Giuseppe
Emeritus
[Source: PLoS Medicine, full page: (LINK). Abstract, edited.]
-------
Multidrug Resistant Pulmonary Tuberculosis Treatment Regimens and Patient Outcomes: An Individual Patient Data Meta-analysis of 9,153 Patients
Shama D. Ahuja<SUP>1</SUP>, David Ashkin<SUP>2</SUP>, Monika Avendano<SUP>3</SUP>, Rita Banerjee<SUP>4</SUP>, Melissa Bauer<SUP>5</SUP>, Jamie N. Bayona<SUP>6</SUP>, Mercedes C. Becerra<SUP>7</SUP><SUP>,</SUP><SUP>8</SUP>, Andrea Benedetti<SUP>5</SUP>, Marcos Burgos<SUP>9</SUP>, Rosella Centis<SUP>10</SUP>, Eward D. Chan<SUP>11</SUP>, Chen-Yuan Chiang<SUP>12</SUP>, Helen Cox<SUP>13</SUP>, Lia D'Ambrosio<SUP>10</SUP>, Kathy DeRiemer<SUP>14</SUP>, Nguyen Huy Dung<SUP>15</SUP>, Donald Enarson<SUP>16</SUP>, Dennis Falzon<SUP>17</SUP>, Katherine Flanagan<SUP>18</SUP>, Jennifer Flood<SUP>19</SUP>, Maria L. Garcia-Garcia<SUP>20</SUP>, Neel Gandhi<SUP>21</SUP>, Reuben M. Granich<SUP>17</SUP>, Maria G. Hollm-Delgado<SUP>5</SUP>, Timothy H. Holtz<SUP>22</SUP>, Michael D. Iseman<SUP>23</SUP>, Leah G. Jarlsberg<SUP>24</SUP>, Salmaan Keshavjee<SUP>7</SUP>, Hye-Ryoun Kim<SUP>25</SUP>, Won-Jung Koh<SUP>26</SUP>, Joey Lancaster<SUP>27</SUP>, Christophe Lange<SUP>28</SUP>, Wiel C. M. de Lange<SUP>29</SUP>, Vaira Leimane<SUP>30</SUP>, Chi Chiu Leung<SUP>31</SUP>, Jiehui Li<SUP>32</SUP>, Dick Menzies<SUP>5</SUP><SUP>*</SUP>, Giovanni B. Migliori<SUP>10</SUP>, Sergey P. Mishustin<SUP>33</SUP>, Carole D. Mitnick<SUP>7</SUP>, Masa Narita<SUP>34</SUP>, Philly O'Riordan<SUP>35</SUP>, Madhukar Pai<SUP>5</SUP>, Domingo Palmero<SUP>36</SUP>, Seung-kyu Park<SUP>37</SUP>, Geoffrey Pasvol<SUP>38</SUP>, Jose Pe?a<SUP>39</SUP>, Carlos P?rez-Guzm?n<SUP>40</SUP>, Maria I. D. Quelapio<SUP>41</SUP>, Alfredo Ponce-de-Leon<SUP>42</SUP>, Vija Riekstina<SUP>30</SUP>, Jerome Robert<SUP>43</SUP>, Sarah Royce<SUP>24</SUP>, H. Simon Schaaf<SUP>44</SUP>, Kwonjune J. Seung<SUP>45</SUP>, Lena Shah<SUP>5</SUP>, Tae Sun Shim<SUP>46</SUP>, Sonya S. Shin<SUP>45</SUP>, Yuji Shiraishi<SUP>47</SUP>, Jos? Sifuentes-Osornio<SUP>48</SUP>, Giovanni Sotgiu<SUP>49</SUP>, Matthew J. Strand<SUP>23</SUP>, Payam Tabarsi<SUP>50</SUP>, Thelma E. Tupasi<SUP>41</SUP>, Robert van Altena<SUP>29</SUP>, Martie Van der Walt<SUP>27</SUP>, Tjip S. Van der Werf<SUP>29</SUP>, Mario H. Vargas<SUP>51</SUP>, Pirett Viiklepp<SUP>52</SUP>, Janice Westenhouse<SUP>53</SUP>, Wing Wai Yew<SUP>54</SUP>, Jae-Joon Yim<SUP>55</SUP>, on behalf of the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB<SUP>?</SUP>
<SUP></SUP>
1 Bureau of Tuberculosis, New York, New York, United States of America, 2 A.G. Holley Hospital, Lantana, Florida, United States of America, 3 University of Toronto, Toronto, Canada, 4 Mayo Clinic, Rochester, Minnesota, United States of America, 5 Montreal Chest Institute, McGill University, Montreal, Canada, 6 The Dartmouth Center for Health Care Delivery Science, Hanover, New Hampshire, United States of America, 7 Harvard Medical School, Boston, Massachusetts, United States of America, 8 Partners in Health, Boston, Massachusetts, United States of America, 9 