The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.
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Author(s)
Type
Journal Article
Abstract
Background: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: 15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: This first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes. Funding: UNITAID, Wellcome, MRC, BMGF.
Date Issued
2022-04
Date Acceptance
2022-03-01
Citation
The Lancet Microbe, 2022, 3 (4), pp.e265-e273
ISSN
2666-5247
Publisher
Elsevier
Start Page
e265
End Page
e273
Journal / Book Title
The Lancet Microbe
Volume
3
Issue
4
Copyright Statement
© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license
License URL
Sponsor
Wellcome Trust
National Institute for Health Research
Identifier
https://www.ncbi.nlm.nih.gov/pubmed/35373160
Grant Number
WDAI_P83556
NIHR200927
Subjects
CRyPTIC Consortium
Seq&Treat Consortium
Publication Status
Published
Coverage Spatial
England
Date Publish Online
2022-03-08