Three Months of Rifapentine and Isoniazid for Latent Tuberculosis Infection
Timothy R. Sterling, M.D., M. Elsa Villarino, M.D., M.P.H., Andrey S. Borisov, M.D., M.P.H., Nong Shang, Ph.D., Fred Gordin, M.D., Erin Bliven-Sizemore, M.P.H., Judith Hackman, R.N., Carol Dukes Hamilton, M.D., Dick Menzies, M.D., Amy Kerrigan, R.N., M.S.N., Stephen E. Weis, D.O., Marc Weiner, M.D., Diane Wing, R.N., Marcus B. Conde, M.D., Lorna Bozeman, M.S., C. Robert Horsburgh, Jr., M.D., and Richard E. Chaisson, M.D. for the TB Trials Consortium PREVENT TB Study Team
N Engl J Med 2011; 365:2155-2166December 8, 2011
Treatment of latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control and elimination. The current standard regimen of isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion.
We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain and followed for 33 months. The primary end point was confirmed tuberculosis, and the noninferiority margin was 0.75%.
In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P=0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001).
The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.)
Preliminary results of this work were presented at the International Union Against Tuberculosis and Lung Disease International Conference, Berlin, November 15, 2010. Final results of this work were presented at the American Thoracic Society International Conference, Denver, May 16, 2011.
The findings and conclusions in this article are those of the authors and do not necessarily represent the views of the CDC or the Agency for Toxic Substances and Disease Registry.
Supported by the CDC.
Dr. Sterling reports receiving research grant funding from Bristol-Myers Squibb and Pfizer for HIV observational studies; Dr. Hamilton, being employed by Family Health International; Dr. Weiner, receiving research grant funding from Sanofi-Aventis; and Dr. Horsburgh, receiving payments from Otsuka America Pharmaceutical for scientific reviews of study protocols. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
Drs. Horsburgh and Chaisson contributed equally to this article.
We thank all the subjects for their participation in the study; George McSherry, William Burman, and Sharon Nachman for advice on pediatric issues; Debra Benator and Constance Benson for advice on HIV issues; William MacKenzie for assistance with pharmacokinetics issues; Margaret Jackson for assistance with coordination of institutional review board and consortium meetings; Connie Henderson, Crystal Carter, Marie Hannett, and Melissa Fagley for assistance with study-site support, study enrollment, patient education, data management, and data entry; Chris Allen, Cindy Dougherty, and Lori Hall for distributing the study drug to sites; Anil Sharma, Silver Wang, Howard Davis, Kumar Batra, Sharon Burks, Max Mirabito, Awal Khan, Nigel Scott, Ruth Moro, and Ben Appenheimer for assistance with data management, application development, and analysis; Andrew Nunn, Lawrence Moulton, and Charles Heilig for providing statistical consultation; Stefan Goldberg and Kimberly Chapman for assistance with the study participant decline log; Beverly Metchock, Lois Diem, Denise Hartline, David Sikes, and David Temporado for performing resistance testing of M. tuberculosis isolates; the Sanofi-Aventis group (Francois Bompart, Isabelle Cieren-Puiseux, and Brigitte Demers) for providing the study drug (rifapentine); Jonathan Kaplan, James Neaton, and David Ashkin for serving on the data and safety monitoring board; Mark Cotton, Wing Wei Yew, and John Johnson for making up the tuberculosis end points committee; Westat (Bert Arevalo, Nancy Dianis, and Kathleen Robergeau) for providing site monitoring; and Andrew Vernon, Jose Becerra, and Kenneth Castro for providing advice and support.
From the Vanderbilt University School of Medicine, Nashville (T.R.S., A.K.); the Centers for Disease Control and Prevention, Atlanta (M.E.V., A.S.B., N.S., E.B.-S., L.B.); the Washington DC Veterans Affairs Medical Center and George Washington University — both in Washington, DC (F.G.); the Johns Hopkins University School of Medicine, Baltimore (J.H., R.E.C.); Family Health International and Duke University — both in Durham, NC (C.D.H.); Montreal Chest Institute, McGill University, Montreal (D.M.); the University of North Texas Health Science Center at Fort Worth, Fort Worth (S.E.W.); the South Texas Veterans Health Care System and University of Texas Health Science Center at San Antonio — both in San Antonio (M.W.); and the South Texas Consortium, Harlingen (D.W.); the Federal University of Rio de Janeiro, Rio de Janeiro (M.B.C.); and Boston University School of Medicine, Boston (C.R.H.).
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