Dick Menzies, MD, MSc; Richard Long, MD; Anete Trajman, MD, PhD; Marie-Jose 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; Kevin Schwartzman, MD, MPH
Acknowledgment: The authors are deeply indebted to Drs. George Comstock (deceased), Kevin Elwood, Richard O'Brien, and Michael Lauzardo for serving as the independent review panel and the data safety monitoring board for this study. The authors thank Dr. Eric Rousseau and his team at the University of Sherbrooke for developing the Web-based registration and randomization software. The authors also thank the staff of the many tuberculosis clinics involved.
Grant Support: From the Canadian Institutes of Health Research (grant MCT#44154). Dr. Menzies currently holds a Chercheur National Salary Award, and Dr. Schwartzman holds a Chercheur Boursier Clinicien Award from the Fonds de recherche en sant du Qubec. Dr. Trajman receives salary support from the International Clinical, Operational, and Health Services Research Training Award for AIDS and Tuberculosis, the Fogart International Center, National Institutes of Health grant 5U2 R TW006883-03.
Potential Financial Conflicts of Interest: None disclosed.
Reproducible Research Statement:Study protocol: Available at www.mcgill.ca/recru/researchers/menzies/. Statistical code and data set: Will be available from Dr. Menzies (e-mail, email@example.com) after 1 September 2011 on written request and after establishing written agreement.
Requests for Single Reprints: Dick Menzies, MD, MSc, Montreal Chest Institute, 3650 St-Urbain, Room K1.24, Montreal, Quebec H2X 2P4, Canada; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Menzies, Benedetti, and Schwartzman and Ms. Dion: Montreal Chest Institute, 3650 St-Urbain, Montreal, Quebec H2X 2P4, Canada.
Dr. Long: Room 8325, Aberhart Hospital, 11402 University Avenue, Edmonton, Alberta T6G 2J3, Canada.
Dr. Trajman: Rua Macedo Sobrinho 74/203, Humait, Rio de Janeiro 22271-080, Brazil.
Dr. Yang: St. Michael's Hospital, 30 Bond Street, 6-045 Bond Wing, Toronto, Ontario M5B 1W8, Canada.
Drs. Al Jahdali and Memish: King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Khashm Alaan, PO Box 22490, Riyadh 11426, Saudi Arabia.
Dr. Khan: Centre for Research on Inner City Health, Li Ka Shing Knowledge Institute of St. Michael's Hospital, 30 Bond Street, Toronto, Ontario M5B 1W8, Canada.
Dr. Gardam: Tuberculosis Clinic, University Health Network, 200 Elizabeth Street, 9 CSB, Toronto, Ontario M5G 2C4, Canada.
Dr. Hoeppner: Royal University Hospital, 101 College Drive, Saskatoon, Saskatchewan S0K 0Y0, Canada.
Author Contributions: Conception and design: D. Menzies.
Analysis and interpretation of the data: D. Menzies, A. Benedetti, A. Trajman, K. Khan, K. Schwartzman.
Drafting of the article: D. Menzies.
Critical revision of the article for important intellectual content: D. Menzies, R. Long, A. Trajman, A. Benedetti, H. Al Jahdali, Z. Memish, J. Yang K. Khan, M. Gardam, V. Hoeppner, K. Schwartzman.
Final approval of the article: D. Menzies, R. Long, A. Trajman, M.J. Dion, A. Benedetti, H. Al Jahdali, Z. Memish, K. Khan, M. Gardam, V. Hoeppner, K. Schwartzman.
Provision of study materials or patients: D. Menzies, R. Long, A. Trajman, M.J. Dion, J. Yang, H. Al Jahdali, Z. Memish, K. Khan, M. Gardam, V. Hoeppner.
Statistical expertise: D. Menzies, A. Benedetti.
Obtaining of funding: D. Menzies.
Administrative, technical, or logistic support: D. Menzies, M.J. Dion.
Collection and assembly of data: D. Menzies, A. Trajman, M.J. Dion.
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.
To compare the frequency of adverse events and treatment completion in 2 treatment regimens for latent tuberculosis infection.
Multicenter, randomized, open-label trial.
Tuberculosis clinics located in university hospitals in Canada, Brazil, and Saudi Arabia.
847 patients without a contraindication for rifampin and requiring treatment for latent tuberculosis infection.
Four months of daily rifampin therapy or 9 months of daily isoniazid therapy.
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).
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##lt## 0.001]).
The study did not measure efficacy, and the open-label design may increase the chance of bias in ascertainment of adverse events.
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.
Dick Menzies, Richard Long, Anete Trajman, Marie-Jose Dion, Jae Yang, Hamdan Al Jahdali, et al. Adverse Events with 4 Months of Rifampin Therapy or 9 Months of Isoniazid Therapy for Latent Tuberculosis Infection: A Randomized Trial. Ann Intern Med. 2008;149:689–697. doi: 10.7326/0003-4819-149-10-200811180-00003
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Published: Ann Intern Med. 2008;149(10):689-697.
Infectious Disease, Mycobacterial Infections.
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