Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients

Abstract

Drug-induced liver injury (DILI) is a common adverse drug reaction in patients receiving antituberculosis (anti-TB) treatment. Among the anti-TB agents, isoniazid (INH) is the primary drug that causes hepatotoxicity in TB patients with DILI. Previous reports in several populations have consistently demonstrated an association between polymorphisms in the N-acetyltransferase 2 (NAT2) gene, which is responsible for INH hepatic metabolism, and a risk of DILI in TB patients. In this study, the genetic and baseline clinical data from 366 Japanese patients with TB (73 patients with DILI and 293 without DILI) were used to develop a system to predict DILI risk due to anti-TB agents. The distribution of the NAT2 acetylator status among the TB patients with DILI was 31 (42.5%), 29 (39.7%), and 13 (17.8%) for rapid, intermediate, and slow acetylators, respectively. A significant association was observed between NAT2 slow acetylators and DILI risk (odds ratio 4.32, 95% confidence interval 1.93-9.66, P value=5.56×10-4). A logistic regression model based on age and NAT2 genotype revealed that the area under the curve for the receiver-operating characteristic curve was 0.717. The findings demonstrated that slow NAT2 acetylator status is a significant predictor of the risk of DILI by anti-TB agents, and a personalized anti-TB treatment approach may aid in making treatment decisions and reducing the incidence of DILI.