Targeted next-generation sequencing for drug-resistant tuberculosis diagnosis: implementation considerations for bacterial load, regimen selection and diagnostic algorithm placement

IntroductionEarly and accurate diagnosis of drug-resistant tuberculosis (DR-TB) is essential for improving treatment outcomes. Phenotypic drug susceptibility testing (pDST) is comprehensive but slow, while rapid molecular assays provide resistance information for a limited number of drugs. Targeted...

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Veröffentlicht in:BMJ global health Jg. 10; H. 11; S. e019135
Hauptverfasser: Georghiou, Sophia B, Tukvadze, Nestani, Rodrigues, Camilla, Omar, Shaheed Vally, Cabibbe, Andrea Maurizio, Seifert, Marva, Uplekar, Swapna, Ismail, Nazir, Ruhwald, Morten, Suresh, Anita, Colman, Rebecca E
Format: Journal Article
Sprache:Englisch
Veröffentlicht: England BMJ Publishing Group Ltd 04.11.2025
BMJ Publishing Group LTD
BMJ Publishing Group
Schlagworte:
Algorithms
Antitubercular Agents - pharmacology
Antitubercular Agents - therapeutic use
Diagnostics and tools
Drug resistance
Global Health
High-Throughput Nucleotide Sequencing - methods
Humans
Microbial Sensitivity Tests - methods
Mutation
Mycobacterium tuberculosis - drug effects
Mycobacterium tuberculosis - genetics
Mycobacterium tuberculosis - isolation & purification
Original research
Other diagnostic or tool
Respiratory infections
Tuberculosis
Tuberculosis, Multidrug-Resistant - diagnosis
Tuberculosis, Multidrug-Resistant - drug therapy
Tuberculosis, Multidrug-Resistant - microbiology
Whole genome sequencing
Tuberculosis
Global Health
Other diagnostic or tool
Diagnostics and tools
Respiratory infections
ISSN:2059-7908, 2059-7908
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Zusammenfassung:IntroductionEarly and accurate diagnosis of drug-resistant tuberculosis (DR-TB) is essential for improving treatment outcomes. Phenotypic drug susceptibility testing (pDST) is comprehensive but slow, while rapid molecular assays provide resistance information for a limited number of drugs. Targeted next-generation sequencing (tNGS) offers the potential for broad and rapid resistance detection, but its integration into diagnostic algorithms has been hindered by uncertainty about its placement within existing workflows.MethodsThis study evaluated the extent to which two tNGS solutions—Deeplex Myc-TB (GenoScreen) and TB Drug Resistance Test (Oxford Nanopore Technologies, ONT)—provided interpretable drug resistance results that could inform regimen design, in comparison to other WHO-recommended molecular assays and pDST. Data were collected from three high-burden DR-TB settings under the Seq&Treat study. Sequencing success rates and drug resistance detection were analysed based on: (1) the initial Xpert MTB/RIF result (very low, low, medium, high), (2) resistance results for drugs in WHO-recommended regimens and (3) performance relative to other WHO-endorsed assays. The potential impact of different algorithms on the estimates was also considered. Key factors influencing successful tNGS adoption within diagnostic pathways were identified, leveraging insights from the Seq&Treat diagnostic accuracy study.ResultsSequencing success rates were 88.5% (GenoScreen) and 93.1% (ONT) across 763 samples. While tNGS provided complete resistance data for 73%–86% of drugs in recommended regimens, pDST achieved 92%–93%. Both tNGS solutions matched or exceeded the sensitivity of WHO-recommended molecular assays.ConclusionsThis study highlights the critical role of tNGS as a centralised tool for comprehensive drug resistance testing to inform DR-TB treatment decisions following initial screening assays. By complementing existing molecular tests with tNGS, diagnostic workflows can be optimised to ensure timely and comprehensive resistance detection. These findings support policy updates to integrate tNGS into global TB diagnostic algorithms.Trial registration number NCT04239326.
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ISSN:2059-7908
2059-7908
DOI:10.1136/bmjgh-2025-019135