INTRODUCTION:Children and adolescents living with HIV in sub-Saharan Africa (SSA) continue to face significant barriers to diagnosis, treatment adherence, retention in care and psychosocial support, despite progress in prevention and treatment coverage. Family-centred care (FCC) has emerged as a promising model that positions families-not just individual children-as the central unit of care, with potential to improve clinical and psychosocial outcomes while addressing persistent gaps in health system responsiveness. METHODS:Our scoping review synthesized evidence on FCC implementation strategies and outcomes for children and adolescents living with HIV in SSA, to inform the development of a contextually relevant FCC intervention. We followed Arksey and O'Malley's five-stage framework and the PRISMA-ScR guidelines. A comprehensive search of peer-reviewed and grey literature published between 2000 and 2025 was conducted across multiple databases and organizational websites between May and July 2025. Fourteen studies met the inclusion criteria and were selected for analysis. RESULTS:FCC was conceptualized as a multidimensional framework integrating clinical care, psychosocial support, caregiver engagement, treatment literacy and community-based delivery. Implementation models ranged from facility-based integrated services to community-driven and hybrid approaches. Interventions commonly included antiretroviral therapy provision, family-based testing, counselling and enhanced psychosocial wellbeing. Community-based and decentralized models showed particular promise in improving retention and reducing structural barriers. However, gaps persist, including limited longitudinal data, underrepresentation of fathers and adolescent caregivers, narrow assumptions of nuclear family structures and a lack of standardized FCC frameworks. DISCUSSION:Most FCC interventions were small-scale and donor-funded, raising concerns regarding sustainability and health-system integration. Additionally, many studies assumed nuclear family structures, overlooking the role of extended and non-biological caregivers common in African contexts. The limited engagement of diverse caregiving networks and inconsistent conceptualization of FCC constrain its broader applicability and scalability. CONCLUSIONS:FCC offers a compelling and contextually appropriate model for strengthening HIV care for children and adolescents in SSA. Advancing the FCC requires standardized frameworks, inclusive and context-sensitive programme design, and integration into national health systems to ensure equitable and sustainable delivery of holistic HIV care.

INTRODUCTION:The development of approaches and interventions to achieve HIV remission continues to accelerate. Children living with HIV who started antiretroviral therapy (ART) at a young age and sustain viral suppression are an ideal clinical trial population. Trials may require analytic treatment interruptions (ATIs). Paediatric trials depend on the willingness of guardians to consent to child participation, yet there are few data about guardian willingness or attitudes. Here, we investigated the opinions of guardians of children likely to be eligible for ATI trials. METHODS:Children and youth who started ART ≤ 3 months of age, and who remained well-controlled on ART older than 7 years, were recruited in South Africa, Mozambique, Uganda, Mali and Thailand. A survey was conducted among guardians of these paediatric participants. The survey utilized a vignette describing a trial with ATI and assessed attitudes and intentions (measured on 7-point scales) of the guardians regarding their children's participation in a hypothetical trial. RESULTS:Guardians of 99 children were recruited. Guardians' median age was 45 years (range 24-73) and most (89.9%) were female. The median age of the child or youth with HIV was 13.2 years (range 7-18.5 years). Most respondents endorsed a positive intention to enrol their child in a future HIV remission trial (mean 6.5 [SD:1.3] on a 7-point scale), with significant variation across the sites (p = 0.0024). Most respondents strongly endorsed a range of trial benefits, including better future HIV treatments (93.8%) and access to better care (88.0%). Some endorsed concern about the trial burden to themselves (33.3%) and the child (35.4%). Almost half strongly believed that the trial would result in the child no longer needing ART (48%) and the child being cured of HIV (46.5%). CONCLUSIONS:Across multiple countries, guardians of children and youth who were treated early were positive about participation in trials with ATI. Only a third expressed some concern about trial burden, while almost half had unrealistic expectations about potential benefits. Recruitment into trials involving ATI will need to include effective communication strategies to ensure that participants and caregivers are adequately informed about burden, potential risks and the likelihood of personal benefit.

ABSTRACT Background The 2023 South African antiretroviral therapy (ART) guidelines recommend dolutegravir-based ART for children and adolescents with HIV (CAWH) >4 weeks old, including transition to dolutegravir-based ART if previously taking another regimen. Objectives We audited uptake of dolutegravir-based ART, viral load (VL) testing, and viral suppression among CAWH in care in eThekwini, South Africa. We also aimed to assess and improve the quality of routinely collected ART and VL data in the national HIV electronic register (TIER.Net) in this population. Methods We used TIER.Net line lists to identify CAWH aged ≤19 years in care in 54 eThekwini Municipality clinics between February and July 2025. CAWH who had died, transferred out, or were lost to follow-up were excluded. We reviewed clinical files and TIER.Net records simultaneously to compare all recorded ART regimens and recent (last 12 months) VL results. High or missing VLs were flagged for medical review, and data discrepancies were corrected. Results Among 3838 eligible CAWH, we reviewed files of 3379 (88%). 1991 (59%) were female and 2812 (83%) were aged 10-19 years. All 3379 (100%) were receiving dolutegravir-based ART. 193 (6%) had no recent VL result. Of those who did, 303 (10%) had a last VL ≥1000 copies/mL. We identified 941 (28%), 438 (13%), and 199 (6%) TIER.Net data capture errors for ART regimens, ART regimen start/stop dates, or recent VLs, respectively. Conclusion This audit at 54 facilities showed complete transition to dolutegravir among reviewed files of CAWH in care, but highlighted gaps in viral suppression and documentation.

