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Published in: Journal of Gastroenterology 12/2014

01-12-2014 | Original Article—Liver, Pancreas, and Biliary Tract

Predictive value of the IFNL4 polymorphism on outcome of telaprevir, peginterferon, and ribavirin therapy for older patients with genotype 1b chronic hepatitis C

Authors: Hatsue Fujino, Michio Imamura, Yuko Nagaoki, Yoshiiku Kawakami, Hiromi Abe, C. Nelson Hayes, Hiromi Kan, Takayuki Fukuhara, Tomoki Kobayashi, Keiichi Masaki, Atsushi Ono, Takashi Nakahara, Youji Honda, Noriaki Naeshiro, Ayako Urabe, Satoe Yokoyama, Daisuke Miyaki, Eisuke Murakami, Tomokazu Kawaoka, Nobuhiko Hiraga, Masataka Tsuge, Akira Hiramatsu, Hideyuki Hyogo, Hiroshi Aikata, Shoichi Takahashi, Daiki Miki, Hidenori Ochi, Waka Ohishi, Kazuaki Chayama, Hiroshima Liver Study Group

Published in: Journal of Gastroenterology | Issue 12/2014

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Abstract

Background

Older patients with chronic hepatitis C have a lower virological response to interferon (IFN) treatment compared to younger patients. The efficacy of telaprevir (TVR) and PEG-IFN plus ribavirin combination therapy and the predictive value of recently identified IFN lambda (IFNL) 4 polymorphisms on the outcome of therapy for older patients have not been addressed.

Methods

We assessed predictive factors for sustained virological response (SVR) to triple therapy in 226 younger (≤65 years) and 87 older (>65 years) Japanese patients with chronic genotype 1 hepatitis C. IFNL4 polymorphism ss469415590 was analyzed by Invader assay.

Results

The SVR rate for older patients was slightly lower than for younger patients (69 vs. 82 %, P = 0.043). In the older group, the SVR rate for patients with the IFNL4 TT/TT genotype was significantly higher than patients with TT/ΔG or ΔG/ΔG genotypes (81.8 and 42.9 %, P = 0.003). In multivariate regression analysis, rapid virological response (OR 36.601, P = 0.002) and IFNL4 TT/TT genotype (OR 19.502, P = 0.009) were identified as significant independent predictors for SVR in older patients. Treatment-related decreases in hemoglobin and increases in serum creatinine were higher in older patients than younger patients. Reduction of initial TVR dose to 1,500 mg per day alleviated these adverse events without compromising SVR rate in older patients.

