Xpert MTB/RIF Assay Shows Faster Clearance of Mycobacterium tuberculosis DNA with Higher Levels of Rifapentine Exposure

Abstract

The Xpert MTB/RIF assay is both sensitive and specific as a diagnostic test. Xpert also reports quantitative output in cycle threshold (CT) values, which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert CT trajectory and drug exposure during tuberculosis (TB) treatment to assess the potential utility of Xpert CT for treatment monitoring. We obtained serial sputum samples from patients with smear-positive pulmonary TB who were consecutively enrolled at 10 international clinical trial sites participating in study 29X, a CDC-sponsored Tuberculosis Trials Consortium study evaluating the tolerability, safety, and antimicrobial activity of rifapentine at daily doses of up to 20 mg/kg of body weight. Xpert was performed at weeks 0, 2, 4, 6, 8, and 12. Longitudinal CT data were modeled using a nonlinear mixed effects model in relation to rifapentine exposure (area under the concentration-time curve [AUC]). The rate of change of CT was higher in subjects receiving rifapentine than in subjects receiving standard-dose rifampin. Moreover, rifapentine exposure, but not assigned dose, was significantly associated with rate of change in CT (P = 0.02). The estimated increase in CT slope for every additional 100 μg · h/ml of rifapentine drug exposure (as measured by AUC) was 0.11 CT/week (95% confidence interval [CI], 0.05 to 0.17). Increasing rifapentine exposure is associated with a higher rate of change of Xpert CT, indicating faster clearance of Mycobacterium tuberculosis DNA. These data suggest that the quantitative outputs of the Xpert MTB/RIF assay may be useful as a dynamic measure of TB treatment response.

New Paradigm for Translational Modeling to Predict Long‐term Tuberculosis Treatment Response

“…Because the murine studies demonstrated a clear exposure‐response relationship for both rifamycins, another clinical trial (TBTC study 29X) was performed in which rifapentine doses ranged from 10 to 20 mg/kg . As expected, patients with rifapentine plasma exposures in the two higher tertiles had more rapid sputum culture conversion and higher rate of change in Xpert MTB/RIF assays than the lowest tertile . This result corroborated the hypothesis that increasing rifapentine doses would increase efficacy in humans, but again demonstrated that rifapentine doses required to achieve superior efficacy over rifampin were higher than anticipated based on results in mice.…”

Can we predict tuberculosis cure? What tools are available?

“…Among HIV-negative pulmonary TB patients tested at baseline and at different time points during treatment, the measure of cycle thresholds and relative changes in Ct values (ΔCt) correlated with culture conversion, predicted treatment failure with 75% sensitivity and 89% specificity [55]. In a multicentre trial of rifapentine-based treatment of smear-positive TB, modelling of longitudinal Xpert Ct values (measured at weeks 0, 2, 4, 6, 8 and 12) in relation to drug exposure showed higher ΔCt in subjects receiving rifapentine than in subjects receiving standard-dose rifampin, indicating the potential of Xpert ΔCts as a dynamic measure of response to therapy [56].…”

Spot sputum samples are at least as good as early morning samples for identifying Mycobacterium tuberculosis

“…However, this difference may impact the results of molecular identification methods that are used to confirm both the presence of M. tuberculosis complex and genotypic resistance patterns, as these have an operational limit for detection and interpretation. As Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is increasingly being considered as a predictor of treatment outcome, and for diagnostic use in resource-limited settings, this difference may indeed prove important [ 23 , 24 ].…”