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Background: The ambitious goal to eliminate new pediatric HIV infections by 2030 requires accelerated prevention strategies in high-risk settings such as South Africa. One approach could be pre-exposure prophylaxis (PrEP) with broadly neutralizing anti-HIV-1 monoclonal antibodies (bNAbs). The aim of our study is to define the optimal dose(s), the ideal combination(s) of bNAbs in terms of potency and breadth, and timing of subcutaneous (SC) administration(s) to prevent breast milk transmission of HIV., Methods: Two bNAbs, CAP256V2LS and VRC07-523LS, will be assessed in a sequential and randomized phase I, single-site, single-blind, dose-finding trial. We aim to investigate the 28-day safety and pharmacokinetics (PK) profile of incrementally higher doses of these bNAbs in breastfeeding HIV-1 exposed born without HIV neonates alongside standard of care antiretroviral (ARV) medication to prevent (infants) or treat (mothers) HIV infection. The trial design includes 3 steps and 7 arms (1, 2, 3, 4, 5, 6 and 6b) with 8 infants in each arm. The first step will evaluate the safety and PK profile of the bNAbs when given alone as a single subcutaneous (SC) administration at increasing mg/kg body weight doses within 96 h of birth: arms 1, 2 and 3 at doses of 5, 10, and 20 mg/kg of CAP256V2LS, respectively; arms 4 and 5 at doses of 20 and 30 mg/kg of VRC07-523LS, respectively. Step two will evaluate the safety and PK profile of a combination of the two bNAbs administered SC at fixed doses within 96 h of birth. Step three will evaluate the safety and PK profile of the two bNAbs administered SC in combination at fixed doses, after 3 months. Arms 1 and 6 will follow sequential recruitment, whereas randomization will occur sequentially between arms (a) 2 & 4 and (b) 3 & 5. Before each randomization, a safety pause will allow review of safety data of the preceding arms., Discussion: The results of this trial will guide further studies on bNAbs to prevent breast milk transmission of HIV., Protocol Version: Version 4.0 dated 15 March 2024., Trial Registration: Pan African Clinical Trial Registry (PACTR): PACTR202205715278722, 21 April 2022; South African National Clinical Trial Registry (SANCTR): DOH-27-062022-6058., (© 2024. The Author(s).)

Background: South African women have the highest burden of HIV infections globally. We investigated the temporal trends and the impact of key factors associated with HIV diagnosis among a nationally representative cohort of South African women., Methods: Total of 24,657 women who participated in the National HIV, Behaviour and Health Surveys conducted from 2002-to-2017., Results: Despite decades-long prevention efforts, we observed a significant increase in HIV prevalence over time (22% in 2002 to 21% in 2005-2008 and 29% in 2012-2017). Overall, 46% of the women living with HIV were not aware of their risk of HIV with age-specific disparities. Our findings revealed compelling evidence between HIV seropositivity and high HIV risk-perception (adjusted Odds Ratio (aOR):1.47 to 3.29) which increased overtime and exceeded the other factors. At a population-level, 45% of the HIV diagnoses were exclusively associated with women who believed they were at risk of HIV in 2012-2017. Women who reported using condoms at last sexual act were also at increased risk of HIV infection, with a population attributable risk of 18% (2002) to 21% (2012-2017)., Conclusion: There is an urgent need for culturally, socially, and linguistically appropriate prevention and awareness campaigns with realistic, non-confrontational messages., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Adolescent girls and young women (AGYW) in South Africa are at a three times higher risk of acquiring HIV than their male counterparts. The HIV prevention cascade is a tool which can be used to measure coverage of HIV prevention services, although there is limited empirical evidence to demonstrate its application in low-resourced settings. The unifying framework is a conceptualisation of the HIV prevention cascade which theorises that both motivation and access are required for an individual to effectively use an HIV prevention method. We applied this framework to data from a random sample of 127,951 beneficiaries of a combination HIV prevention programme for AGYW aged 15-24 in South Africa to measure the steps to, and identify key barriers to, effective use of male condoms and oral pre-exposure prophylaxis (PrEP) among this vulnerable population. Barriers to each step were analysed using univariate and multivariable logistic regression. Among self-reported HIV-negative AGYW who had sex in the past 6 months, effective use of condoms (15.2%), access to PrEP (39.1%) and use of PrEP (3.8%) were low. AGYW were: less likely to be motivated to use condoms if they believed that they had a faithful partner (aOR 0.44, 95% CI 0.22-0.90) or disliked condoms (aOR 0.26, 95% CI 0.11-0.57), less likely to access condoms if the place where AGYW accessed them was far away (aOR 0.25, 95% CI 0.10-0.64), more likely to effectively use condoms if they received counselling on how to use them (aOR 2.24, 95% CI 1.05-4.76), less likely to be motivated to use PrEP if they did not believe PrEP was efficacious (aOR 0.35, 95% CI 0.17-0.72), more likely to be motivated if they felt confident that they could use PrEP, and more likely to have access to PrEP if they had ever been offered PrEP (aOR 2.94, 95% CI 1.19-7.22). This combination HIV prevention programme and similar programmes should focus on risk-reduction counselling interventions for AGYW and their male partners to improve effective use of condoms and ensure easy access to condoms and PrEP by making them available in youth-friendly spaces. Our findings demonstrate that the application of HIV prevention cascades can inform AGYW HIV prevention programming in low-resourced settings., (© 2023. The Author(s).)

Objectives: We investigated the coverage of contraception services (excluding condoms) to prevent unintended pregnancy among young women and girls aged 15 to 24 years who were beneficiaries of one of the two largest combination HIV and pregnancy prevention program in South Africa., Study Design: We invited 2160 randomly sampled beneficiaries who were living in six of the 12 program districts across six provinces to participate in a telephone survey. We created pregnancy prevention coverage cascades and conducted univariate and multivariable analyses to identify key barriers and facilitators associated with each step of the cascade., Results: We achieved a response rate of 23.8%, resulting in 515 respondents, of whom 303 had sex in the 6 months before the survey. Of this subsample, 80.4% had access to contraception services, 60.6% had access and motivation to use contraceptives, and 21.9% had access to, motivation to use, and effectively used contraceptives. Distance to travel to services and not ever being offered contraceptives by health workers were access barriers, while low pregnancy risk perception was a barrier to motivation., Conclusions: Most respondents had access to and were motivated to use contraceptives other than condoms but were not effectively using them. Having been offered contraceptives facilitated better access, while distance to the services was a barrier, suggesting the importance of improving supply-side interventions, such as increasing the number and accessibility of spaces where Sexual and Reproductive Health (SRH) services are offered. We recommend longitudinal behavioral counseling for young people, especially adolescents, as well as risk reduction and information-tailored interventions., Implications: Pregnancy prevention cascades are a promising tool to monitor progress toward universal access to contraception services and to identify barriers that need to be addressed to achieve the effective use of contraceptives., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

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.

We examined power and decision-making in heterosexual relationships amongst South African adolescents and young people. A survey conducted with 515 adolescent girls and young women (AGYW) included items from the Sexual Relationship Power Scale (SRPS) adapted for South African women. Qualitative interviews with fifty AGYW aged between 15 and 24, and nine males aged 18 years and above, explored decision-making in heterosexual relationships, particularly relating to timing of sex and condom use. Theories of gendered power, sexual relationship power and sexual scripting were used in interpreting the data. Findings showed that the power AGYW have in sexual relationships determines their ability to use condoms, and that males generally control condom use and timing of sex. Both survey and interview data suggest that male control over female partners' behaviour also extends beyond the sexual domain. Although while male power is pervasive and enduring, it is simultaneously contested and negotiated. Despite some young people believing that gendered power in decision-making should be equal, it is not always possible for AGYW to enact agency in the dyadic context of heterosexual relationships. Whilst adolescents and young people in South Africa move away from traditional cultural gendered expectations, relationship power inequity and hegemonic masculinities continue to legitimise men's power over women, constraining the sexual agency of adolescent girls and young women and discouraging them from taking control of their own sexual interests and sexual health., (© 2022. The Author(s).)

