Research ArticleTuberculosis

Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis

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Science Translational Medicine  03 Feb 2021:
Vol. 13, Issue 579, eabd7618
DOI: 10.1126/scitranslmed.abd7618

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Imaging early TB drug responses

Monitoring bacterial counts in the sputum of individuals with tuberculosis (TB) during 2 weeks of drug treatment is a key part of developing new TB drugs. However, such studies do not always correlate with the clinical response seen during a full 6-month drug regimen. Xie et al. performed these studies for three first-line TB drugs as well as moxifloxacin. One hundred sixty participants with TB underwent FDG-PET/CT imaging at the start and finish of the 2-week drug regimen. The PET/CT findings correlated better with the clinical response to TB drugs than did bacterial counts in sputum. PET/CT imaging may improve new TB drug evaluation before phase 3 clinical trials.

Abstract

Early bactericidal activity studies monitor daily sputum bacterial counts in individuals with tuberculosis (TB) for 14 days during experimental drug treatment. The rate of change in sputum bacterial load over time provides an informative, but imperfect, estimate of drug activity and is considered a critical step in development of new TB drugs. In this clinical study, 160 participants with TB received isoniazid, pyrazinamide, or rifampicin, components of first-line chemotherapy, and moxifloxacin individually and in combination. In addition to standard bacterial enumeration in sputum, participants underwent 2-deoxy-2-[18F]fluoro-d-glucose positron emission tomography and computerized tomography ([18F]FDG-PET/CT) at the beginning and end of the 14-day drug treatment. Quantitating radiological responses to drug treatment provided comparative single and combination drug activity measures across lung lesion types that correlated more closely with established clinical outcomes when combined with sputum enumeration compared to sputum enumeration alone. Rifampicin and rifampicin-containing drug combinations were most effective in reducing both lung lesion volume measured by CT imaging and lesion-associated inflammation measured by PET imaging. Moxifloxacin was not superior to rifampicin in any measure by PET/CT imaging, consistent with its performance in recent phase 3 clinical trials. PET/CT imaging revealed synergy between isoniazid and pyrazinamide and demonstrated that the activity of pyrazinamide was limited to lung lesion, showing the highest FDG uptake during the first 2 weeks of drug treatment. [18F]FDG-PET/CT imaging may be useful for measuring the activity of single drugs and drug combinations during evaluation of potential new TB drug regimens before phase 3 trials.

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