Spatial variations in STIs among women enrolled in HIV prevention clinical trials in Durban, KwaZulu-Natal, South Africa.

South Africa is faced with a high HIV and STI prevalence and incidence, respectively, with pockets of high burden areas driving these diseases. Localised monitoring of the HIV epidemic and STI endemic would enable more effective targeted prevention strategies. We assessed spatial variations in curable STI incidence among a cohort of women enrolled in HIV prevention clinical trials between 2002 and 2012. STI incidence rates from 7557 South African women enrolled in five HIV prevention trials were geo-mapped using participant household GPS coordinates. Age and period standardised incidence rates were calculated for 43 recruitment areas and Bayesian conditional autoregressive areal spatial regression (CAR) was used to identify significant patterns and spatial patterns of STI infections in recruitment communities. Overall age and period standardised STI incidence rate were estimated as 15 per 100 PY and ranged from 6 to 24 per 100 PY. We identified five significant STI high risk areas with higher-than-expected incidence of STIs located centrally (three-locations) and southern neighbouring areas of Durban (two-locations). Younger age (<25), not married/cohabitating, parity <3 and poor education were all significant correlates of high STI communities. Findings demonstrate sustained STI incidence rates across the greater Durban area. The role of STI incidence in HIV acquisition in high HIV endemic areas need to be revisited as current highly effective PrEP interventions do not protect from STI acquisition. In these settings there is an urgent need for integrative HIV and STI prevention and treatment services.

Quantifying Vulnerabilities of Single Women and Sexually Transmitted Infections in South Africa (2002-2016): Is It Getting Better (or Worse)?

Curable sexually transmitted infections (STIs) affect millions of people across the world. Besides unacceptably high HIV rates, South Africa also has the highest burden of STIs in the world. The aim of the study was to investigate temporal changes in STI incidence rates using the data from ~ 10,000 women who enrolled in several HIV prevention trials, KwaZulu-Natal, South Africa (2002-2016). We particularly focused on the changes in distribution of the most influential factors and their population-level impacts on STI incidence rates over time. Characteristics of the women were compared across the study periods: 2002-2004, 2005-2008, 2009-2011, and 2012-2016. Besides multivariable Cox regression models, population attributable risks were calculated for the significant factors. Despite the significant progress in prevention, testing, and treatment programs, infection rates increased substantially from 13.6 to 20.0 per 100 person-year over the study period. Our findings provided a compelling evidence for single/non-cohabiting South African women to be the most vulnerable population who consistently and substantially contributed to increasing STI rates during the 15 years of study duration (PAR%: 44%-47%). We also highlighted the impact of women's lack of knowledge related to their partner, using injectable contraceptives, less parity, and baseline STI positivity which were increased substantially over time. Our findings suggest that a significant proportion of STIs could be prevented by targeting single/non-cohabiting. These results may provide guidance in developing more effective STI prevention programs by targeting women at highest risk of infections and delivering more realistic messages.

Broadly neutralizing antibody responses in the longitudinal primary HIV-1 infection Short Pulse Anti-Retroviral Therapy at Seroconversion cohort.

OBJECTIVE: Development of immunogens that elicit an anti-HIV-1 broadly neutralizing antibody (bnAb) response will be a key step in the development of an effective HIV-1 vaccine. Although HIV-1 bnAb epitopes have been identified and mechanisms of action studied, current HIV-1 envelope-based immunogens do not elicit HIV-1 bnAbs in humans or animal models. A better understanding of how HIV-1 bnAbs arise during infection and the clinical factors associated with bnAb development may be critical for HIV-1 immunogen design efforts. DESIGN AND METHODS: Longitudinal plasma samples from the treatment-naive control arm of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) primary HIV-1 infection cohort were used in an HIV-1 pseudotype neutralization assay to measure the neutralization breadth, potency and specificity of bnAb responses over time. RESULTS: In the SPARTAC cohort, development of plasma neutralization breadth and potency correlates with duration of HIV infection and high viral loads, and typically takes 3-4 years to arise. bnAb activity was mostly directed to one or two bnAb epitopes per donor and more than 60% of donors with the highest plasma neutralization having bnAbs targeted towards glycan-dependent epitopes. CONCLUSION: This study highlights the SPARTAC cohort as an important resource for more in-depth analysis of bnAb developmental pathways.

