A Systematic Review of Potential Biomarkers for Bacterial Burden and Treatment Efficacy Assessment in Tuberculosis Platform-Based Clinical Trials

Adaptive platform trials can be more efficient than classic trials for developing new treatments. Moving from culture-based to simpler- or faster-to-measure biomarkers as efficacy surrogates may enhance this advantage. We performed a systematic review of treatment efficacy biomarkers in adults with tuberculosis. Platform trials can span different development phases. We grouped biomarkers as: α, bacterial load estimates used in phase 2a trials; β, early and end-of treatment end points, phase 2b-c trials; γ, posttreatment or trial-level estimates, phase 2c-3 trials. We considered as analysis unit (biomarker entry) each combination of biomarker, predicted outcome, and their respective measurement times or intervals. Performance metrics included: sensitivity, specificity, area under the receiver-operator curve (AUC), and correlation measures, and classified as poor, promising, or good. Eighty-six studies included 22 864 participants. From 1356 biomarker entries, 318 were reported with the performance metrics of interest, with 103 promising and 41 good predictors. Group results were: α, mycobacterial RNA and lipoarabinomannan (LAM) in sputum, and host metabolites in urine; β, mycobacterial RNA and host transcriptomic or cytokine signatures for early treatment response; and γ, host transcriptomics for recurrence. A combination of biomarkers from different categories could help in designing more efficient platform trials. Efforts to develop efficacy surrogates should be better coordinated.