Conclusions

Analysis of IFNL4 polymorphisms is a valuable predictor in older patients receiving TVR triple therapy. 1,500 mg per day is a suitable initial TVR dose for older Japanese patients.
Literature
1.
go back to reference NIH. National Institutes of Health Consensus Development Conference Statement. Management of hepatitis C 2002 (June 10–12, 2002). Gastroenterology. 2002;123:2082–99. NIH. National Institutes of Health Consensus Development Conference Statement. Management of hepatitis C 2002 (June 10–12, 2002). Gastroenterology. 2002;123:2082–99.
2.
go back to reference Seeff LB, Buskell-Bales Z, Wright EC, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. N Engl J Med. 1992;327:1906–11.PubMedCrossRef Seeff LB, Buskell-Bales Z, Wright EC, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. N Engl J Med. 1992;327:1906–11.PubMedCrossRef
3.
go back to reference Ogawa E, Furusyo N, Kajiwara E, et al. Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma of patients with chronic hepatitis C: a prospective, multicenter study. J Hepatol. 2013;58:495–501.PubMedCrossRef Ogawa E, Furusyo N, Kajiwara E, et al. Efficacy of pegylated interferon alpha-2b and ribavirin treatment on the risk of hepatocellular carcinoma of patients with chronic hepatitis C: a prospective, multicenter study. J Hepatol. 2013;58:495–501.PubMedCrossRef
4.
go back to reference Tanaka Y, Hanada K, Mizokami M, et al. A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence in the United States will increase over the next two decades. Proc Natl Acad Sci USA. 2002;99:15584–9.PubMedCentralPubMedCrossRef Tanaka Y, Hanada K, Mizokami M, et al. A comparison of the molecular clock of hepatitis C virus in the United States and Japan predicts that hepatocellular carcinoma incidence in the United States will increase over the next two decades. Proc Natl Acad Sci USA. 2002;99:15584–9.PubMedCentralPubMedCrossRef
5.
go back to reference Lee SS, Heathcote EJ, Reddy KR, et al. Prognostic factors and early predictability of sustained viral response with peginterferon alfa-2a (40 KD). J Hepatol. 2002;37:500–6.PubMedCrossRef Lee SS, Heathcote EJ, Reddy KR, et al. Prognostic factors and early predictability of sustained viral response with peginterferon alfa-2a (40 KD). J Hepatol. 2002;37:500–6.PubMedCrossRef
6.
go back to reference Zeuzem S. Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well. Ann Intern Med. 2004;140:370–81.PubMed Zeuzem S. Heterogeneous virologic response rates to interferon-based therapy in patients with chronic hepatitis C: who responds less well. Ann Intern Med. 2004;140:370–81.PubMed
7.
go back to reference Kainuma M, Furusyo N, Kajiwara E, et al. Kyushu University Liver Disease Study Group pegylated interferon a-2b plus ribavirin for older patients with chronic hepatitis C. World J Gastroenterol. 2010;16:4400–9.PubMedCentralPubMedCrossRef Kainuma M, Furusyo N, Kajiwara E, et al. Kyushu University Liver Disease Study Group pegylated interferon a-2b plus ribavirin for older patients with chronic hepatitis C. World J Gastroenterol. 2010;16:4400–9.PubMedCentralPubMedCrossRef
8.
go back to reference Iwasaki Y, Ikeda H, Araki Y, et al. Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis C. Hepatology. 2006;43:54–63.PubMedCrossRef Iwasaki Y, Ikeda H, Araki Y, et al. Limitation of combination therapy of interferon and ribavirin for older patients with chronic hepatitis C. Hepatology. 2006;43:54–63.PubMedCrossRef
9.
go back to reference Hiramatsu N, Oze T, Tsuda N, et al. Should aged patients with chronic hepatitis C be treated with interferon and ribavirin combination therapy. Hepatol Res. 2006;35:185–9.PubMed Hiramatsu N, Oze T, Tsuda N, et al. Should aged patients with chronic hepatitis C be treated with interferon and ribavirin combination therapy. Hepatol Res. 2006;35:185–9.PubMed
10.
go back to reference McHutchison JG, Everson GT, Gordon SC, PROVE1 Study Team, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827–38.PubMedCrossRef McHutchison JG, Everson GT, Gordon SC, PROVE1 Study Team, et al. Telaprevir with peginterferon and ribavirin for chronic HCV genotype 1 infection. N Engl J Med. 2009;360:1827–38.PubMedCrossRef
11.
go back to reference Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–16.PubMedCrossRef Jacobson IM, McHutchison JG, Dusheiko G, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364:2405–16.PubMedCrossRef
12.
go back to reference Kumada H, Toyota J, Okanoue T, et al. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56:78–84.PubMedCrossRef Kumada H, Toyota J, Okanoue T, et al. Telaprevir with peginterferon and ribavirin for treatment-naive patients chronically infected with HCV of genotype 1 in Japan. J Hepatol. 2012;56:78–84.PubMedCrossRef
