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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: Pre-exposure prophylaxis (PrEP) is an emerging biomedical prevention intervention. Documenting PrEP service delivery models (SDMs) that promote linkage to and continuation of PrEP will inform guidelines and maximise roll-out., Objectives: To synthesise and appraise the effectiveness and feasibility of PrEP SDMs designed to promote linkage to PrEP care among adolescent girls and young women (AGYW) and men in sub-Saharan Africa (SSA)., Eligibility Criteria: Primary quantitative and qualitative studies published in English and conducted in SSA were included. No restrictions on the date of publication were applied., Sources of Evidence: Methodology outlined in the Joanna Briggs Institute reviewers' manual was followed. PubMed, Cochrane library, Scopus, Web of Science and online-conference abstract archives were searched., Charting Methods: Data on article, population, intervention characteristics and key outcomes was charted in REDCap., Results and Conclusion: Of the 1204 identified records, 37 (met the inclusion criteria. Health facility-based integrated models of PrEP delivery with family planning, maternal and child health or sexual and reproductive services to AGYW resulted in PrEP initiation of 16%-90%. Community-based drop-in centres (66%) was the preferred PrEP outlet for AGYW compared with public clinics (25%) and private clinics (9%). Most men preferred community-based delivery models. Among individuals who initiated PrEP, 50% were men, 62% were <35 years old and 97% were tested at health fairs compared with home testing. Integrated antiretroviral therapy (ART)-PrEP delivery was favoured among serodiscordant couples with 82.9% of couples using PrEP or ART with no HIV seroconversions. PrEP initiation within healthcare facilities was increased by perceived client-friendly services and non-judgemental healthcare workers. Barriers to PrEP initiation included distance to travel to and time spent at health facilities and perceived community stigma. PrEP SDMs for AGYW and men need to be tailored to the needs and preferences for each group. Programme implementers should promote community-based SDMs to increase PrEP initiation among AGYW and men., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Adolescent girls and young women (AGYW) aged 15-24 years and adolescent boys and young men (ABYM) aged 15-34 years represent one of the populations at highest risk for HIV-infection in South Africa. The National Department of Health adopted the universal test and treat (UTT) strategy in 2016, resulting in increases in same-day antiretroviral therapy initiations and linkage to care. Monitoring progress towards attainment of South Africa's 95-95-95 targets amongst AGYW and ABYM relies on high quality data to identify and address gaps in linkage to care. The aim of this study is to describe the current approaches for engaging AGYW and ABYM in the treatment continuum to generate knowledge that can guide efforts to improve linkage to, and retention in, HIV care among these populations in KwaZulu-Natal, South Africa., Methods and Analysis: This is a mixed methods study, which will be conducted in uMgungundlovu district of KwaZulu-Natal, over a 24-month period, in 22 purposively selected HIV testing and treatment service delivery points (SDPs). For the quantitative component, a sample of 1100 AGYW aged 15-24 years and ABYM aged 15-35 years old will be recruited into the study, in addition to 231 healthcare providers (HCPs) involved in the implementation of the UTT program. The qualitative component will include 30 participating patients who were successfully linked to care, 30 who were not, and 30 who have never tested for HIV. Key informant interviews will also be conducted with 24 HCPs. Logistic regression will be used to model the primary outcomes on SDP types, while a time to event analysis will be conducted using a Cox regression model and adjusting the standard errors of the hazard ratio for the clustering of participants within SDPs. For qualitative data, a general inductive approach of analysis will be used., Dissemination: Findings from the study will be communicated to the study population and results will be presented to stakeholders and at appropriate local and international conferences. Outputs will also include a policy brief, peer reviewed journal articles and research capacity building through research degrees., Competing Interests: The authors declare no competing interest., (Copyright: This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.)

