ABSTRACT OF PROPOSED RESEARCH Antiretroviral agents (ARV) have proven successful in preventing new HIV transmission and improving survival and quality of life in people living with HIV (PLWH). However, there is still no cure, and issues of poor medication and medical care adherence and limited access to medication are proving challenging and warrant long-term release formulations. Currently, ARVs available or in development are either long-acting or self-administered, but not both. Islatravir (EFdA) is a highly potent, sub-nanomolar HIV-1 nucleoside reverse transcriptase translocation inhibitor that is in Phase 3 development by Merck for the prevention and treatment of HIV-1. A low dose has recently proven to be safe and effective in PLWH. The high potency of EFdA and the long intracellular half-life of its active metabolite EFdA 5'-triphosphate (EFdA-TP) make it a strong contender for long-acting regimens. The overall goal of this study is to develop biodegradable microneedle patches (MNPs) that encapsulate ARV (such as EFdA) for long-acting release using a self-administered patch. This sustained drug release can minimize the dosing interval from daily to monthly or longer, which will provide substantial benefits to PLWH, will address issues of adherence in therapy and prophylaxis, and serve as a good drug administration route for pediatric patients and persons experiencing homelessness, and be particularly beneficial in certain parts of the world such as sub-Saharan Africa. The specific aims are: 1) To formulate self-administrable microneedle patches for EFdA delivery and optimize their extended release in vitro for at least one month; 2) To determine the in vivo pharmacokinetics of EFdA and its intracellular active metabolites after delivery by a drug-loaded microneedle patch. Towards these goals, we will investigate biodegradable polymers and casting solvents for the microneedle, and water-soluble materials for the patch backing, to formulate, fabricate, and characterize EFdA-loaded MNPs. We will test the release of EFdA from MNPs in vitro and select one or two MNP designs that release EFdA for at least one month to determine the in vivo pharmacokinetic profile first in rats and then in larger animal such as rabbits. We will compare EFdA release from MNPs to delivery by subcutaneous injection and oral administration. We anticipate that at least one MNP design that releases EFdA for at least one month will have a pharmacokinetic profile where the concentration of EFdA in plasma and of active metabolite EFdA-TP in lymphocytes will be maintained above the target level for at least one month. We believe PLWH or persons at risk for HIV (including pediatric persons) will greatly benefit from the potential long-term outcomes of these novel therapeutic and prophylactic patches designed to increase medication adherence and access.