Elsevier

The Lancet

Volume 392, Issue 10150, 8–14 September 2018, Pages 821-834
The Lancet

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

https://doi.org/10.1016/S0140-6736(18)31644-1Get rights and content

Summary

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 I2 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.

Introduction

WHO estimated that in 2016, there were almost 600 000 new cases of multidrug-resistant tuberculosis, defined as disease due to Mycobacterium tuberculosis that is resistant to isoniazid and rifampin; of the 99 165 people with multidrug-resistant tuberculosis that started treatment in 2014, only 53 549 (54%) were cured.1 These poor cure rates reflect the lengthy treatment with second-line tuberculosis drugs, which are less effective and more toxic than those used for drug-susceptible tuberculosis.2, 3 To date, there have been very few phase 3 randomised controlled trials investigating the treatment of multidrug-resistant tuberculosis, so most evidence for regimen selection is still from observational studies,3 or individual patient data (meta-analyses of these studies).4

In the past decade, several experimental and observational studies have documented the use of new and repurposed drugs, such as bedaquiline,5, 6 linezolid,7, 8 delamanid, clofazimine,9 and the carbapenems.10, 11 We assembled a database of individual records of patients treated for multidrug-resistant tuberculosis to estimate the association of treatment outcomes with use of specific anti-tuberculosis drugs, as well the optimal number and duration of treatment with those drugs.

Section snippets

Search strategy and selection criteria

The protocol for this study followed PRISMA guidelines and is available from the authors.

In September 2015, we did a systematic review to identify studies published between Jan 1, 2009, and Sept 15, 2015, of treatment of multidrug-resistant tuberculosis, including extensively drug-resistant tuberculosis.12 We updated the search in April, 2016, using the same search terms in MEDLINE, Embase, and the Cochrane library (appendix p 2). We also searched reference lists from all systematic reviews of

Results

We identified 87 individual studies, of which 50 (57%) provided adequate data for patients with confirmed pulmonary rifampin resistance (n=12 030; figure).5, 7, 8, 10, 11, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77 Of these patients, 11 918 (99·1%) had documented isoniazid resistance, 31 (0·3%) had

Discussion

We assessed 50 datasets from 25 countries, with 12 030 patients treated for multidrug-resistant tuberculosis. Of the drugs analysed, levofloxacin, moxifloxacin, linezolid, and bedaquiline were associated with greater treatment success and reduced death. Clofazimine and the carbapenems were associated with significantly improved treatment success but not reduced death. Pyrazinamide, streptomycin, amikacin, and cycloserine and terizidone were associated with modest benefits, but only in patients

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