Janneke van de Wijgert

Hormonal Contraception and the Risk of HIV Acquisition: An Individual Participant Data Meta-analysis:

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.

Intravaginal Practices, Bacterial Vaginosis, and HIV Infection in Women: Individual Participant Data Meta-analysis

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.

The vaginal microbiota: what have we learned after a decade of molecular characterization?

We conducted a systematic review of the Medline database (U.S. National Library of Medicine, National Institutes of Health, Bethesda, MD, U.S.A) to determine if consistent molecular vaginal microbiota (VMB) composition patterns can be discerned after a decade of molecular testing, and to evaluate demographic, behavioral and clinical determinants of VMB compositions. Studies were eligible when published between 1 January 2008 and 15 November 2013, and if at least one molecular technique (sequencing, PCR, DNA fingerprinting, or DNA hybridization) was used to characterize the VMB. Sixty three eligible studies were identified. These studies have now conclusively shown that lactobacilli-dominated VMB are associated with a healthy vaginal micro-environment and that bacterial vaginosis (BV) is best described as a polybacterial dysbiosis. The extent of dysbiosis correlates well with Nugent score and vaginal pH but not with the other Amsel criteria. Lactobacillus crispatus is more beneficial than L. iners. Longitudinal studies have shown that a L. crispatus-dominated VMB is more likely to shift to a L. iners-dominated or mixed lactobacilli VMB than to full dysbiosis. Data on VMB determinants are scarce and inconsistent, but dysbiosis is consistently associated with HIV, human papillomavirus (HPV), and Trichomonas vaginalis infection. In contrast, vaginal colonization with Candida spp. is more common in women with a lactobacilli-dominated VMB than in women with dysbiosis. Cervicovaginal mucosal immune responses to molecular VMB compositions have not yet been properly characterized. Molecular techniques have now become more affordable, and we make a case for incorporating them into larger epidemiological studies to address knowledge gaps in etiology and pathogenesis of dysbiosis, associations of different dysbiotic states with clinical outcomes, and to evaluate interventions aimed at restoring and maintaining a lactobacilli-dominated VMB.

Factors affecting transmission of mucosal human papillomavirus

Human papillomavirus (HPV) is the most common sexually transmitted infection. The effect of HPV on public health is especially related to the burden of anogenital cancers, most notably cervical cancer. Determinants of exposure to HPV are similar to those for most sexually transmitted infections, but determinants of susceptibility and infectivity are much less well established. Gaps exist in understanding of interactions between HPV, HIV, and other sexually transmitted infections. The roles of mucosal immunology, human microbiota at mucosal surfaces, host genetic factors and hormonal concentrations on HPV susceptibility and infectivity are poorly understood, as are the level of effectiveness of some primary or secondary preventive measures other than HPV vaccination (such as condoms, male circumcision, and combination antiretroviral therapy for HIV). Prospective couples studies, studies focusing on mucosal immunology, and in-vitro raft culture studies mimicking HPV infection might increase understanding of the dynamics of HPV transmission.

Treatment of sexually transmitted infections for HIV prevention: end of the road or new beginning?

Observational and biological data provide compelling evidence of the importance of sexually transmitted infections (STIs) in HIV transmission, but only one of nine intervention trials has shown an effect. This article reviews the observational studies, critically examines the nine randomized controlled trials evaluating the impact of STI treatment interventions on HIV incidence, and discusses implications for HIV prevention policy, programs and future research. The role of other vaginal infections is also briefly considered. In aggregate, the evidence strongly supports the concept that STI treatment prevents HIV infection. However, issues in trial design and conduct, including HIV epidemic phase, STI prevalence, intervention in comparison groups, and power have affected five of the six trials of treatment of curable STIs. In the three herpes intervention trials, antivirals for HSV suppression were insufficiently potent to alleviate persistent genital inflammation in HIV-negative HSV2-positive persons, and the reduction in HIV levels in HIV-positive persons was insufficient to reduce HIV transmission. It is time for a new phase of exploration of how, when, and in whom to include STI control as a key component of HIV prevention, driven by basic research to elucidate the mechanisms by which STIs and vaginal infections facilitate HIV transmission. From a policy perspective, treatment of curable STIs is an essential part of primary healthcare and is a cheap, simple, and effective intervention when appropriately targeted and delivered. It should be promoted as an essential component of HIV control programs in communities in which the burden of STIs is substantial.