Quantifying geographical diversity in sexually transmitted infections using population attributable risk: results from HIV prevention trials in South Africa.

In this study, we investigated spatial diversities of sexually transmitted infections (STIs) and quantified their impacts on the STIs using population attributable risk (PAR%). The study population was 7,557 women who participated in several HIV prevention trials from KwaZulu-Natal, South Africa. Our results provide compelling evidence for substantial geographical diversities on STI incidence rates in the region. Their population-level impacts on the STIs exceeded the combined impacts of the individual risk factors considered in this study (PAR%: 41% (<25 years), 52% (25-34 years) and 34% (35+ years). When all these factors are considered together, PAR% was the highest among younger women (PAR%: 67%, 82% and 50% for <25, 25-34 and 35+ years old respectively). Results from our study will bring greater insight into the previous research by increasing our understanding of the impacts of the sub-geographical level variations of STI prevalence and incidence rates in the region.

Predictors of antiretroviral therapy initiation in eThekwini (Durban), South Africa: Findings from a prospective cohort study.

Despite expanded antiretroviral therapy (ART) eligibility in South Africa, many people diagnosed with HIV do not initiate ART promptly, yet understanding of the reasons is limited. Using data from an 8-month prospective cohort interview study of women and men newly-diagnosed with HIV in three public-sector primary care clinics in the eThekwini (Durban) region, South Africa, 2010-2014, we examined if theoretically-relevant social-structural, social-cognitive, psychosocial, and health status indicators were associated with time to ART initiation. Of 459 diagnosed, 350 returned to the clinic for their CD4+ test results (linkage); 153 (33.3%) were ART-eligible according to treatment criteria at the time; 115 (75.2% of those eligible) initiated ART (median = 12.86 weeks [95% CI: 9.75, 15.97] after linkage). In adjusted Cox proportional hazard models, internalized stigma was associated with a 65% decrease in the rate of ART initiation (Adjusted hazard ratio [AHR] 0.35, 95% CI: 0.19-0.80) during the period less than four weeks after linkage to care, but not four or more weeks after linkage to care, suggesting that stigma-reduction interventions implemented shortly after diagnosis may accelerate ART uptake. As reported by others, older age was associated with more rapid ART initiation (AHR for 1-year age increase: 1.04, 95% CI: 1.01-1.07) and higher CD4+ cell count (≥300µL vs. <150µL) was associated with a lower rate of initiation (AHR 0.38, 95% CI: 0.19-0.80). Several other factors that were assessed prior to diagnosis, including stronger belief in traditional medicine, higher endorsement of stigma toward people living with HIV, food insecurity, and higher psychological distress, were found to be in the expected direction of association with ART initiation, but confidence intervals were wide and could not exclude a null finding.

Safety, uptake, and use of a dapivirine vaginal ring for HIV-1 prevention in African women (HOPE): an open-label, extension study.

BACKGROUND: Two phase 3 clinical trials showed that use of a monthly vaginal ring containing 25 mg dapivirine was well tolerated and reduced HIV-1 incidence in women by approximately 30% compared with placebo. We aimed to evaluate use and safety of the dapivirine vaginal ring (DVR) in open-label settings with high background rates of HIV-1 infection, an important step for future implementation. METHODS: We did a phase 3B open-label extension trial of the DVR (MTN-025/HIV Open-label Prevention Extension [HOPE]). Women who were HIV-1-negative and had participated in the MTN-020/ASPIRE phase 3 trial were offered 12 months of access to the DVR at 14 clinical research centres in Malawi, South Africa, Uganda, and Zimbabwe. At each visit (monthly for 3 months, then once every 3 months), women chose whether or not to accept the offer of the ring. Used, returned rings were tested for residual amounts of dapivirine as a surrogate marker for adherence. HIV-1 serological testing was done at each visit. Dapivirine amounts in returned rings and HIV-1 incidence were compared with data from the ASPIRE trial, and safety was assessed. This study is registered with ClinicalTrials.gov, NCT02858037. FINDINGS: Between July 16, 2016, and Oct 10, 2018, of 1756 women assessed for eligibility, 1456 were enrolled and participated in the study. Median age was 31 years (IQR 27-37). At baseline, 1342 (92·2%) women chose to take the DVR; ring acceptance was more than 79% at each visit up until 12 months and 936 (73·2%) of 1279 chose to take the ring at all visits. 12 530 (89·3%) of 14 034 returned rings had residual dapivirine amounts consistent with some use during the previous month (>0·9 mg released) and the mean dapivirine amount released was greater than in the ASPIRE trial (by 0·21 mg; p<0·0001). HIV-1 incidence was 2·7 per 100 person-years (95% CI 1·9-3·8, 35 infections), compared with an expected incidence of 4·4 per 100 person-years (3·2-5·8) among a population matched on age, site, and presence of a sexually transmitted infection from the placebo group of ASPIRE. No serious adverse events or grade 3 or higher adverse events observed were assessed as related to the DVR. INTERPRETATION: High uptake and persistent use in this open-label extension study support the DVR as an HIV-1 prevention option for women. With an increasing number of HIV-1 prophylaxis choices on the horizon, these results suggest that the DVR will be an acceptable and practical option for women in Africa. FUNDING: The Microbicide Trials Network and the National Institute of Allergy and Infectious Diseases, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health, all components of the US National Institutes of Health.

