Diagnostic Accuracy of Therapeutic Drug Monitoring During Tuberculosis Treatment

Abstract

Patients with tuberculosis (TB) coinfected with HIV are more likely to have low blood concentrations of the first‐line anti‐TB drugs (associated with poor outcomes). Therapeutic drug monitoring (TDM) is recommended for certain patient populations with TB at increased risk for a poor outcome. Our objective was to estimate the diagnostic accuracy of a 2‐hour TDM serum sample for the first‐line anti‐TB drugs among patients with HIV/TB and evaluate the information gained by an additional 6‐hour sample. We created a virtual (n = 1000) HIV/TB patient population and performed pharmacokinetic simulations using published population models for isoniazid, rifampin, pyrazinamide, and ethambutol. We performed receiver operating characteristic analysis to compare the diagnostic performance of a single 2‐hour serum sample with samples obtained at 2 and 6 hours after dosing. The sensitivity of a single 2‐hour serum concentration to identify patients with HIV/TB with adequate serum exposures was lowest for rifampin (54.9%; 95%CI, 50.79%‐59.41%) and highest for ethambutol (70.8%; 95%CI, 66.06%‐72.61%) for maximum concentration (Cmax) targets. Diagnostic accuracy of a single 2‐hour serum sample for the area under the concentration‐time curve (AUC) from time 0 to 24 hours target was highest for isoniazid (93%; 95%CI, 90.9%‐94.1%) and lowest for pyrazinamide (66.3%; 95%CI, 62.6%‐70.0%). In summary, the diagnostic performance of TDM for Cmax and AUC from time 0 to 24 hours targets demonstrated variability across the first‐line anti‐TB drugs. The addition of a 6‐hour serum sample led to the highest statistically significant improvement (P < .001) and highest increase in diagnostic accuracy (area under the receiver operating characteristic curve) for rifampin for Cmax and AUC. The other first‐line drugs had modest/negligible increases in diagnostic accuracy.