High prevalence and incidence of gonorrhoea and chlamydia in young women eligible for HIV pre-exposure prophylaxis in South Africa and Zimbabwe: results from the HPTN 082 trial.

INTRODUCTION: We investigated the prevalence, incidence and factors associated with sexually transmitted infections (STIs) among young African women seeking HIV pre-exposure prophylaxis (PrEP). METHODS: HPTN 082 was a prospective, open-label PrEP study enrolling HIV-negative sexually active women aged 16-25 years in Cape Town and Johannesburg, South Africa, and Harare, Zimbabwe. Endocervical swabs from enrolment, months 6 and 12 were tested for Neisseria gonorrhoeae (GC) and Chlamydia trachomatis (CT) by nucleic acid amplification, and Trichomonas vaginalis (TV) by a rapid test. Intracellular tenofovir-diphosphate (TFV-DP) concentrations in dried blood spots were measured at months 6 and 12. Associations between risk characteristics and STI outcomes were assessed using Poisson regression. RESULTS: Of 451 enrolled participants, 55% had an STI detected at least once. CT incidence was 27.8 per 100 person-years (py) (95% CI 23.1, 33.2), GC incidence was 11.4 per 100 py (95% CI 8.5, 15.0) and TV incidence was 6.7 per 100 py (95% CI 4.5, 9.5). 66% of incident infections were diagnosed in women uninfected at baseline. Baseline cervical infection (GC or CT) risk was highest in Cape Town (relative risk (RR) 2.38, 95% CI 1.35, 4.19) and in those not living with family (RR 1.87, 95% 1.13, 3.08); condom use was protective (RR 0.67, 95% CI 0.45, 0.99). Incident CT was associated with baseline CT (RR 2.01; 95% CI 1.28, 3.15) and increasing depression score (RR 1.05; 95% CI 1.01, 1.09). Incident GC was higher in Cape Town (RR 2.40; 95% CI 1.18, 4.90) and in participants with high PrEP adherence (TFV-DP concentrations ≥700 fmol/punch) (RR 2.04 95% CI 1.02, 4.08). CONCLUSION: Adolescent girls and young women seeking PrEP have a high prevalence and incidence of curable STIs. Alternatives to syndromic management for diagnosis and treatment are needed to reduce the burden of STIs in this population. TRIAL REGISTRATION NUMBER: NCT02732730.

Impact of universal testing and treatment on sexual risk behaviour and herpes simplex virus type 2: a prespecified secondary outcomes analysis of the HPTN 071 (PopART) community-randomised trial.

BACKGROUND: Comprehensive HIV prevention strategies have raised concerns that knowledge of interventions to reduce risk of HIV infection might mitigate an individual's perception of risk, resulting in riskier sexual behaviour. We investigated the prespecified secondary outcomes of the HPTN 071 (PopART) trial to determine whether a combination HIV prevention strategy, including universal HIV testing and treatment, changed sexual behaviour; specifically, we investigated whether there was evidence of sexual risk compensation. METHODS: HPTN 071 (PopART) was a cluster-randomised trial conducted during 2013-18, in which we randomly assigned 21 communities with high HIV prevalence in Zambia and South Africa (total population, approximately 1 million) to combination prevention intervention with universal antiretroviral therapy (ART; arm A), prevention intervention with ART provided according to local guidelines (universal since 2016; arm B), or standard of care (arm C). The trial included a population cohort of approximately 2000 randomly selected adults (aged 18-44 years) in each community (N=38 474 at baseline) who were followed up for 36 months. A prespecified secondary objective was to evaluate the impact of the PopART intervention compared with standard of care on herpes simplex virus type 2 (HSV-2) and sexual behaviour (N=20 422 completed final visit). Secondary endpoints included differences in sexual risk behaviour measures at 36 months and were assessed using a two-stage method for matched cluster-randomised trials. This trial is registered with ClinicalTrials. gov, number NCT01900977. FINDINGS: The PopART intervention did not substantially change probability of self-reported multiple sex partners, sexual debut, or pregnancy in women at 36 months. Adjusted for baseline community prevalence, reported condomless sex was significantly lower in arm A versus arm C (adjusted prevalence ratio 0·80 [95% CI 0·64-0·99]; p=0·04) but not in arm B versus arm C (0·94 [0·76-1·17]; p=0·55). 3-year HSV-2 incidence was reduced in arm B versus arm C (adjusted risk ratio 0·76 [95% CI 0·63-0·92]; p=0·010); no significant change was shown between arm A versus arm C (0·89 [0·73-1·08]; p=0·199). INTERPRETATION: We found little evidence of any change in sexual behaviour owing to the PopART interventions, and reassuringly for public health, we saw no evidence of sexual risk compensation. The findings do not help to explain the differences between the two intervention groups of the HPTN 071 (PopART) trial. FUNDING: National Institute of Allergy and Infectious Diseases, the National Institutes of Health, the International Initiative for Impact Evaluation (3ie), the Bill & Melinda Gates Foundation, the US President's Emergency Plan for AIDS Relief, and the Medical Research Council UK.