After decades of research, South African women continue to have the highest burden of HIV in the world. The aim of the study is to investigate the impact of marital status on HIV using population and community-level data sources. We included data 13,469 and 5682 South African women who participated to South African HIV behavioural surveys in 2002-2012 and 2017, respectively. HIV prevalence and incidence rates were significantly higher among single/not-cohabiting women compared to those married/cohabiting with a partner in all survey participants (adjusted odds ratio (aOR): 1.60 and 1.58 in 2002-2012 and 2017, respectively). A quarter of the HIV diagnoses were attributed to those who were single/not-cohabiting women (population attributable risk (PAR%): 25% and 24%, respectively). More than 40% of the HIV infections were exclusively associated with single women (PAR%: 42%, 95% CI: 33%, 51%). Our results provided strong evidence for the profound impact of marital status on excess HIV infection rates. Targeting and reaching single/not-cohabiting women with multiple risk factors can potentially play a crucial role in the trajectories of the epidemic.

Background: Nef performs multiple cellular activities that enhance HIV-1 pathogenesis. The role of Nef-mediated down-regulation of the host restriction factor SERINC5 in HIV-1 pathogenesis is not well-defined. We aimed to investigate if SERINC5 down-regulation activity contributes to HIV-1 subtype C disease progression, to assess the relative contribution of this activity to overall Nef function, and to identify amino acids required for optimal activity. We measured the SERINC5 down-regulation activity of 106 subtype C Nef clones, isolated from individuals in early infection, for which the Nef activities of CD4 and HLA-I down-regulation as well as alteration of TCR signalling were previously measured. The relationship between SERINC5 down-regulation and markers of disease progression, and the relative contribution of SERINC5 down-regulation to a Nef fitness model-derived E value (a proxy for overall Nef fitness in vivo), were assessed., Results: No overall relationship was found between SERINC5 down-regulation and viral load set point (p = 0.28) or rate of CD4 + T cell decline (p = 0.45). CD4 down-regulation (p = 0.02) and SERINC5 down-regulation (p = 0.003) were significant determinants of E values in univariate analyses, with the greatest relative contribution for SERINC5 down-regulation, and only SERINC5 down-regulation remained significant in the multivariate analysis (p = 0.003). Using a codon-by-codon analysis, several amino acids were significantly associated with increased (10I, 11V, 38D, 51T, 65D, 101V, 188H and, 191H) or decreased (10K, 38E, 65E, 135F, 173T, 176T and, 191R) SERINC5 down-regulation activity. Site-directed mutagenesis experiments of selected mutants confirmed a substantial reduction in SERINC5 down-regulation activity associated with the mutation 173T, while mutations 10K, 135F, and 176T were associated with more modest reductions in activity that were not statistically significant., Conclusions: These results suggest that SERINC5 down-regulation is a significant contributor to overall Nef function and identify potential genetic determinants of this Nef function that may have relevance for vaccines or therapeutics., (© 2023. The Author(s).)

Background: The association structure linking the longitudinal and survival sub-models is of fundamental importance in the joint modeling framework and the choice of this structure should be made based on the clinical background of the study. However, this information may not always be accessible and rationale for selecting this association structure has received relatively little attention in the literature. To this end, we aim to explore four alternative functional forms of the association structure between the CD4 count and the risk of death and provide rationale for selecting the optimal association structure for our data. We also aim to compare the results obtained from the joint model to those obtained from the time-varying Cox model., Methods: We used data from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) AIDS Treatment programme, the Starting Antiretroviral Therapy at Three Points in Tuberculosis (SAPiT) study, an open-label, three armed randomised, controlled trial between June 2005 and July 2010 (N=642). In our analysis, we combined the early and late integrated arms and compared results to the sequential arm. We utilized the Deviance Information Criterion (DIC) to select the final model with the best structure, with smaller values indicating better model adjustments to the data., Results: Patient characteristics were similar across the study arms. Combined integrated therapy arms had a reduction of 55% in mortality (HR:0.45, 95% CI:0.28-0.72) compared to the sequential therapy arm. The joint model with a cumulative effects functional form was chosen as the best association structure. In particular, our joint model found that the area under the longitudinal profile of CD4 count was strongly associated with a 21% reduction in mortality (HR:0.79, 95% CI:0.72-0.86). Where as results from the time-varying Cox model showed a 19% reduction in mortality (HR:0.81, 95% CI:0.77-0.84)., Conclusions: In this paper we have shown that the "current value" association structure is not always the best structure that expresses the correct relationship between the outcomes in all settings, which is why it is crucial to explore alternative clinically meaningful association structures that links the longitudinal and survival processes., (© 2022. The Author(s).)

Background: There is limited understanding of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogenesis in African populations with a high burden of infectious disease comorbidities such as human immunodeficiency virus (HIV). The kinetics, magnitude, and duration of virus-specific antibodies and B-cell responses in people living with HIV (PLWH) in sub-Saharan Africa have not been fully characterized., Methods: We longitudinally followed SARS-CoV-2-infected individuals in Durban, KwaZulu-Natal, South Africa, and characterized SARS-CoV-2 receptor-binding domain-specific immunoglobulin (Ig) M, IgG, and IgA weekly for 1 month and at 3 months post-diagnosis. Thirty of 72 (41.7%) were PLWH, 25/30 (83%) of whom were on antiretroviral therapy (ART) with full HIV suppression. Plasma neutralization was determined using a live virus neutralization assay, and antibody-secreting cell population frequencies were determined by flow cytometry., Results: Similar seroconversion rates, time to peak antibody titer, peak magnitude, and durability of anti-SARS-CoV-2 IgM, IgG, and IgA were observed in people not living with HIV and PLWH with complete HIV suppression on ART. In addition, similar potency in a live virus neutralization assay was observed in both groups. Loss of IgA was significantly associated with age (P = .023) and a previous diagnosis of tuberculosis (P = .018)., Conclusions: Similar antibody responses and neutralization potency in people not living with HIV and PLWH on stable ART in an African setting suggest that coronavirus disease 2019 (COVID-19) natural infections may confer comparable antibody immunity in these groups. This provides hope that COVID-19 vaccines will be effective in PLWH on stable ART., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Comprehensive sexuality education (CSE) seeks to reduce risky sexual behaviour and subsequent incidence of unintended pregnancy and HIV among schoolgoing adolescents. This study estimates the association between exposure to CSE and key biomedical and behavioural indicators among adolescent girls in South Africa., Setting: Four DREAMS implementation districts in Gauteng and KwaZulu-Natal provinces in South Africa., Methods: Data from a household-based representative sample of adolescent girls (between the ages 12-18 years) (n = 9673) was collected. Independent variables included school attendance and exposure to CSE, with outcome variables measuring prevalence of HIV, pregnancy, and sexual risky behaviour, including condom use, incidence of age-disparate relationships, and transactional sex., Results: Adolescent girls in school and who had attended CSE classes in the previous 12 months were associated with reduced adjusted odds of being HIV-positive [full sample: adjusted odds ratios (AOR): 0.76, 95% confidence interval [CI]: 0.61 to 0.95, P < 0.05; sexually active sample: AOR: 0.62, 95% CI: 0.40 to 0.96, P < 0.05]. Those in school who attended CSE in the previous 12 months were also more likely to get tested for HIV (AOR: 1.48, 95% CI: 1.32 to 1.65, P < 0.001)., Conclusions: The results indicate that school attendance and exposure to CSE is associated with a reduction in risky sexual behaviour. Exposure to CSE is also associated with increased access to HIV testing for adolescent girls both in and out of school. Keeping adolescent girls in school produces the greatest positive sexual behavioural effect; this, coupled with the delivery of quality CSE, is a key strategy for reducing HIV risk., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: HIV incidence among adolescent girls and young women (AGYW) remains high, with their male partners a prominent factor in sustaining these elevated rates. Partnership characteristics remain important metrics for determining HIV risk, with evidence indicating that AGYW engaged in transactional and age-disparate relationships face greater HIV exposure. This study examines the risk posed to AGYW in a relationship with a "Blesser", defined as male who provides his female partner with their material needs or desires in exchange for a sexual relationship, an age-disparate (5 or more years older) partner, and the potential compounded risk of being a relationship with a partner or partners who are considered both a "Blesser" and age-disparate., Methods: A cross -sectional household based representative sample of AGYW (aged between 12-24 years) were enrolled in the study (n = 18 926) from the districts of City of Johannesburg and Ekurhuleni in the Gauteng province and the Districts of eThekwini and uMgungundlovu in the province of KwaZulu-Natal (KZN) in South Africa between March 13, 2017 to June 22, 2018. Participants completed a structured questionnaire and provided finger-prick blood samples for laboratory measurements. Our analysis used descriptive statistics and multiple binary logistic regressions accounting for survey weights, clustering and stratification., Findings: The median age of the sample was 21 years old (Interquartile range: 19-23) and nearly three quarters (73.7%) were currently attending school. Whilst all relationships exposed AGYW to potential HIV risk, multiple binary logistic regression analysis revealed that AGYW in a relationship with both a Blesser and an age-disparate partner were more likely to be HIV positive (AOR: 3.12, 95% CI: 1.76-5.53, p < 0.001), diagnosed with an STI (AOR: 4.60, 95% CI: 2.99-7.08, p < 0.001), had 2 or more sexual partners in the previous 12 months (AOR: 6.37, 95% CI: 3.85-10.54, p < 0.001), engaged in sexual activity at age 15 or younger (AOR: 3.67, 95% CI: 2.36-5.69, p < 0.001) and more likely to have ever been pregnant (AOR: 2.60, 95% CI: 1.24-5.45, p < 0.05) than those not in a relationship with either a Blesser or age-disparate partner., Conclusion: Different relationships present different HIV risk to AGYW. AGYW who had engaged in relationships with both a Blesser and an age-disparate partner were at greater HIV risk when examined against these relationships independent of one another. The data reveals the compounded HIV risk of being in both a transactional and age-disparate relationship., (© 2022. The Author(s).)

