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Treatment of chronic hepatitis C: Impact of combination therapy

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Abstract

Interferon as a single agent results in normalization of the serum alanine aminotransferase (ALT) levels, loss of detectable serum hepatitis C virus RNA, and histologic improvement in approximately 40% of patients. However, regardless of the duration of initial therapy, most patients relapse within the first few months after the drug is stopped, and only a small proportion have a sustained response. Ribavirin is a nucleoside analogue that is known to have in vitro activity against a number of both RNA and DNA viruses. As a single agent, oral ribavirin treatment transiently lowers serum ALT values into the normal range in about 40% of cases of chronic hepatitis C, but it does not affect the level of viremia. However, when given in combination with interferon for 6 to 12 months, ribavirin results in a sustained normalization of serum ALT levels and loss of detectable hepatitis C virus RNA in 30% to 40% of previously untreated patients. Retreatment of interferon relapsers with the combination of interferon and oral ribavirin for 6 months results in a sustained viral-negative response in about half of patients. Thus far, there is little evidence that combination therapy is effective in patients in whom ALT fails to normalize and who have lost hepatitis C virus RNA during a previous treatment course (nonresponders). Studies are ongoing in this group.

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References and Recommended Reading

  1. Davis GL, Balart LA, Schiff ER, et al.: Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized controlled study. N Engl J Med 1989, 321:1501–1506.

    Article  PubMed  CAS  Google Scholar 

  2. Shindo M, Arai K, Sokawa Y, Okuna T: Hepatic hepatitis C virus RNA as a predictor of long term response to interferona therapy. Ann Intern Med 1995, 122:586–591.

    PubMed  CAS  Google Scholar 

  3. Poynard T, Bedossa P, Chevallier M, et al.: A comparison of three interferon alfa-2b regimens for the long term treatment of chronic non-A, non-B hepatitis. N Engl J Med 1995, 332:1457–1462.

    Article  PubMed  CAS  Google Scholar 

  4. 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. This meta-analysis reviews the clinical trials of interferon monotherapy prior to 1996 and clearly demonstrates the impact of duration of therapy on sustained responses.

    Article  PubMed  CAS  Google Scholar 

  5. Davis GL: Combination therapy with interferon alfa and ribavirin as retreatment of interferon relapse in chronic hepatitis C. Semin Liver Dis 1999, in press.

  6. Peters M, Davis GL, Dooley JS, et al.: The interferon system in acute and chronic viral hepatitis. In Progress in Liver Diseases, Vol. 8. Edited by Popper H, Schaffner F. New York: Grune & Stratton; 1986:453–467.

    Google Scholar 

  7. Lam NP, Neumann AU, Gretch DR, et al.: Dose-dependent acute clearance of hepatitis C genotype 1 virus with interferon alfa. Hepatology 1997, 26:226–231.

    Article  PubMed  CAS  Google Scholar 

  8. Crumpacker CS: Overview of ribavirin treatment of infection caused by RNA viruses. In Clinical Applications of Ribavirin. Edited by Smith RA, Knight V, Smith JAD. Orlando, FL: Academic Press; 1984: 33–38.

    Google Scholar 

  9. Patterson JL, Fernandez-Larson R: Molecular action of ribavirin. Rev Infect Dis 1990, 12:1132–1146.

    Google Scholar 

  10. Ning Q, Brown D, Parodo J, et al.: Ribavirin inhibits viral induced macrophage production of tumor necrosis factor, interleukin 1, and procoagulant activity and preserves TH1 cytokine production, but inhibits TH2 cytokine response. J Immunol 1998, 160:3487–3493.

    PubMed  CAS  Google Scholar 

  11. Reichard O, Norkrans G, Fryden A, et al.: Alfa-interferon and ribavirin vs alfa-interferon alone as therapy for chronic hepatitis C: a randomized, double-blind, placebo-controlled study. Lancet 1998, 351:83–87.