The association between HIV stigma and HIV incidence in the context of universal testing and treatment: analysis of data from the HPTN 071 (PopART) trial in Zambia and South Africa.

INTRODUCTION: To investigate the association between individual and community-level measures of HIV stigma and HIV incidence within the 21 communities participating in the HPTN (071) PopART trial in Zambia and South Africa. METHODS: Secondary analysis of data from a population-based cohort followed-up over 36 months between 2013 and 2018. The outcome was rate of incident HIV infection among individuals who were HIV negative at cohort entry. Individual-level exposures, measured in a random sample of all participants, were: (1) perception of stigma in the community, (2) perception of stigma in health settings and (3) fear and judgement towards people living with HIV. Individual-level analyses were conducted with adjusted, individual-level Poisson regression. Community-level HIV stigma exposures drew on data reported by people living with HIV, health workers and community members. We used linear regression to explore the association between HIV stigma and community-level HIV incidence. RESULTS: Among 8172 individuals who were HIV negative and answered individual-level stigma questions at enrolment to the cohort, there was no evidence of a statistically significant association between any domain of HIV stigma and risk of incident HIV infection. Among the full cohort of 26,110 individuals among whom HIV incidence was measured, there was no evidence that community-level HIV incidence was associated with any domain of HIV stigma. CONCLUSIONS: HIV stigma is often cited as a barrier to the effectiveness of HIV prevention programming. However, in the setting for the HPTN 071 "PopART trial," measured stigma alone was not associated with the risk of HIV infection.

Characterization of Human Immunodeficiency Virus (HIV) Infections in Women Who Received Injectable Cabotegravir or Tenofovir Disoproxil Fumarate/Emtricitabine for HIV Prevention: HPTN 084.

BACKGROUND: HIV Prevention Trials Network 084 demonstrated that long-acting injectable cabotegravir (CAB) was superior to daily oral tenofovir (TFV) disoproxil fumarate (TDF)/emtricitabine (FTC) for preventing human immunodeficiency virus (HIV) infection in sub-Saharan African women. This report describes HIV infections that occurred in the trial before unblinding. METHODS: Testing was performed using HIV diagnostic assays, viral load testing, a single-copy RNA assay, and HIV genotyping. Plasma CAB, plasma TFV, and intraerythrocytic TFV-diphosphate concentrations were determined by liquid chromatography-tandem mass spectrometry. RESULTS: Forty HIV infections were identified (CAB arm, 1 baseline infection, 3 incident infections; TDF/FTC arm, 36 incident infections). The incident infections in the CAB arm included 2 with no recent drug exposure and no CAB injections and 1 with delayed injections; in 35 of 36 cases in the TDF/FTC arm, drug concentrations indicated low or no adherence. None of the cases had CAB resistance. Nine women in the TDF/FTC arm had nonnucleoside reverse-transcriptase inhibitor resistance; 1 had the nucleoside reverse-transcriptase inhibitor resistance mutation, M184V. CONCLUSIONS: Almost all incident HIV infections occurred in the setting of unquantifiable or low drug concentrations. CAB resistance was not detected. Transmitted nonnucleoside reverse-transcriptase inhibitor resistance was common; 1 woman may have acquired nucleoside reverse-transcriptase inhibitor resistance from study drug exposure.

PrEP uptake, persistence, adherence, and effect of retrospective drug level feedback on PrEP adherence among young women in southern Africa: Results from HPTN 082, a randomized controlled trial.

