title: Currently Used Low-Dose Pyrazinamide Does Not Increase Liver-Injury in the First Two Months of Tuberculosis Treatment.
abstract: OBJECTIVE
  In the 1950s, a high-dose (40-70 mg/kg/day) of pyrazinamide (PZA), was reported to cause drug-induced liver injury (DILI) at an unacceptable frequency. It remains unclear whether adding PZA (Z) at the currently accepted low-dose (20-25 mg/kg/day) for two months to a regimen of isoniazid (H) + rifampicin (R) + ethambutol (E) actually increases the risk of DILI.
  
  
  METHODS
  Smear-positive tuberculosis patients were treated with daily HRE or HRZE regimen under direct observation. We used three independent models. Model 1 was analyzed with a multivariate Cox-analysis using a pre-matched cohort. Next, propensity score matching was conducted using the nearest neighbor method with caliper of 0.03. Models 2 and 3 were analyzed by univariate and multivariate Cox-analyses, respectively, with the matched cohort. DILI was assessed based on the guidelines of the American Thoracic Society.
  
  
  RESULTS
  We reviewed the records of 383 patents (male, n=260; female n=123; mean age, 64±20 years). Among these patients, 75 patients were treated with HRE and 308 were treated with HRZE. DILI occurred in the first two months in 24% (18/75) and 8% (24/308) of the HRE-treated and HRZE-treated cases, respectively. In all three of the models, DILI was less frequent in patients treated with the HRZE regimen: Model 1, HR of 0.30 (95% confidence interval (CI) 0.14-0.68, p=0.004); Model 2, HR of 0.37 (95%CI 0.14-0.96, p=0.041); and Model 3, HR of 0.34 (95%CI 0.12-0.94, p=0.038).
  
  
  CONCLUSIONS
  The addition of the currently accepted low dose (20-25 mg/kg/day) of PZA to the HRE regimen did not increase the incidence of DILI during the first two months of treatment.
authors.affiliation: Department of Pulmonology, Yokohama City University Graduate School of Medicine, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Horita
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyazawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Yoshiyama
authors.forename: Ryota
authors.initials: R
authors.lastname: Kojima
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Ishigatsubo
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kaneko
mesh_terms: D000368:Aged; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000175:diagnosis / Q000453:epidemiology / Q000209:etiology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017410:Practice Guidelines as Topic; D057216:Propensity Score; D011718:Pyrazinamide / Q000008:administration & dosage* / Q000009:adverse effects; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide