Novel High-Dose Tuberculosis Retreatment Regimens: How to overcome resistance without Creating More (TriDoRe)

Globally, Tuberculosis (TB) is a leading cause of death from infectious cause. Drug-resistance to the most powerful drugs, rifampicin and isoniazid, hampers TB control. Those with resistance to rifampicin need multidrug resistant TB treatment, but evidence is lacking for how to best treat recurrent TB resistant to isoniazid but not rifampicin. For decennia a longer streptomycin strengthened regimen (Cat.2) was used to overcome isoniazid-resistant TB. But recent reviews casted doubt on its effectiveness, and streptomycin may cause irreversible deafness. Since 2018, based on “very low certainty on the estimates of the effects” in the absence of clinical trials, WHO recommends to replace Cat.2 by a fluoroquinolone (FQ) strengthened regimen. However, we expect this may result in widespread resistance to FQs, which are essential to cure rifampicin-resistant TB. With the current proposal we aim to conduct a pragmatic open-label three-arm individual randomized clinical trial to compare the effectiveness of regimens using highly-dosed first-line TB core drugs, isoniazid and rifampicin, with the FQ strengthened regimen in recurrent, rifampicin sensitive TB. If one of the high-dose regimens is non-inferior to the FQ-strengthened regimen, it would be preferable since it does not risk creating resistance to the FQ. We will use a novel assay, Deeplex®-MycTB, to map initial resistance and estimate its effect on outcomes. Additionally, we will study if FQ resistance enhances the mycobacterial mutation rate and the predictive values of vital staining sputum microscopy at 2 weeks of treatment for initial rifampicin resistance and for relapse.

Project type:Samenwerkingsproject