Importance: In South Africa, adolescent girls and young women aged 15 to 24 years are among the most high-risk groups for acquiring HIV. Progress in reducing HIV incidence in this population has been slow., Objective: To describe HIV prevalence and HIV risk behaviors among a sample of adolescent girls and young women and to model the association between exposure to multiple or layered interventions and key HIV biological and behavioral outcomes., Design, Setting, and Participants: This cross-sectional survey was conducted between March 13, 2017, and June 22, 2018, in 2 districts in Gauteng province and in 2 districts in KwaZulu-Natal province in South Africa. A stratified cluster random sampling method was used. Participants included adolescent girls and young women aged 12 to 24 years who lived in each sampled household. Overall, 10 384 participants were enrolled in Gauteng province and 7912 in KwaZulu-Natal province. One parent or caregiver was interviewed in each household. Data analysis was performed from March 12, 2021, to March 1, 2022., Exposures: DREAMS (Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe)-like interventions., Main Outcomes and Measures: The primary outcome was HIV prevalence. HIV status was obtained from laboratory-based testing of peripheral blood samples. Secondary outcomes included HIV testing and antiretroviral therapy uptake as well as numerous HIV risk variables that the DREAMS program sought to improve, such as pregnancy, sexually transmitted infection, intimate partner violence, and age-disparate sex., Results: The final sample included 18 296 adolescent girls and young women (median [IQR] age, 19 [15-21] years) in 10 642 households. Approximately half of participants (49.9%; n = 8414) reported engaging in sexual activity, and 48.1% (n = 3946) reported condom use at the most recent sexual encounter. KwaZulu-Natal province had a higher HIV prevalence than Gauteng province (15.1% vs 7.8%; P < .001). Approximately one-fifth of participants (17.6%; n = 3291) were not exposed to any interventions, whereas 43.7% (n = 8144) were exposed to 3 or more interventions. There was no association between exposure to DREAMS-like interventions and HIV status. Adolescent girls and young women who accessed 3 or more interventions were more likely to have undergone HIV testing (adjusted odds ratio, 2.39; 95% CI, 2.11-2.71; P < .001) and to have used condoms consistently in the previous 12 months (adjusted odds ratio, 1.68; 95% CI, 1.33-2.12; P < .001) than those who were not exposed to any interventions., Conclusions and Relevance: Results of this study suggest that self-reported exposures to multiple or layered DREAMS-like interventions were associated with favorable behavioral outcomes. The beneficial aspects of layering HIV interventions warrant further research to support the sexual and reproductive health of adolescent girls and young women.

Background: We aimed to assess the effectiveness of a single dose of the Ad26.COV2.S vaccine (Johnson & Johnson) in health-care workers in South Africa during two waves of the South African COVID-19 epidemic., Methods: In the single-arm, open-label, phase 3B implementation Sisonke study, health-care workers aged 18 years and older were invited for vaccination at one of 122 vaccination sites nationally. Participants received a single dose of 5 × 10 10 viral particles of the Ad26.COV2.S vaccine. Vaccinated participants were linked with their person-level data from one of two national medical insurance schemes (scheme A and scheme B) and matched for COVID-19 risk with an unvaccinated member of the general population. The primary outcome was vaccine effectiveness against severe COVID-19, defined as COVID-19-related admission to hospital, hospitalisation requiring critical or intensive care, or death, in health-care workers compared with the general population, ascertained 28 days or more after vaccination or matching, up to data cutoff. This study is registered with the South African National Clinical Trial Registry, DOH-27-022021-6844, ClinicalTrials.gov, NCT04838795, and the Pan African Clinical Trials Registry, PACTR202102855526180, and is closed to accrual., Findings: Between Feb 17 and May 17, 2021, 477 102 health-care workers were enrolled and vaccinated, of whom 357 401 (74·9%) were female and 119 701 (25·1%) were male, with a median age of 42·0 years (33·0-51·0). 215 813 vaccinated individuals were matched with 215 813 unvaccinated individuals. As of data cutoff (July 17, 2021), vaccine effectiveness derived from the total matched cohort was 83% (95% CI 75-89) to prevent COVID-19-related deaths, 75% (69-82) to prevent COVID-19-related hospital admissions requiring critical or intensive care, and 67% (62-71) to prevent COVID-19-related hospitalisations. The vaccine effectiveness for all three outcomes were consistent across scheme A and scheme B. The vaccine effectiveness was maintained in older health-care workers and those with comorbidities including HIV infection. During the course of the study, the beta (B.1.351) and then the delta (B.1.617.2) SARS-CoV-2 variants of concerns were dominant, and vaccine effectiveness remained consistent (for scheme A plus B vaccine effectiveness against COVID-19-related hospital admission during beta wave was 62% [95% CI 42-76] and during delta wave was 67% [62-71], and vaccine effectiveness against COVID-19-related death during beta wave was 86% [57-100] and during delta wave was 82% [74-89])., Interpretation: The single-dose Ad26.COV2.S vaccine shows effectiveness against severe COVID-19 disease and COVID-19-related death after vaccination, and against both beta and delta variants, providing real-world evidence for its use globally., Funding: National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation, and the Bill & Melinda Gates Foundation., Competing Interests: Declaration of interests L-GB declares honoraria for advisory roles from MSD, ViiV Health Care, and Gilead. RJL declares Department of Science and Innovation and South African Medical Research Council (SAMRC) funding to the KwaZulu-Natal Research Innovation and Sequencing Platform at the University of KwaZulu-Natal for the Network for Genomic Surveillance South Africa, which supported the genomic sequencing for this study; and committee membership of the Ministerial Advisory Committee on COVID-19 Vaccines (a committee that makes recommendations to the Minister of South Africa on the national COVID-19 vaccine programme. CC declares grants or contracts from CDC, PATH, the Bill & Melinda Gates Foundation, SAMRC, Wellcome Trust, and Sanofi Pasteur in the past 36 months. MG reports grants from SAMRC during the conduct of the study, and grants from the Bill & Melinda Gates Foundation outside of the submitted work. DBa reports grants from US National Institutes of Health (NIH) and Janssen during the conduct of the study; grants from Defense Advanced Research projects Agency, Massachusetts Consortium on Pathogen Readiness, Ragon Institute, the Bill & Melinda Gates Foundation, SAMRC, Henry Jackson Foundation, Musk Foundation, Gilead, Legend Bio, CureVac, Sanofi, Intima Bio, Alkermes, and Zentalis; and personal fees from SZQ Bio, Pfizer, Celsion, Avidea, Laronde, Meissa, and Vector Sciences outside of the submitted work DBr has three patents (63/121,482; 63/133,969; 63/135,182) licensed to Janssen. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: South Africa, with the highest burden of HIV infection globally, has made huge strides in its HIV/ART programme, but AIDS deaths have not decreased proportionally to ART uptake. Advanced HIV disease (CD4 < 200 cells/mm 3 ) persists, and CD4 count testing is being overlooked since universal test-and-treat was implemented. Point-of-care CD4 testing could address this gap and assure differentiated care to these vulnerable patients with low CD4 counts., Methods: A time randomised implementation trial was conducted, enrolling 603 HIV positive non-ART, not pregnant patients at a primary health care clinic in Durban, South Africa. Weeks were randomised to either point-of-care CD4 testing (n = 305 patients) or standard-of-care central laboratory CD4 testing (n = 298 patients) to assess the proportion initiating ART at 3 months. Cox regression, with robust standard errors adjusting for clustering by week, were used to assess the relationship between treatment initiation and arm., Results: Among the 578 (299 point-of-care and 279 standard-of-care) patients eligible for analysis, there was no significant difference in the number of eligible patients initiating ART within 3 months in the point-of-care (73%) and the standard-of-care (68%) groups ( P  = 0.112). The time-to-treat analysis was not significantly different in patients with CD4 counts of 201-500 cells/mm 3 which could have been due to appointment scheduling to cope with the large burden of cases. However, in patients with advanced HIV disease (CD4 < 200cells/mm 3 ) 65% more patients started ART earlier in the point-of-care group (HR 1.65 (95% confidence interval (CI) = 0.99-2.75; P  = 0.052) compared to the standard-of-care group., Conclusions: Point-of-care testing decreased time-to-treatment in those with advanced HIV disease. With universal test and treat for HIV, rollout of simple point-of-care CD4 testing would ensure early diagnosis of advanced HIV disease and facilitate differentiated care for these vulnerable patients as per the World Health Organisation 2020 target product profile for point-of-care CD4 testing., Trial Registration: ISRCTN14220457., Competing Interests: Competing interests: The authors completed the ICMJE Unified Competing Interest Form (available upon request from the corresponding author), and declare no conflicts of interest., (Copyright © 2022 by the Journal of Global Health. All rights reserved.)

