Current Hepatitis Reports

, Volume 3, Issue 4, pp 148–156

Acute hepatitis C infection: Can immunology teach us the right way to treat?

  • Johannes Wiegand
  • Andrej Potthoff
  • Michael P. Manns
  • Heiner Wedemeyer
Article

Abstract

Management of acute hepatitis C has been discussed controversially in recent years. Early administration of interferon alpha prevents chronicity in almost all cases. However, interferon treatment is associated with significant side effects and costs; thus, alternative treatment strategies were also investigated. These data also suggested that a delayed therapy may cure the infection in 80% to 90% of cases. A detailed understanding of the pathophysiologic mechanisms of acute hepatitis C virus infection may help to find the best way to treat our patients. It has been shown that antiviral humoral and cellular immune responses may influence the outcome of the disease. While a weak T-cell immunity is associated with chronicity, a strong and multispecific cellular immune response is observed in self-limited infection. This article summarizes very recent immunologic and clinical studies on acute hepatitis C and illustrates the knowledge transfer from bench to bedside.

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References and Recommended Reading

  1. 1.
    Ohnishi K, Nomura F, Nakano M: Interferon therapy for acute posttransfusion non-A, non-B hepatitis: response with respect to anti-hepatitis C virus antibody status. Am J Gastroenterol 1991, 86:1041–1049.PubMedGoogle Scholar
  2. 2.
    Viladomiu L, Genesca J, Esteban JI, et al.: Interferon-alpha in acute posttransfusion hepatitis C: a randomized, controlled trial. Hepatology 1992, 15:767–769.PubMedCrossRefGoogle Scholar
  3. 3.
    Hwang SJ, Lee SD, Chan CY, et al.: A randomized controlled trial of recombinant interferon alpha-2b in the treatment of Chinese patients with acute post-transfusion hepatitis C. J Hepatol 1994, 21:831–836.PubMedCrossRefGoogle Scholar
  4. 4.
    Lampertico P, Rumi M, Romeo R, et al.: A multicenter randomized controlled trial of recombinant interferon-alpha 2b in patients with acute transfusion-associated hepatitis C. Hepatology 1994, 19:19–22.PubMedGoogle Scholar
  5. 5.
    Omata M, Yokosuka O, Takano S, et al.: Resolution of acute hepatitis C after therapy with natural beta interferon. Lancet 1991, 338:914–915.PubMedCrossRefGoogle Scholar
  6. 6.
    Vogel W, Graziadei I, Umlauft F, et al.: High-dose interferonalpha2b treatment prevents chronicity in acute hepatitis C: a pilot study. Dig Dis Sci 1996, 41:81S-85S.PubMedCrossRefGoogle Scholar
  7. 7.
    Calleri G, Colombatto P, Gozzelino M, et al.: Natural beta interferon in acute type-C hepatitis patients: a randomized controlled trial. Ital J Gastroenterol Hepatol 1998, 30:181–184.PubMedGoogle Scholar
  8. 8.
    Seeff LB: Natural history of chronic hepatitis C. Hepatology 2002, 36:S35-S46.PubMedCrossRefGoogle Scholar
  9. 9.
    Farci P, Alter HJ, Wong D, et al.: A long-term study of hepatitis C virus replication in non-A, non-B hepatitis. N Engl J Med 1991, 325:98–104.PubMedCrossRefGoogle Scholar
  10. 10.
    Bertoletti A, Ferrari C: Kinetics of the immune response during HBV and HCV infection. Hepatology 2003, 38:4–13.PubMedCrossRefGoogle Scholar
  11. 11.
    Alter MJ, Margolis HS, Krawczynski K, et al.: The natural history of community-acquired hepatitis C in the United States. The Sentinel Counties Chronic non-A, non-B Hepatitis Study Team. N Engl J Med 1992, 327:1899–1905.PubMedCrossRefGoogle Scholar
  12. 12.
