Dick Menzies, MD, MSc; Richard Long, MD; Anete Trajman, MD, PhD; Marie-Jose´e Dion, MSc; Jae Yang, MD; Hamdan Al Jahdali, MD; Ziad Memish, MD; Kamran Khan, MD, MPH; Michael Gardam, MD; Vernon Hoeppner, MD; Andrea Benedetti, PhD; and Kevin Schwartzman, MD, MPH
Background: Treatment of latent tuberculosis infection with isoniazid for 9 months is complicated by poor patient adherence and the need for close follow-up of side effects, especially hepatotoxicity. Shorter and safer regimens are needed.
Objective: To compare the frequency of adverse events and treatment completion in 2 treatment regimens for latent tuberculosis infection.
Design: Multicenter, randomized, open-label trial.
Setting: Tuberculosis clinics located in university hospitals in Canada, Brazil, and Saudi Arabia.
Patients: 847 patients without a contraindication for rifampin and requiring treatment for latent tuberculosis infection.
Intervention: Four months of daily rifampin therapy or 9 months of daily isoniazid therapy.
Measurements: Grade 3 to 4 drug-related adverse events resulting in drug discontinuation (primary outcome), and on-time treatment completion, grade 1 to 2 drug-related adverse events, and changes in liver enzymes and hematologic variables (secondary outcomes).
Results: Seventeen of 422 participants who started isoniazid therapy developed grade 3 to 4 adverse events compared with 7 of 418 who started rifampin therapy (risk difference [rifampin minus isoniazid], 2.3% [95% CI, 5% to 0.1%]; P 0.040). Grade 3 or 4 hepatitis occurred in 16 of 422 isoniazid recipients compared with 3 of 418 rifampin recipients (risk difference, 3.1% [CI, 5% to 1%]; P 0.003). Grade 1 or 2 adverse events attributed to study drugs occurred with similar frequency. Asymptomatic reduction in platelet and leukocyte counts were more frequent in rifampin recipients. More patients completed rifampin treatment (78%) than isoniazid treatment (60%) (difference, 18% [CI, 12% to 24%]; P 0.001]).
Limitation: The study did not measure efficacy, and the open-label design may increase the chance of bias in ascertainment of adverse events.
Conclusion: Treatment of latent tuberculosis with 4 months of rifampin leads to fewer serious adverse events and better adherence than 9 months of isoniazid. These findings justify a large-scale trial to compare the efficacy of rifampin with that of isoniazid.
Ann Intern Med. 2008;149:689-697. www.annals.org
For author affiliations, see end of text.
ClinicalTrials.gov registration number: NCT00170209.