Joint Clinical Research Centre

The study analyses robust, causal evidence of transformational change. We approach this topic by systematically reviewing literature that has the potential to document causal evidence for transformational change across a broad set of interventions and outcomes. Our focus is on evidence found in developing countries to inform climate interventions. We approach this learning exercise directly by looking at the energy sector and indirectly by reviewing the evidence on behavioural change in the public health sector. Both sectors show examples of transformational change with scale, depth and duration. We identify lessons on transformational change from these two sectors relevant to policymakers.

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.

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.

Karamoja continues to experience a substantial TB burden, and supporting preventive treatment among high-risk groups such as household contacts is essential for reducing progression from latent infection to active TB. Despite national efforts, adult TPT uptake in the region remained low prior to 2022. This study explored factors associated with uptake among adult TB contacts at Matany Hospital.We carried out a cross-sectional assessment involving 357 adults aged 18 years and above who were listed as contacts of bacteriologically confirmed TB patients between May 2022 and May 2023. Data were obtained through structured questionnaires and medical record extraction. Initiation of any recommended TPT regimen constituted uptake. Analysis was performed using STATA 14.2, employing chi-square tests for preliminary associations and multivariable logistic regression for adjusted estimates.Of 357 participants (59.4% female; mean age 44.6 years), 277 (77.6%) had initiated TPT. Contacts whose index patient was still on treatment had higher odds of uptake (OR=2.93; 95% CI: 1.31–6.54). Waiting times between 15 minutes and one hour markedly decreased TPT initiation (OR=0.33; 95% CI: 0.15–0.73). Catholics were more likely to initiate TPT compared to Anglicans (OR=3.68; 95% CI: 1.36–9.92). Limited exposure to community sensitization campaigns and inadequate knowledge of TPT significantly lowered uptake.High TPT uptake in this pastoralist setting appears to be influenced by early engagement of contacts, strong faith-based networks, and active community awareness efforts. Addressing knowledge gaps, reducing waiting times, and partnering with religious institutions may strengthen TPT coverage in similar high-burden regions.

Background Persistent global health security risks require countries to establish effective, standards-aligned biosafety and biosecurity systems. Sub-Saharan Africa carries a disproportionate burden of infectious disease threats, yet systematic laboratory biorisk management (BRM) remains nascent in most low-income countries. Uganda's National Health Laboratory and Diagnostic Services (NHLDS) launched a national, risk- and performance-based BRM programme spanning the human health, animal health, water, and environmental laboratory sectors. This article describes the programme design, implementation trajectory, and outcomes between 2022 and 2025. Methods A national implementation evaluation employing a repeated cross-sectional design with a within-facility matched-cohort sub-analysis was conducted across Uganda’s One Health laboratory sectors. Four national BRM instruments were developed and validated: a biosafety and biosecurity manual, a training curriculum, a structured mentorship toolkit, and an ISO 35001:2019/ISO 15190:2020-aligned assessment checklist. Capacity was built through a three-tier cascade training model. Compliance assessments were conducted in 200 laboratories generating 337 assessment events. Within-facility change was analyzed for 29 mentored laboratories with paired 2023–2025 data; statistical testing used the paired t-test and Wilcoxon signed-rank test. Results The programme trained more than 1,500 laboratory personnel, including 25 national master trainers, 41 mentors, and 27 ISO 19011-certified auditors, and provided structured mentorship to 80 laboratories. System-level mean BRM compliance increased from 26.3% in 2022 to 48.7% in 2025 across all assessed laboratories. Within the matched mentored cohort (n = 29), mean compliance rose from 57.2% to 66.3% (within-facility mean change + 9.1 percentage points; 95% CI + 2.0 to + 16.3; p = 0.019; Wilcoxon p = 0.024; Cohen’s d = 0.46). The proportion of mentored laboratories classified as Low Risk or better (≥ 65%) increased from 21% to 55%. An inverse gradient was observed between baseline performance and subsequent gain. Conclusion A standardized, ISO-aligned BRM framework is operationally feasible at national scale in a low-resource, One Health setting. Structured multi-cycle mentorship, cascade training, and engaged leadership were associated with measurable within-facility performance gains. The programme provides a replicable model for countries seeking to operationalize international BRM standards across heterogeneous laboratory sectors.