Intravaginal Practices, Bacterial Vaginosis, and HIV Infection in Women: Individual Participant Data Meta-analysis
University of Bern1, University of the Witwatersrand2, Ghent University3, University of London4, University of Amsterdam5, University of Washington6, University of California, Los Angeles7, University of Toronto8, Africa Center9, Research Triangle Park10, Columbia University11, University of Cape Town12, RTI International13
TL;DR: 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.
Abstract: 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 (I 2 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. Citation: Low N, Chersich MF, Schmidlin K, Egger M, Francis SC, et al. (2011) Intravaginal Practices, Bacterial Vaginosis, and HIV Infection in Women: Individual
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TL;DR: The results suggest that highly prevalent genital bacteria increase HIV risk by inducing mucosal HIV target cells, and specific taxa highly prevalent in young healthy South African women that increase their HIV risk might be leveraged to reduce HIV acquisition in women.
447 citations
Cites background from "Intravaginal Practices, Bacterial V..."
...The sequencing-based identification of cervicovaginal bacteria and viruses provides a substantial advancement over previous prospective studies that used Gram-stained vaginal smears (Low et al., 2011; Martin et al., 1999; Myer et al., 2005)....
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...A small number of prospective studies indicate that women with cervicovaginal bacteria deficient in lactobacilli, a bacterial genus considered beneficial for vaginal health (Spurbeck and Arvidson, 2011), are at higher risk of acquiring HIV (Low et al., 2011; Martin et al., 1999; Myer et al., 2005)....
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TL;DR: At the epicentre of the HIV epidemic in southern Africa, adolescent girls and young women aged 15–24 contribute a disproportionate ~30% of all new infections and seroconvert 5–7 years earlier than their male peers.
Abstract: Introduction : At the epicentre of the HIV epidemic in southern Africa, adolescent girls and young women aged 15–24 contribute a disproportionate ~30% of all new infections and seroconvert 5–7 years earlier than their male peers. This age–sex disparity in HIV acquisition continues to sustain unprecedentedly high incidence rates, and preventing HIV infection in this age group is a pre-requisite for achieving an AIDS-free generation and attaining epidemic control. Discussion : Adolescent girls and young women in southern Africa are uniquely vulnerable to HIV and have up to eight times more infection than their male peers. While the cause of this vulnerability has not been fully elucidated, it is compounded by structural, social and biological factors. These factors include but are not limited to: engagement in age-disparate and/or transactional relationships, few years of schooling, experience of food insecurity, experience of gender-based violence, increased genital inflammation, and amplification of effects of transmission co-factors. Despite the large and immediate HIV prevention need of adolescent girls and young women, there is a dearth of evidence-based interventions to reduce their risk. The exclusion of adolescents in biomedical research is a huge barrier. School and community-based education programmes are commonplace in many settings, yet few have been evaluated and none have demonstrated efficacy in preventing HIV infection. Promising data are emerging on prophylactic use of anti-retrovirals and conditional cash transfers for HIV prevention in these populations. Conclusions : There is an urgent need to meet the HIV prevention needs of adolescent girls and young women, particularly those who are unable to negotiate monogamy, condom use and/or male circumcision. Concerted efforts to expand the prevention options available to these young women in terms of the development of novel HIV-specific biomedical, structural and behavioural interventions are urgently needed for epidemic control. In the interim, a pragmatic approach of integrating existing HIV prevention efforts into broader sexual reproductive health services is a public health imperative. Keywords: HIV prevention; adolescent girls; young women; prevention interventions. (Published: 26 February 2015) Citation: Dellar RC et al. Journal of the International AIDS Society 2015, 18(Suppl 1) :19408 http://www.jiasociety.org/index.php/jias/article/view/19408 | http://dx.doi.org/10.7448/IAS.18.2.19408
392 citations
Cites background from "Intravaginal Practices, Bacterial V..."
...although establishing causal relationships is challenging, intra-vaginal cleaning practices are more prevalent in younger women, suggesting thesewomen are consequentlymore likely to have an altered vaginal flora, potentially heightening their HIV susceptibility [55,56]....
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Durham University1, University of Washington2, University of California, Los Angeles3, University College London4, Bill & Melinda Gates Foundation5, University of the Witwatersrand6, University of London7, Population Council8, Africa University9, Memorial Sloan Kettering Cancer Center10, University of Toronto11, University of Southampton12, University of Cape Town13, RTI International14, University of Liverpool15, University of Bern16
TL;DR: 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.
