title: Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid.
abstract: OBJECTIVE
  Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.
  
  
  OBJECTIVE
  To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.
  
  
  METHODS
  A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.
  
  
  METHODS
  Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.
  
  
  METHODS
  We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.
  
  
  RESULTS
  Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion.
  
  
  CONCLUSIONS
  Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.
  
  
  BACKGROUND
  clinicaltrials.gov Identifier: NCT00023452.
authors.affiliation: Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia.
authors.forename: M Elsa
authors.initials: ME
authors.lastname: Villarino
authors.affiliation: Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia2CDC Foundation, Atlanta, Georgia.
authors.forename: Nigel A
authors.initials: NA
authors.lastname: Scott
authors.affiliation: Department of Medicine, University of North Texas Health Science Center at Ft Worth.
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Weis
authors.affiliation: Department of Medicine, Audie L. Murphy San Antonio Veterans Administration Medical Center, San Antonio, Texas.
authors.forename: Marc
authors.initials: M
authors.lastname: Weiner
authors.affiliation: Department of Medicine, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Marcus B
authors.initials: MB
authors.lastname: Conde
authors.affiliation: Department of Medicine, University of Southern California, Los Angeles.
authors.forename: Brenda
authors.initials: B
authors.lastname: Jones
authors.affiliation: Department of Pediatrics, State University of New York at Stony Brook.
authors.forename: Sharon
authors.initials: S
authors.lastname: Nachman
authors.affiliation: Department of Pediatrics, Pediatric Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Oliveira
authors.affiliation: Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia2CDC Foundation, Atlanta, Georgia.
authors.forename: Ruth N
authors.initials: RN
authors.lastname: Moro
authors.affiliation: Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia.
authors.forename: Nong
authors.initials: N
authors.lastname: Shang
authors.affiliation: Division of Tuberculosis Elimination, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia.
authors.forename: Stefan V
authors.initials: SV
authors.lastname: Goldberg
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Sterling
mesh_terms: D000293:Adolescent; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D055985:Latent Tuberculosis / Q000517:prevention & control*; D008297:Male; D012293:Rifampin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin; C018421:rifapentine