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Semin Liver Dis 2003; 23: 035-046
DOI: 10.1055/s-2003-41633
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Clinical Trial Results of Peginterferons in Combination with Ribavirin

Antonio Craxi1 , Anna Licata2
  • 1Professor, Academic Department of Gastroenterology and Hepatology, University of Palermo, Palermo, Italy
  • 2Academic Department of Gastroenterology and Hepatology, University of Palermo, Palermo, Italy
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Publication History

Publication Date:
21 August 2003 (online)

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ABSTRACT

Of the large number of patients chronically infected with hepatitis C virus (HCV), only about one third have progressive liver disease, and will eventually develop cirrhosis and hepatocellular carcinoma. These are the patients for whom effective antiviral treatment is most needed. Therapy is currently recommended for patients with chronic hepatitis C who have abnormal alanine aminotransferase (ALT) levels, detectable hepatitis C virus ribonucleic acid (HCV RNA) in the blood, and significant necroinflammatory changes and/or fibrosis on liver biopsy.

The current gold standard in terms of treatment efficacy is the combination of peginterferon (PEG-IFN) and ribavirin. The overall sustained virological response rate (SVR) with these regimens is 54 to 61% following 48 weeks of therapy. Patients with genotype 1 infection have a 42 to 51% likelihood of response to 48 weeks of therapy. Those with genotypes 2 or 3 infection will respond to 24 weeks of therapy in 78 to 82% of cases. These SVR rates are 5 to 10 percentage points higher in all patient groups than in those obtained with standard doses of interferon (IFN) and ribavirin.

Retreatment of nonresponders to standard IFN monotherapy using PEG-IFN and ribavirin has achieved SVR rates of 34 to 40%. Retreatment of patients who relapsed after IFN monotherapy has resulted in an SVR rate of about 60%. A SVR after retreatment of relapsers and nonresponders with PEG-IFN and ribavirin is more likely in patients previously treated with IFN monotherapy, those with HCV genotypes 2 or 3, patients with low viral load (< 2 million copies/mL), and individuals who had a significant decrease in HCV RNA levels during the initial treatment. The potential benefits of long-term anti-HCV suppressive therapy in nonresponders are currently under investigation.

KEYWORDS

Antiviral therapy - chronic hepatitis C - hepatitis C virus (HCV) - genotype - interferon - peginterferon - nonresponder - ribavirin - sustained virological response (SVR)

