Pyrazinamide clearance is impaired among HIV/tuberculosis patients with high levels of systemic immune activation.

Christopher Vinnard,Jotam Pasipanodya,Tawanda Gumbo,Neo Tamuhla,Chawangwa Modongo,Shruthi Ravimohan,Drew Weissman,Nicola M Zetola,Shashikant Srivastava,Gregory P Bisson,Esaki M Shankar

doi:10.1371/journal.pone.0187624

Abstract

Pyrazinamide is the main driver of sterilizing effect in the standard regimen in adults and older children, and this effect is concentration-dependent. Tuberculosis patients co-infected with human immunodeficiency virus (HIV) have an increased risk for poor tuberculosis treatment outcomes and adverse drug events. We sought to determine whether measures of systemic immune activation were related to pyrazinamide pharmacokinetics among HIV/tuberculosis patients. We conducted a prospective cohort study of pyrazinamide pharmacokinetics in HIV/tuberculosis patients in Gaborone, Botswana. Patients underwent intensive pharmacokinetic sampling before and after the initiation of antiretroviral therapy, which can increase immune activation in HIV/tuberculosis. Compartmental pharmacokinetic modeling was performed to determine whether variability in systemic immune activation was related to variability in pyrazinamide pharmacokinetic parameters. Forty HIV/tuberculosis patients completed the first pharmacokinetic sampling visit, and 24 patients returned for a second visit following antiretroviral therapy initiation. The pyrazinamide plasma concentration-versus-time data were best explained by a one-compartment model with first-order elimination, and a combined additive and proportional residual error model. Pyrazinamide clearance was higher in men than women. Expression of CD38 and HLA- DR on CD8+T cells, a measure of HIV-associated immune activation, was inversely related to pyrazinamide clearance, with increasing immune activation associated with decreasing pyrazinamide clearance. Future studies should verify this finding in larger numbers of tuberculosis patients with and without HIV co-infection.

Highlights

Pyrazinamide is the key sterilizing-effect drug in the first-line tuberculosis treatment regimen [1,2,3,4]
Tuberculosis patients co-infected with human immunodeficiency virus (HIV) have an increased risk for poor tuberculosis treatment outcomes, which include delays in achieving sputum sterilization, episodes of relapse after completing tuberculosis therapy, development of acquired drug resistant tuberculosis during therapy, and death [6,7,8,9]
We conducted a prospective study of pyrazinamide pharmacokinetics among HIV/tuberculosis patients in Gaborone, Botswana

Summary

Introduction

Pyrazinamide is the key sterilizing-effect drug in the first-line tuberculosis treatment regimen [1,2,3,4]. Four prospective clinical studies have demonstrated that pyrazinamide efficacy is concentration driven, with the sterilizing effect and long-term outcomes driven by peak concentrations [1,2], the 24-hour area under the concentration-time curve (AUC0-24) [3], or the AUC0-24 to minimum inhibitory concentration ratio [4]. These findings are consistent with preclinical studies [5]. The potential for treatment-related hepatotoxicity places a burden on tuberculosis control programs, and contributes to treatment interruptions [12]

Methods

Results

Discussion

Conclusion