title: Pharmacodynamics of PEG-IFN alpha differentiate HIV/HCV coinfected sustained virological responders from nonresponders.
abstract: Pegylated interferon (PEG-IFN) has become standard therapy for hepatitis C virus (HCV) infection. We evaluated whether PEG-IFN pharmacodynamics and pharmacokinetics account for differences in treatment outcome and whether these parameters might be predictors of therapeutic outcome. Twenty-four IFN-naïve, HCV/human immunodeficiency virus-coinfected patients received PEG-IFN alpha-2b (1.5 microg/kg) once weekly plus daily ribavirin (1000 or 1200 mg) for up to 48 weeks. HCV RNA and PEG-IFN alpha concentrations were obtained from samples collected frequently after the first 3 PEG-IFN doses. We modeled HCV kinetics incorporating pharmacokinetic and pharmacodynamic parameters. Although PEG-IFN concentrations and pharmacokinetic parameters were similar in sustained virological responders (SVRs) and nonresponders (NRs), the PEG-IFN alpha-2b concentration that decreases HCV production by 50% (EC50) was lower in SVRs compared with NRs (0.04 vs. 0.45 microg/L [P = .014]). Additionally, the median therapeutic quotient (i.e., the ratio between average PEG-IFN concentration and EC50 [C/EC50]), and the PEG-IFN concentration at day 7 divided by EC50 (C(7)/EC50) were significantly increased in SVRs compared with NRs after the first (10.1 vs. 1.0 [P = .012], 2.8 vs. 0.3 [P = .007], respectively) and second (14.0 vs. 1.1 [P = .016], 5.4 vs. 0.4 [P = .02], respectively) PEG-IFN doses. All 3 parameters may be used to identify NRs. In conclusion, PEG-IFN concentrations and pharmacokinetic parameters do not differ between SVRs and NRs. In contrast, pharmacodynamic measurements-namely EC50, the therapeutic quotient, and C(7)/EC50--are different in coinfected SVRs and NRs. These parameters might be useful predictors of treatment outcome during the first month of therapy.
authors.affiliation: Department of Medicine and the Center for the Study of Hepatitis C, Weill Medical College of Cornell University, New York, NY 10021, USA. aht2002@med.cornell.edu
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Talal
authors.forename: Ruy M
authors.initials: RM
authors.lastname: Ribeiro
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Powers
authors.forename: Michael
authors.initials: M
authors.lastname: Grace
authors.forename: Constance
authors.initials: C
authors.lastname: Cullen
authors.forename: Musaddeq
authors.initials: M
authors.lastname: Hussain
authors.forename: Marianthi
authors.initials: M
authors.lastname: Markatou
authors.forename: Alan S
authors.initials: AS
authors.lastname: Perelson
mesh_terms: D000998:Antiviral Agents / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006526:Hepatitis C / Q000097:blood* / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000097:blood* / Q000494:pharmacology* / Q000627:therapeutic use; D011092:Polyethylene Glycols; D012313:RNA / Q000097:blood*; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*; D016896:Treatment Outcome
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D012313:RNA; C417083:peginterferon alfa-2b