Medizinische Klinik

, Volume 92, Issue 3, pp 147–161

Therapie der Hepatitis C

  • Dominik M. Alscher
  • J. Christian Bode
Übersicht
  • 22 Downloads

Zusammenfassung

Ziel dieser Arbeit ist zum einen ein Fortschrittsbericht der Therapie der Hepatitis C insbesondere mit Interferon-α. Zum anderen wird aus einer großen Zahl von Publikationen das für die Therapie Gesicherte aufgearbeitet und hieraus Empfehlungen für das praktische Vorgehen abgeleitet. Ein dritter Schwerpunkt der Übersicht gilt neuen, im Stadium der Erprobung befindlichen Therapieformen sowie zur Zeit noch nicht eindeutig zu beurteilenden Aspekten zur Therapie der chronischen Hepatitis C.

Bei der vergleichsweise selten erfaßten akuten Phase einer Hepatitis C wird durch eine Behandlung mit Interferon-α (dreimal drei Mio E/Woche über einen Zeitraum von drei bis vier Monaten) der Anteil der Patienten, bei denen eine Elimination von HCV-RNA aus dem Serum erreicht wird, erhöht. Bei Patienten mit chronischer Hepatitis C ist nach Indikationsstellung zur Therapie außerhalb von Studien ein Standardschema einer Monotherapie mit rekombinantem Interferon-α zu empfehlen. Als Dosis sollten fünf bis sechs Mio E dreimal/Woche für die ersten zwölf bis 16 Wochen angestrebt werden. Anschließend sollte die Behandlung mit drei Mio E dreimal wöchentlich fortgesetzt werden. Die Therapiedauer sollte in der Regel zwölf Monate betragen. Ein langfristiger oder dauerhafter Therapieerfolg, gemessen an einer anhaltenden Normalisierung der Transaminasewerte und einem negativen HCV-RNA-Befund im Serum, ist bei unausgewählten Patientengruppen bei etwa 20% der behandelten Patienten zu erwarten. Wichtige Faktoren, die den durchschnittlichen Therapierfolg beeinflussen, wie der HCV-Genotyp, der Virustiter im Serum, die Erkrankungsdauer, ein höherer Eisengehalt in der Leber und das Vorliegen einer Zirrhose, werden besprochen. Bei Nicht-Ansprechen und bei erneutem Anstieg der Transaminasen während und nach Beendigung der Therapie existieren noch keine klaren Empfehlungen. Die Kombinationstherapie von INFα mit anderen Medikamenten, wie Nukleotidanaloga (Ribavirin), nicht-steroidalen Antirheumatika und Ursodeoxycholsäure (UDCS) werden in kontrollierten klinischen Studien erprobt.

Summary

The purpose of this review is an update of the therapy of hepatitis C especially with Interferon-α. From the large number of publications on this topic the established facts were worked out. Taking these facts as a base guidelines for the therapy in practical use were defined. In addition the aspects of therapeutic strategies of chronic hepatitis C which until now can not definitely be judged are discussed.

In the relatively few patients in whom hepatitis C is diagnosed already in the acute phase. Interferon-α-treatment (3×3 million units 3 times a week) for 3 to 4 months increases the percentage of patients in whom HCV-RNA in serum is climinated.

