Project Summary/Abstract The goal of this study is to elicit preference-driven strategies to tailor contextually appropriate antiretroviral therapy (ART) packages, including long-acting injectables (LAI), for youth living with HIV (YLWH) in South Africa. Adolescents and young adults comprise 42% of all new infections in southern and eastern Africa, and among this population in South Africa, estimated ranges of viral suppression are from 10-50%. LAIs offer a potential solution for ART adherence and retention challenges faced by YLWH but may not work for all youth. We hypothesize that if guided by preferences and paired with appropriate implementation strategies, LAI can improve treatment outcomes among YLWH. Specific Aim 1: Guided by the Consolidated Framework for Implementation Research (CFIR), we will conduct 32 interviews with YLWH aged 12-29 years, parents, and pediatric and adult HIV providers (counselors, nurses, doctors) to identify context-informed bottlenecks to future implementation and opportunities for LAI delivery. Specific Aim 2: Evaluate acceptability, appropriateness and revealed preferences for LAI among YLWH 18-29 years in a partial patient preference trial pilot. YLWH will choose between treatment packages that include 8-weekly (2-monthly) LAI vs 2-monthly standard oral ART pills; those with no preference will be randomized (1:1) to receive LAI vs. pills. Active follow- up will continue for 6-months; in each arm, YLWH will be allowed to cross-over arms with clinical supervision between 8-16 weeks. The primary endpoints will be revealed ART preference (pills vs. LAI vs. no preference) at 0-months; and pill vs. LAI at 6-mos. Secondary clinical endpoints will include viral suppression (<50 copies per ml) and retention on ART; other secondary endpoints will include assessments of acceptability, feasibility and appropriateness of LAIs and adjacent strategies to retain YLWH in care. Specific Aim 3: Use preference and clinical outcomes data from Aim 2 along with other clinical trial and emerging observational data to model outcomes scenarios amongst YLWH. These aims will inform a fully powered R01 implementation trial, comparing viral load-informed, tailored LAI delivery and support strategies for YLWH using a sequential multiple assignment randomized trial (SMART) design.