Use of whole-genome sequencing to predict Mycobacterium tuberculosis drug resistance in Indonesia

Abstract Objectives Whole-genome sequencing (WGS) is rarely used for drug resistance testing of Mycobacterium tuberculosis in high-endemic settings. Here we present the first study from Indonesia, which has the third highest tuberculosis (TB) burden worldwide, with Methods WGS was applied for strains from 322 human immunodeficiency virus (HIV)-negative adult TB patients. Phenotypic drug susceptibility testing (DST) was performed for a proportion of the patients. Results Using WGS, mutations associated with drug resistance to any TB drug were identified in 51 (15.8%) of the 322 patients, including 42 patients (13.0%) with no prior TB treatment (primary resistance). Eight isolates (2.5%) were multidrug-resistant (MDR) and one was extensively drug-resistant (XDR). Most mutations were found in katG ( n  = 18), pncA ( n  = 18), rpoB ( n  = 10), fabG1 ( n  = 9) and embB ( n  = 9). Agreement of WGS-based resistance and phenotypic DST to first-line drugs was high for isoniazid and rifampicin but was lower for ethambutol and streptomycin. Drug resistance was more common in Indo-Oceanic lineage strains (37.5%) compared with Euro-American (18.2%) and East-Asian lineage strains (10.3%) ( P  = 0.044), but combinations of multiple mutations were most common among East-Asian lineage strains ( P  = 0.054). Conclusions These data support the potential use of WGS for more rapid and comprehensive prediction of drug-resistant TB in Indonesia. Future studies should address potential barriers to implementing WGS, the distribution of specific resistance mutations, and the association of particular mutations with endemic M. tuberculosis lineages in Indonesia.