In 2020, 10 million people developed tuberculosis (TB) and 1.5 million people died from TB, marking the first time TB deaths rose in over a decade.1,2 Approximately one-fourth of the world's population has a latent TB infection (LTBI) with the potential for reactivation. These billions of people serve as an ever-present source of new TB cases, independent of ongoing transmission events 3. For people with LTBI, the greatest risk factor for developing TB is HIV co-infection. HIV-infection increases the risk of latent TB reactivation by 20-fold. Further, TB is the leading cause of death of HIV positive individuals. It is thus critical to develop LTBI treatments that are compatible with HIV treatments.4 Short-course, rifamycin-based, 3- or 4-month latent TB infection treatment regimens are preferentially recommended over 6- or 9-month isoniazid monotherapy.5 A single-drug LTBI therapy with a four-month rifampin or rifabutin regimen has been show efective when taken consistently.6- 8 While rifabutin has not been studied in a randomized trial for latent TB treatment, it has reduced potential for drug-drug interactions, which makes it more suitable for treatment of Mtb/HIV coinfections compared to other rifamycins.9-13 Non-adherence to drug regimens has grave consequences and can lead to loss of therapeutic effectiveness and the development of drug resistance.14,15 Long acting (LA) parenteral drug formulations that provide sustained drug release over weeks or months have the potential to reduce dosing frequency such that only one or a few injections of the drug formulation could be sufficient for LTBI treatment. This would dramatically increase treatment compliance and efficacy of treatment16-18. Recently, we developed long-acting formulation of the anti-TB drug rifabutin (RFB) based on In Situ Forming Implant (ISFI) technology (RFB-ISFI). RFB-ISFI is injectable, forms an implant after subcutaneous injection, provides sustained release of RFB for 16 weeks, and is highly effective in mouse models of TB prevention and treatment of acute TB infection (Kim et al 2022). Due to the biocompatible and biodegradable nature of the ISFI polymer, the implant does not need to be removed at the end of treatment. However, if adverse events such as toxicity, drug-drug interactions, or an allergic response occurs, the implant can be safely removed. Drug release properties of ISFI formulations can be manipulated by changes in composition of the liquid formulation and adjusted to meet the specific needs of a given treatment. The scientific premise of this proposal is that the highly effective RFB-ISFI formulation we developed can be used for treatment of LTBI. Our ultimate goal is to develop an injectable formulation, that can be administered once every two months bi-monthly or less frequently and be effective for LTBI treatment, including patients on antiretroviral therapy. To accomplish this goal, we have assembled an outstanding, multi- disciplinary team of investigato...