Diagnostic Accuracy of Therapeutic Drug Monitoring During Tuberculosis Treatment

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 (C_max) 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 C_max 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 C_max and AUC. The other first-line drugs had modest/negligible increases in diagnostic accuracy.