Journal Mobile Options
Table of Contents
Vol. 55, No. 3, 2012
Issue release date: February 2012
Intervirology 2012;55:231–241
(DOI:10.1159/000328327)

Amino Acid Substitution in HCV Core/NS5A Region and Genetic Variation Near IL28B Gene Affect Treatment Efficacy to Interferon plus Ribavirin Combination Therapy

Akuta N.a · Suzuki F.a · Hirakawa M.a · Kawamura Y.a · Sezaki H.a · Suzuki Y.a · Hosaka T.a · Kobayashi M.a · Kobayashi M.b · Saitoh S.a · Arase Y.a · Ikeda K.a · Chayama K.c · Nakamura Y.d · Kumada H.a
aDepartment of Hepatology, and bLiver Research Laboratory, Toranomon Hospital, Tokyo, cDepartment of Medical and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Science, Hiroshima University, Hiroshima, and dLaboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan
email Corresponding Author

Abstract

Objective: To evaluate predictive factors of treatment efficacy to interferon (IFN)/ribavirin in patients infected with HCV genotype 1b (HCV-1b). Methods: This study investigated pretreatment predictors, including viral- (aa substitutions in core aa 70/91 and NS5A-ISDR/IRRDR) and host-related factors (genetic variation near IL28B gene), to 48-week IFN/ribavirin in 490 Japanese adults infected with HCV-1b. Results: The proportion of patients who showed end-of-treatment response (ETR), sustained virological response (SVR), and SVR after ETR was 76, 54, and 76%, respectively. There was a significant positive correlation between the number of aa substitutions in ISDR and those in IRRDR. Concerning the substitution of core aa 91, the number of aa substitutions in ISDR/IRRDR of patients with Leu91 was significantly higher than that of patients with Met91. Furthermore, levels of viremia were influenced by aa substitutions in core aa 91 and ISDR/IRRDR. By multivariate analysis, rs8099917 genotype was an important predictor of ETR and SVR. With regard to viral factors, core aa 70/91 was an important predictor of ETR, and SVR after ETR. ISDR was an important predictor of SVR, and SVR after ETR. Conclusion: aa substitution in core/NS5A region and genetic variation near IL28B were important predictors of treatment efficacy to IFN/ribavirin.


 goto top of outline Key Words

  • Hepatitis C virus
  • Interferon
  • Ribavirin
  • Core region
  • NS5A region
  • ISDR
  • IRRDR
  • IL28B

 goto top of outline Abstract

Objective: To evaluate predictive factors of treatment efficacy to interferon (IFN)/ribavirin in patients infected with HCV genotype 1b (HCV-1b). Methods: This study investigated pretreatment predictors, including viral- (aa substitutions in core aa 70/91 and NS5A-ISDR/IRRDR) and host-related factors (genetic variation near IL28B gene), to 48-week IFN/ribavirin in 490 Japanese adults infected with HCV-1b. Results: The proportion of patients who showed end-of-treatment response (ETR), sustained virological response (SVR), and SVR after ETR was 76, 54, and 76%, respectively. There was a significant positive correlation between the number of aa substitutions in ISDR and those in IRRDR. Concerning the substitution of core aa 91, the number of aa substitutions in ISDR/IRRDR of patients with Leu91 was significantly higher than that of patients with Met91. Furthermore, levels of viremia were influenced by aa substitutions in core aa 91 and ISDR/IRRDR. By multivariate analysis, rs8099917 genotype was an important predictor of ETR and SVR. With regard to viral factors, core aa 70/91 was an important predictor of ETR, and SVR after ETR. ISDR was an important predictor of SVR, and SVR after ETR. Conclusion: aa substitution in core/NS5A region and genetic variation near IL28B were important predictors of treatment efficacy to IFN/ribavirin.