Bacterial vaginosis and vaginal yeast, but not vaginal cleansing, increase HIV-1 acquisition in African women

Objective:To evaluate interrelationships between bacterial vaginosis (BV), vaginal yeast, vaginal practices (cleansing and drying/tightening), mucosal inflammation, and HIV acquisition. Methods:A multicenter, prospective, observational cohort study was conducted, enrolling 4531 HIV-negative women aged 18 to 35 years attending family planning clinics in Zimbabwe and Uganda. Participants were tested for HIV and reproductive tract infections and were interviewed about vaginal practices every 3 months for 15 to 24 months. BV was measured by Gram stain Nugent scoring, vaginal yeast by wet mount, and mucosal inflammation by white blood cells on Gram stain. Results:HIV incidence was 4.12 and 1.53 per 100 woman-years of follow-up in Zimbabwe and Uganda, respectively (a total of 213 incident infections). Women with BV or vaginal yeast were more likely to acquire HIV, especially if the condition was present at the same visit as the new HIV infection and the visit preceding it (hazard ratio [HR] = 2.50, 95% confidence interval [CI]: 1.68 to 3.72 and HR = 2.97, 95% CI: 1.67 to 5.28 for BV and yeast, respectively). These relationships did not seem to be mediated by mucosal inflammation. Vaginal drying/tightening was associated with HIV acquisition in univariate (HR = 1.49, 95% CI: 1.03 to 2.15) but not multivariate models. Vaginal cleansing was not associated with HIV acquisition. Conclusions:BV and yeast may contribute more to the HIV epidemic than previously thought.

Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women.

Objectives:To assess the local and systemic safety of dapivirine vaginal gel vs. placebo gel as well as the systemic absorption of dapivirine in healthy, HIV-negative women. Methods:Two prospective, randomized, double-blind, placebo-controlled phase I/II studies were conducted at five research centers, four in Africa and one in Belgium. A total of 119 women used dapivirine gel (concentrations of 0.001, 0.002, 0.005, or 0.02%), and 28 used placebo gel twice daily for 42 days. The primary endpoints were colposcopic findings, adverse events, Division of AIDS grade 3 or grade 4 laboratory values, and plasma levels of dapivirine. Results:Safety data were similar for the dapivirine and placebo gels. None of the adverse events with incidence more than 5% occurred with greater frequency in the dapivirine than placebo groups. Similar percentages of placebo and dapivirine gel users had adverse events that were considered by the investigator to be related to study gel. A total of five serious adverse events occurred in the two studies, and none was assessed as related to study gel. Mean plasma concentrations of dapivirine were approximately dose proportional, and, within each dose group, mean concentrations were similar on days 7, 28, and 42. The maximum observed mean concentration was 474 pg/ml in the 0.02% gel group on day 28. Two weeks after the final application of study gel, mean concentrations decreased to 5 pg/ml or less. Conclusion:Twice daily administration of dapivirine vaginal gel for 42 days was safe and well tolerated with low systemic absorption in healthy, HIV-negative women suggesting that continued development is warranted.

Disentangling contributions of reproductive tract infections to HIV acquisition in African women.

Objective: To estimate the effects of reproductive tract infections (RTIs) on HIV acquisition among Zimbabwean and Ugandan women. Methods: A multicenter prospective observational cohort study enrolled 4439 HIV-uninfected women aged 18 to 35 attending family planning clinics in Zimbabwe and Uganda. Participants were interviewed, and tested for HIV and RTIs every 3 months for 15 to 24 months. They received HIV risk reduction counseling, male condoms, and treatment for curable RTIs. Results: Despite HIV risk reduction counseling and regular screening and treatment for RTIs, the HIV incidence did not decline during the study. Positive HSV-2 serostatus at baseline (hazard ratio [HR] = 3.69, 95% confidence interval = 2.45–5.55), incident HSV-2 (HR = 5.35, 3.06–9.36), incident Neisseria gonorrhoeae (HR = 5.46, 3.41–8.75), and altered vaginal flora during the study (bacterial vaginosis [BV]: HR = 2.12, 1.50–3.01; and intermediate flora: HR = 2.02, 1.39–2.95) were independently associated with HIV acquisition after controlling for demographic and behavioral covariates and other RTIs (Treponema pallidum, Chlamydia trachomatis, Trichomonas vaginalis, and vaginal yeasts). For N. gonorrhoeae, C. trachomatis, T. vaginalis, and vaginal yeasts, the risk of HIV acquisition increased when the infection was identified at the visit before the HIV-detection visit or with the duration of infection. Population attributable risk percent (PAR%) calculations show that HSV-2 contributes most to acquisition of new HIV infections (50.4% for baseline HSV-2 and 7.9% for incident HSV-2), followed by altered vaginal flora (17.2% for bacterial vaginosis and 11.8% for intermediate flora). Conclusions: A substantial proportion of new HIV infections in Zimbabwean and Ugandan women are attributable to RTIs, particularly HSV-2 and altered vaginal flora.