BACKGROUND: Pre-exposure prophylaxis (PrEP) is highly effective and an important prevention tool for African adolescent girls and young women (AGYW), but adherence and persistence are challenging. PrEP adherence support strategies for African AGYW were studied in an implementation study. METHODS AND FINDINGS: HIV Prevention Trials Network (HPTN) 082 was conducted in Cape Town, Johannesburg (South Africa) and Harare (Zimbabwe) from October 2016 to October 2018 to evaluate PrEP uptake, persistence, and the effect of drug level feedback on adherence. Sexually active HIV-negative women ages 16-25 were offered PrEP and followed for 12 months; women who accepted PrEP were randomized to standard adherence support (counseling, 2-way SMS, and adherence clubs) or enhanced adherence support with adherence feedback from intracellular tenofovir-diphosphate (TFV-DP) levels in dried blood spots (DBS). PrEP uptake, persistence through 12 months (no PrEP hold or missed visits), and adherence were assessed. The primary outcome was high adherence (TFV-DP ≥700 fmol/punch) at 6 months, compared by study arm. Of 451 women enrolled, median age was 21 years, and 39% had curable sexually transmitted infections (STIs). Most (95%) started PrEP, of whom 55% had uninterrupted PrEP refills through 12 months. Of those with DBS, 84% had detectable TFV-DP levels at month 3, 57% at month 6, and 31% at month 12. At 6 months, 36/179 (21%) of AGYW in the enhanced arm had high adherence and 40/184 (22%) in the standard adherence support arm (adjusted odds ratio [OR] of 0.92; 95% confidence interval [CI] 0.55, 1.34; p = 0.76). Four women acquired HIV (incidence 1.0/100 person-years), with low or undetectable TFV-DP levels at or prior to seroconversion, and none of whom had tenofovir or emtricitabine resistance mutations. The study had limited power to detect a modest effect of drug level feedback on adherence, and there was limited awareness of PrEP at the time the study was conducted. CONCLUSIONS: In this study, PrEP initiation was high, over half of study participants persisted with PrEP through month 12, and the majority of young African women had detectable TFV-DP levels through month 6 with one-fifth having high adherence. Drug level feedback in the first 3 months of PrEP use did not increase the proportion with high adherence at month 6. HIV incidence was 1% in this cohort with 39% prevalence of curable STIs and moderate PrEP adherence. Strategies to support PrEP use and less adherence-dependent formulations are needed for this population. TRIAL REGISTRATION: ClinicalTrials.gov NCT02732730.

HIV Stigma and Viral Suppression Among People Living With HIV in the Context of Universal Test and Treat: Analysis of Data From the HPTN 071 (PopART) Trial in Zambia and South Africa.

BACKGROUND: The impact of HIV stigma on viral suppression among people living with HIV (PLHIV) is not well characterized. SETTING: Twenty-one communities in Zambia and South Africa, nested within the HPTN 071 (PopART) trial. METHODS: We analyzed data on viral suppression (<400 copies HIV RNA/mL) among 5662 laboratory-confirmed PLHIV aged 18-44 years who were randomly sampled within the PopART trial population cohort 24 months after enrolment (PC24). We collected data on experiences and internalization of stigma from those PLHIV who self-reported their HIV status (n = 3963/5662) and data on perceptions of stigma from a 20% random sample of all PLHIV (n = 1154/5662). We also measured stigma at the community-level among PLHIV, community members, and health workers. We analyzed the association between individual- and community-level measures of HIV stigma and viral suppression among PLHIV, adjusting for confounding. RESULTS: Of all 5662 PLHIV, 69.1% were virally suppressed at PC24. Viral suppression was highest among those 3963 cohort participants who self-reported living with HIV and were on ART (88.3%), and lower among those not on treatment (37.5%). Self-identifying PLHIV who reported internalized stigma were less likely to be virally suppressed (75.0%) than those who did not (80.7%; adjusted risk ratio, 0.94 95% CI: 0.89 to 0.98). Experiences, perceptions, and community-level measures of stigma were not associated with viral suppression. CONCLUSION: Internalized stigma among PLHIV was associated with a lower level of viral suppression; other dimensions of stigma were not. Stigma reduction approaches that address internalized stigma should be an integral component of efforts to control the HIV epidemic.

Determination of HIV status and identification of incident HIV infections in a large, community-randomized trial: HPTN 071 (PopART).

