Short, Highly Effective, and Inexpensive Standardized Treatment of Multidrug-resistant Tuberculosis

Abstract

RATIONALE: Based on expert opinion, the global guidelines for management of multidrug-resistant tuberculosis impose lengthy and often poorly tolerated treatments. OBJECTIVES: This observational study evaluates the effectiveness of standardized regimens for patients with proven multidrug-resistant tuberculosis previously untreated with second-line drugs in low-income countries. METHODS: Consenting patients were sequentially assigned to one of six standardized treatment regimens. Subsequent cohorts were treated with regimens adapted according to results in prior cohorts. The study was designed to minimize failure and default while reducing total treatment duration without increasing relapse frequency. MEASUREMENTS AND MAIN RESULTS: We report the treatment outcome of all patients with laboratory-confirmed, multidrug-resistant tuberculosis enrolled from May 1997 to December 2007. The most effective treatment regimen required a minimum of 9 months of treatment with gatifloxacin, clofazimine, ethambutol, and pyrazinamide throughout the treatment period supplemented by prothionamide, kanamycin, and high-dose isoniazid during an intensive phase of a minimum of 4 months, giving a relapse-free cure of 87.9% (95% confidence interval, 82.7-91.6) among 206 patients. Major adverse drug reactions were infrequent and manageable. Compared with the 221 patients treated with regimens based on ofloxacin and commonly prothionamide throughout, the hazard ratio of any adverse outcome was 0.39 (95% confidence interval, 0.26-0.59). CONCLUSIONS: Serial regimen formulation guided by overall treatment effectiveness resulted in treatment outcomes comparable to those obtained with first-line treatment. Confirmatory formal trials in populations with high levels of human immunodeficiency virus coinfection and in populations with a higher initial prevalence of resistance to second-line drugs are required.