Novel high-dose tuberclosis retreatment regimens: How to overcome resistance without creating more? (TriDoRe)

Drug-resistance hampers tuberculosis (TB) control is an important cause of TB mortality. Patients falling ill with TB repeatedly despite treatment (recurrent TB) often have bacilli resistant to the most powerful drugs, rifampicin and isoniazid. Those with resistance to rifampicin need retreatment with other TB drugs, but this is not yet clear for recurrent TB resistant to isoniazid but not to rifampicin. For decennia a longer treatment with more drugs (Cat 2 regimen) was used, thought to overcome isoniazid-resistant TB. But recent reviews have cast doubt on its effectiveness. Therefore we will compare the effectiveness of two strengthened regimens against Cat 2 in patients with recurrent TB in Bangladesh. First, a high-dose isoniazid regimen will be tried, as studies show that high-dose isoniazid may overcome most initial resistance, and then a levofloxacin strengthened regimen, expected to be recommended soon by WHO. If both are equally good and better than Cat 2, the high-dose regimen would be preferable to replace Cat 2 since it does not risk creating resistance to levofloxacin, the main drug needed to cure rifampicin resistant TB. Using a novel assay, Deeplex, we will map resistance to isoniazid and other drugs and estimate their effect on outcomes. Moreover, fluorescein diacetate vital staining microscopy will be used to assess if patients without detectable bacilli at 2 weeks of treatment are cured definitively, to inform future studies on shorter high-dose regimens.

Project type:Post-doctoral project