Safety and Side Effects of Rifampin versus Isoniazid in Children

N Engl J Med. 2018 Aug 2;379(5):454-463. doi: 10.1056/NEJMoa1714284.


Background: The treatment of latent infection with Mycobacterium tuberculosis is important in children because of their vulnerability to life-threatening forms of tuberculosis disease. The current standard treatment - 9 months of isoniazid - has been associated with poor adherence and toxic effects, which have hampered the effectiveness of the drug. In adults, treatment with 4 months of rifampin has been shown to be safer and to have higher completion rates than 9 months of isoniazid.

Methods: In this multicenter, open-label trial, we randomly assigned 844 children (<18 years of age) with latent M. tuberculosis infection to receive either 4 months of rifampin or 9 months of isoniazid. The primary outcome was adverse events of grade 1 to 5 that resulted in the permanent discontinuation of a trial drug. Secondary outcomes were treatment adherence, side-effect profile, and efficacy. Independent review panels whose members were unaware of trial-group assignments adjudicated all adverse events and progression to active tuberculosis.

Results: Of the children who underwent randomization, 829 were eligible for inclusion in the modified intention-to-treat analysis. A total of 360 of 422 children (85.3%) in the rifampin group completed per-protocol therapy, as compared with 311 of 407 (76.4%) in the isoniazid group (adjusted difference in the rates of treatment completion, 13.4 percentage points; 95% confidence interval [CI], 7.5 to 19.3). There were no significant between-group differences in the rates of adverse events, with fewer than 5% of the children in the combined groups with grade 1 or 2 adverse events that were deemed to be possibly related to a trial drug. Active tuberculosis, including 1 case with resistance to isoniazid, was diagnosed in 2 children in the isoniazid group during 542 person-years of follow-up, as compared with no cases in the rifampin group during 562 person-years (rate difference, -0.37 cases per 100 person-years; 95% CI, -0.88 to 0.14).

Conclusions: Among children under the age of 18 years, treatment with 4 months of rifampin had similar rates of safety and efficacy but a better rate of adherence than 9 months of treatment with isoniazid. (Funded by the Canadian Institutes of Health Research and Conselho Nacional de Pesquisa; number, NCT00170209 .).

Publication types

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

MeSH terms

  • Adolescent
  • Antibiotics, Antitubercular / administration & dosage*
  • Antibiotics, Antitubercular / adverse effects*
  • Child
  • Child, Preschool
  • Drug Administration Schedule
  • Female
  • Follow-Up Studies
  • Humans
  • Infant
  • Intention to Treat Analysis
  • Isoniazid / administration & dosage*
  • Isoniazid / adverse effects*
  • Latent Tuberculosis / drug therapy*
  • Male
  • Medication Adherence
  • Patient Safety
  • Rifampin / administration & dosage*
  • Rifampin / adverse effects*
  • Treatment Outcome


  • Antibiotics, Antitubercular
  • Isoniazid
  • Rifampin

Associated data