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 (C_T) values, which may provide a dynamic measure of sputum bacillary burden when used longitudinally. We evaluated the relationship between Xpert C_T trajectory and drug exposure during tuberculosis (TB) treatment to assess the potential utility of Xpert C_T 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 C_T 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 C_T 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 C_T (P = 0.02). The estimated increase in C_T slope for every additional 100 μg · h/ml of rifapentine drug exposure (as measured by AUC) was 0.11 C_T/week (95% confidence interval [CI], 0.05 to 0.17). Increasing rifapentine exposure is associated with a higher rate of change of Xpert C_T, 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.

FIG 1

Cycle threshold (C_T) trajectories for 115 individual study participants (gray lines) across treatment arms, demonstrating large intrasubject and intersubject variability over time. The estimated mean C_T for each treatment arm (colored lines) rises over time, reflecting clearance of M. tuberculosis DNA with treatment. No significant difference can be seen in overall C_T trajectory between treatment arms.

FIG 2

Relationship between C_T slope and AUC (μg · hr/ml) in 115 study participants. As rifapentine exposure increases, rate of change in C_T also increases, indicating faster M. tuberculosis DNA clearance.