Abstract
More efficacious treatment regimens are needed for tuberculosis, however, drug development is impeded by a lack of reliable biomarkers of disease severity and of treatment effect. We conducted a directed screen of host biomarkers in participants enrolled in a tuberculosis clinical trial to address this need. Serum samples from 319 protocol-correct, culture-confirmed pulmonary tuberculosis patients treated under direct observation as part of an international, phase 2 trial were screened for 70 markers of infection, inflammation, and metabolism. Biomarker assays were specifically developed for this study and quantified using a novel, multiplexed electrochemiluminescence assay. We evaluated the association of biomarkers with baseline characteristics, as well as with detailed microbiologic data, using Bonferroni-adjusted, linear regression models. Across numerous analyses, seven proteins, SAA1, PCT, IL-1β, IL-6, CRP, PTX-3 and MMP-8, showed recurring strong associations with markers of baseline disease severity, smear grade and cavitation; were strongly modulated by tuberculosis treatment; and had responses that were greater for patients who culture-converted at 8weeks. With treatment, all proteins decreased, except for osteocalcin, MCP-1 and MCP-4, which significantly increased. Several previously reported putative tuberculosis-associated biomarkers (HOMX1, neopterin, and cathelicidin) were not significantly associated with treatment response. In conclusion, across a geographically diverse and large population of tuberculosis patients enrolled in a clinical trial, several previously reported putative biomarkers were not significantly associated with treatment response, however, seven proteins had recurring strong associations with baseline radiographic and microbiologic measures of disease severity, as well as with early treatment response, deserving additional study.
Highlights
The lack of reliable surrogate markers of efficacy has hampered tuberculosis (TB) drug development
Efforts to identify host biomarkers predictive of treatment outcomes have resulted in the identification of a number of biomarkers that change during TB treatment, albeit most are described in observational cohorts or smaller case-control studies.(Andrade et al, 2013; Azzurri et al, 2005; Coussens et al, 2012; Djoba Siawaya et al, 2009; Djoba Siawaya et al, 2008; Huang et al, 2014; Jayakumar et al, 2015; Lee and Chang, 2003; Mihret et al, 2013; Ostrowski et al, 2006) Such studies acknowledge a variety of limitations including being single center studies, focusing on single markers, using convenience samples, having modest sample sizes, or relying on case-control designs
We identified biomarkers associated with radiographic and microbiologic measures of severity, as well as biomarkers associated with treatment response
Summary
The lack of reliable surrogate markers of efficacy has hampered tuberculosis (TB) drug development. The current standard for use as a surrogate endpoint in phase 2 studies remains focused on culture conversion and the most studied is the two month culture status, which has low sensitivity and modest specificity for predicting outcomes after treatment completion.(Horne et al, 2010; Phillips et al, 2016; Phillips et al, 2013; Nahid et al, 2011) being dependent on sputum, culture-based monitoring can be challenging to use in extrapulmonary TB, and in patients with paucibacillary disease such as is seen in HIV-coinfected patients and in children.(Wallis et al, 2013; Zumla et al, 2013) Both sputum volume and quality decreases in response to treatment and many patients cannot provide sputum samples for culture after a few weeks of treatment. Efforts to identify host biomarkers predictive of treatment outcomes have resulted in the identification of a number of biomarkers that change during TB treatment, albeit most are described in observational cohorts or smaller case-control studies.(Andrade et al, 2013; Azzurri et al, 2005; Coussens et al, 2012; Djoba Siawaya et al, 2009; Djoba Siawaya et al, 2008; Huang et al, 2014; Jayakumar et al, 2015; Lee and Chang, 2003; Mihret et al, 2013; Ostrowski et al, 2006) Such studies acknowledge a variety of limitations including being single center studies, focusing on single markers, using convenience samples, having modest sample sizes, or relying on case-control designs
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