Background: Intimate partner violence (IPV) may affect the HIV-treatment cascade., Setting: Four high HIV-prevalence DREAMS health districts in South Africa., Methods: Secondary analysis of cross-sectional data collected March 2017-June 2018, using random household sample of young (12-24 years) girls and women. Face-to-face interviews assessed IPV and HIV-status knowledge, and finger-prick blood draws assessed ART (antiretroviral therapy) uptake and viral suppression. We used logistic regression to estimate crude and adjusted effects of IPV on HIV knowledge, ART uptake, and viral suppression., Results: Of 18,230 adolescent girls and young women, 8413 (46%) reported ever having had sex, of whom 1118 (13%) were HIV positive. The 90:90:90 benchmarks were 61% knew their status, 86% had ART present in their blood sample, and 91% were virally suppressed. Among the entire sample of young women living with HIV, 65.6% were virally suppressed. Past year IPV was reported by 15%. In adjusted models, IPV trended toward increasing the odds that a young woman was aware she was living with HIV [adjusted odds ratios (aOR) = 1.40, 2.00-9.98, P = 0.067]. There was no association between IPV and reduced treatment use (aOR = 0.73, 0.41-1.29). IPV was independently associated with reduced viral suppression (aOR = 0.30, 0.13-0.66)., Conclusions: Addressing the role of IPV in undermining the treatment cascade for adolescent and young women is a critical issue for HIV programming., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Adolescents are at increased risk of HIV infection compared to other age groups. There is an urgent need for strategic information that will inform programmes to reduce risk and vulnerability to HIV and reverse the pattern of increasing HIV infection as they transition to adulthood. This paper analysed trends and factors associated with HIV prevalence among adolescents in South Africa using the national HIV population-based household surveys conducted in 2008, 2012 and 2017., Methods: All three surveys used a multistage cross-sectional design. A trend analysis was conducted to assess the differences in HIV prevalence and covariates overtime using P-trend Chi-squared statistic. Univariate and multivariate logistic regression models were used to determine factors associated with HIV prevalence., Results: Overall there was a significant increase in HIV prevalence among adolescents aged 12-19 years from 3.0% (n = 2892) in 2008 to 3.2% (n = 4829) in 2012 and 4.1% (n = 3937) in 2017 (p = 0.031). The odds of being HIV positive among adolescents aged 12-19 years was significantly higher among females [AOR = 2.24; 95% CI (1.73-2.91); p < 0.001] than males, those residing in KwaZulu-Natal province [AOR = 2.01; 95% CI (1.-3.99); p = 0.027] than Northern Cape, and those who did not attend an educational institution and were unemployed [AOR = 2.66; 95% CI (1.91-3.67); p < 0.001] compared to those attending an educational institution. The odds were significantly lower among Whites [AOR = 0.29; 95% CI (0.09-0.93); p = 0.037], Coloureds [AOR = 0.21; 95% CI (0.11-0.37); p ≤ 0.001] and Indian/Asian [AOR = 0.08; 95% CI (0.02-0.34); p = 0.001] population groups than Black Africans., Conclusion: The observed increasing trend and gender disparities in HIV prevalence suggests an urgent need for age appropriate and gender specific HIV interventions tailored and targeted at identified drivers of HIV infection among adolescents., (© 2021. The Author(s).)

Background: HIV is one of the greatest public health challenges in South Africa. Potential HIV vaccines and antibodies are thought to be cost-effective biomedical HIV prevention methods and are currently under investigation in phase I, II, and III trials. Consequently, current and future clinical trials need to ensure sufficient recruitment and retention. To achieve this goal, clinical trial staff need to understand the socio-demographic and behavioural characteristics of people volunteering to screen for these trials and their reasons for volunteering., Methods: We conducted a secondary analysis of participant screening data across five vaccine and monoclonal antibody trials at four sites in KwaZulu-Natal, South Africa. Our study reviewed the demographic, behavioural, motivational, and health-related data from the case report forms and screening questionnaires. Descriptive statistics, chi-squared, and one-way ANOVA tests were used to analyse participants' characteristics and motivation to participate in HIV vaccine and monoclonal antibody trials. Analyses were conducted using R version 3.5.2., Results: Screening data from 1934 participants, including 79.2% of women, were obtained across all five trials (1034 enrolled, 900 screened out/declined). Screened participants predominately self-identified as black, heterosexual, cisgender women or men, many with lower educational backgrounds (43.9% did not complete secondary/high school), and several self-reported HIV-risk behaviours among themselves and their partners. 10.8% of the screened participants were living with HIV. Avoiding HIV risk was the main motivation to participate in clinical trials, followed by altruistic reasons such as a desire to help the community or helping to find a vaccine., Discussion: The current recruitment approach of these trials attracts heterosexual participants who seek to reduce HIV risk and support their community. Hence, the data suggest the need for and potential acceptance of continued ongoing HIV prevention efforts. Current trials attract participants with lower educational levels, which may be driven by the site locations, current community mobilisation strategies and research site opening hours. The sites could consider more flexible working hours to accommodate working participants and find ways to connect participants to educational support and opportunities to upgrade education levels for the current clientele., Trial Registration: HVTN 100: A Safety and Immune Response Study of 2 Experimental HIV Vaccines, NCT02404311 . Registered on March 17, 2015. HVTN 111: Safety and Immune Response to a Clade C DNA HIV Vaccine, NCT02997969. Registered on December 16, 2016. HVTN 108: Evaluating the Safety and Immunogenicity of HIV Clade C DNA Vaccine and MF59- or AS01B-Adjuvanted Clade C Env Protein Vaccines in Various Combinations in Healthy, HIV-Uninfected Adults, NCT02915016. Registered on September 22, 2016. HVTN 702: Pivotal Phase 2b/3 ALVAC/Bivalent gp120/MF59 HIV Vaccine Prevention Safety and Efficacy Study in South Africa, NCT02968849. Registered on November 1, 2016. HVTN 703/HPTN 081: Evaluating the Safety and Efficacy of the VRC01 Antibody in Reducing Acquisition of HIV-1 Infection in Women, NCT02568215 . Registered on October 1, 2015., (© 2021. The Author(s).)

After several decades of research, South Africa is still considered to be the epicentre of HIV epidemic. The country also has the highest burden of sexually transmitted infections (STIs) which have been frequently linked to increasing rates of HIV transmission due to biological and behavioural associations between these two pathogeneses. We investigated the cumulative impact of recurrent STIs on subsequent HIV seroconversion among a cohort of South African women. We used the ' frailty' models which can account for the heterogeneity due to the recurrent STIs in a longitudinal setting. The lowest HIV incidence rate was 5.0/100 person-year among women who had no baseline STI and remained negative during the follow-up. This estimate was three times higher among those who had recurrent STIs in the follow-up period regardless of their STI status at baseline (15.8 and 14.0/100 person-year for women with and without STI diagnosis at baseline, respectively). Besides younger age and certain partnership characteristics, our data provided compelling evidence for the impact of recurrent STI. diagnoses on increasing rates of HIV. At the population-level, 65% of HIV infections collectively associated with recurrent STIs. These results have significant clinical and epidemiological implications and may play critical role in the trajectory of the infections in the region.

