PROJECT ABSTRACT With the increasing demand for and emerging data regarding long-acting injectable (LAI) antiretroviral therapy (ART), there is a growing need to understand its impact on and potential among adolescents and young adults (AYA), a group with historically low adherence to oral ART and high risk of virologic failure. Despite promising new data on long-acting cabotegravir and rilpivirine's (LA-CAB/RPV) efficacy and safety, critical questions remain about its long-term effectiveness and the risks associated with prior low adherence. The AFINAty study addresses these gaps by investigating the effectiveness and feasibility of LA-CAB/RPV in AYA in Cape Town, South Africa. The AFINAty study team has unexpectedly acquired two additional years of study drug (from Johnson and Johnson) providing us with the serendipitous and unforeseen opportunity to obtain new data on virologic suppression, drug concentrations and genotypes within the study cohort. By integrating these findings into a validated computer simulation model, we aim to project the clinical and economic impact of incorporating baseline genotypic information into clinical decision-making. This comprehensive analysis will provide actionable insights into optimizing LA-ART usage, enhancing adherence and clinical outcomes for AYA with HIV. Ultimately, the study will inform global HIV treatment strategies and improve long-term health outcomes for this understudied population. Supplement Aim 1. To collect and analyze predictors of durable virologic suppression in the AFINAty cohort, including both drug concentrations and genotypic information. Supplement Aim 2. Using the CEPAC-AYA simulation model, to determine the clinical impact, cost and cost- effectiveness of baseline genotyping vs. clinical history to inform LA-CAB/RPV selection among individuals who are virologically suppressed and initiating this treatment modality. Our overall objective is to leverage a critical opportunity to understand viral suppression, drug concentration and genotypic data over a three-year period among AYA in AFINAty. These data are not available anywhere in the world, and will add tremendous value to the parent grant, consistent with its originally approved objectives.