    Article  PubMed  CAS  Google Scholar 

  12. Nyberg L, McHutchison J, Albrecht J, et al.: Early changes in HCV RNA kinetics with interferon and ribavirin compared to interferon alone suggest an additive antiviral effect with ribavirin [abstract]. Hepatology 1997, 26:367A.

    Article  Google Scholar 

  13. Gross JB, Brandhagen DJ, Poterucha JJ, et al.: Daily high-dose interferon suppresses viremia in patients with chronic hepatitis C without a previous sustained response to standard treatment [abstract]. Gastroenterology 1998, 114:A1248.

    Article  Google Scholar 

  14. Stewart CA, Hofmann CM, Luketic VA, et al.: A randomized controlled trial of daily vs three times weekly interferon a2A in patients with chronic hepatitis HCV and either elevated or persistently normal ALT [abstract]. Gastroenterology 1997, 114:A1345.

    Article  Google Scholar 

  15. Gonzalez HJ, Ho SB, Gross JB, et al.: High dose induction therapy with alpha interferon is effective in patients with high hepatitis C viral load [abstract]. Gastroenterology 1998, 114:A1247.

    Article  Google Scholar 

  16. Ferenci P, Stauber R, Hackl W, et al.: A prospective, randomized controlled trial of high dose interferon plus ribavirin in interferon nonresponders with chronic hepatitis [abstract]. Gastroenterology 1998, 114:A1240.

    Article  Google Scholar 

  17. Freilich BL, Eisnach JB, Raines J, et al.: Sustained response rates of chronic hepatitis C patients treated with interferon alpha with doses tailored to pretreatment HCV RNA levels [abstract]. Gastroenterology 1998, 114:A1242.

    Article  Google Scholar 

  18. Reichard O, Andersson J, Schvarcz R, et al.: Ribavirin treatment for chronic hepatitis C. Lancet 1991, 337:1058–1061. The first randomized controlled trial to demonstrate the efficacy of interferon-ribavirin combination therapy for the treatment of chronic hepatitis C.

    Article  PubMed  CAS  Google Scholar 

  19. Di Bisceglie AM, Shindo M, Fong T-L, et al.: Pilot study of ribavirin therapy for chronic hepatitis C. Hepatology 1992, 16:649–654.

    Article  PubMed  Google Scholar 

  20. 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, 25:591–59.

    Article  PubMed  CAS  Google Scholar 

  21. Bodenheimer HC, Lindsay KL, Davis GL, et al.: Tolerance and efficacy of oral ribavirin treatment of chronic hepatitis C: a multicenter trial. Hepatology 1997, 26:473–477.

    Article  PubMed  CAS  Google Scholar 

  22. Hayden FG, Schlepushkin AN, Pushkarskay NL: Combined interferon-α-2, rimantadine hydrochloride and ribavirin inhibition of influenza virus replication in vitro. In Clinical Applications of Ribavirin. Edited by Smith RA, Knight V, Smith JAD. Orlando, FL: Academic Press, 1984: 39–48.

    Google Scholar 

  23. Kakumu S, Yoshioka K, Wakita T, et al.: A pilot study of ribavirin and interferon beta for the treatment for chronic hepatitis C. Gastroenterology 1993, 105:507–512.

    PubMed  CAS  Google Scholar 

  24. Braconier JH, Paulsen O, Engman K, Widell A: Combined alpha-interferon and ribavirin treatment in chronic hepatitis C: a pilot study. Scand J Infect Dis 1995, 27:325–329.

    PubMed  CAS  Google Scholar 

  25. Chemello L, Cavaletto L, Bernardinello E, et al.: The effect of interferon alfa and ribavirin combination therapy in naive patients with chronic hepatitis C. J Hepatol 1995, 23(suppl):8–12.

    Article  PubMed  CAS  Google Scholar 

  26. Lai MY, Kao JH, Yang PM, et al.: Long-term efficacy of ribavirin plus interferon alfa in the treatment of chronic hepatitis C. Gastroenterology 1996, 111:1307–1312.

