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The impetus for, and efforts in the past 20 years toward a women-initiated method for preventing sexual transmission of HIV has been previously well described. To date, four classes of topical agents categorized by mechanism of action as: surfactants, buffers, cell entry blockers and antiretroviral agents have undergone advanced clinical testing. Thus far, only coitally linked use of 1% tenofovir gel has demonstrated moderate effectiveness in preventing HIV and HSV-2 infection and has generated renewed hope for microbicide development. Studies of new antiviral agents, novel delivery mechanisms and combination/multipurpose products that address challenges of adherence and enhance the effectiveness of tenofovir gel are already underway to further enhance sexual and reproductive health needs of men and women and efforts to prevent HIV infection.

We investigated the validity of self-reporting of genital symptoms amongst rural women attending primary health care clinics in rural KwaZulu-Natal. Random samples of 226 women were interviewed to measure self-reporting (unprompted), prompted and pelvic examination findings of genital symptoms. Against the presence of any STI self-reporting (unprompted) of symptoms had a sensitivity of 46.1%, specificity of 64.7%, positive predictive value (PPV) of 80.0% and negative predictive value (NPV) of 28.0% compared to prompted symptoms which had a sensitivity of 78.5%, specificity of 52.9%, PPV of 80.4% and NPV of 50.0%. The agreement between self-reporting (unprompted) and prompted symptoms was 0.54 (Kappa statistic). Our results suggest that in rural areas, by prompting women with a simple set of questions, the identification and treatment of STIs in this population would be enhanced, leading to better reproductive health outcomes including reduction of risk of infection with HIV.

Background: The presence of semen in the vagina from unprotected sex may influence the immune and microbial environment of the female genital tract. Inflammatory cytokine concentrations and BV-associated bacteria in female genital secretions may influence HIV risk, although the effect of recent sexual intercourse on incident BV and the cytokine milieu of cervicovaginal secretions has rarely been measured in previous studies. Here, we investigated the extent to which partner semen impacts the cytokine response and incident BV. Methods: At baseline, we assessed the recency of semen exposure in menstrual cup supernatants by quantifying prostate specific antigen (PSA) levels using ELISA in 248 HIV-uninfected women at high risk for HIV infection. Luminex was used to measure 48 cytokines in menstrual cup supernatants and vaginal swabs to diagnose BV by Nugent score. Point-of-care screening for Chlamydia trachomatis and Neisseria gonorrhoeae was conducted using GeneXpert while OSOM was used for Trichomonas vaginalis detection. Multivariable models, adjusted for age, sexually transmitted infections, BV, current contraception use and condom use, were used to assess the impact of semen exposure on biomarkers of inflammation and BV. Results: Presence of PSA, indicating recent semen exposure within 48 hours prior to sampling, was observed in menstrual cup supernatants of 17% (43/248) of women. Of these women, 70% (30/43) had self-reported condom use at their last sex act and 84% (36/43) had BV (Nugent score >7). PSA presence was significantly associated with prevalent BV (Relative Risk (RR), 2.609; 95% Confidence Interval (CI), 1.104 - 6.165; p = 0.029). Furthermore, women with detectable PSA had high median concentrations of macrophage inflammatory protein- beta (MIP-1α, p=0.047) and low median concentration of the stem cell growth factor beta (SCGF-β, p=0.038) compared to those without PSA. Conclusion: A degree of discordance between self-reports of consistent condom use and PSA positivity was observed. There was also evidence of a relationship between recent semen exposure, BV prevalence and altered cytokine concentrations. These findings suggest that PSA, as a semen biomarker, should be taken into consideration when investigating biological markers in the female genital tract and self-reported condom use in studies on reproductive and sexual health. [ABSTRACT FROM AUTHOR]

Background: High rates of bacterial vaginosis (BV) have been described in nonpregnant South African women. Studies of BV in South African pregnant women are sparse. Diagnosis and prompt treatment of BV in pregnancy are expected to have a positive impact on pregnancy outcomes and HIV prevention. This study was undertaken to determine the prevalence of BV in pregnant women in a high HIV burden periurban setting in KwaZulu-Natal and explore how to enhance BV diagnosis in this setting where syndromic management of sexually transmitted diseases is the standard of care.Methods: In this cross-sectional study, consenting HIV uninfected pregnant women were examined for abnormal vaginal discharge; nurses determined the vaginal pH and collected a vaginal swab for Gram-stain and Nugent scoring.Findings: Among 750 HIV uninfected pregnant women, 280 (37.3%; 95%CI 33.9-40.9) tested positive for BV. Using a vaginal pH > 4.4, 65% of women with BV were correctly identified, while an abnormal vaginal discharge correctly identified a significantly lower proportion (52.9%) of women with BV (p=0.005). The sensitivity, specificity, and positive and negative predictive values of vaginal pH testing were 65.9% (95%CI 60.0 - 71.5%), 61.4% (95%CI 56.8 - 65.9%), and 50.1% and 75.4%, respectively. The 20-24 year-old pregnant women were twice more likely to test positive for BV than the adolescent pregnant women (43.6% vs 21.1%) (p = 0.037) and BV was not associated with the duration of a sexual relationship, frequency of unprotected sex during pregnancy, number of lifetime sex partners, or the partner's age.Conclusion: There is a high burden of primarily asymptomatic BV in HIV uninfected pregnant women in this periurban setting. Both the sensitivity and specificity of vaginal pH testing are superior to the symptomatic diagnosis of BV but not good enough to be used as a screening tool. [ABSTRACT FROM AUTHOR]