Women design their own vaginal microbicide trial: Suggestions on how to improve adherence from former participants of HIV prevention trials.

Low adherence in vaginal microbicide clinical trials for HIV prevention has impeded interpretation of trial results and hindered evaluation of potentially efficacious HIV prevention gels. Understanding the underlying reasons why women join trials and their barriers to product use can support identification of ways to improve adherence and its reporting. Eight focus group discussion workshops were conducted with 46 former microbicide trial participants in Durban, South Africa and Mwanza, Tanzania. Participants provided feedback on why women join trials, the barriers to using study gel and reporting adherence accurately, and how clinical trial design can be improved to support better adherence and its reporting. Women join microbicide trials for a number of important reasons such as healthcare and financial reimbursement. Fear of adverse effects from the investigational product was the most important reason why participants reported not using the gel. The key reason for inaccurate reporting of gel use was fear of removal from the trial. Participants made concrete suggestions for improving microbicide trial design such as applicator use testing and real time feedback, improving education to participants about how trials answer their research questions, and improving transparency and clarity about study procedures. Participants also gave feedback on an innovative trial design with a non-randomised arm. Identifying HIV prevention products for women requires better understanding of the lives of women asked to join these trials, and application of that understanding to microbicide trial design. This study has demonstrated that participants and research teams can work collaboratively to design clinical trials that meet needs of both the research and of participants.

Prevalence and Incidence of Sexually Transmitted Infection in Injectable Progestin Contraception Users in South Africa.

Introduction: Whether intramuscular depot medroxyprogesterone acetate (DMPA-IM) and norethisterone enanthate (NET-EN) have a differential impact on the incidence of sexually transmitted infection (STI) remains unclear. In the Vaginal and Oral Interventions to Control the Epidemic (VOICE) trial, HIV-1 acquisition was higher for DMPA-IM users vs. NET-EN users. We compared DMPA-IM and NET-EN users with regard to chlamydia, gonorrhea, trichomoniasis, syphilis, and herpes simplex virus type 2 (HSV-2) infection. Materials and Methods: Prospective data were analyzed from VOICE, a randomized trial of HIV-1 chemoprophylaxis. Participants were evaluated annually and as indicated for chlamydia, gonorrhea, trichomoniasis, and syphilis. Stored specimens were tested for HSV-2. Proportional hazards models compared the risk of STI between DMPA-IM and NET-EN users. Results: Among 2,911 injectable contraception users in South Africa, 1,800 (61.8%) used DMPA-IM and 1,111 used NET-EN (38.2%). DMPA-IM and NET-EN users did not differ in baseline chlamydia: 15.1 vs. 14.3%, p= 0.54; gonorrhea: 3.4 vs. 3.7%, p= 0.70; trichomoniasis: 5.7 vs.5.0%, p= 0.40; or syphilis: 1.5 vs. 0.7%, p= 0.08; but differed for baseline HSV-2: (51.3 vs. 38.6%, p < 0.001). Four hundred forty-eight incident chlamydia, 103 gonorrhea, 150 trichomonas, 17 syphilis, and 48 HSV-2 infections were detected over 2,742, 2,742, 2,783, 2,945, and 756 person-years (py), respectively (chlamydia 16.3/100 py; gonorrhea 3.8/100 py; trichomoniasis 5.4/100 py; syphilis 0.6/100 py; HSV-2 6.4/100 py). Comparing DMPA-IM with NET-EN users, no difference was noted in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV2 infections, including when adjusted for confounders [chlamydia (aHR 1.03, 95% CI 0.85-1.25), gonorrhea (aHR 0.88, 95% CI 0.60-1.31), trichomoniasis (aHR 1.07, 95% CI 0.74-1.54), syphilis (aHR 0.41, 95% CI 0.15-1.10), and HSV-2 (aHR 0.83, 95% CI 0.45-1.54, p= 0.56)]. Discussion: Among South African participants enrolled in VOICE, DMPA-IM and NETEN users differed in prevalence of HSV-2 at baseline but did not differ in the incidence of chlamydia, gonorrhea, trichomoniasis, syphilis, or HSV-2 infection. Differential HIV-1 acquisition, previously demonstrated in this cohort, does not appear to be explained by differential STI acquisition. However, the high incidence of multiple STIs reinforces the need to accelerate access to comprehensive sexual and reproductive health services.