University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America, 10 WHO Collaborating Centre for TB and Lung Diseases, Care and Research Institute, Fondazione S. Maugeri, Tradate, Italy, 11 Denver Veterans Affair Medical Center, Denver, Colorado, United States of America, 12 Wan Fang Hospital, School of Medicine-Taipei Medical University, Taiwan, 13 M?decins Sans Fronti?res, Capetown, South Africa, 14 UC Davis School of Medicine, Davis, California, United States of America, 15 National TB Control Program, Hanoi, Vietnam, 16 International Union against Tuberculosis and Lung Disease, Paris, France, 17 World Health Organization, Geneva, Switzerland, 18 MRC Laboratories, Banjul, The Gambia, 19 California Department of Public Health, Sacramento, California, United States of America, 20 Instituto Nacional de Salud P?blica, Mexico, Mexico, 21 Albert Einstein College of Medicine, Bronx, New York, United States of America, 22 Thailand MOPH & US CDC Collaboration, Bangkok, Thailand, 23 National Jewish Health, Denver, Colorado, United States of America, 24 University of California, San Francisco, San Francisco, United States of America, 25 Korea Cancer Center Hospital, Seoul, Korea, 26 Samsung Medical Center, Seoul, Korea, 27 South African Medical Research Council, Pretoria, South Africa, 28 Medical Clinic, Tuberculosis Center Borstel, Borstel, Germany, 29 University Medical Center Groningen, Groningen, The Netherlands, 30 Clinic of Tuberculosis and Lung Diseases, Riga, Latvia, 31 Tuberculosis and Chest Services, Hong Kong, 32 New York City Health and Mental Hygiene, New York, New York, United States of America, 33 Tomsk Oblast Tuberculosis Dispensary, Tomsk, Russia, 34 University of Washington, Seattle, Washington, United States of America, 35 City Road Medical Centre, London, United Kingdom, 36 Hospital F.J. Mu?iz, Buenos Aires, Argentina, 37 TB Center, Seoul, Korea, 38 Imperial College London, London, United Kingdom, 39 Universidad Autonoma Madrid, Madrid, Spain, 40 Instituto de Salud del Estado de Aguascalientes, Mexico, Mexico, 41 Tropical Disease Foundation, Makati City, Philippines, 42 Instituto Nacional de Ciencias M?dicas y de Nutrici?n ?Salvador Zubir?n?, Mexico, Mexico, 43 Bact?riologie-Hygi?ne ? UPMC, Paris, France, 44 Stellenbosch University, Stellenbosch, South Africa, 45 Brigham and Women's Hospital, Boston, Massachusetts, United States of America, 46 University of Ulsan College of Medicine, Seoul, Korea, 47 Fukujuji Hospital, Tokyo, Japan, 48 Instituto Nacional de Ciencias M?dicas y de Nutrici?n ?Salvador Zubir?n?, Mexico, Mexico, 49 University of Sassari, Sassari, Italy, 50 Shaheed Beheshti Medical University, Tehran, Iran, 51 Instituto Nacional de Enfermedades Respiratorias, Mexico, Mexico, 52 National Institute for Health Development, Tallinn, Estonia, 53 Center for Infectious Diseases-California Department of Public Health, Sacramento, California, United States of America, 54 Grantham Hospital, Hong Kong, 55 Seoul National University College of Medicine, Seoul, Korea
Abstract
Background
Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.