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., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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.

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.

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., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Purpose: Women's choice of contraceptive can have broader implications and may play a significant role in shaping their sexual practices. We aim to identify the characteristics of women who use hormonal injectables and those at high-risk of HIV infection. We also quantify the population-level impact of their shared characteristics on HIV incidence rates., Materials and Methods: Data from 9948 women who enrolled in six-HIV prevention trials conducted in South Africa (2002-2016) were included. We used logistic and Cox regression models and estimated the population-level impact of the use of injectables on HIV incidence in the multifactorial-model setting., Results: Using hormonal injectables were associated with increased risk of HIV infection (adjusted Hazard ratio (aHR):1.51, 95% CI:1.22, 1.86). At the population level less than 20% of the infections were associated with injectable contraceptives among younger women (i.e., less than 35 years of age). Factors including being single/not-cohabiting, using condoms at last sex, partner-related factors, and STI diagnosis were all identified as shared characteristics of women who preferred using hormonal injectables and those at high-risk of HIV infection. At the population level, these factors were associated with more than 50% of the infections among women younger than 35 years of age., Conclusions: Our analysis presented evidence for the overlapping characteristics of the women who used hormonal injectables and those at high-risk of HIV infection. These findings reinforce the importance of comprehensive contraceptive counselling to women about the importance of dual protection, such as male condoms and hormonal contraceptives use.

Background: Modelling of longitudinal biomarkers and time-to-event data are important to monitor disease progression. However, these two variables are traditionally analyzed separately or time-varying Cox models are used. The former strategy fails to recognize the shared random-effects from the two processes while the latter assumes that longitudinal biomarkers are exogenous covariates, resulting in inefficient or biased estimates for the time-to-event model. Therefore, we used joint modelling for longitudinal and time-to-event data to assess the effect of longitudinal CD4 count on mortality., Methods: We studied 4014 patients from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) who initiated ART between June 2004 and August 2013. We used proportional hazards regression model to assess the effect of baseline characteristics (excluding CD4 count) on mortality, and linear mixed effect models to evaluate the effect of baseline characteristics on the CD4 count evolution over time. Thereafter, the two analytical approaches were amalgamated to form an advanced joint model for studying the effect of longitudinal CD4 count on mortality. To illustrate the virtues of the joint model, the results from the joint model were compared to those from the time-varying Cox model., Results: Using joint modelling, we found that lower CD4 count over time was associated with a 1.3-fold increase in the risk of death, (HR: 1.34, 95% CI: 1.27-1.42). Whereas, results from the time-varying Cox model showed lower CD4 count over time was associated with a 1.2-fold increase in the risk of death, (HR: 1.17, 95% CI: 1.12-1.23)., Conclusions: Joint modelling enabled the assessment of the effect of longitudinal CD4 count on mortality while correcting for shared random effects between longitudinal and time-to-event models. In the era of universal test and treat, the evaluation of CD4 count is still crucial for guiding the initiation and discontinuation of opportunistic infections prophylaxis and assessment of late presenting patients. CD4 count can also be used when immunological failure is suspected as we have shown that it is associated with mortality.

To assess i) whether there is an independent association between HIV-prevalence and settlement types (urban formal, urban informal, rural formal, rural informal), and, ii) whether this changes over time, in South Africa. We draw on four (2002; 2005; 2008; 2012) cross-sectional South African household surveys. Data is analysed by sex (male/female), and for women by age categories (15-49; and 15-24; 25-49) at all-time points, for men in 2012 data is analysed by age categories (15-24; 25-49). By settlement type and sex/age combinations, we descriptively assess the association between socio-demographic and HIV-risk factors; HIV-prevalence; and trends in HIV-prevalence by time. Relative risk ratios assess unadjusted and adjusted risk for HIV-prevalence by settlement type. All estimates are weighted, and account for survey design. In all survey years, and combinations of sex/age categorisations, HIV-prevalence is highest in urban informal settlements. For men (15-49) an increasing HIV-prevalence over time in rural informal settlements was seen (p = 0.001). For women (15-49) HIV-prevalence increases over time for urban informal, rural informal, rural formal, and women (15-24) decreases in urban formal and urban informal, and women (25-49) increases urban informal and rural informal settlements. In analyses adjusting for potential socio-demographic and risk factors, compared to urban formal settlements, urban informal settlements had consistently higher relative risk of HIV for women, in all age categorisations, for instance in 2012 this was RR1.89 (1.50, 2.40) for all women (15-49), for 15-24 (RR1.79, 1.17-2.73), and women 25-49 (RR1.91, 1.47-2.48). For men, in the overall age categorization, urban informal settlements had a higher relative risk for HIV in all years. In 2012, when this was disaggregated by age, for men 15-24 rural informal (IRR2.69, 1.28-5.67), and rural formal (RR3.59, 1.49-8.64), and for men 25-49 it was urban informal settlements with the highest (RR1.68, 1.11-2.54). In 2012, rural informal settlements also had higher adjusted relative risk for HIV-prevalence for men (15-49) and women (15-49; 15-24; 25-49). In South Africa, HIV-prevalence is patterned geographically, with urban informal settlements having a particularly high burden. Geographical targeting of responses is critical for the HIV-response., Competing Interests: The authors have declared that no competing interests exist.

Background: Young women in sub-Saharan Africa remain at the epicentre of the HIV epidemic, with surveillance data indicating persistent high levels of HIV incidence. In South Africa, adolescent girls and young women (AGYW) account for a quarter of all new HIV infections. Determined, Resilient, Empowered, AIDS-free, Mentored and Safe (DREAMS) is a strategy introduced by the United States President's Emergency Plan for AIDS Relief (PEPFAR) aimed at reducing HIV incidence among AGYW in 10 countries in sub-Saharan Africa by 25% in the programme's first year, and by 40% in the second year. This study will assess the change in HIV incidence and reduction in risk associated behaviours that can be attributed to the DREAMS initiative in South Africa, using a population-based cross-sectional survey., Methods: Data will be collected from a household-based representative sample of AGYW (between the ages 12-24 years) in four high prevalence districts (more than 10% of the population have HIV in these districts) in South Africa in which DREAMS has been implemented. A stratified cluster-based sampling approach will be used to select eligible participants for a cross-sectional survey with 18,500, to be conducted over 2017/2018. A questionnaire will be administered containing questions on sexual risk behaviour, selected academic and developmental milestones, prevalence of gender based violence, whilst examining exposure to DREAMS programmes. Biological samples, including two micro-containers of blood and self-collected vulvovaginal swab samples, are collected in each survey to test for HIV infection, HIV incidence, sexually transmitted infections (STIs) and pregnancy. This study will measure trends in population level HIV incidence using the Limiting antigen (LAg) Avidity Enzyme Immuno-Assay (EIA) and monitor changes in HIV incidence., Discussion: Ending the HIV/AIDS pandemic by 2030 requires the continual monitoring and evaluation of prevention programmes, with the aim of optimising efforts and ensuring the achievement of epidemic control. This study will determine the impact DREAMS interventions have had on HIV incidence among AGYW in a 'real world, non-trial setting'.

Objective: We identified the geographical clustering of HIV as well as those at highest risk of infection using a decade long data (2002-2012) from KwaZulu-Natal, South Africa., Methods: A total of 5,776 women who enrolled in several HIV prevention trials were included in the study. Geo-coded individual-level data were linked to the community-level characteristics using the South African Census. High-risk women were identified using a risk scoring algorithm. Generalized additive models were used to identify the significant geographical clustering of high-risk women and HIV., Results: Overall, 60% of the women were classified as high risk of HIV. HIV infection rates were estimated as high as 10 to 15 per 100 person year. Areas with high rates of HIV infections were spatially clustered and overlapped particularly in the Northern part of Durban., Conclusion: Targeting multifactorial and complex nature of the epidemic is urgently needed to identify the "high transmission" areas., (Copyright © 2019. Published by Elsevier Ltd.)