INTRODUCTION: The HPTN 071 (PopART) trial evaluated the impact of an HIV combination prevention package that included "universal testing and treatment" on HIV incidence in 21 communities in Zambia and South Africa during 2013-2018. The primary study endpoint was based on the results of laboratory-based HIV testing for> 48,000 participants who were followed for up to three years. This report evaluated the performance of HIV assays and algorithms used to determine HIV status and identify incident HIV infections in HPTN 071, and assessed the impact of errors on HIV incidence estimates. METHODS: HIV status was determined using a streamlined, algorithmic approach. A single HIV screening test was performed at centralized laboratories in Zambia and South Africa (all participants, all visits). Additional testing was performed at the HPTN Laboratory Center using antigen/antibody screening tests, a discriminatory test and an HIV RNA test. This testing was performed to investigate cases with discordant test results and confirm incident HIV infections. RESULTS: HIV testing identified 978 seroconverter cases. This included 28 cases where the participant had acute HIV infection at the first HIV-positive visit. Investigations of cases with discordant test results identified cases where there was a participant or sample error (mixups). Seroreverter cases (errors where status changed from HIV infected to HIV uninfected, 0.4% of all cases) were excluded from the primary endpoint analysis. Statistical analysis demonstrated that exclusion of those cases improved the accuracy of HIV incidence estimates. CONCLUSIONS: This report demonstrates that the streamlined, algorithmic approach effectively identified HIV infections in this large cluster-randomized trial. Longitudinal HIV testing (all participants, all visits) and quality control testing provided useful data on the frequency of errors and provided more accurate data for HIV incidence estimates.

Depression and Incident HIV in Adolescent Girls and Young Women in HIV Prevention Trials Network 068: Targets for Prevention and Mediating Factors.

The human immunodeficiency virus (HIV) epidemic among adolescent girls and young women (AGYW) in sub-Saharan Africa is a critical public health problem. We assessed whether depressive symptoms in AGYW were longitudinally associated with incident HIV, and identified potential social and behavioral mediators. Data came from a randomized trial of a cash transfer conditional on school attendance among AGYW (ages 13-21 years) in rural Mpumalanga Province, South Africa, during 2011-2017. We estimated the relationship between depressive symptoms and cumulative HIV incidence using a linear probability model, and we assessed mediation using inverse odds ratio weighting. Inference was calculated using the nonparametric bootstrap. AGYW with depressive symptoms had higher cumulative incidence of HIV compared with those without (risk difference = 3.5, 95% confidence interval (CI): 0.1, 7.0). The strongest individual mediators of this association were parental monitoring and involvement (indirect effect = 1.6, 95% CI: 0.0, 3.3) and reporting a partner would hit her if she asked him to wear a condom (indirect effect = 1.5, 95% CI: -0.3, 3.3). All mediators jointly explained two-thirds (indirect effect = 2.4, 95% CI: 0.2, 4.5) of the association between depressive symptoms and HIV incidence. Interventions addressing mental health might reduce risk of acquiring HIV among AGYW.

The Mediating Role of Partner Selection in the Association Between Transactional Sex and HIV Incidence Among Young Women.

OBJECTIVE: In sub-Saharan Africa, transactional sex is associated with an increased risk of HIV infection in adolescent girls and young women, but the mechanisms for this relationship remain unclear. We hypothesize that young women who report transactional sex may have multiple partners and older partners, thereby increasing their HIV risk. SETTING: We used longitudinal data from the HPTN 068 trial in rural South Africa where young women aged 13-20 who were HIV-negative at enrolment (n = 2362) were followed approximately annually for up to 6 years. METHODS: We used the parametric g-formula to estimate the total effect of time-varying, frequent transactional sex (receipt of gifts/money at least weekly versus monthly or less) on HIV incidence and the controlled direct effect for mediation in a simulated cohort using 20,000 bootstrapped observations. We calculated rates and hazard ratios (HRs) over the entire study period. RESULTS: The HR for the total effect of frequent transactional sex on HIV incidence was 1.56 (95% confidence interval: 1.28 to 1.85). However, this effect was mediated by partner age (>5+) and number of partners (>1) and the HR was attenuated to 1.09 (95% confidence interval: 0.90 to 1.28) when setting both partner age and partner number constant. CONCLUSION: Both partner age difference and partner number mediate the relationship between transactional sex and incident HIV infection. Through this mediation analysis, we provide important longitudinal evidence to suggest that young women who engage in frequent transactional sex select multiple partners, often older male partners that may be part of higher risk sexual networks.

Prevalence and Associations, by Age Group, of IPV Among AGYW in Rural South Africa.