Methods and Findings
Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1?6.0]), ofloxacin (aOR: 2.5 [1.6?3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3?2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3?3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7?4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7?4.3]), ofloxacin (aOR: 2.3 [1.3?3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4?2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9?3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4?6.0]).
Conclusions
In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
In 2010, 8.8 million people developed tuberculosis?a contagious bacterial infection?and 1.4 million people died from the disease. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze and usually infects the lungs (pulmonary tuberculosis). The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Tuberculosis can be cured by taking several powerful antibiotics regularly for at least 6 months. The standard treatment for tuberculosis comprises an initial intensive phase lasting 2 months during which four antibiotics are taken daily followed by a 4-month continuation phase during which two antibiotics are taken. However, global efforts to control tuberculosis are now being thwarted by the emergence of M. tuberculosis strains that are resistant to several antibiotics, including isoniazid and rifampicin, the two most powerful, first-line (standard) anti-tuberculosis drugs.
Why Was This Study Done?
Although multi-drug resistant tuberculosis (MDR-TB) can be cured using second-line anti-tuberculosis drugs, these are more expensive and more toxic than first-line drugs and optimal treatment regimens for MDR-TB have not been determined. Notably, there have been no randomized controlled trials of treatments for MDR-TB. Such trials, which compare outcomes (cure, treatment failure, relapse, and death) among patients who have been randomly assigned to receive different treatments, are the best way to compare different anti-tuberculosis drug regimens. It is possible, however, to get useful information about the association of various treatments for MDR-TB with outcomes from observational studies using a statistical approach called ?individual patient data meta-analysis.? In observational studies, because patients are not randomly assigned to different treatments, differences in outcomes between treatment groups may not be caused by the different drugs they receive but may be due to other differences between the groups. An individual patient data meta-analysis uses statistical methods to combine original patient data from several different studies. Here, the researchers use this approach to investigate the association of specific drugs, numbers of drugs and treatment duration with the clinical outcomes of patients with pulmonary MDR-TB.
What Did the Researchers Do and Find?
The researchers used three recent systematic reviews (studies that use predefined criteria to identify all the research on a given topic) to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. They obtained individual patient data from the authors of these studies and estimated adjusted odds (chances) of treatment success from the treatment and outcome data of 9,153 patients with MDR-TB provided by 32 centers. The use of later generation quinolones, ofloxacin, and ethionamide/prothionamide as part of multi-drug regimens were all associated with treatment success compared to failure, relapse or death, as were the use of four or more likely effective drugs (based on drug susceptibility testing of mycobacteria isolated from study participants) during the initial intensive treatment phase and the use of three or more likely effective drugs during the continuation phase. The researchers also report that among patients who did not die or stop treatment, the chances of treatment success increased with the duration of the initial treatment phase up to 7.1?8.5 months and with the total duration of treatment up to 18.6?21.5 months.
What Do These Findings Mean?
These findings suggest that the use of specific drugs, the use of a greater number of effective drugs, and longer treatments may be associated with treatment success and the survival of patients with MDR-TR. However, these findings need to be interpreted with caution because of limitations in this study that may have affected the accuracy of its findings. For example, the researchers did not include all the studies they found through the systematic reviews in their meta-analysis (some authors did not respond to requests for individual patient data, for example), which may have introduced bias. Moreover, because the patients included in the meta-analysis were treated at 32 centers, there were many differences in their management, some of which may have affected the accuracy of the findings. Because of these and other limitations, the researchers note that, although their findings highlight several important questions about the treatment of MDR-TB, randomized controlled trials are urgently needed to determine the optimal treatment for MDR-TB.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001300.