Abstract: 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 (I(2) < 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 (p(interaction) = 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.
360 citations
Cites methods or result from "Intravaginal Practices, Bacterial V..."
...Results We included the ten studies [15, 16, 20, 30, 32–42] (Table 1) that contributed to the VPRP meta-analysis [21]....
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...First, we used a database containing IPD from ten studies that contributed to an IPD meta-analysis of the effects of vaginal practices on the risk of HIV acquisition among women [21], amassed by the Vaginal Practices Research Partnership (VPRP)....
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...Study Selection The ten studies contributing to the VPRP IPD meta-analysis [21] all had prospective hormonal contraceptive use data and met all other inclusion criteria....
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TL;DR: The widely documented beneficial role of vaginal Lactobacillus species demonstrates the potential of data on the composition and activity of lactobacilli as biomarkers for vaginal health, and the substantiation and further validation of such biomarkers will allow the design of better targeted probiotic strategies.
Abstract: The human body is colonized by a vast number of microorganisms collectively referred to as the human microbiota. One of the main microbiota body sites is the female genital tract, commonly dominated by Lactobacillus spp., in approximately 70% of women. Each individual species can constitute approximately 99% of the ribotypes observed in any individual woman. The most frequently isolated species are Lactobacillus crispatus, Lactobacillus gasseri, Lactobacillus jensenii and Lactobacillus iners. Residing at the port of entry of bacterial and viral pathogens, the vaginal Lactobacillus species can create a barrier against pathogen invasion since mainly products of their metabolism secreted in the cervicovaginal fluid can play an important role in the inhibition of bacterial and viral infections. Therefore, a Lactobacillus-dominated microbiota appears to be a good biomarker for a healthy vaginal ecosystem. This balance can be rapidly altered during processes such as menstruation, sexual activity, pregnancy and various infections. An abnormal vaginal microbiota is characterized by an increased diversity of microbial species, leading to a condition known as bacterial vaginosis. Information on the vaginal microbiota can be gathered from the analysis of cervicovaginal fluid, by using the Nugent scoring or the Amsel’s criteria, or at the molecular level by investigating the number and type of Lactobacillus species. However, when translating this to the clinical setting, it should be noted that the absence of a Lactobacillus-dominated microbiota does not appear to directly imply a diseased condition or dysbiosis. Nevertheless, the widely documented beneficial role of vaginal Lactobacillus species demonstrates the potential of data on the composition and activity of lactobacilli as biomarkers for vaginal health. The substantiation and further validation of such biomarkers will allow the design of better targeted probiotic strategies.
336 citations
Cites background from "Intravaginal Practices, Bacterial V..."
...A significant association was detected between women with BV, and thus lack of predominant Lactobacillus spp., and increased susceptibility to HIV acquisition (Atashili et al., 2008; Low et al., 2011)....
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TL;DR: The impact of suboptimal product adherence on PrEP efficacy in the context of variable drug concentration at the exposure site, integrity of the vaginal epithelium, and the role of acute infection is discussed.
Abstract: Although the balance of recent evidence supports the efficacy of antiretroviral (ARV)-based pre-exposure prophylaxis (PrEP) against HIV-1 infection, recent negative trial results are perplexing. Of seven trials with available HIV endpoints, three different products have been tested: tenofovir 1% vaginal gel, oral tenofovir disoproxil fumarate (TDF) tablets, and TDF/emtricitabine tablets. Six of these trials were conducted exclusively in sub-Saharan Africa; all found the products to be well tolerated, and four demonstrated effectiveness. Furthermore, the HIV Prevention Trial Network (HPTN) 052 trial recently confirmed that antiretroviral treatment leads to 96% reduction in transmission to HIV-negative partners in HIV-serodiscordant couples. These results, along with human and animal data, provide substantial evidence for the efficacy of antiretroviral-based HIV prevention. Yet assessment of oral TDF/emtricitabine in the FEM-PrEP study and of oral and vaginal tenofovir in the Microbicide Trial Network (MTN)-003 trial (VOICE) was stopped for futility. How do we make sense of these discrepant results? We believe that adherence is a key factor, although it cannot be the only factor. Expanding upon a recent editorial in the Lancet, we discuss the impact of suboptimal product adherence on PrEP efficacy in the context of variable drug concentration at the exposure site, integrity of the vaginal epithelium, and the role of acute infection.
299 citations
Cites background from "Intravaginal Practices, Bacterial V..."
...A meta-analysis confirmed that intravaginal use of soap, cloth, paper, or drying products increased risk of acquiring HIV [42]....