In patients with chronic hepatitis C, after decision finding for treatment, a standard scheme is recommended which consists of a monotherapy with recombinant Interferon-α. The dosage of Interferon-α is in the first 12 to 16 weeks 5 up to 6 million units given 3 times a week. For the further therapy 3 million units 3 times a week seems to be appropriate. The recommended duration of Interferon-α-therapy is 12 months. A long-term benefit of about 20% can be achieved in unselected groups of patients when judged on the permanent normalisation of serum transaminases and elimination of HCV-RNA in the serum. Important factors which may influence the probability of a sustained response, like HCV genotype, virus titer in serum, duration of the disease, high hepatic iron content and the presence of cirrhosis, are discussed. Up to now there exist no reliable guidelines in the case of a “no change” situation and for patients with a flare-up of inflammatory activity during or after therapy. Combination therapy of Interferon-α with other drugs like analogous of nucleotides (for example ribavarin), non steroidal antirheumatic drugs and ursodesoxycholic acid (UDCA) have still to be evaluated in controlled clinical trials.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. 1.
    Alba, R. D., M. Sampietro, S. Fargion, L. Roffi, S. Parma, M. Pozzi, C. Nicoli, N. Corbetta, V. Arosio, A. Piperno: Iron stores and virus genotypes in chronic hepatitis C. Relation with alfa-interferon response. Hepatology 22 (1995). 294.Google Scholar
  2. 2.
    Alberti, A., L. Chemello, P. Bonetti, C. Casarin, G. Diodati, L. Cavaletto, D. Cavaletto, M. Frezza, C. Donada, F. Belussi, P. Casarin, G. Pozzato, A. Ruol and the TVVH study group: Treatment with interferon(s) of community-acquired chronic hepatitis and cirrhosis type C. J. Hepatol. 17, Suppl. 3 (1993), S123-S126.PubMedCrossRefGoogle Scholar
  3. 3.
    Alscher, D. M., J. Ch. Bode: Therapie der akuten und chronischen Virushepatitis C (Non-A-non-B) mit Interferon-Alpha. Med. Klin. 87 (1992), 532–539.Google Scholar
  4. 4.
    Alter, H. J.: Clinical, virological and epidemiological basis for the treatment of chronic non-A, non-B hepatitis. J. Hepatol. 11 (1990), S19-S25.PubMedCrossRefGoogle Scholar
  5. 5.
    Alter, H. J.: To C or not to C: These are the questions. Blood 85 (1995), 1681–1695.PubMedGoogle Scholar
  6. 6.
    Andreone, P., A. Gramenzi, C. Cursaro, L. Di Giammarino, S. Fiorino, P. Scrivano, A. D’Errico, R. Miniero, M. Bernardi, G. Gasbarrini: A randomized controlled trial of IFN-alfa+ketoprofen or IFN-alfa+ribavarin in HCV chronic active hepatitis (CAH) non-responder to IFN alfa alone. Hepatology 22 (1995), 119A.Google Scholar
  7. 7.
    Arber, N., M. Moshkowitz, F. Konokoff, Z. Halpern, A. Hallak, M. Santo, E. Tiomny, M. Baratz, T. Gilat: Elevated serum iron predicts poor response to interferon treatment in patients with chronic HCV infection. Dig. Dis. Sci. 40 (1995), 2431–2433.PubMedCrossRefGoogle Scholar
  8. 8.
    Ascione, A., M. DeLuca, C. Canestrini, L. Amitiano, T. Gigliotti, L. Addario, A. Sergio, G. B. Forte, P. Rocco, O. Biceglia, D. Faleo, F. Vinelli, E. M. Cela, G. Manno, R. Sabatino, G. Rodinó, G. Raimondo: Three versus six MU interferon (IFN) alfa-2b in the therapy of HCV-related chronic liver disease: Randomized multicenter study. Hepatology 20 (1994), 155A.CrossRefGoogle Scholar
  9. 9.
    Attili, A. F., A. Rusticali, M. Varriale, L. Carli, A. M. Repice, F. Calea: The effect of ursodeoxycholic acid on serum enzymes and liver histology in patients with chronic active hepatitis. A 12 month double-blind, placebo-controlled trial. J. Hepatol. 20 (1994), 315–320.PubMedCrossRefGoogle Scholar
  10. 10.
    Balart, L. A., R. Perillo, J. Roddenberry, F. Regenstein, K.-S. Shim, Y. S. C. Shieh, B. Taylor, S. Dash, M. A. Gerber: Hepatitis C RNA in liver of chronic hepatitis C patients before and after interferon alfa treatment. Gastroenterology 104 (1993), 1472–1477.PubMedGoogle Scholar
  11. 11.
    Battochia, A., P. Residori, L. Biti: Durable response to alpha-interferon treatment in patients with chronic hepatitis C. Gut 35, Suppl. 4 (1994), A54.Google Scholar
  12. 12.
    Bellati, G., M. G. Colloredo, L. Roffi, G. Sarraco, D. Tempesta, A. Bellobuono, A. Rho, M. D’Acquino, G. Angeli, G. Idéo, F. Bonino: Prevalence of breakthrough during alpha interferon therapy for chronic hepatitis C. Hepatology 20 (1994) 331A.CrossRefGoogle Scholar
  13. 13.
    Bellobuono, A., L. Mondazzi, S. Tempini, G. Bellati, L. Cassarà, M. Lombino, E. Silini, F. Bono, G. Idéo: Efficacy of different regimens of alpha interferon in chronic hepatitis C and relationship between response and HCV genotyp. J. Hepatol. 21, Suppl. 1 (1994), S 35.Google Scholar
  14. 14.
    Bode, J. Ch., D. M. Alscher, H. Wisser, Ch. Bode: Detection of hepatitis C virus antibodies and hepatitis C virus RNA in patients with alcoholic liver disease. Alcohol and Alcoholism 30 (1995), 97–103.PubMedGoogle Scholar
  15. 15.
