The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis

In silico evaluation of WHO-endorsed molecular methods to detect drug resistant tuberculosis

“…For our exhaustive list of resistance associated mutations, we used the WHO 2021 catalogue and included mutations that were categorised as 1) associated with resistance or 2) associated with resistance interim 15,22 . We evaluated WHO endorsed molecular diagnostic tests that detected resistance to one or more of the following drugs: rifampicin, isoniazid, pyrazinamide, ethionamide, levo oxacin, moxi oxacin, amikacin, capreomycin or kanamycin.…”

“…The list of mutations detected by each diagnostic test for use in in silico evaluations of the tests is summarised in Table 1. were considered for this analysis 15,22 . Isolates with known resistance conferring mutations identi ed via sequencing and a susceptible phenotype for the corresponding drug were not removed from this sample set; although these samples may have been mislabelled, they were kept in the dataset to re ect real world performance, where there will be a degree of mislabelling and phenotypic error.…”

“…For this analysis we excluded phenotypic data for drugs where one or more of the corresponding genes interrogated by either the catalogue or a molecular test (Table S1) had an excessive number of lter-fail or null calls for the variants identi ed, on the assumption that the genetic data were unreliable. The de nition used for 'excessive' was the probability of that many lter fail or null calls being less than 1%, assuming a Poisson distribution 15,22 . Upon application of these ltering criteria, 38,111 isolates remained for further analysis; a breakdown of the number of isolates with phenotypic and genetic information for each drug is presented in Table 2.…”

Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

“…The fourth was a systematic review of the CCs for the rifamycins and isoniazid [13]. Finally, WHO released its first official catalogue of resistance mutations to inform the interpretation of genotypic AST results [14,15]. Together, these reports prompted WHO to make major changes to its recommendations for TB treatment (e.g.…”

“…Between 2011 and 2014, for instance, the WHO-endorsed GenoType MTBDRplus VER 2.0 by Hain Lifescience was designed not to detect rpoB L452P because this mutation was not considered to be a rifampicin resistance mutation at that time [18,19]. It took more than a decade for eis c-14t and rrs c1402t to be recognised as resistance mutations for amikacin [14,15,22]. Hence, the full potential of the GenoType MTBDRsl VER 2.0 was not exploited because these two mutations were only interpreted as markers for kanamycin and capreomycin resistance.…”