Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis

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. Citation: Menzies D, Benedetti A, Paydar A, Royce S, Pai M, et al. (2009) Standardized Treatment of Active Tuberculosis in Patients with Previous Treatment and/or with Mono-resistance to Isoniazid: A Systematic Review and Meta-analysis. PLoS Med 6(9): e1000150. doi:10.1371/journal.pmed.1000150 Academic Editor: Megan Murray, Harvard School of Public Health, United States of America Received February 20, 2009; Accepted August 5, 2009; Published September 15, 2009 This is an open-access article distributed under the terms of the Creative Commons Public Domain declaration which stipulates that, once placed in the public domain, this work may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. Funding: Funding for this review was provided in part from the World Health Organization. Salary support was provided by the Canadian Institutes of Health Research for MP, Fonds de la recherche en santé du Québec for DM and AB. None of these agencies had any direct role in the conduct of the study, nor the decision to submit the manuscript for publication. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. Abbreviations: DOT, Directly Observed Therapy; DOTS, directly observed treatment short-course; DST, drug susceptibility testing; INH, isoniazid; MDR, multidrug resistant; RCT, randomized controlled trial; TB, tuberculosis; WHO, World Health Organization. * E-mail: [email protected] PLoS Medicine | www.plosmedicine.org 1 September 2009 | Volume 6 | Issue 9 | e1000150