Copyright © 2011 S. Karger AG, Basel


 goto top of outline References
  1. Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Watahiki S, Sato J, Matsuda M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology 2005;48:372–380.
  2. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J Hepatol 2007;46:403–410.
  3. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Predictors of viral kinetics to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b. J Med Virol 2007;79:1686–1695.
  4. Donlin MJ, Cannon NA, Yao E, Li J, Wahed A, Taylor MW, Belle SH, Di Bisceglie AM, Aurora R, Tavis JE: Pretreatment sequence diversity differences in the full-length hepatitis C virus open reading frame correlate with early response to therapy. J Virol 2007;81:8211–8224.
  5. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Amino acid substitutions in the hepatitis C virus core region are the important predictor of hepatocarcinogenesis. Hepatology 2007;46:1357–1364.
  6. Fishman SL, Factor SH, Balestrieri C, Fan X, Dibisceglie AM, Desai SM, Benson G, Branch AD: Mutations in the hepatitis C virus core gene are associated with advanced liver disease and hepatocellular carcinoma. Clin Cancer Res 2009;15:3205–3213.
  7. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C: Comparison of full-length sequences of interferon sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region. J Clin Invest 1995;96:224–230.
  8. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C: Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996;334:77–81.
  9. El-Shamy A, Sasayama M, Nagano-Fujii M, Sasase N, Imoto S, Kim SR, Hotta H: Prediction of efficient virological response to pegylated interferon/ribavirin combination therapy by NS5A sequences of hepatitis C virus and anti-NS5A antibodies in pre-treatment sera. Microbiol Immunol 2007;51:471–482.
  10. El-Shamy A, Nagano-Fujii M, Sasase N, Imoto S, Kim SR, Hotta H: Sequence variation in hepatitis C virus nonstructural protein 5A predicts clinical outcome of pegylated interferon/ribavirin combination therapy. Hepatology 2008;48:38–47.
  11. Shirakawa H, Matsumoto A, Joshita S, Komatsu M, Tanaka N, Umemura T, Ichijo T, Yoshizawa K, Kiyosawa K, Tanaka E: Nagano Interferon Treatment Research Group: Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors. Hepatology 2008;48:1753–1760.
  12. Mori N, Imamura M, Kawakami Y, Saneto H, Kawaoka T, Takaki S, Aikata H, Takahashi S, Chayama K: Hiroshima Liver Study Group: Randomized trial of high-dose interferon-α-2b combined with ribavirin in patients with chronic hepatitis C: Correlation between amino acid substitutions in the core/NS5A region and virological response to interferon therapy. J Med Virol 2009;81:640–649.
  13. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB: Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399–401.
  14. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M: Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41:1105–1109.
  15. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V, Müller T, Bahlo M, Stewart GJ, Booth DR, George J: IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nat Genet 2009;41:1100–1104.
  16. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, Bochud M, Battegay M, Bernasconi E, Borovicka J, Colombo S, Cerny A, Dufour JF, Furrer H, Günthard HF, Heim M, Hirschel B, Malinverni R, Moradpour D, Müllhaupt B, Witteck A, Beckmann JS, Berg T, Bergmann S, Negro F, Telenti A, Bochud PY: Swiss Hepatitis C Cohort Study; Swiss HIV Cohort Study: Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010;138:1338–1345.
  17. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M: Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798–801.
