Project Summary/Abstract The goal of this project is to increase an understanding of substance use, how it impacts HIV care, and how to address it in a critical population, female sex workers (FSW) aged 18 years and older, in South Africa (SA), using data and infrastructure from an ongoing adaptive intervention, the Siyaphambili trial. Mathematical models suggest that nearly half of the 200,000 annual HIV infections among adults in SA are acquired by FSW, their clients, or partners of their clients and thus treating these unmet needs could result in better health outcomes for women and the population as a whole. Specific Aim 1: Characterize substance use among the FSW living with HIV who participated in the Siyaphambili trial, with a focus on identifying temporal patterns of polysubstance use, using Latent Transition Analysis (LTA), their associated determinants (e.g., violence, stigma, economic vulnerability), and if they modify the effectiveness of the sequentially adaptive strategy to improve HIV care outcomes. Specific Aim 2: Conduct mixed methods formative research on how to deliver substance use treatment for FSW in the context of HIV care through semi-structured interviews with 200 FSW engaged in the Siyaphambili study or in the TB HIV Care (THC) treatment and prevention sex worker program who report any illicit drug use, to ascertain experiences with substances, treatment (e.g. types, relapse), willingness for treatment, and preferences for treatment using a discrete choice experiment. This data will be supplemented by in-depth interviews with 10 implementation partners (e.g., nurses, clinic management) recruited through our partnership with THC. Specific Aim 3: Organize an Implementation Development Workgroup to initiate crosstalk with domestic and international collaborators on substance in FSW to refine emergent implementation strategies for evaluation across contexts. This R21 will allow an additional focus on substance use in the Siyaphambili trial, including bringing on the additional content and methodological expertise needed to achieve the proposed aims. We will also collect primary data to inform the development and implementation of interventions that address substance use among FSW in the context of HIV care, as well as conduct activities that strengthen international collaborations working toward this end. The proposed R21 is aligned with multiple NIH OAR priorities, including reducing HIV incidence (through optimized treatment), has a high likelihood of success by leveraging an existing cohort, and will directly inform an R01 study on the implementation of substance use treatment and HIV care among this key population.