Treatment of Hepatitis C Virus: The First Decade

Interferon alfa therapy emerged as an early treatment option for patients with chronic hepatitis C. This therapy, however, fails to produce a sustained virological response in most patients. Various host and viral baseline characteristics, some of which include hepatitis C virus genotype, viral load, presence of cirrhosis, and patient age, affect the response to interferon therapy. The addition of ribavirin to interferon therapy significantly improves long-term virological response in treatment-naive patients and is also more effective than repeat interferon therapy is in patients who fail to initially achieve sustained virological or biochemical responses. However, ribavirin can induce reversible hemolytic anemia, and combination therapy with a ribavirin/interferon regimen is not tolerated as well as interferon is alone. Pegylated interferons used alone or in combination with ribavirin provide improved treatment options for different patient groups with chronic hepatitis C.

KEYWORDS

Interferon - ribavirin - hepatitis C - sustained virological response - fibrosis

REFERENCES

• 1 Hoofnagle J H, Mullen K D, Jones D B et al.. Treatment of chronic non-A, non-B hepatitis with recombinant human alpha interferon.  N Engl J Med. 1986;  315 1575-1578
• 2 Di Bisceglie A M, Martin P, Kassianides C et al.. Recombinant interferon alfa therapy for chronic hepatitis C. A randomized, double-blind, placebo-controlled trial.  N Engl J Med. 1989;  321 1506-1510
• 3 Davis G L, Balart L A, Schiff E R et al.. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group.  N Engl J Med. 1989;  321 1501-1506
• 4 Choo Q L, Kuo G, Weiner A J et al.. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome.  Science. 1989;  244 359-362
• 5 Pockros P J, Tong M, Lee W M et al.. Relationship between biochemical and virological responses to interferon therapy in chronic hepatitis C infection.  J Viral Hepat. 1998;  5 271-276
• 6 Dorr R T. Interferon-alfa in malignant and viral diseases. A review.  Drugs. 1993;  45 177-211
• 7 Tilg H. New insights into the mechanisms of interferon alfa: an immunoregulatory and anti-inflammatory cytokine.  Gastroenterology. 1997;  112 1017-1021
• 8 Nieforth K A, Nadeau R, Patel I H, Mould D. Use of an indirect pharmacodynamic stimulation model of MX protein induction to compare in vivo activity of interferon alfa-2a and a polyethylene glycol-modified derivative in healthy subjects.  Clin Pharmacol Ther. 1996;  59 636-646
• 9 Poynard T, Leroy V, Cohard M et al.. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C: effects of dose and duration.  Hepatology. 1996;  24 778-789
• 10 Thevenot T, Regimbeau C, Ratziu V et al.. Meta-analysis of interferon randomized trials in the treatment of viral hepatitis C in naive patients: 1999 update.  J Viral Hepat. 2001;  8 48-62
• 11 Lindsay K L, Davis G L, Schiff E R et al.. Response to higher doses of interferon alfa-2b in patients with chronic hepatitis C: a randomized multicenter trial. Hepatitis Interventional Therapy Group.  Hepatology. 1996;  24 1034-1040
• 12 Shiffman M L. Use of high-dose interferon in the treatment of chronic hepatitis C.  Semin Liver Dis. 1999;  19(suppl 1) 25-33
• 13 Hoofnagle J H, Lau D, Conjeevaram H et al.. Prolonged therapy of chronic hepatitis C with ribavirin.  J Viral Hepat. 1996;  3 247-252
• 14 Bodenheimer H C, Lindsay K L, Davis G L et al.. Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial.  Hepatology. 1997;  26 473-477
• 15 Di Bisceglie A M, Conjeevaram H S, Fried M W et al.. Ribavirin as therapy for chronic hepatitis C.  Ann Intern Med. 1995;  123 897-903
• 16 Dusheiko G, Main J, Thomas H et al.. Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study.  J Hepatol. 1996;  25 591-598
• 17 Tam R C, Ramasamy K, Bard J et al.. The ribavirin analog ICN 17261 demonstrates reduced toxicity and antiviral effects with retention of both immunomodulatory activity and reduction of hepatitis-induced serum alanine aminotransferase levels.  Antimicrob Agents Chemother. 2000;  44 1276-1283
• 18 Brillanti S, Garson J, Foli M et al.. A pilot study of combination therapy with ribavirin plus interferon alfa for interferon-alfa-resistant chronic hepatitis C.  Gastroenterology. 1994;  107 812-817