    Article  PubMed  CAS  Google Scholar 

  27. McHutchison JG, Gordon S, Schiff ER, et al.: Interferon alfa-2b monotherapy versus interferon alfa-2b plus ribavirin as initial treatment for chronic hepatitis C: results of a U.S. multicenter randomized controlled study. New Engl J Med 1998, 339:1485 1492. A large randomized controlled trial in previously untreated patients with chronic hepatitis C that demonstrates the efficacy of combination therapy and the impact of genotype and dose duration on longterm virologic responses.

    Article  PubMed  Google Scholar 

  28. Poynard T, Marcellin P, Lee S, et al.: An international randomized trial of interferon alfa-2b and ribavirin (Intron A / Rebetol) 48 or 24 weeks vs Intron A 48 weeks for first line treatment of chronic hepatitis C [abstract]. Hepatology 1998, 28:in press.

  29. 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.

    PubMed  CAS  Google Scholar 

  30. Schvarcz R, Yun ZB, Sonnerborg A, Weiland O. Combined treatment with interferon alpha-2b and ribavirin for chronic hepatitis C in patients with a previous non-response or nonsustained response to interferon alone. J Med Virol 1995, 46:43 47.

    Article  PubMed  Google Scholar 

  31. Bellobouno A, Mondazzi L, Tempini S, et al.: Ribavirin and interferon-alpha combination therapy vs interferon-alpha alone in the retreatment of chronic hepatitis C: a randomized clinical trial. J Viral Hepatol 1997, 4:185–191.

    Article  Google Scholar 

  32. Caremani M, Benci A, Castellacci R, Tacconi D: A randomized controlled trial of leukocyte IFN alpha + ribavirin in HCV chronic hepatitis relapsing patients [abstract] Hepatology 1996, 24:395A.

    Google Scholar 

  33. Davis GL, Estaban-Mur R, Rustgi V, et al., for the International Hepatitis Interventional Therapy Group: Retreatment of relapse after interferon therapy for chronic hepatitis C: an international randomized controlled trial of interferon plus ribavirin vs interferon alone. New Engl J Med 1998, 338:1493–1499. A large randomized trial comparing combination therapy to interferon alone for the retreatment of patients with chronic hepatitis C who had relapsed after biochemical response to a prior course of interferon alone.

    Article  Google Scholar 

  34. Alberti A, Chemello L, Noventa F, et al.: Therapy of hepatitis C: retreatment with alpha interferon. Hepatology 1997, 26(suppl):137–142.

    Article  Google Scholar 

  35. Marcellin P, Poutea M, Boyer N, et al.: Retreatment with recombinant interferon-alfa in patients with chronic hepatitis C. J Infect Dis 1993, 167:780–781.

    PubMed  CAS  Google Scholar 

  36. Picciotti A, Brizzolara R, Campo N, et al.: Two year interferon retreatment may induce a sustained response in relapsing patients with chronic hepatitis [abstract]. Hepatology 1996, 24:273A.

    Google Scholar 

  37. Craxi A, Almasio P, Fuschi P, et al.: Should patients with chronic hepatitis C who relapse after interferon be retreated? [abstract]. J Hepatol 1997, 26:192.

    Article  Google Scholar 

  38. Heathcote EJ, Keeffe EB, Lee SS, et al.: Re-treatment of chronic hepatitis C with consensus interferon. Hepatology 1998, 27:1136–1143. The paper reports sustained virologic responses to retreatment of relapsers with one year high dose consensus interferon.

    Article  PubMed  CAS  Google Scholar 

  39. Pol S, Berthelot P, Brechot C, and the French Multicenter Study Group: Ribavirin-interferon vs interferon alone in nonresponders to α-IFN in chronic hepatitis [abstract]. Hepatology 1996, 24:356A.