Introduction: Recent advances in the HIV care continuum have shown that an individual diagnosed with HIV should be initiated on antiretroviral therapy as soon as possible regardless of the CD4 count levels and retained in HIV care services. Studies have reported large losses in the HIV continuum of care, before and after the era of universal test and treat. Several systematic reviews have reported on the strategies for improving linkage to and retention in HIV treatment and care. The purpose of this overview of systematic reviews is to identify HIV care interventions or service delivery models (SDMs) and synthesise evidence on the effects of these to link adolescent girls and young women (AGYW) and adolescent boys and young men (ABYM) to care and retain them in care. We also aim to highlight gaps in the evidence on interventions and SDMs to improve linkage and retention in HIV care of AGYW and ABYM., Methods and Analysis: An electronic search of four online databases: PubMed, Cochrane Database of Systematic Reviews, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and Web of Science will be performed to identify systematic reviews on the effects of linkage to and retention in HIV care interventions or SDMs for AGYW aged 15-24 years and ABYM aged 15-35 years. Our findings on the effects of interventions and SDMs will be interpreted considering the intervention and or SDMs' effectiveness by the time period, setting and population of interest. Two or more authors will independently screen articles for inclusion using a priori criteria., Ethics and Dissemination: Ethics approval is not required for this study as only published secondary data will be used. Our findings will be disseminated through peer-reviewed publication, conference abstracts and through presentations to stakeholders and other community fora. The findings from this overview of systematic reviews will inform mixed-methods operations research on HIV intervention programming and delivery of HIV care services for AGYW and ABYM in South Africa., Prospero Registration Number: CRD42020177933., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Monitoring HIV prevalence using antenatal HIV sentinel surveillance is important for efficient epidemic tracking, programme planning and resource allocation. HIV sentinel surveillance usually employs unlinked anonymous HIV testing which raises ethical, epidemiological and public health challenges in the current era of universal test and treat. The World Health Organization (WHO) recommends that countries should consider using routine prevention of mother-to-child transmission of HIV (PMTCT) data for surveillance. We audited antenatal care clinics to assess the quality of HIV rapid testing practices as the first step to assess whether South Africa is ready to utilize PMTCT programme data for antenatal HIV surveillance. In 2017, we conducted a cross-sectional survey in 360 randomly sampled antenatal care clinics using the adapted WHO Stepwise-Process-for-Improving-the-Quality-of-HIV-Rapid-Testing (SPI-RT) checklist. We calculated median percentage scores within a domain (domain-specific median score), and across all domains (overall median percentage scores). The latter was used to classify sites according to five implementation levels; (from 0:<40% to 4: 90% or higher). Of 346 (96.1%) facilities assessed, an overall median percentage score of 62.1% (inter-quartile range (IQR): 50.8-71.9%) was obtained. The lowest domain-specific median percentage scores were obtained under training/certification (35% IQR: 10.0-50.0%) and external quality assurance (12.5% IQR: 0.0-50.0%), respectively. The majority (89%) of sites had an overall median score at level 2 or below; of these, 37% required improvement in specific areas and 6.4% in all areas. Facilities in districts implementing the HIV Rapid Test Quality Improvement Initiative and supported by the President's Emergency Plan for AIDS Relief (PEPFAR) had significantly higher median overall scores (65.6% IQR: 53.9-74.2%) (P-value from rank sum test: <0.001) compared with non-PEPFAR-supported facilities (56.6% IQR:47.7-66.0%). We found sub-optimal implementation of HIV rapid testing practices. We recommend the expansion of the PEPFAR-funded Rapid Test Continuous Quality Improvement (RTCQI) support to all antenatal care testing sites., Competing Interests: The authors have declared that no competing interests exist.

Background: We aimed to develop and validate a tool to identify which pregnant/lactating young South African women (≤ 24 years) are at risk of HIV infection., Methods: Data from three national South African Prevention of Mother-to-Child Transmission (PMTCT) evaluations were used to internally validate three HIV acquisition risk models for young postpartum women. We used univariate and multivariable logistic regression analysis to determine which risk factors were significant. Model coefficients were rounded and stratified into risk groups and the area under the receiver operating curve (AUROC) was computed. Models were developed to determine which risk factors provided the most predictive accuracy whilst remining clinically meaningful., Results: Data from 9 456 adult and 4 658 young pregnant and lactating women were included in the development and validation data sets, respectively. The optimal model included the following risk factors: age (20-24 years old), informal house structure, two or more pregnancies, mothers who had knowledge of when they received their last HIV test result, no knowledge of the infant's father's HIV status, no knowledge of breastfeeding as a mode of MTCT and knowledge of PMTCT programme. The mean AUROC was 0.71 and 0.72 in the development and validation datasets respectively. The optimum cut off score was ≥ 27, having 84% sensitivity, 44% specificity, and identifying 44% of high-risk women eligible for PrEP., Conclusion: The optimal model to be used as a possible risk scoring tool to allow for early identification of those pregnant/lactating women most at-risk of HIV acquisition included both statistically as well as clinically meaningful risk factors. A field-based study is needed to test and validate the effectiveness of this targeted approach., (© 2022. The Author(s).)