Background: Untreated sexually transmitted infections (STIs) and bacterial vaginosis (BV) cause genital inflammation and increase the risk of HIV infection. WHO-recommended syndromic STI and BV management is severely limited as many women with asymptomatic infections go untreated. The purpose of this cross-sectional study was to evaluate genital cytokine profiles as a biomarker of STIs and BV to identify women with asymptomatic, treatable infections.Methods: Concentrations of 42 cytokines in cervicovaginal lavages from 227 HIV-uninfected women were measured using Luminex. All women were screened for BV by microscopy and STIs using molecular assays. Multivariate analyses were used to identify cytokine profiles associated with STIs/BV.Results: A multivariate profile of seven cytokines (interleukin (IL)-1α, IL-1β, tumour necrosis factor-β, IL-4, fractalkine, macrophage-derived chemokine, and interferon-γ) most accurately predicted the presence of a treatable genital condition, with 77% classification accuracy and 75% cross-validation accuracy (sensitivity 72%; specificity 81%, positive predictive value (PPV) 86%, negative predictive value (NPV) 64%). Concomitant increased IL-1β and decreased IP-10 concentrations predicted the presence of a treatable genital condition without a substantial reduction in predictive value (sensitivity 77%, specificity 72%, PPV 82% and NPV 65%), correctly classifying 75% of the women. This approach performed substantially better than clinical signs (sensitivity 19%, specificity 92%, PPV 79% and NPV 40%).Conclusions: Supplementing syndromic management with an assessment of IL-1β and IP-10 as biomarkers of genital inflammation may improve STI/BV management for women, enabling more effective treatment of asymptomatic infections and potentially reducing their risk of HIV infection. [ABSTRACT FROM AUTHOR]

The article presents a study on the use of tenofovir gel in preventing herpes simplex virus type 2 infections. Topics include the global strategy to prevent and control sexually transmitted diseases of the World Health Organization, the participation of women at the Centre for the AIDS Programme of Research in South Africa (CAPRISA), and the use of the Western blot assay in testing.

Objective Adolescents in southern African high schools are a key population for HIV prevention interventions. We report on the prevalence of HIV, HSV-2 and pregnancy as indicators of high-risk sexual behaviour among high school students in rural KwaZulu-Natal. Design Bio-behavioural cross-sectional survey. Methods Students completed a self-administered structured, standardised demographic and sexual behavioural questionnaire. Dried blood spot specimens were collected for HIV and HSV-2 testing. Urine specimens were used for pregnancy testing in female students. Results A total of 2675 (1423 females, 1252 males) consenting students were enrolled from 14 high schools between September and November 2010. The median age of students was 16 years (IQR 15-18). HIV prevalence was 1.4% (95% CI 0.9 to 1.9) in males and 6.4% (95% CI 4.6 to 8.3) in females ( p<0.001). HSV-2 prevalence was 2.6% (95% CI 1.6 to 3.7) in males and 10.7% (95% CI 8.8 to 12.6) in females ( p<0.001). Pregnancy prevalence was 3.6% (95% CI 2.6 to 4.5). Risk factors for prevalent HIV infection in female students included being over 18 years of age (adjusted OR (aOR)=2.67, 95% CI 1.67 to 4.27; p<0.001), prevalent HSV-2 infection (aOR=4.35, 95% CI 2.61 to 7.24; p<0.001), previous pregnancy (aOR=1.66, 95% CI 1.10 to 2.51; p=0.016) and experience of two or more deaths in the household in the previous year (aOR=1.97, 95% CI 1.13 to 3.44; p=0.016). Conclusions The high prevalence of HIV, HSV-2 and pregnancy underscore the need for school-based sexual and reproductive health services, and provide further impetus for the inclusion of adolescents in behavioural and biomedical trials with HIV incidence endpoints. [ABSTRACT FROM AUTHOR]

Objectives Sexually transmitted infections (STI) and bacterial vaginosis (BV) cause female genital tract inflammation. This inflammation, which is often present in the absence of symptoms, is associated with increased susceptibility to HIV infection. We aimed to evaluate genital cytokine profiles and the degree of inflammation associated with common STIs and BV. Methods HIV-uninfected women (n=227) were screened for BV, Chlamydia trachomatis, Neisseria gonorrhoeae, Herpes simplex virus type 2 (HSV-2), and Trichomonas vaginalis. Concentrations of 42 cytokines in cervicovaginal lavages and 13 cytokines in plasma were measured using Luminex. Changes in cytokine profiles were evaluated using Mann-Whitney U test, logistic regression and factor analysis. p Values were adjusted for multiple comparisons using a false discovery rate step-down procedure. Results Women with chlamydia or gonorrhoea had the highest genital cytokine concentrations, with 17/42 and 14/42 cytokines upregulated compared with women with no infection, respectively. BV was associated with elevated proinflammatory cytokine concentrations, but lower chemokine and haematopoietic cytokine concentrations. HSV-2 reactivation was associated with lower levels of inflammation, while trichomoniasis did not cause significant differences in genital cytokine concentrations. Genital infections did not influence plasma cytokine concentrations. Although certain STIs, in particular chlamydia and gonorrhoea, were associated with high genital cytokine concentrations, only 19% of women with an STI/BV had clinical signs. Conclusions Chlamydia was associated with the highest genital cytokine levels, followed by gonorrhoea, HSV-2, trichomoniasis, and BV. In regions where HIV is prevalent and STIs are managed syndromically, better STI/BV screening is urgently needed, as certain infections were found to be highly inflammatory. [ABSTRACT FROM AUTHOR]

