P55
Variants in bedaquiline candidate resistance genes: prevalence in bedaquiline-naive patients, effect on MIC and association with Mycobacterium tuberculosis lineage
E Rivière(1) L Verboven(1) A Dippenaar(1) S Goossens(1) E De Vos(1) E Streicher(2) B Cuypers(1) K Laukens(1) F Ben-Rached(3) T C Rodwell(4,5) A Pain(3,6) R M Warren(2) T Heupink(1) A Van Rie(1)
1:University of Antwerp; 2:Stellenbosch University; 3:King Abdullah University of Science and Technology; 4:University of California, San Diego; 5:FIND; 6:Hokkaido University
Studies have shown that variants in bedaquiline resistance genes can occur in isolates from bedaquiline-naïve patients. We assessed the prevalence of variants in all bedaquiline candidate resistance genes in bedaquiline naïve patients, investigated the association between these variants and lineage, and the effect on phenotype. We used whole genome sequencing to identify variants in bedaquiline resistance genes in isolates from 509 bedaquiline treatment naïve South African tuberculosis patients. A phylogenetic tree was constructed to investigate the association with the isolate lineage background. Bedaquiline minimal inhibitory concentration (MIC) was determined using the UKMYC6 microtiter assay. Variants were identified in 502 of 509 isolates (98.6%), with the highest (85%) prevalence of variants in the Rv0676c (mmpL5) gene. We identified 36 unique variants, including 19 variants not reported previously. Only four isolates had a bedaquiline MIC equal to or above the epidemiological cut-off value of 0.25µg/ml. Phylogenetic analysis showed that 14 of the 15 variants observed more than once occurred monophyletically in one Mycobacterium tuberculosis (sub-)lineage. The bedaquiline MIC differed between isolates belonging to lineage 2 and 4 (Fisher’s exact test, p = 0.0004). The prevalence of variants in bedaquiline resistance genes in isolates from bedaquiline naïve patients is high, but very few (<2%) isolates were phenotypically resistant. We found an association between variants in bedaquiline resistance genes and Mycobacterium tuberculosis (sub-)lineage, resulting in a lineage-dependent difference in bedaquiline phenotype. Future studies should investigate the impact of the presence of variants on bedaquiline resistance acquisition and treatment outcome.