Phase 1 Human Immunodeficiency Virus (HIV) Vaccine Trial to Evaluate the Safety and Immunogenicity of HIV Subtype C DNA and MF59-Adjuvanted Subtype C Envelope Protein.

BACKGROUND: The Pox-Protein Public-Private Partnership is performing a suite of trials to evaluate the bivalent subtype C envelope protein (TV1.C and 1086.C glycoprotein 120) vaccine in the context of different adjuvants and priming agents for human immunodeficiency virus (HIV) type 1 (HIV-1) prevention. METHODS: In the HIV Vaccine Trials Network 111 trial, we compared the safety and immunogenicity of DNA prime followed by DNA/protein boost with DNA/protein coadministration injected intramuscularly via either needle/syringe or a needle-free injection device (Biojector). One hundred thirty-two healthy, HIV-1-uninfected adults were enrolled from Zambia, South Africa, and Tanzania and were randomized to 1 of 6 arms: DNA prime, protein boost by needle/syringe; DNA and protein coadministration by needle/syringe; placebo by needle/syringe; DNA prime, protein boost with DNA given by Biojector; DNA and protein coadministration with DNA given by Biojector; and placebo by Biojector. RESULTS: All vaccinations were safe and well tolerated. DNA and protein coadministration was associated with increased HIV-1 V1/V2 antibody response rate, a known correlate of decreased HIV-1 infection risk. DNA administration by Biojector elicited significantly higher CD4+ T-cell response rates to HIV envelope protein than administration by needle/syringe in the prime/boost regimen (85.7% vs 55.6%; P = .02), but not in the coadministration regimen (43.3% vs 48.3%; P = .61). CONCLUSIONS: Both the prime/boost and coadministration regimens are safe and may be promising for advancement into efficacy trials depending on whether cellular or humoral responses are desired. CLINICAL TRIALS REGISTRATION: South African National Clinical Trials Registry (application 3947; Department of Health [DoH] no. DOH-27-0715-4917) and ClinicalTrials.gov (NCT02997969).

Temporal trends in sexual behaviours and their impacts on HIV incidence among South African women: 2002-2016.

South Africa has the highest number of HIV infected individuals in the world. The primary objective of the current study was to describe temporal changes in HIV incidence rates using the data from 9,948 women who enrolled in one of the six HIV prevention trials conducted in KwaZulu-Natal, South Africa. Characteristics of the study population were presented and compared across the four study periods: 2002-2004, 2005-2008, 2009-2011 and 2012-2016. HIV infection rates increased from 6.2 to 9.3 per 100 person-year over the 15 years. These rates were as high as 14 per 100 person-year among women younger than 20 years age. Being single/not cohabiting, using injectable contraceptives, having less than two children, and diagnosed with STI(s) were associated with increased risk of HIV infection. These four factors were associated with 71%, 75%, 80% and 88% of the HIV seroconversions in four study periods. As the research continues to find ways of controlling the spread of the infections, quantifying the temporal trends in risk factors and their population-level impacts on HIV infection may have significant implications. This information may assist in developing effective counselling and education programs by targeting the sexually active single women and delivering more realistic messages.