Safety and acceptability of the candidate microbicide Carraguard in Thai Women: findings from a Phase II Clinical Trial

Objective:To determine the safety and acceptability of vaginal application of Carraguard, a carrageenan-derived candidate microbicide gel. Design:A randomized, placebo-controlled, triple-blinded clinical trial was conducted in Chiang Rai, northern Thailand. Methods:Women were asked to insert one applicator of study gel vaginally at least three times per week (with or without sex) and to use gel with condoms every time they had sex. Safety was assessed by visual inspection of the vagina and cervix, changes in vaginal flora and self-reported symptoms at day 14, month 1 and then monthly for up to 1 year. Acceptability was assessed through reported use of the gel, return of used and unused applicators, and quarterly interviews. Results:One hundred sixty-five women were randomized: 83 to Carraguard and 82 to the placebo (methylcellulose gel) group. Study gel use was similarly high in both groups throughout the trial with an average of four applicators per week. Carraguard use was not associated with abnormal genital clinical findings, abnormal vaginal flora, Pap smear abnormalities or other abnormal clinical signs or symptoms. Adverse events were mostly mild, not attributed to gel use, and similarly distributed between groups. Participants in both groups reported high acceptability. Conclusions:Carraguard can safely be used an average of four times per week with or without sex and is acceptable to Thai women. A Phase III efficacy trial of Carraguard is warranted and is currently ongoing in South Africa.

Lactobacillus-dominated cervicovaginal microbiota associated with reduced HIV/STI prevalence and genital HIV viral load in african women

Cervicovaginal microbiota not dominated by lactobacilli may facilitate transmission of HIV and other sexually transmitted infections (STIs), as well as miscarriages, preterm births and sepsis in pregnant women. However, little is known about the exact nature of the microbiological changes that cause these adverse outcomes. In this study, cervical samples of 174 Rwandan female sex workers were analyzed cross-sectionally using a phylogenetic microarray. Furthermore, HIV-1 RNA concentrations were measured in cervicovaginal lavages of 58 HIV-positive women among them. We identified six microbiome clusters, representing a gradient from low semi-quantitative abundance and diversity dominated by Lactobacillus crispatus (cluster R-I, with R denoting ‘Rwanda’) and L. iners (R-II) to intermediate (R-V) and high abundance and diversity (R-III, R-IV and R-VI) dominated by a mixture of anaerobes, including Gardnerella, Atopobium and Prevotella species. Women in cluster R-I were less likely to have HIV (P=0.03), herpes simplex virus type 2 (HSV-2; P<0.01), and high-risk human papillomavirus (HPV; P<0.01) and had no bacterial STIs (P=0.15). Statistically significant trends in prevalence of viral STIs were found from low prevalence in cluster R-I, to higher prevalence in clusters R-II and R-V, and highest prevalence in clusters R-III/R-IV/R-VI. Furthermore, only 10% of HIV-positive women in clusters R-I/R-II, compared with 40% in cluster R-V, and 42% in clusters R-III/R-IV/R-VI had detectable cervicovaginal HIV-1 RNA (Ptrend=0.03). We conclude that L. crispatus-dominated, and to a lesser extent L. iners-dominated, cervicovaginal microbiota are associated with a lower prevalence of HIV/STIs and a lower likelihood of genital HIV-1 RNA shedding.