Risk and Protective Factors Associated With HIV-Related Mortality in Children Receiving Antiretroviral Therapy

Abstract

Importance: Mortality among children and young adolescents receiving antiretroviral therapy (ART) remains substantially higher in resource-limited settings compared with resource-rich regions. The role of modifiable risk and protective factors in explaining this global variation remains poorly understood. Objective: To identify and quantify country-level modifiable risk and protective factors associated with HIV-related mortality among children and young adolescents receiving ART. Design, Setting, and Participants: This model-based meta-regression analysis linked HIV-related mortality data from cohort studies included in a published systematic review of children and adolescents (aged 0-14 years) receiving ART, with biomedical, behavioral, and structural factors from the Global Burden of Diseases, Injuries, and Risk Factors study 2023. Data were analyzed using penalized regression (ridge regression with cross-validation) and an ensemble machine-learning algorithm (XGBoost). Study data were analyzed from August 2024 to October 2025. Exposures: Country-level modifiable covariates, including access to improved water, vaccine coverage against different pathogens, maternal education, underweight proportion, and oral rehydration coverage. Main Outcomes and Measures: Measures included the odds ratios (ORs) of HIV-related mortality while receiving ART associated with modifiable factors, simulations of hypothetical 10% and 20% increases in covariates, and variable importance via Shapley Additive Explanation (SHAP) values. Results: HIV-related mortality data from 67 cohort studies were included in this analysis. Access to improved water, pneumococcal conjugate vaccine third-dose (PCV3) coverage, and maternal education demonstrated the strongest independent associations with HIV-related mortality while receiving ART. A 10% increase in improved water access, PCV3 coverage, and maternal education was associated with lower odds of mortality (OR, 0.83; 95% CI, 0.826-0.843; OR, 0.980; 95% CI, 0.972-0.987; and OR, 0.997; 95% CI, 0.996-0.998, respectively). At 20% increases, these protective associations with HIV-related mortality were stronger (OR, 0.695; 95% CI, 0.682-0.711; OR, 0.959; 95% CI, 0.945-0.974; and OR, 0.994; 95% CI, 0.992-0.997, respectively). SHAP-based analyses consistently ranked these 3 factors as most predictive of HIV-related mortality. Conclusions and Relevance: Findings of this model-based meta-regression analysis show that improved water access, PCV3 coverage, and maternal education were associated with lower HIV-related mortality among children receiving ART, underscoring the need for integrated public health strategies beyond ART alone. Interventions to strengthen water infrastructure, vaccination programs, and maternal education may help reduce global survival disparities among children and adolescents living with HIV and receiving ART.