title: Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa.
abstract: To determine if the clearance of hepatitis C genotype 1 virus (HCV) is dependent on the dose of interferon alfa-2b (IFN-alpha2b), the acute clearance of HCV after a single dose of either 3, 5, or 10 mIU of IFN-alpha was compared in patients with chronic hepatitis C. HCV-RNA levels following IFN-alpha administration were measured. At 24 hours, mean percentage serum viral reduction was 41.4%, 63.7%, and 85.5% for 3, 5, and 10 mIU, respectively (P < .001). At 48 hours, the mean viral reduction was consistently less than the reduction at 24 hours, averaging 22.9%, 61.9%, and 74.3%, respectively (P < .001), indicating that the drug effect diminishes before 48 hours. Regression analysis showed a positive correlation between dose and percent reduction of HCV-RNA levels (r = .6; P < .001). A mathematical model showed that such dose dependence is expected if IFN-alpha partially blocks viral production. Minimum clearance and production rates of HCV were estimated from measurements of HCV-RNA levels after the 10-mIU dose. HCV decay followed an exponential decline with a minimum estimate of the viral clearance rate constant of 2.8 per day, corresponding to a virion half-life of 0.3 days or less. A minimal estimate of the daily HCV production and clearance is 3.7 x 10(11) virions per day, indicating a high rate of replication and turnover. These results indicate that there is a dose-dependent effect of IFN-alpha in clearance of HCV genotype 1. Because the virion production rate is very rapid and because the current recommended dose of IFN-alpha (3 mIU) is often ineffective, larger doses should be considered to treat genotype 1-infected patients.
authors.affiliation: Department of Pharmacy Practice, College of Pharmacy, University of Illinois at Chicago, 60612, USA.
authors.forename: N P
authors.initials: NP
authors.lastname: Lam
authors.forename: A U
authors.initials: AU
authors.lastname: Neumann
authors.forename: D R
authors.initials: DR
authors.lastname: Gretch
authors.forename: T E
authors.initials: TE
authors.lastname: Wiley
authors.forename: A S
authors.initials: AS
authors.lastname: Perelson
authors.forename: T J
authors.initials: TJ
authors.lastname: Layden
mesh_terms: D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006526:Hepatitis C / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D013997:Time Factors; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins