title: HIV-1 Coinfection Does Not Reduce Exposure to Rifampin, Isoniazid, and Pyrazinamide in South African Tuberculosis Outpatients.
abstract: There are contrasting data in the literature about antituberculosis plasma drug concentrations in HIV-1-coinfected patients. We report the pharmacokinetics of rifampin, isoniazid, and pyrazinamide in a cohort of patients being treated for active tuberculosis, the majority of whom were coinfected with HIV-1 and had commenced antiretroviral therapy within 2 months of starting antituberculosis treatment. We also examined the association between antituberculosis drug concentrations and reported drug side effects at the 2-month clinical review. One hundred patients with pulmonary tuberculosis (65% coinfected with HIV-1) were intensively sampled to determine rifampin, isoniazid, and pyrazinamide plasma concentrations after 7 to 8 weeks of a daily quadruple-therapy regimen dosed according to World Health Organization (WHO) weight bands. Pharmacokinetic parameters were determined for each patient by using nonlinear mixed-effects models. HIV-1-coinfected patients had lower clearance rates for rifampin (21% decrease) and isoniazid (23% decrease) than HIV-1-uninfected patients, with resulting higher areas under the concentration-time curve from 0 to 24 h (AUC0-24) and maximum concentrations of drug in serum (Cmax). Antiretroviral therapy (ART) that included double-standard-dose lopinavir/ritonavir further lowered rifampin clearance, by 46%, and increased the AUC0-24 The current uniform dosing (per kilogram of body weight) across WHO weight bands was associated with a trend of decreased pharmacokinetic exposures for the lowest weight band. Use of fat-free mass as opposed to total body weight for allometric scaling of clearance significantly improved the model. Ambulant HIV-1-coinfected patients, the majority of whom were coprescribed ART, did not have reduced antituberculosis drug concentrations compared to HIV-1-uninfected patients.
authors.affiliation: Department of Medicine, Imperial College, London, United Kingdom Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Neesha
authors.identifier: 0000-0002-7830-1394
authors.initials: N
authors.lastname: Rockwood
authors.affiliation: Department of Medicine, Imperial College, London, United Kingdom Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Graeme
authors.initials: G
authors.lastname: Meintjes
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Maxwell
authors.initials: M
authors.lastname: Chirehwa
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Lubbe
authors.initials: L
authors.lastname: Wiesner
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa.
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.affiliation: Department of Medicine, Imperial College, London, United Kingdom Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa Department of Medicine, University of Cape Town, Cape Town, South Africa Francis Crick Institute Mill Hill Laboratory, London, United Kingdom.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wilkinson
authors.affiliation: Division of Clinical Pharmacology, Department of Medicine, University of Cape Town, Cape Town, South Africa paolo.denti@uct.ac.za.
authors.forename: Paolo
authors.initials: P
authors.lastname: Denti
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D000995:Antitubercular Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D060085:Coinfection; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007538:Isoniazid / Q000097:blood / Q000493:pharmacokinetics*; D061466:Lopinavir / Q000627:therapeutic use; D008297:Male; D015233:Models, Statistical; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000254:growth & development; D010045:Outpatients; D011446:Prospective Studies; D011718:Pyrazinamide / Q000097:blood / Q000493:pharmacokinetics*; D012293:Rifampin / Q000097:blood / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000627:therapeutic use; D013019:South Africa; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D061466:Lopinavir; D011718:Pyrazinamide; D019438:Ritonavir; D007538:Isoniazid; D012293:Rifampin