Prevention, Partners, and Power Imbalances: Women's Views on How Male Partners Affected Their Adherence to Vaginal Microbicide Gels During HIV Prevention Trials in Africa.

BACKGROUND: Low adherence has contributed to disappointing results for trials testing vaginal microbicides for HIV prevention. This study engaged former gel trial participants to understand the reasons behind low adherence and seek suggestions on how to improve products and adherence to microbicides. This analysis examines the impact of participant perceptions of male partners on participant adherence and suggestions on how to address those issues. METHODS: Eight focus group discussion workshops were conducted with 46 former microbicide trial participants in South Africa and Tanzania. Participants provided feedback on why women join trials, barriers to using gels and reporting adherence accurately, and how adherence and adherence reporting can be improved. RESULTS: Participants reported that male partners can affect women's ability to use gels. For some, the lubricating effects caused relationship conflicts due to suspicion of male partners about infidelity. Needing to provide sex to partners on demand was a barrier to gel use. Participants suggested a gel formulation which was thicker and less noticeable, and explicit male partner engagement to enhance understanding of the purpose of the gels. CONCLUSIONS: The imbalance of power in intimate relationships affects the ability of women to use microbicides as directed. To improve adherence to HIV prevention methods within trials and for successful rollout of proven HIV prevention methods in populations, it is important that the complicated dynamics of sex and relationships be taken into greater consideration and that women receive targeted support to navigate product use and communication within the context of these gender dynamics.

Responding to the ECHO trial results: modelling the potential impact of changing contraceptive method mix on HIV and reproductive health in South Africa.

INTRODUCTION: Some observational data suggest that the progestogen injectable contraceptive depot medroxyprogesterone acetate (DMPA) may increase a woman's risk of HIV acquisition but a randomized clinical trial did not find a statistically significant increase in HIV risk for women using DMPA compared to two other methods. However, it could not rule out up to 30% increased HIV risk for DMPA users. We evaluate changes to contraceptive method mix in South Africa under different assumptions about the existence and strength of a possible undetected relationship between DMPA use and HIV risk. METHODS: A mathematical model was developed to simulate the ongoing HIV epidemic and contraceptive method mix in South Africa to estimate how changes in method mix could impact HIV- and reproductive health-related outcomes. We made different assumptions about the relationship between DMPA use and HIV risk, from no relationship to a 30% increase in HIV risk for women using DMPA. Scenario analyses were used to investigate the impact of switching away from DMPA predominance to new patterns of contraceptive use. RESULTS: In South Africa, the HIV-related benefits of reduced DMPA use could be as great as the harms of increased adverse reproductive health outcomes over 20 years, if DMPA did increase the risk of HIV acquisition by a relative hazard of infection of 1.1 or greater. A reduction in DMPA use among HIV-positive women would have no benefit in terms of HIV infections, but would incur additional negative reproductive health outcomes. The most important driver of adverse reproductive health outcomes is the proportion of women who switch away from DMPA to no contraceptive method. CONCLUSIONS: If there is any real increased HIV risk for DMPA users that has not been detected by the recent randomized trial, a reduction in DMPA use could reduce the ongoing number of new HIV infections. However, such a change would place more women at risk of adverse reproductive health effects. It is imperative that these effects are minimized by focusing on expanding access to safe, effective and acceptable alternative contraceptive methods for all women.

The Impact of Male Partner Circumcision on Women's Health Outcomes.

Medical male circumcision is a proven method of HIV risk reduction in men with no known direct benefit to women. We investigated the benefit of partner circumcision on women's health. We conducted a secondary analysis of 5,029 women enrolled in the Vaginal and Oral Interventions to Control the Epidemic trial across 15 African sites, to look at the impact of partner circumcision status on sexually transmitted infections, pregnancy, frequency of sex, and condom use in women. Of 4,982 participants with a baseline response, 31% had circumcised partners. Women with circumcised partners had a significantly reduced risk of syphilis acquisition, hazard ratio 0.51 (0.26, 1.00), p value = .05. Participants with uncircumcised partners were significantly less likely to have used a condom at the last sex act than the other two groups, adj. relative risk 0.86 (0.80, 0.92), adj. p value < .0001. We found no evidence of sexual risk compensation in women with circumcised partners.

