Abstract
Background A standardized regimen recommended by the World Health Organization for retreatment of active tuberculosis (TB) is widely used, but treatment outcomes are suspected to be poor. We conducted a systematic review of published evidence of treatment of patients with a history of previous treatment or documented isoniazid mono-resistance. Methods and Findings PubMed, EMBASE, and the Cochrane Central database for clinical trials were searched for randomized trials in previously treated patients and/or those with with mono-resistance to isoniazid, published in English, French, or Spanish between 1965 and June 2008. The first two sources were also searched for cohort studies evaluating specifically the current retreatment regimen. In studies selected for inclusion, rifampin-containing regimens were used to treat patients with bacteriologically confirmed pulmonary TB, in whom bacteriologically confirmed failure and/or relapse had been reported. Pooled cumulative incidences and 95% CIs of treatment outcomes were computed with random effects meta-analyses and negative binomial regression. No randomized trials of the currently recommended retreatment regimen were identified. Only six cohort studies were identified, in which failure rates were 18%–44% in those with isoniazid resistance. In nine trials, using very different regimens in previously treated patients with mono-resistance to isoniazid, the combined failure and relapse rates ranged from 0% to over 75%. From pooled analysis of 33 trials in 1,907 patients with mono-resistance to isoniazid, lower failure, relapse, and acquired drug resistance rates were associated with longer duration of rifampin, use of streptomycin, daily therapy initially, and treatment with a greater number of effective drugs. Conclusions There are few published studies to support use of the current standardized retreatment regimen. Randomized trials of treatment of persons with isoniazid mono-resistance and/or a history of previous TB treatment are urgently needed. Please see later in the article for the Editors' Summary
Highlights
A key component of the directly observed treatment shortcourse (DOTS) strategy of the World Health Organization (WHO) is the use of a limited number of standardized regimens [1]
A single 8-mo ‘‘retreatment’’ regimen (8 mo of isoniazid, rifampin, ethambutol, with pyrazinamide added for the first 3 mo, and streptomycin added for the first 2 mo—2SHRZE/1HRZE/5HRE) is recommended for all patients with a history of previous treatment [1] and is used in more than 90 countries [2]. This WHO retreatment regimen was initially designed for resource-poor settings with low prevalence of initial drug resistance, and for patients previously treated with a regimen that used rifampin only for the first 2 mo of therapy [3]
In the 24 randomized trials in new cases, randomization was high quality in 16, but not specified in eight, and treatment phase losses were less than 10% in 18 (67%)
Summary
A key component of the directly observed treatment shortcourse (DOTS) strategy of the World Health Organization (WHO) is the use of a limited number of standardized regimens [1]. A single 8-mo ‘‘retreatment’’ regimen (8 mo of isoniazid, rifampin, ethambutol, with pyrazinamide added for the first 3 mo, and streptomycin added for the first 2 mo—2SHRZE/1HRZE/5HRE) is recommended for all patients with a history of previous treatment [1] and is used in more than 90 countries [2] This WHO retreatment regimen was initially designed for resource-poor settings with low prevalence of initial drug resistance, and for patients previously treated with a regimen that used rifampin only for the first 2 mo of therapy [3]. Patients who need re-treatment are often infected with bacteria that are resistant to one or more of the antibiotics commonly used to treat tuberculosis
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