HIV-1 co-infection does not reduce exposure to rifampicin, isoniazid, and pyrazinamide in South African tuberculosis outpatients
File(s)
Author(s)
Type
Journal Article
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.
Date Issued
2016-08-01
Date Acceptance
2016-07-21
ISSN
1098-6596
Publisher
American Society for Microbiology
Start Page
6050
End Page
6059
Journal / Book Title
Antimicrobial Agents and Chemotherapy
Volume
60
Issue
10
Copyright Statement
© 2016 Rockwood et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution 4.0 International license.
the terms of the Creative Commons Attribution 4.0 International license.
Sponsor
Wellcome Trust
Wellcome Trust
Wellcome Trust
Grant Number
088316/Z/09/Z
097816/Z/11/ZR
104803/Z/14/ZR
Subjects
Microbiology
0605 Microbiology
1108 Medical Microbiology
1115 Pharmacology And Pharmaceutical Sciences
Publication Status
Published
OA Location
http://aac.asm.org/content/early/2016/07/26/AAC.00480-16.long