Abstract In the US most (~70%) annual newly diagnosed HIV infections are among substance-using sexual minority cisgender men (MSM) and gender minority transgender women (TW).1 TW/MSM are more likely to report or be diagnosed with a substance use disorder (SUD) than their cisgender or heterosexual counterparts2-5 and the presence of a SUD substantially increases risk of HIV infection in both groups.6-16Although PrEP is highly effective, initiation, adherence, and persistence are exclusively behavioral outcomes, and the biomedical benefits of PrEP are abrogated by substance use. SUD is also associated with reduced quality-of-life, and increased overdose deaths, utilization of high-cost healthcare services, engagement in a street economy, and cycles of incarceration.17-26 This application builds upon the highly promising findings from our open-label Phase I A.S.K.- PrEP (Assistance Services Knowledge-PrEP) pilot, which utilized PrEP navigation with text message (SMS) support to increase PrEP initiation among TW/MSM. The Phase II study will implement a RCT with a Stepped Care design of ASK-PREP vs. standard of care (SOC) to determine optimal intervention response among TW/MSM with a SUD (N=285; n=95 TW; n=190 MSM) for advancement along the PrEP Care Continuum. Participants will be randomized (3:1) to Stepped Care (n=214) or SOC (n=71). Participants in the Stepped Care arm will receive the same ASK-PrEP intervention that was delivered in the pilot study and will be assessed at 3- months for intervention response; responders will be maintained in ASK-PrEP, while non-responders will receive added attention to their SUD via contingency management (CM). Non-responders will be re-randomized (1:1) to either a) receive ASK-PrEP + CM, or b) shift the primary focus to their SUD (CM alone). The ASK-PrEP navigation intervention is based on mechanisms of the Reasoned Action Approach, SMS support is based in Social Support Theory, and CM is based on behavioral economics. The specific aims are to: 1) Evaluate a Stepped Care approach promoting advancement along the PrEP Care Continuum (initiation, adherence, persistence), and reductions in substance use among TW/MSM with a SUD; 2) Estimate the cost of implementing and sustaining each intervention and conduct a cost-effectiveness analysis to determine the value of each intervention relative to SOC, and to each other, from the healthcare-sector, state-policymaker, and societal perspectives; Secondary Aim 1) Determine the individual effects of specific substances, routes of administration, severity of SUD, social and structural determinants of health, and differing individual-level characteristics as moderators of outcomes; and Exploratory Aim) Evaluate intervention engagement and response by chosen PrEP modality (oral daily or long-acting injectable). The “intent-to-treat” RCT uses repeated assessments at baseline and at 3-, 6-, 9-, and 12-months post enrollment. The study will be conducted in Los Angeles County, an EHE priority County.27, 28 This study could have significant public health impact by identifying scalable and effective PrEP interventions that match intensity and participant needs to maximize efficacy while minimizing costs.

Project Narrative Sexual (i.e., MSM) and gender (i.e., trans women) minority populations with a substance use disorder (SUD) have the two highest HIV prevalence rates in the US, which constitutes a call for action to determine scalable behavioral interventions to promote PrEP initiation, adherence and persistence. This study will implement a RCT with a Stepped Care design to determine the optimal (considering effectiveness and cost-effectiveness) intervention for advancement along the PrEP Care Continuum. The public health significance of this study is very high as the application of PrEP among SGM populations with a SUD would generate significant and lasting reductions in HIV incidence.