  18. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H: Amino acid substitution in HCV core region and genetic variation near the interleukin-28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology 2010;52:421–429.
  19. Kato N, Hijikata M, Ootsuyama Y, Nakagawa M, Ohkoshi S, Sugimura T, Shimotohno K: Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci USA 1990;87:9524–9528.
  20. Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y: A high-throughput SNP typing system for genome-wide association studies. J Hum Genet 2001;46:471–477.
  21. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K: Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003;34:395–402.
  22. Kurosaki M, Tanaka Y, Nishida N, Sakamoto N, Enomoto N, Honda M, Sugiyama M, Matsuura K, Sugauchi F, Asahina Y, Nakagawa M, Watanabe M, Sakamoto M, Maekawa S, Sakai A, Kaneko S, Ito K, Masaki N, Tokunaga K, Izumi N, Mizokami M: Pre-treatment prediction of response to pegylated-interferon plus ribavirin for chronic hepatitis C using genetic polymorphism in IL28B and viral factors. J Hepatol 2011;54:439–448.
  23. Hayes CN, Kobayashi M, Akuta N, Suzuki F, Kumada H, Abe H, Miki D, Imamura M, Ochi H, Kamatani N, Nakamura Y, Chayama K: HCV substitutions and IL28B polymorphisms on outcome of peg-interferon plus ribavirin combination therapy. Gut 2011;60:261–267.
  24. McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ: PROVE1 Study Team: Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1827–1838.
  25. McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, Heathcote EJ, Zeuzem S, Reesink HW, Garg J, Bsharat M, George S, Kauffman RS, Adda N, Di Bisceglie AM: PROVE3 Study Team: Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292–1303.
  26. Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S: PROVE2 Study Team: Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839–1850.
  27. Jouet P, Roudot-Thoraval F, Dhumeaux D, Metreau JM: Comparative efficacy of interferon alfa in cirrhotic and noncirrhotic patients with non-A, non-B, C hepatitis. Gastroenterology 1994;106:686–690.
  28. Poynard T, McHutchinson J, Goodman Z, Ling MH, Albrecht J: Is an ‘a la carte’ combination interferon alfa-2b plus ribavirin regimen possible for the first-line treatment in patients with chronic hepatitis C? The ALGOVIRC Group. Hepatology 2000;31:211–218.
  29. Bruno S, Camma C, Di Marco V, Rumi M, Vinci M, Camozzi M, Rebucci C, Di Bona D, Colombo M, Craxi A, Mondelli MU, Pinzello G: Peginterferon alfa-2b plus ribavirin for naïve patients with genotype 1 chronic hepatitis C: a randomized controlled trial. J Hepatol 2004;41:474–481.
  30. Bayati N, Silverman AL, Gordon SC: Serum α-fetoprotein levels and liver histology in patients with chronic hepatitis C. Am J Gastroenterol 1998;93:2452–2456.
  31. Chu CW, Hwang SJ, Luo JC, Lai CR, Tsay SH, Li CP, Wu JC, Chang FY, Lee SD: Clinical, virological, and pathologic significance of elevated serum α-fetoprotein levels in patients with chronic hepatitis C. J Clin Gastroenterol 2001;32:240–244.
  32. Hu KQ, Kyulo NL, Lim N, Elhazin B, Hillebrand DJ, Bock T: Clinical significance of elevated α-fetoprotein in patients with chronic hepatitis C, but not hepatocellular carcinoma. Am J Gastroenterol 2004;99:860–865.
  33. McHutchison JG, Poynard T, Pianko S, Gordon SC, Reid AE, Dienstag J, Morgan T, Yao R, Albrecht J: The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interventional Therapy Group. Gastroenterology 2000;119:1317–1323.
  34. Kaplan DE, Sugimoto K, Ikeda F, Stadanlick J, Valiga M, Shetty K, Reddy KR, Chang KM: T-cell response relative to genotype and ethnicity during antiviral therapy for chronic hepatitis C. Hepatology 2005;41:1365–1375.
  35. Nakano I, Fukuda Y, Katano Y, Nakano S, Kumada T, Hayakawa T: Why is the interferon sensitivity-determining region (ISDR) system useful in Japan? J Hepatol 1999;30:1014–1022.