Abstract Background Global HIV programmes are transitioning virally suppressed children and adolescents with HIV (CAWH) from prior regimens to dolutegravir-based antiretroviral therapy (ART). However, the supporting evidence largely stems from randomised trials in viraemic CAWH. The effect of transition for virally suppressed CAWH is unknown. Methods We used observational, de-identified data from 724 clinics in KwaZulu-Natal, South Africa. We sequentially emulated three distinct target trials to estimate the effect of transitioning to dolutegravir-based ART in three paediatric populations: i) ages 8-17 years taking efavirenz-based ART, ii) 8-17 years taking ritonavir-boosted lopinavir (LPV/r)-based ART, and iii) 0-7 years taking LPV/r-based ART, all with a last viral load <1,000 copies/mL. The risk difference (RD) of death or viraemia>1,000 copies/mL through 12 and 24 months was estimated using an inverse probability weighting approach. Findings From January 2020 to August 2024, 37,145 CAWH contributed 454,081 person-trials. In CAWH initially taking efavirenz, the standardised 12-month risk of death or viraemia was 11·9% with continued efavirenz and 6·7% with transition to dolutegravir (RD -5·2 [95% CI -5·8 to -4·6]). In older CAWH initially taking LPV/r, these risks were 17·8% and 9·5%, respectively (RD -8·3 [-10·0 to -6·8]). In younger children, the respective risks were 15·8% and 6·7% (RD -9·0% [-12·7 to -5·4]). Where available, 24-month endpoints showed slightly greater RDs. Interpretation This large-scale, causal analysis highlights improvements in viral suppression and strongly supports ongoing transition to dolutegravir-based ART for virally suppressed CAWH. Funding Gates Foundation, National Institute for Health and Care Research, Swiss National Science Foundation Research in context Evidence before this study We searched PubMed on 23 June 2026 for randomised controlled trials or trial emulations comparing dolutegravir (DTG)-based antiretroviral therapy (ART) with non-DTG-based ART among children and adolescents with HIV (CAWH). The search string is shown in Table S1. Two major trials, ODYSSEY and CHAPAS-4, compared DTG-based with non-DTG-based ART regimens among CAWH with viraemia (i.e. newly starting first-line ART or switching to second-line ART after treatment failure with a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen). Both trials showed better treatment outcomes with DTG-based ART, informing the ongoing programmatic rollout of DTG-based ART for CAWH. In practice, the majority of CAWH eligible for DTG will be virally suppressed on a non-DTG regimen, a group which was not included in ODYSSEY and CHAPAS-4. To date, there is a lack of empirical evidence demonstrating outcomes after paediatric transition to DTG in case of viral suppression. On the one hand, unnecessary ART modification may disrupt adherence; on the other hand, DTG-based ART may be favourable considering the complexity and unpalatability of some prior standard of care regimens. Therefore, there is a need to evaluate the causal effect of transitioning to DTG-based ART in case of viral suppression, specifically among CAWH as a priority group for improving treatment outcomes. Added value of this study Here, we compared treatment outcomes among three distinct paediatric groups in the South African HIV programme who became eligible to transition to DTG-based ART at different time points: older CAWH initially taking efavirenz (EFV)-based ART, older CAWH initially taking ritonavir-boosted lopinavir (LPV/r)-based ART, and young children initially taking LPV/r-based ART. To our knowledge, this study of 38,041 CAWH is the largest clinical cohort of CAWH receiving DTG and presents the first estimate on the effect of transitioning to DTG-based ART among CAWH with viral suppression. Across all groups, the standardised cumulative risk of death or viraemia was lowered by switching to ART containing DTG compared with remaining on the former standard of care, with risk differences (RDs) ranging from -5·2% to -9·0% at 12 months and increasing over follow-up time. Implications of all the available evidence We observed substantial improvements in treatment outcomes with transition to DTG. These findings strongly support the continued transition to DTG-based ART among virally suppressed CAWH.

Community-acquired pneumonia (CAP) causes high pediatric mortality especially in sub-Saharan Africa. In a secondary analysis of samples from the PediCAP trial (ISRCTN63115131), we tracked gastrointestinal resistome and microbiota dynamics of 149 children (<6 years) from South Africa, Zambia, Zimbabwe and Uganda presenting with severe CAP. Patients received initial WHO-standard IV therapy before being randomized to continue IV therapy or step-down to oral amoxicillin or co-amoxiclav for different total treatment durations. Samples were obtained after starting IV antibiotics, at discharge, and at four weeks follow-up. Microbiota dynamics were strongly associated with age and country of origin with specific bacterial genera unique to each country. Oral step-down to either antibiotic regimen or duration did not show any differential effects on the gastrointestinal microbiota and resistome dynamics compared to continuous IV therapy. The data of this secondary analysis complement the primary PediCAP trial analysis, supporting earlier hospital discharge for paediatric CAP patients.