The prevalence of intimate partner violence (IPV) is alarmingly high among South African adolescent girls and young women (AGYW). Limited data exist exploring how IPV prevalence and its risk factors differ by age. Study data were from the baseline visit of HPTN 068, a randomized controlled trial (RCT) conducted from 2011 to 2015 in Mpumalanga, South Africa. A cohort of 2,533 AGYW, aged 13 years to 20 years, answered survey questions on demographics and behaviors, including their experiences of physical and sexual violence ever and in the past 12 months. We calculated the prevalence of IPV and related risk factors, as well as prevalence ratios with 95% confidence intervals, stratified by age. Nearly one quarter (19.5%, 95% CI = [18.0, 21.2]) of AGYW experienced any IPV ever (physical or sexual) by a partner. The prevalence of any IPV ever among AGYW aged 13 years to 14 years, 15 years to 16 years, and 17 years to 20 years was 10.8%, 17.7%, and 32.1%, respectively. Key variables significantly associated with any IPV ever across all age groups included borrowing money from someone outside the home in the past 12 months, ever having had vaginal sex, ever having had anal sex, and consuming any alcohol. Few statistically significant associations were unique to specific age groups. The history of IPV among the youngest AGYW is a critical finding and should be a focus of prevention efforts.

The Relationship Between School Dropout and Pregnancy Among Adolescent Girls and Young Women in South Africa: A HPTN 068 Analysis.

Background. Prevention of both school dropout and teen pregnancy represent clear public health priorities for South Africa, yet their complex and potentially cyclical relationship has not been fully explored. Objective. To further understand how this relationship operates, we analyzed data from a randomized trial of young women aged 13 to 20 years enrolled in school in rural South Africa to estimate the association between pregnancy and subsequent dropout and between dropout and subsequent pregnancy. Method. We examined inverse probability (IP) of exposure-weighted survival curves for school dropout by pregnancy and for pregnancy by school dropout. We used weighted curves to calculate 1-, 2-, and 3-year risk differences and risk ratios. Additionally, we used an IP-weighted marginal structural cox model to estimate a hazard ratio (HR) for each relationship. Results. Dropout from school was associated with subsequent pregnancy (HR 3.58; 95% confidence interval [CI] [2.04, 6.28]) and pregnancy was associated with subsequent school dropout (HR 2.36; 95% CI [1.29, 4.31]). Young women who attended school but attended fewer days had a higher hazard of pregnancy than those who attended more school (HR 3.64; 95% CI [2.27, 5.84]). Conclusion. Pregnancy is both a cause and a consequence of school dropout. Consideration of school attendance and academic performance could ultimately enhance pregnancy prevention efforts in this population. Programs should be tailored differently for (1) girls who have dropped out of school, (2) those who are in school and at risk for pregnancy, and (3) those who are in school and become pregnant.

The association between perceived household educational support and HIV risk in young women in a rural South African community (HPTN 068): A cross sectional study.

OBJECTIVE: To characterise perceived household support for female education and the associations between educational support and HIV prevalence, HSV-2 prevalence and sexual risk behaviours. METHODS: This cross-sectional study used baseline survey data from the Swa Koteka HPTN 068 trial undertaken in Mpumalanga, South Africa. The study included 2533 young women aged 13-20, in grades 8-11 at baseline. HIV and HSV-2 status were determined at baseline. Information about patterns of sexual behaviour and household support for education was collected during the baseline survey. Linear regression and binary logistic regression were used to determine associations between household support for education and both biological and behavioural outcomes. RESULTS: High levels of educational support were reported across all measures. HIV prevalence was 3.2% and HSV-2 prevalence was 4.7%, both increasing significantly with age. Over a quarter (26.6%) of young women reported vaginal sex, with 60% reporting condom use at last sex. The median age of sexual debut was 16 years. Household educational support was not significantly associated with HIV or HSV-2; however, the odds of having had vaginal sex were significantly lower in those who reported greater homework supervision (OR 0.82, 95%CI: 0.72-0.94), those who engaged in regular discussion of school marks with a caregiver (OR 0.82, 95%CI: 0.71-0.95) and when caregivers had greater educational goals for the young woman (OR 0.82, 95%CI: 0.71-0.96). In contrast, greater caregiver disappointment at dropout was significantly associated with reported vaginal sex (OR 1.29, 95%CI: 1.14-1.46). CONCLUSION: Young women in rural South Africa report experiencing high levels of household educational support. This study suggests that greater household educational support is associated with lower odds of having vaginal sex and engaging in risky sexual behaviour, though not with HIV or HSV-2 prevalence.

Age-disparate partnerships and incident HIV infection in adolescent girls and young women in rural South Africa.

