risis of substance use in the US. In 2021, more than 107,000 overdose deaths occurred, setting yet another grim record. The substance use epidemic continues to threaten hard-fought gains in prevention and control of HIV and hepatitis C virus (HCV) and related diseases. Identifying the best approach to reduce HIV and HCV transmission stemming from the substance use epidemic is of critical public health importance. In this extension to our MERIT award, our overall aims remain the same but we seek to extend and broaden our work in each of the aims in 3 key areas by: 1) developing new methods and conducting analyses that address health disparities; 2) incorporating social determinants of health in assessing barriers to program delivery and implementation and evaluating interventions to address those barriers; 3) expanding our work to encompass the intersecting syndemics of stimulant use, Covid-19, and other related conditions. We will: 1. Model the effect of the opioid and stimulant epidemic on transmission of HIV, HCV, and related diseases. 2. Model the epidemiologic and population impacts of individual strategies to prevent and mitigate the harms of opioid and stimulant use on HIV, HCV, and other disease-related outcomes. 3. Model the epidemiologic and population impact of portfolios of strategies to mitigate the harms of opioid and stimulant use on HIV, HCV, and other disease-related outcomes. 4. Model the impact of barriers (including social determinants of health) and enablers to implementation of effective strategies and portfolios of strategies to reduce the harms of opioid and stimulant use. Our work will provide clinicians, policymakers, and community organizations with critically needed guidance about strategies to mitigate the consequences of opioid and stimulant use and improve quality of life and health equity for people with substance use disorder.