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


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          Performing a systematic review of studies evaluating retreatment of tuberculosis or treatment of isoniazid mono-resistant infection, Dick Menzies and colleagues find a paucity of evidence to support the WHO-recommended regimen.



          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.


          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

          Editors' Summary


          Every year, nearly ten million people develop tuberculosis—a contagious infection, usually of the lungs—and about 2 million people die from the disease. Tuberculosis is caused by Mycobacterium tuberculosis, bacteria that are spread in airborne droplets when people with the disease cough or sneeze. Its symptoms include a persistent cough, fever, weight loss, and night sweats. Diagnostic tests for tuberculosis include chest X-rays and sputum slide exams and cultures in which bacteriologists try to grow M. tuberculosis from mucus brought up from the lungs by coughing. The disease can be cured by taking several powerful antibiotics regularly (daily or several times a week) for at least 6 months. However, 10%–20% of patients treated for tuberculosis in low- and middle-income countries need re-treatment because the initial treatment fails to clear M. tuberculosis from their body or because their disease returns after they have apparently been cured (treatment relapse). 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.

          Why Was This Study Done?

          As part of its strategy to reduce the global burden of tuberculosis, the World Health Organization (WHO) recommends standardized treatment regimens for tuberculosis. For re-treatment, WHO recommends an 8-month course of isoniazid, rifampin, and ethambutol with pyrazinamide and streptomycin added for the first 3 and 2 months, respectively. All these drugs are given daily (the preferred regimen) or three times a week. Unfortunately, although this regimen is now used to treat about 1 million patients each year, it yields poor results, particularly in regions where drug resistance is common. In this study (which was commissioned by WHO to provide the evidence needed for a revision of its treatment guidelines), the researchers undertake a systematic review (a search using specific criteria to identify relevant research studies, which are then appraised) and a meta-analysis (a statistical approach that pools the results of several studies) of randomized trials and cohort studies (two types of study that investigate the efficacy of medical interventions) of re-treatment regimens in previously treated tuberculosis patients, and in patients with infection that was resistant to isoniazid (“mono-resistance”).

          What Did the Researchers Do and Find?

          The researchers' systematic search for published reports of randomized trials and cohort studies of the currently recommended re-treatment regimen identified no relevant randomized trials and only six cohort studies. In the three cohort studies in which the participants carried M. tuberculosis strains that were sensitive to all the antibiotics in the regimen, failure rates were generally low. However, in the studies in which the participants carried drug-resistant bacteria, failure rates ranged from 9% to 45%. The researchers also identified and analyzed the results of nine trials in which several re-treatment regimens, all of which deviated from the standardized regimen, were used in previously treated patients with isoniazid mono-resistance. In these trials, the combined failure and relapse rates ranged from 0% to more than 75%. Finally, the researchers analyzed the pooled results of 33 trials that investigated the effect of various regimens on nearly 2,000 patients (some receiving their first treatment for tuberculosis, some being re-treated) with isoniazid mono-resistance. This meta-analysis showed that lower relapse, failure, and acquired drug resistance rates were associated with longer duration of rifampicin treatment, use of streptomycin, daily therapy early in the treatment, and regimens that included a greater number of drugs to which the M. tuberculosis carried by the patient were sensitive.

          What Do These Findings Mean?

          These findings reveal that there is very little published evidence that supports the regimen currently recommended by WHO for the re-treatment of tuberculosis. Furthermore, this limited body of evidence is a patchwork of results gleaned from a few cohort studies and a set of randomized trials not specifically designed to test the efficacy of the standardized regimen. There is an urgent need, therefore, for a concerted international effort to initiate randomized trials of potential treatment regimens in both previously untreated and previously treated patients with all forms of drug-resistant tuberculosis. Because these trials will take some time to complete, the limited findings of the meta-analysis presented here may be used in the meantime to redesign and, hopefully, improve the current standardized re-treatment regimen. In fact, the revised WHO TB treatment guidelines will provide updated recommendations for patients with previously treated TB.

          Additional Information

          Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000150.

