7. PROJECT SUMMARY/ABSTRACT Achieving sustained viral suppression is the pinnacle of HIV management conferring individual-level benefits by improving survival and societal benefits through secondary prevention. While there has been dramatic progress to improve viral suppression among people living with HIV, this progress has been uneven. Globally, 15.2% of the 14.8 million people who inject drugs (PWID) are living with HIV and drug use accounts for 20% of infections outside of Sub-Saharan Africa. PWID lag behind other populations with viral suppression <20% in some settings resulting in high AIDS-related mortality and HIV incidence. Long-acting antiretroviral therapy (LA ART) represents a new way to deliver ART that can improve viral suppression in a population where sociostructural issues such as homelessness and unemployment in addition to substance use complicate adherence to oral ART. Yet, to date, there has been no serious scholarship evaluating the role of LA ART in virologically unsuppressed persons (including PWID) particularly in low- and middle-income countries. Accordingly, our overarching objective is to evaluate the efficacy, safety, acceptability, and cost-effectiveness of LA ART on viral suppression among virally unsuppressed PWID in New Delhi, India. We will utilize a mix of ethnography, a randomized clinical trial and modeling to achieve these objectives. We will first conduct ethnographic work to inform clinical trial design. Ethnography will be conducted among PWID living with HIV, outreach workers and health care personnel. Key topics to be explored during this phase will be attributes of LA-ART including duration of effect (one week vs. six months), mode (oral vs. intramuscular vs. subcutaneous) and site of administration (facility vs. field-based). We anticipate conducting a three arm open-label randomized clinical trial where treatment naïve and treatment experienced unsuppressed PWID will be randomly assigned at an allocation ratio of 1:1:1 across three study arms – Arm 1: TLD (Tenofovir DF [300mg] + Lamivudine [300mg] + Dolutegravir [50mg]); Arm 2: CAB/RPV (Cabotegravir [900mg in 3ml] + Rilpivirine [600mg in 3ml]); two intramuscular injections at Months 0, 1 and every 2 months thereafter); and Arm 3 – CAB/RPV/LEN (Cabotegravir [900mg in 3ml] + Rilpivirine [600mg in 3ml] + Lenacapvir [927mg in 2 x 1.5ml vials]). All participants will be followed for 24 months. The primary short-term and long-term endpoints of this trial will be viral suppression (HIV RNA<50 copies/ml) at Months 6 and 24, respectively. We will then model the impact of Treatment as Prevention on HIV transmission in PWID for each study arm by simulating HIV transmission through injecting and sexual networks based on survey responses incorporating exposure to other interventions (e.g., syringe service programs) and accounting for the cyclical patterns drug use. We will extend transmission models to assess cost savings and cost-effectiveness of each of the inte...