Estimating prevalence and incidence of sexually transmitted infections among South African women: Implications of combined impacts of risk factors.

In addition to being the epicentre of the HIV epidemic, South Africa also has the highest burden of sexually transmitted infections (STIs) in the world. Therefore, understanding the most influential risk factors of STIs is a research priority. Using the data from 9948 women who resided in KwaZulu Natal, South Africa, we estimated the population attributable risk to quantify the combined impacts of the most influential factors on STI diagnosis. Overall STI prevalence was 20%, and STI incidence was 15 per 100 person-years. Four factors: age at sexual debut, single/not cohabiting, two or more sex partners and parity <3 were identified as the most influential risk factors for STI prevalence and incidence rates. However, these factors collectively associated with only 51% and 53% of the excess STI prevalence and incidence rates, respectively. These relatively modest impacts provide empirical evidence for the significant impacts of unmeasured factors on STIs. Culturally and socially appropriate prevention programs may be more effective to target those at highest risk of STIs.

Contraceptives and sexual behaviours in predicting pregnancy rates in HIV prevention trials in South Africa: Past, present and future implications.

OBJECTIVE: Despite all efforts, high pregnancy rates are often reported in HIV biomedical intervention trials conducted in African countries. We therefore aimed to develop a pregnancy risk scoring algorithm for targeted recruitment and screening strategies among a cohort of women in South Africa. METHODS: The study population was ~ 10,000 women who enrolled in one of the six biomedical intervention trials conducted in KwaZulu Natal, South Africa. Cox regression models were used to create a pregnancy risk scoring algorithm which was internally validated using standard statistical measures. RESULTS: Five factors were identified as significant predictors of pregnancy incidence:<25 years old, not using injectable contraceptives, parity (<3), being single/not cohabiting and having ≥ 2 sexual partners in the past three months. Women with total scores of 21-24, 25-35 and 36+ were classified as being at "moderate", "high", "severe" risk of pregnancy. Sensitivity of the development and validation models were reasonably high (sensitivity 76% and 74% respectively). CONCLUSION: Our risk scoring algorithm can identify and alert researchers to women who need additional non-routine pregnancy assessment and counselling, with statistically acceptable accuracy and robustness.

Assessment of the Impact of Rapid Point-of-Care CD4 Testing in Primary Healthcare Clinic Settings: A Survey Study of Client and Provider Perspectives.

BACKGROUND: The high burden of disease in South Africa presents challenges to public health services. Point-of-care (POC) technologies have the potential to address these gaps and improve healthcare systems. This study ascertained the acceptability and impact of POC CD4 testing on patients' health and clinical management. METHODS: We conducted a qualitative survey study with patients (n = 642) and healthcare providers (n = 13) at the Lancers Road (experienced POC) and Chesterville (non-experienced POC) primary healthcare (PHC) clinics from September 2015 to June 2016. RESULTS: Patients (99%) at Lancers and Chesterville PHCs were positive about POC CD4 testing, identifying benefits: No loss/delay of test results (6.4%), cost/time saving (19.5%), and no anxiety (5.1%), and 58.2% were ready to initiate treatment. Significantly more patients at Chesterville than Lancers Road PHC felt POC would provide rapid clinical decision making (64.7% vs. 48.1%; p < 0.0001) and better clinic accessibility (40.4% vs. 24.7%; p < 0.0001) respectively. Healthcare providers thought same-day CD4 results would impact: Clinical management (46.2%), patient readiness (46.2%), and adherence (23.0%), and would reduce follow-up visits (7.7%), while 38.5% were concerned that further tests and training (15.4%) were required before antiretroviral therapy (ART) initiation. CONCLUSION: The high acceptability of POC CD4 testing and the immediate health, structural, and clinical management benefits necessitates POC implementation studies.

Correlates of Sexually Transmitted Infections Among South African Women Using Individual- and Community-Level Factors: Results from Generalized Additive Mixed Models.