          • The results of another WHO-commissioned study into the treatment of tuberculosis are presented in a separate PLoS Medicine Research Article by Menzies et al. (Menzies D, Benedetti A, Paydar A, Martin I, Royce S, et al. (2009) Effect of Duration and Intermittency of Rifampin on Tuberculosis Treatment Outcomes: A Systematic Review and Meta-Analysis. PLoS Med 6(9): e1000146.)

          • The US National Institute of Allergy and Infectious Diseases provides information on all aspects of tuberculosis

          • The American Thoracic Society, US Centers for Disease Control and Prevention, and Infectious Diseases Society of America offer guidelines on TB treatment

          • The US Centers for Disease Control and Prevention provide several facts sheets and other information resources about tuberculosis

          • The 2003 (2004 revision) WHO guidelines for national programs for the treatment of tuberculosis are available; WHO also provides information on efforts to reduce the global burden of tuberculosis (in several languages) and its 2009 annual report on global control of tuberculosis describes the current situation (key points are available in several languages)

          • The WHO publishes guidelines on TB treatment

          • For guidelines on drug susceptibility testing (DST) and other information on TB diagnostic tests, the Stop TB Partnership's New Diagnostics Working Group has created a new Web site called Evidence-Based Tuberculosis Diagnosis

          Related collections

          Most cited references62

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          American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis.

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            Explaining heterogeneity in meta-analysis: a comparison of methods.

            Exploring the possible reasons for heterogeneity between studies is an important aspect of conducting a meta-analysis. This paper compares a number of methods which can be used to investigate whether a particular covariate, with a value defined for each study in the meta-analysis, explains any heterogeneity. The main example is from a meta-analysis of randomized trials of serum cholesterol reduction, in which the log-odds ratio for coronary events is related to the average extent of cholesterol reduction achieved in each trial. Different forms of weighted normal errors regression and random effects logistic regression are compared. These analyses quantify the extent to which heterogeneity is explained, as well as the effect of cholesterol reduction on the risk of coronary events. In a second example, the relationship between treatment effect estimates and their precision is examined, in order to assess the evidence for publication bias. We conclude that methods which allow for an additive component of residual heterogeneity should be used. In weighted regression, a restricted maximum likelihood estimator is appropriate, although a number of other estimators are also available. Methods which use the original form of the data explicitly, for example the binomial model for observed proportions rather than assuming normality of the log-odds ratios, are now computationally feasible. Although such methods are preferable in principle, they often give similar results in practice. Copyright 1999 John Wiley & Sons, Ltd.
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              Studies on the treatment of tuberculosis undertaken by the British Medical Research Council tuberculosis units, 1946-1986, with relevant subsequent publications.


                Author and article information

                Role: Academic Editor
                PLoS Med
                PLoS Medicine
                Public Library of Science (San Francisco, USA )
                September 2009
                September 2009
                15 September 2009
                : 6
                : 9
                : e1000150
                [1 ]Respiratory and Epidemiology Clinical Research Unit, Montreal Chest Institute, McGill University, Montreal, Canada
                [2 ]University of California at San Francisco, San Francisco, California, United States of America
                [3 ]Denver Public Health, Denver, Colorado, United States of America
                [4 ]Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America
                [5 ]International Union against Tuberculosis and Lung Diseases, and Institut de Recherche pour le Développement, Paris, France
                Harvard School of Public Health, United States of America
                Author notes

                ICMJE criteria for authorship read and met: DM AB AP SR MP WB AV CL. Agree with the manuscript's results and conclusions: DM AB AP SR MP WB AV CL. Designed the experiments/the study: DM. Analyzed the data: DM. Collected data/did experiments for the study: DM AP. Wrote the first draft of the paper: DM. Contributed to the writing of the paper: DM AB AP SR MP WB AV CL. Formulated idea, wrote protocol, performed literature search, participated in the final selection of articles for inclusion: DM. Helped with statistical analysis plan, and data analysis: AB. Provided input on systematic review methodology: MP. Critically reviewed initial draft and assisted in revision of manuscript, based on individual interpretations of data reported: AV.

                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.
                : 20 February 2009
                : 5 August 2009
                Page count
                Pages: 14
                Research Article
                Infectious Diseases/Antimicrobials and Drug Resistance
                Infectious Diseases/Neglected Tropical Diseases
                Public Health and Epidemiology/Global Health
                Public Health and Epidemiology/Infectious Diseases



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