NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: a randomized controlled trial for pharmacogenetics-based therapy

Eur J Clin Pharmacol. 2013 May;69(5):1091-101. doi: 10.1007/s00228-012-1429-9. Epub 2012 Nov 14.

Abstract

Objective: This study is a pharmacogenetic clinical trial designed to clarify whether the N-acetyltransferase 2 gene (NAT2) genotype-guided dosing of isoniazid improves the tolerability and efficacy of the 6-month four-drug standard regimen for newly diagnosed pulmonary tuberculosis.

Methods: In a multicenter, parallel, randomized, and controlled trial with a PROBE design, patients were assigned to either conventional standard treatment (STD-treatment: approx. 5 mg/kg of isoniazid for all) or NAT2 genotype-guided treatment (PGx-treatment: approx. 7.5 mg/kg for patients homozygous for NAT2 4: rapid acetylators; 5 mg/kg, patients heterozygous for NAT2 4: intermediate acetylators; 2.5 mg/kg, patients without NAT2 4: slow acetylators). The primary outcome included incidences of 1) isoniazid-related liver injury (INH-DILI) during the first 8 weeks of therapy, and 2) early treatment failure as indicated by a persistent positive culture or no improvement in chest radiographs at the 8th week.

Results: One hundred and seventy-two Japanese patients (slow acetylators, 9.3 %; rapid acetylators, 53.5 %) were enrolled in this trial. In the intention-to-treat (ITT) analysis, INH-DILI occurred in 78 % of the slow acetylators in the STD-treatment, while none of the slow acetylators in the PGx-treatment experienced either INH-DILI or early treatment failure. Among the rapid acetylators, early treatment failure was observed with a significantly lower incidence rate in the PGx-treatment than in the STD-treatment (15.0 % vs. 38 %). Thus, the NAT2 genotype-guided regimen resulted in much lower incidences of unfavorable events, INH-DILI or early treatment failure, than the conventional standard regimen.

Conclusion: Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.

Trial registration: ClinicalTrials.gov NCT00298870.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Antitubercular Agents / adverse effects*
  • Antitubercular Agents / therapeutic use
  • Arylamine N-Acetyltransferase / genetics*
  • Asian Continental Ancestry Group / genetics
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Genetic Predisposition to Disease / genetics
  • Genotype
  • Humans
  • Isoniazid / adverse effects*
  • Isoniazid / therapeutic use
  • Male
  • Middle Aged
  • Precision Medicine / methods
  • Treatment Failure
  • Tuberculosis / drug therapy*
  • Tuberculosis / genetics*

Substances

  • Antitubercular Agents
  • Arylamine N-Acetyltransferase
  • NAT2 protein, human
  • Isoniazid

Associated data

  • ClinicalTrials.gov/NCT00298870