Extensive Endemic Transmission of Multidrug-Resistant Mycobacterium tuberculosis in Bhutan: A Retrospective...

The proportion of multidrug-resistant tuberculosis (MDR-TB) cases is increasing in Bhutan. We conducted the first retrospective genomic-epidemiological study to provide insights into the population structure, resistance patterns, and recent transmission in Bhutan.

Whole genome sequencing was performed on randomly selected drug-resistant (DR-TB) and drug-sensitive TB (DS-TB) isolates from Bhutan, collected between 2018 and 2022 at the Microbiological Diagnostic Unit Public Health Laboratory in Melbourne, Australia. Bioinformatic analysis was performed to identify drug-resistance mutations and genomic clustering of cases.

Approximately 40% of DR-TB and 2.5% of DS-TB were sequenced each year. Of the 203 sequences that passed the quality control, 126 (62.1%) were MDR-TB and 15 (7.4%) were isoniazid-resistant TB. There were 4 different circulating lineages, with the majority belonging to lineage 2 (86.2%). Using a SNP-threshold of ≤12 SNPs, 71% of sequences formed 12 genomic clusters; the largest comprised 88% of all MDR-TB sequences and spanned the entire study period and the country. These cases were highly clonal, with a mean pairwise SNP distance of 10 (range 0-25). Phylogenetic analysis with publicly available international sequence data showed that this MDR-TB cluster formed a distinct clade.

Contrary to current assumptions of repeat importations, the major burden of MDR-TB in Bhutan appears to be due to recent local transmission resulting in a large endemic cluster, advocating for targeted and enhanced contact tracing and screening for this MDR-TB clade. This study highlights the significant value of investing in TB genomics in resource-limited settings to gain actionable insights to inform policy decisions.