Published ahead of print on June 19, 2009, doi:10.1164/rccm.200904-0536OC Am. J. Respir. Crit. Care Med., Volume 180, Number 6, September 2009, 558-563 A more recent version of this article appeared on September 15, 2009
Submitted on April 7, 2009 Shortening Treatment in Adults with Non-cavitary Tuberculosis and Two-month Culture ConversionJohn L Johnson1*,1 Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio, United States, 2 Nùcleo de Doenças Infecciosas, Centro de Ciências da Saúde, Universidade Federal do Espírito Santo, Vitória, Brazil, 3 Uganda-Case Western Reserve University Research Collaboration, Makerere University College of Health Sciences, Mulago Hospital, Kampala, Uganda, 4 Uganda-Case Western Reserve University Research Collaboration, Makerere University College of Health Sciences, Mulago Hospital, Kampala, Uganda; Ugandan National Tuberculosis and Leprosy Programme, Kampala, Uganda, 5 Tropical Diseases Foundation, Makati City, Philippines, 6 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio, United States, 7 University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States * To whom correspondence should be addressed. E-mail: jlj{at}case.edu.
Rationale: Cavitary disease and delayed culture conversion have been associated with relapse. Combining patient characteristics and measures of bacteriologic response might allow treatment shortening with current drugs in some patients. Objectives: Assess whether treatment could be shortened from 6 to 4 months in patients with non-cavitary tuberculosis whose sputum cultures converted to negative after 2 months. Methods: Randomized, open label equivalence trial. HIV-uninfected adults with non-cavitary tuberculosis were treated daily with isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months followed by 2 months of isoniazid and rifampin. After 4 months, patients with drug susceptible TB whose sputum cultures on solid media were negative after 8 weeks of treatment were randomly assigned to continue treatment for 2 more months or stop treatment. Patients were followed for relapse for 30 months after beginning treatment. Measurements and Main Results: Enrollment was stopped by the safety monitoring committee after 394 patients were enrolled due to apparent increased risk for relapse in the 4 month arm. Three hundred seventy patients were eligible for per protocol analysis. Thirteen patients in the 4 month arm relapsed compared to 3 subjects in the 6 month arm (7.0 % vs. 1.6 %, risk difference 0.054, 95% CI with Hauck-Anderson correction 0.01, 0.10). Conclusion: Shortening treatment from 6 to 4 months in adults with non-cavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of non-cavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse. Clinical Trials Registry Information: ID#NCT00130247 registered at www.clinicaltrials.gov Key words: tuberculosis • antitubercular agents • isoniazid • rifampin
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