PROJECT SUMMARY/ ABSTRACT Youth with HIV and adherence struggles stand to benefit from long-acting antiretrovirals (LAARV), soon to be available in the U.S., more than other groups. Youth living with HIV between 13 and 29 years of age are less engaged in all steps of the HIV care cascade, resulting in exaggerated HIV-related disparities in health and an low rates of overall viral suppression in this group. Stigma, mental health issues, deficits in cognition and executive functioning, and obstacles within multiple categories of social determinants of health can hamper youths’ ability to sustain antiretroviral adherence and reap the benefits of this technology for themselves, their families, and their social networks and communities. The primary goal of this project, nested within the funded trial International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) 2022, is to develop an independent scholarly research program addressing the optimization of the use of LAARV in youth, with the ultimate goal of designing practical interventions to maximize their benefit. This four-year training and research program will consist of: 1) employing novel methods to understand the role of biopsychosocial and cognitive factors in the success of LAARV and potentially establish predictors of the efficacy of LAARV based on various pre-use characteristics in youth; 2) developing and piloting novel bioassays to enable in-the-field collections of Dried Blood Spot (DBS) or Dried Plasma Extractor (DPE) LAARV measurements for use in clinical trials or as therapeutic drug monitoring among YLHIV receiving LAARV; and 3) Learning and leveraging population PK modelling approaches to understand the sources of PK variability in YHIV on LAARV. The training will include formal coursework, direct mentoring, and guided practice-based experience with new methodologies in biostatistics, cognitive neuroscience, quantitative pharmacology and assay development, and advanced population pharmacokinetics. By gaining training from her mentors and collaborators in all these methods, Dr. Weld will establish herself as a clinician-researcher in long-acting infectious disease therapeutics equipped to assess new delivery strategies and technologies as they emerge, and capable of transforming her field. Results of the investigations conducted during the award period will establish a foundation for the subsequent design of interventional studies to improve HIV-related outcomes in youth with less-frequent dosing strategies, and submission of further funding proposals to support this line of inquiry.