Background: Antiretroviral prophylaxis may be a critical strategy to reduce periconception HIV transmission. Maximizing the benefit of periconception pharmacologic HIV risk-reduction requires an understanding of the links between pregnancy and adherence to this prevention strategy. Methods: We assessed study gel adherence among women with pregnancies compared to women without pregnancies enrolled in the CAPRISA 004 phase IIB trial of 1% vaginal tenofovir gel. Pregnancy was assessed with monthly urine tests. Adherence was measured monthly and defined as proportion of sex acts covered by two returned, used applicators based on pre- and post-coital dosing. High adherence was defined as a median adherence score of >80%, that is, more than 80% of sex acts were covered by two applications of study gel. A multivariate generalized estimating equations (GEE) model with a binomial distribution was used to assess covariates associated with high adherence (>80%) over time. Median adherence before and after pregnancy was compared using Wilcoxon signed rank test. Results: Among 868 women, 53 had at least 1 pregnancy (4.06 per 100 woman years, 95% CI: 3.04, 5.31). Women with pregnancies had lower median adherence compared to women without pregnancies (50% [IQR: 45–83] vs. 60% [IQR: 50–100], p = 0.02). Women with pregnancies also had a 48% lower odds of high adherence compared to women without pregnancies when adjusting for confounders (aOR 0.52, 95%CI: 0.41–0.66, p<0.0001). Among women with pregnancies, adherence before and after pregnancy was not different (50% [IQR: 46–83] vs. 55% [IQR: 20–100], p = 0.68). Conclusions: Women with pregnancies were less likely to have high adherence to study gel compared to women without pregnancies. Understanding these differences may inform findings from HIV prevention trials and future implementation of antiretroviral prophylaxis for at-risk women who choose to conceive. The protocol for the parent trial is registered on ClinicalTrials.gov, NCT00441298, http://www.clinicaltrials.gov/ct2/show/NCT00441298. [ABSTRACT FROM AUTHOR]

Background: Recent reports suggest that Natural Killer (NK) cells may modulate pathogenesis of primary HIV-1 infection. However, HIV dysregulates NK-cell responses. We dissected this bi-directional relationship to understand how HIV impacts NK-cell responses during primary HIV-1 infection. Methodology/Principal Findings: Paired samples from 41 high-risk, initially HIV-uninfected CAPRISA004 participants were analysed prior to HIV acquisition, and during viraemic primary HIV-1 infection. At the time of sampling post-infection five women were seronegative, 11 women were serodiscordant, and 25 women were seropositive by HIV-1 rapid immunoassay. Flow cytometry was used to measure NK and T-cell activation, NK-cell receptor expression, cytotoxic and cytokine-secretory functions, and trafficking marker expression (CCR7, α\(_4\)β\(_7\)). Non-parametric statistical tests were used. Both NK cells and T-cells were significantly activated following HIV acquisition (p = 0.03 and p<0.0001, respectively), but correlation between NK-cell and T-cell activation was uncoupled following infection (pre-infection r = 0.68;p<0.0001; post-infection, during primary infection r = 0.074;p = 0.09). Nonetheless, during primary infection NK-cell and T-cell activation correlated with HIV viral load (r = 0.32'p = 0.04 and r = 0.35;p = 0.02, respectively). The frequency of Killer Immunoglobulin-like Receptor-expressing (KIR\(_{pos}\)) NK cells increased following HIV acquisition (p = 0.006), and KIR\(_{pos}\) NK cells were less activated than KIR\(_{neg}\) NK cells amongst individuals sampled while seronegative or serodiscordant (p = 0.001;p<0.0001 respectively). During HIV-1 infection, cytotoxic NK cell responses evaluated after IL-2 stimulation alone, or after co-culture with 721 cells, were impaired (p = 0.006 and p = 0.002, respectively). However, NK-cell IFN-y secretory function was not significantly altered. The frequency of CCR7+ NK cells was elevated during primary infection, particularly at early time-points (p<0.0001). Conclusions/Significance: Analyses of immune cells before and after HIV infection revealed an increase in both NK-cell activation and KIR expression, but reduced cytotoxicity during acute infection. The increase in frequency of NK cells able to traffic to lymph nodes following HIV infection suggests that these cells may play a role in events in secondary lymphoid tissue.