoms did not change the risk of BV in comparison to the provision of condoms alone.
doi:10.1155/2012/921519
PMCID: PMC3485870  PMID: 23133307
10.  Bridewealth and sexual and reproductive practices among women in Harare, Zimbabwe 
AIDS care  2010;22(6):705-710.
This paper examines the relationship between bridewealth, socio-demographics, and sexual and reproductive practices among a group of women in Harare, Zimbabwe. The study sample was recruited as part of a six-month safety trial of the diaphragm and a microbicide, between August 2004 and April 2005 in Harare, Zimbabwe. Women underwent two screening visits: first, women completed a demographic and behavioral interviewer-administered questionnaire which included questions on bridewealth; at the second visit, women were offered HIV testing and counseling. Our results included: 417 women were married (currently or in the past) and almost half had had bridewealth negotiated as part of the marriage process. In multivariate analyses, women who were married with bridewealth had more years of education (OR 1.17, 95%CI 1.03–1.32), a higher age of coital debut (OR 1.37, 95%CI 1.09–1.71), and increased likelihood of having ever used male condoms (OR 1.54, 95%CI 1.01–2.37) compared with women who had been married without bridewealth. Bridewealth may be a relevant area of traditional culture to further examine in relation to HIV risk, for its potential association with co-factors that can reduce risk of HIV infection among women in Southern Africa.
doi:10.1080/09540120903349094
PMCID: PMC3139542  PMID: 20467936
bridewealth; Zimbabwe; women’s sexual health; HIV/AIDS; reproductive health
11.  Intravaginal Practices, Bacterial Vaginosis, and HIV Infection in Women: Individual Participant Data Meta-analysis 
PLoS Medicine  2011;8(2):e1000416.
Pooling of data from 14,874 women in an individual participant data meta-analysis by Nicola Low and colleagues reveals that some intravaginal practices increase the risk of HIV acquisition.
Background
Identifying modifiable factors that increase women's vulnerability to HIV is a critical step in developing effective female-initiated prevention interventions. The primary objective of this study was to pool individual participant data from prospective longitudinal studies to investigate the association between intravaginal practices and acquisition of HIV infection among women in sub-Saharan Africa. Secondary objectives were to investigate associations between intravaginal practices and disrupted vaginal flora; and between disrupted vaginal flora and HIV acquisition.
Methods and Findings
We conducted a meta-analysis of individual participant data from 13 prospective cohort studies involving 14,874 women, of whom 791 acquired HIV infection during 21,218 woman years of follow-up. Data were pooled using random-effects meta-analysis. The level of between-study heterogeneity was low in all analyses (I2 values 0.0%–16.1%). Intravaginal use of cloth or paper (pooled adjusted hazard ratio [aHR] 1.47, 95% confidence interval [CI] 1.18–1.83), insertion of products to dry or tighten the vagina (aHR 1.31, 95% CI 1.00–1.71), and intravaginal cleaning with soap (aHR 1.24, 95% CI 1.01–1.53) remained associated with HIV acquisition after controlling for age, marital status, and number of sex partners in the past 3 months. Intravaginal cleaning with soap was also associated with the development of intermediate vaginal flora and bacterial vaginosis in women with normal vaginal flora at baseline (pooled adjusted odds ratio [OR] 1.24, 95% CI 1.04–1.47). Use of cloth or paper was not associated with the development of disrupted vaginal flora. Intermediate vaginal flora and bacterial vaginosis were each associated with HIV acquisition in multivariable models when measured at baseline (aHR 1.54 and 1.69, p<0.001) or at the visit before the estimated date of HIV infection (aHR 1.41 and 1.53, p<0.001), respectively.