    Orland JR, Wright TL, Cooper S: Acute hepatitis C. Hepatology 2001, 33:321–327.PubMedCrossRefGoogle Scholar
  13. 13.
    National Institutes of Health: National Institutes of Health Consensus Development Conference Statement: Management of hepatitis C: 2002—June 10–12, 2002. Hepatology 2002, 36(suppl 1):S3-S20.Google Scholar
  14. 14.
    Williams I: Epidemiology of hepatitis C in the United States. Am J Med 1999, 107:2S-9S.PubMedCrossRefGoogle Scholar
  15. 15.
    Chou R, Clark EC, Helfand M: Screening for hepatitis C virus infection: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2004, 140:465–479.PubMedGoogle Scholar
  16. 16.
    Robert Koch Institute: Virus hepatitis B, C und D im Jahr 2002. Epid Bull Nr. 2. 16–1-2004. http://www.rki.de.Google Scholar
  17. 17.
    Thierfelder W, Hellenbrand W, Meisel H, et al.: Prevalence of markers for hepatitis A, B and C in the German population. Results of the German National Health Interview and Examination Survey 1998. Eur J Epidemiol 2001, 17:429–435.PubMedCrossRefGoogle Scholar
  18. 18.
    Alberti A, Noventa F, Benvegnu L, et al.: Prevalence of liver disease in a population of asymptomatic persons with hepatitis C virus infection. Ann Intern Med 2002, 137:961–964.PubMedGoogle Scholar
  19. 19.
    Roy K, Hay G, Andragetti R, et al.: Monitoring hepatitis C virus infection among injecting drug users in the European Union: a review of the literature. Epidemiol Infect 2002, 129:577–585.PubMedCrossRefGoogle Scholar
  20. 20.
    Chien DY, Choo QL, Tabrizi A, et al.: Diagnosis of hepatitis C virus (HCV) infection using an immunodominant chimeric polyprotein to capture circulating antibodies: reevaluation of the role of HCV in liver disease. Proc Natl Acad Sci U S A 1992, 89:10011–10015.PubMedCrossRefGoogle Scholar
  21. 21.
    Zibert A, Kraas W, Ross RS, et al.: Immunodominant B-cell domains of hepatitis C virus envelope proteins E1 and E2 identified during early and late time points of infection. J Hepatol 1999, 30:177–184.PubMedCrossRefGoogle Scholar
  22. 22.
    Farci P, Shimoda A, Coiana A, et al.: The outcome of acute hepatitis C predicted by the evolution of the viral quasispecies. Science 2000, 288:339–344.PubMedCrossRefGoogle Scholar
  23. 23.
    Ray SC, Wang YM, Laeyendecker O, et al.: Acute hepatitis C virus structural gene sequences as predictors of persistent viremia: hypervariable region 1 as a decoy. J Virol 1999, 73:2938–2946.PubMedGoogle Scholar
  24. 24.
    Cooper S, Erickson AL, Adams EJ, et al.: Analysis of a successful immune response against hepatitis C virus. Immunity 1999, 10:439–449.PubMedCrossRefGoogle Scholar
  25. 25.
    Beld M, Penning M, van Putten M, et al.: Quantitative antibody responses to structural (Core) and nonstructural (NS3, NS4, and NS5) hepatitis C virus proteins among seroconverting injecting drug users: impact of epitope variation and relationship to detection of HCV RNA in blood. Hepatology 1999, 29:1288–1298.PubMedCrossRefGoogle Scholar
  26. 26.
    Bassett SE, Brasky KM, Lanford RE: Analysis of hepatitis C virus-inoculated chimpanzees reveals unexpected clinical profiles. J Virol 1998, 72:2589–2599.PubMedGoogle Scholar
  27. 27.
    Bjoro K, Skaug K, Haaland T, Froland SS: Long-term outcome of chronic hepatitis C virus infection in primary hypogammaglobulinaemia. QJM 1999, 92:433–441.PubMedCrossRefGoogle Scholar
  28. 28.
    Christie JM, Healey CJ, Watson J, et al.: Clinical outcome of hypogammaglobulinaemic patients following outbreak of acute hepatitis C: 2-year follow-up. Clin Exp Immunol 1997, 110:4–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Adams G, Kuntz S, Rabalais G, et al.: Natural recovery from acute hepatitis C virus infection by agammaglobulinemic twin children. Pediatr Infect Dis J 1997, 16:533–534.PubMedCrossRefGoogle Scholar