 goto top of outline Author Contacts

Norio Akuta, MD
Department of Hepatology, Toranomon Hospital
2-2-2 Toranomon, Minato-ku
Tokyo 105-0001 (Japan)
Tel. +81 44 877 5111, E-Mail akuta-gi@umin.ac.jp


 goto top of outline Article Information

Received: September 22, 2010
Accepted after revision: March 28, 2011
Published online: July 5, 2011
Number of Print Pages : 11
Number of Figures : 8, Number of Tables : 5, Number of References : 35


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 55, No. 3, Year 2012 (Cover Date: February 2012)

Journal Editor: Liebert U.G. (Leipzig)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Objective: To evaluate predictive factors of treatment efficacy to interferon (IFN)/ribavirin in patients infected with HCV genotype 1b (HCV-1b). Methods: This study investigated pretreatment predictors, including viral- (aa substitutions in core aa 70/91 and NS5A-ISDR/IRRDR) and host-related factors (genetic variation near IL28B gene), to 48-week IFN/ribavirin in 490 Japanese adults infected with HCV-1b. Results: The proportion of patients who showed end-of-treatment response (ETR), sustained virological response (SVR), and SVR after ETR was 76, 54, and 76%, respectively. There was a significant positive correlation between the number of aa substitutions in ISDR and those in IRRDR. Concerning the substitution of core aa 91, the number of aa substitutions in ISDR/IRRDR of patients with Leu91 was significantly higher than that of patients with Met91. Furthermore, levels of viremia were influenced by aa substitutions in core aa 91 and ISDR/IRRDR. By multivariate analysis, rs8099917 genotype was an important predictor of ETR and SVR. With regard to viral factors, core aa 70/91 was an important predictor of ETR, and SVR after ETR. ISDR was an important predictor of SVR, and SVR after ETR. Conclusion: aa substitution in core/NS5A region and genetic variation near IL28B were important predictors of treatment efficacy to IFN/ribavirin.



 goto top of outline Author Contacts

Norio Akuta, MD
Department of Hepatology, Toranomon Hospital
2-2-2 Toranomon, Minato-ku
Tokyo 105-0001 (Japan)
Tel. +81 44 877 5111, E-Mail akuta-gi@umin.ac.jp


 goto top of outline Article Information

Received: September 22, 2010
Accepted after revision: March 28, 2011
Published online: July 5, 2011
Number of Print Pages : 11
Number of Figures : 8, Number of Tables : 5, Number of References : 35


 goto top of outline Publication Details

Intervirology (International Journal of Basic and Medical Virology)

Vol. 55, No. 3, Year 2012 (Cover Date: February 2012)

Journal Editor: Liebert U.G. (Leipzig)
ISSN: 0300-5526 (Print), eISSN: 1423-0100 (Online)

