Image: The BACTEC mycobacterial growth indicator tubes (Photo courtesy of Becton, Dickinson and Company).
Tuberculosis (TB) kills more people than any other infectious disease, and new regimens are essential. The primary endpoint for confirmatory phase III trials for new regimens is a composite outcome that includes bacteriological treatment failure and relapse.
Patients in clinical trials can have positive cultures after treatment ends that may not necessarily indicate relapse. Such post-treatment positives have been attributed to laboratory cross-contamination leading to a false positive or to the breakdown of an old cavity, releasing organisms into the sputum from a patient who has no signs and symptoms of TB and will eventually be classified as having a favorable outcome, therefore defined as an isolated positive.
A group of scientists collaborating with the MRC Clinical Trials Unit at UCL (London, UK) conducted a randomized placebo-controlled double-blind drug trial of 1,931 patients were randomized across sites in Africa and Asia and followed for 18 months from randomization. During the trial, sputum samples were taken for smear and culture (Löwenstein-Jensen [LJ] and Mycobacteria Growth Indicator Tube [MGIT] in parallel) weekly to 8 weeks during treatment, monthly thereafter to 6 months and 3-monthly thereafter to 18 months from randomization. One sputum sample was collected and inoculated into both LJ medium and MGIT system.
A total of 12,209 sputum samples were available from 1,652 patients; cultures were more often positive on MGIT than LJ. In 1,322 patients with a favorable trial outcome, 126 (9.5%) had cultures that were positive in MGIT compared to 34 (2.6%) patients with positive cultures on LJ. Among patients with a favorable outcome, the incidence of isolated positives on MGIT differed by study laboratory with 21.9% of these coming from one laboratory investigating only 4.9% of patients. Compared to negative MGIT cultures, positive MGIT cultures were more likely to be associated with higher-grade TB symptoms reported within seven days either side of sputum collection in patients with an unfavorable primary outcome, but not in patients with a favorable outcome.
The authors concluded that MGIT can replace LJ in phase III TB trials, but there are implications for the definition of the primary outcome and patient management in trials in such settings. Most importantly, the methodologies differ in the incidence of isolated positives and in their capacity for capturing non-tuberculosis mycobacteria. It emphasizes the importance of effective medical monitoring after treatment ends and consideration of clinical signs and symptoms for determining treatment failure and relapse. The study was published on November 24, 2017, in the journal BMC Medicine.
MRC Clinical Trials Unit at UCL