Children have distinct therapeutic needs arising from age-dependent physiology, disease epidemiology, formulation requirements, dosing considerations, and safety vulnerabilities. Despite substantial reductions in childhood mortality over the past three decades, nearly 5 million children under five died in 2023, with infectious diseases continuing to contribute substantially to preventable morbidity and mortality. Long-acting therapeutics (LATs) may help address selected pediatric health priorities by sustaining therapeutic or prophylactic exposure, reducing dosing frequency, and improving adherence and implementation feasibility. This review synthesizes insights from the pediatric health session of the Community of Practice for Long-acting Therapeutics for Maternal and Paediatric Health workshop. The session considered priority pediatric conditions in which existing or emerging LAT approaches could have clinical or public health impact, including lower respiratory tract infections, malaria, tuberculosis, HIV, and syphilis, as well as selected noninfectious indications such as childhood cancer and growth hormone deficiency. We then examine clinical pharmacology and safety considerations central to pediatric LAT development, including developmental pharmacokinetics, absorption-limited disposition and flip-flop kinetics, pharmacokinetic tailing, dose selection, model-informed development, and injection-site tolerability. The review also discusses long-acting technology platforms with potential pediatric applications, route-of-administration considerations, excipient safety, formulation design, acceptability, and implementation challenges. Finally, we propose recommendations to support pediatric LAT development, including early integration of developmental pharmacology, age- and weight-informed dosing, standardized acceptability assessment, product-attribute frameworks, regulatory engagement, and equitable access planning. Realizing the potential of LATs for children will require coordinated, child-centered, and equity-driven approaches that address evidence generation, formulation suitability, implementation context, and affordability from the outset.

BACKGROUND:ODYSSEY trial showed superior efficacy of dolutegravir-based antiretroviral therapy (ART) versus then-current, non-dolutegravir standard of care over 96 weeks in children and adolescents living with HIV. The aim of this ancillary analysis was to compare anthropometric and body composition outcomes, including weight, height, BMI-for-age Z score, weight-for-age and height-for-age Z scores (<14 kg), mid-upper-arm circumference (MUAC), waist circumference, hip circumference, and body fat percentage, as well as metabolic outcomes (lipids and glucose), between dolutegravir and standard of care over approximately 5 years of follow-up. METHODS:In this open-label, randomised, non-inferiority trial, children (aged ≥4 weeks and <18 years), weighing 3 kg or more, starting first-line ART (ODYSSEY-A) or switching to second-line ART (ODYSSEY-B) were enrolled in 29 centres in Germany, Portugal, South Africa, Spain, Thailand, Uganda, Zimbabwe, and the UK in two cohorts (children weighing ≥14 kg and children weighing <14 kg). Treatment effects (dolutegravir vs standard of care) were estimated on randomised allocation, accounting for treatment switches (substantial in standard of care arm during extended follow-up) through censoring and inverse-probability-of-censoring-weights. Changes in continuous outcomes were compared using linear mixed models, accounting for correlated slope and baseline value. Proportions of participants with unfavourable outcomes were compared using logistic mixed models. ODYSSEY is registered with ClinicalTrials.gov, NCT02259127, EUDRACT, 2014-002632-14, and ISRCTN, ISRCTN91737921. FINDINGS:Between Sept 20, 2016, and Aug 26, 2019, 792 children were randomly assigned (392 to dolutegravir and 400 to standard of care). Of 707 children in the 14 kg or more cohort, 311 received first-line ART (ODYSSEY-A; 145 [92%] of 157 received efavirenz-based ART as standard of care) and 396 received second-line ART (ODYSSEY-B; 195 [98%] of 200 received boosted protease inhibitors as standard of care). Of 85 children in the less than 14 kg cohort, 72 received first-line ART (32 [74%] of 43 received lopinavir-ritonavir as first-line or second-line standard of care). Median follow-up on randomised allocation was 287 weeks (IQR 240-311) on dolutegravir-based ART and 205 weeks (168-240) on standard of care in the 14 kg or more cohort, and 220 weeks (208-232) on dolutegravir-based ART and 144 weeks (127-192) on standard of care in the less than 14 kg cohort. In the 14 kg or more cohort, 345 (49%) were female and 362 (51%) were male, 623 (88%) were Black African, median enrolment age was 12·2 years (IQR 9·1 to 14·9), weight 30·7 kg (23·4 to 43·0), and BMI-for-age Z score -0·6 (-1·4 to 0·1); 35 (5%) were overweight and six (1%) were obese. At week 240, adjusted mean differences (dolutegravir minus standard of care) were 1·0 kg for weight (95% CI -0·2 to 2·2; p=0·095) and 0·4 cm for MUAC (0·0 to 0·8; p=0·030), driven by differences in first-line participants, where higher increases were also observed in height, waist circumference, and hip circumference. Increases in BMI-for-age Z score, body fat percentage, and cross-sectional waist-to-height ratio were similar on dolutegravir-based ART and standard of care. Total cholesterol (-15·3 mg/dL [-21·0 to -9·5]; p<0·0001), triglycerides (-14·4 mg/dL [-25·2 to -3·6]; p=0·0089), and glucose (-4·4 mg/dL [-6·8 to -1·9]; p=0·0004) were lower with dolutegravir than standard of care. In the less than 14 kg cohort, 44 (52%) were female and 41 (48%) were male, 83 (98%) were Black African, median enrolment age was 1·4 years (IQR 0·6 to 2·0), weight 8·1 kg (5·4-10·0) and BMI-for-age Z score -0·8 (-1·9 to 0·2); three (4%) were overweight and none obese. Changes in weight, weight-for-age, BMI-for-age and height-for-age Z scores by 192 weeks were similar on dolutegravir and standard of care; there were small differences in MUAC (0·6 cm [-0·1 to 1·3]; p=0·070) and height (-2·5 cm [-4·5 to -0·5]; p=0·016). No significant differences in lipid biomarkers were observed; glucose decreased with standard of care but not with dolutegravir. INTERPRETATION:Over approximately 5 years, indices defining excessive weight gain and central adiposity were similar with dolutegravir and other anchor drugs, and lipid and glycaemia profiles with dolutegravir were reassuring, providing supporting evidence for dolutegravir-based ART as the preferred treatment in children and adolescents. FUNDING:Fondazione Penta ETS, ViiV Healthcare, and UK Medical Research Council.