  30. 30.
    Forns X, Thimme R, Govindarajan S, et al.: Hepatitis C virus lacking the hypervariable region 1 of the second envelope protein is infectious and causes acute resolving or persistent infection in chimpanzees. Proc Natl Acad Sci U S A 2000, 97:13318–13323.PubMedCrossRefGoogle Scholar
  31. 31.
    Takaki A, Wiese M, Maertens G, et al.: Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat Med 2000, 6:578–582. Cellular and humoral immunity during long-term follow-up of hepatitis C.PubMedCrossRefGoogle Scholar
  32. 32.
    Wiegand J, Jackel E, Cornberg M, et al.: Long-term follow-up after successful interferon therapy of acute hepatitis C. Hepatology 2004, 40:98–107.PubMedCrossRefGoogle Scholar
  33. 33.
    Diepolder HM, Zachoval R, Hoffmann RM, et al.: Possible mechanism involving T-lymphocyte response to non-structural protein 3 in viral clearance in acute hepatitis C virus infection. Lancet 1995, 346:1006–1007.PubMedCrossRefGoogle Scholar
  34. 34.
    Gerlach JT, Diepolder HM, Jung MC, et al.: Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C. Gastroenterology 1999, 117:933–941.PubMedCrossRefGoogle Scholar
  35. 35.
    Chang KM, Gruener NH, Southwood S, et al.: Identification of HLA-A3 and -B7-restricted CTL response to hepatitis C virus in patients with acute and chronic hepatitis C. J Immunol 1999, 162:1156–1164.PubMedGoogle Scholar
  36. 36.
    Gruner NH, Gerlach TJ, Jung MC, et al.: Association of hepatitis C virus-specific CD8(+) T cells with viral clearance in acute hepatitis C. J Infect Dis 2000, 181:1528–1536.PubMedCrossRefGoogle Scholar
  37. 37.
    Lechner F, Gruener NH, Urbani S, et al.: CD8+ T lymphocyte responses are induced during acute hepatitis C virus infection but are not sustained. Eur J Immunol 2000, 30:2479–2487.PubMedCrossRefGoogle Scholar
  38. 38.
    Thimme R, Bukh J, Spangenberg HC, et al.: Viral and immunological determinants of hepatitis C virus clearance, persistence, and disease. Proc Natl Acad Sci U S A 2002, 99:15661–15668.PubMedCrossRefGoogle Scholar
  39. 39.
    Grakoui A, Shoukry NH, Woollard DJ, et al.: HCV persistence and immune evasion in the absence of memory T cell help. Science 2003, 302:659–662.PubMedCrossRefGoogle Scholar
  40. 40.
    Shoukry NH, Grakoui A, Houghton M, et al.: Memory CD8+ T cells are required for protection from persistent hepatitis C virus infection. J Exp Med 2003, 197:1645–1655.PubMedCrossRefGoogle Scholar
  41. 41.
    Thimme R, Oldach D, Chang KM, et al.: Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med 2001, 194:1395–1406. CD4+ and CD8+ T-cell immunity during the natural course of acute hepatitis C.PubMedCrossRefGoogle Scholar
  42. 42.
    Lechner F, Wong DK, Dunbar PR, et al.: Analysis of successful immune responses in persons infected with hepatitis C virus. J Exp Med 2000, 191:1499–1512.PubMedCrossRefGoogle Scholar
  43. 43.
    Wedemeyer H, He XS, Nascimbeni M, et al.: Impaired effector function of hepatitis C virus-specific CD8+ T cells in chronic hepatitis C virus infection. J Immunol 2002, 169:3447–3458.PubMedGoogle Scholar
  44. 44.
    Gruener NH, Lechner F, Jung MC, et al.: Sustained dysfunction of antiviral CD8+ T lymphocytes after infection with hepatitis C virus. J Virol 2001, 75:5550–5558.PubMedCrossRefGoogle Scholar
  45. 45.
