Christine Sekaggya-Wiltshire1, Amrei von Braun2, Mohammed Lamorde1, Bruno Ledergerber2, Allan Buzibye1, Lars Henning2,3, Joseph Musaazi1, Ursula Gutteck4, Paolo Denti5, Miné de Kock5, Alexander Jetter6, Pauline Byakika-Kibwika1,7, Nadia Eberhard2, Joshua Matovu1, Moses Joloba8, Daniel Muller4, Yukari C Manabe9, Moses R Kamya7, Natascia Corti6, Andrew Kambugu1, Barbara Castelnuovo1, Jan S Fehr2,10. 1. Infectious Diseases Institute, College of Health Sciences, Makerere University, Kampala, Uganda. 2. Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Switzerland. 3. Division of Tropical Health and Medicine, James Cook University, Queensland, Australia. 4. Department of Clinical Chemistry, University Hospital Zurich, University of Zurich, Switzerland. 5. Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, South Africa. 6. Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland. 7. School of Medicine, Makerere University, Kampala, Uganda. 8. School of Biomedical Sciences, College of Health Sciences, Makerere University, Kampala, Uganda. 9. Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore. 10. Department of Public Health at Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Switzerland.
Abstract
Background: The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs. Methods: We enrolled HIV-infected Ugandans with pulmonary tuberculosis. Estimation of first-line antituberculosis drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of tuberculosis treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion. Results: We enrolled 268 HIV-infected patients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of tuberculosis treatment (hazard ratio, 0.54; 95% confidence interval, .37-.77; P = .001) or by the end of follow-up (0.61; .44-.85; P = .003). Patients in the highest quartile for area under the rifampicin and isoniazid concentration-time curves for were twice as likely to experience sputum conversion than those in the lowest quartile. Rifampicin and isoniazid concentrations below the thresholds and weight <55 kg were both risk factors for unfavorable tuberculosis treatment outcomes. Only 4.4% of the participants had treatment failure. Conclusion: Although low antituberculosis drug concentrations did not translate to a high proportion of patients with treatment failure, the association between low concentrations of rifampicin and isoniazid and delayed culture conversion may have implications for tuberculosis transmission. Clinical Trials Registration: NCT01782950.
Background: The relationship between concentrations of antituberculosis drugs, sputum culture conversion, and treatment outcome remains unclear. We sought to determine the association between antituberculosis drug concentrations and sputum conversion among patients coinfected with tuberculosis and human immunodeficiency virus (HIV) and receiving first-line antituberculosis drugs. Methods: We enrolled HIV-infected Ugandans with pulmonary tuberculosis. Estimation of first-line antituberculosis drug concentrations was performed 1, 2, and 4 hours after drug intake at 2, 8, and 24 weeks of tuberculosis treatment. Serial sputum cultures were performed at each visit. Time-to-event analysis was used to determine factors associated with sputum culture conversion. Results: We enrolled 268 HIV-infectedpatients. Patients with low isoniazid and rifampicin concentrations were less likely to have sputum culture conversion before the end of tuberculosis treatment (hazard ratio, 0.54; 95% confidence interval, .37-.77; P = .001) or by the end of follow-up (0.61; .44-.85; P = .003). Patients in the highest quartile for area under the rifampicin and isoniazid concentration-time curves for were twice as likely to experience sputum conversion than those in the lowest quartile. Rifampicin and isoniazid concentrations below the thresholds and weight <55 kg were both risk factors for unfavorable tuberculosis treatment outcomes. Only 4.4% of the participants had treatment failure. Conclusion: Although low antituberculosis drug concentrations did not translate to a high proportion of patients with treatment failure, the association between low concentrations of rifampicin and isoniazid and delayed culture conversion may have implications for tuberculosis transmission. Clinical Trials Registration: NCT01782950.
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