Conclusions
This study provides evidence to suggest that some intravaginal practices increase the risk of HIV acquisition but a direct causal pathway linking intravaginal cleaning with soap, disruption of vaginal flora, and HIV acquisition has not yet been demonstrated. More consistency in the definition and measurement of specific intravaginal practices is warranted so that the effects of specific intravaginal practices and products can be further elucidated.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Since the first reported case of acquired immunodeficiency syndrome (AIDS) in 1981, the number of people infected with the human immunodeficiency virus (HIV), which causes AIDS, has risen steadily. By the end of 2009, an estimated 33.3 million people were living with HIV/AIDS. At the beginning of the epidemic, more men than women were infected with HIV but now, globally, more than half of all adults living with HIV/AIDS are women, and HIV/AIDS is the leading cause of death among women of child-bearing age. In sub-Saharan Africa, where more than two-thirds of HIV-positive people live, the situation for women is particularly bad. About 12 million women live with HIV/AIDS in this region compared with about 8 million men; among 15–24 year-olds, women are eight times more likely than men to be HIV-positive. This pattern of infection has developed because in sub-Saharan Africa most people contract HIV through heterosexual sex.
Why Was This Study Done?
If modifiable factors that increase women's vulnerability to HIV infection could be identified, it might be possible to develop effective female-initiated prevention interventions. Some experts think that intravaginal practices such as cleaning the vagina with soap or a cloth increase the risk of HIV infection by damaging the vagina's lining or by increasing bacterial vaginosis (a condition in which harmful bacteria disrupt the healthy vaginal flora) but the evidence for such an association is inconclusive. In this meta-analysis, the researchers pool individual participant data from several prospective longitudinal cohort studies to assess the association between intravaginal practices and HIV acquisition among women in sub-Saharan Africa. Meta-analysis is a statistical method that combines data from several studies to get a clearer view of the factors associated with of a disease than is possible from individual studies. In a prospective longitudinal cohort study, groups of participants with different baseline characteristics (here, women who did or did not use intravaginal practices), who do not have the outcome of interest at the start of the study (here, HIV infection) are followed to see whether these characteristics affect disease development.
What Did the Researchers Do and Find?
The researchers pooled individual participant data from 13 prospective cohort studies in sub-Saharan Africa involving nearly 15,000 women, 791 of whom acquired HIV, and asked whether HIV infection within 2 years of study enrollment was associated with self-reported intravaginal practices. That is, were women who used specific intravaginal practices more likely to become infected with HIV than women who did not use these practices? After controlling for age, marital status, and the number of recent sex partners, women who used cloth or paper to clean their vagina were nearly one and half times more likely to have acquired HIV infection as women who did not use this practice (a pooled adjusted hazard ratio [aHR] of 1.47). The insertion of products to dry or tighten the vagina and intravaginal cleaning with soap also increased women's chances of acquiring HIV (aHRs of 1.31 and 1.24, respectively). Moreover, intravaginal cleaning with soap was associated with the development of bacterial vaginosis, and disrupted vaginal flora and bacterial vaginosis were both associated with an increased risk of HIV acquisition.
What Do These Findings Mean?
These findings suggest that some intravaginal practices increase the risk of HIV acquisition but they do not prove that there is a causal link between any intravaginal practice, disruption of vaginal flora, and HIV acquisition. It could be that the women who use intravaginal practices share other unknown characteristics that affect their vulnerability to HIV infection. The accuracy of these findings is also likely to be affected by the use of self-reported data and inconsistent definitions of intravaginal practices. Nevertheless, given the widespread use of intravaginal practices in some sub-Saharan countries (95% of female sex workers in Kenya use such practices, for example), these findings suggest that encouraging women to use less harmful intravaginal practices (for example, washing with water alone) should be included in female-initiated HIV prevention research strategies in sub-Saharan Africa and other regions where intravaginal practices are common.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000416
The US National Institute of Allergy and Infectious Diseases provides information on HIV infection and AIDS and on bacterial vaginosis
The US Centers for Disease Control and Prevention has information on all aspects of HIV/AIDS, including specific information about HIV/AIDS and women; it also has information on bacterial vaginosis (in English and Spanish)
HIV InSite has information on all aspects of HIV/AIDS
Information is available from Avert, an international AIDS nonprofit on all aspects of HIV/AIDS, including HIV/AIDS and women and HIV/AIDS in Africa (in English and Spanish)
A full description of the researchers' study protocol is available
Several Web sites provide information on microbicides Global Campaign for Microbicides, Microbicides Development Programme, Microbicides Trials Network, and International Partnership for Microbicides
doi:10.1371/journal.pmed.1000416
PMCID: PMC3039685  PMID: 21358808
12.  Change in condom and other barrier method use during and after an HIV prevention trial in Zimbabwe 
Background
We examined the use of male condoms and the diaphragm following completion of a clinical trial of the diaphragm's HIV prevention effectiveness. In the trial, called Methods for Improving Reproductive Health in Africa (MIRA), women were randomized to a diaphragm group (diaphragm, gel and condoms) or a condom-only control group. At trial exit, all women were offered the diaphragm and condoms.
