Larger Doses of Interferon Needed in Those with Genotype 1


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Larger than normal doses of interferon alpha may be needed to treat hepatitis C virus patients with genotype 1, according to a multicenter report.

In those with hepatitis C virus (HCV) disease, several pretreatment factors are predictive of response to interferon (IFN) including baseline serum HCV RNA levels and HCV genotype. Recent studies showed that patients with HCV genotype 1a or 1b respond less favorably to IFN-(alpha) treatment (3 mIU tiw), with sustained response rates of less than 10 percent to 20 percent (Mahaney et al., Hepatology 1994;20:1405-1411; Yoshioka et al., Hepatology 1992;16:293-299).

"It is unknown whether a different dosing regimen of IFN-(alpha) would result in a better-sustained response in patients infected with HCV genotype 1, and whether serum HCV RNA can be cleared at a faster rate with higher doses of IFN-(alpha)," researcher Nancy P. Lam and colleagues wrote ("Dose-Dependent Acute Clearance of Hepatitis C Genotype 1 Virus with IFN-(alpha)," Hepatology, July 1997;26(1):226-231).

To determine if the clearance of hepatitis C genotype 1 virus is dependent on the dose of interferon alpha-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 levels following IFN-(alpha) administration were measured.

At 24 hours, mean percentage serum viral reduction was 41.4 percent, 63.7 percent, and 85.5 percent for 3, 5, and 10 mIU, respectively (P less than .001).

At 48 hours, the mean viral reduction was consistently less than the reduction at 24 hours, averaging 22.9 percent, 61.9 percent, and 74.3 percent, respectively (P less than .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 less than .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 3.7x10(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," Lam et al. wrote. "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."

The corresponding author for this study is Nancy P. Lam, PharmD, Department of Pharmacy Practice (M/C 886), College of Pharmacy, The University of Illinois at Chicago, 833 S. Wood St., Chicago, Illinois 60612.

Source: Hepatitis Weekly, 8/18/97, p14, 2p.

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