OBJECTIVE: Adolescent girls and young women (AGYW) have a much higher risk of HIV infection than young men of the same age. One hypothesis for this disparity is AGYW are more likely to be in sexual partnerships with older men with HIV; however, evidence has been inconclusive. DESIGN: We used longitudinal data from a randomized trial in South Africa (HPTN 068) to determined whether partner age difference is associated with incident HIV infection in AGYW. METHODS: Age difference was examined continuously and dichotomously (≥5 years). We examined inverse probability of exposure weighted survival curves and calculated time-specific risk differences and risk ratios over 5.5 years of follow-up. We also used a marginal structural Cox model to estimate hazard ratios over the entire study period. RESULTS: Risk of HIV was higher in AGYW with an age-disparate partnership versus not and the risk difference was largest at later time points. At 5.5 years, AGYW with an age-disparate partnership had a 12.6% (95% confidence interval 1.9-23.3) higher risk than AGYW with no age-disparate partnerships. The weighted hazard ratio was 1.91 (95% confidence interval 1.33-2.74), an association that remained after weighting for either transactional or condomless sex, and after examining continuous age-differences. CONCLUSION: Age-disparate partnerships increased risk of HIV infection, even after accounting for transactional sex and condomless sex. The relationship between age-disparate partnerships and HIV infection may be explained by increased exposure to infection from men in a higher HIV prevalence pool rather than differences in sexual behaviour within these partnerships.

Antiretroviral Drug Use and HIV Drug Resistance Among Young Women in Rural South Africa: HPTN 068.

BACKGROUND: Antiretroviral (ARV) drugs are used for HIV treatment and prevention. We analyzed ARV drug use and HIV drug resistance in a cohort of young women in rural South Africa enrolled in the HIV Prevention Trials Network (HPTN) 068 study, which evaluated the use of a cash transfer conditional on school attendance to reduce HIV incidence. METHODS: ARV drug testing was performed using plasma samples from 2526 young women. This included 2526 enrollment samples (80 HIV-infected and 2446 HIV-uninfected) and 162 seroconversion samples (first HIV-positive study visit). Testing was performed using a qualitative assay that detects 20 ARV drugs from 5 drug classes. HIV drug resistance testing was performed with the ViroSeq HIV-1 Genotyping System for samples that had HIV viral loads ≥400 copies per milliliter. RESULTS: At enrollment, ARV drugs were detected in 10 (12.5%) of 80 HIV-infected young women. None of 2446 HIV-uninfected young women had ARV drugs detected at enrollment. ARV drugs were also detected in 16 (9.9%) of 162 seroconverters. At enrollment, 9 (13.4%) of 67 young women with genotyping results had HIV drug resistance; resistance was also detected in 9 (6.9%) of 131 seroconverters with genotyping results. CONCLUSIONS: Most of the HIV-infected young women in this cohort from rural South Africa were not taking ARV drugs, suggesting they were unaware of their HIV status or were not in care. HIV drug resistance was detected in young women with both prevalent and new HIV infection.

HIV-1 diversity among young women in rural South Africa: HPTN 068.

BACKGROUND: South Africa has one of the highest rates of HIV-1 (HIV) infection world-wide, with the highest rates among young women. We analyzed the molecular epidemiology and evolutionary history of HIV in young women attending high school in rural South Africa. METHODS: Samples were obtained from the HPTN 068 randomized controlled trial, which evaluated the effect of cash transfers for school attendance on HIV incidence in women aged 13-20 years (Mpumalanga province, 2011-2015). Plasma samples from HIV-infected participants were analyzed using the ViroSeq HIV-1 Genotyping assay. Phylogenetic analysis was performed using 200 pol gene study sequences and 2,294 subtype C reference sequences from South Africa. Transmission clusters were identified using Cluster Picker and HIV-TRACE, and were characterized using demographic and other epidemiological data. Phylodynamic analyses were performed using the BEAST software. RESULTS: The study enrolled 2,533 young women who were followed through their expected high school graduation date (main study); some participants had a post-study assessment (follow-up study). Two-hundred-twelve of 2,533 enrolled young women had HIV infection. HIV pol sequences were obtained for 94% (n = 201/212) of the HIV-infected participants. All but one of the sequences were HIV-1 subtype C; the non-C subtype sequence was excluded from further analysis. Median pairwise genetic distance between the subtype C sequences was 6.4% (IQR: 5.6-7.2). Overall, 26% of study sequences fell into 21 phylogenetic clusters with 2-6 women per cluster. Thirteen (62%) clusters included women who were HIV-infected at enrollment. Clustering was not associated with study arm, demographic or other epidemiological factors. The estimated date of origin of HIV subtype C in the study population was 1958 (95% highest posterior density [HPD]: 1931-1980), and the median estimated substitution rate among study pol sequences was 1.98x10-3 (95% HPD: 1.15x10-3-2.81x10-3) per site per year. CONCLUSIONS: Phylogenetic analysis suggests that multiple HIV subtype C sublineages circulate among school age girls in South Africa. There were no substantive differences in the molecular epidemiology of HIV between control and intervention arms in the HPTN 068 trial.

