Chronic Hepatitis C Non-Responder Study With AdoMet and Betaine

Summary

50-60% of patients with chronic hepatitis C are not cured by treatment with pegylated IFNα plus ribavirin. Retreatment of non-responders of previous (pegylated) IFNα plus ribavirin therapies with pegylated IFNα plus ribavirin results in a sustained response in less than 10% of the patients. Extensive analysis of IFNα signaling in cells expressing HCV proteins, in transgenic mice expressing HCV proteins, and in liver biopsies from patients with chronic hepatitis C point to STAT1 methylation as an important posttranslational modification targeted by HCV to inhibit IFNα signaling. STAT1 methylation can be increased and IFNα can be improved by adding AdoMet and betaine. The study is designed to test the hypothesis that a combination treatment with pegylated IFNα2b, ribavirin, AdoMet and betaine is superior to the current standard combination therapy with pegylated IFNα plus ribavirin.

Timeline

Start

2006-08

Primary completion

2009-08

Completion

2009-09

Publications

• Background Duong FH, Christen V, Filipowicz M, Heim MH. S-Adenosylmethionine and betaine correct hepatitis C virus induced inhibition of interferon signaling in vitro. Hepatology. 2006 Apr;43(4):796-806. doi: 10.1002/hep.21116.
• Background Duong FH, Christen V, Berke JM, Penna SH, Moradpour D, Heim MH. Upregulation of protein phosphatase 2Ac by hepatitis C virus modulates NS3 helicase activity through inhibition of protein arginine methyltransferase 1. J Virol. 2005 Dec;79(24):15342-50. doi: 10.1128/JVI.79.24.15342-15350.2005.
• Background Duong FH, Filipowicz M, Tripodi M, La Monica N, Heim MH. Hepatitis C virus inhibits interferon signaling through up-regulation of protein phosphatase 2A. Gastroenterology. 2004 Jan;126(1):263-77. doi: 10.1053/j.gastro.2003.10.076.
• Background Blindenbacher A, Duong FH, Hunziker L, Stutvoet ST, Wang X, Terracciano L, Moradpour D, Blum HE, Alonzi T, Tripodi M, La Monica N, Heim MH. Expression of hepatitis c virus proteins inhibits interferon alpha signaling in the liver of transgenic mice. Gastroenterology. 2003 May;124(5):1465-75. doi: 10.1016/s0016-5085(03)00290-7.
• Background Heim MH, Moradpour D, Blum HE. Expression of hepatitis C virus proteins inhibits signal transduction through the Jak-STAT pathway. J Virol. 1999 Oct;73(10):8469-75. doi: 10.1128/JVI.73.10.8469-8475.1999.
• Filipowicz M, Bernsmeier C, Terracciano L, Duong FH, Heim MH. S-adenosyl-methionine and betaine improve early virological response in chronic hepatitis C patients with previous nonresponse. PLoS One. 2010 Nov 8;5(11):e15492. doi: 10.1371/journal.pone.0015492.

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Indications