    Erickson AL, Kimura Y, Igarashi S, et al.: The outcome of hepatitis C virus infection is predicted by escape mutations in epitopes targeted by cytotoxic T lymphocytes. Immunity 2001, 15:883–895.PubMedCrossRefGoogle Scholar
  46. 46.
    Chang KM, Thimme R, Melpolder JJ, et al.: Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection. Hepatology 2001, 33:267–276.PubMedCrossRefGoogle Scholar
  47. 47.
    Scognamiglio P, Accapezzato D, Casciaro MA, et al.: Presence of effector CD8+ T cells in hepatitis C virus-exposed healthy seronegative donors. J Immunol 1999, 162:6681–6689.PubMedGoogle Scholar
  48. 48.
    Koziel MJ, Wong DK, Dudley D, et al.: Hepatitis C virus-specific cytolytic T lymphocyte and T helper cell responses in seronegative persons. J Infect Dis 1997, 176:859–866.PubMedCrossRefGoogle Scholar
  49. 49.
    Kubitschke AK, Bahr M, Aslan N, et al.: Induction of hepatitis C virus specific T cells by needle stick injury in the absence of HCV-viremia [abstract]. Hepatology 2003, 38:173A.CrossRefGoogle Scholar
  50. 50.
    Heller T, Sobao Y, Mizukoshi E, et al.: HCV exposure in humans: stimulation of cellular, but not humoral immune responses in the absence of detectable viremia [abstract]. Hepatology 2003, 38:182A.CrossRefGoogle Scholar
  51. 51.
    Wedemeyer H, Mizukoshi E, Davis AR, et al.: Cross-reactivity between hepatitis C virus and influenza A virus determinantspecific cytotoxic T cells. J Virol 2001, 75:11392–11400.PubMedCrossRefGoogle Scholar
  52. 52.
    Takano S, Satomura Y, Omata M: Effects of interferon beta on non-A, non-B acute hepatitis: a prospective, randomized, controlled-dose study. Japan Acute Hepatitis Cooperative Study Group. Gastroenterology 1994, 107:805–811.PubMedGoogle Scholar
  53. 53.
    Jaeckel E, Cornberg M, Wedemeyer H, et al.: Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med 2001, 345:1452–1457. Key reference for early therapy of acute hepatitis C with interferon alpha.PubMedCrossRefGoogle Scholar
  54. 54.
    Manns MP, McHutchison JG, Gordon SC, 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.PubMedCrossRefGoogle Scholar
  55. 55.
    Fried MW, Shiffman ML, Reddy KR, et al.: Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002, 347:975–982.PubMedCrossRefGoogle Scholar
  56. 56.
    Wiegand J, Boecher W, Buggisch P, et al.: 24 weeks of monotherapy with pegylated interferon alfa-2b in patients with acute hepatitis C [abstract]. Hepatology 2003, 38:277A.CrossRefGoogle Scholar
  57. 57.
    Santantonio T, Mazzola M, Guastadisegni A, et al.: A cohort study of acute hepatitis C virus (HCV) infection: natural course and outcome [abstract]. Hepatology 1999, 30:205A.CrossRefGoogle Scholar
  58. 58.
    Wedemeyer H, Jackel E, Wiegand J, et al.: Whom? When? How? Another piece of evidence for early treatment of acute hepatitis C. Hepatology 2004, 39:1201–1203.PubMedCrossRefGoogle Scholar
  59. 59.
    Hofer H, Watkins-Riedel T, Janata O, et al.: Spontaneous viral clearance in patients with acute hepatitis C can be predicted by repeated measurements of serum viral load. Hepatology 2003, 37:60–64.PubMedCrossRefGoogle Scholar
  60. 60.
    Berg T, Pascu M, Moller B: Prediction of spontaneous viral clearance in acute hepatitis C by viral load measurements. Hepatology 2003, 37:1495–1496.PubMedCrossRefGoogle Scholar
  61. 61.
    Gerlach JT, Diepolder HM, Zachoval R, et al.: Acute hepatitis C: high rate of both spontaneous and treatment-induced viral clearance. Gastroenterology 2003, 125:80–88. Key reference for delayed therapy of acute hepatitis C with interferon alpha.PubMedCrossRefGoogle Scholar
  62. 62.