Introduction: Pre-exposure prophylaxis (PrEP) is an effective prevention intervention that can be used to control HIV incidence especially among people who are at increased risk for HIV such as adolescent girls and young women (AGYW) and adolescent boys and young men (ABYM). In South Africa, various approaches of delivering PrEP have been adopted at different service delivery points (facility-based only, school-based only, community-based only and hybrid school-facility and community-facility models) to overcome challenges associated with individual, structural, and health systems related barriers that may hinder access to and uptake of PrEP among these populations. However, little is known about how to optimize PrEP implementation and operational strategies to achieve high sustained uptake of good quality services for AGYW and ABYM. This study aims to identify effective and feasible PrEP models of care for improving PrEP uptake, continuation, and adherence among AGYW and ABYM., Methods and Analysis: A sequential explanatory mixed-methods study will be conducted in 22 service delivery points (SDPs) in uMgungundlovu district, KwaZulu-Natal, South Africa. We will recruit 600 HIV negative, sexually active, high risk, AGYW (aged 15-24 years) and ABYM (aged 15-35 years). Enrolled participants will be followed up at 1-, 4- and 7-months to determine continuation and adherence to PrEP. We will conduct two focus group discussions (with 8 participants in each group) across four groups (i. Initiated PrEP within 1 month, ii. Did not initiate PrEP within 1 month, iii. Continued PrEP at 4/7 months and iv. Did not continue PrEP at 4/7 months) and 48 in-depth interviews from each of the four groups (12 per group). Twelve key informant interviews with stakeholders working in HIV programs will also be conducted. Associations between demographic characteristics stratified by PrEP initiation and by various service-delivery models will be assessed using Chi-square/Fishers exact tests or t-test/Mann Whitney test. A general inductive approach will be used to analyze the qualitative data., Ethics and Dissemination: The protocol was approved by the South African Medical Research Council Health Research Ethics Committee (EC051-11/2020). Findings from the study will be communicated to the study population and results will be presented to stakeholders and at appropriate local and international conferences. Outputs will also include a policy brief, peer-reviewed journal articles and research capacity building through research degrees., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: the authors declare no competing interest.

Background: We analysed the impact of breastfeeding, antiretroviral drugs and health service factors on cumulative (6 weeks to 18 months) vertical transmission of HIV (MTCT) and 'MTCT-or-death', in South Africa, and compared estimates with global impact criteria to validate MTCT elimination: (1) <5% final MTCT and (2) case rate ≤50 (new paediatric HIV infections/100 000 live births)., Methods: 9120 infants aged 6 weeks were enrolled in a nationally representative survey. Of 2811 HIV-exposed uninfected infants (HEU), 2644 enrolled into follow-up (at 3, 6, 9, 12, 15 and 18 months). Using Kaplan-Meier analysis and weighted survey domain-based Cox proportional hazards models, we estimated cumulative risk of MTCT and 'MTCT or death' and risk factors for time-to-event outcomes, adjusting for study design and loss-to-follow-up., Results: Cumulative (final) MTCT was 4.3% (95% CI 3.7% to 5.0%); case rate was 1290. Postnatal MTCT (>6 weeks to 18 months) was 1.7% (95% CI 1.2% to 2.4%). Cumulative 'MTCT-or-death' was 6.3% (95% CI 5.5% to 7.3%); 81% and 62% of cumulative MTCT and 'MTCT-or-death', respectively, occurred by 6 months. Postnatal MTCT increased with unknown maternal CD4-cell-count (adjusted HR (aHR 2.66 (1.5-5.6)), undocumented maternal HIV status (aHR 2.21 (1.0-4.7)) and exclusive (aHR 2.3 (1.0-5.2)) or mixed (aHR 3.7 (1.2-11.4)) breastfeeding. Cumulative 'MTCT-or death' increased in households with 'no refrigerator' (aHR 1.7 (1.1-2.9)) and decreased if infants used nevirapine at 6 weeks (aHR 0.4 (0.2-0.9))., Conclusions: While the <5% final MTCT target was met, the case rate was 25-times above target. Systems are needed in the first 6 months post-delivery to optimise HEU health and fast-track ART initiation in newly diagnosed mothers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: All authors have read and understood the BMJ policy on declaration of interests and declare no competing interests.

