Pharmacodynamics of PEG-IFN-α-2a in HIV/HCV co-infected patients: Implications for treatment outcomes

Harel Dahari; Evaldo S. Affonso De Araujo; Bart L. Haagmans; Thomas J. Layden; Scott J. Cotler; Antonio A. Barone; Avidan U. Neumann

doi:10.1016/j.jhep.2010.03.019

Pharmacodynamics of PEG-IFN-α-2a in HIV/HCV co-infected patients: Implications for treatment outcomes

Harel Dahari, Evaldo S. Affonso De Araujo, Bart L. Haagmans, Thomas J. Layden, Scott J. Cotler, Antonio A. Barone, Avidan U. Neumann

The Mina and Everard Goodman Faculty of Life Sciences

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

Abstract

Background & Aims: The pharmacokinetics and pharmacodynamics of pegylated-interferon-α-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome. Methods: Twenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180 μg/week) plus ribavirin (11 mg/kg/day). HCV RNA and PEG-IFN concentrations were obtained from samples collected until week 12. A modeling framework that includes pharmacokinetic and pharmacodynamic parameters was developed. Results: Five patients discontinued treatment. Seven patients achieved a sustained virological response (SVR). PEG-IFN concentrations at day 8 were similar to steady-state levels (p = 0.15) and overall pharmacokinetic parameters were similar in SVRs and non-SVRs. The maximum PEG-IFN effectiveness during the first PEG-IFN dose and the HCV-infected cell loss rate (δ), were significantly higher in SVRs compared to non-SVRs (median 95% vs. 86% [p = 0.013], 0.27 vs. 0.11 day^-1 [p = 0.006], respectively). Patients infected with HCV genotype 1 had a significantly lower average first-week PEG-IFN effectiveness (median 70% vs. 88% [p = 0.043]), however, 4- to 12-week PEG-IFN effectiveness was not significantly different compared to those with genotype 3 (p = 0.114). Genotype 1 had a significantly lower δ compared to genotype 3 (median 0.14 vs. 0.23 day^-1 [p = 0.021]). The PEG-IFN concentration that decreased HCV production by 50% (EC₅₀) was lower in genotype 3 compared to genotype 1 (median 1.3 vs. 3.4 [p = 0.034]). Conclusions: Both the HCV-infected cell loss rate (δ) and the maximum effectiveness of the first dose of PEG-IFN-α-2a characterised HIV co-infected patients and were highly predictive of SVR. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of response in patients with HCV and HIV.

Original language	English
Pages (from-to)	460-467
Number of pages	8
Journal	Journal of Hepatology
Volume	53
Issue number	3
DOIs	https://doi.org/10.1016/j.jhep.2010.03.019
State	Published - Sep 2010

Bibliographical note

Funding Information:
H.D is supported by the University of Illinois Walter Payton Liver Center GUILD and by NIH grant P20-RR018754. Grant support (AAB and ESAA): Study carried out with the assistance of Roche Laboratories of Brazil, which provided financial support in the form of the pegylated-interferon α-2a, kits for molecular assays and the shipping of samples.

Funding

H.D is supported by the University of Illinois Walter Payton Liver Center GUILD and by NIH grant P20-RR018754. Grant support (AAB and ESAA): Study carried out with the assistance of Roche Laboratories of Brazil, which provided financial support in the form of the pegylated-interferon α-2a, kits for molecular assays and the shipping of samples.

Funders	Funder number
University of Illinois Walter Payton Liver Center
National Institutes of Health	P20-RR018754

Keywords

Mathematical modeling
Viral kinetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jhep.2010.03.019

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title = "Pharmacodynamics of PEG-IFN-α-2a in HIV/HCV co-infected patients: Implications for treatment outcomes",

abstract = "Background & Aims: The pharmacokinetics and pharmacodynamics of pegylated-interferon-α-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome. Methods: Twenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180 μg/week) plus ribavirin (11 mg/kg/day). HCV RNA and PEG-IFN concentrations were obtained from samples collected until week 12. A modeling framework that includes pharmacokinetic and pharmacodynamic parameters was developed. Results: Five patients discontinued treatment. Seven patients achieved a sustained virological response (SVR). PEG-IFN concentrations at day 8 were similar to steady-state levels (p = 0.15) and overall pharmacokinetic parameters were similar in SVRs and non-SVRs. The maximum PEG-IFN effectiveness during the first PEG-IFN dose and the HCV-infected cell loss rate (δ), were significantly higher in SVRs compared to non-SVRs (median 95% vs. 86% [p = 0.013], 0.27 vs. 0.11 day-1 [p = 0.006], respectively). Patients infected with HCV genotype 1 had a significantly lower average first-week PEG-IFN effectiveness (median 70% vs. 88% [p = 0.043]), however, 4- to 12-week PEG-IFN effectiveness was not significantly different compared to those with genotype 3 (p = 0.114). Genotype 1 had a significantly lower δ compared to genotype 3 (median 0.14 vs. 0.23 day-1 [p = 0.021]). The PEG-IFN concentration that decreased HCV production by 50% (EC50) was lower in genotype 3 compared to genotype 1 (median 1.3 vs. 3.4 [p = 0.034]). Conclusions: Both the HCV-infected cell loss rate (δ) and the maximum effectiveness of the first dose of PEG-IFN-α-2a characterised HIV co-infected patients and were highly predictive of SVR. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of response in patients with HCV and HIV.",