BACKGROUND:HIV-1 drug resistance (HIVDR) complicates antiretroviral therapy (ART) in children and adolescents living with HIV (CALWH), particularly in high-prevalence areas such as KwaZulu-Natal, South Africa. This study describes trends in HIVDR and patterns by drug class and geographic location among ART-experienced CALWH in KwaZulu-Natal. METHODS:We analysed 914 routine HIV-1 genotypic resistance tests (GRTs) obtained between January 2018 and June 2022 from 0-17-year-old CALWH, integrating facility-linked Geographic Information Systems (GIS) coordinates for geospatial, descriptive and logistic regression analyses. RESULTS:Here we show that 80.96% (740/914) of GRTs from CALWH (median age 13, interquartile range 7-15 years) across 114 facilities demonstrate HIVDR. Of the 740 individuals with HIVDR, 609 (82.30%) had non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations, and among them, 32 (5.25%) were on NNRTI treatment. Additionally, 525 (70.95%) had nucleoside reverse transcriptase inhibitor (NRTI) mutations, and 181 (24.46%) had major protease inhibitor (PI) mutations. One in every 6 GRTs with HIVDR (129/740; 17.43%) have triple-class NRTI, NNRTI and PI mutations. When analysed by age, ~9 in every 10 GRTs from CALWH aged 0-9 years (237/257, 92.22%) have HIVDR, compared to 76.56% (503/657) aged 10-17 years (OR = 3.63, 95% CI: 2.22-5.93, p < 0.001). GIS-interpolation maps show potential-low-level resistance to tenofovir, low-to-intermediate-level resistance to abacavir (high-level in northern localities) and intermediate-to-high-level resistance to lamivudine, nevirapine and efavirenz. CONCLUSIONS:Routine GRTs demonstrate high HIVDR prevalence among younger children, while ART susceptibility maps show overall uniformity with variations in certain regions, such as northern KwaZulu-Natal localities. GIS-linked real-time monitoring of HIVDR is crucial to assess the impact of the revised HIV-1 treatment guidelines for CALWH in South Africa.

South Africa has the highest number of adolescents living with HIV (AHIV) globally, many of whom face disengagement and virologic failure when transitioning from pediatric to adult care. Using the Social-ecological Model of Adolescent and Young Adult Readiness to Transition (SMART) and the Technology Acceptance Model (TAM), we evaluated the acceptability, feasibility, and perceived effectiveness of an in-person and virtual adolescent support intervention (InTSHA VIP). We conducted eight focus groups with 41 AHIV aged 15-19 who received the intervention (mean age: 18.5 years, 70.1% female) and 20 in-depth interviews with youth-facing healthcare workers (HCWs) at participating clinics (mean age 43.3 years). Transcripts were coded and thematically analyzed, framed by SMART and TAM. Participants reported improved knowledge, self-efficacy, psychosocial wellness, and relationships with family and HCWs. HCWs perceived InTSHA VIP as highly useful for improving retention in care and viral suppression. Barriers included technology challenges, scheduling conflicts, and transportation access. Future implementation should address structural barriers to access while leveraging the intervention's adaptability to optimize impact and sustainability.

As use cases for long-acting therapeutics expand across clinical indications, there is a critical need to ensure the inclusion of women who are pregnant or breastfeeding, infants and children-populations with a historical gap in the availability of interventions already approved for use in adults. This White Paper synthesizes insights from a special session during the 1st of July 2025 workshop of the Community of Practice for Long-Acting Therapeutics for Maternal and Paediatric Health. It was hosted by the University of Liverpool Centre of Excellence for Long-acting Therapeutics. Attendees included stakeholders drawn from clinical practice, patient advocacy groups, academia, pharmaceutical industry, regulatory agencies, product development partners, and public health organizations. Four focus groups-centered on maternal health, pediatric health, access, and regulation-addressed three key questions: (i) What are the most urgent gaps that could hinder the adoption of long-acting therapeutics for maternal and pediatric health indications? (ii) What critical actions are needed to address these gaps? (iii) What partnerships must be initiated or strengthened to enable or accelerate these actions? Actionable strategies to accelerate progress were identified. Key themes that emerged from the discussion included the need for inclusive and context-sensitive research designs, harmonized regulatory frameworks, culturally responsive implementation strategies, and sustainable funding mechanisms. Platforms for fostering interdisciplinary collaboration, amplifying diverse stakeholder voices, and promoting transparency in innovation are needed. Partnership models that support inclusive development and equitable deployment will be central to successful integration and to realize the full potential of long-acting therapeutics in advancing maternal and pediatric health.

