ABSTRACT In this competing renewal, we propose to continue a 30-year cohort of people who inject drugs (PWID). Since 1988, the AIDS Linked to the IntraVenous Experience (ALIVE) study has followed >5200 PWID in a community-based cohort in Baltimore, MD, providing critical insight into the natural and treated course of HIV among urban predominantly minority, disadvantaged PWID. Our team has been highly productive (107 publications in past cycle) and will continue cutting-edge investigations into high HIV/AIDS priority research questions, while serving as a foundation for an array of HIV-related epidemiological and pathogenesis studies. The opioid crisis across the US continues and has not abated in Baltimore. Baltimore has one of the highest US overdose rates and is experiencing demographic and behavioral transitions in the population most affected by opioid use -- from one that is primarily male, older and minority -- to one that affects more women, younger and white individuals. At the same time, there has also been a shift in the expression of HIV infection among PWID. Much of the population of PWID that the ALIVE study has traditionally followed is aging into the decade of life where HIV and its treatment are complicated by the onset of other chronic age-associated health conditions; in 2016, 40% of our cohort had >2 non-communicable diseases (NCD). At the same time <50% of our HIV-positive participants currently have suppressed HIV viral load highlighting a need for a more holistic approach to HIV care one that more broadly incorporates NCDs. Our proposed continuation will address the spectrum of the intersecting HIV and opioid epidemics with an eye towards understanding the impact of opioid use and HIV across the PWID life course. Our Specific Aims are: 1) To monitor temporal trends in the opioid epidemic comparing HIV infected and uninfected PWID across the lifespan, including characterization of shifting drug profiles and context over time and their impact on the incidence of fatal and non-fatal overdose, HIV and HCV infection and mortality. 2) To evaluate the dynamic associations between HIV care continuum outcomes and prevalence and control of NCDs (e.g., diabetes, hypertension, hyperlipidemia, chronic obstructive pulmonary disease [COPD]) and their joint impact on morbidity, mortality and quality of life; and 3) To continue to provide a platform for independently-funded investigations of HIV and drug use. To achieve these aims, we will 1) continue follow-up of HIV positive and negative PWID (~1500); 2) open recruitment once; and 3) evolve our data collection methods to include novel field-based, mHealth and drug testing assessments. The ALIVE cohort is unique in that it comprises a community-based PWID population of both genders with significant representation of African-Americans who are both in and out of medical care; these populations have been underrepresented in HIV and drug use research. Given the scientific rigor of the proposed methods, existing infrastructure, experienced investigators and multiple NIH-funded ancillary studies, we anticipate continued success and substantial scientific impact in the future. !