HIV-related mortality time trends among children and young adolescents on antiretroviral therapy by age, treatment duration, and region: a systematic review and meta-regression analysis.

BACKGROUND Past cohort studies have examined mortality among children and young adolescents (aged 0-14 years) who have received antiretroviral therapy (ART), but no systematic reviews have been undertaken to synthesise these findings. Our study aims to provide the most comprehensive global estimates of paediatric mortality among children and adolescents receiving ART. METHODS For this systematic review and meta-regression analysis, we searched PubMed and Embase from Jan 1, 1990 to July 31, 2024 for studies reporting mortality among children and young adolescents living with HIV who were on ART. We employed the meta-regression with Bayesian priors, regularisation, and trimming tool, developed for the Global Burden of Disease study 2019, for meta-regression analysis to estimate on-ART mortality by region, CD4 cell count or percentage, age, sex, and treatment duration. We assessed the robustness of our results by doing a sensitivity analysis, restricting it to studies of good quality using the quality assessment tool adapted from the Newcastle-Ottawa Scale and the National Heart, Lung, and Blood Institute. This study has been registered with PROSPERO (CRD42022382702). FINDINGS Our literature search identified 7588 records, of which 5853 were determined relevant for title and abstract review. Following screening, 1068 records were selected for full-text assessment. We included 84 studies in our systematic review, of which 66 were included in the meta-regression analysis. Our analysis indicated that HIV-related mortality for all children and young adolescents (aged 0-14 years) decreased over time, between 2000 and 2020 globally, after adjusting for region, baseline CD4 cell count, age, treatment duration, and sex. Additionally, HIV-related mortality decreased with increasing CD4 cell count at ART initiation and longer treatment duration. There have been considerable geographical variations in the risk of mortality. Among the high-mortality group in 2020 (ART duration <6 months, age <1 year, male, and the lowest CD4 cell counts), HIV-related mortality across regions ranged from 11·7 deaths (95% CI 8·3-15·4) per 100 person-years in eastern Sub-Saharan Africa to 72·0 deaths (47·1-98·1) per 100 person-years in Asia-Pacific. Among the low-mortality group in 2020 (ART duration ≥1 year, age 5-9 years, female, and the highest CD4 cell counts), HIV-related mortality ranged from 0·09 deaths (0·07-0·10) per 100 person-years in eastern Sub-Saharan Africa to 0·20 deaths (0·03-0·80) per 100 person-years in Latin America and the Caribbean. INTERPRETATION A comprehensive approach to paediatric HIV care is essential to improving outcomes for children and young adolescents living with HIV. Clinically, this approach includes strengthening the prevention of vertical transmission, ensuring early diagnosis in infants, and initiating treatment promptly-ideally at higher CD4 cell counts. From a policy perspective, health systems need to address disparities in treatment access and outcomes across regions, age groups, and sex. Efforts should also prioritise minimising treatment dropout and expanding access to high-quality HIV services. These strategies could collectively support global goals to reduce the burden of paediatric HIV. FUNDING The National Institute of Allergy and Infectious Diseases and the National Institutes of Health.