    Bonkovsky, H. L., B. D. Clifford, L. J. Smith, C. Allan, B. Banner: High-dose interferon-alpha 2b for re-treatment of nonresponders or relapsing patients with chronic hepatitis C — a controlled randomized trial. Dig. Dis. Sci. 41 (1996), 149–154.PubMedCrossRefGoogle Scholar
  16. 16.
    Boucher, E., H. Jouanolle, P. Andre, A. Ruffault, D. Guyader, R. Moirand, B. Turlin, C. Jacquelinet, P. Brissot, Y. Deugnier: Interferon and ursodeoxycholic acid combined therapy in the treatment of chronic viral C hepatitis: results from a controlled randomized trial in 80 patients. Hepatology 21 (1995), 322–327.PubMedGoogle Scholar
  17. 17.
    Booth, J. C. L., G. R. Foster, U. Kumar, R. Galassini, R. D. Goldin, J. L. Brown, H. C. Thomas: Chronic hepatitis C virus infections: predictive value of genotype and level of viraemia on disease progression and response to interferon alfa. Gut 36 (1995), 427–432.PubMedCrossRefGoogle Scholar
  18. 18.
    Bréchot, C., D. Kremsdorf: Genetic variation of the hepatitis C virus (HCV) genome: Random Events or a clinically relevant issue? J. Hepatol. 17 (1993), 265–268.PubMedCrossRefGoogle Scholar
  19. 19.
    Brillanti, S., M. Miglioli, L. Barbara: Combination antiviral therapy with ribavarin and interferon alfa in interferon alfa relapsers and non-responders: Italian experience. J. Hepatol. 23, Suppl. 2 (1995), 13–16.PubMedGoogle Scholar
  20. 20.
    Brouwer, J. T., F. Nevens, P. Michielsen, M. L. Hautekeete, R. A. F. M. Chamuleau, M. Adler, J. Delwaide, R. A. Heijtink, S. W. Schalm: What options are left when hepatitis C does not respond to interferon? Placebo-controlled benelux multicentre retreatment trial on ribavarin monotherapy versus combination with interferon. J. Hepatol. 24. Suppl. 1 (1994), S17.Google Scholar
  21. 21.
    Camma, C., P. Almasio, A. Craxi: Interferon as treatment for acute hepatitis C — a meta-analysis. Dig. Dis. Sci. 41 (1996), 1248–1255.PubMedCrossRefGoogle Scholar
  22. 22.
    Camps, J., A. Castilla, J. Ruiz, M. P. Civeira, J. Prieto: Randomised trial of lymphoblastoid alfa-interferon in chronic hepatitis C. J. Hepatol. 17 (1993), 390–396.PubMedCrossRefGoogle Scholar
  23. 23.
    Camps, J., N. García, J. I. Riezu-Boj, M. P. Civeira, J. Prieto: Ribavirin in the treatment of chronic hepatitis C unresponsive to alfa interferon. J. Hepatol. 19 (1993), 408–412.PubMedCrossRefGoogle Scholar
  24. 24.
    Carreno, V., A. Quiroga: Biologic response modifiers in chronic hepatitis C. J. Hepatol. 22, Suppl. 1 (1995), 122–126.PubMedGoogle Scholar
  25. 25.
    Causse, X., H. Godinot, M. Chevallier, Ph. Chossegros, F. Zouli, D. Ouzan, J.-P. Heyraud, Th. Fontanges, J. Albrecht, C. Meschievitz, Ch. Trepo: Comparison of 1 or 3 MU of interferonalfa-2b and placebo in patients with chronic Non-A, Non-B hepatitis. Gastroenterology 101 (1991), 497–502.PubMedGoogle Scholar
  26. 26.
    Causse, X., H. Godinot, D. Ouzan, Ph. Chossegros, M. Chevallier, C. Meschievitz, C. Trépo: Recombinant alpha interferon for chronic non-A non-B hepatitis: Optimal dose and factors associated with favorable response. Hepatology 10 (1989), 643.Google Scholar
  27. 27.
    Chayama, K., A. Tsubota, Y. Arase, S. Saitoh, K. Ikeda, T. Matsumoto, M. Hashimoto, M. Kobayashi, M. Kanda, T. Morinaga, H. Kumad: Genotype, slow decrease in virus titer during interferon treatment and high degree of sequence variability of hypervariable region are indicative of poor response to interferon treatment in patients with chronic hepatitis type C. J. Hepatol. 23 (1995), 648–653.PubMedCrossRefGoogle Scholar
  28. 28.
    Chemello, L., L. Cavaletto, E. Bernardinello, M. Guido, P. Pontisso, A. Alberti: The effect of interferon alfa and ribavarin combination therapy in naive patients with chronic hepatitis C. J. Hepatol 23, Suppl. 2 (1995), 8–12.PubMedGoogle Scholar
  29. 29.
    Chemello, L., P. Bonetti, L. Cavaletto, F. Talato, V. Donadon, P. Casarin, F. Belussi, M. Frezza, F. Noventa, P. Pontisso, L. Benvegnù, C. Casarin, A. Alberti: Randomized trial comparing three different regimens of alpha-2a-interferon in chronic hepatitis C. Hepatology 22 (1995), 700–706.PubMedGoogle Scholar
  30. 30.
    Choo, Q.-L., G. Kuo, A. J. Weiner, L. R. Overby, D. W. Bradley, M. Houghton: Isolation of a cDNA clone derived from a blood-borne Non-A, Non-B viral hepatitis genome. Science 244 (1989), 359–362.PubMedCrossRefGoogle Scholar
  31. 31.
    Craxi, A., V. DiMarco, O. Lo Iacono, P. Almasio, R. Bruno, C. Cammà, R. Volpes, L. Pagliaro: Transfusion-associated chronic hepatitis C: alpha-n1 interferon for 6 vs. 12 months. J. Hepatol. 24 (1996), 539–546.PubMedCrossRefGoogle Scholar
  32. 32.
    Craxi, A., O. Lolacono, V. DiMarco, P. Almasio, A. Vaccaro, C. Cammà, C. Fabiano, S. Magrin, P. Simmonds, L. Pagliaro: Community-aquired chronic hepatitis C in an area of high serotyp 1 endemicity: Interferon for 6 or 12 months? Hepatology 20 (1994), 162A.Google Scholar
  33. 33.
