PROJECT SUMMARY HIV prevention requires improvements in effectiveness, reduction of side-effects, and removing barriers to adherence for antiretroviral pre-exposure prophylaxis (PrEP). Evaluation of these improvements through randomized trials remains difficult due to sample size requirements, strict eligibility criteria, and assessments limited to active comparators. Addressing these challenges has made novel analytical approaches increasingly necessary. The proposed research will use cutting-edge quantitative methods to evaluate new PrEP combinations by combining diverse sources of information. Data from the HIV Prevention Trials Network 083 and iPrEx (Preexposure Prophylaxis Initiative) trials will be used to compare long-acting injectable cabotegravir PrEP to placebo among men who have sex with men and transgender women. Results will provide a reliable estimate of the efficacy of long-acting injectable cabotegravir in lieu of direct randomized comparisons, which are not forthcoming. Next, data from the VOICE (Vaginal and Oral Interventions to Control the Epidemic) trial will be integrated with subject- matter expert knowledge through statistical and mechanistic modeling to evaluate the expected efficacy of tenofovir alafenamide and emtricitabine daily oral PrEP among cisgender women. Results from this second analysis can aid in the planning of randomized trials of tenofovir alafenamide in cisgender women (e.g., assess whether a planned trial would likely fail to demonstrate efficacy under previously observed adherence patterns). Finally, flexible analytic tools to apply the quantitative methods used in the proposed research will be developed and made freely available through open-source software. Provision of these tools will decrease barriers to future applications. Scientific results from this proposal will accelerate and strengthen how we can learn from randomized trials and make strides in the prevention of HIV. The candidate will benefit from strong mentorship and additional training in HIV epidemiology, mechanistic modeling, semiparametric theory, and guided development as an independent scientist. Through additional quantitative methods training, the candidate will be uniquely prepared to jointly use statistical and mechanistic modeling to bring field-specific strengths to address deficiencies that neither field can easily address on its own. Completion of the training and research aims of this mentored developmental award will situate the candidate at the forefront of HIV epidemiology and methodological research and prepare the candidate to become to an independent researcher.