Pilot study of interferon-α high-dose induction therapy in combination with ribavirin plus amantadine for nonresponder patients with chronic hepatitis C

Summary

Ribavirin plus interferon-α (IFNα) combination has led to a marked advance in the treatment of IFNα-naive or relapser patients with chronic hepatitis C but was shown to be only marginally effective in IFNα-nonresponders. We therefore conducted a pilot study to see whether an intensified treatment protocol might be more effective in inducing a virological response in patients who had not responded virologically to previous IFNα monotherapy. 14 nonresponder patients with histologically proven chronic hepatitis C were included in the study. Patients received 9 MU IFNα-2a daily for one week followed by 9 MU IFNα every second day for further 5 weeks. With the beginning of the seventh week, patients were treated with 6 MU IFNα thrice in week (tiw) for a period of 6 weeks (until week 12). IFNα was continued up to 48 weeks at a dose of 3 MU IFNα tiw. Ribavirin (1000-1200 mg/day) and amantadine sulphate (200 mg/day) was given orally for 48 weeks. One patient discontinued therapy after first IFNα injection and one other patient after 12 weeks of therapy because of side effects. The remaining 12 patients completed treatment according to the protocol. An initial virological response at week 24 was achieved in 2 of the 14 patients (14 %) and both patients remained HCV RNA negative at the end of treatment. However, both patients relapsed 4 weeks after completion of therapy, and therefore none of the patients achieved a virological sustained response. Viral dynamics studies showed a marked decline in hepatitis C viremia during the first 6 weeks of high-dose IFNα. After IFNα dose reduction, however, viremia stabilized or increased in most patients. These data indicate, that even triple therapy with high-dose IFNα plus ribavirin and amantadine fails to improve significantly the response rates in IFNα-nonresponders.

Interferon-α-Hochdosis-Induktionstherapie in Kombination mit Ribavirin plus Amantadin bei Nonresponderpatienten mit chronischer Hepatitis C: Ergebnisse einer Pilotstudie

Die Kombinatonstherapie aus Interferon-α (IFNα) plus Ribavirin hat zu einer deutlichen Verbesserung der Ansprechraten bei unvorbehandelten bzw. Relapsepatienten mit chronischer Hepatitis C geführt, war jedoch nur marginal wirksam bei IFNα-Nonrespondern. In der vorliegenden Pilotstudie sind wir der Frage nachgegangen, ob durch eine intensivierte antivirale Therapie eine Verbesserung der Responseraten bei virologischen Nonrespondern erzielt werden kann. 14 Nonresponderpatienten mit histologisch gesicherter chronischer Hepatitis C wurden in die Studie eingeschlossen. Die Patienten erhielten 9 Mio. Einh. IFNα-2a täglich für 7 Tage gefolgt von 9 Mio. Einh. IFNα alle 2 Tage für 5 Wochen. Anschließend (Woche 7-12) wurden die Patienten mit 3 × 6 Mio. Einh. IFNα/Woche gefolgt von 3 × 3 Mio. Einh./Woche (Woche 13-48) behandelt. Zusätzlich erhielten alle Patienten Ribavirin (1000-1200 mg/Tag) und Amantadinsulfat (200 mg/Tag) für 48 Wochen. Ein Patient beendete die Therapie nach der ersten IFNα-Injektion und ein weiterer nach der 12. Therapiewoche aufgrund von Nebenwirkungen. Die übrigen 12 Patienten führten die Therapie protokollgemäß durch. Eine initiale virologische Response zur Woche 24 wurde nur bei 2 der 14 Patienten (14 %) erreicht, und beide Patienten erlitten 4 Wochen nach Therapieende einen Relapse. Untersuchungen zur Dynamik der Hepatitis-C-Virämie zeigten eine signifikante Reduktion der Virusreplikation während der ersten 6 Induktionstherapiewochen. Nach IFNα-Dosisreduktion zeigten allerdings die meisten Patienten eine Stabilisierung bzw. einen Anstieg der Virämie. Unsere Daten zeigen, dass eine antivirale Tripeltherapie mit Hochdosis-IFNα plus Ribavirin und Amantadin nicht in der Lage ist, die dauerhaften Responseraten bei IFNα- Nonrespondern mit ungünstigen Responsefaktoren zu verbessern.