keywords = "Mathematical modeling, Viral kinetics",

author = "Harel Dahari and {Affonso De Araujo}, {Evaldo S.} and Haagmans, {Bart L.} and Layden, {Thomas J.} and Cotler, {Scott J.} and Barone, {Antonio A.} and Neumann, {Avidan U.}",

note = "Funding Information: H.D is supported by the University of Illinois Walter Payton Liver Center GUILD and by NIH grant P20-RR018754. Grant support (AAB and ESAA): Study carried out with the assistance of Roche Laboratories of Brazil, which provided financial support in the form of the pegylated-interferon α-2a, kits for molecular assays and the shipping of samples. ",

year = "2010",

month = sep,

doi = "10.1016/j.jhep.2010.03.019",

language = "אנגלית",

volume = "53",

pages = "460--467",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

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T1 - Pharmacodynamics of PEG-IFN-α-2a in HIV/HCV co-infected patients

T2 - Implications for treatment outcomes

AU - Dahari, Harel

AU - Affonso De Araujo, Evaldo S.

AU - Haagmans, Bart L.

AU - Layden, Thomas J.

AU - Cotler, Scott J.

AU - Barone, Antonio A.

AU - Neumann, Avidan U.

N1 - Funding Information: H.D is supported by the University of Illinois Walter Payton Liver Center GUILD and by NIH grant P20-RR018754. Grant support (AAB and ESAA): Study carried out with the assistance of Roche Laboratories of Brazil, which provided financial support in the form of the pegylated-interferon α-2a, kits for molecular assays and the shipping of samples.

PY - 2010/9

Y1 - 2010/9

N2 - Background & Aims: The pharmacokinetics and pharmacodynamics of pegylated-interferon-α-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome. Methods: Twenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180 μg/week) plus ribavirin (11 mg/kg/day). HCV RNA and PEG-IFN concentrations were obtained from samples collected until week 12. A modeling framework that includes pharmacokinetic and pharmacodynamic parameters was developed. Results: Five patients discontinued treatment. Seven patients achieved a sustained virological response (SVR). PEG-IFN concentrations at day 8 were similar to steady-state levels (p = 0.15) and overall pharmacokinetic parameters were similar in SVRs and non-SVRs. The maximum PEG-IFN effectiveness during the first PEG-IFN dose and the HCV-infected cell loss rate (δ), were significantly higher in SVRs compared to non-SVRs (median 95% vs. 86% [p = 0.013], 0.27 vs. 0.11 day-1 [p = 0.006], respectively). Patients infected with HCV genotype 1 had a significantly lower average first-week PEG-IFN effectiveness (median 70% vs. 88% [p = 0.043]), however, 4- to 12-week PEG-IFN effectiveness was not significantly different compared to those with genotype 3 (p = 0.114). Genotype 1 had a significantly lower δ compared to genotype 3 (median 0.14 vs. 0.23 day-1 [p = 0.021]). The PEG-IFN concentration that decreased HCV production by 50% (EC50) was lower in genotype 3 compared to genotype 1 (median 1.3 vs. 3.4 [p = 0.034]). Conclusions: Both the HCV-infected cell loss rate (δ) and the maximum effectiveness of the first dose of PEG-IFN-α-2a characterised HIV co-infected patients and were highly predictive of SVR. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of response in patients with HCV and HIV.

AB - Background & Aims: The pharmacokinetics and pharmacodynamics of pegylated-interferon-α-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome. Methods: Twenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180 μg/week) plus ribavirin (11 mg/kg/day). HCV RNA and PEG-IFN concentrations were obtained from samples collected until week 12. A modeling framework that includes pharmacokinetic and pharmacodynamic parameters was developed. Results: Five patients discontinued treatment. Seven patients achieved a sustained virological response (SVR). PEG-IFN concentrations at day 8 were similar to steady-state levels (p = 0.15) and overall pharmacokinetic parameters were similar in SVRs and non-SVRs. The maximum PEG-IFN effectiveness during the first PEG-IFN dose and the HCV-infected cell loss rate (δ), were significantly higher in SVRs compared to non-SVRs (median 95% vs. 86% [p = 0.013], 0.27 vs. 0.11 day-1 [p = 0.006], respectively). Patients infected with HCV genotype 1 had a significantly lower average first-week PEG-IFN effectiveness (median 70% vs. 88% [p = 0.043]), however, 4- to 12-week PEG-IFN effectiveness was not significantly different compared to those with genotype 3 (p = 0.114). Genotype 1 had a significantly lower δ compared to genotype 3 (median 0.14 vs. 0.23 day-1 [p = 0.021]). The PEG-IFN concentration that decreased HCV production by 50% (EC50) was lower in genotype 3 compared to genotype 1 (median 1.3 vs. 3.4 [p = 0.034]). Conclusions: Both the HCV-infected cell loss rate (δ) and the maximum effectiveness of the first dose of PEG-IFN-α-2a characterised HIV co-infected patients and were highly predictive of SVR. Further studies are needed to validate these viral kinetic parameters as early on-treatment prognosticators of response in patients with HCV and HIV.

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KW - Viral kinetics

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Pharmacodynamics of PEG-IFN-α-2a in HIV/HCV co-infected patients: Implications for treatment outcomes

Abstract

Bibliographical note

Funding

Keywords

UN SDGs

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