SUMMARY: Despite advances in treatment and prevention over the past decades, human immunodeficiency virus (HIV) imposes substantial burdens in the United States (US). US HIV infections are increasing concentrated in Southern states with a disproportionate number of rural infections, particularly among racial, ethnic, and sexual minorities. Rural epidemics in these states are linked to high-intensity urban epidemics, and driven by racial/ethnic disparities, poverty, inadequate insurance, limited access to healthcare, and housing insecurity. Additionally, the opioid epidemic disproportionately affects rural communities, increases HIV transmission, and hinders HIV control efforts. The Ending the HIV Epidemic (EHE) Initiative seeks to reduce HIV incidence by 90% over a decade. Ending the US HIV epidemic will require interventions tailored to local-level epidemic dynamics that address underlying drivers of transmission. Mathematical models of HIV transmission are powerful tool to forecast epidemics, and can provide evidence-based guidance on the optimal way to prioritize limited public health resources, but these models have focused primarily on urban epidemics. We have previously developed the Johns Hopkins Epidemiologic and Economic Model (JHEEM), a platform for modelling local HIV epidemics. Our objective is to generate projections of local HIV epidemics in states with a high rural burden of HIV to inform policy decisions by local health departments. We will partner health departments in three states where we have established relationships (Alabama, Louisiana, and Mississippi) to develop a suite of transmission models, based on JHEEM, that rigorously leverage local surveillance data to make projections of the HIV epidemic in each state. In Aim 1, we will develop an integrated, statewide modeling approach that links rural and urban regions using mobility data. We will use the models to identify which combinations of HIV testing, pre-exposure prophylaxis (PrEP), and viral suppression – targeted to which demographic subgroups and geographic regions – will yield the greatest reductions in incidence and disparities. In Aim 2, we will incorporate three social determinants of health: insurance, access to healthcare, and housing instability, and the racial and ethnic disparities in their distribution across the population. We will project the impact on HIV incidence and disparities of strategies that include both traditional HIV interventions and increase insurance, access to care, or stable housing. In Aim 3, we will expand JHEEM to include the opioid epidemic, and evaluate the potential reductions in HIV incidence achievable by strategies that combine harm reduction for opioid use disorder with HIV control interventions. These aims will yield a comprehensive modeling framework that links traditional HIV interventions with underlying drivers of the epidemic in rural America. Our results will provide data-driven projections, tailored to the specific needs ...