Project Summary The discovery of effective antibiotic treatment and chemoprevention for tuberculosis was among the most impactful scientific and public health advances in history. However, it is increasingly clear that providing the same doses to all individuals leads to highly variable drug concentrations, resulting in excess risk of toxicities and poor treatment outcomes. For isoniazid, the most widely used drug for tuberculosis treatment and preventive therapy, there is a high degree of interindividual variation in metabolism due to common polymorphisms in the NAT2 gene. Individuals who have two NAT2 copies with mutations conferring reduced activity (“slow acetylators”) are at increased risk of drug toxicities, while individuals without mutations reducing activity (“rapid acetylators”), are at increased risk of treatment failure, relapse, and acquired drug resistance. Major barriers to implementing pharmacogenomic-guided dosing to address these problems have been the lack of a diagnostic and lack of data on how to adjust isoniazid doses according to acetylator genotype. We recently developed a cartridge-based, rapid molecular diagnostic for the key NAT2 polymorphisms and an algorithm that accurately predicts acetylator genotype. We propose to: 1) validate this assay in a diverse population in Brazil using non-invasive samples, including fingerstick blood and oral swabs; and 2) perform a Phase I clinical trial to determine whether pharmacogenomic-guided dose modification among people receiving weekly isoniazid and rifapentine for preventive therapy can reduce variation in drug levels. Overall, this project will generate foundational data in the move towards personalizing tuberculosis treatment and preventive therapy to reduce adverse events and improve outcomes for this disease of global importance.

Project Narrative Common mutations in the human genome cause highly variable metabolism of isoniazid, the most widely used antibiotic for treatment of tuberculosis, leading to increased risk of toxicities or poor treatment outcomes. We have developed a novel, point-of-care test for these genetic mutations that can identify which individuals are likely to have too high or too low of isoniazid blood levels with standard dosing. We will validate this diagnostic test using fingerstick and oral swab samples, and we will perform a clinical study to determine whether modifying isoniazid doses according to genotype can reduce variation in drug levels.