Background: With Universal Health Coverage and Integrated People-centred Health Care, streamlined health-systems and respectful care are necessary. South Africa has made great strides in prevention of mother-to-child transmission (PMTCT) but with the great burden of HIV, a minimum of birth and 10-week HIV-PCR testing are required for the estimated 360,000 HIV-exposed infants born annually which presents many challenges including delayed results and loss to follow-up. Point-of-care (POC) HIV testing of infants addresses these challenges well and facilitates initiation of HIV-infected infants rapidly after diagnosis for best clinical outcomes., Methods: Objectives were to determine accuracy, feasibility and acceptability of POC testing compared to standard-of-care (SOC) central-laboratory testing. HIV-exposed infants for birth PCR testing in hospital (n = 323) and follow-up at a primary health care clinic (n = 117) in Durban, South Africa were included. A baseline situational-analysis reviewed registers and phoned mothers of HIV-exposed infants prior to the intervention. An effectiveness-implementation study of the Alere™q HIV-1/2 Detect POC test (heel-prick specimen processed in 50 min) was compared with SOC with questionnaires to mothers and staff. Stata 14 was used for analysis., Results: At baseline 2% of birth HIV tests were missed; only 40% of mothers could be contacted; 17% did not receive birth test result; 19% did not have a 10-week test; 39% had not received the 10-week results. There were 5(1.5%) HIV-infected and 318(98.5%) HIV-negative infants detected in hospital with all clinic babies negative. All positive infants commenced ART before discharge. Ultimately POC and SOC had perfect concordance but for 10 SOC tests researchers actively tracked-down results or repeated tests. Turn around times for SOC tests were on average 8-days (IQR 6-10  days) and for POC testing was 0-days. The POC error-rate was 9,6% with all giving a result when repeated. The majority of mothers (92%) preferred POC testing with 7% having no preference. No staff preferred SOC testing with 79% preferring POC and 21% having no preference., Conclusions: Point-of-care HIV testing for EID is accurate, feasible and acceptable, with benefits of early ART for all positive infants at birth facilities. We recommend that it be considered best practice for EID., Trial Registration: ISRCTN38911104 registered 9 January 2018 - retrospectively registered.

Background: Fine scale geospatial analysis of HIV infection patterns can be used to facilitate geographically targeted interventions. Our objective was to use the geospatial technology to map age and time standardized HIV incidence rates over a period of 10 years to identify communities at high risk of HIV in the greater Durban area., Methods: HIV incidence rates from 7557 South African women enrolled in five community-based HIV prevention trials (2002-2012) were mapped using participant household global positioning system (GPS) coordinates. Age and period standardized HIV incidence rates were calculated for 43 recruitment clusters across greater Durban. Bayesian conditional autoregressive areal spatial regression (CAR) was used to identify significant patterns and clustering of new HIV infections in recruitment communities., Results: The total person-time in the cohort was 9093.93 years and 613 seroconversions were observed. The overall crude HIV incidence rate across all communities was 6·74 per 100PY (95% CI: 6·22-7·30). 95% of the clusters had HIV incidence rates greater than 3 per 100PY. The CAR analysis identified six communities with significantly high HIV incidence. Estimated relative risks for these clusters ranged from 1.34 to 1.70. Consistent with these results, age standardized HIV incidence rates were also highest in these clusters and estimated to be 10 or more per 100 PY. Compared to women 35+ years old younger women were more likely to reside in the highest incidence areas (aOR: 1·51, 95% CI: 1·06-2·15; aOR: 1.59, 95% CI: 1·19-2·14 and aOR: 1·62, 95% CI: 1·2-2·18 for < 20, 20-24, 25-29 years old respectively). Partnership factors (2+ sex partners and being unmarried/not cohabiting) were also more common in the highest incidence clusters (aOR 1.48, 95% CI: 1.25-1.75 and aOR 1.54, 95% CI: 1.28-1.84 respectively)., Conclusion: Fine geospatial analysis showed a continuous, unrelenting, hyper HIV epidemic in most of the greater Durban region with six communities characterised by particularly high levels of HIV incidence. The results motivate for comprehensive community-based HIV prevention approaches including expanded access to PrEP. In addition, a higher concentration of HIV related services is required in the highest risk communities to effectively reach the most vulnerable populations.

South Africa has the highest burden of human immunodeficiency virus (HIV) infections in the world with significant geographical variations. We identified the predictors of HIV infections and their sub-geographical-level contributions to the epidemic using a decade long data (2002-2012) from 6484 South African women. Generalized additive models were used to uncover the most significant features of these estimates across the region. In the overall analysis, younger age, not married or cohabiting with a partner, partner has another partner(s) and null/prim parity, using injectable contraceptives and presence of other sexually transmitted infections (STIs) were identified as independent predictors of HIV seroconversions. Overall, the top three highest contributors to infections were women's marital status (PAR% = 73%, 95% CI: 68%, 77%), parity (PAR% = 47%, 95% CI: 42%, 53%) and partnership factors (PAR% = 37%, 95% CI: 30%, 44%). However, their contributions varied remarkably at sub-geographical level. This was mainly due to the substantial localized variations in their prevalence and hazard ratios across the region. Our results will guide policy makers to develop tailored prevention strategies in order to allocate scarce resources by targeting the most significant contributors of HIV infection at sub-geographical level.

Sustained viremia after acute HIV infection is associated with profound CD4 + T cell loss and exhaustion of HIV-specific CD8 + T cell responses. To determine the impact of combination antiretroviral therapy (cART) on these processes, we examined the evolution of immune responses in acutely infected individuals initiating treatment before peak viremia. Immediate treatment of Fiebig stages I and II infection led to a rapid decline in viral load and diminished magnitude of HIV-specific (tetramer + ) CD8 + T cell responses compared to untreated donors. There was a strong positive correlation between cumulative viral antigen exposure before full cART-induced suppression and immune responses measured by MHC class I tetramers, IFN-γ ELISPOT, and CD8 + T cell activation. HIV-specific CD8 + T responses of early treated individuals were characterized by increased CD127 and BCL-2 expression, greater in vitro IFN-γ secretion, and enhanced differentiation into effector memory (T em ) cells. Transcriptional analysis of tetramer + CD8 + T cells from treated persons revealed reduced expression of genes associated with activation and apoptosis, with concurrent up-regulation of prosurvival genes including BCL-2 , AXL , and SRC Early treatment also resulted in robust HIV-specific CD4 + T cell responses compared to untreated HIV-infected individuals. Our data show that limiting acute viremia results in enhanced functionality of HIV-specific CD4 + and CD8 + T cells, preserving key antiviral properties of these cells., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY).)

Functional characterisation of different HIV-1 subtypes may improve understanding of viral pathogenesis and spread. Here, we evaluated the ability of 345 unique HIV-1 Nef clones representing subtypes A, B, C and D to inhibit NFAT signalling following TCR stimulation. The contribution of this Nef function to disease progression was also assessed in 211 additional Nef clones isolated from unique subtype C infected individuals in early or chronic infection. On average, subtype A and C Nef clones exhibited significantly lower ability to inhibit TCR-mediated NFAT signalling compared to subtype B and D Nef clones. While this observation corroborates accumulating evidence supporting relative attenuation of subtypes A and C that may paradoxically contribute to their increased global prevalence and spread, no significant correlations between Nef-mediated NFAT inhibition activity and clinical markers of HIV-1 infection were observed, indicating that the relationship between Nef function and pathogenesis is complex., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Women enrolled in human immunodeficiency virus (HIV) prevention efficacy trials receive counseling on prevention of HIV, sexually transmitted infections (STIs), and pregnancy during every visit. Incident pregnancy has an impact on efficacy outcomes. Incidence rates of pregnancy and HIV/STIs among women who became pregnant and associated risk factors were assessed., Methods: Data from 9165 women participating in HIV prevention trials in KwaZulu-Natal, South Africa from 2002-2012 were combined. Demographic and behavioral predictors of incidence pregnancy and incidence HIV and STIs were determined using Cox regression models., Results: Overall pregnancy incidence was 9.6 per 100 person-year (py) (95% confidence interval [Cl], 9.1-10.3). Human immunodeficiency virus incidence among pregnant women was 5.93 per 100 py (95% Cl, 4.73-7.44). Incidence of STIs among pregnant women for Chlamydia trachomatis, Trichomonas vaginalis, Neisseria gonorrhoeae, and Treponema pallidum (syphilis) were 10.87, 7.42, 3.92, and 1.43 per 100 py, respectively. In the adjusted analyses, we observed overlapping risk factors for HIV acquisition during pregnancy, ie, young age, not married/not cohabitating, and low parity. The risk of pregnancy and HIV acquisition is more than 3 times higher among young women (<20 years of age)., Conclusions: We identified overlapping risk factors for pregnancy and HIV incidence, suggesting an urgent need for appropriate, targeted, individual-centred counseling for women participating in HIV prevention trials.

