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Low Isoniazid Concentrations and Outcome of Tuberculosis Treatment with Once-Weekly Isoniazid and Rifapentine

University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX; Denver Public Health and Department of Medicine, University of Colorado Health Science Center and National Jewish Medical and Research Center, University of Colorado Schools of Pharmacy and Medicine, Denver, CO; Division of Tuberculosis Elimination, Centers for Disease Control and Prevention, Atlanta, GA; VAMC and George Washington University Medical Center, Washington, DC; and University of North Texas Health Sciences Center, Fort Worth, TX

Correspondence and requests for reprints should be addressed to Marc Weiner, M.D., Department of Medicine (111F), South Texas Veterans Health Care System, 7400 Merton Minter Boulevard, San Antonio, TX 78284. E-mail: weiner{at}uthscsa.edu

To understand why once-weekly isoniazid/rifapentine therapy for tuberculosis was less effective than twice-weekly isoniazid/rifampin, we studied human immunodeficiency virus–seronegative patients with either failure (n = 4), relapse (n = 35), or cure (n = 94), recruited from a comparative treatment trial. In multivariate analyses that were adjusted for severity of disease, low plasma concentrations of isoniazid were associated with failure/relapse with once-weekly isoniazid/rifapentine (median isoniazid area under the concentration–time curve for 12 hours after the dose [AUC_0–12] was 36 µg · hour/ml in failure/relapse versus 56 µg · hour/ml in control cases p = 0.005), but not with twice-weekly isoniazid/rifampin. Furthermore, two patients who relapsed with Mycobacterium tuberculosis monoresistant to rifamycin had very low concentrations of isoniazid. Finally, isoniazid acetylator status determined by N-acetyltransferase type 2 genotype was associated with outcome with once-weekly isoniazid/rifapentine (p = 0.03) but not twice-weekly isoniazid/rifampin. No rifamycin pharmacokinetic parameter was consistently and significantly associated with outcome (p > 0.10). Because low isoniazid concentrations were associated with failure/relapse, a drug with consistently greater area under the concentration–time curve than isoniazid may be needed to achieve highly active once-weekly therapy with rifapentine.

Key Words: tuberculosis • isoniazid • rifapentine • treatment • pharmacokinetics

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