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We conducted a prospective study to establish factors associated with survival in tuberculosis patients in Russia including social, clinical and pathogen-related genetic parameters. Specifically we wished to determine whether different strains/clades of the Beijing lineage exerted a differential effect of survival. HIV-negative culture-confirmed cases were recruited during 2008-2010 across Samara Oblast and censored in December 2011. Molecular characterization was performed by a combination of spoligotyping, multilocus VNTR typing and whole genome sequencing (WGS). We analyzed 2602 strains and detected a high prevalence of Beijing family (n=1933; 74%) represented largely by two highly homogenous dominant clades A (n=794) and B (n=402) and non-A/non-B (n=737). Multivariable analysis of 1366 patients with full clinical and genotyping data showed that multi- and extensive drug resistance (HR=1.86; 95%CI: 1.52, 2.28 and HR=2.19; 95%CI: 1.55, 3.11) had the largest impact on survival. In addition older age, extensive lung damage, shortness of breath, treatment in the past and alcohol abuse reduced survival time. After adjustment for clinical and demographic predictors there was evidence that clades A and B combined were associated with poorer survival than other Beijing strains (HR=0.48; 95%CI 0.34, 0.67). All other pathogen-related factors (polymorphisms in genes plcA, plcB, plcC, lipR, dosT and pks15/1) had no effect on survival. In conclusion, drug resistance exerted the greatest effect on survival of TB patients. Nevertheless we provide evidence for the independent biological effect on survival of different Beijing family strains even within the same defined geographical population. Better understanding of the role of different strain factors in active disease and their influence on outcome is essential., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Extensively drug-resistant (XDR) tuberculosis (TB), which is resistant to both first- and second-line antibiotics, is an escalating problem, particularly in the Russian Federation. Molecular fingerprinting of 2348 Mycobacterium tuberculosis isolates collected in Samara Oblast, Russia, revealed that 72% belonged to the Beijing lineage, a genotype associated with enhanced acquisition of drug resistance and increased virulence. Whole-genome sequencing of 34 Samaran isolates, plus 25 isolates representing global M. tuberculosis complex diversity, revealed that Beijing isolates originating in Eastern Europe formed a monophyletic group. Homoplasic polymorphisms within this clade were almost invariably associated with antibiotic resistance, indicating that the evolution of this population is primarily driven by drug therapy. Resistance genotypes showed a strong correlation with drug susceptibility phenotypes. A novel homoplasic mutation in rpoC, found only in isolates carrying a common rpoB rifampicin-resistance mutation, may play a role in fitness compensation. Most multidrug-resistant (MDR) isolates also had mutations in the promoter of a virulence gene, eis, which increase its expression and confer kanamycin resistance. Kanamycin therapy may thus select for mutants with increased virulence, helping preserve bacterial fitness and promoting transmission of drug-resistant TB strains. The East European clade was dominated by two MDR clusters, each disseminated across Samara. Polymorphisms conferring fluoroquinolone resistance were independently acquired multiple times within each cluster, indicating that XDR TB is currently not widely transmitted.