DOSE-DEPENDENT ACUTE CLEARANCE OF HEPATITIS-C GENOTYPE-1 VIRUS WITH INTERFERON-ALFA

To determine if the clearance of hepatitis C genotype 1 virus (HCV) is dependent on the dose of interferon alfa-2b (IFN-alpha 2b), 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 leve ls 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 red uction 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 lev els (r = .6; P < .001). A mathematical model showed that such dose dep endence is expected if IFN-alpha partially blocks viral production. Mi nimum clearance and production rates of HCV were estimated from measur ements of HCV-RNA levels after the 10-mIU dose. HCV decay followed an exponential decline with a minimum estimate of the viral clearance rat e 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 clear ance is 3.7 X 10(11) virions per day, indicating a high rate of replic ation and turnover. These results indicate that there is a dose-depend ent effect of IFN-alpha in clearance of HCV genotype 1. Because the vi rion production rate is very rapid and because the current recommended dose of IFN-alpha (3 mIU) is often ineffective, larger doses should b e considered to treat genotype 1-infected patients.