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Shortening Treatment in Adults with Noncavitary Tuberculosis and 2-Month Culture Conversion

¹ Tuberculosis Research Unit, Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals Case Medical Center, Cleveland, Ohio; ² Núcleo 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 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; and ⁷ University of Arkansas for Medical Sciences, Little Rock, Arkansas

Correspondence and requests for reprints should be addressed to John L. Johnson, M.D., Division of Infectious Diseases, University Hospitals Case Medical Center, Room 406 Foley Building, Mailstop Foley 5083, 11100 Euclid Avenue, Cleveland, OH 44106-5083. 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: To assess whether treatment could be shortened from 6 to 4 months in patients with noncavitary tuberculosis whose sputum cultures converted to negative after 2 months.

Methods: This study was a randomized, open-label equivalence trial. HIV-uninfected adults with noncavitary 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 to 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. A total of 370 patients were eligible for per protocol analysis. Thirteen patients in the 4-month arm relapsed, compared with three subjects in the 6-month arm (7.0 vs. 1.6%; risk difference, 0.054; 95% confidence interval with Hauck-Anderson correction, 0.01–0.10).

Conclusion: Shortening treatment from 6 to 4 months in adults with noncavitary disease and culture conversion after 2 months using current drugs resulted in a greater relapse rate. The combination of noncavitary disease and 2-month culture conversion was insufficient to identify patients with decreased risk for relapse.

Key Words: tuberculosis • antitubercular agents • isoniazid • rifampin

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Noncavitary disease and sputum culture conversion after 2 months of treatment have been associated with favorable treatment outcomes in patients with pulmonary tuberculosis. What This Study Adds to the Field Shortening treatment from 6 to 4 months in adults with noncavitary disease and sputum culture conversion after 2 months of treatment resulted in significantly more relapses among those treated for 4 months with current first line drugs. Better biomarkers, optimized dosing, and the introduction of drugs with new mechanisms of action are likely needed to shorten tuberculosis treatment.

 

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