title: Using pharmacokinetic and viral kinetic modeling to estimate the antiviral effectiveness of telaprevir, boceprevir, and pegylated interferon during triple therapy in treatment-experienced hepatitis C virus-infected cirrhotic patients.
abstract: Triple therapy combining a protease inhibitor (PI) (telaprevir or boceprevir), pegylated interferon (PEG-IFN), and ribavirin (RBV) has dramatically increased the chance of eradicating hepatitis C virus (HCV). However, the efficacy of this treatment remains suboptimal in cirrhotic treatment-experienced patients. Here, we aimed to better understand the origin of this impaired response by estimating the antiviral effectiveness of each drug. Fifteen HCV genotype 1-infected patients with compensated cirrhosis, who were nonresponders to prior PEG-IFN/RBV therapy, were enrolled in a nonrandomized study. HCV RNA and concentrations of PIs, PEG-IFN, and RBV were frequently assessed in the first 12 weeks of treatment and were analyzed using a pharmacokinetic/viral kinetic model. The two PIs achieved similar levels of molar concentrations (P=0.5), but there was a significant difference in the 50% effective concentrations (EC50) (P=0.008), leading to greater effectiveness for telaprevir than for boceprevir in blocking viral production (99.8% versus 99.0%, respectively, P=0.002). In all patients, the antiviral effectiveness of PEG-IFN was modest (43.4%), and there was no significant contribution of RBV exposure to the total antiviral effectiveness. The second phase of viral decline, which is attributed to the loss rate of infected cells, was slow (0.19 day(-1)) and was higher in patients who subsequently eradicated HCV (P=0.03). The two PIs achieved high levels of antiviral effectiveness. However, the suboptimal antiviral effectiveness of PEG-IFN/RBV and the low loss of infected cells suggest that a longer treatment duration might be needed in cirrhotic treatment-experienced patients and that a future IFN-free regimen may be particularly beneficial in these patients.
authors: INSERM, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France AP-HP, Hôpital Bichat, Department of Biostatistics, Paris, France cedric.laouenan@inserm.fr.
authors: Cédric
authors: C
authors: Laouénan
authors: INSERM, CRI Paris Montmartre, UMR 1149, University Paris Diderot, Clichy, France AP-HP, Hôpital Beaujon, Hepatology, Physiopathology and Treatment of Viral Hepatitis, Clichy, France.
authors: Patrick
authors: P
authors: Marcellin
authors: INSERM, CRI Paris Montmartre, UMR 1149, University Paris Diderot, Clichy, France.
authors: Martine
authors: M
authors: Lapalus
authors: AP-HP, Hôpital Beaujon, Hepatology, Physiopathology and Treatment of Viral Hepatitis, Clichy, France.
authors: Feryel
authors: F
authors: Khelifa-Mouri
authors: AP-HP, Hôpital Beaujon, Hepatology, Physiopathology and Treatment of Viral Hepatitis, Clichy, France.
authors: Nathalie
authors: N
authors: Boyer
authors: INSERM, UMR 1052, University of Lyon, Lyon, France Hospices Civils de Lyon, Department of Hepatology, Lyon, France.
authors: Fabien
authors: F
authors: Zoulim
authors: AP-HP, Hôpital Saint-Antoine, Department of Hepatology, Paris, France.
authors: Lawrence
authors: L
authors: Serfaty
authors: INSERM, UMR 954, University of Lorraine, Vandoeuvre-les-Nancy, France Centre Hospitalier Universitaire de Nancy, Department of Hepatology, Vandoeuvre-les-Nancy, France.
authors: Jean-Pierre
authors: JP
authors: Bronowicki
authors: INSERM, CRI Paris Montmartre, UMR 1149, University Paris Diderot, Clichy, France.
authors: Michelle
authors: M
authors: Martinot-Peignoux
authors: INSERM, CRI Paris Montmartre, UMR 1149, University Paris Diderot, Clichy, France.
authors: Olivier
authors: O
authors: Lada
authors: INSERM, CRI Paris Montmartre, UMR 1149, University Paris Diderot, Clichy, France AP-HP, Hôpital Beaujon, Hepatology, Physiopathology and Treatment of Viral Hepatitis, Clichy, France.
authors: Tarik
authors: T
authors: Asselah
authors: INSERM, UMR 707, University Pierre et Marie Curie, Paris, France.
authors: Céline
authors: C
authors: Dorival
authors: INSERM, UMR 955, University Paris-Est, Créteil, France AP-HP, Hôpital Henri Mondor, Department of Hepatology, Créteil, France.
authors: Christophe
authors: C
authors: Hézode
authors: INSERM, UMR 707, University Pierre et Marie Curie, Paris, France AP-HP, Hôpital Saint-Antoine, Department of Public Health, Paris, France.
authors: Fabrice
authors: F
authors: Carrat
authors: CHU Toulouse, IFB Purpan, Virology Laboratory, Toulouse, France.
authors: Florence
authors: F
authors: Nicot
authors: INSERM, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France AP-HP, Hôpital Bichat, Department of Clinical Pharmacokinetics, Paris, France.
authors: Gilles
authors: G
authors: Peytavin
authors: INSERM, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France AP-HP, Hôpital Bichat, Department of Biostatistics, Paris, France.
authors: France
authors: F
authors: Mentré
authors: INSERM, IAME, UMR 1137, University Paris Diderot, Sorbonne Paris Cité, Paris, France.
authors: Jeremie
authors: J
authors: Guedj
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D016898:Interferon-alpha / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D009842:Oligopeptides / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011392:Proline / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D016898:Interferon-alpha; D009842:Oligopeptides; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C486464:telaprevir; C512204:N-(3-amino-1-(cyclobutylmethyl)-2,3-dioxopropyl)-3-(2-((((1,1-dimethylethyl)amino)carbonyl)amino)-3,3-dimethyl-1-oxobutyl)-6,6-dimethyl-3-azabicyclo(3.1.0)hexan-2-carboxamide; D011392:Proline; C100416:peginterferon alfa-2a