    Cutler, D. L.: Pharmacology of interferon. In: Arroyo, V., J. Bosch, J. Rodés: Treatments in hepatlogy. Masson, Barcelone 1995.Google Scholar
  34. 34.
    Davis, G. L., L. A. Balart, E. R. Schiff, K. Lindsay, H. C. Bodenheimer R. P. Perrilo, W. Carey, I. M. Jacobson J. Payne, J. L. Dienstag, D. H. Van Thiel, C. Tamburro, J. Lefkowitch, J. Albrecht, C. Meschievitz, T. J. Ortego, A. Gibas: Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. New Engl. J. Med. 32 (1989), 1501–1506.Google Scholar
  35. 35.
    Davis, G. L.: Prediction of response to interferon treatment of chronic hepatitis C. J. Hepatol. 21 (1994), 1–3.PubMedCrossRefGoogle Scholar
  36. 36.
    Davis, G. L., J. Y. N. Lau: Choice of appropiated endpoints of response to interferon therapy in chronic hepatitis C virus infection. J. Hepatol. 22, Suppl. 1 (1995), 110–114.PubMedGoogle Scholar
  37. 37.
    Di Bisceglie, A. M., P. Martin, Ch. Kassianides, M. Lisker-Melman, L. Murray, J. Waggoner, Z. Goodman, S. Banks, J. H. Hoofnagle: Recombinant interferon alpha therapy for chronic hepatitis C. New Engl. J. Med. 321 (1989), 1506–1510.PubMedGoogle Scholar
  38. 38.
    Dienstag, J. L.: Non-A, non-B hepatitis. I. Recognition, epidemiology and clinical features. Gastroenterology 85 (1983), 439–462.PubMedGoogle Scholar
  39. 39.
    Diodati, G., P. Bonetti, F. Noventa, C. Casarin, R. Rugge, S. Scaccabarozzi, A. Tagger, L. Pollice, F. Tremolada, C. Davite, G. Realdi, A. Ruol: Treatment of chronic hepatitis C with recombinant human interferon-alpha 2a: Results of a randomized controlled clinical trial. Hepatology 19 (1994), 1–5.PubMedCrossRefGoogle Scholar
  40. 40.
    Enomoto, N., I. Sakuma, Y. Asahina, M. Kurosaki, T. Murakami, C. Yamamoto, Y. Ogura, N. Izumi, F. Marumo, C. Sato: Mutations in the nonstructural protein 5a gene and response to interferon in patients with chronic hepatitis C virus 1b infection. New Engl. J. Med. 334 (1996), 77–81.PubMedCrossRefGoogle Scholar
  41. 41.
    Farrell, G. C., W. G. E. Cooksley, F. J. Dudley, K. Watson: Intensive 6-month course of Interferon treatment for chronic hepatitis C and cirrhosis. Hepatology 22 (1995), 118A.Google Scholar
  42. 42.
    Felaco, F. M., L. Aprea, V. Messina, P. Filippini, E. Sagnelli, F. Picinino: Effect of a 24 month alpha IFN treatment in HCV chronic hepatitis. J. Hepatol. 21, Suppl. 1 (1994), S105.Google Scholar
  43. 43.
    Fernández, I., G. Castellano, F. Canga, F. Colina, A. Fuertes, A. Martin, B. Casis, P. Sanchez, J. A. Solis: A randomized, comparative study of the long-term effiacy of interferon alfa-2b and IFN alfa-2a for the therapy of chronic hepatitis C. J. Hepatol. 21, Suppl. 1 (1994), S26.Google Scholar
  44. 44.
    Ferri, C., E. Marzo, G. Longombardo, L. La Civita, F. Lmbardini, D. Giuggioli, R. Vanacore, A. M. Liberati, A. Mazzoni, F. Greco, S. Bombardieri: Interferon alfa-2b in mixed cryoglobulinaemia: a controlled crossover trial. Gut Suppl. (1993), S144–S145.Google Scholar
  45. 45.
    Gerber, M. A.: Pathobiologic effects of hepatitis C. J. Hepatol. 22 Suppl. 1 (1995), 83–86.PubMedGoogle Scholar
  46. 46.
    Giostra, F., R. Francesconi, P. Groff, A. Manzin, L. Solfroi, F. Lari, G. Ballardini, M. Lenzi, M. Clementi, F. B. Bianchi: Wide fluctuation of plasmatic HCV genome levels in serial samples of patients before interferon treatment. Hepatology 22 (1995), 341A.CrossRefGoogle Scholar
  47. 47.
    Gerken, G., G. Teuber, B. Goergen, K. H. Meyer zum Büschenfelde: Interferon-alpha retreatment in chronic hepatitis C. J. Hepatol. 22, Suppl. 1 (1995), 118–121.PubMedGoogle Scholar
  48. 48.
    Glück, T., H. Dürk, I. Kötter, C. Zimmermann, J. G. Saal: Kryoglobulinämie bei chronischer Hepatitis C. Med. Klin. 90 (1995), 674–680.Google Scholar
  49. 49.
    Gonzalez-Peralta, R. P., G. L. Davis, J. Y. Lau: Pathogenetic mechanisms of hepatocellular damage in chronic hepatitis C virus infection. J. Hepatol. 21 (1994), 255–259.PubMedCrossRefGoogle Scholar
  50. 50.
    Goeser, T., U. Töx, H. M. Müller, J. C. Arnold, L. Teilmann: Bedeutung der Genotypen bei chronischer Hepatitis-C-Virusinfektion und Hepatitis-C-Virus-bedingter Leberzirrhose in Deutschland. Dtsch. med. Wschr. 120 (1995), 1070–1073.PubMedGoogle Scholar
  51. 51.
    Gomez-Rubio, M., J. C. Porres, I. Castillo, J. A. Quiroga, A. Moreno, V. Carreno: Prolonged treatment (18 months) of chronic hepatitis C with recombinant alphainterferon in comparison with a control group. J. Hepatol. 11, Suppl. 1 (1990), S63-S67.PubMedCrossRefGoogle Scholar
  52. 52.
    Gordon, S. C., V. P. Kodali, A. L. Silverman, C. F. Dmuchowski, M. S. Urdea, C. S. Chan, J. C. Wilber: Levels of hepatitis C virus RNA and liver histology in chronic type C hepatitis. Amer. J. Gastroent. 89 (1994), 1458–1461.PubMedGoogle Scholar
  53. 53.
    Gumber, S. C., S. Chopra: Hepatitis C: A multifaceted disease. Ann. intern. Med. 123 (1995), 615–620.PubMedGoogle Scholar
  54. 54.
    Haber, M. M., A. B. West, A. D. Haber, A. Reuben: Relationship of aminotransferases to liver histological status in chronic hepatitis C. Amer. J. Gastroent. 90 (1995), 1250–1257.PubMedGoogle Scholar
