GL18

Interpreting next generation sequencing data represents one of the main challenges in the uptake of this technology in routine laboratory diagnosis. In 2021 the WHO released the first catalogue of mutations and their association with drug resistance for interpreting genetic variants in M. tuberculosis complex.

A genotype-phenotype association study based on (i) phenotypic antimicrobial susceptibility testing (AST) results derived with WHO-endorsed methods, (ii) standardized WGS raw sequence data, and bioinformatics pipeline, and (iii) standardized, validated methodological approach for identifying variants associated with resistance phenotypes, generating statistics on the strength of the associations and confidence grading-associated variants was used to identify mutations associated with drug resistance for 13 anti-TB drugs. The dataset included WGS and phenotypic AST for 38.215 clinical isolates from 41 countries.

1.149/15.667 (7.3%) mutations have been classified associated with drug resistance, whereas 107/15.667 (0.7%) were found to be not relevant for drug resistance. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin the sensitivity of the catalogue was >80%. The specificity was found >95% for all the drugs except for ethionamide (91.4%), moxifloxacin (91.6%), and ethambutol (93.3%). Only two mutations have been classified as marker of resistance for bedaquiline, delamanid, clofazimine and linezolid. This is mainly due to the low prevalence of phenotypic resistance for these drugs in the dataset.  

The first catalogue of genetic markers of drug resistance in M. tuberculosis has been approved by the WHO and provides a global standard for the interpretation of mutations, thus encouraging the uptake and development of molecular AST for TB.