South Africa has the highest burden of human immunodeficiency virus (HIV) infections in the world. There is also growing evidence that an individual's risk of contracting HIV is increased by the presence of other sexually transmitted infections (STIs). The primary objective of this study was to examine the association between the prevalence of STIs in a cohort of South African women who enrolled in HIV prevention trials (2002-2012). The current study linked the individual factors with the community-level characteristics using geo-referencing. These multi-level data were analyzed in generalized additive mixed models settings. In the multivariate logistic regression model, younger age (odds ratio [OR] 4.30, 95% CI 3.20, 5.77 and OR 2.72, 95% CI 2.02, 3.66 for age < 25 and 25-29, respectively); being single/not cohabiting (OR 4.57, 95% CI 3.18, 6.53), two + sex partners (OR 1.46, 95% CI 1.18,1.80); parity < 2 (OR 2.04, 95% CI 1.53, 2.72), parity = 2 (OR 1.85, 95% CI 1.37, 2.48), and using injectables (contraceptive) (OR 1.53, 95% CI 1.13, 2.06) were all significantly associated with increased prevalence of STIs. Women who resided in the communities with high proportions of female headed-households were also significantly at higher risk for STIs (OR 1.20, p = .0025). Because these factors may reflect characteristics of the larger groups who share similar cultural norms and social environments, they can provide considerable insight into the spread of STIs. Prevention strategies based on individual and community-level drivers of STIs are likely to be the most effective means of targeting and reaching those at greatest risk of infection. This strategy has the potential to play a significant role in the epidemic's trajectory.

Linkage to Care Following an HIV Diagnosis in Three Public Sector Clinics in eThekwini (Durban), South Africa: Findings from a Prospective Cohort Study.

Linkage to care following an HIV diagnosis remains an important HIV care continuum milestone, even in the era of universal ART eligibility. In an 8-month prospective cohort study among 459 (309 women, 150 men) newly-diagnosed HIV-positive individuals in three public-sector clinics in Durban metropolitan region, South Africa, from 2010 to 2013, median time to return to clinic for CD4+ results (linkage) was 10.71 weeks (95% CI 8.52-12.91), with 54.1% 3-month cumulative incidence of linkage. At study completion (9.23 months median follow-up), 26.2% had not linked. Holding more positive outcome-beliefs about enrolling in care was associated with more rapid linkage [adjusted hazard ratio (AHR)each additional belief 1.31; 95% CI 1.05-1.64] and lower odds of never linking [adjusted odds ratio (AOR) 0.50; 95% CI 0.33-0.75]. Holding positive ARV beliefs was strongly protective against never linking to care. Age over 30 years (AHR 1.59; 95% CI 1.29-1.97) and disclosing one's HIV-positive status within 30 days of diagnosis (AHR 1.52; 95% CI 1.10-2.10) were associated with higher linkage rates and lower odds of never linking. Gender was not associated with linkage and did not alter the effect of other predictors. Although expanded access to ART has reduced some linkage barriers, these findings demonstrate that people's beliefs and social relations also matter. In addition to structural interventions, consistent ART education and disclosure support, and targeting younger individuals for linkage are high priorities.

Exploring the immunomodulatory role of depot medroxyprogesterones acetate and endogenous progesterone levels in HIV infected and uninfected women.

OBJECTIVE: The aim of this proof of concept study was to determine the effect of depot medroxyprogesterone acetate on host and viral factors in HIV infected and uninfected women. RESULTS: In this study, the gene expression levels for CCL5, CCR5 and CXCR4 was significantly higher in HIV positive women when compared to HIV negative women (p < 0.05). An upregulation of CCR5 and CXCR4 was evident in less than 20% of the HIV infected women and none of the HIV uninfected women. The mean fold change for CCL3 was much higher in HIV uninfected when compared to infected women with a borderline significance (p = 0.062). In HIV uninfected women, the mean fold change in CCL3, CCL4, and CCL5 gene expression was not statistically different between women on DMPA versus women not on hormonal contraception. The proportion of women with an upregulation of CCL4 and CCR5 was higher in HIV infected women on DMPA. There was no association between endogenous progesterone level and chemokines and the HIV-1 receptors. The gene expression levels in the chemokine receptors CCR5 and CXCR4 were significantly higher in the HIV infected women when compared to the women who remained HIV uninfected.

Effect of co-trimoxazole prophylaxis on morbidity and mortality of HIV-exposed, HIV-uninfected infants in South Africa: a randomised controlled, non-inferiority trial.

