PROJECT SUMMARY Cocaine and methamphetamine-related deaths have risen steeply in the United States, the majority associated with fentanyl. Stimulant use is prevalent among people living with or at risk for HIV, and in this population, it is unknown what proportion of mixed stimulant-opioid overdose deaths are due to unintentional fentanyl exposure. As overdose deaths threaten gains in life expectancy among PWH in recent years, we need to use all available tools at our disposal to prevent unintentional opioid exposure and overdose. We propose a novel concept of opioid overdose pre-exposure prophylaxis (PrEP) for individuals using stimulants and living with or at risk for HIV. We will perform a randomized controlled trial of a long-acting injectable opioid antagonist (intramuscular naltrexone) vs. a conventional in-clinic harm reduction bundle, with stratified randomization based on baseline antiretroviral therapy delivery strategy (i.e., injectable vs. oral HIV prevention/treatment). Our three key objectives are: 1) investigate the feasibility, acceptability, and preliminary effectiveness of intramuscular naltrexone as a preventive measure for opioid overdose in individuals using stimulants, 2) capture the experiences of patients receiving concurrent long-acting injectable medicines for HIV and substance use, 3) employ short and long-term biomarkers of substance use, supplemented by participant interviews, to craft an epidemiological profile detailing intentional and unintentional opioid exposure among individuals living with or at risk of HIV. Our creative approach repurposes intramuscular naltrexone, conventionally used for opioid and/or alcohol use disorders, as an innovative method for opioid overdose prevention. This trial will be performed at University of California San Francisco (UCSF) at San Francisco General Hospital’s Ward 86 clinic, home to the largest known cohort of people who use drugs receiving long- acting injectable HIV treatment/prevention. San Francisco county's high per capita overdose death rate underscores the urgent need for our research, and our study promises to provide valuable insights into the interplay of HIV prevention/treatment, stimulant use, and opioid overdose prevention. .

PROJECT NARRATIVE Amidst an explosive increase in overdose deaths linked to stimulants (e.g., cocaine, methamphetamine) along with fentanyl, it is unknown what proportion of deaths are due to unintentional exposure to fentanyl, particularly in people living with or at risk of HIV who have had relatively prevalent stimulant use alone. We propose a randomized controlled trial to test an innovative approach to opioid overdose prevention that repurposes a known injectable, long-acting opioid blocking medication (naltrexone) and when possible, couples it with injectable HIV prevention or treatment medication. Aiming to shield people living with or at risk of HIV who use stimulants from unintentional opioid exposure, this study seeks to combine overdose prevention with HIV care, addressing two critical health concerns in one integrated approach.