Purpose: Adolescent females aged 15-19 account for 62% of new HIV infections and give birth to 16 million infants annually. We quantify the risk of early mother-to-child transmission (MTCT) of HIV among adolescents enrolled in nationally representative MTCT surveillance studies in South Africa., Methods: Data from 4,814 adolescent (≤19 years) and 25,453 adult (≥20 years) mothers and their infants aged 4-8 weeks were analyzed. These data were gathered during three nationally representative, cross-sectional, facility-based surveys, conducted in 2010, 2011-2012, and 2012-2013. All infants were tested for HIV antibody (enzyme immunoassay), to determine HIV exposure. Enzyme immunoassay-positive infants or those born to self-reported HIV-positive mothers were tested for HIV infection (total nucleic acid polymerase chain reaction). Maternal HIV positivity was inferred from infant HIV antibody positivity. All analyses were weighted for sample realization and population live births., Results: Adolescent mothers, compared with adult mothers, have almost three times less planned pregnancies 14.4% (95% confidence interval [CI]: 12.5-16.5) versus 43.9% (95% CI: 42.0-45.9) in 2010 and 15.2% (95% CI: 13.0-17.9) versus 42.8% (95% CI: 40.9-44.6) in 2012-2013 (p < .0001), less prevention of MTCT uptake (odds ratio [OR] in favor of adult mothers = 3.36, 95% CI: 2.95-3.83), and higher early MTCT (adjusted OR = 3.0, 95% CI: 1.1-8.0), respectively. Gestational age at first antenatal care booking was the only significant predictor of early MTCT among adolescents., Conclusions: Interventions that appeal to adolescents and initiate sexual and reproductive health care early should be tested in low- and middle-income settings to reduce differential service uptake and infant outcomes between adolescent and adult mothers., (Copyright © 2017 The Society for Adolescent Health and Medicine. All rights reserved.)

Introduction Increasing access to HIV-related care and treatment for children aged 0-18 years in resource-limited settings is an urgent global priority. In 2011-2012 the percentage increase in children accessing antiretroviral therapy was approximately half that of adults (11 vs. 21 %). We propose a model for increasing access to, and retention in, paediatric HIV care and treatment in resource-limited settings. Methods Following a rapid appraisal of recent literature seven main challenges in paediatric HIV-related care and treatment were identified: (1) lack of regular, integrated, ongoing HIV-related diagnosis; (2) weak facility-based systems for tracking and retention in care; (3) interrupted availability of dried blood spot cards (expiration/stock outs); (4) poor quality control of rapid HIV testing; (5) supply-related gaps at health facility-laboratory interface; (6) poor uptake of HIV testing, possibly relating to a fatalistic belief about HIV infection; (7) community-associated reasons e.g. non-disclosure and weak systems for social support, resulting in poor retention in care. Results To increase sustained access to paediatric HIV-related care and treatment, regular updating of Policies, review of inter-sectoral Plans (at facility and community levels) and evaluation of Programme implementation and impact (at national, subnational, facility and community levels) are non-negotiable critical elements. Additionally we recommend the intensified implementation of seven main interventions: (1) update or refresher messaging for health care staff and simple messaging for key staff at early childhood development centres and schools; (2) contact tracing, disclosure and retention monitoring; (3) paying particular attention to infant dried blood spot (DBS) stock control; (4) regular quality assurance of rapid HIV testing procedures; (5) workshops/meetings/dialogues between health facilities and laboratories to resolve transport-related gaps and to facilitate return of results to facilities; (6) community leader and health worker advocacy at creches, schools, religious centres to increase uptake of HIV testing and dispel fatalistic beliefs about HIV; (7) use of mobile communication technology (m-health) and peer/community supporters to maintain contact with patients. Discussion and Conclusion We propose that this package of facility, community and family-orientated interventions are needed to change the trajectory of the paediatric HIV epidemic and its associated patterns of morbidity and mortality, thus achieving the double dividend of improving HIV-free survival.

