Isoniazid, Rifampin, Ethambutol, and Pyrazinamide Pharmacokinetics and Treatment Outcomes among a Predominantly HIV-Infected Cohort of Adults with Tuberculosis from Botswana

Background. We explored the association between antituberculosis drug pharmacokinetics and treatment outcomes among patients with pulmonary tuberculosis in Botswana. Methods. Consenting outpatients with tuberculosis had blood samples collected 1, 2, and 6 h after simultaneous isoniazid, rifampin, ethambutol, and pyrazinamide ingestion. Maximum serum concentrations (C-max) and areas under the serum concentration time curve were determined. Clinical status was monitored throughout treatment. Results. Of the 225 participants, 36 (16%) experienced poor treatment outcome ( treatment failure or death); 155 (69%) were infected with human immunodeficiency virus (HIV). Compared with published standards, low isoniazid C-max occurred in 84 patients (37%), low rifampin C-max in 188 (84%), low ethambutol C-max in 87 (39%), and low pyrazinamide C-max in 11 (5%). Median rifampin and pyrazinamide levels differed significantly by HIV status and CD4 cell count category. Only pyrazinamide pharmacokinetics were significantly associated with treatment outcome; low pyrazinamide C-max was associated with a higher risk of documented poor treatment outcome, compared with normal C-max (50% vs. 16%; P < .01). HIV-infected patients with a CD4 cell count <200 cells/mu L had a higher risk of poor treatment outcome (27%) than did HIV-uninfected patients (11%) or HIV-infected patients with a CD4 cell count >= 200 cells/mu L (12%; P = .01). After adjustment for HIV infection and CD4 cell count, patients with low pyrazinamide C-max were 3 times more likely than patients with normal pyrazinamide C-max to have poor outcomes ( adjusted risk ratio, 3.38; 95% confidence interval, 1.84-6.22). Conclusions. Lower than expected antituberculosis drug C-max occurred frequently, and low pyrazinamide C-max was associated with poor treatment outcome. Exploring the global prevalence and significance of these findings may suggest modifications in treatment regimens that could improve tuberculosis cure rates.