NAT2 polymorphisms and Antituberculosis-Induced Hepatotoxicity in Thai People Living with HIV: Insights from a Pharmacogenetic–Pharmacokinetic Cohort Study

Background The N-Acetyltransferase (NAT2) slow acetylator phenotype has been associated with a higher risk of isoniazid (INH)-induced hepatotoxicity. We investigated the association between NAT2 genotypes with inferred acetylator status, hepatotoxicity and INH pharmacokinetics in Thai people living with HIV (PLWH) receiving INH-based Tuberculosis (TB) preventive or treatment regimens. Methods In this prospective cohort study of Thai PLWH initiating INH-based regimens; NAT2 genotyping classified participants as slow (SA), intermediate (IA), or rapid acetylators (RA). Hepatotoxicity was defined as transaminase elevations more than 2.5 times the upper limit of normal (ULN). Multivariable logistic regression identified genotypes and factors associated with hepatotoxicity. A pharmacokinetic (PK) substudy assessed INH exposure across phenotypes. Results Of 894 participants, 32.4% were SA, 41.2% IA, and 26.4% RA. Hepatotoxicity occurred in 10.9% overall and was highest in SA (15.2%). SA had increased hepatotoxicity risk vs RA (adjusted odds ratio [aOR] 2.43; 95%CI: 1.32–4.48). Genotypes NAT2*6A/*6A (aOR 1.84) and NAT2*7B/*7B (aOR 4.46) were associated with increased risk; NAT2*4/*4 was protective (aOR 0.33). Other independent risk factors included high baseline alanine aminotransferase (ALT), HCV co-infection, 2HRZE/4HR regimen (vs. 1HP), and efavirenz-based antiviral therapy (vs. dolutegravir). In the PK substudy (n=93), INH exposure assessed by the area under the concentration time curve from 0-24 hours, was significantly increased by approximately 2-fold in SA, regardless of anti-TB regimen. Conclusions NAT2 SA phenotype, particularly *6A/*6A and *7B/*7B genotypes, is associated with an increased risk of antituberculosis-induced hepatotoxicity and higher INH exposure in Thai PLWH. Incorporating NAT2-guided dosing may enhance safety of INH-containing regimens in PLWH.