Background: Eliminating mother-to-child transmission of HIV (EMTCT), defined as ≤50 infant HIV infections per 100 000 live births, is a global priority. Since 2011 policies to prevent mother-to-child transmission of HIV (PMTCT) shifted from maternal antiretroviral (ARV) treatment or prophylaxis contingent on CD4 cell count to lifelong maternal ARV treatment (cART). We sought to measure progress with early (4-8 weeks postpartum) MTCT prevention and elimination, 2011-2013, at national and sub-national levels in South Africa, a high antenatal HIV prevalence setting ( ≈ 29%), where early MTCT was 3.5% in 2010., Methods: Two surveys were conducted (August 2011-March 2012 and October 2012-May 2013), in 580 health facilities, randomly selected after two-stage probability proportional to size sampling of facilities (the primary sampling unit), to provide valid national and sub-national-(provincial)-level estimates. Data collectors interviewed caregivers of eligible infants, reviewed patient-held charts, and collected infant dried blood spots (iDBS). Confirmed positive HIV enzyme immunoassay (EIA) and positive total HIV nucleic acid polymerase chain reaction (PCR) indicated infant HIV exposure or infection, respectively. Weighted survey analysis was conducted for each survey and for the pooled data., Findings: National data from 10 106 and 9120 participants were analyzed (2011-12 and 2012-13 surveys respectively). Infant HIV exposure was 32.2% (95% confidence interval (CI) 30.7-33.6%), in 2011-12 and 33.1% (95% CI 31.8-34.4%), provincial range of 22.1-43.6% in 2012-13. MTCT was 2.7% (95% CI 2.1%-3.2%) in 2011-12 and 2.6% (95% CI 2.0-3.2%), provincial range of 1.9-5.4% in 2012-13. HIV-infected ARV-exposed mothers had significantly lower unadjusted early MTCT (2.0% [2011-12: 1.6-2.5%; 2012-13:1.5-2.6%]) compared to HIV-infected ARV-naive mothers [10.2% in 2011-12 (6.5-13.8%); 9.2% in 2012-13 (5.6-12.7%)]. Pooled analyses demonstrated significantly lower early MTCT among exclusive breastfeeding (EBF) mothers receiving >10 weeks ARV prophylaxis or cART compared with EBF and no ARVs: (2.2% [95% CI 1.25-3.09%] vs 12.2% [95% CI 4.7-19.6%], respectively); among HIV-infected ARV-exposed mothers, 24.9% (95% CI 23.5-26.3%) initiated cART during or before the first trimester, and their early MTCT was 1.2% (95% CI 0.6-1.7%). Extrapolating these data, assuming 32% EIA positivity and 2.6% or 1.2% MTCT, 832 and 384 infants per 100 000 live births were HIV infected, respectively., Conclusions: Although we demonstrate sustained national-level PMTCT impact in a high HIV prevalence setting, results are far-removed from EMTCT targets. Reducing maternal HIV prevalence and treating all maternal HIV infection early are critical for further progress.

In January 2015, the South African National Department of Health released new consolidated guidelines for the prevention of mother to child transmission (PMTCT) of HIV, in line with the World Health Organization's (WHO) PMTCT Option B+. Implementing these guidelines should make it possible to eliminate mother to child transmission (MTCT) of HIV and improve long-term maternal and infant outcomes. The present article summarises the key recommendations of the 2015 guidelines and highlights current gaps that hinder optimal implementation; these include late antenatal booking (as a result of poor staff attitudes towards 'early bookers' and foreigners, unsuitable clinic hours, lack of transport to facilities, quota systems being applied to antenatal clients and clinic staff shortages); poor compliance with rapid HIV testing protocols; weak referral systems with inadequate follow-up; inadequate numbers of laboratory staff to handle HIV-related monitoring procedures and return of results to the correct facility; and inadequate supply chain management, leading to interrupted supplies of antiretroviral drugs. Additionally, recommendations are proposed on how to address these gaps. There is a need to evaluate the implementation of the 2015 guidelines and proactively communicate with ground-level implementers to identify operational bottlenecks, test solutions to these bottlenecks, and develop realistic implementation plans., Competing Interests: The authors declare that they have no financial or personal relationships which may have inappropriately influenced them in writing this article.