Key words

Hepatitis C Virus Kinetics - High-Dose Interferon-α - Triple Therapy - Amantadine - Ribavirin

Schlüsselwörter

Hepatitis-C-Virus-Kinetik - Hochdosis-Interferon-α - Tripeltherapie - Amantadin - Ribavirin

References

• 1 Alberti A, Chemello L, Noventa F, Cavaletto L, DE Salvo G. Therapy of hepatitis C: Re-treatment with alpha interferon.  Hepatology. 1997;  26 (Suppl. 1) 137-142S
• 2 Kakumu S, Yoshioka K, Wakita T. et al . A pilot study of ribavirin and interferon beta for the retreatment of chronic hepatitis C.  Gastroenterology. 1993;  105 507-512
• 3 Brillanti S, Migliolo M, Barbara L. Combination antiviral therapy with ribavirin and interferon alfa in interferon alfa relapsers and nonresponders: Italian experience.  J Hepatol. 1995;  23 (Suppl. 2) 13-16
• 4 Schvarcz R, Yun Z B, Sonnerborg A, Weiland O. Combined treatment with interferon alpha-2b and ribavirin for chronic hepatitis C in patients with a previous non-response or non-sustained response to interferon alone.  J Med Virol. 1995;  46 43-47
• 5 Schalm S W, Brouwer J T, Chemello L. et al . Interferon-ribavirin combination therapy for chronic hepatitis C.  Dig Dis Sci (Suppl.):. 1996;  41 131-134
• 6 Teuber G, Berg T, Hoffmann R M. et al . Retreatment wit interferon-alpha and ribavirin in primary interferon-alpha non-responders with chronic hepatitis C.  Digestion. 2000;  61 90-97
• 7 Bellobuono A, Mondazzi L, Tempini S. et al . Ribavirin and interferon-alpha combination therapy vs. interferon-alpha alone in the treatment of chronic hepatitis C: A randomized clinical trial.  J Viral Hepat. 1997;  4 185-191
• 8 Wedemeyer H, Jäckel E, Wedemeyer J. et al . Is combination therapy of chronic hepatitis C with interferon alpha and ribavirin in primary interferon nonresponders indicated? An analysis of personal experiences and review of the literature.  Z Gastroenterol. 1998;  36 819-827
• 9 Salmeron J, Ruiz-Extremera A, Torres C. et al . Interferon versus ribavirin plus interferon in chronic hepatitis C previously resistant to interferon: A randomized trial.  Liver. 1999;  19 275-280
• 10 Andreone P, Gramenzi A, Cursaro C. et al . Interferon-alpha plus ribavirin in chronic hepatitis C resistant to previous interferon-alpha course: Results of a randomized multicenter trial.  J Hepatol. 1999;  30 788-793
• 11 Pol S, Couzigou P, Bourliere M. et al . A randomized trial of ribavirin and interferon-alpha in patients with chronic hepatitis C who were nonresponders to a previous treatment.  Multicenter Study Group under the coordination of Necker Hospital, Paris, France. J Hepatol. 1999;  31 1-7
• 12 Tromm  A, Greving I, Griga T, Mankel K, Huppe D. Interferon-alpha-2b + ribavirin for the treatment of chronic hepatitis C in non-responders to interferon-alpha-monotherapy.  Z Gastroenterol. 2000;  38 159-164
• 13 Smith J P. Treatment of chronic hepatitis C with amantadine.  Dig Dis Sci. 1997;  42 1681-1687
• 14 Younossi Z M, Perillo R P. The roles of amantadine, rimatadine, ursodeoxycholic acid, and NSAIDs, alone or in combination with alpha interferons, in the treatment of chronic hepatitis C.  Sem Liver Dis. 1999;  19 (Suppl. 1) 95-102
• 15 Caronia S, Crossey M, Murray-Lyon I. et al . A pilot study of interferon plus amantadine versus interferon alone in the treatment of chronic hepatitis C.  J Hepatol. 1999;  30 (Suppl. 1) 138
• 16 Brillanti S, Foli M, Di Tomaso M. et al . Pilot study of triple antiviral therapy for chronic hepatitis C in interferon alpha non-responders.  Ital J Gastroenterol Hepatol. 1999;  31 130-134
• 17 Dolin R, Reichmann R C, Madore H P. et al . A controlled trial of amantadine and rimantadine in the prophylaxis of influenza A infection.  N Engl J Med. 1982;  307 580-584
• 18 Hay A J, Wolstenholme A J, Skehel J J, Smith M H. The molecular basis of the specific anti-influenza action of amantadine.  EMBO J. 1985;  4 3021-3024