    Kamal SM, Ismail A, Graham CS, et al.: Pegylated interferon alpha therapy in acute hepatitis C: relation to hepatitis C virus-specific T cell response kinetics. Hepatology 2004, 39:1721–1731.PubMedCrossRefGoogle Scholar
  63. 63.
    Santantonio T, Sinisi E, Signorile F, et al.: Successful treatment of acute hepatitis C with alpha 2b PEG-interferon monotherapy: an interim analysis [abstract]. Hepatology 2003, 38(suppl_1):642A.CrossRefGoogle Scholar
  64. 64.
    Nomura H, Sou S, Tanimoto H, et al.: Short-term interferonalfa therapy for acute hepatitis C: a randomized controlled trial. Hepatology 2004, 39:1213–1219.PubMedCrossRefGoogle Scholar
  65. 65.
    Delwaide J, Bourgeois N, Gerard C, et al.: Treatment of acute hepatitis C with interferon alpha-2b: early initiation of treatment is the most effective predictive factor of sustained viral response. Aliment Pharmacol Ther 2004, 20:15–22.PubMedCrossRefGoogle Scholar
  66. 66.
    Manns MP, Meyer S, Wedemeyer H: The German network of excellence for viral hepatitis (Hep-Net). Hepatology 2003, 38:543–544.PubMedCrossRefGoogle Scholar
  67. 67.
    Lehmann M, Meyer MF, Monazahian M, et al.: High rate of spontaneous clearance of acute hepatitis C virus genotype 3 infection. J Med Virol 2004, 73:387–391.PubMedCrossRefGoogle Scholar
  68. 68.
    Zeuzem S, Hultcrantz R, Bourliere M, et al.: Peginterferon alfa-2b plus ribavirin for treatment of chronic hepatitis C in previously untreated patients infected with HCV genotypes 2 or 3. J Hepatol 2004, 40:993–999.PubMedCrossRefGoogle Scholar
  69. 69.
    Rahman F, Heller T, Sobao Y, et al.: Effects of antiviral therapy on the cellular immune response in acute hepatitis C. Hepatology 2004, 40:87–97. CD4+ and CD8+ T-cell immunity during interferon therapy of acute hepatitis C.PubMedCrossRefGoogle Scholar
  70. 70.
    Lauer GM, Lucas M, Ouchi K, et al.: T-cell responses during early therapy for HCV infection [abstract]. Hepatology 2003, 38:354A.CrossRefGoogle Scholar
  71. 71.
    Tester IA, Smyk-Pearson S, Dean S, Rosen HR: Acute hepatitis C infection following patellar tendon transplantation: immunologic correlates of recovery [abstract]. Hepatology 2003, 38:358A.CrossRefGoogle Scholar
  72. 72.
    Thomson M, Nascimbeni M, Havert MB, et al.: The clearance of hepatitis C virus infection in chimpanzees may not necessarily correlate with the appearance of acquired immunity. J Virol 2003, 77:862–870.PubMedCrossRefGoogle Scholar
  73. 73.
    Rosenberg ES, Billingsley JM, Caliendo AM, et al.: Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997, 278:1447–1450.PubMedCrossRefGoogle Scholar
  74. 74.
    Rosenberg SA: Progress in human tumour immunology and immunotherapy. Nature 2001, 411:380–384.PubMedCrossRefGoogle Scholar
  75. 75.
    Stevens AB, Coyle PV: Hepatitis C virus: an important occupational hazard? Occup Med (Lond) 2000, 50:377–382.Google Scholar
  76. 76.
    The German Consensus Conference on the treatment of viral hepatitis 2003. Accessible at http://www.kompetenznetz-hepatitis. de. Accessed March 2, 2004.Google Scholar
  77. 77.
    Jullien-Depradeux AM, Bloch J, Quellec-Nathan M, Abenhaim A: National campaign against hepatitis C in France (1999-2002). Acta Gastroenterol Belg 2002, 65:112–114.PubMedGoogle Scholar

Copyright information

© Current Science Inc 2004

Authors and Affiliations

  • Johannes Wiegand
  • Andrej Potthoff
  • Michael P. Manns
    • 1
  • Heiner Wedemeyer
  1. 1.Department of Gastroenterology, Hepatology and EndocrinologyHannover Medical SchoolHannoverGermany

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