Medea Gegia1, Nicholas Winters2, Andrea Benedetti2, Dick van Soolingen3, Dick Menzies4. 1. Global TB Programme, WHO, Geneva, Switzerland. 2. Montreal Chest Institute, McGill University, Montreal, QC, Canada. 3. Mycobacterial Reference Lab, Bilthoven, Netherlands. 4. Montreal Chest Institute, McGill University, Montreal, QC, Canada. Electronic address: dick.menzies@mcgill.ca.
Abstract
BACKGROUND: The results of some reports have suggested that treatment of isoniazid-resistant tuberculosis with the recommended regimens of first-line drugs might be suboptimal. We updated a previous systematic review of treatment outcomes associated with use of first-line drugs in patients with tuberculosis resistant to isoniazid but not rifampicin. METHODS: In this systematic review, we updated the results of a previous review to include randomised trials and cohort studies published in English, French, or Spanish to March 31, 2015, containing results of standardised treatment of patients with bacteriologically confirmed isoniazid-resistant tuberculosis (but not multidrug-resistant tuberculosis-ie, not resistant to rifampicin) in whom failure and relapse were bacteriologically confirmed. Results in patients with drug-sensitive tuberculosis included in the same studies were also analysed. We pooled treatment outcomes with random-effects meta-analysis. FINDINGS: We identified 19 cohort studies and 33 trials with 3744 patients with isoniazid-resistant tuberculosis and 19 012 patients with drug-sensitive disease. The pooled rates of failure or relapse, or both, and acquired drug resistance with all drug regimens were 15% (95% CI 12-18) and 3·6% (2-5), respectively, in patients with isoniazid-resistant tuberculosis and 4% (3-5) and 0·6% (0·3-0·9) in those with drug-sensitive tuberculosis. Of patients with initial isoniazid-resistant tuberculosis with acquired drug resistance, 96% (93-99) had acquired multidrug-resistant disease. Treatment of isoniazid-resistant tuberculosis with the WHO standard regimen for new patients resulted in treatment failure, relapse, and acquired multidrug resistance in 11% (6-17), 10% (5-15) and 8% (3-13), respectively; treatment with the standard WHO regimen for previously treated patients resulted in treatment failure in 6% (2-10), relapse in 5% (2-8), and acquisition of multidrug resistance in 3% (0-6). For patients with drug-sensitive disease treated with the standard retreatment regimen the rates were 1% (0-2), 5% (4-7), and 0·3% (0-0·6). INTERPRETATION: Treatment of isoniazid-resistant tuberculosis with first-line drugs resulted in suboptimal outcomes, supporting the need for better regimens. Standardised empirical treatment of new cases could be contributing substantially to the multidrug-resistant epidemic, particularly in settings where the prevalence of isoniazid resistance is high. FUNDING: Canadian Institutes of Health Research.
BACKGROUND: The results of some reports have suggested that treatment of isoniazid-resistant tuberculosis with the recommended regimens of first-line drugs might be suboptimal. We updated a previous systematic review of treatment outcomes associated with use of first-line drugs in patients with tuberculosis resistant to isoniazid but not rifampicin. METHODS: In this systematic review, we updated the results of a previous review to include randomised trials and cohort studies published in English, French, or Spanish to March 31, 2015, containing results of standardised treatment of patients with bacteriologically confirmed isoniazid-resistant tuberculosis (but not multidrug-resistant tuberculosis-ie, not resistant to rifampicin) in whom failure and relapse were bacteriologically confirmed. Results in patients with drug-sensitive tuberculosis included in the same studies were also analysed. We pooled treatment outcomes with random-effects meta-analysis. FINDINGS: We identified 19 cohort studies and 33 trials with 3744 patients with isoniazid-resistant tuberculosis and 19 012 patients with drug-sensitive disease. The pooled rates of failure or relapse, or both, and acquired drug resistance with all drug regimens were 15% (95% CI 12-18) and 3·6% (2-5), respectively, in patients with isoniazid-resistant tuberculosis and 4% (3-5) and 0·6% (0·3-0·9) in those with drug-sensitive tuberculosis. Of patients with initial isoniazid-resistant tuberculosis with acquired drug resistance, 96% (93-99) had acquired multidrug-resistant disease. Treatment of isoniazid-resistant tuberculosis with the WHO standard regimen for new patients resulted in treatment failure, relapse, and acquired multidrug resistance in 11% (6-17), 10% (5-15) and 8% (3-13), respectively; treatment with the standard WHO regimen for previously treated patients resulted in treatment failure in 6% (2-10), relapse in 5% (2-8), and acquisition of multidrug resistance in 3% (0-6). For patients with drug-sensitive disease treated with the standard retreatment regimen the rates were 1% (0-2), 5% (4-7), and 0·3% (0-0·6). INTERPRETATION: Treatment of isoniazid-resistant tuberculosis with first-line drugs resulted in suboptimal outcomes, supporting the need for better regimens. Standardised empirical treatment of new cases could be contributing substantially to the multidrug-resistant epidemic, particularly in settings where the prevalence of isoniazid resistance is high. FUNDING: Canadian Institutes of Health Research.
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