Academic Editor: Carlton Evans, Universidad Peruana Cayetano Heredia, Peru
Received: September 27, 2011; Accepted: July 17, 2012; Published: August 28, 2012
Copyright: ? 2012 Ahuja et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 bioM?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 and 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.
Abbreviations: AFB, acid fast bacilli; aOR, adjusted odds ratio; MDR-TB, multidrug resistant tuberculosis
* E-mail: Dick.Menzies@McGill.ca
? All members of the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB are the authors and are listed in the manuscript byline.
-Shama D. Ahuja<SUP>1</SUP>, David Ashkin<SUP>2</SUP>, Monika Avendano<SUP>3</SUP>, Rita Banerjee<SUP>4</SUP>, Melissa Bauer<SUP>5</SUP>, Jamie N. Bayona<SUP>6</SUP>, Mercedes C. Becerra<SUP>7</SUP><SUP>,</SUP><SUP>8</SUP>, Andrea Benedetti<SUP>5</SUP>, Marcos Burgos<SUP>9</SUP>, Rosella Centis<SUP>10</SUP>, Eward D. Chan<SUP>11</SUP>, Chen-Yuan Chiang<SUP>12</SUP>, Helen Cox<SUP>13</SUP>, Lia D'Ambrosio<SUP>10</SUP>, Kathy DeRiemer<SUP>14</SUP>, Nguyen Huy Dung<SUP>15</SUP>, Donald Enarson<SUP>16</SUP>, Dennis Falzon<SUP>17</SUP>, Katherine Flanagan<SUP>18</SUP>, Jennifer Flood<SUP>19</SUP>, Maria L. Garcia-Garcia<SUP>20</SUP>, Neel Gandhi<SUP>21</SUP>, Reuben M. Granich<SUP>17</SUP>, Maria G. Hollm-Delgado<SUP>5</SUP>, Timothy H. Holtz<SUP>22</SUP>, Michael D. Iseman<SUP>23</SUP>, Leah G. Jarlsberg<SUP>24</SUP>, Salmaan Keshavjee<SUP>7</SUP>, Hye-Ryoun Kim<SUP>25</SUP>, Won-Jung Koh<SUP>26</SUP>, Joey Lancaster<SUP>27</SUP>, Christophe Lange<SUP>28</SUP>, Wiel C. M. de Lange<SUP>29</SUP>, Vaira Leimane<SUP>30</SUP>, Chi Chiu Leung<SUP>31</SUP>, Jiehui Li<SUP>32</SUP>, Dick Menzies<SUP>5</SUP><SUP>*</SUP>, Giovanni B. Migliori<SUP>10</SUP>, Sergey P. Mishustin<SUP>33</SUP>, Carole D. Mitnick<SUP>7</SUP>, Masa Narita<SUP>34</SUP>, Philly O'Riordan<SUP>35</SUP>, Madhukar Pai<SUP>5</SUP>, Domingo Palmero<SUP>36</SUP>, Seung-kyu Park<SUP>37</SUP>, Geoffrey Pasvol<SUP>38</SUP>, Jose Pe?a<SUP>39</SUP>, Carlos P?rez-Guzm?n<SUP>40</SUP>, Maria I. D. Quelapio<SUP>41</SUP>, Alfredo Ponce-de-Leon<SUP>42</SUP>, Vija Riekstina<SUP>30</SUP>, Jerome Robert<SUP>43</SUP>, Sarah Royce<SUP>24</SUP>, H. Simon Schaaf<SUP>44</SUP>, Kwonjune J. Seung<SUP>45</SUP>, Lena Shah<SUP>5</SUP>, Tae Sun Shim<SUP>46</SUP>, Sonya S. Shin<SUP>45</SUP>, Yuji Shiraishi<SUP>47</SUP>, Jos? Sifuentes-Osornio<SUP>48</SUP>, Giovanni Sotgiu<SUP>49</SUP>, Matthew J. Strand<SUP>23</SUP>, Payam Tabarsi<SUP>50</SUP>, Thelma E. Tupasi<SUP>41</SUP>, Robert van Altena<SUP>29</SUP>, Martie Van der Walt<SUP>27</SUP>, Tjip S. Van der Werf<SUP>29</SUP>, Mario H. Vargas<SUP>51</SUP>, Pirett Viiklepp<SUP>52</SUP>, Janice Westenhouse<SUP>53</SUP>, Wing Wai Yew<SUP>54</SUP>, Jae-Joon Yim<SUP>55</SUP>, on behalf of the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB<SUP>?</SUP>
<SUP></SUP>
