Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis

The Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017

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Abstract

Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. Findings: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (–0·20, –0·23 to –0·16), levofloxacin (–0·06, –0·09 to –0·04), moxifloxacin (–0·07, –0·10 to –0·04), or bedaquiline (–0·14, –0·19 to –0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I 2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. Interpretation: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. Funding: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

Original languageEnglish (US)
Pages (from-to)821-834
Number of pages14
JournalThe Lancet
Volume392
Issue number10150
DOIs
StatePublished - Sep 8 2018

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Multidrug-Resistant Tuberculosis
Pulmonary Tuberculosis
Meta-Analysis
Linezolid
bedaquiline
Pharmaceutical Preparations
Clofazimine
Therapeutics
Levofloxacin
Carbapenems
Recurrence
Capreomycin
Propensity Score
Kanamycin
Amikacin
Fluoroquinolones
Drug Combinations
Centers for Disease Control and Prevention (U.S.)
MEDLINE
Libraries

ASJC Scopus subject areas

  • Medicine(all)

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The Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017 (2018). Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. The Lancet, 392(10150), 821-834. https://doi.org/10.1016/S0140-6736(18)31644-1

Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis : an individual patient data meta-analysis. / The Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017.

In: The Lancet, Vol. 392, No. 10150, 08.09.2018, p. 821-834.

Research output: Contribution to journalArticle

The Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017 2018, 'Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis', The Lancet, vol. 392, no. 10150, pp. 821-834. https://doi.org/10.1016/S0140-6736(18)31644-1
The Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017. Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis: an individual patient data meta-analysis. The Lancet. 2018 Sep 8;392(10150):821-834. https://doi.org/10.1016/S0140-6736(18)31644-1
The Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017. / Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis : an individual patient data meta-analysis. In: The Lancet. 2018 ; Vol. 392, No. 10150. pp. 821-834.
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TY - JOUR

T1 - Treatment correlates of successful outcomes in pulmonary multidrug-resistant tuberculosis

T2 - an individual patient data meta-analysis

AU - The Collaborative Group for the Meta-Analysis of Individual Patient Data in MDR-TB treatment–2017

AU - Ahmad, Nafees

AU - Ahuja, Shama D.

AU - Akkerman, Onno W.

AU - Alffenaar, Jan Willem C.

AU - Anderson, Laura F.

AU - Baghaei, Parvaneh

AU - Bang, Didi

AU - Barry, Pennan M.

AU - Bastos, Mayara L.

AU - Behera, Digamber

AU - Benedetti, Andrea

AU - Bisson, Gregory P.

AU - Boeree, Martin J.

AU - Bonnet, Maryline

AU - Brode, Sarah K.

AU - Brust, James C.M.

AU - Cai, Ying

AU - Caumes, Eric

AU - Cegielski, J. Peter

AU - Centis, Rosella

AU - Chan, Pei Chun

AU - Chan, Edward D.

AU - Chang, Kwok Chiu

AU - Charles, Macarthur

AU - Cirule, Andra

AU - Dalcolmo, Margareth Pretti

AU - D'Ambrosio, Lia

AU - de Vries, Gerard

AU - Dheda, Keertan

AU - Esmail, Aliasgar

AU - Flood, Jennifer

AU - Fox, Gregory J.

AU - Fréchet-Jachym, Mathilde

AU - Fregona, Geisa

AU - Gayoso, Regina

AU - Gegia, Medea

AU - Gler, Maria Tarcela

AU - Gu, Sue

AU - Guglielmetti, Lorenzo

AU - Holtz, Timothy H.

AU - Hughes, Jennifer

AU - Isaakidis, Petros

AU - Jarlsberg, Leah

AU - Kempker, Russell R.

AU - Keshavjee, Salmaan

AU - Khan, Faiz Ahmad

AU - Kipiani, Maia

AU - Koenig, Serena P.

AU - Koh, Won Jung

AU - Kritski, Afranio

PY - 2018/9/8

Y1 - 2018/9/8

N2 - Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. Findings: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (–0·20, –0·23 to –0·16), levofloxacin (–0·06, –0·09 to –0·04), moxifloxacin (–0·07, –0·10 to –0·04), or bedaquiline (–0·14, –0·19 to –0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I 2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. Interpretation: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. Funding: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

AB - Background: Treatment outcomes for multidrug-resistant tuberculosis remain poor. We aimed to estimate the association of treatment success and death with the use of individual drugs, and the optimal number and duration of treatment with those drugs in patients with multidrug-resistant tuberculosis. Methods: In this individual patient data meta-analysis, we searched MEDLINE, Embase, and the Cochrane Library to identify potentially eligible observational and experimental studies published between Jan 1, 2009, and April 30, 2016. We also searched reference lists from all systematic reviews of treatment of multidrug-resistant tuberculosis published since 2009. To be eligible, studies had to report original results, with end of treatment outcomes (treatment completion [success], failure, or relapse) in cohorts of at least 25 adults (aged >18 years). We used anonymised individual patient data from eligible studies, provided by study investigators, regarding clinical characteristics, treatment, and outcomes. Using propensity score-matched generalised mixed effects logistic, or linear regression, we calculated adjusted odds ratios and adjusted risk differences for success or death during treatment, for specific drugs currently used to treat multidrug-resistant tuberculosis, as well as the number of drugs used and treatment duration. Findings: Of 12 030 patients from 25 countries in 50 studies, 7346 (61%) had treatment success, 1017 (8%) had failure or relapse, and 1729 (14%) died. Compared with failure or relapse, treatment success was positively associated with the use of linezolid (adjusted risk difference 0·15, 95% CI 0·11 to 0·18), levofloxacin (0·15, 0·13 to 0·18), carbapenems (0·14, 0·06 to 0·21), moxifloxacin (0·11, 0·08 to 0·14), bedaquiline (0·10, 0·05 to 0·14), and clofazimine (0·06, 0·01 to 0·10). There was a significant association between reduced mortality and use of linezolid (–0·20, –0·23 to –0·16), levofloxacin (–0·06, –0·09 to –0·04), moxifloxacin (–0·07, –0·10 to –0·04), or bedaquiline (–0·14, –0·19 to –0·10). Compared with regimens without any injectable drug, amikacin provided modest benefits, but kanamycin and capreomycin were associated with worse outcomes. The remaining drugs were associated with slight or no improvements in outcomes. Treatment outcomes were significantly worse for most drugs if they were used despite in-vitro resistance. The optimal number of effective drugs seemed to be five in the initial phase, and four in the continuation phase. In these adjusted analyses, heterogeneity, based on a simulated I 2 method, was high for approximately half the estimates for specific drugs, although relatively low for number of drugs and durations analyses. Interpretation: Although inferences are limited by the observational nature of these data, treatment outcomes were significantly better with use of linezolid, later generation fluoroquinolones, bedaquiline, clofazimine, and carbapenems for treatment of multidrug-resistant tuberculosis. These findings emphasise the need for trials to ascertain the optimal combination and duration of these drugs for treatment of this condition. Funding: American Thoracic Society, Canadian Institutes of Health Research, US Centers for Disease Control and Prevention, European Respiratory Society, Infectious Diseases Society of America.

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