Resolution of tuberculosis blood RNA signatures fails to discriminate persistent sputum culture positivity after 8 weeks of anti-tuberculous treatment

Background Concerted efforts aim to reduce the burden of 6 months of anti-tuberculous treatment for tuberculosis (TB). Treatment cessation at 8 weeks is effective for most but incurs increased risk of disease relapse. We tested the hypothesis that blood RNA signatures or C-reactive protein (CRP) measurements discriminate 8-week sputum culture status, as a prerequisite for a biomarker to stratify risk of relapse following treatment cessation at this time-point. Methods We identified blood RNA signatures of TB disease or cure by systematic review. We evaluated these signatures and CRP measurements in a pulmonary TB cohort, pre-treatment, at 2 and 8 weeks of treatment, and sustained cure after treatment completion. We tested biomarker discrimination of 8-week sputum culture status using area under the receiver operating characteristic curve (AUROC) analysis and, secondarily, assessed correlation of biomarker scores with time to culture positivity at 8 weeks of treatment. Results 12 blood RNA signatures were reproduced in the dataset from 44 individuals with sputum culture-positive pulmonary TB. These normalised over time from TB treatment initiation. 11 out of 44 cases with blood RNA, CRP and sputum culture results were sputum culture-positive at 8 weeks of treatment. None of the contemporary blood RNA signatures discriminated sputum culture status at this time-point or correlated with bacterial load. CRP achieved modest discrimination with AUROC 0.69 (95% CI 0.52-0.87). Conclusions Selected TB blood RNA signatures and CRP do not provide biomarkers of microbiological clearance to support TB treatment cessation at 8 weeks. Resolution of blood transcriptional host responses in sputum culture-positive individuals suggests Mycobacterium tuberculosis may colonise the respiratory tract without triggering a detectable immune response.