Background:The World Health Organization recommends dolutegravir (DTG) as the anchor antiretroviral therapy (ART) drug for children with HIV. Methods:The ODYSSEY randomized trial evaluated DTG-based ART vs non-DTG standard of care (SOC) over 96 weeks in children starting first-line ART or switching to second-line. Participant follow-up was extended to 240 weeks; ART in extended follow-up was per national guidelines. Flexible parametric survival models estimated the proportion of participants with treatment failure on randomized allocation, accounting for treatment switches through censoring and inverse probability of censoring weights. Adverse events were analyzed in the intention-to-treat population. Results:ODYSSEY enrolled 792 participants (392 DTG, 400 SOC): 311 started first-line (SOC, 92% efavirenz) and 396 second-line (SOC, 98% ritonavir-boosted protease inhibitors). The median (range) age at enrollment was 11.4 years (0.1-18.0); weight was 28.7 kg (3.4-85.0); and 89% were from Africa. Median follow-up on randomized allocation was 286 weeks (IQR, 230-310) for DTG and 204 weeks (168-240) for SOC. Among SOC participants, 23% switched to DTG before 192 weeks, 65% before 240 weeks. By 240 weeks, 74 participants on DTG and 131 on SOC had treatment failure (estimated, 19% vs 34%; difference [DTG-SOC], -15%; 95% CI, -21% to -9%; P < .001). Treatment effects were similar between first- and second-line (P = .10). The proportions of participants with serious adverse events (52 DTG vs 53 SOC, P = .92) or grade ≥3 adverse events (98 DTG vs 121 SOC, P = .09) were similar by arm over 192 weeks. Conclusions:DTG showed superior efficacy vs SOC over 240 weeks in children, with no safety concerns.

BACKGROUND:WHO recommends 5 days of intravenous antibiotics for children hospitalised with severe community-acquired pneumonia (CAP). We aimed to investigate the safety of a step-down to different oral antibiotics and the shortest effective duration. METHODS:PediCAP was an open-label, parallel group, 2 × 5 factorial randomised controlled trial of children aged 2 months to 6 years hospitalised with severe CAP without complicating factors in 13 hospitals across five sub-Saharan African countries. Children weighing 3-30 kg and with point-of-care C-reactive protein of more than 10 mg/L were randomly assigned (5:5:1) to either a step-down from intravenous antibiotics to oral amoxicillin (250 mg) or amoxicillin-clavulanate (co-amoxiclav; 200 mg amoxicillin to 28·5 mg clavulanate) via dispersible tablets twice daily (superiority comparison) for five total (intravenous plus oral) durations (4-8 days; non-inferiority comparison), or a 5-day, fixed-duration, intravenous-only treatment (non-inferiority comparison). Children were stepped down when clinically improved and able to take oral antibiotics. Clinicians could change antibiotics if clinically indicated. The primary outcome was the proportion of readmission or death at day 28 (non-inferiority margin vs intravenous only: +10%). The study was registered with the ISRCTN registry (ISRCTN63115131) and is complete. FINDINGS:Between Dec 7, 2020, and Aug 14, 2023, 2248 children were screened for eligibility and 1101 were randomly allocated (480 [43·6%] girls and 621 [56·4%] boys). The primary outcome was available in 1055 (95·8%) children. For children in the step-down groups, the mean total antibiotic exposure was 6·0 days (SD 3·5) in the 4-day group, 6·8 days (4·2) in the 5-day group, 7·4 (3·6) in the 6-day group, 8·3 days (3·4) in the 7-day group, and 9·2 days (2·9) in the 8-day group (p<0·0001), with 140 (68·6%) of 204, 151 (76·3%) of 198, 167 (85·2%) of 196, 179 (89·5%) of 200, and 186 (91·6%) of 203, respectively, stepping down within their randomised duration (p<0·0001). Primary outcomes occurred in 33 (6·9%) of 475 in the co-amoxiclav group, 27 (5·6%) of 484 in the amoxicillin group, and six (6·3%) of 96 in the intravenous-only group, with both oral step-down strategies non-inferior to the intravenous-only strategy (upper 95% CIs of 6·0 for co-amoxiclav and 5·7 for amoxicillin) and no evidence of superiority for co-amoxiclav over amoxicillin (adjusted risk difference 1·3% [95% CI -1·8 to 4·4]; p=0·40). Primary outcomes occurred in eight (4·1%) of 194 in the 4-day group, ten (5·3%) of 190 in the 5-day group, 16 (8·5%) of 188 in the 6-day group, 16 (8·3%) of 193 in the 7-day group, and ten (5·2%) of 194 in the 8-day group; all durations were non-inferior to the 8-day group (all upper 95% CIs ≤6·0%). There was no evidence of consistent differences in adverse events for oral antibiotic or duration comparisons. For antibiotic-related or serious adverse events, there was one (1·0%) in the intravenous-only group and 12 (2·5%) in the amoxicillin group (adjusted risk difference -2·3% [95% CI -4·2 to -0·3]; p=0·025), and 16 (3·4%) in the co-amoxiclav group (+0·8% [-1·2 to 2·8]; p=0·42); rates increased with randomised duration (slope estimate +0·9% [0·1 to 1·7]; p=0·032). INTERPRETATION:For sub-Saharan African children hospitalised with severe CAP without complicating factors, a strategy of stepping down upon clinical improvement to oral amoxicillin after initial intravenous antibiotics, with a total treatment duration of 4-5 days, is non-inferior to WHO-recommended 5-day intravenous treatment. FUNDING:The Second European and Developing Countries Clinical Trials Partnership (EDCTP2).