Methods
Our sample consisted of 801 Zimbabwean MIRA participants who completed one post-trial visit (median lapse: nine months; range two to 20 months). We assessed condom, diaphragm and any barrier method use at last sex act at enrolment, final MIRA and post-trial visits. We used multivariable random effects logistic regression to examine changes in method use between these three time points.
Results and discussion
In the condom group, condom use decreased from 86% at the final trial visit to 67% post trial (AOR = 0.20; 95% CI: 0.12 to 0.33). In the diaphragm group, condom use was 61% at the final trial visit, and did not decrease significantly post trial (AOR = 0.77; 95% CI: 0.55 to 1.09), while diaphragm use decreased from 79% to 50% post trial (AOR = 0.18; 95% CI: 0.12 to 0.28). Condom use significantly decreased between the enrolment and post-trial visits in both groups. Use of any barrier method was similar in both groups: it significantly decreased between the final trial and the post-trial visits, but did not change between enrolment and the post-trial visits.
Conclusions
High condom use levels achieved during the trial were not sustained post trial in the condom group. Post-trial diaphragm use remained relatively high in the diaphragm group (given its unknown effectiveness), but was very low in the condom group. Introducing "new" methods for HIV prevention may require time and user skills before they get adopted. Our findings underscore the potential benefit of providing a mix of methods to women as it may encourage more protected acts.
doi:10.1186/1758-2652-13-39
PMCID: PMC2984577  PMID: 20955629
13.  Biomarker Validation of Reports of Recent Sexual Activity: Results of a Randomized Controlled Study in Zimbabwe 
American Journal of Epidemiology  2009;170(7):918-924.
Challenges in the accurate measurement of sexual behavior in human immunodeficiency virus (HIV) prevention research are well documented and have prompted discussion about whether valid assessments are possible. Audio computer-assisted self-interviewing (ACASI) may increase the validity of self-reported behavioral data. In 2006–2007, Zimbabwean women participated in a randomized, cross-sectional study that compared self-reports of recent vaginal sex and condom use collected through ACASI or face-to-face interviewing (FTFI) with a validated objective biomarker of recent semen exposure (prostate-specific antigen (PSA) levels). Of 910 study participants, 196 (21.5%) tested positive for PSA, an indication of semen exposure during the previous 2 days. Of these 196 participants, 23 (11.7%) reported no sex in the previous 2 days, with no difference in reported sexual activity between interview modes (12.5% ACASI vs. 10.9% FTFI; Fisher's exact test: P = 0.72). In addition, 71 PSA-positive participants (36.2%) reported condom-protected vaginal sex only; their reports also indicated no difference between interview modes (33.7% ACASI vs. 39.1% FTFI; P = 0.26). Only 52% of PSA-positive participants reported unprotected sex during the previous 2 days. Self-report was a poor predictor of recent sexual activity and condom use in this study, regardless of interview mode, providing evidence that such data should be interpreted cautiously.
doi:10.1093/aje/kwp219
PMCID: PMC3888136  PMID: 19741042
biological markers; condoms; data collection; epidemiologic measurements; HIV; prostate-specific antigen; sexual behavior
14.  The Importance of Male Partner Involvement for Women’s Acceptability and Adherence to Female-Initiated HIV Prevention Methods in Zimbabwe 
AIDS and Behavior  2010;15(5):959-969.
