Comorbidities and treatment outcomes in multidrug resistant tuberculosis: a systematic review and meta-analysis

www.nature.com/scientificreports OPEN Received: 10 October 2017 Accepted: 9 March 2018 Published: xx xx xxxx Comorbidities and treatment outcomes in multidrug resistant tuberculosis: a systematic review and meta-analysis Joel Philip Samuels 1, Aashna Sood2, Jonathon R. Campbell3, Faiz Ahmad Khan4,5,6 & James Cameron Johnston7,8 Little is known about the impact of comorbidities on multidrug resistant (MDR) and extensively drug resistant (XDR) tuberculosis (TB) treatment outcomes. We aimed to examine the effect of human immunodeficiency virus (HIV), diabetes, chronic kidney disease (CKD), alcohol misuse, and smoking on MDR/XDRTB treatment outcomes. We searched MEDLINE, EMBASE, Cochrane Central Registrar and Cochrane Database of Systematic Reviews as per PRISMA guidelines. Eligible studies were identified and treatment outcome data were extracted. We performed a meta-analysis to generate a pooled relative risk (RR) for unsuccessful outcome in MDR/XDRTB treatment by co-morbidity. From 2457 studies identified, 48 reported on 18,257 participants, which were included in the final analysis. Median study population was 235 (range 60–1768). Pooled RR of unsuccessful outcome was higher in people living with HIV (RR = 1.41 [95%CI: 1.15–1.73]) and in people with alcohol misuse (RR = 1.45 [95%CI: 1.21–1.74]). Outcomes were similar in people with diabetes or in people that smoked. Data was insufficient to examine outcomes in exclusive XDRTB or CKD cohorts. In this systematic review and meta-analysis, alcohol misuse and HIV were associated with higher pooled OR of an unsuccessful outcome in MDR/XDRTB treatment. Further research is required to understand the role of comorbidities in driving unsuccessful treatment outcomes. A major barrier to global tuberculosis (TB) elimination is the emergence of multidrug resistant TB (MDRTB) and extensively drug resistant TB (XDRTB)1–3. MDRTB is defined as resistance to at least rifampin and isoniazid1,3,4, while XDRTB is defined as resistance to rifampin, isoniazid, a fluoroquinolone and at least one second-line injectable agent2,3,5. MDR- and XDRTB require prolonged medical therapy and are associated with high rates of failure, loss to follow-up, relapse and death, largely the result of less effective and highly toxic TB treatment regimens3. In 2013, only 52% of MDRTB and 26% of XDRTB patients were successfully treated6. Understanding the drivers of unsuccessful treatment outcomes will be crucial in addressing the global MDR/XDRTB epidemic. One driver of unsuccessful treatment outcomes may be comorbid conditions. The impact of comorbidities on drug sensitive TB treatment is well-described, with conditions such as human immunodeficiency virus (HIV) infection, diabetes mellitus (DM), chronic kidney disease (CKD) and alcohol misuse all associated with worse treatment outcomes3,7–10. MDR/XDRTB treatment programs often report high proportions of these comorbidities, with the prevalence of HIV, DM and alcohol misuse exceeding 10–20% in several large MDR/XDRTB cohort studies11–15. Unfortunately, the relationship between comorbid conditions and MDR/XDRTB treatment outcomes remains poorly described. We performed a systematic review of the published, peer-reviewed literature examining the association between specific comorbidities, including of HIV, diabetes, CKD, smoking and alcohol misuse, 1 Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada. 2Royal College of Surgeons in Ireland, Dublin, Ireland. 3Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada. 4Respiratory Epidemiology & Clinical Research Unit, Centre for Outcomes Research and Evaluation, MUHC-RI, Montreal, Quebec, Canada. 5Division of Respiratory Medicine, McGill University Health Centre, Montreal, Quebec, Canada. 6McGill International TB Centre, Montreal, Quebec, Canada. 7TB Services, BC Centre for Disease Control, Vancouver, British Columbia, Canada. 8Division of Respiratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada. Correspondence and requests for materials should be addressed to J.P.S. (email: ) or J.C.J. (email: ) SCIEnTIFIC REPorTS | (2018) 8:4980 | DOI:10.1038/s41598-018-23344-z 1 www.nature.com/scientificreports/ and MDR/XDRTB treatment outcomes3,7,8,16–19. We aimed to examine the relationship between comorbidities and standardized treatment outcomes including death, default, failure and a combined endpoint of unsuccessful treatment outcome. Methods This systematic review and meta-analysis conforms to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines20. Our research protocol is registered in PROSPERO (http://www.crd.york. ac.uk/PROSPERO/display_record.asp?ID=CRD42016039866, registration number CRD42016039866). Objectives. Our primary objective was to estimate the association between individual comorbidities and risk of unsuccessful MDR/XDRTB treatment outcome (failure, death or default, as defined below). Our secondary objectives were to estimate the association between each comorbid condition with each specific treatment outcome. Search strategy. Studies were identified by searching MEDLINE, EMBASE, Cochrane Central Registrar of Controlled Trials and Cochrane Database of Systematic Reviews for articles reporting MDRTB and XDRTB outcomes, published between January 1, 1980 and June 1, 2016. The full search strategy is provided in the online Appendix (Supp. Appendix). The database search was supplemented by reviewing bibliographies from all included full text articles and previous systematic reviews on MDRTB or XDRTB treatment outcomes3,5,18,19,21–24, as well as searching manually through all published titles from the International Journal of Tuberculosis and Lung Disease for relevant studies. Eligibility Criteria and Study Selection. We included studies that enrolled at least 50 participants with microbiologically-confirmed MDRTB and/or XDRTB. Eligible studies included randomized control trials (RCTs), case-control (CC), retrospective cohort (RC) and prospective cohort (PC) studies. We examined studies reported in the peer-reviewed literature in English, French and Spanish. Studies were excluded if they reported on exclusively surgical or non-medical therapy, exclusively used standardized first-line therapy or had non-consecutive enrolment. We also excluded studies with >30% loss to follow-up, default, or treatment outcomes otherwise unaccounted for. If two studies reported duplicate data, the publication with the more detailed reports on treatment outcomes was included for meta-analysis. Studies that did not report data necessary for calculating associations between comorbidities and outcomes were excluded from the meta-analysis but their data is reported in the Appendix (Supp. Tables 7–10)25–34. Two authors (JS, AS) performed the search strategy. Titles then abstracts were reviewed; studies were excluded for lack (...truncated)