Tuberculosis (TB) is the leading cause of death among persons living with HIV (PLWH); TB disease rates for PLWH engaging in heavy alcohol use are 2-3 times those of alcohol abstainers and TB treatment outcomes are poorer. TB preventive therapy (TPT) reduces the risk of progression from latent TB infection (LTBI) to TB disease, and is being scaled up for PLWH in many high HIV/TB incidence settings. However, TPT does not prevent new or repeat TB infection after TPT has ended, therefore PLWH who engage in heavy alcohol use may be at increased risk for acquiring new TB infection even after receiving TPT. There has been little research examining the impact of alcohol use on acquiring new TB infection separately from progressing to active TB disease; this limits our ability to understand the role of alcohol use on the separate phases of TB to optimize intervention strategies most appropriate for each. We propose to examine the risk of acquiring TB infection and of incident active TB disease among PLWH with heavy alcohol use after receipt of TPT in PLWH in Uganda, a high HIV/TB country. Our goal is to inform interventions to reduce the risk for acquiring new TB infection in this group, including behavioral interventions to reduce alcohol use, and TPT strategies, such as repeat short-course TPT to prevent active TB disease. First, we propose to examine the acquisition of new TB infection by level of alcohol use among a cohort of PLWH with prior negative tuberculin skin test (TST) results, in a sample of PLWH enriched for heavy alcohol use (Aim 1). We will adjust for key confounders such as cigarette smoking, second-hand smoke, socio-economic status, household crowding, gender, age, nadir CD4+ T cell count, and prior TPT receipt. We will also examine the mediators of alcohol use on risk of TB infection, such as lack of HIV viral suppression, bar attendance, and low body mass index, to determine if existing alcohol interventions should incorporate these as additional targets. To accomplish this aim, we will leverage a large cohort of PLWH including 50% engaging in high-risk drinking, that we previously tested for LTBI from 2017 to 2020 who were TST negative. We will re-enroll 500 persons and conduct repeat TST and active TB screening yearly, over 4 years, to determine the rate of acquiring new TB infection. We will also determine whether PLWH who engage in heavy alcohol use and have LTBI are at increased risk of progressing to active TB disease, despite receipt of TPT, compared to persons engaging in lower risk or no alcohol use (Aim 2). For Aim 2, we will leverage our prior cohort of 990 PLWH with LTBI who received TPT, with over 5000 person- years of follow-up and well-characterized alcohol use and TPT electronic adherence measurement. Both aims will leverage cohorts uniquely suited for these analyses and use objective alcohol biomarkers. These studies will provide unprecedented prospective evidence needed to effectively target alcohol reduction interventions and inform TPT strategies—such as repeated short courses of TPT—to prevent new TB infection and reduce the risk of progression to TB disease for a high-risk group of PLWH: those engaging in heavy alcohol use.