  55. 55.
    Hakozaki, Y., T. Shirahama, M. Katou, K. Nakagawa, K. Oba, K. Mitamura: A controlled study to determine the optimal dose regimen of interferon-alpha 2b in chronic hepatitis C. Amer. J. Gastroent. 90 (1995), 1246–1249.PubMedGoogle Scholar
  56. 56.
    Hatanaka, Y., Y. Yamashita, M. Takahashi, Y. Koga, R. Saito, K. Nakashima, J. Urata, M. Miyao: Unresectable hepatocellular carcinoma: analysis of prognostic factors in transcatheter managment. Radiology 195 (1995), 747–752.PubMedGoogle Scholar
  57. 57.
    Healey, C. J., R. W. G. Chapman, K. A. Fleming: Liver histology in hepatitis C infection: a comparsion between patients with persistently normal or abnormal transaminases. Gut 37 (1995), 274–278.PubMedCrossRefGoogle Scholar
  58. 58.
    Hoofnagle, J. H., D. Lau: Chronic viral hepatitis — benefits of current therapies. New Engl. J. Med. 334 (1996), 1470–1471.PubMedCrossRefGoogle Scholar
  59. 59.
    Hoofnagle, J. H., K. P. Mullen, B. D. Jones, V. Rustgi, A. DiBisceghe, M. Peters, J. G. Waggoner, Y. Park, E. A. Jones: Treatment of chronic non-A, non-B hepatitis with recombinant human alpha-interferon. New Engl. J. Med. 315 (1986), 1575–1578.PubMedCrossRefGoogle Scholar
  60. 60.
    Hoofngle, J. H., H. S. Conjeevaram, D. E. Kleiner, D. Lau, A. M. DiBisceglie: Two year course of ribavarin for chronic hepatitis C. Hepatology 22 (1995), 48.Google Scholar
  61. 61.
    Hopf, U., T. Berg, V. König, S. Küther, H.-G. Heuft, H. Lobeck: Treatment of chronic hepatitis C with interferon alpha: long-term folow-up and prognostic relevance of HCV genotypes. J. Hepatol. 24, Suppl. 2 (1996), 67–73.PubMedGoogle Scholar
  62. 62.
    Hwang, S.-J., S.-D. Lee, C.-Y. Chan, R.-H. Lu, K.-J. Lo: A randomized controlled trial of interferon alfa-2b in the treatment of chinese patients with acute post-transfusion hepatitis C. J. Hepatol. 21 (1994), 831–836.PubMedCrossRefGoogle Scholar
  63. 63.
    Ideo, G., G. Bellati, E. Pedraglio, G. Alfieri: Recombinant alpha 2a interferon (r-IFN), lymphoblastoid alpha interferon (I-IFN) or no treatment for nonA nonB chronic active hepatitis (CAH): A prospective randomized controlled trial. Hepatology 10 (1989), 637.Google Scholar
  64. 64.
    Ideo, G., G. Bellati, E. Pedraglio, G. Leandro: One year of therapy of nonA, nonB C chronic hepatitis with recombinant alfa2a interferon (r-IFN) or lymphoblastoid alfa interferon (l-FN). J. Hepatol. 11, Suppl. 2 (1990), 122.Google Scholar
  65. 65.
    Ilno, S., K. Hino, T. Kuroki, H. Suzuki, S. Yamamoto: Treatment of chronic hepatitis C with high-dose interferon alfa-2b. Dig. Dis. Sci. 38 (1993), 612–618.CrossRefGoogle Scholar
  66. 66.
    Jacyna, M. R., M. G. Brooks, R. H. T. Loke, J. Main, I. M. Murray-Lyon, H. C. Thoms: Randomised controlled trial of interferon alfa (lymphoblastoid interferon) in chronic non-A non-B hepatitis. Brit. med. J. 298 (1989), 80–82.PubMedCrossRefGoogle Scholar
  67. 67.
    Janssen, H. L. A., J. T. Brouwer, R. C. van der Mast, S. W. Schalm: Suicide associated with alfa-interferon ther apy for chronic viral hepatitis. J. Hepatol. 21 (1994), 241–243.PubMedCrossRefGoogle Scholar
  68. 68.
    Kagawa, T., T. Morizane, H. Saito, S. Miyaguchi, S. Tsunematsu, S. Tada, F. M. Guevara, N. Kumagi, K. Tsuchimoto, T. Watanabe, M. Tsuchiya: A randomized, controlled trial of weekly administration of lymphoblastoid interferon in patients with chronic hepatitis C. J. Hepatol. 17 (1993), 91–96.PubMedCrossRefGoogle Scholar
  69. 69.
    Kakumu, S., M. Arao, K. Yoshioka, H. Hayashi, A. Kusakabe, H. Hirofuji, M. Kawabe: Recombinant human alpha-interferon therapy for chronic non-A, non-B hepatitis: Second report. Amer. J. Gastroent. 85 (1990), 655–659.PubMedGoogle Scholar
  70. 70.
    Kanazawa, Y., N. Hayashi, E. Mita, T. Li, H. Hagiwara, A. Kasahara, H. Fusamoto, T. Kamada. Influence of viral quasispecies on effectiveness of interferon therapy in chronic hepatitis C patients. Hepatology 20 (1994), 1121–1130.PubMedCrossRefGoogle Scholar
  71. 71.
    Kao, J.-H., P.-J. Chen, M.-Y. Lai, T.-H. Wang, D.-S. Chen: Quasispecies of hepatitis C virus and genetic drift of the hypervariable region in chronic type C hepatitis. J. infect. Dis. 172 (1995), 261–264.PubMedGoogle Scholar
  72. 72.
    Kashara, A., N. Hayashi, N. Hiramatsu, M. Oshit, H. Hagiwara, K. Katayama, M. Kato, M. Masuzawa, H. Toshihara, V. Kishida, Y. Shimizu, A. Inoue, H. Fusamoto, T. Kamada. Ability of prolonged interferon treatment to supress relapse after cessation of therapy in patients with chronic hepatitis C: a multicenter randomized controlled trial. Hepatology 21 (1995), 291–297.CrossRefGoogle Scholar
  73. 73.
    Kitis, G., E. Papagianni, D. Tzilves, F. Kordits, G. Kokozidis: Co-administration of granulocyte colony-stimulating factor allows completion of interferon therapy in chronic viral hepatitis with neutropenia. Hepatology 20 (1994), 171A.Google Scholar
  74. 74.
