Marissa Becker

Lack of Effectiveness of Cellulose Sulfate Gel for the Prevention of Vaginal HIV Transmission

BACKGROUND Women make up more than 50% of adults living with human immunodeficiency virus (HIV) infection or the acquired immunodeficiency syndrome (AIDS) in sub-Saharan Africa. Thus, female-initiated HIV prevention methods are urgently needed. METHODS We performed a randomized, double-blind, placebo-controlled trial of cellulose sulfate, an HIV-entry inhibitor formulated as a vaginal gel, involving women at high risk for HIV infection at three African and two Indian sites. The primary end point was newly acquired infection with HIV type 1 or 2. The secondary end point was newly acquired gonococcal or chlamydial infection. The primary analysis was based on a log-rank test of no difference in the distribution of time to HIV infection, stratified according to site. RESULTS A total of 1398 women were enrolled and randomly assigned to receive cellulose sulfate gel (706 participants) or placebo (692 participants) and had follow-up HIV test data. There were 41 newly acquired HIV infections, 25 in the cellulose sulfate group and 16 in the placebo group, with an estimated hazard ratio of infection for the cellulose sulfate group of 1.61 (P=0.13). This result, which is not significant, is in contrast to the interim finding that led to the trial being stopped prematurely (hazard ratio, 2.02 [corrected]; P=0.05 [corrected]) and the suggestive result of a preplanned secondary (adherence-based) analysis (hazard ratio, 2.02; P=0.05). No significant effect of cellulose sulfate as compared with placebo was found on the risk of gonorrheal infection (hazard ratio, 1.10; 95% confidence interval [CI], 0.74 to 1.62) or chlamydial infection (hazard ratio, 0.71; 95% CI, 0.47 to 1.08). CONCLUSIONS Cellulose sulfate did not prevent HIV infection and may have increased the risk of HIV acquisition. (ClinicalTrials.gov number, NCT00153777; and Current Controlled Trials number, ISRCTN95638385.)

AIDS in South Asia : understanding and responding to a heterogenous epidemic

South Asias HIV epidemic is highly heterogeneous. As a result, informed, prioritized, and effective responses necessitate an understanding of the epidemic diversity between and within countries. Further spread of HIV in South Asia is preventable. The future size of South Asias epidemic will depend on an effective two-pronged approach: firstly, on the scope and effectiveness of HIV prevention programs for sex workers and their clients, injecting drug users and their sexual partners, and men having sex with men and their other sexual partners; and secondly, on the effectiveness of efforts to address the underlying socio-economic determinants of the epidemic, and to reduce stigma and discrimination towards people engaging in high risk behaviors, often marginalized in society, as well as people living with HIV and AIDS.

Prevalence and determinants of HIV infection in South India : a heterogeneous, rural epidemic

Objectives: To assess the prevalence and determinants of HIV infection in the general population in Bagalkot district, a largely rural district in the southern Indian state of Karnataka. Methods: Approximately 6700 individuals aged 15–49 years were randomly sampled from 10 villages and six towns, from three of Bagalkots six sub-districts. Each consenting respondent was administered a questionnaire, followed by blood collection and testing for HIV, syphilis, and herpes simplex virus type 2 (HSV-2) on a 25% sub-sample. Results: HIV prevalence was 2.9% overall, 2.4% in urban areas and 3.6% in rural areas [odds ratio (OR), 0.65; 95% confidence interval (CI), 0.45–0.95]. Significant differences in HIV prevalence were seen between the three sub-districts, with prevalences of 1.1, 3.0 and 6.4% (P < 0.05), and HIV prevalence in the 10 villages ranged from 0 to 8.2%. Reported multiple sexual partners, receiving money for sex and a history of medical injections were significantly associated with HIV infection, as were older age, being widowed, divorced, separated or deserted, lower education levels and being a woman of a lower caste. There was a strong association between HSV-2 and HIV infection (OR, 5.2; 95% CI, 2.3–11.5). Conclusions: The rural nature of this epidemic has important implications for prevention and care programs. The striking differentials observed in HIV prevalence between sub-districts and even villages suggest that risk and vulnerability for HIV are highly heterogeneous. Further research is required to understand the individual and community-level factors behind these differentials, so that preventive interventions can be directed to where they are most needed.

