Treatment Outcomes of Multidrug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis

Fitzgerald JM (2009) Treatment Outcomes of Multidrug-Resistant Tuberculosis: A Systematic Review and Meta- Analysis. PLoS ONE 4(9): e6914. doi:10.1371/journal.pone.0006914 Treatment Outcomes of Multidrug-Resistant Tuberculosis: A Systematic Review and Meta-Analysis James C. Johnston 0 Neal C. Shahidi 0 Mohsen Sadatsafavi 0 J. Mark Fitzgerald 0 Madhukar Pai, McGill University, Canada 0 1 Tuberculosis Control, British Columbia Centre for Disease Control , Vancouver , Canada , 2 Centre for Clinical Epidemiology and Evaluation, Vancouver Coastal Health Research , Vancouver , Canada , 3 Collaboration for Outcome Research and Evaluation, University of British Columbia , Vancouver , Canada Background: Treatment outcomes for multidrug-resistant Mycobacterium Tuberculosis (MDRTB) are generally poor compared to drug sensitive disease. We sought to estimate treatment outcomes and identify risk factors associated with poor outcomes in patients with MDRTB. Methodology/Principal Findings: We performed a systematic search (to December 2008) to identify trials describing outcomes of patients treated for MDRTB. We pooled appropriate data to estimate WHO-defined outcomes at the end of treatment and follow-up. Where appropriate, pooled covariates were analyzed to identify factors associated with worse outcomes. Among articles identified, 36 met our inclusion criteria, representing 31 treatment programmes from 21 countries. In a pooled analysis, 62% [95% CI 57-67] of patients had successful outcomes, while 13% [9-17] defaulted, 11% [9-13] died, and 2% [1-4] were transferred out. Factors associated with worse outcome included male gender 0.61 (OR for successful outcome) [0.46-0.82], alcohol abuse 0.49 [0.39-0.63], low BMI 0.41[0.23-0.72], smear positivity at diagnosis 0.53 [0.31-0.91], fluoroquinolone resistance 0.45 [0.22-0.91] and the presence of an XDR resistance pattern 0.57 [0.41-0.80]. Factors associated with successful outcome were surgical intervention 1.91 [1.44-2.53], no previous treatment 1.42 [1.051.94], and fluoroquinolone use 2.20 [1.19-4.09]. Conclusions/Significance: We have identified several factors associated with poor outcomes where interventions may be targeted. In addition, we have identified high rates of default, which likely contributes to the development and spread of MDRTB. - Competing Interests: The authors have declared that no competing interests exist. Multidrug-Resistant Tuberculosis (MDRTB) refers to Mycobacterium tuberculosis (TB) strains with in vitro resistance to the two most effective anti-tuberculosis drugs, isoniazid (INH) and rifampin (RFP). MDRTB has become a major barrier to achieving successful control of TB, as therapy is less effective, associated with more adverse events and is more costly to treat when compared with standard first line therapy. According to a recent WHO report, approximately 490,000 MDRTB cases occur globally every year, corresponding to approximately 4.8% of the worlds TB cases [1,2]. The importance of addressing drug resistant TB is further amplified by more recent reports on extensively drug resistant TB (XDRTB) [3], which represented 7% of MDR isolates referred to supranational reference laboratories from 20002004 [1]. Inadequate treatment of MDRTB can lead to worse patient outcomes, while increasing the risk of extensive drug resistance [46]. Guidelines for the management of MDRTB have been developed over the past decade, but there is little evidence based on randomized controlled trials to support current recommendations [7,8]. Moreover, treatment strategies have varied significantly and are difficult to compare between populations [8,9]. This lack of evidence reflects a lack of political and financial will, in part from the perception that MDRTB is of limited epidemiological importance [7]. It also reflects the limited number of second line drugs that are available and the unequal distribution of access depending on local resources. The recent recognition of the increasing magnitude of MDRTB, along with the poor prognosis of XDRTB has created the impetus for a more evidence-based approach to the treatment of MDRTB. Recently, standardized definitions were established to allow comparison between treatment groups and facilitate the development of a more evidence-based approach [9,10]. We therefore decided to complete a systematic review of MDRTB treatment regimens. Where appropriate, we performed a meta-analysis to explore associations between MDRTB treatment outcomes and the clinical and microbiological factors that influence outcome. We aimed to identify all the published literature and to establish the best possible evidence base of clinical and microbiological predictors of treatment response. Search strategy Several search strategies were used to identify potentially relevant studies. Search strategy was developed by the investigators (Johnston and Shahidi) with consultation of a medical librarian. Selection of Studies Studies obtained from the literature search were checked by title and citation. If an article appeared relevant, the abstract was reviewed. Relevant abstracts were examined in full text. Inclusion criteria were as follows: an original study; reported in English; reported treatment outcomes in a population of adult, cultureconfirmed MDRTB patients; reported outcomes presented in a format allowing for comparison with other studies. Exclusion criteria were as follows: exclusive surgical series; exclusive use of first-line therapy in the treatment protocol. Validity assessment Studies were assessed for quality, with only high quality studies included for analysis. High quality studies reported outcomes on at least 10 patients; were prospective cohort, retrospective consecutive cohort, consecutive case control or randomized control in design; reported an average treatment duration of $12 months within an average follow-up duration $18 months; reported basic demographic data; reported less than 1/3 default or lost to followup. When study populations overlapped, we included the more recent and larger study population in the analysis. If the smaller population provided data on an outcome or variable not reported in the larger study, results were included for that specific variable. Outcome measures Measured outcomes reflect the definitions proposed by Laserson et al., and published in recent WHO guidelines [9,10]. Successful outcomes included patients meeting the definition of Cure or Treatment Completed. Unsuccessful outcomes included patients meeting the definition of Death, Defaulted, Failed or Transferred Out. When follow-up data was used, relapse was included as an unsuccessful outcome. To homogenize data, end-of-treatment (EOT) and follow-up (FUP) outcomes were separated for analysis. FUP outcomes refer to post-treatment follow-up, with follow-up duration measured in months. If studies were unable to meet WHO definitions, reviewers established outcomes to reflect these definitions. Certain (...truncated)