CD8 + T cell-mediated escape mutations in Gag can reduce HIV-1 replication capacity (RC) and alter disease progression, but less is known about immune-mediated attenuation in other HIV-1 proteins. We generated 487 recombinant viruses encoding RT-integrase from individuals with chronic ( n = 406) and recent ( n = 81) HIV-1 subtype C infection and measured their in vitro RC using a green fluorescent protein (GFP) reporter T cell assay. In recently infected individuals, reverse transcriptase (RT)-integrase-driven RC correlated significantly with viral load set point ( r = 0.25; P = 0.03) and CD4 + T cell decline ( P = 0.013). Moreover, significant associations between RT integrase-driven RC and viral load ( r = 0.28; P < 0.0001) and CD4 + T cell count ( r = -0.29; P < 0.0001) remained in chronic infection. In early HIV infection, host expression of the protective HLA-B*81 allele was associated with lower RC ( P = 0.05), as was expression of HLA-B*07 ( P = 0.02), suggesting early immune-driven attenuation of RT-integrase by these alleles. In chronic infection, HLA-A*30:09 (in linkage disequilibrium with HLA-B*81) was significantly associated with lower RC ( P = 0.05), and all 6 HLA-B alleles with the lowest RC measurements represented protective alleles, consistent with long-term effects of host immune pressures on lowering RT-integrase RC. The polymorphisms V241I, I257V, P272K, and E297K in reverse transcriptase and I201V in integrase, all relatively uncommon polymorphisms occurring in or adjacent to optimally described HLA-restricted cytotoxic T-lymphocyte epitopes, were associated with reduced RC. Together, our data suggest that RT-integrase-driven RC is clinically relevant and provide evidence that immune-driven selection of mutations in RT-integrase can compromise RC. IMPORTANCE Identification of viral mutations that compromise HIV's ability to replicate may aid rational vaccine design. However, while certain escape mutations in Gag have been shown to reduce HIV replication and influence clinical progression, less is known about the consequences of mutations that naturally arise in other HIV proteins. Pol is a highly conserved protein, but the impact of Pol function on HIV disease progression is not well defined. Here, we generated recombinant viruses using the RT-integrase region of Pol derived from HIV-1C-infected individuals with recent and chronic infection and measured their ability to replicate in vitro We demonstrate that RT-integrase-driven replication ability significantly impacts HIV disease progression. We further show evidence of immune-mediated attenuation in RT-integrase and identify specific polymorphisms in RT-integrase that significantly decrease HIV-1 replication ability, suggesting which Pol epitopes could be explored in vaccine development., (Copyright © 2018 American Society for Microbiology.)

We aimed to develop a HIV risk scoring algorithm for targeted screening among women in South Africa. We used data from five biomedical intervention trials (N = 8982 Cox regression models were used to create a risk prediction algorithm and it was internally and externally validated using standard statistical measures; 7-factors were identified as significant predictors of HIV infection: <25 years old, being single/not cohabiting, parity (<3), age at sexual debut (<16), 3+ sexual partners, using injectables and diagnosis with a sexually transmitted infection(s). A score of ≥25 (out of 50) was the optimum cut point with 83% (80%) sensitivity in the development (validation) dataset. Our tool can be used in designing future HIV prevention research and guiding recruitment strategies as well as in health care settings. Identifying, targeting and prioritising women at highest risk will have significant impact on preventing new HIV infections by scaling up testing and pre-exposure prophylaxis in conjunction with other HIV prevention modalities.

In longitudinal studies of biomarkers, an outcome of interest is the time at which a biomarker reaches a particular threshold. The CD4 count is a widely used marker of human immunodeficiency virus progression. Because of the inherent variability of this marker, a single CD4 count below a relevant threshold should be interpreted with caution. Several studies have applied persistence criteria, designating the outcome as the time to the occurrence of two consecutive measurements less than the threshold. In this paper, we propose a method to estimate the time to attainment of two consecutive CD4 counts less than a meaningful threshold, which takes into account the patient-specific trajectory and measurement error. An expression for the expected time to threshold is presented, which is a function of the fixed effects, random effects and residual variance. We present an application to human immunodeficiency virus-positive individuals from a seroprevalent cohort in Durban, South Africa. Two thresholds are examined, and 95% bootstrap confidence intervals are presented for the estimated time to threshold. Sensitivity analysis revealed that results are robust to truncation of the series and variation in the number of visits considered for most patients. Caution should be exercised when interpreting the estimated times for patients who exhibit very slow rates of decline and patients who have less than three measurements. We also discuss the relevance of the methodology to the study of other diseases and present such applications. We demonstrate that the method proposed is computationally efficient and offers more flexibility than existing frameworks. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

In South Africa, a large proportion of young women are in age disparate relationships, which is believed to be a risk factor for human immunodeficiency virus (HIV). The aim of this study was to determine the generational effect of age disparity on HIV and sexually transmitted infection (STI) incidence. Socio-demographic and behavioural data were collected from women, aged 16 and older, who were followed for up to 24 months. Women who reported having a steady sexual partner older than themselves were categorised into: (1) non-age disparate partnerships (age difference between partners was 0-4 years); (2) intra-generational age disparate partnerships (5-9 year age gap between sexual partners); and (3) inter-generational age disparate partnerships (age gap of 10 years or more between sexual partners). Of the 1355 women included in the analysis, 759, 429 and 167 were in non-age disparate, intra-generational age disparate and inter-generational age disparate partnerships, respectively. Strong predictors of inter-generational age disparate partnerships include age, marital status and concurrency of sexual partners. No significant relationship between age disparity and risk of HIV acquisition was found. The highest crude STI incidence was observed among those in intra-generational age disparate relationships followed by those in non-age disparate relationships (31.86 [26.41-38.44] and 25.60 [21.92-29.91] per 100 person-years, respectively). Reduction of multiple partnerships remains key to HIV prevention; however, in light of partner concurrency being more prevalent than individual concurrency partnerships, female-initiated HIV prevention options remain critical., (© The Author(s) 2016.)

Objective: Initiation of antiretroviral therapy (ART) during tuberculosis (TB) treatment improves survival in TB-HIV coinfected patients. In patients with CD4 counts <50 cells per cubic millimeter, there is a substantial clinical and survival benefit of early ART initiation. The purpose of this study was to assess the costs and cost-effectiveness of starting ART at various time points during TB treatment in patients with CD4 counts ≥50 cells per cubic millimeter., Methods: In the SAPiT trial, 642 HIV-TB coinfected patients were randomized to 3 arms: receiving ART within 4 weeks of starting TB treatment (early treatment arm; Arm-1), after the intensive phase of TB treatment (late treatment arm; Arm-2), or after completing TB treatment (sequential arm; Arm-3). Direct health care costs were measured from a provider perspective using a micro-costing approach. The incremental cost per death averted was calculated using the trial outcomes., Results: For patients with CD4 count ≥50 cells per cubic millimeter, median monthly variable costs per patient were US $116, US $113, and US $102 in Arm-1, Arm-2 and Arm-3, respectively. There were 12 deaths in 177 patients in Arm-1, 8 deaths in 180 patients in the Arm-2, and 19 deaths in 172 patients in Arm-3. Although the costs were lower in Arm-3, it had a substantially higher mortality rate. The incremental cost per death averted associated with moving from Arm-3 to Arm-2 was US $4199. There was no difference in mortality between Arm-1 and Arm-2, but Arm-1 was slightly more expensive., Conclusions: Initiation of ART after the completion of the intensive phase of TB treatment is cost-effective for patients with CD4 counts ≥50 cells per cubic millimeter.

Background: Couples' voluntary HIV counseling and testing (CVCT) is an evidence-based intervention that significantly reduces HIV incidence in couples. Despite the high prevalence of HIV and HIV couple serodiscordance in South Africa, there are few CVCT services., Methods: From February-June 2013, The Rwanda Zambia HIV Research Group provided support, training, and technical assistance for local counselors and promoters to pilot CVCT services in five hospital-based clinics in Durban, South Africa. Client-level data (age, gender, years cohabiting, pregnancy status, previous testing, antiretroviral treatment (ART) status, neighborhood, and test site) collected as a component of routine CVCT service operation is presented stratified by couple serostatus., Results: Twenty counselors and 28 promoters completed training. Of 907 couples (1,814 individuals) that underwent CVCT, prevalence of HIV was 41.8% and prevalence of HIV serodiscordance was 29.5% (19.3% M-F+, 10.3% M + F-). Most participants were 25-34 years of age, and this group had the highest prevalence. Previous individual HIV testing was low (50% for men, 63% for women). Only 4% of couples reported previous CVCT. Most (75%) HIV+ partners were not on ART, and HIV+ individuals in discordant couples were more likely to be on ART than those in concordant positive couples. Pregnancy among HIV+ women was not associated with previous HIV testing or ART use., Conclusions: Implementation of standard CVCT services was found to be feasible in Durban. The burden of HIV and couple serodiscordance in Durban was extremely high. CVCT would greatly benefit couples in Durban as an HIV prevention strategy.

