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Background Multidrug-resistant (MDR) and extensively drug resistant (XDR) Mycobacterium tuberculosis complex (MTBC) strains are a great challenge for tuberculosis (TB) control in India. Still, factors driving the MDR/XDR epidemic in India are not well defined. Methods Whole genome sequencing (WGS) data from 1 852 MTBC strains obtained from patients from a tertiary care hospital laboratory in Mumbai were used for phylogenetic strain classification, resistance prediction, and cluster analysis (12 allele distance threshold). Factors associated with pre-XDR/XDR-TB were defined by odds ratios and a multivariate logistic regression model. Results 1 017 MTBC strains were MDR, out of which 57.8 % (n=591) were pre-XDR, and 17.9 % (n=183) were XDR. Lineage 2 (L2) strains represented 41.7 % of the MDR, 77.2 % of the pre-XDR, and 86.3 % of the XDR strains, and were significantly associated with pre-XDR/XDR-TB (P Conclusions High rates of pre-XDR/XDR strains among MDR-TB patients require rapid changes in treatment and control strategies. Transmission of particular pre-XDR/XDR L2 strains is the main driver of the pre-XDR/XDR-TB epidemic. Accordingly, control of the epidemic in the region requires measures with stopping transmission esp. of pre-XDR/XDR L2 strains. Funding source Parts of this work have been supported within the CRYPTIC consortium by the Bill & Melinda Gates Foundation [OPP1133541] and the Wellcome Trust [200205/Z/15/Z], the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanys Excellence Strategy – EXC 2167 Precision Medicine in Inflammation, and the Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG). The funders had no role in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. Research in context Evidence before this study India is particularly affected by multidrug resistant (MDR), and extremely drug resistant (XDR) tuberculosis (TB), e.g., accounting for 27 % of the globally newly emerging MDR-TB cases. Over the past 2 decades several studies have highlighted high rates of drug resistance in Mumbai. More recently in the Mumbai metropolitan area, around 5,000 new MDR-TB cases are notified annually, with a more than 30% increase over a three-year period from 2015 to 2017. These data are extremely alarming, threatening human health and TB control in one of the most populated regions of the world. To tackle this dramatic situation, a better understanding of the epidemiological reasons is urgently needed to better guide TB control interventions. Small studies employing whole genome sequencing (WGS) of clinical Mycobacterium tuberculosis complex (MTBC) strains suggest that occurrence and transmission of particular MDR MTBC strain types may be important factors, however, large scale data on the determinants of the MDR/XDR-TB epidemic in the region are missing. Added value of this study To understand more precisely the reasons for the high MDR/XDR-TB rates, we performed WGS of 1 852 MTBC strains obtained from patients from a tertiary care hospital laboratory in Mumbai. We found a high rate of pre-XDR (57.8%) and XDR (17.9 %) among the 1017 MDR MTBC strains. Cluster rates were high among MDR (78 %) and pre-XDR/XDR (85 %) strains with three dominant L2 (Beijing) strain clusters (Cl 1-3) representing half of the pre-XDR and two thirds of the XDR-TB cases. Just cluster 1 strains accounted for 52.5 % of the XDR MTBC strains. Cluster 1-3 strains also had very high combined resistance rates to first line and second line drugs, thus, reducing available group A, B, and C drugs proposed for the treatment of MDR-TB cases to a minimal set and making the application of the short MDR-TB regimen impossible. Transmission could be further confirmed by identical mutation patterns of particular pre-XDR/XDR strains. Implication of all the available evidence Our study documents extremely high pre-XDR and XDR-TB levels in the MDR-TB strain population that has not been described before. This remarkable shift towards pre-XDR is mediated by high frequency FQ resistance mutations that, in combination with particular injectable drug resistance mutations, result in XDR-TB. In addition, pre-XDR, and XDR strains are virtually all L2 strains and show high cluster rates as an indication of ongoing transmission. Thus, successful control of the DR epidemic urgently requires measures stopping transmission of MDR/pre-XDR/XDR L2 strains in this region. As the majority of pre-XDR strains are already FQ resistant, treatment options are limited and urgent modification in treatment strategies are needed, for example, comprehensive resistance detection for all cases accompanied by design of new effective treatment combinations. It is likely, that the uniform use of treatment regimens including newest MDR-TB drugs without precise knowledge of each case ‘s resistance patterns combined with close patient monitoring likely results in ongoing transmission and further resistance development as described previously. In light of previously reported associations between BCG vaccine escape and rapid spread of L2 strains, vaccine non-responsiveness of MDR/pre-XDR/XDR L2 strains may prove to be a likely scenario in Mumbai. |