Does Partner Selection Mediate the Relationship Between School Attendance and HIV/Herpes Simplex Virus-2 Among Adolescent Girls and Young Women in South Africa: An Analysis of HIV Prevention Trials Network 068 Data.

OBJECTIVE: School attendance prevents HIV and herpes simplex virus-2 (HSV-2) in adolescent girls and young women, but the mechanisms to explain this relationship remain unclear. Our study assesses the extent to which characteristics of sex partners, partner age, and number mediate the relationship between attendance and risk of infection in adolescent girls and young women in South Africa. DESIGN: We use longitudinal data from the HIV Prevention Trials Network 068 randomized controlled trial in rural South Africa, where girls were enrolled in early adolescence and followed in the main trial for more than 3 years. We examined older partners and the number of partners as possible mediators. METHODS: We used the parametric g-formula to estimate 4-year risk differences for the effect of school attendance on the cumulative incidence of HIV/HSV-2 overall and the controlled direct effect (CDE) for mediation. We examined mediation separately and jointly for the mediators of interest. RESULTS: We found that young women with high attendance in school had a lower cumulative incidence of HIV compared with those with low attendance (risk difference = -1.6%). Partner age difference (CDE = -1.2%) and the number of partners (CDE = -0.4%) mediated a large portion of this effect. In fact, when we accounted for the mediators jointly, the effect of schooling on HIV was almost removed, showing full mediation (CDE = -0.3%). The same patterns were observed for the relationship between school attendance and cumulative incidence of HSV-2 infection. CONCLUSION: Increasing school attendance reduces the risk of acquiring HIV and HSV-2. Our results indicate the importance of school attendance in reducing partner number and partner age difference in this relationship.

Transactional sex and incident HIV infection in a cohort of young women from rural South Africa.

OBJECTIVE: In sub-Saharan Africa, young women who engage in transactional sex (the exchange of sex for money or gifts) with a male partner show an elevated risk of prevalent HIV infection. We analyse longitudinal data to estimate the association between transactional sex and HIV incidence. DESIGN: We used longitudinal data from a cohort of 2362 HIV-negative young women (aged 13-20 years) enrolled in a randomized controlled trial in rural, South Africa who were followed for up to four visits over 6 years. METHODS: The effect of transactional sex on incident HIV was analysed using stratified Cox proportional hazards models and cumulative incidence curves. Risk ratios were estimated using log-binomial models to compare the effects across visits. RESULTS: HIV incidence was higher for young women that reported transactional sex (hazard ratio 1.59, 95% confidence interval 1.02-2.19), particularly when money and/or gifts were received frequently (at least weekly) (hazard ratio 2.71, 95% confidence interval 1.44-5.12). We also find that effects were much stronger during the main trial and dissipate at the postintervention visit, despite an increase in both transactional sex and HIV. CONCLUSION: Transactional sex elevates the risk of HIV acquisition among young women, especially when it involves frequent exchanges of money and/or gifts. However, the effect was attenuated after the main trial, possibly due to the changing nature of transactional sex and sexual partners as women age. These findings suggest that reducing transactional sex among young women, especially during adolescence, is important for HIV prevention.

The effect of school attendance and school dropout on incident HIV and HSV-2 among young women in rural South Africa enrolled in HPTN 068.

