Nanopore targeted sequencing for the detection of drug-resistant tuberculosis compared to standard of care drug susceptibility testing in Kyrgyzstan

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The World Health Organization recommends the implementation of targeted next-generation sequencing (tNGS) for the diagnosis of drug-resistant TB. We compared the diagnostic performance of the Oxford Nanopore Technologies (ONT) tNGS TB assay to standard of care (SOC) drug susceptibility testing (DST) in in three regions of Kyrgyzstan. From an ongoing study, we analyzed data from participants enrolled between January 2024 and January 2025 who were aged ≥18 years and had TB detected using GeneXpert MTB/Rif Ultra. Sputum samples were collected and subjected to SOC-DST (i.e., Xpert, line probe assay (LPA) and/or phenotypic DST (pDST)). Sequencing for TB was done using the ONT-CUST-kit on a MinION device, targeting 24 genes related to 16 anti-TB drugs (here referred to as ONT tNGS), and data were analysed using EPI2ME software version v2.0.0-beta.5. Of 870 patients enrolled thus far, 550 (63%) had results available on ONT tNGS. SOC DST was completed for 551 (pDST for 418, first-line LPA for 536) participants. SOC DST revealed isoniazid (INH) but not rifampicin (RIF) resistance in 98 (17%), RIF but not INH resistance in 6 (1%), and RIF plus INH resistance in 94 patients (17%). ONT tNGS results were generally concordant with SOC DST. Compared to SOC DST, ONT tNGS identified additional resistance, e.g., of 5 patients with bedaquiline resistance, 3 were only detected using ONT tNGS, while of 21 patients with levofloxacin resistance, 7 were detected using ONT tNGS, 2 by pDST, and 12 by both methods. In conclusion, these results show the potential of incorporating tNGS into routine TB diagnostic algorithms to reach accurate treatment decisions.

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