Semin Liver Dis 2003; 23: 001-002
DOI: 10.1055/s-2003-41395
INTRODUCTION

Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Peginterferons in Hepatitis C Virus: Virological, Pharmacokinetic, and Clinical Implications

Emmet B. Keeffe
  • Division of Gastroenterology and Hepatology, Department of Medicine, Stanford University School of Medicine, Stanford, California
Further Information

Publication History

Publication Date:
21 August 2003 (online)

Chronic infection with hepatitis C virus (HCV) affects approximately 300 million people worldwide and is the most frequent indication for liver transplantation in the United States and Europe.[1] It is estimated that up to 4 million people in the United States have been infected with HCV,[2] and natural history studies suggest that 5% and perhaps as many as 20% of patients develop cirrhosis after 20 years of infection.[3] In 2003, it is estimated that over 30,000 people in the United States will die from chronic liver disease. Moreover, the incidence of chronic liver failure is expected to increase over the next ten years as a result of the "silent epidemic" of HCV infection. In 1991, when screening for HCV infection first became widely available, approximately 18% of liver transplants were performed on patients with end-stage liver disease associated with HCV infection. This proportion has increased every year since 1991 and is currently well over 30%.[4] In addition to the rising incidence of chronic liver disease and liver failure, an increasing number of patients with cirrhosis will progress to the development of hepatocellular carcinoma (HCC). The increasing incidence of HCC in many countries is due primarily to chronic HCV infection.

Measurement of quantitative serum HCV RNA and determination of HCV genotype have become important tools in the diagnosis and monitoring of therapy in patients with chronic HCV infection. In an analysis of over 6800 chronic HCV patients, Blatt and colleagues[5] showed that 73% of patients are infected with HCV genotype 1, while 22% of patients have genotypes 2 or 3, and < 5% of patients are infected with genotypes 4, 5, 6, or mixed genotypes. About two thirds of Americans have a high serum HCV RNA level, defined as > 2 million copies/mL, and thus approximately 50% of patients with chronic hepatitis C have genotype 1 in combination with a high viral load-the most challenging virological profile to treat.

Other difficult-to-treat special patient populations include African Americans, patients with human immunodeficiency virus (HIV) co-infection, and patients with obesity. Reddy and colleagues[6] first showed that African American patients with chronic HCV infection were less likely to respond to standard interferon therapy. In a cross-sectional analysis of the U.S. adult acquired immunodeficiency syndrome (AIDS) Clinical Trials Group database, the weighted overall estimate of the prevalence of HCV infection in the study cohort was 16.1%, with HCV genotype 1 in over 83% of infected patients, and a high median HCV RNA level of 6.08 × 106 IU/mL.[7] Preliminary results of these studies suggest that patients with HCV/HIV co-infection respond less well to HCV antiviral therapy.[8] Finally, in obese patients with chronic hepatitis C, it was recognized early in antiviral trials that response rates were lower,[9] and a key issue may be impaired pharmacokinetics of interferon, with resultant adverse effects on HCV viral kinetics.[10]

Stimulated by the high prevalence rate of HCV infection, there have been significant scientific and clinical advances in the understanding and treatment of chronic hepatitis C. Specifically, advances in the understanding of HCV viral kinetics and dynamics have enhanced the ability to predict response to treatment. It is now appreciated that an early virological response (EVR) of ≥ 2 log10 decrease in HCV RNA at 12 weeks is predictive of a sustained virological response (SVR) at 48 weeks of therapy.[11] Similarly, the use of mathematical modeling has provided insights into understanding HCV viral dynamics as well as the ability to predict response to therapy.[12] [13]

The most noteworthy therapeutic advance over the past two years has been the introduction of peginterferon, which in combination with ribavirin has significantly increased SVR rates in patients with chronic hepatitis C. In clinical trials comparing treatment with peginterferon plus ribavirin to standard interferon plus ribavirin, significant increases in overall SVR rates with peginterferon plus ribavirin therapy have been demonstrated, including patients with HCV genotype 1.[11] [14] This progress in antiviral therapy offers hope for achieving higher SVR rates in patients with HCV and HIV co-infection, and in African American or obese patients with chronic hepatitis C. These increases in response rates are likely due to the pegylation of the interferon protein with resultant significant improvement in the biologic activity of the molecule. There are structural differences between the two commercially available peginterferons, peginterferon alfa-2a and peginterferon alfa-2b, in terms of the polyethylene glycol moiety attached to the native protein, the site of attachment, and the type of chemical bond, leading to differences in the pharmacokinetics between the two peginterferons.

A scientific and clinical expert panel meeting was held in February 2003 to examine the virological, pharmacokinetic, and clinical trial results to date with the peginterferons, and to discuss the implications of these data for the treatment of patients with chronic hepatitis C, especially difficult-to-treat patients. Based on the presentations at the meeting, a series of articles have been written and compiled in this supplement to address issues such as diagnostic testing for HCV infection, modeling of viral and drug kinetics, structure and pharmacokinetics of the peginterferons, clinical trial results of treatment of chronic hepatitis C with peginterferon plus ribavirin, and viral kinetics and results of treatment in special difficult-to-treat populations. The information presented in the articles is provocative and will hopefully stimulate the conduct of additional virological and clinical studies of the two peginterferons-alone or in combination with ribavirin-in a variety of patient populations and with different dosing schedules.

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