ABSTRACTIn this paper, we describe the central role of caregivers in shaping adolescent engagement with long-acting injectable antiretroviral therapy (LAI-ART) within the Long-Acting Treatment for Adolescents (LATA) trial conducted in South Africa and Uganda. Adolescents' participation in HIV care is embedded within emotional, moral, and cultural relationships rather than individual decision-making. Drawing on the bioecological model of human development and the adolescent well-being framework, we conceptualise caregiver support as an evolving relational process that fosters adolescents' connectedness, competence, optimism, and autonomy - psychosocial attributes critical to sustained treatment adherence. Our findings reveal that caregivers provide emotional anchoring, interpretive guidance, and motivational reinforcement, while adolescents' growing agency reshapes caregiving dynamics toward collaborative partnership. By addressing disclosure-related guilt and emotional burdens among caregivers, we advance a relational model of adolescent-centred HIV care. We call for interventions that recognise caregivers as co-participants essential to improving treatment uptake, adherence, and long-term well-being.

BACKGROUND:Data on predictors of treatment failure in children starting antiretroviral therapy (ART) are limited, particularly on dolutegravir-based regimens (DTG). METHODS:ODYSSEY demonstrated superior efficacy of DTG versus standard-of-care (SOC). We assessed predictors at ART initiation of treatment failure by 96 weeks. RESULTS:Three hundred and eighty-one children started first-line ART (82% African). At ART-initiation, median age was 10.5 years (IQR: 6.5, 14.0, 67 < 3 years), CD4% 20% (IQR: 12, 28), BMI-for-age Z-score -.58 (IQR:-1.48, +.25). One hundred and eighty-nine children started DTG, 192 started SOC (91% ≥3 years started efavirenz; 79% <3 years started lopinavir). Seventy-five children experienced treatment failure (24 DTG, 51 SOC). Failure risk was lower on DTG than SOC (hazard ratio [HR] = 0.47, 95% CI: 0.29-0.77, P = .002). Lower BMI-for-age Z-score (HR = 0.82 for each unit gain, 95% CI: 0.70-0.96, P = .01) and being at an African site (HR = 2.09, 95% CI: 0.82-5.31, P = .09) were associated with higher failure risk. Risk was also higher at younger ages with the steepest increase in the youngest children and increased at lower CD4%, with a stronger CD4% effect at younger ages. At CD4% = 20, HRs relative to age 10 years were 2.40 (95% CI: 1.58-3.65) at age 1 year, 1.30 (95% CI: 1.15-1.48) at age 5 years, and 0.80 (95% CI: 0.72-0.89) at age 18 years. At age 1 year, HRs relative to CD4% = 20 were 1.39 (95% CI: 1.16-1.66) at CD4% = 15, and 0.52 (95% CI: 0.36-0.75) at CD4% = 30; at age 10, corresponding estimates were 1.07 (95% CI: 0.94-1.20) at CD4% = 15, and 0.88 (95% CI: 0.69-1.13) at CD4% = 30. CONCLUSIONS:Young age, low BMI-for-age, and low CD4% at ART initiation predicted higher risk of treatment failure and can guide targeted support.

Importance Clesrovimab is a long-acting monoclonal antibody approved for the prevention of respiratory syncytial virus (RSV) lower respiratory tract disease in neonates and infants who are born during or entering their first RSV season; data concerning clesrovimab from a second RSV season among children who remain at risk for severe disease are needed. Objective To evaluate the safety and tolerability of clesrovimab (105 mg) vs palivizumab in RSV season 1 in infants at increased risk for severe RSV disease. Key secondary objectives include describing the safety of 210 mg of clesrovimab in RSV season 2 in children who remain at increased risk for severe RSV disease, clesrovimab pharmacokinetics, and the incidence of RSV-associated disease. Design, Setting, and Participants SMART (MK-1654-007) was a randomized, partially masked, palivizumab-controlled, phase 3 clinical trial, conducted at 110 sites in 27 countries and territories between November 30, 2021, and November 20, 2025. The population constituted palivizumab-eligible infants, including those with prematurity, chronic lung disease of prematurity, or hemodynamically significant congenital heart disease. Interventions Participants, randomized 1:1 and stratified by region and condition, received clesrovimab (105 mg) on day 1 followed by placebo on day 28 or monthly palivizumab (15 mg/kg) up to 5 doses (1 dose per month). Eligible infants received open-label clesrovimab (210 mg) before their second RSV season. Main Outcomes and Measures The primary outcome was the observed proportions of participants experiencing adverse events (AEs) after clesrovimab or palivizumab in season 1. Results Overall, 997 infants (500 [50.2%] male; median age, 2.6 [range, 0.0-12.0] months) received clesrovimab, 105 mg (n = 498) or palivizumab (n = 499) in season 1; 276 received clesrovimab, 210 mg open-label in season 2. In season 1, the proportions of participants experiencing AEs were comparable between treatment groups. In season 2, clesrovimab, 210 mg was well tolerated. Incidence rates of RSV-associated medically attended lower respiratory infection (MALRI) were comparable between clesrovimab and palivizumab (3.2% [95% CI, 1.8%-5.2%] and 3.4% [95% CI, 2.0%-5.6%], respectively) through day 150 in season 1; total RSV-associated MALRI incidence through day 180 after a 210-mg dose in season 2 was 7.3% (95% CI, 4.4%-11.4%). Conclusions and Relevance In this randomized clinical trial, clesrovimab was well tolerated in infants at increased risk for severe RSV disease through 2 RSV seasons. These findings support the use of clesrovimab in children who remain at risk for severe RSV disease in their second RSV season. Trial Registration ClinicalTrials.gov Identifier: NCT04938830

