Modified Project Summary/Abstract Section Despite major advances in treatment and prevention of HIV infection, the HIV/AIDS pandemic continues to cause tremendous morbidity and mortality. Of the 37.7 million people living with HIV worldwide, only 73% are receiving antiretroviral therapy. In 2020 alone, an estimated 680,000 people died from AIDS-related illness, and nearly two million people are newly infected with HIV each year. The HIV burden is highest in parts of the world that face the additional challenge of highly constrained resources. HIV testing and treatment guidelines have continually evolved; however, assessing the benefits associated with improved testing, more effective antiretroviral therapy, and increasingly effective prevention interventions is difficult. It is unclear which specific strategies and overall approach would be most effective for specific populations, given the critical reality of budget constraints. This competing continuation proposes to expand upon the Cost-Effectiveness of Preventing AIDS Complications International (CEPAC-I) Model, a computer microsimulation of the natural history, management, outcomes, costs, and cost-effectiveness of HIV clinical care. This proposal includes cutting-edge, guideline-informing studies of novel treatments and development of innovative modeling optimization methods to advance the field. There are two specific aims: Specific Aim 1: To expand the CEPAC-I microsimulation to address new clinical policy questions focused on important populations, using data from recent clinical trials and implementation research studies. Specific Aim 2: To expand upon the optimization model and better determine the combination of HIV care interventions that most decreases HIV incidence in countries with different epidemic characteristics and resource constraints. In close alignment with the 2022 research priorities of the NIH Office of AIDS Research, the goals of this proposal include reducing HIV incidence, identifying optimal prevention and treatment responses, and improving population outcomes. The assembled research team has the ideal combination of skills and experience to address critical questions around the cost-effectiveness of new interventions for HIV. The results will lead to new insights to inform clinicians and policymakers, leading to improved HIV treatment guidelines.