Role of Amantadine and Other Adjuvant Therapies in the Treatment of Hepatitis C

There is room for improvement in the treatment of chronic hepatitis C with standard interferon (IFN) alfa. In the search for treatment adjuvants, the antiviral compound ribavirin has been found to significantly increase sustained virological response. Despite this improvement, the rate of “cure” remains low at approximately 40%, thus stimulating the search for additional adjuvants. In 1997, it was suggested that amantadine monotherapy could be used successfully to treat patients with chronic hepatitis C who had previously failed IFN alfa therapy, but ensuing studies could not support these findings. Instead, researchers have studied amantadine as an adjuvant to either IFN alfa alone or IFN alfa plus ribavirin, and promising results have been published. In this article, the author reviews the role of amantadine alone or as part of combination therapy regimens for chronic hepatitis C and briefly looks at the use of other agents as potential adjuvants.

Triple therapy - retreatment - nonresponders - difficult patients

REFERENCES

• 1 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
• 2 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
• 3 Rasenack J, Zeuzem S, Feinman S V et al.. Therapy with pegylated (40 KDa) interferon alfa-2a (PEGASYS) significantly enhances quality of life compared with standard interferon alfa-2a (ROFERON-A) in patients with chronic hepatitis C.  Hepatology. 2000;  32 307A
• 4 Zeuzem S, Feinman S V, Rasenack J et al.. Peginterferon alfa-2a in patients with chronic hepatitis C.  N Engl J Med. 2000;  343 1666-1672
• 5 Martin J, Navas S, Fernandez M et al.. In vitro effect of amantadine and interferon alpha-2a on hepatitis C virus markers in cultured peripheral blood mononuclear cells from hepatitis C virus-infected patients.  Antiviral Res. 1999;  42 59-70
• 6 Jubin R, Murray M G, Howe A Y et al.. Amantadine and rimantadine have no direct inhibitory effects against hepatitis C viral protease, helicase, ATPase, polymerase, and internal ribosomal entry site-mediated translation.  J Infect Dis. 2000;  181 331-334
• 7 Smith J P. Treatment of chronic hepatitis C with amantadine.  Dig Dis Sci. 1997;  42 1681-1687
• 8 Andant C, Lamoril J, Deybach J C et al.. Amantadine for chronic hepatitis C: pilot study in 14 patients.  Eur J Gastroenterol Hepatol. 2000;  12 1319-1322
• 9 Goff J S, Reveille R M, Johnson J. Treatment of chronic hepatitis C with amantadine.  Dig Dis Sci. 2000;  45 1389-1391
• 10 Senturk H, Mert A, Akdogan M et al.. Amantadine monotherapy of chronic hepatitis C patients infected with genotype lb.  Scand J Infect Dis. 2000;  32 575-576
• 11 Mangia A, Minerva N, Annese M et al.. A randomized trial of amantadine and interferon versus interferon alone as initial treatment for chronic hepatitis C.  Hepatology. 2001;  33 989-993
• 12 Berg T, Kronenberger B, Hinrichsen H et al.. Triple therapy with amantadine in treatment-naïve patients with chronic hepatitis C: a placebo-controlled trial.  Hepatology. 2003;  37 1359-1367
• 13 Khalili M, Denham C, Perrillo R. Interferon and ribavirin versus interferon and amantadine in interferon nonresponders with chronic hepatitis C.  Am J Gastroenterol. 2000;  95 1284-1289
• 14 Gaeta G B, Stornaiuolo G, Stanzione M et al.. Interferon-alpha plus amantadine in chronic hepatitis C resistant to interferon alone: a pilot randomized study.  J Viral Hepat. 2001;  8 284-286
• 15 Teuber G, Berg T, Naumann U et al.. Randomized, placebo-controlled, double-blind trial with interferon-alpha with and without amantadine sulphate in primary interferon-alpha nonresponders with chronic hepatitis C.  J Viral Hepat. 2001;  8 276-283
• 16 Bacosi M, Ursitti A, De Angelis A et al.. Treatment of HCV chronic infection with amantadine and interferon in elderly patient.  Hepatology. 1998;  28 208A
• 17 Younossi Z M, Mullen K D, Zakko W et al.. A randomized, double-blind controlled trial of interferon alpha-2b and ribavirin vs interferon alpha-2b and amantadine for treatment of chronic hepatitis C non-responder to interferon monotherapy.  J Hepatol. 2001;  34 128-133
• 18 Brillanti S, Levantesi F, Masi L et al.. Triple antiviral therapy as a new option for patients with interferon nonresponsive chronic hepatitis C.  Hepatology. 2000;  32 630-634
• 19 Zilly M, Lingenauber C, Desch S et al.. Triple antiviral re-therapy for chronic hepatitis C with interferon- alpha, ribavirin and amantadine in nonresponders to interferon-alpha and ribavirin.  Eur J Med Res. 2002;  7 149-154
• 20 Carlsson T, Lindahl K, Schvarcz R et al.. HCV RNA levels during therapy with amantadine in addition to interferon and ribavirin in chronic hepatitis C patients with previous nonresponse or response/relapse to interferon and ribavirin.  J Viral Hepat. 2000;  7 409-413