1 Bureau of Tuberculosis, New York, New York, United States of America, 2 A.G. Holley Hospital, Lantana, Florida, United States of America, 3 University of Toronto, Toronto, Canada, 4 Mayo Clinic, Rochester, Minnesota, United States of America, 5 Montreal Chest Institute, McGill University, Montreal, Canada, 6 The Dartmouth Center for Health Care Delivery Science, Hanover, New Hampshire, United States of America, 7 Harvard Medical School, Boston, Massachusetts, United States of America, 8 Partners in Health, Boston, Massachusetts, United States of America, 9 University of New Mexico School of Medicine, Albuquerque, New Mexico, United States of America, 10 WHO Collaborating Centre for TB and Lung Diseases, Care and Research Institute, Fondazione S. Maugeri, Tradate, Italy, 11 Denver Veterans Affair Medical Center, Denver, Colorado, United States of America, 12 Wan Fang Hospital, School of Medicine-Taipei Medical University, Taiwan, 13 M?decins Sans Fronti?res, Capetown, South Africa, 14 UC Davis School of Medicine, Davis, California, United States of America, 15 National TB Control Program, Hanoi, Vietnam, 16 International Union against Tuberculosis and Lung Disease, Paris, France, 17 World Health Organization, Geneva, Switzerland, 18 MRC Laboratories, Banjul, The Gambia, 19 California Department of Public Health, Sacramento, California, United States of America, 20 Instituto Nacional de Salud P?blica, Mexico, Mexico, 21 Albert Einstein College of Medicine, Bronx, New York, United States of America, 22 Thailand MOPH & US CDC Collaboration, Bangkok, Thailand, 23 National Jewish Health, Denver, Colorado, United States of America, 24 University of California, San Francisco, San Francisco, United States of America, 25 Korea Cancer Center Hospital, Seoul, Korea, 26 Samsung Medical Center, Seoul, Korea, 27 South African Medical Research Council, Pretoria, South Africa, 28 Medical Clinic, Tuberculosis Center Borstel, Borstel, Germany, 29 University Medical Center Groningen, Groningen, The Netherlands, 30 Clinic of Tuberculosis and Lung Diseases, Riga, Latvia, 31 Tuberculosis and Chest Services, Hong Kong, 32 New York City Health and Mental Hygiene, New York, New York, United States of America, 33 Tomsk Oblast Tuberculosis Dispensary, Tomsk, Russia, 34 University of Washington, Seattle, Washington, United States of America, 35 City Road Medical Centre, London, United Kingdom, 36 Hospital F.J. Mu?iz, Buenos Aires, Argentina, 37 TB Center, Seoul, Korea, 38 Imperial College London, London, United Kingdom, 39 Universidad Autonoma Madrid, Madrid, Spain, 40 Instituto de Salud del Estado de Aguascalientes, Mexico, Mexico, 41 Tropical Disease Foundation, Makati City, Philippines, 42 Instituto Nacional de Ciencias M?dicas y de Nutrici?n ?Salvador Zubir?n?, Mexico, Mexico, 43 Bact?riologie-Hygi?ne ? UPMC, Paris, France, 44 Stellenbosch University, Stellenbosch, South Africa, 45 Brigham and Women's Hospital, Boston, Massachusetts, United States of America, 46 University of Ulsan College of Medicine, Seoul, Korea, 47 Fukujuji Hospital, Tokyo, Japan, 48 Instituto Nacional de Ciencias M?dicas y de Nutrici?n ?Salvador Zubir?n?, Mexico, Mexico, 49 University of Sassari, Sassari, Italy, 50 Shaheed Beheshti Medical University, Tehran, Iran, 51 Instituto Nacional de Enfermedades Respiratorias, Mexico, Mexico, 52 National Institute for Health Development, Tallinn, Estonia, 53 Center for Infectious Diseases-California Department of Public Health, Sacramento, California, United States of America, 54 Grantham Hospital, Hong Kong, 55 Seoul National University College of Medicine, Seoul, Korea
Abstract
Background
Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB.