Enlisting male partner involvement is perceived as an important component of women’s successful uptake of female-initiated HIV prevention methods. We conducted a longitudinal study among a cohort of 955 Zimbabwean women participating in a clinical trial of the effectiveness of a female-initiated HIV prevention method (the diaphragm and lubricant gel) to: (a) describe the extent to which women involved their male partners in the decision to use the study products, and (b) measure the effect perceived male partner support had on their acceptability and consistent use of these methods. Reported levels of male partner involvement in discussions and decisions regarding: joining the study, study activities, the outcome of HIV/STI test results, and product use were very high. In multivariate analyses, regular disclosure of study product use and partner approval for the diaphragm and gel were significantly associated with women’s acceptability and consistent use of the products; an essential component for determining efficacy of investigational prevention methods. These results support the need for more sophisticated measurement of how couples interact to make decisions that impact study participation and investigational product use as well as more rigorous adaptations and evaluations of existing strategies to involve male partners in female-initiated HIV prevention trials.
doi:10.1007/s10461-010-9806-9
PMCID: PMC3111667  PMID: 20844946
HIV prevention; Female-initiated methods; Zimbabwe; Male involvement; Adherence; Acceptability; Couples
15.  Analyzing Direct Effects in Randomized Trials with Secondary Interventions: An Application to HIV Prevention Trials 
Summary
The Methods for Improving Reproductive Health in Africa (MIRA) trial is a recently completed randomized trial that investigated the effect of diaphragm and lubricant gel use in reducing HIV infection among susceptible women. 5,045 women were randomly assigned to either the active treatment arm or not. Additionally, all subjects in both arms received intensive condom counselling and provision, the “gold standard” HIV prevention barrier method. There was much lower reported condom use in the intervention arm than in the control arm, making it difficult to answer important public health questions based solely on the intention-to-treat analysis. We adapt an analysis technique from causal inference to estimate the “direct effects” of assignment to the diaphragm arm, adjusting for condom use in an appropriate sense. Issues raised in the MIRA trial apply to other trials of HIV prevention methods, some of which are currently being conducted or designed.
doi:10.1111/j.1467-985X.2009.00585.x
PMCID: PMC2935183  PMID: 20827388
Causal inference; Intention-to-treat; Randomized trials; Time-dependent confounding
16.  An acceptability and safety study of the Duet® cervical barrier and gel delivery system in Zimbabwe 
Background
Adherence problems with coitally dependent, female-initiated HIV prevention methods have contributed to several trials' failure to establish efficacy. Continuous use of a cervical barrier with once-daily cleaning and immediate reinsertion may simplify use for women and improve adherence. We assessed the acceptability and safety of precoital and continuous use of the Duet®, a cervical barrier and gel delivery system, in Zimbabwean women.
Methods
Using a two-arm crossover design with a parallel observation group, we randomized 103 women in a 2:2:1 ratio: (1) to use the Duet continuously for 14 days, followed by a minimum of seven days of washout and then 14 days of precoital use; (2) to use the same Duet regimens in reverse order; or (3) for observation only. Women were aged 18 to 40 years; half were recruited from a pool of previous diaphragm study participants and the other half from the general community. Acceptability and adherence were assessed through an interviewer-administered questionnaire at each of two follow-up visits. Safety was monitored through pelvic speculum exams and report of adverse events.
Results
The proportion of women who reported consistent Duet use during sex was virtually identical during continuous and precoital regimens (88.6% vs. 88.9%). Partner refusal was the most common reason cited for non-use during sex in both use regimens. Not having the device handy was the most common reason cited for non-daily use (in the continuous regimen). Most women were "very comfortable" using it continuously (86.3%) and inserting it precoitally (92.8%). The most favoured Duet attribute was that it did not interfere with "natural" sex (55%). The least favoured Duet attribute was the concern that it might come out during sex (71.3%). No serious adverse events were reported during the study; 57 participants reported 90 adverse events classified as mild or moderate. There were no statistically significant differences in: (1) the proportion of women reporting adverse events; (2) the severity of events among those using the Duet and observational controls; or (3) event severity reported during each regimen use period.
