Exploring a combined biomarker for tuberculosis treatment response: Protocol for a prospective observational cohort study

Frank Kloprogge*, Ibrahim Abubakar, Hanif Esmail, Vanessa Hack, Heinke Kunst, Timothy D. McHugh, Mahdad Noursadeghi, Julian Surey, Simon Tiberi, Marc Lipman

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Introduction An improved understanding of factors explaining tuberculosis (TB) treatment response is urgently needed to help clinicians optimise and personalise treatment and assist scientists undertaking novel treatment regimen trials. Promising outcome proxy measures, including sputum bacillary load and host immune response, are widely reported with variable results. However, they have not been studied together in combination with antibiotic exposure. The aim of this observational cohort study is to investigate which antibiotic exposures correlate with sputum bacillary load and which with the host immune response. Subsequently, we will explore if these correlations can be used to inform a candidate combined biomarker predicting cure. Methods and analysis All patients aged ≥ 18, diagnosed with drug-sensitive pulmonary TB (culture or molecular test), eligible for standard anti-TB treatment, at selected London, UK TB Services, will be invited to participate in this observational cohort study (target sample size=210). Patients will be asked to give blood for host transcriptomics and antibiotic plasma exposure, in addition to standard of care sputum samples for bacillary load. Antibiotic plasma concentrations will be quantified using a validated liquid chromatograph triple quadrupole mass spectrometer (LC-MS/MS) assay and sputum bacillary load by mycobacterial growth incubator tube time to positivity. Expression from a total of 35 prespecified host blood genes will be quantified using NanoString®. Antibiotic exposure, sputum bacillary load and host blood transcriptomic time series data will be analysed using nonlinear mixed-effects models. Correlations between combinations of longitudinal biomarkers and microbiological cure at the end of treatment and remaining relapse free for 1 year thereafter will be analysed using logistic regression and Cox proportional hazard models. Ethics and dissemination The observational cohort study has been approved by the UK's HRA REC (20/SW/0007). Written informed consent will be obtained. Results will be disseminated via publication, presentation and through engagement with institutes/companies developing novel anti-TB treatment combinations.

Original languageEnglish
Article numbere052885
JournalBMJ Open
Volume11
Issue number7
DOIs
Publication statusPublished - 8 Jul 2021
Externally publishedYes

Bibliographical note

Funding Information:
Funding The study is funded through a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 220587/Z/20/Z) and part of the medication record boxes was funded through a UKRI Medical Research Council fellowship (grant number MR/P014534/1), both awarded to FK.

Publisher Copyright:
© Author(s) (or their employer(s)) 2021.

Keywords

  • bacteriology
  • clinical pharmacology
  • tuberculosis

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