Methods and Findings
Three recent systematic reviews were used to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. Study authors were contacted to solicit individual patient data including clinical characteristics, treatment given, and outcomes. Random effects multivariable logistic meta-regression was used to estimate adjusted odds of treatment success. Adequate treatment and outcome data were provided for 9,153 patients with MDR-TB from 32 observational studies. Treatment success, compared to failure/relapse, was associated with use of: later generation quinolones, (adjusted odds ratio [aOR]: 2.5 [95% CI 1.1?6.0]), ofloxacin (aOR: 2.5 [1.6?3.9]), ethionamide or prothionamide (aOR: 1.7 [1.3?2.3]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.3 [1.3?3.9]), and three or more likely effective drugs in the continuation phase (aOR: 2.7 [1.7?4.1]). Similar results were seen for the association of treatment success compared to failure/relapse or death: later generation quinolones, (aOR: 2.7 [1.7?4.3]), ofloxacin (aOR: 2.3 [1.3?3.8]), ethionamide or prothionamide (aOR: 1.7 [1.4?2.1]), use of four or more likely effective drugs in the initial intensive phase (aOR: 2.7 [1.9?3.9]), and three or more likely effective drugs in the continuation phase (aOR: 4.5 [3.4?6.0]).
Conclusions
In this individual patient data meta-analysis of observational data, improved MDR-TB treatment success and survival were associated with use of certain fluoroquinolones, ethionamide, or prothionamide, and greater total number of effective drugs. However, randomized trials are urgently needed to optimize MDR-TB treatment.
Please see later in the article for the Editors' Summary.
Editors' Summary
Background
In 2010, 8.8 million people developed tuberculosis?a contagious bacterial infection?and 1.4 million people died from the disease. Mycobacterium tuberculosis, the bacterium that causes tuberculosis, is spread in airborne droplets when people with the disease cough or sneeze and usually infects the lungs (pulmonary tuberculosis). The characteristic symptoms of tuberculosis are a persistent cough, weight loss, and night sweats. Tuberculosis can be cured by taking several powerful antibiotics regularly for at least 6 months. The standard treatment for tuberculosis comprises an initial intensive phase lasting 2 months during which four antibiotics are taken daily followed by a 4-month continuation phase during which two antibiotics are taken. However, global efforts to control tuberculosis are now being thwarted by the emergence of M. tuberculosis strains that are resistant to several antibiotics, including isoniazid and rifampicin, the two most powerful, first-line (standard) anti-tuberculosis drugs.
Why Was This Study Done?