Conclusions
In this study, the Duet was found to be acceptable and safe when inserted precoitally or used continuously for 14 days. Assignment to use of the Duet continuously did not increase adherence to the Duet during sex. Future HIV prevention trials should evaluate use of the Duet (precoitally and continuously) with promising microbicide candidates.
doi:10.1186/1758-2652-13-30
PMCID: PMC2924266  PMID: 20687954
17.  Type-Specific Cervico-Vaginal Human Papillomavirus Infection Increases Risk of HIV Acquisition Independent of Other Sexually Transmitted Infections 
PLoS ONE  2010;5(4):e10094.
Background
Sexually transmitted infections (STIs) such as herpes simplex virus (HSV)-2 are associated with an increased risk of HIV infection. Human papillomavirus (HPV) is a common STI, but little is know about its role in HIV transmission. The objective of this study was to determine whether cervico-vaginal HPV infection increases the risk of HIV acquisition in women independent of other common STIs.
Methods and Findings
This prospective cohort study followed 2040 HIV-negative Zimbabwean women (average age 27 years, range 18–49 years) for a median of 21 months. Participants were tested quarterly for 29 HPV types (with L1 PCR primers) and HIV (antibody testing on blood samples with DNA or RNA PCR confirmation). HIV incidence was 2.7 per 100 woman-years. Baseline HPV prevalence was 24.5%, and the most prevalent HPV types were 58 (5.0%), 16 (4.7%), 70 (2.4%), and 18 (2.3%). In separate regression models adjusting for baseline variables (including age, high risk partner, positive test for STIs, positive HSV-2 serology and condom use), HIV acquisition was associated with having baseline prevalent infection with HPV 58 (aHR 2.13; 95% CI 1.09–4.15) or HPV 70 (aHR 2.68; 95% CI 1.08–6.66). In separate regression models adjusting for both baseline variables and time-dependent variables (including HSV-2 status, incident STIs, new sexual partner and condom use), HIV acquisition was associated with concurrent infection with any non-oncogenic HPV type (aHR 1.70; 95% CI 1.02–2.85), any oncogenic HPV type (aHR 1.96; 95% CI 1.16–3.30), HPV 31 (aHR 4.25; 95% CI 1.81–9.97) or HPV 70 (aHR 3.30; 95% CI 1.50–7.20). Detection of any oncogenic HPV type within the previous 6 months was an independent predictor of HIV acquisition, regardless of whether HPV status at the HIV acquisition visit was included (aHR 1.95; 95% CI 1.19–3.21) or excluded (aHR 1.96; 95% CI 1.02–2.85) from the analysis.
Conclusions/Significance
Cervico-vaginal HPV infection was associated with an increased risk of HIV acquisition in women, and specific HPV types were implicated in this association. The observational nature of our study precludes establishment of causation between HPV infection and HIV acquisition. However, given the high prevalence of HPV infection in women, further investigation of the role of HPV in HIV transmission is warranted.
doi:10.1371/journal.pone.0010094
PMCID: PMC2851652  PMID: 20386706
18.  Vaginal Practices and Associations with Barrier Methods and Gel Use Among Sub-Saharan African Women Enrolled in an HIV Prevention Trial 
AIDS and Behavior  2010;14(3):590-599.
Vaginal practices may interfere with the use and/or the effectiveness of female-initiated prevention methods. We investigated whether vaginal practices differed by randomization group in a phase III trial of the diaphragm with lubricant gel (MIRA) in Sub-Saharan Africa (n = 4925), and if they were associated with consistent use of study methods. At baseline, vaginal practices were commonly reported: vaginal washing (82.77%), wiping (56.47%) and insertion of dry or absorbent materials (20.58%). All three practices decreased during the trial. However, women in the intervention group were significantly more likely to report washing or wiping during follow-up compared to those in the control group. Additionally, washing, wiping, and insertion, were all independently and inversely associated with consistent diaphragm and gel use and with condom use as well, regardless of study arm. A better understanding of the socio-cultural context in which these practices are embedded could improve educational strategies to address these potentially modifiable behaviors, and may benefit future HIV prevention interventions of vaginal methods.
doi:10.1007/s10461-010-9690-3
PMCID: PMC2865639  PMID: 20352318
Vaginal practices; HIV prevention trials; Female-initiated methods; Condoms; Africa
19.  Adherence and its Measurement in Phase 2/3 Microbicide Trials 
AIDS and Behavior  2009;14(5):1124-1136.