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References
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TL;DR: It is concluded that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity, and one or both should be presented in publishedMeta-an analyses in preference to the test for heterogeneity.
Abstract: The extent of heterogeneity in a meta-analysis partly determines the difficulty in drawing overall conclusions. This extent may be measured by estimating a between-study variance, but interpretation is then specific to a particular treatment effect metric. A test for the existence of heterogeneity exists, but depends on the number of studies in the meta-analysis. We develop measures of the impact of heterogeneity on a meta-analysis, from mathematical criteria, that are independent of the number of studies and the treatment effect metric. We derive and propose three suitable statistics: H is the square root of the chi2 heterogeneity statistic divided by its degrees of freedom; R is the ratio of the standard error of the underlying mean from a random effects meta-analysis to the standard error of a fixed effect meta-analytic estimate, and I2 is a transformation of (H) that describes the proportion of total variation in study estimates that is due to heterogeneity. We discuss interpretation, interval estimates and other properties of these measures and examine them in five example data sets showing different amounts of heterogeneity. We conclude that H and I2, which can usually be calculated for published meta-analyses, are particularly useful summaries of the impact of heterogeneity. One or both should be presented in published meta-analyses in preference to the test for heterogeneity.
25,460 citations
"Intravaginal Practices, Bacterial V..." refers methods in this paper
...We pooled data if the level of between-study heterogeneity was mild or moderate, defined as a value from the I(2) statistic below 50% [22]....
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TL;DR: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) initiative developed recommendations on what should be included in an accurate and complete report of an observational study, resulting in a checklist of 22 items (the STROBE statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles.
Abstract: Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study's generalisability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control, and cross-sectional studies. We convened a 2-day workshop in September 2004, with methodologists, researchers, and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results, and discussion sections of articles. 18 items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the Web sites of PLoS Medicine, Annals of Internal Medicine, and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.
15,454 citations
TL;DR: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study, resulting in a checklist of 22 items that relate to the title, abstract, introduction, methods, results, and discussion sections of articles.
Abstract: Much biomedical research is observational. The reporting of such research is often inadequate, which hampers the assessment of its strengths and weaknesses and of a study’s generalizability. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Initiative developed recommendations on what should be included in an accurate and complete report of an observational study. We defined the scope of the recommendations to cover three main study designs: cohort, case-control and cross-sectional studies. We convened a two-day workshop, in September 2004, with methodologists, researchers and journal editors to draft a checklist of items. This list was subsequently revised during several meetings of the coordinating group and in e-mail discussions with the larger group of STROBE contributors, taking into account empirical evidence and methodological considerations. The workshop and the subsequent iterative process of consultation and revision resulted in a checklist of 22 items (the STROBE Statement) that relate to the title, abstract, introduction, methods, results and discussion sections of articles. Eighteen items are common to all three study designs and four are specific for cohort, case-control, or cross-sectional studies. A detailed Explanation and Elaboration document is published separately and is freely available on the web sites of PLoS Medicine, Annals of Internal Medicine and Epidemiology. We hope that the STROBE Statement will contribute to improving the quality of reporting of observational studies.
13,974 citations
"Intravaginal Practices, Bacterial V..." refers methods in this paper
...Assessment of the Risk of Bias We assessed the potential for bias in each cohort study, arising from prespecified methodological domains [21]: description of participation and evidence of bias; definitions of diagnostic Intravaginal Practices and HIV Infection...
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TL;DR: In this article, a general class of regression models for ordinal data is developed and discussed, which utilize the ordinal nature of the data by describing various modes of stochastic ordering and this eliminates the need for assigning scores or otherwise assuming cardinality instead of ordinality.
Abstract: SUMMARY A general class of regression models for ordinal data is developed and discussed. These models utilize the ordinal nature of the data by describing various modes of stochastic ordering and this eliminates the need for assigning scores or otherwise assuming cardinality instead of ordinality. Two models in particular, the proportional odds and the proportional hazards models are likely to be most useful in practice because of the simplicity of their interpretation. These linear models are shown to be multivariate extensions of generalized linear models. Extensions to non-linear models are discussed and it is shown that even here the method of iteratively reweighted least squares converges to the maximum likelihood estimate, a property which greatly simplifies the necessary computation. Applications are discussed with the aid of examples.
3,647 citations
"Intravaginal Practices, Bacterial V..." refers methods in this paper
...We used ordered logistic regression with a proportional odds model [25]....
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Journal Article•
3,569 citations