For additional information: http://www.karger.com/INT


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Akuta N, Suzuki F, Sezaki H, Suzuki Y, Hosaka T, Someya T, Kobayashi M, Saitoh S, Watahiki S, Sato J, Matsuda M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Association of amino acid substitution pattern in core protein of hepatitis C virus genotype 1b high viral load and non-virological response to interferon-ribavirin combination therapy. Intervirology 2005;48:372–380.
  2. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Predictive factors of early and sustained responses to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b: amino acid substitutions in the core region and low-density lipoprotein cholesterol levels. J Hepatol 2007;46:403–410.
  3. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Predictors of viral kinetics to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b. J Med Virol 2007;79:1686–1695.
  4. Donlin MJ, Cannon NA, Yao E, Li J, Wahed A, Taylor MW, Belle SH, Di Bisceglie AM, Aurora R, Tavis JE: Pretreatment sequence diversity differences in the full-length hepatitis C virus open reading frame correlate with early response to therapy. J Virol 2007;81:8211–8224.
  5. Akuta N, Suzuki F, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Arase Y, Ikeda K, Kumada H: Amino acid substitutions in the hepatitis C virus core region are the important predictor of hepatocarcinogenesis. Hepatology 2007;46:1357–1364.
  6. Fishman SL, Factor SH, Balestrieri C, Fan X, Dibisceglie AM, Desai SM, Benson G, Branch AD: Mutations in the hepatitis C virus core gene are associated with advanced liver disease and hepatocellular carcinoma. Clin Cancer Res 2009;15:3205–3213.
  7. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Izumi N, Marumo F, Sato C: Comparison of full-length sequences of interferon sensitive and resistant hepatitis C virus 1b. Sensitivity to interferon is conferred by amino acid substitutions in the NS5A region. J Clin Invest 1995;96:224–230.
  8. Enomoto N, Sakuma I, Asahina Y, Kurosaki M, Murakami T, Yamamoto C, Ogura Y, Izumi N, Marumo F, Sato C: Mutations in the nonstructural protein 5A gene and response to interferon in patients with chronic hepatitis C virus 1b infection. N Engl J Med 1996;334:77–81.
  9. El-Shamy A, Sasayama M, Nagano-Fujii M, Sasase N, Imoto S, Kim SR, Hotta H: Prediction of efficient virological response to pegylated interferon/ribavirin combination therapy by NS5A sequences of hepatitis C virus and anti-NS5A antibodies in pre-treatment sera. Microbiol Immunol 2007;51:471–482.
  10. El-Shamy A, Nagano-Fujii M, Sasase N, Imoto S, Kim SR, Hotta H: Sequence variation in hepatitis C virus nonstructural protein 5A predicts clinical outcome of pegylated interferon/ribavirin combination therapy. Hepatology 2008;48:38–47.
  11. Shirakawa H, Matsumoto A, Joshita S, Komatsu M, Tanaka N, Umemura T, Ichijo T, Yoshizawa K, Kiyosawa K, Tanaka E: Nagano Interferon Treatment Research Group: Pretreatment prediction of virological response to peginterferon plus ribavirin therapy in chronic hepatitis C patients using viral and host factors. Hepatology 2008;48:1753–1760.
  12. Mori N, Imamura M, Kawakami Y, Saneto H, Kawaoka T, Takaki S, Aikata H, Takahashi S, Chayama K: Hiroshima Liver Study Group: Randomized trial of high-dose interferon-α-2b combined with ribavirin in patients with chronic hepatitis C: Correlation between amino acid substitutions in the core/NS5A region and virological response to interferon therapy. J Med Virol 2009;81:640–649.
  13. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, Heinzen EL, Qiu P, Bertelsen AH, Muir AJ, Sulkowski M, McHutchison JG, Goldstein DB: Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature 2009;461:399–401.
  14. Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, Nakagawa M, Korenaga M, Hino K, Hige S, Ito Y, Mita E, Tanaka E, Mochida S, Murawaki Y, Honda M, Sakai A, Hiasa Y, Nishiguchi S, Koike A, Sakaida I, Imamura M, Ito K, Yano K, Masaki N, Sugauchi F, Izumi N, Tokunaga K, Mizokami M: Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin therapy for chronic hepatitis C. Nat Genet 2009;41:1105–1109.
  15. Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, Bassendine M, Spengler U, Dore GJ, Powell E, Riordan S, Sheridan D, Smedile A, Fragomeli V, Müller T, Bahlo M, Stewart GJ, Booth DR, George J: IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy. Nat Genet 2009;41:1100–1104.
  16. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, Bochud M, Battegay M, Bernasconi E, Borovicka J, Colombo S, Cerny A, Dufour JF, Furrer H, Günthard HF, Heim M, Hirschel B, Malinverni R, Moradpour D, Müllhaupt B, Witteck A, Beckmann JS, Berg T, Bergmann S, Negro F, Telenti A, Bochud PY: Swiss Hepatitis C Cohort Study; Swiss HIV Cohort Study: Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010;138:1338–1345.