Adherence optimization and measurement have emerged as critically challenging issues for clinical trials of topical microbicides. Although microbicide trials have routinely collected adherence data, their utilization in trial design, implementation, and interpretation has been inconsistent. Drawing on data-driven presentations from several focused meetings, this paper synthesizes lessons from past microbicide trials and provides recommendations for future trials of microbicide and other HIV prevention technologies. First, it describes four purposes for adherence data collection, with particular attention to intention-to-treat versus adherence-adjusted analyses for determining effectiveness. Second, the microbicide field’s experiences with adherence measures and data collection modes are discussed, including the strengths and weaknesses of various options and approaches for improving measurement. Then, several approaches to optimizing trial participants’ adherence are presented. The paper concludes with a set of recommendations for immediate use or further research.
Electronic supplementary material
The online version of this article (doi:10.1007/s10461-009-9635-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s10461-009-9635-x
PMCID: PMC2944966  PMID: 19924525
Adherence; Microbicides; Clinical trials; HIV prevention
20.  Diaphragms and lubricant gel for prevention of HIV(Authors’ reply) 
Lancet  2007;370(9602):1823-1824.
doi:10.1016/S0140-6736(07)61764-4
PMCID: PMC2742775  PMID: 18061048
21.  Acceptability and Use of the Diaphragm and Replens® Lubricant Gel for HIV Prevention in Southern Africa 
AIDS and Behavior  2009;14(3):629-638.
The acceptability and use of the diaphragm and lubricant gel were assessed as part of a large randomized controlled trial to determine the effectiveness of the methods in women’s HIV acquisition. 2,452 intervention-arm women were enrolled at five Southern African clinics and followed quarterly for 12–24 months. Acceptability and use data were collected by face-to-face interviews at Month 3 and Exit. Participants were “very comfortable” with the physical mechanics of diaphragm use throughout the trial, and approval of the gel consistency, quantity and the applicator was high. At Exit, consistent disclosure of use (AOR 1.97, 95% CI: 1.10–3.55); an overall high diaphragm rating (AOR 1.84, 95% CI: 1.45–2.34) and perception of partner approval (AOR 1.75, 95% CI: 1.35–2.26) were the most significant acceptability factors independently associated with consistent use. Despite being female-initiated, disclosure of use to male partners and his perceived approval of the products were factors significantly associated with their consistent use.
doi:10.1007/s10461-009-9609-z
PMCID: PMC2865647  PMID: 19757018
Diaphragm; Lubricant gel; HIV prevention; Zimbabwe; South Africa; Acceptability; Product adherence
22.  What the better half is thinking: A comparison of men’s and women’s responses and agreement between spouses regarding reported sexual and reproductive behaviors in Rwanda 
Objective
To compare responses to a sexual behavioral survey of spouses in cohabiting heterosexual relationships in Kigali, Rwanda.
Design
Cross-sectional survey.
Methods
Husbands and wives in 779 cohabiting couples were interviewed separately with parallel questionnaires. Participants were recruited from a three-year old cohort of 1458 antenatal clinic attendees enrolled in a prospective study in 1988. Analyses compared responses at the gender- and couple-level for agreement and disagreement.
Results
Couples were in disagreement more than agreement. Women reported occasionally refusing sex, suggesting condom use, and believing married men were unfaithful. Men reported being in a faithful relationship, greater condom use, and being understanding when wives refused sex. Agreement included relationship characteristics, safety of condoms, and whether condoms had ever been used in the relationship. Disagreement included the preferred timing of next pregnancy, desire for more children, and whether a birth control method was currently used and type of method.
Conclusions
Rwandan husbands and wives differed in sexual behavior and reproductive-related topics. Couple-level reporting provides the most reliable measure for relationship aspects as couples’ agreement cannot be assumed among cohabiting partnerships. Furthermore, HIV prevention programs for couples should incorporate communication skills to encourage couple agreement of HIV-related issues.