REFERENCES

  • 1 Reichard O, Andersson J, Schvarcz R. et al . Ribavirin treatment for chronic hepatitis C.  Lancet . 1991;  337 1058-1061
    CrossrefPubMedSearch in Google Scholar
  • 2 McHutchison J G, Gordon S C, Schiff E R. et al . Interferon alfa-2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. Hepatitis Interventional Therapy Group.  N Engl J Med . 1998;  339 1485-1492
    CrossrefPubMedSearch in Google Scholar
  • 3 Poynard T, Marcellin P, Lee S. et al . Randomised trial of interferon alpha2b plus ribavirin for 48 weeks or for 24 weeks versus interferon alpha2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus. International Hepatitis Interventional Therapy Group (IHIT).  Lancet . 1998;  352 1426-1432
    CrossrefPubMedSearch in Google Scholar
  • 4 Reichard O, Norkrans G, Fryden A. et al . Randomised, double-blind, placebo-controlled trial of interferon alpha-2b with and without ribavirin for chronic hepatitis C. The Swedish Study Group.  Lancet . 1998;  351 83-87
    CrossrefPubMedSearch in Google Scholar
  • 5 Heathcote E J, Shiffman M L, Cooksley W G. et al . Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis.  N Engl J Med . 2000;  343 1673-1680
    CrossrefPubMedSearch in Google Scholar
  • 6 Zeuzem S, Feinman S V, Rasenack J. et al . Peginterferon alfa-2a in patients with chronic hepatitis C.  N Engl J Med . 2000;  343 1666-1672
    CrossrefPubMedSearch in Google Scholar
  • 7 Lindsay K L, Trepo C, Heintges T. et al . A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C.  Hepatology . 2001;  34 395-403
    CrossrefPubMedSearch in Google Scholar
  • 8 Manns M P, McHutchison J G, Gordon S C. et al . Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial.  Lancet . 2001;  358 958-965
    CrossrefPubMedSearch in Google Scholar
  • 9 Fried M W, Shiffman M L, Reddy K R. et al . Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection.  N Engl J Med . 2002;  347 975-982
    CrossrefPubMedSearch in Google Scholar
  • 10 Hadziyannis S J, Cheinquier H, Morgan T. et al . Peginterferon alfa-2a (40 KD) (Pegasys) in combination with ribavirin (RBV): efficacy and safety results from a phase III, randomized, double blind, multicentre study examining effects of duration of treatment and RBV dose.  J Hepatol . 2002;  36 3
    PubMedSearch in Google Scholar
  • 11 Bruno S, Cammà C, Di Marco V. et al . Chronic hepatitis C (CH-C) genotype 1: an independent, multicenter RCT comparing PEG-IFN alpha-2b 12 KD plus ribavirin (RBV) and high IFN alpha-2b plus RBV in naive patients.  Hepatology . 2002;  36 571A
    PubMedSearch in Google Scholar
  • 12 Di Bisceglie M A, Hoofnagle J H. Optimal therapy of hepatitis C.  Hepatology . 2002;  36 S121-127
    CrossrefPubMedSearch in Google Scholar
  • 13 Falck-Ytter Y, Kale H, Mullen K D. et al . Surprisingly small effect of antiviral treatment in patients with hepatitis C.  Ann Intern Med . 2002;  136 288-292
    PubMedSearch in Google Scholar
  • 14 Reddy K R, Wright T L, Pockros P J. et al . Efficacy and safety of pegylated (40-kd) interferon alpha-2a compared with interferon alpha-2a in noncirrhotic patients with chronic hepatitis C.  Hepatology . 2001;  33 433-438
    CrossrefPubMedSearch in Google Scholar
  • 15 Saracco G, Olivero A, Ciancio A. et al . Therapy of chronic hepatitis C: a critical review.  Curr Drug Targets Infect Disord . 2003;  3 25-32
    CrossrefPubMedSearch in Google Scholar
  • 16 Forns X, Bukh J. The molecular biology of hepatitis C virus. Genotypes and quasispecies.  Clin Liver Dis . 1999;  3 693-716
    PubMedSearch in Google Scholar
  • 17 el-Zayadi A, Simmonds P, Dabbous H. et al . Response to interferon-alpha of Egyptian patients infected with hepatitis C virus genotype 4.  J Viral Hepatol . 1996;  3 261-264
    PubMedSearch in Google Scholar
  • 18 Diago M, Hadziyannis S J, Bodenheimer H C. et al . Optimized virological response in genotype 4 chronic hepatitis C patients treated with peginterferon alfa-2a (Pegasys) in combination with ribavirin (RBV).  Hepatology . 2002;  36 365A
    PubMedSearch in Google Scholar
  • 19 Ortiz V, Berenguer M, Rayon J M. et al . Contribution of obesity to hepatitis C-related fibrosis progression.  Am J Gastroenterol . 2002;  97 2408-2414
    CrossrefPubMedSearch in Google Scholar
  • 20 Poynard T. Hepatitis C: natural history, biology, treatment monitoring [in French].  Pathol Biol (Paris) . 1999;  47 911-916
    PubMedSearch in Google Scholar
  • 21 FDA Antiviral Drugs Advisory Committee (AVAC) hearing report from December 12, 2001 www.fda.gov/ohrms/dockets/ac/01/transcripts/3819t1.htm. 
  • 22 Jen J, Laughlin M, Chung C. et al . Ribavirin dosing in chronic hepatitis C: application of population pharmacokinetic-pharmacodynamic models.  Clin Pharmacol Ther . 2002;  72 349-361
    CrossrefPubMedSearch in Google Scholar
  • 23 Siebert U, Sroczynski G, Rossol S. et al . Cost effectiveness of peginterferon alpha-2b plus ribavirin versus interferon alpha-2b plus ribavirin for initial treatment of chronic hepatitis C.  Gut . 2003;  52 425-432
    CrossrefPubMedSearch in Google Scholar
  • 24 Buti M, Medina M, Casado M A. et al . A cost-effectiveness analysis of peginterferon alfa-2b plus ribavirin for the treatment of naive patients with chronic hepatitis C.  Aliment Pharmacol Ther . 2003;  17 687-694
    CrossrefPubMedSearch in Google Scholar
  • 25 McHutchison J G, Manns M, Patel K. et al . Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C.  Gastroenterology . 2002;  123 1061-1069
    CrossrefPubMedSearch in Google Scholar
  • 26 Fried M W. Side effects of therapy of hepatitis C and their management.  Hepatology . 2002;  36 S237-S244
    CrossrefPubMedSearch in Google Scholar
  • 27 Davis G L, Esteban-Mur R, Rustgi V. et al . Interferon alfa-2b alone or in combination with ribavirin for the treatment of relapse of chronic hepatitis C. International Hepatitis Interventional Therapy Group.  N Engl J Med . 1998;  339 1493-1499
    CrossrefPubMedSearch in Google Scholar
  • 28 Marco V D, Almasio P, Vaccaro A. et al . Combined treatment of relapse of chronic hepatitis C with high-dose alpha2b interferon plus ribavirin for 6 or 12 months.  J Hepatol . 2000;  33 456-462
    CrossrefPubMedSearch in Google Scholar
  • 29 Herrine S K, Brown R, Esposito S. et al . Efficacy and safety of peginterferon alfa-2a (Pegasys) combination therapies in patients who relapsed on Rebetron therapies.  Hepatology . 2002;  36 359A
    PubMedSearch in Google Scholar
  • 30 Camma C, Bruno S, Schepis F. et al . Retreatment with interferon plus ribavirin of chronic hepatitis C non-responders to interferon monotherapy: a meta-analysis of individual patient data.  Gut . 2002;  51 864-869
    CrossrefPubMedSearch in Google Scholar
  • 31 Shiffman M L. Management of interferon therapy nonresponders.  Clin Liver Dis . 2001;  5 1025-1043
    PubMedSearch in Google Scholar
  • 32 Shiffman M L, Hofmann C M, Contos M J. et al . A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia.  Gastroenterology . 1999;  117 1164-1172
    CrossrefPubMedSearch in Google Scholar
  • 33 Shiffman M. et al . Retreatment of HCV non-responders with peginterferon and ribavirin: results from the lead-in phase of the HALT-C Trial.  Hepatology . 2002;  36 295A
    PubMedSearch in Google Scholar