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

Published version
Peer-reviewed

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Type

Article

Change log

Authors

Walker, Timothy M 
Miotto, Paolo 
Köser, Claudio U 
Fowler, Philip W 
Knaggs, Jeff 

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.

Description

Keywords

Antitubercular Agents, Drug Resistance, Ethambutol, Microbial Sensitivity Tests, Mutation, Mycobacterium tuberculosis, World Health Organization

Journal Title

Lancet Microbe

Conference Name

Journal ISSN

2666-5247
2666-5247

Volume Title

3

Publisher

Elsevier BV
Sponsorship
Wellcome Trust (101237/Z/13/B, 203583/Z/16/Z, 098316, 203135/Z/16/Z, 203141/Z/16/Z, 214321/Z/18/Z, 214560, 201470/Z/16/Z, 206724/Z/17/Z, 200205/Z/15/Z, 203919/Z/16/Z, 200205, 214560/Z/18/Z)
NIAID NIH HHS (R01 AI131939)
World Health Organization (001)
European Research Council (101001038)
Medical Research Council (MC_PC_16027)
Swiss National Science Foundation (153442, 320030)