    Google Scholar 

  40. Scotto G, Fazio V, Tantimonaco G: Pilot study of a short course of ribavirin and alpha interferon in the treatment of chronic hepatitis C not responding to alpha-interferon alone. Ital J Gastroenterol 1996, 28:505–511.

    PubMed  CAS  Google Scholar 

  41. Davis GL, Lau JYN: Factors predictive of a beneficial response to therapy of hepatitis C. Hepatology 1997, 26(suppl):122–127.

    Article  Google Scholar 

  42. Martinot-Peignoux M, Marcellin P, Poutea M, et al.: Pretreatment serum hepatitis C virus RNA levels and hepatitis C virus genotype are the main and independent prognostic factors of sustained response to interferon alfa therapy in chronic hepatitis C. Hepatology 1995, 22:1050–1056.

    Article  PubMed  CAS  Google Scholar 

  43. Schalm SW, Hansen BE, Chemello L, et al.: Ribavirin enhances the efficacy but not the adverse effects of interferon in chronic hepatitis C: meta-analysis of individual patient data from European centers. J Hepatol 1997, 26:961–966.

    Article  PubMed  CAS  Google Scholar 

  44. El-Zayadi A, Selim O, El Haddad S, Hamdy H: Combination treatment of alpha interferon 2b and ribavirin in chronic hepatitis C genotype 4 patients resistant to interferon therapy [abstract]. Hepatology 1998, 26:1222.

    Google Scholar 

  45. Sarrazin C, Lee JH, Teuber G, et al.: Analysis of the nonstructural 5A gene of European hepatitis C virus isolates and response to interferon alfa and ribavirin [abstract]. Hepatology 1997, 26:215A.

    Article  Google Scholar 

  46. Davis GL: Interferon treatment of cirrhotic patients with chronic hepatitis C: a logical intervention. Am J Gastroenterol 1994, 89:658–66.

    PubMed  CAS  Google Scholar 

  47. Davis GL, Albright JE, Cook SF, Rosenberg DM: Projecting the future healthcare burden from hepatitis C in the United States [abstract]. Hepatology 1998, 28:in press.

  48. Pettit DK, Bonnert TP, Eisenman J, et al.: Structure-function studies of interleukin 15 using site-specific mutagenesis, polyethylene glycol conjugation, and homology modeling. J Biol Chem 1997, 272:2312–2318.

    Article  PubMed  CAS  Google Scholar 

  49. Andreone P, Cursaro C, Gramenzi A, et al.: IFNα-n3 or IFNα-n3 plus ribavirin in chronic hepatitis C resistant to other IFNα treatments: results of a randomized multicenter trial [abstract]. Hepatology 1997, 26:216A.

    Google Scholar 

  50. Smith J: Treatment of chronic hepatitis C with amantadine. Dig Dis Sci 1997, 42:1681–1687.

    Article  PubMed  CAS  Google Scholar 

  51. Olmeda M, Khalili M, Perrillo RP: Amantadine monotherapy in patients with chronic hepatitis C [abstract]. Gastroenterology 1998, 114:A1316.

    Article  Google Scholar 

  52. Khalili M, Olmeda M, Yantsis VA, Perrillo RP: Pilot study of Intron-A and ribavirin vs Intron-A and amantadine in interferon nonresponders with chronic hepatitis C [abstract]. Gastroenterology 1998, 114:A1271.

    Article  Google Scholar 

  53. Brillanti S, Foli M, Gramantieri L, et al.: Triple antiviral therap for chronic hepatitis C in interferon alfa nonresponders: a pilot randomized controlled study [abstract]. Hepatology 1997, 26:367A.

    Google Scholar 

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Davis, G.L. Treatment of chronic hepatitis C: Impact of combination therapy. Curr Gastroenterol Rep 1, 9–14 (1999). https://doi.org/10.1007/s11894-999-0080-9

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  • DOI: https://doi.org/10.1007/s11894-999-0080-9

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