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Increasing Burden of Multidrug Resistant Tuberculosis in HIV Infected Individuals: A Systematic Review and Meta-Analysis

Background: The increasing burden of multidrug-resistant tuberculosis (MDR-TB) in HIV infected individuals is a serious threat to global tuberculosis control programs. The study aimed to summarize the available evidences on the association of HIV infection and the development of MDR-TB and, finally, to provide an up-to-datepooled estimate of risks. 
 
Methods: We searched on PubMed, Google Scholar, and ScienceDirect databases to select eligible studies for our systematic review and meta-analysis, published between January 1, 2010, and July 30,2019. Two sets of reviewers independently extracted data and assessed the methodological quality of the studies using the Newcastle-Ottawa Scale. Subgroup analysis was pre-specified to perform according to the continent, country, income level, study design, mean/median age, and type of MDR-TB. The random-effects model was used to obtain the pooled odds ratio of the crude association between HIV infection and MDR-TB with a 95% confidence interval. We investigated the potential publication bias by checking funnel plot asymmetry and using the Egger’s test. Moreover, we assessed the heterogeneity using Cochran’s Q test and the I2 statistic. 
 
Findings: We identified 1496 studies through a database search, and after subsequent elimination based on our eligibility criteria, we selected 47 articles, including 60,754 participants. The pooled odds ratio was 1.47 (95% CI= 1.19-1.81) with substantial heterogeneity (I2=80.49%), and there was no evidence of publication bias (p=0.13). Subgroup analysis revealed that the estimated pooled odds ratio for European countries (OR=2.31, 95% CI= 1.80-2.96, I2=32.26%) was higher than the other three continents (South American, Asia, and Africa). Further analysis showed that the effect estimate was higher for primary MDR-TB (OR=3.13, 95% CI= 1.59-6.13, I2=13.13%) with no heterogeneity among the studies. There was also a trend towards increased risk of MDR-TB for HIV patients of 40 years and older (OR=1.96, 95% CI= 1.41-2.73, I2=69.11%) and women HIV patients (OR=1.97, 95% CI 1.03-3.78, I2=80.35%). The MDR-TB is found to be significant in high burden of TB/HIV countries (OR=1.51, 95% CI= 1.18-1.92, I2=78.1%) and in high-income countries (OR=2.64, 95% CI= 2.01-3.48, I2=15.01%). 
 
Interpretation:The risk of MDR-TB increases significantly among HIV infected individuals from the last decade. The most considerable burden of MDR-TB in HIV individuals was found in Europe and the women HIV patients with age 40 years and older are most in the risk of MDR-TB. 
 
Funding Statement: The authors stated: "There was a student seed fund for this study. The corresponding author had full access to all study data and the authorized person for the final submission of the paper for publication." 
 
Declaration of Interests: The authors declare no competing interests. 
 
Ethics Approval Statement: The protocol was registered with PROSPERO-CRD42019132752.