    Kobayashi, Y., S. Watanabe, M. Konishi, M.Yokoi, R. Kakehashi, M. Kaito, M. Kondo, Y. Hayashi, T. Jomori, S. Suzuki: Quantitation and typing of serum hepatitis C virus RNA in patients with chronic hepatitis C treated with interferon-alfa. Hepatology 18 (1993), 1319–1325.PubMedCrossRefGoogle Scholar
  75. 75.
    Kurosaki, M., N. Enomoto, F. Marumo, C. Sato: Rapid sequencevariation of the hypervariable region of hepatitis C virus during the course of chronic infection. Hepatology 18 (1993), 1293–1299.PubMedCrossRefGoogle Scholar
  76. 76.
    Lam, N. P., T. E. Wiley, D. R. Gretch, D. L. Pitrak, T. J. Layden: Dose-dependent acute reduction of genotyp 1 hepatitis C virus (HCV) with alpha-interferon (IFN). Hepatology 22 (1995), 172A.Google Scholar
  77. 77.
    Lampertico, P., M. Rumi, R. Romeo, A. Craxi, R. Soffredini, D. Biassoni, M. Colombo: A multicenter randomized controlled trial of recombinant interferon-alfa 2b in patients with acute transfusion-associated hepatitis C. Hepatology 19 (1994), 19–22.PubMedCrossRefGoogle Scholar
  78. 78.
    Lin, R. M., P. Schoeman, J. Craig, J. Mac Donald, R. G. Batey, G. C. Farrell: Randomized controlled trial of interferon alpha 2b for chronic active hepatitis Non A, Non B: Biochemical and histological evidence of remission. Hepatology 10 (1989), 646.CrossRefGoogle Scholar
  79. 79.
    Livraghi, T., L. Bolondi, L. Buscarini, M. Cottone, A. Mazziotti, A. Morabito, G. Torzilli and the italian cooperative HCC study group: No treatment, resection and ethanol injection in hepatocellular carcinome: a retrospektive analysis of survival in 391 patients with cirrhosis. J. Hepatol. 22 (1995), 522–526.PubMedCrossRefGoogle Scholar
  80. 80.
    Maier, K.-P.: Behandlung der chronischen Virushepatitis mit Azetylsalizylsäure. Schweiz med. Wschr. 125 (1995), 755–757.PubMedGoogle Scholar
  81. 81.
    Makris, M., F. E. Preston, D. R. Triger, J. C. E. Underwood, L. Westlake, M. J. Adelman. Interferon alfa for chronic hepatitis C in haemophiliacs. Gut Suppl. (1993), S121–S123.Google Scholar
  82. 82.
    Marcellin, P., N. Boyer, E. Giostra, C. Degott, F. Degos, H. Copperé, P. Calès, P. Couzigou, M. Martinot, M. A. Loriot, J.-P. Bernhamou: Recombinant human alpha-interferon in patients with chronic non-A, non-B hepatitis: A multicenter randomized controlled trial from France. Hepatology 13 (1991): 393–397.PubMedCrossRefGoogle Scholar
  83. 83.
    Martinot-Peignoux, M., P. Marcellin, M. Pouteau, C. Castelau, N. Boyer, M. Poliquin, C. Degott, I. Descombes, V. Le Breton, V. Milotova, J. P. Benhamou, S. Erlinger: Pretreatment serum hepatitis C virus RNA levels and hepatitis C virus genotyp are the main and independent prognostic factors of sustained response to interferon alfa therapy in chronic hepatitis C. Hepatology 22 (1995), 1050–1056.PubMedCrossRefGoogle Scholar
  84. 84.
    Matsumoto, A., E. Tanaka, T. Suzuki, H. Ogata, K. Kiyosawa: Viral and host factors that contribute to efficacy of interferon-alfa-2a therapy in patients with chronic hepatitis C. Dig. Dis. Sci. 39 (1994), 1273–1280.PubMedCrossRefGoogle Scholar
  85. 85.
    Mazella, G., E. Accogli, S. Sottili, D. Festi, M. Orsini, A. Salzetta, V. Novelli, A. Cipolla, C. Babbri, A. Pezzoli, E. Roda: Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis. J. Hepatol. 24 (1996), 141–147.CrossRefGoogle Scholar
  86. 86.
    Métreau, J. M.: Results of long term interferon treatment in non A non B/C chronic active hepatitis. Gut Suppl. (1993), S112–S113.Google Scholar
  87. 87.
    Misiani, R., P. Bellavita, D. Fenili, O. Vicari, D. Marchesi, P. L. Sironi, P. Zilio, A. Vernocchi, M. Massazza, G. Vendramin, E. Tanzi, A. Zanetti: Interferon Alpha-2a therapy in cryoglobulinemia associated with hepatitis C virus. New Engl. J. Med. 330 (1994), 751–756.PubMedCrossRefGoogle Scholar
  88. 88.
    Mita E., N. Hayashi, H. Hagiwara, K. Ueda, Y. Kanazawa, A. Kasahara, H. Fusamoto, T. Kamada: Predicting interferon therapy efficiacy from hepatitis C virus genotype and RNA titer. Dig. Dis. Sci. 39 (1994), 977–982.PubMedCrossRefGoogle Scholar
  89. 89.
    Moribe, T., N. Hayashi, Y. Kanazawa, E. Mita, H. Fusamoto, M. Negi, T. Kaneshige, H. Igimi, T. Kamada, K. Uchida: Hepatitis C viral complexity detected by single-strand conformation polymorphism and response to interferon therapy. Gastroenterology 108 (1995), 789–795.PubMedCrossRefGoogle Scholar
  90. 90.
    Müller, R., R. Baumgarten, R. Markus, K. H. Beckh, K. Loeschke, W. Stremmel, C. Niederau, K.-H. Wiedmann, P. Weber: Long-term treatment with low doses of interferon alfa-2b (rIFNa2b) in patients with chronic non-A, non-B (NANB) hepatitis: Data of a multicenter randomized prospectively controlled trial. J. Hepatol. 11, Suppl. 2 (1990), 184.Google Scholar
  91. 91.
    Naito, M., N. Hayashi, T. Moribe, H. Hagiwara, E. Mita, V. Kanazawa, A. Kasahara, H. Fusamoto, T. Kamada: Hepatitis C viral quasispecies in hepatitis C virus carrieres with normal liver enzymes and patients with type C chronic liver disease. Hepatology 22 (1995), 407–412.PubMedGoogle Scholar
