HIV-1 Coinfection Does Not Reduce Exposure to Rifampin, Isoniazid, and Pyrazinamide in South African Tuberculosis Outpatients.

TitleHIV-1 Coinfection Does Not Reduce Exposure to Rifampin, Isoniazid, and Pyrazinamide in South African Tuberculosis Outpatients.
Publication TypeJournal Article
Year of Publication2016
AuthorsRockwood N, Meintjes G, Chirehwa M, Wiesner L, McIlleron H, Wilkinson RJ, Denti P
JournalAntimicrob Agents Chemother
Volume60
Issue10
Pagination6050-9
Date Published2016 10
ISSN1098-6596
KeywordsAdult, Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Antitubercular Agents, Area Under Curve, Biological Availability, Coinfection, Female, HIV Infections, HIV-1, Humans, Isoniazid, Lopinavir, Male, Models, Statistical, Mycobacterium tuberculosis, Outpatients, Prospective Studies, Pyrazinamide, Rifampin, Ritonavir, South Africa, Tuberculosis, Pulmonary
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.

DOI10.1128/AAC.00480-16
Alternate JournalAntimicrob. Agents Chemother.
PubMed ID27480859
PubMed Central IDPMC5038257
Grant ListU01 AI068632 / AI / NIAID NIH HHS / United States
UM1 AI068634 / AI / NIAID NIH HHS / United States
UM1 AI068636 / AI / NIAID NIH HHS / United States
UM1 AI106701 / AI / NIAID NIH HHS / United States
WT 104803 / / Wellcome Trust / United Kingdom
WT084323 / / Wellcome Trust / United Kingdom
UKMRC U1175.02.002.00014 / / Medical Research Council / United Kingdom
098316 / / Wellcome Trust / United Kingdom