Although multi-drug resistant tuberculosis (MDR-TB) can be cured using second-line anti-tuberculosis drugs, these are more expensive and more toxic than first-line drugs and optimal treatment regimens for MDR-TB have not been determined. Notably, there have been no randomized controlled trials of treatments for MDR-TB. Such trials, which compare outcomes (cure, treatment failure, relapse, and death) among patients who have been randomly assigned to receive different treatments, are the best way to compare different anti-tuberculosis drug regimens. It is possible, however, to get useful information about the association of various treatments for MDR-TB with outcomes from observational studies using a statistical approach called ?individual patient data meta-analysis.? In observational studies, because patients are not randomly assigned to different treatments, differences in outcomes between treatment groups may not be caused by the different drugs they receive but may be due to other differences between the groups. An individual patient data meta-analysis uses statistical methods to combine original patient data from several different studies. Here, the researchers use this approach to investigate the association of specific drugs, numbers of drugs and treatment duration with the clinical outcomes of patients with pulmonary MDR-TB.
What Did the Researchers Do and Find?
The researchers used three recent systematic reviews (studies that use predefined criteria to identify all the research on a given topic) to identify studies reporting treatment outcomes of microbiologically confirmed MDR-TB. They obtained individual patient data from the authors of these studies and estimated adjusted odds (chances) of treatment success from the treatment and outcome data of 9,153 patients with MDR-TB provided by 32 centers. The use of later generation quinolones, ofloxacin, and ethionamide/prothionamide as part of multi-drug regimens were all associated with treatment success compared to failure, relapse or death, as were the use of four or more likely effective drugs (based on drug susceptibility testing of mycobacteria isolated from study participants) during the initial intensive treatment phase and the use of three or more likely effective drugs during the continuation phase. The researchers also report that among patients who did not die or stop treatment, the chances of treatment success increased with the duration of the initial treatment phase up to 7.1?8.5 months and with the total duration of treatment up to 18.6?21.5 months.
What Do These Findings Mean?
These findings suggest that the use of specific drugs, the use of a greater number of effective drugs, and longer treatments may be associated with treatment success and the survival of patients with MDR-TR. However, these findings need to be interpreted with caution because of limitations in this study that may have affected the accuracy of its findings. For example, the researchers did not include all the studies they found through the systematic reviews in their meta-analysis (some authors did not respond to requests for individual patient data, for example), which may have introduced bias. Moreover, because the patients included in the meta-analysis were treated at 32 centers, there were many differences in their management, some of which may have affected the accuracy of the findings. Because of these and other limitations, the researchers note that, although their findings highlight several important questions about the treatment of MDR-TB, randomized controlled trials are urgently needed to determine the optimal treatment for MDR-TB.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001300.
- The World Health Organization provides information on all aspects of tuberculosis, including MDR-TB; its guidelines for the programmatic management of drug-resistant tuberculosis are available
- The US Centers for Disease Control and Prevention has information about tuberculosis, including information on the treatment of tuberculosis and on MDR-TB
- The US National Institute of Allergy and Infectious Diseases also has information on all aspects of tuberculosis, including a drug-resistant tuberculosis visual tour
- MedlinePlus has links to further information about tuberculosis (in English and Spanish)
- TB & ME, a collaborative blogging project run by patients being treated for multidrug-resistant tuberculosis and Medecins sans Frontieres, provides information about MDR-TB and patient stories about treatment for MDR-TB
- The Tuberculosis Survival Project, which aims to raise awareness of tuberculosis and provide support for people with tuberculosis, also provides personal stories about treatment for tuberculosis
Academic Editor: Carlton Evans, Universidad Peruana Cayetano Heredia, Peru
Received: September 27, 2011; Accepted: July 17, 2012; Published: August 28, 2012
Copyright: ? 2012 Ahuja et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 bioM?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 and 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.
Abbreviations: AFB, acid fast bacilli; aOR, adjusted odds ratio; MDR-TB, multidrug resistant tuberculosis
* E-mail: Dick.Menzies@McGill.ca
? All members of the Collaborative Group for Meta-Analysis of Individual Patient Data in MDR-TB are the authors and are listed in the manuscript byline.
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