  92. 92.
    Nakazawa, T., N. Kato, S. Ohkoshi, A. Shibuya, K. Shimotohno: Characterization of the 5′ noncoding and structural region of the hepatitis C virus genome from patients with non-A, non-B hepatitis responding differently to interferon treatment. J. Hepatol. 20 (1994), 623–629.PubMedCrossRefGoogle Scholar
  93. 93.
    Nishiguchi, S., T. Kuroki, S. Nakatani, H. Morimoto, T. Takeda, S. Nakajima, S. Shiomi, S. Seki, K. Kobayashi, S. Otni: Randomised trial of effects of interferon-alpha on incidence of hepatocellular carcinoma in chronic active hepatitis C with cirrhosis. Lancet 346 (1995), 1051–1055.PubMedCrossRefGoogle Scholar
  94. 94.
    Ohlen, J., J. M. Liegl, H. Selmair: Die Langzeitprognose chronischer Virus B- und Virus C-Hepatitiden. Leber Magen Darm 25 (1995), 205–210.PubMedGoogle Scholar
  95. 95.
    Okada, S.-I., Y. Akahane, H. Suzuki, H. Okamoto, S. Mishiro: The degree of variability in the amino terminal region of the E2/NS1 protein of hepatitis C virus correlates with responsiveness to interferon therapy in viremic patients. Hepatology 16 (1992), 619–624.PubMedCrossRefGoogle Scholar
  96. 96.
    Okanoue, T., S. Sakamoto, Y. Itoh, M. Minami, Y. Yasui, M. Sakamto, M. Nishioji, K. Kashima: Side efects of high-dose interferon therapy for chronic hepatitis C-mass study. Hepatology 22 (1995), 118A.Google Scholar
  97. 97.
    Olynyk, J. K., K. R. Reddy, A. M. DiBisceglie, L. J. Jeffers, T. I. Parker, J. L. Radick, E. R. Schiff, B. R. Bacon: Hepatic iron concentration as a predictor of response to interferon alfa therapy in chronic hepatitis C. Gastroenterology 108 (1995), 1104–1109.PubMedCrossRefGoogle Scholar
  98. 98.
    Pagliaro, L., A. Craxi, C. Cammaá, F. Tiné, V. Di Marco, O. Lo Iacono, P. Almasio: Interferon-alpha for chronic hepatitis C. Hepatology 19 (1994), 820–828.PubMedGoogle Scholar
  99. 99.
    Papa, D., A. Gianmarino, A. Rebuttato, G. Orlando: Treatment of chronic hepatitis with interferon. J. Hepatol. 21, Suppl. 1 (1994), S120.Google Scholar
  100. 100.
    Picciotto, A., G. Varagona, F. Valle, D. A. Coviello, G. Lapertosa, G. Celle: Interferon therapy in chronic hepatitis C. J. Hepatol. 17 (1993), 359–363.PubMedCrossRefGoogle Scholar
  101. 101.
    Poynard, T., P. Bedossa, M. Chevallier, P. Mathurin, C. Lemonnier, C. Trepo, P. Couzigou, J. L. Payen, M. Sajus, J. M. Costa, M. Vidud, J. C. Chaput: A comparison of three interferon alfa-2b regimens for the long-term treatment of chronic non-A, non-B hepatitis. New Engl. J. Med. 332 (1995), 1457–1462.PubMedCrossRefGoogle Scholar
  102. 102.
    Realdi, G., G. Diodati, P. Bonetti, S. Scaccabarozzi, A. Alberti, A. Ruol: Recombinant human interferon alfa-2a in community-acquired non-A, non-B chronic active hepatitis. Preliminary results of a randomized, controlled trial. J. Hepatol. 11 (1990), S68-S71.PubMedCrossRefGoogle Scholar
  103. 103.
    Reichard, O., U. Foberg, A. Frydén, L. Mattsson, G. Norkrans, A. Sönnerborg, R. Wejstal, Z.-B. Yun, O. Weiland: High sustained response rate and clearance of viremia in chronic hepatitis C after treatment with interferon-alpha-2b for 60 weeks. Hepatology 19 (1994), 280–285.PubMedCrossRefGoogle Scholar
  104. 104.
    Roffi, L., G. C. Mels, G. Antonelli, G. Bellati, F. Panizzuti, A. Piperno, M. Pozzi, D. Ravizza, G. Angeli, F. Dianzani, G. Mancia: Breakthrough during recombinant interferon alfa therapy in patients with chronic hepatitis C virus infection: prevalence, etiology and managment. Hepatology 21 (1995), 645–649.PubMedCrossRefGoogle Scholar
  105. 105.
    Rossini, A., A. Ravaggi, L. Biasi, G. B. Gazzola, E. Agostinelli, M. Puoti, E. Radaeli, E. Cariani: HCV infection with normal ALT and chronic hepatitis: Long-term follow-up and genomic characterization of HCV-RNA. Hepatology 20 (1994), 242A.Google Scholar
  106. 106.
    Saez-Royuela, F., J. C. Porres, A. Moreno, I. Castillo, G. Martinez, F. Galiana, V. Carreno: High doses of recombinant alpha-interferon or gamma-interferon for chronic hepatitis C. A randomized, controlled trial. Hepatology 13 (1991), 327–331.PubMedCrossRefGoogle Scholar
  107. 107.
    Saracco, G., F. Rosina, M. R. Torrani Cerenzia, V. Lattore, L. Chiandussi, V. Gallo, R. E. Petrino, A. G. De Miheli, E. Donegani, A. Slinas, A. Deplano, A. Tocco, P. Cossu, C. Pintu, E. David, G. Mazzucco, G. Verme, M. Rizzetto: A randomized controlled trial of interferon alfa-2b as therapy for chronic non-A, non-B hepatitis. J. Hepatol. 11 (1990), S43-S49.PubMedCrossRefGoogle Scholar
  108. 108.
    Saracco, G., F. Rosina, M. L. Abate, L. Chiandusi, V. Gallo, E. Cerutti, A. Di Napoli, A. Solinas, A. Deplano, A. Tocco, P. Cossu, D. Chien, G. Kuo, A. Polito, A. J. Weiner, M. Houghton, G. Verme, F. Bonino, M. Rizzetto: Long-term follow-up of patients with chronic hepatitis C treated with different doses of interferon-alfa-2b. Hepatology 18 (1993), 1300–1305.PubMedCrossRefGoogle Scholar
  109. 109.