BACKGROUND:Low and undetectable HIV-1 DNA levels are associated with greater likelihood of ART-free viral control and may help select candidates for analytic treatment interruption. We investigated predictors of HIV-1 DNA levels in older children and adolescents with perinatally acquired HIV who started ART early in life. METHODS:Children older than 7 years and adolescents on ART and virally suppressed (<50 copies/mL) who started ART <3 months of age were recruited at sites in South Africa, Mozambique, Uganda, Mali, and Thailand. Previous viral rebound or ART interruption was allowed. HIV-1 DNA was measured in peripheral blood mononuclear cells using droplet-digital PCR. Associations between DNA levels and clinical factors were analyzed using descriptive statistics and χ 2 tests. RESULTS:Among 89 participants (50.6% female), ART started at a median age of 66 days (IQR: 53-87) and current median age was 12.8 years (IQR: 9.6-16.7). Median HIV-1 DNA was 355 copies/10 6 cells (IQR: 151-912); 10.1% were undetectable (<1 copy/10 6 cells). Undetectable results were more frequent in those with ART interruption (21.7%) than continuous ART (6.1%), P = 0.0485. This was significant only in females (regardless of ART start age) and only in those who started ART < 60 days of age (regardless of sex). CONCLUSIONS:About 10% of early-treated children and adolescents suppressed on ART had HIV-1 DNA levels below the assay's detection threshold. Previous ART interruption was associated with a greater likelihood of undetectable HIV-1 DNA. These results provide support for the concept of "auto-immunization," where ART interruption may, in certain circumstances, enhance HIV immunity and promote ART-free control.

BACKGROUND:Short-cycle antiretroviral therapy (ART), comprising 5 days on and 2 days off treatment, offers the potential for ART-free weekends, reduced toxicity, and improved quality of life for adolescents living with HIV, who typically have worse treatment outcomes than other age groups. We aimed to compare the efficacy and safety of short-cycle ART containing tenofovir disoproxil fumarate-lamivudine-dolutegravir with continuous ART in adolescents living with HIV in Africa. METHODS:We conducted an open-label, randomised, parallel, two-arm, non-inferiority trial (BREATHER Plus) in five clinical research centres across Kenya, South Africa, Uganda, and Zimbabwe. Adolescents (aged ≥12 years to <20 years) with an HIV-1 viral load of less than 50 copies per mL over the previous 12 months and no documented history of treatment failure were eligible for inclusion. Participants were randomly assigned (1:1) by use of permuted blocks to either short-cycle ART or continuous ART, stratified by clinical centre and mode of HIV acquisition (vertical vs horizontal or other). Participants received a daily oral fixed-dose combination of tenofovir disoproxil fumarate (300 mg), lamivudine (300 mg), and dolutegravir (50 mg); those assigned to short-cycle ART could choose their two consecutive days off (ie, Friday and Saturday or Saturday and Sunday). The primary outcome was confirmed viral rebound (the first of two consecutive viral load measurements ≥50 copies per mL) by week 96, analysed by intention to treat in all participants with viral load data after baseline assessment by use of adjusted Kaplan-Meier estimated proportions. The non-inferiority margin and confidence level depended on the event rate in the continuous ART group (an 8% margin with 99% CI for a 5% event rate). This trial is registered with ISRCTN (85058577), and follow-up is complete. FINDINGS:Between June 29, 2022, and May 10, 2023, 470 adolescents living with HIV were randomly assigned to either short-cycle ART (239 [51%]) or continuous ART (231 [49%]). 263 (56%) participants were female and 207 (44%) were male. Median follow-up was 117 weeks (IQR 108-120). 23 participants in the short-cycle ART group and 11 in the continuous ART group had confirmed viral rebound by 96 weeks, with an estimated probability of confirmed HIV-1 RNA of at least 50 copies per mL of 9·9% (95% CI 6·4-14·3) in the short-cycle ART group versus 4·8% (2·6-7·8) in the continuous ART group. With an estimated difference of 5·1% (99% CI -0·8 to 11·5; bootstrap p=0·034), an 8% higher rate of confirmed virological rebound in the short-cycle ART group was not rejected, and the rate of confirmed virological rebound was significantly higher in the short-cycle ART group than in the continuous ART group. By the end of follow-up, 16 serious adverse events in 15 participants were reported in the short-cycle ART group (including one death unrelated to HIV or ART) and 22 serious adverse events in 16 participants in the continuous ART group. INTERPRETATION:BREATHER Plus findings demonstrate that short-cycle ART with tenofovir disoproxil fumarate-lamivudine-dolutegravir should not be recommended for adolescents living with HIV receiving standard-of-care, routine viral load monitoring every 6-12 months. FUNDING:European and Developing Countries Clinical Trials Partnership, and UK Medical Research Council.

