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Clusters of intrinsically delamanid/pretomanid cross-resistant strains of Mycobacterium tuberculosis in eastern Europe and central Asia

K Wollenberg(1) C Köser(2) M Dohál(3) V Dvoráková(4) C J Meehan(5) A M Cabibbe(6) D Cirillo(6) L Rigouts(7) E Robinson(8) D Machado(9) M Viveiros(9) J Perdigao(10) I Portugal(10) R Anthony(11) A Aubry(12) A Saffarian(12) T Peterson(12) I Barilar(13) S Niemann(13) M Merker(13) T Cohen(14) B Sobkowiak(14) V Crudu(22) M Sharma(23) D Zimenkov(15) A Ushtanit(15) Y Mikhailova(16) J Phelan(17) P Fowler(18) L Žmak(19) M Obrovac(19) B Schulthess(20) N Shubladze(21) S Vashakidze(21) C Loiseau(24) S Gagneux(24) M Harris(1) A Rosenthal(1)

1:National Institute of Allergy and Infectious Diseases; 2:University of Cambridge; 3:Comenius University; 4:National Institute of Public Health; 5:Nottingham Trent University; 6:San Raffaele Scientific Institute; 7:University of Antwerp; 8:UKHSA; 9:Universidade Nova de Lisboa; 10:Universidade de Lisboa; 11:National Institute for Public Health and the Environment (RIVM); 12:Centre National de Référence des Mycobactéries et de la Résistance des Mycobactéries aux Antituberculeux; 13:Research Center Borstel; 14:Yale University; 15:Russian Academy of Sciences; 16:Moscow Research and Clinical Center for Tuberculosis Control of the Moscow Government Health Department; 17:London School of Hygiene and Tropical Medicine; 18:University of Oxford; 19:Croatian Institute of Public Health; 20:University of Zurich; 21:National Centre for Tuberculosis and Lung Diseases; 22:Phthisiopneumology Institute; 23:Public Health Agency of Canada; 24:Swiss Tropical and Public Health Institute

Multidrug-resistant tuberculosis (MDR-TB) is a major public health issue, especially in many eastern European and central Asian countries. Using whole genome sequence data from Georgia, Kazakhstan, Moldova, Tajikistan, and Ukraine we identified a phylogenetically-cohesive cluster of 19 MDR-TB strains that shared the same mutation conferring cross-resistance to delamanid and pretomanid, ddn W88*. Estimation of the date of the most recent common ancestor of these samples indicated that the mutation in this lineage predates the use of both drugs. An additional 121 samples from other studies and multiple European reference laboratories yielded more examples from patients who appear to have travelled across Europe. These data also included samples collected before the clinical use of delamanid, further supporting a natural emergence of this cluster. In fact, ddn W88* evolved at least three times, once in lineage 2 and twice in lineage 4. The lineage 4 samples were from sublineages 4.1 and 4.8 and had different nucleotide mutations leading to the same amino acid change. The lineage 2 samples were from the widespread B0/W148/European/Russia outbreak lineage. To estimate the prevalence of delamanid/pretomanid cross-resistance due to this mutation, we analysed genomic data from published comprehensive surveys of culture-positive samples over proscribed time spans in Georgia and Moldova. Although the prevalence of ddn W88* was found to be low in these two countries, this still underscores the need to scale up the capacity for pretomanid drug-susceptibility testing across the WHO European Region to accompany the rollout of BPaL(M).

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