Estimated cumulative incidence of pandemic (H1N1) influenza among pregnant women during the first wave of the 2009 pandemic

Background: Hospitalization and lab confirmed cases of H1N1 have been reported during the first wave of the 2009 pandemic but these are not accurate measures of influenza incidence in the population. We estimated the cumulative incidence of pandemic (H1N1) influenza among pregnant women in the province of Manitoba during the first wave of the 2009 pandemic. Methods: Two panels of stored frozen serum specimens collected for routine prenatal screening were randomly selected for testing before (March 2009, n = 252) and after (August 2009, n = 296) the first wave of the pandemic. A standard hemagglutination inhibition assay was used to detect the presence of IgG antibodies against the pandemic (H1N1) 2009 virus. The cumulative incidence of pandemic (H1N1) influenza was calculated as the difference between the point prevalence rates in the first and second panels. Results: Of the specimens collected in March, 7.1% were positive for the IgG antibodies (serum antibody titre ≥ 1:40). The corresponding prevalence was 15.7% among the specimens collected in August. The difference indicated a cumulative incidence of 8.6% (95% confidence interval [CI] 3.2%–13.7%). The rate differed geographically, the highest being in the northern regions (20.8%, 95% CI 7.9%–31.8%), as compared with 4.0% (95% CI 0.0%–11.9%) in Winnipeg and 8.9% (95% CI 0.0%–18.8%) in the rest of the province. Interpretation: We estimated that the cumulative incidence of pandemic (H1N1) influenza among pregnant women in Manitoba during the first wave of the 2009 pandemic was 8.6%. It was 20.8% in the northern regions of the province.

HIV controllers are distinguished by chemokine expression profile and HIV-specific T-cell proliferative potential.

Background:HIV controllers demonstrate a natural ability to control HIV replication in the absence of antiretroviral therapy. We performed a comprehensive evaluation of inflammation and T-cell activation in a demographically unique cohort of HIV controllers and noncontrollers. Methods:Plasma concentrations of 22 cytokines and chemokines were evaluated using a multiplex bead array approach. Multicolor flow cytometry was used to measure baseline levels of T-cell activation and regulatory T cells (Tregs) and HIV-specific T-cell cytokine (interferon &ggr;, interleukin 2) and proliferation responses. Results:HIV controllers were characterized by elevated macrophage inflammatory protein 1&agr; and low levels of interferon &ggr;–induced protein 10, monocyte chemotactic protein 1, and Transforming growth factor beta. Activated (CD38+ HLA DR+) CD4+ and CD8+ T cells were reduced in HIV controllers relative to noncontrollers. HIV controllers and noncontrollers had comparable proportions of Tregs within the CD4+ T-cell compartment, but absolute Treg counts were depleted in noncontrollers. Absolute Treg counts correlated inversely with T-cell activation. Proliferative CD4+ and CD8+ T-cell responses directed against HIV gag epitopes were found most frequently among HIV controllers with the lowest viral loads (elite controllers) and were rarely detected among noncontrollers, supporting a relationship between HIV-specific T-cell proliferation and viral control. Conclusions:Collectively, these data suggest a model in which HIV controllers maintain low levels of viral replication through robust HIV-specific T-cell responses in an environment of low inflammation and reduced availability of activated target cells.

