Abstract
Background
Accurate detection of tuberculosis (TB) treatment failure and recurrence can improve disease control, but current sputum-based monitoring tools pose significant limitations. This study aimed to identify sputum-independent biomarkers for detecting and predicting TB treatment failure and recurrence.
Methods
Within the Pan-African TB Sequel study, we conducted a matched case-control study with 40 participants who had recurrent TB or treatment failure and 37 successfully treated controls matched by sex, age, and HIV status. Cases were classified as (a) non-converters with persistently positive sputum Mycobacterium tuberculosis (MTB) results during treatment, (b) reverters at the end of treatment (EOT), or (c) recurrence after EOT. Peripheral blood was collected at baseline, months 2, 4, 6, 9, and 12, and at suspected recurrence. MTB-specific T-cell activation markers (CD38, CD27, HLA-DR, Ki67) and transcriptomic signatures (Sweeney3, Risk6, MAMS6) were assessed and compared to the reference standard MTB culture and smear results.
Results
Here, we show that both MTB-specific T-cell activation and transcriptomic signatures detected non-conversion and TB recurrence at month 9 or 12 after treatment initiation. CD38 expression demonstrates 100% sensitive (95% CI: 56.6–100%) and 78% specific (95% CI: 56.5–99.4%) for detecting TB recurrence, with an AUC of 0.98 (95% CI: 91–100%). Among transcriptomic signatures, MAMS6, RISK6, and Sweeney3 achieve 75% sensitivity (95% CI: 50–100%) and 87–93% specificity (95% CI: MAMS6 0–100%, RISK6 0–93%, Sweeney3 0–100%), with comparable AUCs (0.78–0.83). Neither marker detected TB reversion at EOT.
Conclusion
These sputum-independent biomarkers effectively identify TB disease, non-conversion and recurrence TB after EOT, whereas their utility in detecting TB reversion during treatment remains limited.
Plain Language Summary
Tuberculosis (TB) is a serious infectious disease that can be fatal if untreated. While most patients recover with treatment, some do not respond well or develop TB again after completing therapy. Monitoring how well patients respond to TB treatment currently relies on tests using sputum samples, which can be slow and may be less reliable during treatment. This study aimed to identify alternative host-based markers in blood that could help detect patients with poor treatment response or TB recurrence. We found that specific blood markers can reliably identify patients with TB and detect poor treatment response during therapy, as well as TB recurrence after treatment completion. These findings may help improve early detection, guide treatment decisions, and reduce TB transmission.
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Data availability
Source data underlying the main figures, including the TAM-TB cohort and the relevant clinical datasets, are provided as a single Excel workbook in the Supplementary Data (Supplementary Data 1). The workbook contains multiple sheets corresponding to the individual figures. RNA sequencing data will be deposited in the ENA repository (Accession number PRJEB101203).
Code availability
The code for the analysis of the RNA signatures is provided at https://github.com/TropI-LMU/BauerEtAl2025.
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Acknowledgements
The authors would like to thank all colleagues and partners involved in the TB Sequel project for their dedication and invaluable contributions. Special thanks are extended to all study participants in South Africa, Gambia, Mozambique, and Tanzania, whose involvement made this project possible. The TB Sequel project is funded by the German Ministry for Education and Research (BMBF, 01KA1613) and is part of the Research Networks for Health Innovations in Sub-Saharan Africa. The experimental and data analytical work presented here was supported by the German Ministry for Education and Research through funding from the Deutsches Zentrum für Infektionsforschung (DZIF, TTU-TB personalized medicine TTU 02_813). The funders did not influence the study design, data collection, analysis, or interpretation; the writing of the manuscript; or the decision to submit the paper for publication. All authors confirm they had complete access to the study data and take full responsibility for the decision to submit the manuscript for publication.
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C.G., A.R., and K.H. were responsible for study development, funding acquisition, supervision of study conduct, and data analysis strategy. The setup and conduct of the clinical study, including data and sample collection, were carried out by M.R., S.C., J.S., A.K., M.C., N.N., and C.K. Laboratory data collection and analysis were performed by B.B., O.B., M.A., and A.B. B.B. and C.G. developed the paper and wrote the first draft. Critical review of the paper was performed by C.G., K.H., J.S. and A.R. All co-authors read, commented on, and approved the final version of the paper.
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The authors (M.A., O.B., M.H., K.H., C.G.) have submitted a European patent application related to the MAMS_6 transcriptomic signature presented in the manuscript. The application is currently unpublished and pending. Otherwise, the authors have no competing interests.
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Bauer, B., Ahmed, M.I.M., Baranov, O. et al. Host response biomarkers of tuberculosis recurrence and treatment failure. Commun Med (2026). https://doi.org/10.1038/s43856-026-01424-w
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DOI: https://doi.org/10.1038/s43856-026-01424-w