Background Alternatives to daily oral antiretroviral therapy (ART) are important for adolescents with HIV (AHIV) to improve adherence and outcomes. Long-Acting-injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) has demonstrated excellent efficacy and safety and strong patient preference in adults. Methods LATA is an ongoing randomised, open-label, 96-week, non-inferiority trial evaluating the efficacy, safety and acceptability of LAI CAB/RPV vs. daily oral therapy with tenofovir (disoproxil fumarate or alafenamide)/lamivudine/dolutegravir (TLD). Participants are virologically suppressed AHIV aged 12-

Background:Knowledge gaps persist regarding paediatric COVID-19 clinical presentation, treatment and outcomes in high HIV prevalence settings, with low COVID-19 vaccine coverage. Methods:An ambi-directional cohort study was conducted in 13 South African public sector hospitals. Hospitalised children with SARS-CoV-2 infection or post-infection syndrome were included. Main outcomes measures included severe disease and primary COVID-19 (hospitalisation for SARS-CoV-2 infection). Results:There were 2363 SARS-CoV-2 positive children included (March 2020 through May 2023); median age 23.6 months (interquartile range (IQR) = 4.3-98.2 months). Excluding missing values, 1618 (68.9%) children had primary COVID-19; 1121 (69.3%) of these had severe primary COVID-19. In the primary COVID-19 group with data, 318 / 1588 (20.0%) received intensive or high care, 121/1285 (9.4%) received a blood transfusion and 48/1616 (3.0%) died. Multivariable analyses demonstrated that severe primary COVID-19 was 32% higher in children aged 29-365 days (adjusted Risk Ratio (aRR) = 1.32 (95% confidence interval (CI) = 1.13-1.55); reference: 0-28 days), 13% higher with one or more comorbidities (aRR = 1.13; CI = 1.05-1.22)), and 14-22% lower during the Beta, Delta and Omicron periods (reference: ancestral period). Amongst all hospitalised children with a positive SARS-CoV-2 test, severe disease was commoner in underweight children (aRR 1.09; CI = 1.02-1.17, P = 0.013)). Severe signs were commoner in children living with HIV (CLHIV), 88/121 (72.7%), vs. HIV uninfected 1320 / 2104 (62.7%), P = 0.026, and in antiretroviral therapy-naïve CLHIV, (37 / 41 (90.2%), vs. CLHIV on therapy 51 / 80 (63.8%), P = 0.002). Conclusions:In a high HIV prevalence country, approximately 70% of children with a positive SARS-CoV-2 test were hospitalised for COVID-19 treatment; almost 70% of these children were severely ill. Controlling for other factors, disease severity was highest in the hypothesised pre-immunity Ancestral period. HIV infection and delayed ART initiation were associated with severe signs. In such settings, strengthening general child health programmes to reduce underweight and prevent or treat paediatric HIV may reduce the severity of new diseases of pandemic proportion.

BACKGROUND:Alternatives to daily oral antiretroviral therapy (ART) are important for adolescents with HIV (AHIV) to improve adherence and outcomes. Long-Acting-injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) has demonstrated excellent efficacy and safety and strong patient preference in adults. METHODS:LATA is an ongoing randomised, open-label, 96-week, non-inferiority trial evaluating the efficacy, safety and acceptability of LAI CAB/RPV vs. daily oral therapy with tenofovir (disoproxil fumarate or alafenamide)/lamivudine/dolutegravir (TLD). Participants are virologically suppressed AHIV aged 12- < 20 years in Kenya/South Africa/Uganda/Zimbabwe. Randomisation was 1:1 to LAI CAB/RPV given once every 8 weeks (after optional oral lead-in) or daily oral TLD. The primary outcome is viral rebound (two consecutive viral loads ≥50 copies/mL by 96-weeks). Viral loads are measured every 24 weeks. The trial employs the Smooth Away From the Expected (SAFE) non-inferiority frontier, where the non-inferiority margin depends on the observed event rate in the control arm. Secondary outcomes include confirmed viral load ≥200 copies/mL by 96-weeks, HIV resistance, safety, patient-reported outcomes and cost-effectiveness. LAI participants return to oral ART at confirmed viral load ≥200 copies/mL; LAI participants who become pregnant are given the choice to continue on LAI or to switch back to daily oral ART, with optional pharmacokinetic sampling during pregnancy and post-partum in both groups. Enrolment of 476 AHIV completed in April 2024. Results will be reported in 2026. CONCLUSION:LATA is the first trial comparing the efficacy, safety and acceptability of LAI CAB/RPV to oral ART in AHIV, enrolled in Sub-Saharan Africa, using a programmatic approach to viral load testing. TRIAL REGISTRATION:This trial has been registered with ClinicalTrials.gov (NCT05154747).