Syphilis screening among female sex workers in Bangalore, India: comparison of point-of-care testing and traditional serological approaches

Objectives We undertook a prospective evaluation of the Qualpro Syphicheck-WB rapid syphilis test to measure its diagnostic performance and utility as a point-of-care (POC) screening test among female sex workers (FSWs) in Bangalore, India. Methods From August 2008 to May 2009, FSWs without a laboratory-confirmed history of syphilis attending STI clinics in Bangalore underwent POC syphilis screening using finger-prick whole blood, with onsite treatment if indicated. Serum samples were collected for local laboratory offsite rapid plasma reagin (RPR) testing and reference laboratory RPR, Treponema pallidum haemagglutination assay (TPHA), and rapid syphilis testing. FSWs who participated in standard offsite RPR screening from August 2007 to May 2008 in the same clinics formed the comparison group for treatment coverage. Results Of the 1617 women who underwent POC syphilis testing, 7.4% had laboratory evidence of active syphilis with reactive RPR and TPHA, and 3.7% had an RPR titre ≥1:8. Compared with the reference RPR and TPHA, the sensitivity and specificity of the POC syphilis test were 70.8% (95% CI 62.7 to 79.0) and 97.8% (95% CI 97.1 to 98.5). Because of the low rate of women returning for their test results after offsite RPR screening, the proportion of women with active syphilis who were appropriately treated rose from 44.8% to 68.3% with the use of POC syphilis screening (p=0.003). Conclusion The Syphicheck-WB test utilising finger-prick whole blood has a relatively low sensitivity in detecting active syphilis. However, among hard-to-reach populations who may not return for follow-up treatment, POC screening with this assay could still confer an advantage over offsite RPR testing with respect to treatment coverage.

Etiology and determinants of sexually transmitted infections in Karnataka state, south India.

Background: Syndromic case management remains the cornerstone for STI (sexually transmitted infection) treatment in many countries. We undertook this study to better understand the etiology of STIs in adults in south India and to inform STI management guidelines. Methods: Adult males and females presenting with genital complaints were recruited from clinics in Karnataka state, south India. A questionnaire was administered, physical examination performed, and blood collected for herpes simplex virus-type 2 (HSV-2) and syphilis serology. Men with urethral discharge (UD) and women with vaginal discharge were tested for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV). Vaginal swabs were also tested for bacterial vaginosis and yeast infection. Participants with genital ulcers were tested for Treponema pallidum (TP), Haemophilus ducreyi (HD), and HSV-2. human immunodeficiency virus (HIV) testing was offered to all individuals. Results: There were 401 male and 412 female participants, and rates of HIV infection were high (men, 17%; women, 15%). HSV-2 was significantly associated with HIV in men and women. Among men with the complaint of UD, NG was identified in 35%, CT in 10.5%, and TV in 8.5%. Very little NG or CT was detected among women with vaginal discharge. However, bacterial vaginosis was identified in approximately 40% of women, with significant amounts of TV and Candida also detected. HSV-2 was the most commonly identified pathogen among participants with genital ulcer disease, and the clinical distinction of herpetic versus nonherpetic lesions was not helpful. Conclusions: Current STI management guidelines should be reevaluated in south India. Consideration should be given to treating all persons with GUD for both HSV-2 and syphilis, and to adding initial treatment for TV for men with UD in areas of high background prevalence of HSV-2 and TV, respectively. This population is at high risk for HIV, and should be counseled and tested appropriately.

Rates and determinants of HIV-attributable mortality among rural female sex workers in Northern Karnataka, India:

Female sex workers (FSWs) have among the highest rates of HIV infection in India. However, little is known about their HIV-specific mortality rates. In total, 1561 FSWs participated in a cohort study in Karnataka. Outcome data (mortality) were available on 1559 women after 15 months of follow-up. To gather details on deaths, verbal autopsy (VA) questionnaires were administered to key informants. Two physicians reviewed the VA reports and assigned underlying causes of death. Forty-seven deaths were reported during the follow-up (overall mortality rate was 2.44 per 100 person-years), with VA data available on 45 women. Thirty-five (75.6%) of these women were known to be HIV-positive, but only 42.5% were on antiretroviral therapy (ART). Forty deaths were assessed to be HIV-related, for an HIV-attributable mortality rate of 2.11 deaths per 100 person-years. Absence of a current regular partner (incidence rate ratio: 2.79; 95% confidence interval [CI]: 1.39–5.60) and older age (1.06; 1.01–1.11) were associated with increased HIV-attributable mortality. Reported duration in sex work was not related to HIV-attributable mortality. We found a high HIV-related mortality rate among this cohort of FSWs; nearly 10 times that of national mortality rates among women of a similar age group. Older age, but not reported duration in sex work, was associated with increased mortality, and suggests HIV acquisition prior to self-reported initiation into sex work. Despite significant efforts, there remain considerable gaps in HIV prevention near or before entry into sex work, as well as access and uptake of HIV treatment among FSWs.

