One-year mortality of tuberculosis patients on isoniazid-based treatment and its association with rapid acetylator NAT2 genotypes

BACKGROUND: NAT2 polymorphisms affect isoniazid metabolism, but their effect on mortality among individuals with tuberculosis (TB) remains unclear. METHODS: This study used data from two TB cohorts (2005-2011, 2014-2020) and death certificate records in Thailand. Newly diagnosed Thai individuals treated with isoniazid-containing regimens were included. NAT2 genotypes-rapid, intermediate, and slow acetylator (RA, IA, SA)-were classified via haplotype inference. The primary outcome was 1-year all-cause mortality, while secondary outcomes included TB-related mortality, TB+respiratory disease-related mortality recorded in the vital registration system, and death as a TB treatment outcome. Adjusted hazard ratios (aHRs) relative to the IA type were estimated using stratified Cox proportional hazards models. Subgroup analyses targeted individuals with isoniazid-resistant TB and HIV infection. RESULTS: A total of 1,065 individuals (766 males; mean age=51 years) were analyzed. Individuals with RA had a 1.70-fold greater all-cause mortality risk (95 % CI: 1.03-2.80) than IA. The aHRs for RA were 1.14 (0.43-3.03) for TB-related mortality, 1.59 (0.80-3.18) for TB+respiratory disease-related mortality, and 1.26 (0.67-2.37) for TB treatment outcome death. Among individuals with isoniazid-resistant TB, those with RA had a 4.68-fold (1.14-19.12) greater aHR for all-cause mortality. CONCLUSION: The RA type is associated with increased 1-year all-cause mortality.