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Review
. 2025 May 22:4:1570989.
doi: 10.3389/frabi.2025.1570989. eCollection 2025.

Inclusion of patient-centered, non-microbiological endpoints and biomarkers in tuberculosis drug trials

Andrew R DiNardo  1   2 , Wilbert Sabiiti  3 , Stephen H Gillespie  3 , Sophia B Georghiou  4 , Norbert Heinrich  5   6 , Norbert Hittel  7 , Sami Taghlabi  2 , Danna Carrero Longlax  2 , Mikashmi Kohli  4 , Ursula Panzner  5   6 , Collins Musia  8 , Christoph Lange  2   8   9   10 , Anca Vasiliu  2   8   9 , Rob J W Arts  1 , Anna M Mandalakas  2   8   9 , Morten Ruhwald  4 , Lieven J Stuyver  11 , Reinout van Crevel  3   12
Affiliations
Review

Inclusion of patient-centered, non-microbiological endpoints and biomarkers in tuberculosis drug trials

Andrew R DiNardo et al. Front Antibiot. .

Abstract

Tuberculosis drug trials are primarily designed to identify antibiotic regimens with the strongest potency to kill Mycobacterium tuberculosis. However, microbiologic cure is not synonymous with improved health and recovery. Beyond antimicrobial efficacy, parameters such as morbidity and mortality related to lung function, cardiovascular health, and cancer should be prioritized. This narrative review emphasizes the critical need to emphasize clinical outcomes as much, if not more, than microbiological endpoints. We examine the underlying pathophysiological mechanisms and determinants of non-microbiological outcomes in tuberculosis, providing a synthesis of current knowledge. While there is growing evidence for some biomarkers to risk stratify TB patients for risk of all-cause mortality, relapse, or lung damage, no evidence was found on TB-associated cancer or cardiovascular disease. In addition to monitoring microbiologic outcomes, clinical trials and treatment cohorts need to capture patient-centered health dimensions more broadly. Finally, we highlight key research gaps and opportunities to evaluate non-microbiological biomarkers, aiming to improve patient monitoring and enable stratified approaches to tuberculosis management.

Keywords: biomarker; cancer; cardiovascular; sequelae; tuberculosis.

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Conflict of interest statement

Author NHi was employed by the company Otsuka Novel Products GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

Figure 1
Figure 1
Burden of Post-tuberculosis mortality. Tuberculosis survivors have an increased risk of mortality compared to matched controls. The most common cause of death were cardiovascular, cancer, and respiratory. Source: Based on data from Romanowski et al. (2019).
Figure 2
Figure 2
Contributing factors and biologic mechanisms driving tuberculosis morbidity and mortality. Mycobacterial virulence factors, persistent smoking, alcohol (EtOH) use, drug toxicity, malnutrition, and air pollution result in mitochondrial dysfunction, lipid peroxidation, and epigenetic scars resulting in immune dysregulation and inflammation despite successful antibiotic treatment. Source: Created with BioRender.com.
See this image and copyright information in PMC

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