In the United States, transgender women (TW) are disproportionately impacted by HIV and are prioritized in the US national strategy to end the epidemic. Multiple individual, interpersonal, and structural vulnerabilities fuel the HIV epidemic among TW, as well as fuel syndemic conditions (co-occurring and reinforcing diseases or other health conditions, such as HIV, substance use, and mental health disorder, that are often a consequence of social inequity). National cohorts are critical to monitoring epidemic trends and how major events (e.g., epidemics, policy change, new biomedical interventions) impact HIV and other health conditions; this is particularly important for TW who are often excluded from national surveillance efforts. The objective of this proposal is to use a novel, hybrid “community hub”-supported digital cohort (“hub-supported digital cohort”) model to evaluate HIV incidence, risk factors, and syndemic conditions among TW in the US (N=3,000). In this model, on-the-ground community “hubs” will support enrollment and retention of a racially/ethnically and culturally diverse, nationwide digital cohort. We will refine optimal digital cohort methods while examining the impact of structural and psychosocial syndemic experiences on HIV incidence and parameterizing mathematical models to identify targets for future multi-level combination HIV prevention interventions. The specific aims are: 1) Determine the efficiency and acceptability of using a novel, hub-supported digital cohort model to enroll and retain a sample of racially/ethnically diverse TW for HIV research. 2) Estimate the prevalence and characterize patterns of syndemic experiences among TW. 3) Estimate HIV incidence in TW, followed every 6 months for at least 24 months to identify tailored approaches for combination, multi-disciplinary HIV prevention interventions. 3.1) Examine the effect of syndemic experiences and contextual structural factors on HIV incidence among TW in the US. 3.2) Characterize the PrEP continuum among TW and associations with HIV incidence over time, including uptake of newly emerging formulations, longitudinal patterns of HIV risk and adherence, and the role of syndemic classes and contextual factors in the PrEP continuum PrEP uptake, adherence, and retention. 4.) Develop dynamic models of multi-level combination HIV prevention interventions and scale-up among TW to simulate the impact of evaluated interventions on HIV incidence through 2030, corresponding to the National HIV strategy. There is a need to refine and evaluate hybrid digital cohort models with attention to mitigating selection bias and attrition of vulnerable populations – an area of research particularly important for an epidemic underscored by social and health disparities. Our explicit efforts to develop a hybrid cohort model center on equity to support research participation across diverse populations and provide representative and generalizable data. Study findings will provide crit...