PROJECT ABSTRACT Globally, HIV-related deaths have decreased 60% from their peak in 2004. Adolescents and young adults (AYA) ages 10 to 24, however, comprise the only age group that has not seen improvements in HIV-related mortality since then. Adolescence is a distinct developmental period, in which risk-taking and impulsive decision-making are normative behaviors. Stigma, disclosure concerns, and medication toxicity impact HIV health behaviors at a time when AYA may also experience their first sexual relationships. Differences in HIV health outcomes by age are partly due to late diagnosis, as well as to challenges in accessing treatment and prevention modalities requiring daily adherence. This problem is particularly acute in South Africa, which has the largest HIV epidemic in the world, with one in three new infections there occurring among AYA. Recent advances in long-acting HIV prevention and treatment formulations that avert the need to take a daily pill hold major promise, particularly for AYA. With support to Dr. Neilan from an NICHD K08 HD094638 (2018-2023) as well as from the Adolescent Medicine for HIV/AIDS Interventions Trials Network U24HD089880 (2017-2022), we developed the Cost-effectiveness of Preventing AIDS Complications-Adolescent and Young Adult (CEPAC- AYA) microsimulation model. We have conducted 12 model-based clinical and cost-effectiveness analyses addressing key questions in AYA HIV prevention, diagnosis, and treatment in the United States. In a new US- South Africa collaboration, we now propose to adapt and expand the structure of this simulation model and assemble necessary data inputs, and then to use the model to identify the most effective and cost-effective approaches and monitoring strategies for the treatment and prevention of HIV among AYA in South Africa. We have three specific aims: Aim 1. Develop new structure within the CEPAC-AYA model and derive data to permit modeling of long-acting ART and PrEP regimens for AYA in South Africa. Aim 2. Evaluate the clinical impact, cost, and cost-effectiveness of new AYA-focused treatment interventions to decrease opportunistic infections and mortality among AYA in South Africa. Aim 3. Assess the clinical impact, cost, and cost-effectiveness of new AYA-focused prevention interventions to reduce HIV incidence among AYA in South Africa. The goal of this proposal is to evaluate context-specific, adolescent-tailored care strategies and to identify the best use of limited resources to improve health outcomes for AYA affected by HIV in South Africa. As new treatments and delivery systems emerge, the model will be poised to inform how to best deploy these resources for this vulnerable population.