Abstract
Background The World Health Organization recommends standardised treatment durations for patients with tuberculosis. We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-tuberculosis.
Methods Adult patients with pulmonary tuberculosis were prospectively enrolled into 5 independent cohorts in Germany and Romania. Clinical and microbiological data, and whole-blood for RNA transcriptomic analysis were collected at pre-defined timepoints throughout therapy. Treatment outcomes were ascertained Treatment outcomes were ascertained by TBNET criteria (6-month culture status/one-year follow-up). A whole-blood RNA therapy end model was developed in a multi-step process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment timepoints.
Results Fifty patients with drug-susceptible (DS)-tuberculosis and 30 patients with MDR-tuberculosis were recruited in the German identification cohorts (DS- and MDR-GIC), 28 patients with DS-tuberculosis and 32 patients with MDR-tuberculosis in the German validation cohorts (DS- and MDR-GVC), and 52 patients with MDR-tuberculosis in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model that defined cure-associated end-of-therapy timepoints was derived from the DS- and MDR-GIC data. The model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (AUC=0.94 [95%CI:0.9–0.98]) and suggests that cure may be achieved with shorter treatment durations for tuberculosis patients in the MDR-GIC (mean reduction 218.0 days, 34.2%, p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%, p<0.001), and the MDR-RVC (mean reduction of 161.0 days, 23.4%, p=0.001).
Conclusion Biomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-tuberculosis.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Kohli has nothing to disclose.
Conflict of interest: Dr. Heyckendorf reports no conflicts of interest. The Research Center Borstel has a patent EP20158652.6.
Conflict of interest: Dr. Marwitz has nothing to disclose.
Conflict of interest: Dr. Reimann has nothing to disclose.
Conflict of interest: Dr. Avsar has nothing to disclose.
Conflict of interest: Dr. DiNardo has nothing to disclose.
Conflict of interest: Dr. Günther has nothing to disclose.
Conflict of interest: Dr. Hoelscher has nothing to disclose.
Conflict of interest: Dr. Ibraim reports grants, personal fees and non-financial support from Deutsches Zentrum fur Infektionsforschung - DZIF, during the conduct of the study;.
Conflict of interest: Dr. Kalsdorf has nothing to disclose.
Conflict of interest: Dr. Kaufmann has nothing to disclose.
Conflict of interest: Dr. Kontsevaya reports grants from German Center for Infectious Research (DZIF), German Center for Lung Research (DZL), during the conduct of the study; grants from EU Horizon 2020 AnTBiotic (733079) and CARE (825673), outside the submitted work.
Conflict of interest: Dr. van Leth has nothing to disclose.
Conflict of interest: Dr. Mandalakas has nothing to disclose.
Conflict of interest: Dr. Maurer has nothing to disclose.
Conflict of interest: Dr. Müller has nothing to disclose.
Conflict of interest: Dörte Nitschkowski has nothing to disclose.
Conflict of interest: Dr. Olaru has nothing to disclose.
Conflict of interest: Dr. Popa has nothing to disclose.
Conflict of interest: Dr. Rachow has nothing to disclose.
Conflict of interest: Dr. Rolling has nothing to disclose.
Conflict of interest: Dr. Rybniker has nothing to disclose.
Conflict of interest: Dr. Salzer has nothing to disclose.
Conflict of interest: Dr. Sanchez Carballo has nothing to disclose.
Conflict of interest: Dr. Schuhmann has nothing to disclose.
Conflict of interest: Dr. Schaub has nothing to disclose.
Conflict of interest: Dr. Spinu reports grants, personal fees and non-financial support from Deutsches Zentrum fur Infektionsforschung - DZIF, during the conduct of the study.
Conflict of interest: Dr. Suarez has nothing to disclose.
Conflict of interest: Dr. Terhalle has nothing to disclose.
Conflict of interest: Dr. Unnewehr has nothing to disclose.
Conflict of interest: Dr. Weiner has nothing to disclose.
Conflict of interest: Dr. Goldmann reports In addition, Dr. Goldmann has a patent null pending.Dr. Goldmann reports In addition, Dr. Goldmann has a patent null pending.
Conflict of interest: Dr. Lange reports personal fees from Chiesi, personal fees from Gilead, personal fees from Janssen, personal fees from Lucane, personal fees from Novartis, personal fees from Oxoid, personal fees from Berlin Chemie, personal fees from Thermofisher, personal fees from Oxfordimmunotec, outside the submitted work.
- Received September 14, 2020.
- Accepted January 20, 2021.
- ©The authors 2021. For reproduction rights and permissions contact permissions{at}ersnet.org
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