    Schvarz, R., O. Weiland, R. Wejstal, G. Norkrans, A. Fryden, U. Foberg: A randomized controlled open study of interferon alpha-2b treatment of chronic non-A, non-B posttransfusion hepatitis: no correlation of outcome to presence of hepatitis C virus antibodies. Scand. J. infect. Dis. 21 (1989), 617–625.CrossRefGoogle Scholar
  110. 110.
    Shibata, M., T. Kumada, M. Yamada, S. Nakano, T. Kudo, T. Morishima: Efects of interferon-alpha on serum hepatitis C virus in patients with chronic hepatitis C. Dig. Dis. Sci. 38 (1993), 608–611.PubMedCrossRefGoogle Scholar
  111. 111.
    Shindo, M., K. Arai, Y. Sokawa, T. Okuno: The virological and histological states of anti-hepatitis C virus-positive subjects with normal liver biochemical values. Hepatology 22 (1995), 418–425.PubMedGoogle Scholar
  112. 112.
    Shindo, M., A. M. DiBisceglie, L. Cheung et al.: Decrease in serum hepatitis C viral RNA during alpha-interferon therapy for chronic hepatitis C. Ann. intern. Med. 115 (1991), 700–704.PubMedGoogle Scholar
  113. 113.
    Simmonds, P.: Variability of hepatitis C virus. Hepatology 21 (1995), 570–583.PubMedCrossRefGoogle Scholar
  114. 114.
    Simmonds, P., J. Mellor, A. Craxi, J.-M. Sanchez-Tapias, A. Alberti, J. Prieto, M. Colombo, M. G. Rumi, O. Lo Iacno, S. Ampurdanes-Mingall, X. Forns-Bernhardt, L. Chemello, M.-P. Civeira, C. Frost, G. Dusheiko: Epidemiological, clinical and therapeutic associations of hepatitis C types in Western European patients. J. Hepatol. 24 (1996), 517–524.PubMedCrossRefGoogle Scholar
  115. 115.
    Takada, A., M. Tsutsumi: Efficacy of a combination therapy with interferon and ofloxacin in chronic type C hepatitis. Hepatology 20 (1994), 170A.Google Scholar
  116. 116.
    Takahashi, M., G. Yamada, R. Miyamoto, T. Doi, H. Endo, T. Tsuji: Natural course of chronic hepatitis C. Amer. J. Gastroent. 88 (1993), 240–243.PubMedGoogle Scholar
  117. 117.
    Takano, S., Y. Ito, O. Yokosuka, M. Ohto, K. Uchiumi, K. Hirota, M. Omata: A multicenter randomized controled dose study of ursodeoxycholic acid for chronic hepatitis C. Hepatology 20 (1994), 558–564.PubMedCrossRefGoogle Scholar
  118. 118.
    Thomson, B. J., A. L. Lever, M. Doran, A. D. B. Webster: Alpha-interferon therapy for non-A, non-B hepatitis transmitted by gamaglobulin replacement therapy. Lancet (1987), 539–541.Google Scholar
  119. 119.
    Tong, M. J., N. S. El-Farra, A. R. Rekes, R. L. Co: Clinical outcomes after transfusion-associated hepatitis C. New Engl. J. Med. 332 (1995), 1463–1466.PubMedCrossRefGoogle Scholar
  120. 120.
    Van Thiel, D. H., P. Caraceni, P. J. Molloy, T. Hassanein, R. J. Kania, A. Gurakar, L. Friedlander: Chronic hepatitis C in patients with normal or near normal alanine aminotransferase levels: The role of interferon Alfa-2b therapy. J. Hepatol. 23 (1995), 503–508.PubMedCrossRefGoogle Scholar
  121. 121.
    Yamada, G., M. Takatani, F. Kishi, M. Takahashi, T. Doi, T. Tsuji, S. Shin, M. Tanno, M. S. Urdea, J. A. Kolberg. Efficacy of interferon Alfa therapy in chronic hepatitis C patients depends primarly on hepatitis C virus RNA level. Hepatology 22 (1995), 1351–1354.PubMedGoogle Scholar
  122. 122.
    Yano, M., S. Kakumu, H. Hayashi, T. Takikawa, N. Nishimura: Phlebotomy followed by alfa-interferon therapy in patients with chronic hepatitis C. Hepatology 22 (1995), 51.Google Scholar
  123. 123.
    Yokosuka, O., F. Imazeki, M. Tagawa, T. Ehata, T. Seta, K. Fujiwara, A. Honda, M. Ohto, M. Omata: Spontaneous termination of HCV viremia is a rare event in chronic type C hepatitis. Hepatology 20 (1994), 253A.Google Scholar
  124. 124.
    Yokosuka, O., N. Kato, K. Hosoda, Y. Ito, F. Iazeki, M. Ohto, M. Omata: Efficacy of longterm interferon treatment in chronic liver disease evaluated by sensitive polymerase chain reaction assay for hepatitis C virus RNA. Gut 37 (1995), 721–726.PubMedCrossRefGoogle Scholar
  125. 125.
    Yuki, N., N. Hayashi, A. Kasahara, H. Hagiwara, T. Takehara, M. Oshita, K. Katayama, H. Fusamoto, T. Kamada: Pretreatment viral load and response to prolonged interferon-alfa course for chronic hepatitis C. J. Hepatol. 22 (1995), 457–463.PubMedCrossRefGoogle Scholar
  126. 126.
    Zachoval, R., J. Abb, V. Zachoval, J. Eisenburg, G. R. Pape, G. Paumgartner, T. Deinhardt: Interferon alpha in hepatitis type B and non-A, non-B. Defective production by peripheral blood mononuclear cells in chronic infection and development of serum interferon in acute disease. J. Hepatol. 6 (1988), 364–368.PubMedCrossRefGoogle Scholar
  127. 127.
    Zoulim, F., C. Trepo: Nucleoside analogs in the treatment of chronic viral hepatitis. Efficiency and complications. J. Hepatol. 21 (1994), 142–144.PubMedCrossRefGoogle Scholar

Copyright information

© Urban & Vogel 1997

Authors and Affiliations

  • Dominik M. Alscher
    • 2
  • J. Christian Bode
    • 1
  1. 1.Abteilung Innere Medizin I Zentrum für Innere MedizinRobert-Bosch-KrankenhausStuttgartDeutschland
  2. 2.Zentrum für Innere Medizin, Robert-Bosch-KrankenhausStuttgartDeutschland

Personalised recommendations