Pharmacogenetics of tuberculosis treatment toxicity and effectiveness in a large Brazilian cohort

Abstract

AbstractBackgroundGenetic polymorphisms have been associated with risk of anti-tuberculosis treatment toxicity. We characterized associations with adverse events and treatment failure/recurrence among adults treated for tuberculosis in Brazil.MethodsParticipants were followed in Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil. We included persons with culture-confirmed drug-susceptible pulmonary tuberculosis who started treatment between 2015-2019, and who were evaluable for pharmacogenetics. Treatment included 2 months of isoniazid, rifampin or rifabutin, pyrazinamide, and ethambutol, then 4 months of isoniazid and rifampin or rifabutin, with 24 month follow-up. Analyses included 43 polymorphisms in 20 genes related to anti-tuberculosis drug hepatotoxicity or pharmacokinetics. Whole exome sequencing was done in a case-control toxicity subset.ResultsAmong 903 participants in multivariable genetic association analyses,NAT2slow acetylator status was associated with increased risk of treatment-related grade 2 or greater adverse events, including hepatotoxicity. Treatment failure/recurrence was more likely amongNAT2rapid acetylators, but not statistically significant at the 5% level. AGSTM1polymorphism (rs412543) was associated with increased risk of treatment-related adverse events, including hepatotoxicity.SLCO1B1polymorphisms were associated with increased risk of treatment- related hepatoxicity and treatment failure/recurrence. Polymorphisms inNR1/2were associated with decreased risk of adverse events and increased risk of failure/recurrence. In whole exome sequencing, hepatotoxicity was associated with a polymorphism inVTI1A, and the genesMETTL17andPRSS57, but none achieved genome-wide significance.ConclusionsIn a clinical cohort representing three regions of Brazil,NAT2acetylator status was associated with risk for treatment-related adverse events. Additional significant polymorphisms merit investigation in larger study populations.