P32
Unclassified genetic variants in the WHO catalog for Mycobacterium tuberculosis drug resistance and their effect on treatment guidance for rifampicin resistant TB
L Verboven(1) J Phelan(2) T H Heupink(1) R Warren(3) A Van Rie(1)
1:University of Antwerp; 2:London School of Hygiene and Tropical Medicine; 3:Stellenbosch University
Background: In June 2021, the WHO published a catalog of resistance variants and candidate drug resistance genes (classified as tier 1 and 2) in Mycobacterium tuberculosis (Mtb). Out of 17396 variants, 82% could not be associated with drug resistance or susceptibility.
Design and methods: We used the XBS pipeline and TBProfiler to determine the number of variants of “uncertain significance” in tier 1 and 2 genes in 340 rifampicin resistant Mtb isolates. To assess the feasibility of using whole genome sequencing data for clinical care, we simulated the number of variants with uncertain significance and the time needed to judge the clinical relevance of variants for the first 100 samples in a clinical program.
Results: In the 340 samples, on average 30 unclassified variants were identified per sample. The total number of unclassified variants was highest for linezolid (n=134), streptomycin (n=130), amikacin (n=112), capreomycin (n=111), kanamycin (n=82), rifampicin (n=94), isoniazid (n=83), lower for ethionamide (n=62), ethambutol (n=50), and pyrazinamide (n=53), and lowest for levofloxacin (n=22), moxifloxacin (n=24), clofazimine (n=22), delamanid (n=21), and bedaquiline (n=22). To accurately guide care for the first 100 patients in a care program, literature review and/or expert consultation was needed for 355 variants, an effort that would take almost 14 full working days.
Conclusion: The high prevalence of variants of unclassified significance complicates the clinical use of Mtb sequencing data. Global efforts to develop a database to compile knowledge on unclassified variants is needed to facilitate the clinical use of next generation sequencing data.