The use of newer drugs, a greater number of effective drugs, and a longer treatment regimen may be associated with improved survival of patients with multidrug resistant tuberculosis (MDR-TR), according to a large study by a team of international researchers published in this week’s PLOS Medicine.
Global efforts to control tuberculosis are being challenged by the emergence of strains that are resistant to several antibiotics including isoniazid and rifampicin, the two most powerful, first-line (standard) anti-tuberculosis drugs – so-called multidrug resistant tuberculosis (MDR-TB). The treatment of MDR-TB is lengthy, toxic, expensive, and has mostly resulted in poor outcomes for patients. Importantly, the optimal treatment regimens for MDR-TB have not been determined and, to date, there have been no randomized controlled trials of treatments for MDR-TB.
In this study, a large group of international researchers (the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB) combined data on outcomes of 9153 patients from 32 centers to find out more about the best way of treating MDR-TB. The researchers found that the use of certain drugs, the use of four or more effective drugs, and the duration of treatment were associated with successful patient outcomes.
The authors conclude: “This individual patient data meta-analysis of 9,153 patients suggests that treatment of MDR-TB should include a later generation quinolone, and ethionamide or prothionamide. In patients who have not received second-line drugs before, the optimal number of likely effective drugs appears to be at least four in the initial intensive phase, and at least three in the continuation phase. The duration of therapy associated with highest odds of success was 7-8.5 months for the initial intensive phase, and 25-27 months for total duration.”
However, these findings should be interpreted with caution because of the limitations in the methods and type of data used in the study. The authors say: “In view of the serious limitations of these observational data, these findings should be considered to have highlighted several important questions for future clinical trials.
These questions include the role and choice of injectables (medications that have to be given by injection), the optimal duration of an injectable and total therapy, and the potential value of later generation quinolones as well as certain group 4 and group 5 drugs.”
Funding: Partial funding for the assembly of individual patient data and meta-analysis was provided from the Stop TB Department of the World Health Organization, through a grant from USAID. Funding for data gathering at participating centres came from the following sources: in the State of California from the US Centers for Disease Control Cooperative Agreement Funds; in Italy from the European Community’s Seventh Framework Programme (FP7/2007-2013) under grant agreement FP7- 223681; in Mexico (Veracruz) from the Mexican Secretariat of Health, the National Institutes of Health of the United States (A135969 and K01TW000001), the Wellcome Trust (176W009), the Howard Hughes Medical Institute (55000632), and the Mexican Council of Science and Technology: SEP 2004-C01-47499, FOSSIS 2005-2 (14475), (87332); in South Africa from the South African Medical Research Council funding. Funding was provided to the following investigators: M Bauer and D Menzies were supported by salary awards from the Fonds de Recherche en Sante de Quebec, L Shah was supported by CIHR (Canada Graduate Scholarship), Neel Gandhi received a Doris Duke Charitable Foundation Clinical Scientist Development Award. The funders had no role in study design, data collection and analysis, decisions to publish, or preparation of the manuscript.
Competing Interests: JR is a Consultant for bioMe´rieux. WWY has been indirectly sponsored to participate in International Conferences by GlaxoSmithKline and Pfizer in the last 3 years. CDM is on the Scientific Advisory Board for Otsuka pharmaceuticals development of OPC67683 (Delaminid), a new anti-TB compound. SK received salary support from the Eli Lilly Foundation as part of funding for the activities of Partners In Health by the Foundation’s MDR-TB Partnership. This funder was not involved in the study design; collection, analysis and interpretation of data; writing of the paper; and/or decision to submit for publication. The Partners In Health project in Tomsk received funding from Mr. Tom White, the Open Society Institute, the Bill & Melinda Gates Foundation, and the Global Fund to fight AIDS, Tuberculosis and Malaria. None of these funders were involved in the study design; collection, analysis and interpretation of data; writing of the paper; and/or decision to submit for publication. KD is an unpaid, volunteer member of the New Diagnostics Working Group (NDWG), formed of members of the Stop TB Partnership. The Secretariat of the NDWG is hosted by FIND (Foundation for New Innovative Diagnostics). JB was working as consultant for Otsuka Pharmaceutical for the implementation of clinical trial in Peru. JB was co PI of a NIH grant in Peru, Epidemiology of Tuberculosis. MP and GP are members of the Editorial Board of PLOS Medicine. All other authors have declared that no competing interests exist.
Citation: Ahuja SD, Ashkin D, Avendano M, Banerjee R, Bauer M, et al. (2012) Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients. PLoS Med 9(8): e1001300. doi:10.1371/journal.pmed.1001300
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