PMCID: PMC3218770  PMID: 22110321
HIV; couples; counseling and testing; agreement and disagreement; sexual behavior; condom use; and pregnancy
23.  The Diaphragm and Lubricant Gel for Prevention of Cervical Sexually Transmitted Infections: Results of a Randomized Controlled Trial 
PLoS ONE  2008;3(10):e3488.
Background
We evaluated the effectiveness of the Ortho All-Flex Diaphragm, lubricant gel (Replens®) and condoms compared to condoms alone on the incidence of chlamydial and gonococcal infections in an open-label randomized controlled trial among women at risk of HIV/STI infections.
Methods
We randomized 5045 sexually-active women at three sites in Southern Africa. Participants who tested positive for curable STIs were treated prior to enrollment as per local guidelines. Women were followed quarterly and tested for Chlamydia trachomatis (CT) or Neisseria gonorrhoeae (GC) infection by nucleic-acid amplification testing (Roche Amplicor®) using first-catch urine specimens. STIs detected at follow-up visits were treated. We compared the incidence of first infection after randomization between study arms in both intent-to-treat (ITT) and per-protocol populations.
Findings
Baseline demographic, behavioral and clinical characteristics were balanced across study arms. Nearly 80% of participants were under 35 years of age. Median follow-up time was 21 months and the retention rate was over 93%. There were 471 first chlamydia infections, 247 in the intervention arm and 224 in the control arm with an overall incidence of 6.2/100 woman-years (wy) (relative hazard (RH) 1.11, 95% Confidence Interval (CI): 0.93–1.33; p = 0.25) and 192 first gonococcal infections, 95 in the intervention arm and 97 in the control arm with an overall incidence of 2.4/100wy (RH 0.98, 95%CI: 0.74–1.30; p = 0.90). Per protocol results indicated that when diaphragm adherence was defined as “always use” since the last visit, there was a significant reduction in the incidence of GC infection among women randomized to the intervention arm (RH 0.61, 95%CI: 0.41–0.91, P = 0.02).
Interpretation
There was no difference by study arm in the rate of acquisition of CT or GC. However, our per-protocol results suggest that consistent use of the diaphragm may reduce acquisition of GC.
Trial Registration
ClinicalTrials.gov NCT00121459 [NCT00121459]
doi:10.1371/journal.pone.0003488
PMCID: PMC2567030  PMID: 18941533
24.  Diaphragm and lubricant gel for prevention of HIV acquisition in southern African women: a randomised controlled trial 
Lancet  2007;370(9583):251-261.
Summary
Background
Female-controlled methods of HIV prevention are urgently needed. We assessed the effect of provision of latex diaphragm, lubricant gel, and condoms (intervention), compared with condoms alone (control) on HIV seroincidence in women in South Africa and Zimbabwe.
Methods
We did an open-label, randomised controlled trial in HIV-negative, sexually active women recruited from clinics and community-based organisations, who were followed up quarterly for 12–24 months (median 21 months). All participants received an HIV prevention package consisting of pre-test and post-test counselling about HIV and sexually transmitted infections, testing, treatment of curable sexually transmitted infections, and intensive risk-reduction counselling. The primary outcome was incident HIV infection. This study is registered with ClinicalTrials.gov, number NCT00121459.
Findings
Overall HIV incidence was 4.0% per 100 woman-years: 4.1% in the intervention group (n=2472) and 3.9% in the control group (n=2476), corresponding to a relative hazard of 1.05 (95% CI 0.84–1.32, intention-to-treat analysis). The proportion of women using condoms was significantly lower in the intervention than in the control group (54% vs 85% of visits, p<0.0001). The proportions of participants who reported adverse events (60% [1523] vs 61% [1529]) and serious adverse events (5% [130] vs 4% [101]) were similar between the two groups.
Interpretation
We observed no added protective benefit against HIV infection when the diaphragm and lubricant gel were provided in addition to condoms and a comprehensive HIV prevention package. Our observation that lower condom use in women provided with diaphragms did not result in increased infection merits further research. Although the intervention seemed safe, our findings do not support addition of the diaphragm to current HIV prevention strategies.
doi:10.1016/S0140-6736(07)60950-7
PMCID: PMC2442038  PMID: 17631387

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