Objective: Couples' voluntary HIV counseling and testing (CVCT) significantly decreases HIV transmission within couples, the largest risk group in sub-Saharan Africa, but it is not currently offered in most HIV testing facilities. To roll out such an intervention, understanding locale-specific knowledge barriers is critical. In this study, we measured knowledge of HIV serodiscordance, transmission, and prevention before and after receipt of CVCT services in Durban., Design: Pre- and post-CVCT knowledge surveys were administered to a selection of individuals seeking CVCT services., Methods: Changes in knowledge scores were assessed with McNemar Chi-square tests for balanced data and generalized estimating equation methods for unbalanced data., Results: The survey included 317 heterosexual black couples (634 individuals) who were primarily Zulu (87%), unemployed (47%), and had at least a secondary level education (78%). 28% of couples proved to be discordant. Only 30% of individuals thought serodiscordance between couples was possible pre-CVCT compared to 95% post-CVCT. One-third thought there was at least one benefit of CVCT pre-CVCT, increasing to 96% post-CVCT. Overall, there were positive changes in knowledge about HIV transmission and prevention. However, many respondents thought all HIV positive mothers give birth to babies with AIDS (64% pre-CVCT, 59% post-CVCT) and that male circumcision does not protect negative men against HIV (70% pre-CVCT, 67% post-CVCT)., Conclusions: CVCT was well received and was followed by improvements in understanding of discordance, the benefits of joint testing, and HIV transmission. Country-level health messaging would benefit from targeting gaps in knowledge about serodiscordance, vertical transmission, and male circumcision.

Nef plays a major role in HIV-1 pathogenicity. We studied HIV-1 subtype C infected individuals in acute/early (n = 120) or chronic (n = 207) infection to investigate the relationship between Nef-mediated CD4/HLA-I down-regulation activities and disease progression, and the influence of immune-driven sequence variation on these Nef functions. A single Nef sequence per individual was cloned into an expression plasmid, followed by transfection of a T cell line and measurement of CD4 and HLA-I expression. In early infection, a trend of higher CD4 down-regulation ability correlating with higher viral load set point was observed (r = 0.19, p = 0.05), and higher HLA-I down-regulation activity was significantly associated with faster rate of CD4 decline (p = 0.02). HLA-I down-regulation function correlated inversely with the number HLA-associated polymorphisms previously associated with reversion in the absence of the selecting HLA allele (r = -0.21, p = 0.0002). These data support consideration of certain Nef regions in HIV-1 vaccine strategies designed to attenuate the infection course., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Immunological events in acute HIV-1 infection before peak viremia (hyperacute phase) may contribute to the development of broadly cross-neutralizing antibodies. Here, we used pre-infection and acute-infection peripheral blood mononuclear cells and plasma samples from 22 women, including 10 who initiated antiretroviral treatment in Fiebig stages I–V of acute infection to study B cell subsets and B-cell associated cytokines (BAFF and CXCL13) kinetics for up to ∼90 days post detection of plasma viremia. Frequencies of B cell subsets were defined by flow cytometry while plasma cytokine levels were measured by ELISA. We observed a rapid but transient increase in exhausted tissue-like memory, activated memory, and plasmablast B cells accompanied by decline in resting memory cells in untreated, but not treated women. B cell subset frequencies in untreated women positively correlated with viral loads but did not predict emergence of cross-neutralizing antibodies measured 12 months post detection of plasma viremia. Plasma BAFF and CXCL13 levels increased only in untreated women, but their levels did not correlate with viral loads. Importantly, early CXCL13 but not BAFF levels predicted the later emergence of detectable cross-neutralizing antibodies at 12 months post detection of plasma viremia. Thus, hyperacute HIV-1 infection is associated with B cell subset changes, which do not predict emergence of cross-neutralizing antibodies. However, plasma CXCL13 levels during hyperacute infection predicted the subsequent emergence of cross-neutralizing antibodies, providing a potential biomarker for the evaluation of vaccines designed to elicit cross-neutralizing activity or for natural infection studies to explore mechanisms underlying development of neutralizing antibodies. [ABSTRACT FROM AUTHOR]

Background: The use of readily available biochemical investigations to predict the CD4 cell count in HIV-infected patients may provide clinicians with insight regarding disease severity at first contact. The aims of the study were to determine the relationship of calculated globulin and white cell count (WCC) with CD4 cell count. Methods: Data were collected prospectively from ambulatory HIV-infected, anti-retro viral therapy (ART) naive patients at the HIV clinic of King Edward Hospital, Durban, between 2010 and 2012. Results: The mean age of the participants was 39 ± 9.53 years and 70% were female. Median calculated globulin and WCC was 49 g/l and 4.74 x 109 cells/l respectively, whilst the CD4 cell count was 244 cells/mm³. A significant positive correlation was demonstrated between CD4 cell count and WCC (r = 0.25, p < 0.001). WCC and albumin were identified as potential surrogate markers for CD4 count = 200 cells/mm³. Combination of WCC with either albumin or globulin predicts a CD4 count of less than 200 cells/mm³ with moderate accuracy. Conclusion: The use of combined biomarkers may influence initiation of Pneumocystis jiroveci pneumonia prophylaxis in resource-limited settings. Further evaluation is warranted to assess the role of these markers in disease progression and ART. [ABSTRACT FROM AUTHOR]

Background: Pharmacokinetic interactions between rifampicin and protease inhibitors (PIs) complicate the management of HIV-associated tuberculosis. Rifabutin is an alternative rifamycin, for patients requiring PIs. Recently some international guidelines have recommended a higher dose of rifabutin (150 mg daily) in combination with boosted lopinavir (LPV/r), than the previous dose of rifabutin (150 mg three times weekly {tiw}). But there are limited pharmacokinetic data evaluating the higher dose of rifabutin in combination with LPV/r. Sub-optimal dosing can lead to acquired rifamycin resistance (ARR). The plasma concentration of 25-O-desacetylrifabutin (d-RBT), the metabolite of rifabutin, increases in the presence of PIs and may lead to toxicity. Methods and results: Sixteen patients with TB-HIV co-infection received rifabutin 300 mg QD in combination with tuberculosis chemotherapy (initially pyrazinamide, isoniazid and ethambutol then only isoniazid), and were then randomized to receive isoniazid and LPV/r based ART with rifabutin 150 mg tiw or rifabutin 150 mg daily. The rifabutin dose with ART was switched after 1 month. Serial rifabutin and d-RBT concentrations were measured after 4 weeks of each treatment. The median AUC0-48 and Cmax of rifabutin in patients taking 150 mg rifabutin tiw was significantly reduced compared to the other treatment arms. Geometric mean ratio (90% CI) for AUC0-48 and Cmax was 0.6 (0.5-0.7) and 0.5 (0.4-0.6) for RBT 150 mg tiw compared with RBT 300 mg and 0.4 (0.4-0.4) and 0.5 (0.5-0.6) for RBT 150 mg tiw compared with 150 mg daily. 86% of patients on the tiw rifabutin arm had an AUC0-24 < 4.5 µg.h/mL, which has previously been associated with acquired rifamycin resistance (ARR). Plasma d-RBT concentrations increased 5-fold with tiw rifabutin dosing and 15-fold with daily doses of rifabutin. Rifabutin was well tolerated at all doses and there were no grade 4 laboratory toxicities. One case of uveitis (grade 4), occurred in a patient taking rifabutin 300 mg daily prior to starting ART, and grade 3 neutropenia (asymptomatic) was reported in 4 patients. These events were not associated with increases in rifabutin or metabolite concentrations. Conclusions: A daily 150 mg dose of rifabutin in combination with LPV/r safely maintained rifabutin plasma concentrations in line with those shown to prevent ARR. [ABSTRACT FROM AUTHOR]