OBJECTIVE: To estimate the association between school attendance, school dropout, and risk of incident HIV and herpes simplex virus type 2 (HSV-2) infection among young women. DESIGN: We used longitudinal data from a randomized controlled trial in rural Mpumalanga province, South Africa, to assess the association between school days attended, school dropout, and incident HIV and HSV-2 in young women aged 13-23 years. METHODS: We examined inverse probability of exposure weighted survival curves and used them to calculate 1.5, 2.5, and 3.5-year risk differences and risk ratios for the effect of school attendance on incident HIV and HSV-2. A marginal structural Cox model was used to estimate hazard ratios for the effect of school attendance and school dropout on incident infection. RESULTS: Risk of infection increased over time as young women aged, and was higher in young women with low school attendance (<80% school days) compared with high (≥80% school days). Young women with low attendance were more likely to acquire HIV [hazard ratio (HR): 2.97; 95% confidence interval (CI): 1.62, 5.45] and HSV-2 (HR: 2.47; 95% CI: 1.46, 4.17) over the follow-up period than young women with high attendance. Similarly, young women who dropped out of school had a higher weighted hazard of both HIV (HR 3.25 95% CI: 1.67, 6.32) and HSV-2 (HR 2.70; 95% CI 1.59, 4.59). CONCLUSION: Young women who attend more school days and stay in school have a lower risk of incident HIV and HSV-2 infection. Interventions to increase frequency of school attendance and prevent dropout should be promoted to reduce risk of infection.

The effect of a conditional cash transfer on HIV incidence in young women in rural South Africa (HPTN 068): a phase 3, randomised controlled trial.

BACKGROUND: Cash transfers have been proposed as an intervention to reduce HIV-infection risk for young women in sub-Saharan Africa. However, scarce evidence is available about their effect on reducing HIV acquisition. We aimed to assess the effect of a conditional cash transfer on HIV incidence among young women in rural South Africa. METHODS: We did a phase 3, randomised controlled trial (HPTN 068) in the rural Bushbuckridge subdistrict in Mpumalanga province, South Africa. We included girls aged 13-20 years if they were enrolled in school grades 8-11, not married or pregnant, able to read, they and their parent or guardian both had the necessary documentation necessary to open a bank account, and were residing in the study area and intending to remain until trial completion. Young women (and their parents or guardians) were randomly assigned (1:1), by use of numbered sealed envelopes containing a randomisation assignment card which were numerically ordered with block randomisation, to receive a monthly cash transfer conditional on school attendance (≥80% of school days per month) versus no cash transfer. Participants completed an Audio Computer-Assisted Self-Interview (ACASI), before test HIV counselling, HIV and herpes simplex virus (HSV)-2 testing, and post-test counselling at baseline, then at annual follow-up visits at 12, 24, and 36 months. Parents or guardians completed a Computer-Assisted Personal Interview at baseline and each follow-up visit. A stratified proportional hazards model was used in an intention-to-treat analysis of the primary outcome, HIV incidence, to compare the intervention and control groups. This study is registered at ClinicalTrials.gov (NCT01233531). FINDINGS: Between March 5, 2011, and Dec 17, 2012, we recruited 10 134 young women and enrolled 2537 and their parents or guardians to receive a cash transfer programme (n=1225) or not (control group; n=1223). At baseline, the median age of girls was 15 years (IQR 14-17) and 672 (27%) had reported to have ever had sex. 107 incident HIV infections were recorded during the study: 59 cases in 3048 person-years in the intervention group and 48 cases in 2830 person-years in the control group. HIV incidence was not significantly different between those who received a cash transfer (1·94% per person-years) and those who did not (1·70% per person-years; hazard ratio 1·17, 95% CI 0·80-1·72, p=0·42). INTERPRETATION: Cash transfers conditional on school attendance did not reduce HIV incidence in young women. School attendance significantly reduced risk of HIV acquisition, irrespective of study group. Keeping girls in school is important to reduce their HIV-infection risk. FUNDING: National Institute of Allergy and Infectious Diseases, National Institute of Mental Health of the National Institutes of Health.

HPTN 068: A Randomized Control Trial of a Conditional Cash Transfer to Reduce HIV Infection in Young Women in South Africa-Study Design and Baseline Results.

Young women in South Africa are at high risk for HIV infection. Cash transfers offer promise to reduce HIV risk. We present the design and baseline results from HPTN 068, a phase III, individually randomized trial to assess the effect of a conditional cash transfer on HIV acquisition among South African young women. A total of 2533 young women were randomized to receive a monthly cash transfer conditional on school attendance or to a control group. A number of individual-, partner-, household- and school-level factors were associated with HIV and HSV-2 infection. After adjusting for age, all levels were associated with an increased odds of HIV infection with partner-level factors conveying the strongest association (aOR 3.05 95 % CI 1.84-5.06). Interventions like cash transfers that address structural factors such as schooling and poverty have the potential to reduce HIV risk in young women in South Africa.