PROJECT ABSTRACT The number of adolescents living with HIV (ALHIV) in Uganda is over 170,000 and growing. Ugandan ALHIV are a priority due to social and structural inequities that make them highly vulnerable to HIV infection and sub- optimal access and adherence to antiretroviral therapy (ART). Less than 50% of ALHIV in Uganda are ART- adherent, leading to low rates of viral suppression and high attrition from HIV care. In response to calls for expanding differentiated care approaches for ALHIV and new forms of combination HIV interventions, we seek to intervene on social and structural inequities that exacerbate the risk for viral load non-suppression. Addressing these hardships can improve ALHIV’s livelihoods and give them the knowledge and resources to sustainably manage HIV. We have shown the effectiveness of Suubi (Hope) in four NIH-funded RCTs in Uganda. Suubi is an evidence-based and theory-informed combination intervention with four components: 1) Financial Literacy Training; 2) Incentivized Matched Youth Savings Accounts with income-generating activities; 3) a manualized intervention for ART adherence and stigma reduction; and 4) Engagement with HIV treatment-experienced role models who share lived experiences of HIV. Suubi has shown robust effects on viral suppression and ART adherence, mental health and psychosocial outcomes, and family financial stability. Yet, it is unknown if each component in Suubi had a positive effect, how the components interacted, or if fewer components could have produced equivalent effects. Hence, we propose a factorial experiment to unpack and optimize Suubi to enhance scale up in health systems using the multi-phase optimization strategy (MOST). We define our “optimization objective” as the most cost-effective combination of intervention components considering three real-world constraints: 1) efficiency, 2) affordability, and 3) scalability. We then evaluate the intervention component effect sizes and balance these data against real-world information and costing data to empirically arrive at optimization. The study aims are: Aim 1. Conduct a factorial experiment (optimization trial) to test the main effects of each of the four Suubi intervention components and combinations of components (interactions) on viral suppression (primary outcome); Aim 2. Test mediators and explore moderators that explain and modify the relationship between each of the four Suubi intervention component and viral suppression; and Aim 3. Compare the cost and cost-effectiveness of each of the four Suubi intervention components and every combination of components. We will use a 24 factorial experiment with 16 conditions representing all combinations of the 4 components. Health clinics (N=48) will be randomized to 16 conditions (12 ALHIV per clinic), yielding main effects and interaction effects for the 4 components on sustained viral suppression (defined as an undetectable viral load at 12-, 24- and 36-month follow-up assessments). An ...