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Peer-reviewedCC BY 4.0Frontiers in Cellular and Infection Microbiology

Resistance-gene minority variation and delayed microbiological response in rifampicin-resistant tuberculosis

  • Qing Fang1
  • Xiangchen Li2,3
  • Yewei Lu2,3
  • Dongliang Zhang4
  • Fang Li2
  • Junli Gao2
  • Yang Che4
4 affiliations
  1. 1Departments of Pulmonary Medicine, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang, China
  2. 2Cosmos Wisdom Biotech Co. Ltd, Hangzhou, Zhejiang, China
  3. 3Research and Innovation Center, Cosmos Wisdom Biotech Co. Ltd, Hangzhou, Zhejiang, China
  4. 4Institute of Tuberculosis Prevention and Control, Ningbo Municipal Center for Disease Control and Prevention, Ningbo, Zhejiang, China
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Abstract

Introduction: Routine whole-genome sequencing (WGS) interpretation of Mycobacterium tuberculosis resistance focuses mainly on consensus-level mutations. Minority variants, quantified by allele frequency (AF), may indicate resistant subpopulations under drug pressure, but their association with treatment response in rifampicin-resistant or multidrug-resistant tuberculosis (RR/MDR-TB) remains unclear.

Methods: We retrospectively analysed RR/MDR-TB patients treated in Ningbo, China, from 2021 to 2025, integrating clinical, phenotypic, treatment, microbiological, and WGS data. Minority resistance-associated variants (RAVs) were defined as low-frequency variants matching WHO V2 mutation catalogue entries at AF ≥ 3%, with AF ≥ 5% defining the primary higher-frequency subset. Per-drug analyses excluded patients whose target genes had median depth <200×. Associations with microbiological response were assessed using covariate-adjusted logistic regression, with higher-frequency and treatment-matched variants examined secondarily.

Results: We analysed 229 RR/MDR-TB patients with linked WGS, treatment, and microbiological follow-up data. Fixed RAVs (WHO V2 catalogue-annotated) were carried by 220/229 patients (median 3, IQR 2–5). Minority RAVs at AF ≥ 3% were detected in 13 patients. Overall minority-RAV burden was not clearly associated with microbiological response after adjustment. The clearest signal involved treatment-matched AF ≥ 5% minority RAVs, whose carriers had a higher 6-month culture-positivity rate than non-carriers (4/7 [57.1%] vs 40/198 [20.2%]; adjusted odds ratio [aOR] 7.21, 95% CI 1.38–43.68; p = 0.020; q = 0.034), with a modest AUC increase from 0.675 to 0.695. Six-month positivity was highest among patients with both high fixed RAV burden and treatment-matched AF ≥ 5% minority RAVs (4/5 [80.0%] vs 15/106 [14.2%] in the low-burden non-carrier reference; Fisher’s exact p = 0.003).

Conclusion: Minority variants showed limited overall prognostic value, but higher-frequency treatment-matched variants provided a coherent signal for 6-month culture positivity when considered with fixed RAV burden. These exploratory findings support a cautious, treatment-aware review of selected minority variants and require external validation before clinical use.

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Cite

BibTeXRIS
BibTeX
@article{fang2026resistancegene,
  title = {{Resistance-gene minority variation and delayed microbiological response in rifampicin-resistant tuberculosis}},
  author = {Qing Fang and Xiangchen Li and Yewei Lu and Dongliang Zhang and Fang Li and Junli Gao and Yang Che},
  journal = {Frontiers in Cellular and Infection Microbiology},
  year = {2026},
  month = oct,
  doi = {10.3389/fcimb.2026.1930268},
  url = {https://doi.org/10.3389/fcimb.2026.1930268},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Resistance-gene minority variation and delayed microbiological response in rifampicin-resistant tuberculosis
AU  - Qing Fang
AU  - Xiangchen Li
AU  - Yewei Lu
AU  - Dongliang Zhang
AU  - Fang Li
AU  - Junli Gao
AU  - Yang Che
PY  - 2026
DA  - 2026/10/22
JO  - Frontiers in Cellular and Infection Microbiology
DO  - 10.3389/fcimb.2026.1930268
UR  - https://doi.org/10.3389/fcimb.2026.1930268
AB  - Introduction: Routine whole-genome sequencing (WGS) interpretation of Mycobacterium tuberculosis resistance focuses mainly on consensus-level mutations. Minority variants, quantified by allele frequency (AF), may indicate resistant subpopulations under drug pressure, but their association with treatment response in rifampicin-resistant or multidrug-resistant tuberculosis (RR/MDR-TB) remains unclear.  Methods: We retrospectively analysed RR/MDR-TB patients treated in Ningbo, China, from 2021 to 2025, integrating clinical, phenotypic, treatment, microbiological, and WGS data. Minority resistance-associated variants (RAVs) were defined as low-frequency variants matching WHO V2 mutation catalogue entries at AF ≥ 3%, with AF ≥ 5% defining the primary higher-frequency subset. Per-drug analyses excluded patients whose target genes had median depth <200×. Associations with microbiological response were assessed using covariate-adjusted logistic regression, with higher-frequency and treatment-matched variants examined secondarily.  Results: We analysed 229 RR/MDR-TB patients with linked WGS, treatment, and microbiological follow-up data. Fixed RAVs (WHO V2 catalogue-annotated) were carried by 220/229 patients (median 3, IQR 2–5). Minority RAVs at AF ≥ 3% were detected in 13 patients. Overall minority-RAV burden was not clearly associated with microbiological response after adjustment. The clearest signal involved treatment-matched AF ≥ 5% minority RAVs, whose carriers had a higher 6-month culture-positivity rate than non-carriers (4/7 [57.1%] vs 40/198 [20.2%]; adjusted odds ratio [aOR] 7.21, 95% CI 1.38–43.68; p = 0.020; q = 0.034), with a modest AUC increase from 0.675 to 0.695. Six-month positivity was highest among patients with both high fixed RAV burden and treatment-matched AF ≥ 5% minority RAVs (4/5 [80.0%] vs 15/106 [14.2%] in the low-burden non-carrier reference; Fisher’s exact p = 0.003).  Conclusion: Minority variants showed limited overall prognostic value, but higher-frequency treatment-matched variants provided a coherent signal for 6-month culture positivity when considered with fixed RAV burden. These exploratory findings support a cautious, treatment-aware review of selected minority variants and require external validation before clinical use.
SN  - 2235-2988
ER  -