• 19 Wang C, Takeuchi K, Pinto L H, Lamb R A. Ion channel activity of influenza A virus M2 protein: Characterization of the amantadine block.  J Virol. 1993;  76 5585-5594
• 20 Martin J, Navas S, Fernández M. et al . In vitro effect of amantadine and interferon-2a on hepatitis C virus markers in cultured peripheral blood mononuclear cells from hepatitis C virus infected patients.  Antiviral Res. 1999;  42 59-70
• 21 Schiffmann M L. Use of high-dose interferon in the treatment of chronic hepatitis C.  Semin Liver Dis. 1999;  19 25-33
• 22 Neumann A U, Lam N P, Dahari H. et al . Hepatitis C viral dynamics and the antiviral efficacy of interferon-α therapy.  Science. 1998;  282 103-107
• 23 Lam N, Neumann A, Gretch D. et al . Dose-dependent acute clearance of hepatitis genotype 1 virus with interferon alfa.  Hepatology. 1997;  26 226-231
• 24 Desmet V, Gerber M, Hoofnagle J H, Manns M, Scheuer P J. Classification of chronic hepatitis: Diagnosis, grading and staging.  Hepatology. 1994;  19 1513-1520
• 25 Hytiroglou P, Tung S N, Gerber A M. Histological classification and quantitation of the severity of chronic hepatitis: Keep it simple.  Semin Liver Dis. 1995;  15 414-421
• 26 Poynard T, Marcellin P, Lee S S. et al . Randomized trial of interferon (2b plus ribavirin for 48 weeks or 24 weeks versus interferon (2b plus placebo for 48 weeks for treatment of chronic infection with hepatitis C virus.  Lancet. 1998;  352 1426-1432
• 27 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
• 28 Brillanti S, Levantesi F, Foli M, Di Tomaso M, Bolondi L. Amantadine and Rebetron^TM exert a synergistic antiviral effect on HCV replication in interferon-α non-responders with chronic hepatitis C.  Gastroenterology. 1999;  116 (Suppl. 1) 212 [Abstract]
• 29 Brillanti S, Levantesi F, Masi L, Foli M, Bolondi L. Triple antiviral therapy as a new option for patients with interferon nonresponsive chronic hepatitis C.  Hepatology. 2000;  32 630-634
• 30 Khalili M, Denham C, Perillo R. Interferon and ribavirin versus interferon and amantadine in interferon nonresponders with chronic hepatitis C.  Am J Gastroenterol. 2000;  95 1284-1289
• 31 Hubert I F, Lunel F, Cadranel J -F, Oberti F, Calès P. Treatment of chronic hepatitis C with amantadine.  Am J Gastroenterol. 2000;  95 2316-2317
• 32 Zeuzem S, Teuber G, Naumann U. et al . Randomized, double-blind, placebo-controlled trial of interferon alfa2a with and without amantadine as initial treatment for chronic hepatitis C.  Hepatology. 2000;  32 835-841
• 33 Schiffmann M L, Hofmann C M, Thompson E B. et al . Relationship between biochemical, virological, and histological response during interferon treatment of chronic hepatitis C.  Hepatology. 1997;  26 780-785
• 34 Schiffman M L, Hofmann C M, Contos M J. et al . A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C and persistent viremia.  Gastroenterology. 1999;  117 1164-1172
• 35 Sobesky R, Mathurin P, Charlotte F. et al . Modelling the impact of interferon alfa treatment on liver fibrosis progression in chronic hepatitis C: A dynamic view.  Gastroenterology. 1999;  116 378-386
• 36 Ikeda K, Saitoh S, Arase Y. et al . Effect of interferon therapy on hepatocellular carcinogenesis in patients with chronic hepatitis C: A long-term observation study of 1,643 patients using statistical bias correction with proportional hazard analysis.  Hepatology. 1999;  29 1124-1130
• 37 Bekkering F C, Brouwer J T, Leroux-Roels G. et al . Ultrarapid hepatitis C virus clearance by daily high-dose interferon in nonresponders to standard therapy.  J Hepatol. 1998;  28 960-964
• 38 Berg T, Kaul T, Naumann U, Wiedenmann B, Hopf U. Influence of ribavirin on the dynamics of hepatitis C viremia in interferon-alpha-treated patients with response or nonresponse.  Z Gastroenterol. 2000;  38 1-6

Address for correspondence