Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients with Low Isoniazid and Rifampicin Concentrations

Christine Sekaggya-Wiltshire, Amrei Von Braun, Mohammed Lamorde, Bruno Ledergerber, Allan Buzibye, Lars Henning, Joseph Musaazi, Ursula Gutteck, Paolo Denti, Mini De Kock, Alexander Jetter, Pauline Byakika-Kibwika, Nadia Eberhard, Joshua Matovu, Moses Joloba, Daniel Muller, Yukari C Manabe, Moses R. Kamya, Natascia Corti, Andrew KambuguBarbara Castelnuovo, Jan S. Fehr

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)708-716
Number of pages9
JournalClinical Infectious Diseases
Volume67
Issue number5
DOIs
StatePublished - Aug 16 2018
Externally publishedYes

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Isoniazid
Rifampin
Sputum
Tuberculosis
HIV
Pharmaceutical Preparations
Treatment Failure
Pulmonary Tuberculosis
Confidence Intervals
Weights and Measures
Therapeutics

Keywords

  • anti-tuberculosis drugs.
  • outcomes
  • pharmacokinetics
  • Tuberculosis

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

Cite this

Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients with Low Isoniazid and Rifampicin Concentrations. / Sekaggya-Wiltshire, Christine; Von Braun, Amrei; Lamorde, Mohammed; Ledergerber, Bruno; Buzibye, Allan; Henning, Lars; Musaazi, Joseph; Gutteck, Ursula; Denti, Paolo; De Kock, Mini; Jetter, Alexander; Byakika-Kibwika, Pauline; Eberhard, Nadia; Matovu, Joshua; Joloba, Moses; Muller, Daniel; Manabe, Yukari C; Kamya, Moses R.; Corti, Natascia; Kambugu, Andrew; Castelnuovo, Barbara; Fehr, Jan S.

In: Clinical Infectious Diseases, Vol. 67, No. 5, 16.08.2018, p. 708-716.

Research output: Contribution to journalArticle

Sekaggya-Wiltshire, C, Von Braun, A, Lamorde, M, Ledergerber, B, Buzibye, A, Henning, L, Musaazi, J, Gutteck, U, Denti, P, De Kock, M, Jetter, A, Byakika-Kibwika, P, Eberhard, N, Matovu, J, Joloba, M, Muller, D, Manabe, YC, Kamya, MR, Corti, N, Kambugu, A, Castelnuovo, B & Fehr, JS 2018, 'Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients with Low Isoniazid and Rifampicin Concentrations', Clinical Infectious Diseases, vol. 67, no. 5, pp. 708-716. https://doi.org/10.1093/cid/ciy179
Sekaggya-Wiltshire, Christine ; Von Braun, Amrei ; Lamorde, Mohammed ; Ledergerber, Bruno ; Buzibye, Allan ; Henning, Lars ; Musaazi, Joseph ; Gutteck, Ursula ; Denti, Paolo ; De Kock, Mini ; Jetter, Alexander ; Byakika-Kibwika, Pauline ; Eberhard, Nadia ; Matovu, Joshua ; Joloba, Moses ; Muller, Daniel ; Manabe, Yukari C ; Kamya, Moses R. ; Corti, Natascia ; Kambugu, Andrew ; Castelnuovo, Barbara ; Fehr, Jan S. / Delayed Sputum Culture Conversion in Tuberculosis-Human Immunodeficiency Virus-Coinfected Patients with Low Isoniazid and Rifampicin Concentrations. In: Clinical Infectious Diseases. 2018 ; Vol. 67, No. 5. pp. 708-716.
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AU - Sekaggya-Wiltshire, Christine

AU - Von Braun, Amrei

AU - Lamorde, Mohammed

AU - Ledergerber, Bruno

AU - Buzibye, Allan

AU - Henning, Lars

AU - Musaazi, Joseph

AU - Gutteck, Ursula

AU - Denti, Paolo

AU - De Kock, Mini

AU - Jetter, Alexander

AU - Byakika-Kibwika, Pauline

AU - Eberhard, Nadia

AU - Matovu, Joshua

AU - Joloba, Moses

AU - Muller, Daniel

AU - Manabe, Yukari C

AU - Kamya, Moses R.

AU - Corti, Natascia

AU - Kambugu, Andrew

AU - Castelnuovo, Barbara

AU - Fehr, Jan S.

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N2 - 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.

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