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Adverse Events with 4 Months of Rifampin Therapy or 9 Months of Isoniazid Therapy for Latent Tuberculosis Infection: A Randomized Trial

Dick Menzies, MD, MSc; Richard Long, MD; Anete Trajman, MD, PhD; Marie-Josée 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
[+] Article and Author Information

ClinicalTrials.gov registration number: NCT00170209.


From the Montreal Chest Institute, McGill University, Montreal, Quebec, Canada; University of Alberta, Edmonton, Alberta, Canada; University of Toronto and St. Michael's Hospital, Toronto, Ontario, Canada; University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Gama Filho University, Rio de Janeiro, Brazil; and King Abdulaziz Medical City, King Abdulaziz Bin Saud University, Riyadh, Saudi Arabia.


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 santé du Québec. 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 http://www.mcgill.ca/recru/researchers/menzies/. Statistical code and data set: Will be available from Dr. Menzies (e-mail, dick.menzies@mcgill.ca) 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, dick.menzies@mcgill.ca.

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, Humaitá, 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.


Ann Intern Med. 2008;149(10):689-697. doi:10.7326/0003-4819-149-10-200811180-00003
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In January 2007, the third planned interim analysis revealed that the frequency of serious adverse events was significantly lower in 1 trial group. When the data safety and monitoring board was unblinded and learned that 4 months of rifampin had the lower rate of serious adverse events, they recommended discontinuation of enrollment.

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Figures

Grahic Jump Location
Figure 1.
Study flow diagram.

4RIF = 4-month rifampin therapy; 9INH = 9-month isoniazid therapy.

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Figure 2.
Interval from randomization to dropout or treatment completion.

All patients included.

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Comments

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LTBI and HIV
Posted on November 23, 2008
Ahmad Kaako
UTCOM Internal Medicne Resident
Conflict of Interest: None Declared

This is very good study which opens the door and raises the need for a large scale study to evaluate the efficacy of rifampin compare to isoniazide for treatment of LTBI.

On the other hand, there are other limitations about this study; one of them it was conducted in different centers of the world (Canada, Brazil and Saudi Arabia) with multicultural diversity where exposure and prevalence of HIV and the use of BCG vaccine are different. The compliance and reporting side effects could be variable given the culture difference as well.

Another one; less then of 2% of the study sample are HIV patients. We know that these patients are at higher risk for LTBI in the western world. In this subgroup, treatment using rifabutin rather than rifampin as alternative for isoniazide, is the standard of care.

On LTBI, ART and TST in the developing world.
Posted on November 27, 2008
Ige Abraham George
Christian Medical College, Vellore, Tamil Nadu ,India
Conflict of Interest: None Declared

The study by Menzies et al in the current issue of Annals show encouraging results with 4 month treatment of latent tuberculosis(TB) with Rifampicin compared with conventional treatment with 9 months of Isoniazid. However this raises a few concerns in populations where TB is endemic.

HIV positive patients comprised less than 2 percent of the study population. Many developing countries like India have a Government initiated antiretroviral programme with Nevirapine as a backbone. Due to interactions with Rifampicin, in this population Nevirapine would have to be substituted with an Effavirenz based regimen which has a potential to escalate costs. Secondly it has been shown that Tuberculin Skin Tests (TST) is a poor predictor of both latent TB in HIV-infected individuals in TB endemic countries. Programs offering treatment for latent TB should consider including all HIV-positive patients regardless of TST status, or use other indicators, such as CD4 count(1). May we suggest that these be taken into consideration along with the author's recommendation justifying a large scale trial comparing efficacy of the two drugs

(1) Swaminathan S, Subbaraman R, Venkatesan P, Subramanyam S, Kumar SR, Mayer KH, Narayanan PR. Tuberculin skin test results in HIV-infected patients in India: implications for latent tuberculosis treatment.Int J Tuberc Lung Dis. 2008 ;12:168-73.

Conflict of Interest:

None declared

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