  17. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’Huigin C, Kidd J, Kidd K, Khakoo SI, Alexander G, Goedert JJ, Kirk GD, Donfield SM, Rosen HR, Tobler LH, Busch MP, McHutchison JG, Goldstein DB, Carrington M: Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798–801.
  18. Akuta N, Suzuki F, Hirakawa M, Kawamura Y, Yatsuji H, Sezaki H, Suzuki Y, Hosaka T, Kobayashi M, Kobayashi M, Saitoh S, Arase Y, Ikeda K, Chayama K, Nakamura Y, Kumada H: Amino acid substitution in HCV core region and genetic variation near the interleukin-28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology 2010;52:421–429.
  19. Kato N, Hijikata M, Ootsuyama Y, Nakagawa M, Ohkoshi S, Sugimura T, Shimotohno K: Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci USA 1990;87:9524–9528.
  20. Ohnishi Y, Tanaka T, Ozaki K, Yamada R, Suzuki H, Nakamura Y: A high-throughput SNP typing system for genome-wide association studies. J Hum Genet 2001;46:471–477.
  21. Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K: Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003;34:395–402.
  22. Kurosaki M, Tanaka Y, Nishida N, Sakamoto N, Enomoto N, Honda M, Sugiyama M, Matsuura K, Sugauchi F, Asahina Y, Nakagawa M, Watanabe M, Sakamoto M, Maekawa S, Sakai A, Kaneko S, Ito K, Masaki N, Tokunaga K, Izumi N, Mizokami M: Pre-treatment prediction of response to pegylated-interferon plus ribavirin for chronic hepatitis C using genetic polymorphism in IL28B and viral factors. J Hepatol 2011;54:439–448.
  23. Hayes CN, Kobayashi M, Akuta N, Suzuki F, Kumada H, Abe H, Miki D, Imamura M, Ochi H, Kamatani N, Nakamura Y, Chayama K: HCV substitutions and IL28B polymorphisms on outcome of peg-interferon plus ribavirin combination therapy. Gut 2011;60:261–267.
  24. McHutchison JG, Everson GT, Gordon SC, Jacobson IM, Sulkowski M, Kauffman R, McNair L, Alam J, Muir AJ: PROVE1 Study Team: Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med 2009;360:1827–1838.
  25. McHutchison JG, Manns MP, Muir AJ, Terrault NA, Jacobson IM, Afdhal NH, Heathcote EJ, Zeuzem S, Reesink HW, Garg J, Bsharat M, George S, Kauffman RS, Adda N, Di Bisceglie AM: PROVE3 Study Team: Telaprevir for previously treated chronic HCV infection. N Engl J Med 2010;362:1292–1303.
  26. Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, Bronowicki JP, Bourlière M, Gharakhanian S, Bengtsson L, McNair L, George S, Kieffer T, Kwong A, Kauffman RS, Alam J, Pawlotsky JM, Zeuzem S: PROVE2 Study Team: Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med 2009;360:1839–1850.
  27. Jouet P, Roudot-Thoraval F, Dhumeaux D, Metreau JM: Comparative efficacy of interferon alfa in cirrhotic and noncirrhotic patients with non-A, non-B, C hepatitis. Gastroenterology 1994;106:686–690.
  28. Poynard T, McHutchinson J, Goodman Z, Ling MH, Albrecht J: Is an ‘a la carte’ combination interferon alfa-2b plus ribavirin regimen possible for the first-line treatment in patients with chronic hepatitis C? The ALGOVIRC Group. Hepatology 2000;31:211–218.
  29. Bruno S, Camma C, Di Marco V, Rumi M, Vinci M, Camozzi M, Rebucci C, Di Bona D, Colombo M, Craxi A, Mondelli MU, Pinzello G: Peginterferon alfa-2b plus ribavirin for naïve patients with genotype 1 chronic hepatitis C: a randomized controlled trial. J Hepatol 2004;41:474–481.
  30. Bayati N, Silverman AL, Gordon SC: Serum α-fetoprotein levels and liver histology in patients with chronic hepatitis C. Am J Gastroenterol 1998;93:2452–2456.
  31. Chu CW, Hwang SJ, Luo JC, Lai CR, Tsay SH, Li CP, Wu JC, Chang FY, Lee SD: Clinical, virological, and pathologic significance of elevated serum α-fetoprotein levels in patients with chronic hepatitis C. J Clin Gastroenterol 2001;32:240–244.
  32. Hu KQ, Kyulo NL, Lim N, Elhazin B, Hillebrand DJ, Bock T: Clinical significance of elevated α-fetoprotein in patients with chronic hepatitis C, but not hepatocellular carcinoma. Am J Gastroenterol 2004;99:860–865.
  33. McHutchison JG, Poynard T, Pianko S, Gordon SC, Reid AE, Dienstag J, Morgan T, Yao R, Albrecht J: The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interventional Therapy Group. Gastroenterology 2000;119:1317–1323.
  34. Kaplan DE, Sugimoto K, Ikeda F, Stadanlick J, Valiga M, Shetty K, Reddy KR, Chang KM: T-cell response relative to genotype and ethnicity during antiviral therapy for chronic hepatitis C. Hepatology 2005;41:1365–1375.
  35. Nakano I, Fukuda Y, Katano Y, Nakano S, Kumada T, Hayakawa T: Why is the interferon sensitivity-determining region (ISDR) system useful in Japan? J Hepatol 1999;30:1014–1022.