PROJECT SUMMARY Tuberculosis (TB) is the leading cause of death among people with HIV (PWHIV), and the risk of morbidity and mortality is also high among young children and pregnant women. TB preventive therapy (TPT) to treat TB infection (TBI) is especially important in these priority populations, but it must be safe and well-tolerated given that TPT is largely provided to asymptomatic, healthy individuals. The Tuberculosis Trials Consortium (TBTC) of the Centers for Disease Control and Prevention (CDC) is conducting ASTERoiD, a Phase 3 trial of rifamycin- based TPT comparing six weeks of daily rifapentine (6wP) with local rifamycin-based standard of care (once- weekly isoniazid and rifapentine for twelve weeks, 3HP; four months of daily rifampin (4R), or 3 months of daily isoniazid and rifampin (3HR)). There are currently no pharmacokinetic (PK) assessments in ASTERoiD, and optimal dosing of dolutegravir in PWHIV and rifapentine in priority populations in the context of 6wP has not been firmly established. For this reason, PWHIV taking dolutegravir, children < 12 years, and pregnant women are currently excluded from ASTERoiD We propose to enroll PWHIV taking DTG, children, and pregnant people into a 6wP semi-intensive PK sub-cohort to confirm that model-informed doses of TB and HIV drugs achieve target exposures in these participants (Aim 1). We will employ sparse PK sampling and use population PK modeling to characterize exposure to rifapentine, explore sources of PK variability, and confirm that translational modeling-informed dosing achieves clinical exposure targets in the majority of participants taking 6wP for TPT (Aim 2). We will evaluate TB drug exposures and pharmacogenetics as explanatory factors for drug discontinuation due to adverse drug reactions, as well as other safety and tolerability outcomes, in both the experimental and control arms in ASTERoiD (Aim 3). Finally, nesting clinical pharmacology into ASTERoiD will provide us with the opportunity to understand whether or not key outcomes are related to drug exposures and, importantly, will allow us to include key populations with the highest risk of TB disease and TB-related morbidity and mortality into this Phase 3 trial of 6wP, an ultra-short, single-agent TPT that, if successful, could transform TB prevention.