TY - JOUR T1 - The 2021 WHO catalogue of complex mutations associated with drug resistance: A genotypic analysis. JF - Lancet Microbe Y1 - 2022 A1 - Timothy M Walker A1 - Paolo Miotto A1 - Claudio U Köser A1 - Philip W Fowler A1 - Jeff Knaggs A1 - Iqbal, Zamin A1 - Martin Hunt A1 - Leonid Chindelevitch A1 - Maha Farhat A1 - Daniela Maria Cirillo A1 - Iñaki Comas A1 - James Posey A1 - Shaheed V Omar A1 - Timothy EA Peto A1 - Anita Suresh A1 - Swapna Uplekar A1 - Sacha Laurent A1 - Rebecca E Colman A1 - Carl-Michael Nathanson A1 - Matteo Zignol A1 - Ann Sarah Walker A1 - Derrick W Crook A1 - Nazir Ismail A1 - Timothy C Rodwell A1 - Vanessa Mathys KW - Drug Resistance KW - mutations KW - Tuberculosis AB -

Background: Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for complex (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.

VL - 3 CP - 4 M3 - 10.1016/S2666-5247(21)00301-3 ER -