title: 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.
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.
  
  
  CONCLUSIONS
  Our results clearly indicate a great potential of the NAT2 genotype-guided dosing stratification of isoniazid in chemotherapy for tuberculosis.
authors.affiliation: Clinical Pharmacology and Pharmacogenomics, School of Pharmacy, Hyogo University of Health Sciences, Kobe, Hyogo, Japan. azuma@huhs.ac.jp
authors.forename: Junichi
authors.initials: J
authors.lastname: Azuma
authors.forename: Masako
authors.initials: M
authors.lastname: Ohno
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kubota
authors.forename: Soichiro
authors.initials: S
authors.lastname: Yokota
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nagai
authors.forename: Kazunari
authors.initials: K
authors.lastname: Tsuyuguchi
authors.forename: Yasuhisa
authors.initials: Y
authors.lastname: Okuda
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Takashima
authors.forename: Sayaka
authors.initials: S
authors.lastname: Kamimura
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Fujio
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawase
mesh_terms: D000328:Adult; D000818:Animals; D000995:Antitubercular Agents / Q000009:adverse effects* / Q000627:therapeutic use; D001191:Arylamine N-Acetyltransferase / Q000235:genetics*; D044466:Asian People / Q000235:genetics; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000517:prevention & control*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D007538:Isoniazid / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D057285:Precision Medicine / Q000379:methods; D017211:Treatment Failure; D014376:Tuberculosis / Q000188:drug therapy* / Q000235:genetics*
chemical_list: D000995:Antitubercular Agents; D001191:Arylamine N-Acetyltransferase; C478900:NAT2 protein, human; D007538:Isoniazid