• 19 Lai M-Y, Kao J-H, Yang P-M et al.. Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C.  Gastroenterology. 1996;  111 1307-1312
• 20 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.  N Engl J Med. 1998;  339 1485-1492
• 21 Poynard T, Marcellin P, Lee S 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.  Lancet. 1998;  352 1426-1432
• 22 Reichard O, Nokrans G, Fryden A et al.. Randomised, double-blind, placebo-controlled trial of interferon alfa-2b with and without ribavirin for chronic hepatitis C.  Lancet. 1998;  351 83-87
• 23 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.  N Engl J Med. 1998;  339 1493-1499
• 24 Schalm S W, Weiland O, Hansen B E et al.. Interferon-ribavirin for chronic hepatitis C with and without cirrhosis: analysis of individual patient data of six controlled trials.  Gastroenterology. 1999;  117 408-413
• 25 National Institutes of Health . National Institutes of Health Consensus Development Conference Statement. Management of hepatitis C: June 10-12, 2002.  Hepatology. 2002;  36(suppl 1) S3-S20
• 26 EASL International Consensus Conference on Hepatitis C . Paris 26-28, February 1999. Consensus statement. European Association for the Study of the Liver.  J Hepatol. 1999;  30 956-961
• 27 Idilman R, De Maria M, Colantoni A A D, van Thiel D H. Interferon treatment of cirrhotic patients with chronic hepatitis C.  J Viral Hepat. 1997;  4 81-91
• 28 Poynard T, McHutchison J, Goodman Z et al.. Is an “a la carte” combination interferon alfa-2b plus ribavirin regimen possible for the first line treatment in patients with chronic hepatitis C?.  Hepatology. 2000;  31 211-218
• 29 McHutchison J G, Shad J A, Gordon S C et al.. Predicting response to initial therapy with interferon plus ribavirin in chronic hepatitis C using serum HCV RNA results during therapy.  J Viral Hepat. 2001;  8 414-420
• 30 McHutchison J G, Ware J E, Bayliss M S et al.. The effects of interferon alpha-2b in combination with ribavirin on health related quality of life and work productivity.  J Hepatol. 2001;  34 140-147
• 31 Westin J, Lindh M, Nenonen N et al.. Monitoring virological responses to interferon-ribavirin and interferon monotherapy of chronic hepatitis C re-treated due to relapse or non-response.  Scand J Infect Dis. 2001;  33 110-115
• 32 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
• 33 Camma C, Giunta M, Linea C, Pagliaro L. The effect of interferon on the liver in chronic hepatitis C: a quantitative evaluation of histology by meta-analysis.  J Hepatol. 1997;  26 1187-1199
• 34 Carithers Jr R L, Emerson S S. Therapy of hepatitis C: meta-analysis of interferon alfa-2b trials.  Hepatology. 1997;  26(suppl 1) 83S-88S
• 35 Bedossa P, Bioulacsage P, Callard P et al.. Presentation of a coded form for the assessment of histopathological features in viral chronic hepatitis-C.  Ann Pathol. 1993;  13 260-265
• 36 Bedossa P, Bioulacsage P, Callard P et al.. Which classification for chronic hepatitis? Lessons from hepatitis C virus.  Gastroenterol Clin Biol. 1994;  18 403-406
• 37 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
• 38 Sobesky R, Mathurin P, Charlotte F et al.. Modeling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C: a dynamic view.  Gastroenterology. 1999;  116 378-386
• 39 Poynard T, McHutchison J, Davis G L et al.. Impact of interferon alfa-2b and ribavirin on progression of liver fibrosis in patients with chronic hepatitis C.  Hepatology. 2000;  32 1131-1137
• 40 Shiratori Y, Imazeki F, Moriyama M et al.. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy.  Ann Intern Med. 2000;  132 517-524
• 41 Yoshida H, Arakawa Y, Sata M et al.. Interferon therapy prolonged life expectancy among chronic hepatitis C patients.  Gastroenterology. 2002;  123 483-491
• 42 Bonkovsky H L, Woolley J M. Reduction of health-related quality of life in chronic hepatitis C and improvement with interferon therapy. The Consensus Interferon Study Group.  Hepatology. 1999;  29 264-270
• 43 Ware J, Bayliss M S. Health-related quality of life in chronic hepatitis C: impact of disease and treatment response. The Interventional Therapy Group.  Hepatology. 1999;  3 550-555
• 44 Carithers Jr R L, Zeuzem S, Manns M P et al.. Multicenter, randomized, controlled trial comparing high dose daily induction interferon plus ribavirin versus standard interferon alfa-2b plus ribavirin.  Hepatology. 2000;  32 317