BACKGROUND: WHO guidelines recommend co-trimoxazole prophylaxis for HIV-exposed, HIV-uninfected infants. These guidelines date back to an era in which HIV testing of infants was impossible and mothers had poor access to antiretroviral treatment. To determine whether this guideline requires revision in the current era of effective prevention of mother-to-child transmission and early infant diagnosis programmes, we aimed to investigate whether receiving no co-trimoxazole prophylaxis is inferior to receiving co-trimoxazole prophylaxis in the resulting incidence of grade 3 or 4 common childhood illnesses or mortality in breastfed HIV-exposed, HIV-uninfected infants. METHODS: We investigated our aim in a randomised controlled, non-inferiority trial. We enrolled the HIV-negative infants of mothers living with HIV who were actively involved in transmission prevention programmes in two clinics in Durban, South Africa. Infants were included in the study if they were breastfeeding at the screening and enrolment visits, and their mother was planning to breastfeed for at least 6 months; were a singleton birth and had a birthweight of 2 kg or more; had no clinically observed genetic disorders; and had no serious illnesses and had not received antibiotics or traditional medications (such as herbal remedies). Infants were randomly assigned (1:1) to receive co-trimoxazole or no co-trimoxazole. In the co-trimoxazole group, infants received the drug until all exposure to HIV had ceased (ie, 6 weeks after last exposure to breastmilk) and the infant was confirmed to be uninfected with HIV. The drug was administered by mothers in once-daily regimens of 20 mg trimethoprim and 100 mg sulfamethoxazole orally (age <6 months or bodyweight <5 kg), or 40 mg trimethoprim and 200 mg sulfamethoxazole orally (age >6 months or bodyweight >5 kg). Clinical and laboratory staff always remained masked to group assignment, but mothers and study counsellors were not. Infants and their mothers attended study visits at ages 6 weeks (for enrolment and randomisation), 10 weeks, 14 weeks, and then monthly from 4 to 12 months. Our primary outcome was the incidence of grade 3 or 4 common childhood illnesses (pneumonia or diarrhoea) or mortality in breastfed HIV-exposed, HIV-uninfected infants by age 12 months. A non-inferiority bound of 5% was used. The study is registered with the Pan African Clinical Trials Registry, number PACTR201311000621110, and the South African National Clinical Trials Registry, number DOH-27-0614-4728. FINDINGS: We screened 1570 mother-child pairs for study enrolment, from whom (78%) eligible infants were enrolled into the study between Oct 16, 2013, and May 23, 2018. Of the infants enrolled, 611 (50%) were randomly assigned to the co-trimoxazole group and 609 (50%) were randomly assigned to the no co-trimoxazole group. One (<1%) infant in the no co-trimoxazole group was excluded from the analysis of the final outcomes for having received traditional medicine (which only became apparent after randomisation); therefore, 611 (50%) infants in the co-trimoxazole group and 608 (50%) infants in the no co-trimoxazole group were included in the final intention-to-treat analysis. 136 (22%) infants in the co-trimoxazole group and 139 (23%) infants in the no co-trimoxazole group did not complete the 12-month study visit, predominantly because of loss to follow-up (93 [15%] infants in the co-trimoxazole group; 90 [15%] infants in the no co-trimoxazole group). The cumulative probability of the composite primary outcome was 0·114 (95% CI 0·076 to 0·147; 49 events) in the co-trimoxazole group versus 0·0795 (0·044 to 0·115; 39 events) in the no co-trimoxazole group. The risk difference (no co-trimoxazole group minus co-trimoxazole group) was -0·0319 (-0·075 to 0·011), meaning that the risk was around 3 percentage points lower in the no co-trimoxazole group on the additive scale. INTERPRETATION: We can conclude that no co-trimoxazole is not inferior to daily co-trimoxazole among breastfed HIV-exposed, HIV-uninfected infants whose mothers are accessing a prevention of mother-to-child transmission programme in an area unaffected by malaria. We therefore believe that WHO should revise the co-trimoxazole guidelines for HIV-exposed, HIV-uninfected infants in areas unaffected by malaria. FUNDING: HIV Prevention Research Unit of the South African Medical Research Council and the Family Larsson-Rosenquist Foundation.