Intermediate vaginal flora is associated with HIV prevalence as strongly as bacterial vaginosis in a cross-sectional study of participants screened for a randomised controlled trial

Objective The authors analysed data from female sex workers screened prior to participation in a microbicide trial to examine the association between prevalent vaginal flora abnormalities and HIV infection, with special emphasis on the role of the intermediate vaginal flora (IVF) in this association. Methods Data from the Kampala, Cotonou, Chennai and Mudhol/Jamkhandi sites were analysed. Participants were interviewed and provided blood for HIV and syphilis antibody testing, genital samples for the diagnosis of vaginal flora abnormalities (using Nugent score) and other reproductive tract infections. Log-binomial regression was used to estimate the HIV prevalence ratio (PR) in relation to IVF and bacterial vaginosis (BV). Results Among 1367 women, BV, IVF and HIV prevalences were 47.6% (95% CI=45.0% to 50.3%), 19.2% (95% CI=17.1% to 21.2%) and 27.0% (95% CI=24.6% to 29.3%), respectively. In multivariate analysis, adjusting for study site, age, years of education, occupation, female sterilisation, oral sex, past history of sexually transmitted infection, gonorrhoea and candidiasis, IVF was significantly associated with HIV infection with a PR similar to that of BV (adjusted PR=1.56 (95% CI=1.22 to 1.98) and 1.48 (95% CI=1.20 to 1.84), respectively). Conclusions Though the cross-sectional design of the study precludes directional interpretation of the findings, the data do suggest that IVF may be as important as BV in HIV acquisition. The authors recommend prospective research to better understand the association between IVF and HIV acquisition.

Behavioural and medical predictors of bacterial vaginosis recurrence among female sex workers: longitudinal analysis from a randomized controlled trial

BackgroundData on risk factors of recurrent bacterial vaginosis (RBV) are still scarce. We used data from female sex workers (FSW) participating in a randomized controlled microbicide trial to examine predictors of BV recurrence.MethodsTrial’s participants with at least an episode of BV which was treated and/or followed by a negative BV result and at least one subsequent visit offering BV testing were included in the analysis. Behavioural and medical data were collected monthly while laboratory testing for STI and genital tract infections were performed quarterly. The Andersen-Gill proportional hazards model was used to determine predictors of BV recurrence both in bivariate and multivariate analyses.Results440 women were included and the incidence rate for RBV was 20.8 recurrences/100 person-months (95% confidence interval (CI) =18.1–23.4). In the multivariate analysis controlling for the study site, recent vaginal cleansing as reported at baseline with adjusted hazard-ratio (aHR)=1.30, 95% CI = 1.02-1.64 increased the risk of BV recurrence, whereas consistent condom use (CCU) with the primary partner (aHR=0.68, 95% CI=0.49-0.93) and vaginal candidiasis (aHR=0.70, 95% CI=0.53-0.93), both treated as time-dependent variables, were associated with decreased risk of RBV.ConclusionThis study confirms the importance of counselling high-risk women with RBV about the adverse effects of vaginal cleansing and the protective effects of condom use with all types of partners for the prevention of sexually transmitted infections, including BV. More prospective studies on risk factors of BV recurrence are warranted.Trial registrationTrial registration: NCT00153777