Xpert MTB/RIF(R) cycle threshold as a marker of TB disease severity; Implications for TB treatment stratification

IntroductionRecent trials have demonstrated that shortened four-month treatment durations are effective for the majority of people with tuberculosis (TB). However, there is a population of TB patients who require longer treatment durations. Prospectively identifying those who require shorter versus longer treatment durations would support evaluation and implementation of optimized regimens. MethodsWe analysed data from the RIFASHORT TB treatment-shortening non-inferiority trial to define a TB phenotype classification. The RIFASHORT trial primary outcome was reanalysed using the protocol-defined non-inferiority criterion of eight percentage points, stratifying by those classified as having limited or extensive disease. ResultsXpert MTB/RIF(R) semiquantitative bacterial burden in combination with TB disease involvement grading on chest X-ray achieved the strongest differentiation between relapse and non-relapse. The extensive disease TB phenotype (high semiquantitative bacterial burden and extensive TB disease on X-ray) accounted for one quarter of the RIFASHORT trial population and more than half of all post-treatment TB relapses (13/23). For the limited TB disease phenotype (<high semiquantitative bacterial burden or no extensive TB disease on X-ray), the experimental 4-month 1200mg rifampicin-containing regimen met the protocol-defined non-inferiority criterion in both modified-intention-to-treat (adjusted risk difference: -1.3% (95% confidence interval: -6.7% to 4.0%)) and per protocol analyses (1.7% (95% CI: -3.8% to 7.1%)). ConclusionA four-month treatment duration, with a widely available, tolerable, rifampicin-based TB treatment regimen, was non-inferior to the standard of care for three-quarters of people with TB in the RIFASHORT trial. This finding justifies definitive evaluation of disease-stratified rifampicin-based TB treatment in a phase III randomised trial. summaryXpert MTB/RIF(R) and chest radiography at TB treatment initiation identify a majority of patients for whom a 4-month treatment duration is non-inferior to the standard of care. These widely available measures may facilitate personalised TB treatment durations.