• 21 Afdahl N, Flamm S, Imperial J et al.. Pegylated (40 KDA) interferon alfa-2a (Pegasys) in combination with ribavirin, mycophenolate mofetil (Cellcept), amantadine, or amantadine plus ribavirin in patients that did not respond to Rebetron therapy: a preliminary report of a randomized, multicenter study.  Gastroenterology. 2001;  120 A-383
• 22 Endo Pharmaceuticals Inc. Package insert: Symmetrel®(amantadine hydrochloride) .Chadds Ford, PA; Endo Pharmaceuticals Inc 2000
• 23 Shulman L M, Minagar A, Sharma K, Weiner W J. Amantadine-induced peripheral neuropathy.  Neurology. 1999;  53 1862-1865
• 24 Lau J Y, Lin C-C. Assessment of liver delivery of ribavirin and viramidine, a liver-targeting ribavirin prodrug, using whole body autoradiography.  Hepatology. 2001;  34 427A
• 25 Lin C-C, Luu K, Lourenco D et al.. Viramidine, a prodrug of ribavirin, demonstrated superior liver-targeting properties and a much improved toxicity profile in cynomolgus monkey studies.  Hepatology. 2001;  34 453A
• 26 Lin C-C, Tam R, Orr R et al.. Development of levovirin as a second generation ribavirin for the treatment of chronic hepatitis C.  Gastroenterology. 2001;  120 A-582
• 27 Fong T L, Fried M W, Clarke-Platt J. A pilot study of rimantadine for patients with chronic hepatitis C unresponsive to interferon therapy.  Am J Gastroenterol. 1999;  94 990-993
• 28 Sherman K E, Sickler J, Aranda-Michel J et al.. Rimantadine for treatment of hepatitis C infection in liver transplant recipients.  Liver Transpl Surg. 1999;  5 25-28
• 29 Lirussi F, Beccarello A, Bortolato L et al.. Long-term treatment of chronic hepatitis C with ursodeoxycholic acid: influence of HCV genotypes and severity of liver disease.  Liver. 1999;  19 381-388
• 30 Fabbri C, Marchetto S, Pezzoli A et al.. Efficacy of ursodeoxycholic acid in association with alpha-interferon for chronic hepatitis C in alpha-interferon non-responder patients.  Eur J Gastroenterol Hepatol. 2000;  12 511-515
• 31 Poupon R E, Bonnand A M, Queneau P E et al.. Randomized trial of interferon-alpha plus ursodeoxycholic acid versus interferon plus placebo in patients with chronic hepatitis C resistant to interferon.  Scand J Gastroenterol. 2000;  35 642-649
• 32 Abdelmalek M F, Harrison M E, Gross J B et al.. Treatment of chronic hepatitis C with interferon with or without ursodeoxycholic acid: a randomized prospective trial.  J Clin Gastroenterol. 1998;  26 130-134
• 33 Angulo P. Use of ursodeoxycholic acid in patients with liver disease.  Curr Gastroenterol Rep. 2002;  4 37-44
• 34 Hellstrand K, Brune M, Mellqvist U H et al.. Histamine and the response to IFN-alpha in chronic hepatitis C.  J Interferon Cytokine Res. 1998;  18 21-22
• 35 Lurie Y, Hyle S, Gehlsen K R. A phase II study of the combination of histamine dihydrochloride and interferon alpha-2b (IFB-alfa-2b) as initial therapy in chronic hepatitis C (HCV) patients: 48-week results.  Gastroenterology. 2001;  120 A394-A395
• 36 Andreone P, Cursaro C, Gramenzi A et al.. In vitro effect of thymosin-alfa1 and interferon-alfa on Th1 and Th2 cytokine synthesis in patients with chronic hepatitis C.  J Viral Hepat. 2001;  8 194-201
• 37 Sherman K E, Sjogren M, Creager R L et al.. Combination therapy with thymosin alpha1 and interferon for the treatment of chronic hepatitis C infection: a randomized, placebo-controlled double-blind trial.  Hepatology. 1998;  27 1128-1135
• 38 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
• 39 Berg T, Naumann U, Wiedenmann B, Hopf U. Pilot study of interferon-alpha high-dose induction therapy in combination with ribavirin plus amantadine for nonresponder patients with chronic hepatitis C.  Z Gastroenterol. 2001;  39 145-151
• 40 Caronia S, Bassendine M F, Barry R et al.. Interferon plus amantadine versus interferon alone in the treatment of naive patients with chronic hepatitis C: a UK multicentre study.  J Hepatol. 2001;  35 512-516
• 41 Helbling B, Stamenic I, Viani F et al.. Interferon and amantadine in naive chronic hepatitis C: a double-blind, randomized, placebo-controlled trial.  Hepatology. 2002;  35 447-454
• 42 Tabone M, Laudi C, Delmastro B et al.. Interferon and amantadine in combination as initial treatment for chronic hepatitis C patients.  J Hepatol. 2001;  35 517-521
• 43 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
• 44 Bacosi M, Russo F, Dinnocenzo S et al.. Amantadine and interferon in the combined treatment of hepatitis C in elderly patients.  Hepatol Res. 2002;  22 231-239
• 45 Di Martino V, Boudjema H, Delacour T et al.. Treatment of chronic hepatitis C with amantadine hydrochloride in patients who had not responded to previous treatment with interferon-alpha and/or ribavirin.  Clin Infect Dis. 2001;  32 830-831