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. 2017 Nov 2;12(11):e0187624.
doi: 10.1371/journal.pone.0187624. eCollection 2017.

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

Christopher Vinnard  1 , Shruthi Ravimohan  2 , Neo Tamuhla  3 , Jotam Pasipanodya  4 , Shashikant Srivastava  4 , Chawangwa Modongo  3 , Nicola M Zetola  3 , Drew Weissman  2 , Tawanda Gumbo  4 , Gregory P Bisson  2
Affiliations

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

Christopher Vinnard et al. PLoS One. .

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Histogram of age distribution of study participants.
Fig 2
Fig 2. Mean pyrazinamide concentration-versus-time curves prior to the initiation of antiretroviral therapy.
Legend: open triangles: women, closed circles: men; dashed line: mean pyrazinamide concentrations among women; solid line: mean pyrazinamide concentrations among men.
Fig 3
Fig 3. Mean pyrazinamide concentration-versus-time curves following the initiation of antiretroviral therapy.
Legend: open triangles: women, closed circles: men; dashed line: mean pyrazinamide concentrations among women; solid line: mean pyrazinamide concentrations among men.
Fig 4
Fig 4. Eta covariate box plot of gender versus between-subject variability in pyrazinamide clearance (ηCL).
The dots represent individual values.
Fig 5
Fig 5. Eta covariate plot of %CD38+HLADR+CD8+ versus between-subject variability in pyrazinamide clearance (ηCL).
The dots represent individual values.
Fig 6
Fig 6. Diagnostic plot of observed versus population predicted pyrazinamide concentrations.
Fig 7
Fig 7. Diagnostic plot of observed versus individual predicted pyrazinamide concentrations.
Fig 8
Fig 8. Diagnostic plot of individual weighted residuals versus individual predicted pyrazinamide concentrations.
Fig 9
Fig 9. Diagnostic plot of conditional weighted residuals versus predicted concentrations.
Fig 10
Fig 10. Visual predictive check of final pharmacokinetic model with 1000 replicates.
Dotted line: observed 5th percentile; solid line: observed 50th percentile; dashed line: observed 95th percentiles; blue shaded region: 95% confidence intervals for predicted 5th and 95th percentiles; pink shaded region: 95% confidence interval for 50th percentile.
See this image and copyright information in PMC

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