Evolution and transmission of antibiotic resistance is driven by Beijing lineage
Mycobacterium tuberculosis
in Vietnam
Authors: Silcocks Matthew , Chang Xuling , Thuong Thuong Nguyen Thuy , Qin Youwen , Minh Ha Dang Thi , Khac Thai Phan Vuong , Vijay Srinivasan , Anh Thu Do Dang , Ngoc Ha Vu Thi , Ngoc Nhung Hoang , Huu Lan Nguyen , Quynh Nhu Nguyen Thi , Edwards David , Nath Artika , Pham Kym , Duc Bang Nguyen , Hong Chau Tran Thi , Thwaites Guy , Heemskerk A. Dorothee , Chuen Khor Chiea , Teo Yik Ying , Inouye Michael , Ong Rick Twee-Hee , Caws Maxine , Holt Kathryn E. , Dunstan Sarah J. 
Published: November 2023

ABSTRACT

A previous investigation has elucidated the landscape of
Mtb
genomic diversity and transmission dynamics in Ho Chi Minh City, Vietnam. Here, we expand the scope of this survey by adding a substantial number of additional genomes (total sample size: 2,542) and phenotypic drug susceptibility data for the majority of isolates. We aim to explore the prevalence and evolutionary dynamics of drug resistance and our ability to predict drug resistance from sequencing data. Among isolates tested phenotypically against first-line drugs, we observed high rates of streptomycin [STR, 37.7% (
N
= 573/1,520)] and isoniazid resistance [INH, 25.7% (
N
= 459/1,786)] and lower rates of resistance to rifampicin [RIF, 4.9% (
N
= 87/1,786)] and ethambutol [EMB, 4.2% (
N
= 75/1,785)]. Relative to global benchmarks, resistance to STR and INH was predicted accurately when applying the TB-Profiler algorithm to whole genome sequencing data (sensitivities of 0.81 and 0.87, respectively), while resistance to RIF and EMB was predicted relatively poorly (sensitivities of 0.70 and 0.44, respectively). Exploring the evolution of drug resistance revealed the main phylogenetic lineages to display differing dynamics and tendencies to evolve resistance via mutations in certain genes. The Beijing sublineage L2.2.1 was found to acquire
de novo
resistance mutations more frequently than isolates from other lineages and to suffer no apparent fitness cost acting to impede the transmission of resistance. Mutations conferring resistance to INH and STR arose earlier, on average, than those conferring resistance to RIF and are now more widespread across the phylogeny. The high prevalence of “background” INH resistance, combined with high rates of RIF mono-resistance (20.7%,
N
= 18/87), suggests that rapid assays for INH resistance will be valuable in this setting. These tests will allow the detection of INH mono-resistance and will allow multi-drug-resistant isolates to be distinguished from isolates with RIF mono-resistance.

IMPORTANCE

Drug-resistant tuberculosis (TB) infection is a growing and potent concern, and combating it will be necessary to achieve the WHO’s goal of a 95% reduction in TB deaths by 2035. While prior studies have explored the evolution and spread of drug resistance, we still lack a clear understanding of the fitness costs (if any) imposed by resistance-conferring mutations and the role that
Mtb
genetic lineage plays in determining the likelihood of resistance evolution. This study offers insight into these questions by assessing the dynamics of resistance evolution in a high-burden Southeast Asian setting with a diverse lineage composition. It demonstrates that there are clear lineage-specific differences in the dynamics of resistance acquisition and transmission and shows that different lineages evolve resistance via characteristic mutational pathways.