13.
go back to reference Hayashi N, Okanoue T, Tsubouchi H, et al. Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C. J Viral Hepat. 2012;19:e134–42.PubMedCentralPubMedCrossRef Hayashi N, Okanoue T, Tsubouchi H, et al. Efficacy and safety of telaprevir, a new protease inhibitor, for difficult-to-treat patients with genotype 1 chronic hepatitis C. J Viral Hepat. 2012;19:e134–42.PubMedCentralPubMedCrossRef
14.
go back to reference Chayama K, Hayes CN, Ohishi W, et al. Treatment of chronic hepatitis C virus infection in Japan: update on therapy and guidelines. J Gastroenterol. 2013;48:1–12.PubMedCentralPubMedCrossRef Chayama K, Hayes CN, Ohishi W, et al. Treatment of chronic hepatitis C virus infection in Japan: update on therapy and guidelines. J Gastroenterol. 2013;48:1–12.PubMedCentralPubMedCrossRef
15.
go back to reference Furusyo N, Ogawa E, Nakamuta M, et al. Telaprevir can be successfully and safely used to treat older patients with genotype 1b chronic hepatitis C. J Hepatol. 2013;59:205–12.PubMedCrossRef Furusyo N, Ogawa E, Nakamuta M, et al. Telaprevir can be successfully and safely used to treat older patients with genotype 1b chronic hepatitis C. J Hepatol. 2013;59:205–12.PubMedCrossRef
16.
go back to reference Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401.PubMedCrossRef Ge D, Fellay J, Thompson AJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401.PubMedCrossRef
17.
go back to reference Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–9.PubMedCrossRef Tanaka Y, Nishida N, Sugiyama M, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41:1105–9.PubMedCrossRef
18.
go back to reference Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–4.PubMedCrossRef Suppiah V, Moldovan M, Ahlenstiel G, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–4.PubMedCrossRef
19.
go back to reference Nishiguchi S, et al. Relevance of the Core 70 and IL-28B polymorphism and response-guided therapy of peginterferon alfa-2a ± ribavirin for chronic hepatitis C of Genotype 1b: a multicenter randomized trial. ReGIT-J study. J Gastroenterol. 2013;. doi:10.1007/s00535-013-0785-2. Nishiguchi S, et al. Relevance of the Core 70 and IL-28B polymorphism and response-guided therapy of peginterferon alfa-2a ± ribavirin for chronic hepatitis C of Genotype 1b: a multicenter randomized trial. ReGIT-J study. J Gastroenterol. 2013;. doi:10.​1007/​s00535-013-0785-2.
20.
go back to reference Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology. 2010;52:421–9.PubMedCrossRef Akuta N, Suzuki F, Hirakawa M, et al. Amino acid substitution in hepatitis C virus core region and genetic variation near the interleukin 28B gene predict viral response to telaprevir with peginterferon and ribavirin. Hepatology. 2010;52:421–9.PubMedCrossRef
21.
go back to reference Chayama K, Hayes CN, Abe H, et al. IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C. J Infect Dis. 2011;204:84–93.PubMedCentralPubMedCrossRef Chayama K, Hayes CN, Abe H, et al. IL28B but not ITPA polymorphism is predictive of response to pegylated interferon, ribavirin, and telaprevir triple therapy in patients with genotype 1 hepatitis C. J Infect Dis. 2011;204:84–93.PubMedCentralPubMedCrossRef
22.
go back to reference Prokunina-Olsson L, Muchmore B, Tang W, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45:164–71.PubMedCentralPubMedCrossRef Prokunina-Olsson L, Muchmore B, Tang W, et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat Genet. 2013;45:164–71.PubMedCentralPubMedCrossRef
23.
go back to reference Akuta N, Suzuki F, Kawamura Y, et al. 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;46:403–10.PubMedCrossRef Akuta N, Suzuki F, Kawamura Y, et al. 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;46:403–10.PubMedCrossRef
24.
go back to reference Akuta N, Suzuki F, Sezaki H, et al. Predictive factors of virological non-response to interferon-ribavirin combination therapy for patients infected with hepatitis C virus of genotype 1b and high viral load. J Med Virol. 2006;78:83–90.PubMedCrossRef Akuta N, Suzuki F, Sezaki H, et al. Predictive factors of virological non-response to interferon-ribavirin combination therapy for patients infected with hepatitis C virus of genotype 1b and high viral load. J Med Virol. 2006;78:83–90.PubMedCrossRef
25.
go back to reference Fellay J, Thompson A, Ge D, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature. 2010;464:405–8.PubMedCrossRef Fellay J, Thompson A, Ge D, et al. ITPA gene variants protect against anaemia in patients treated for chronic hepatitis C. Nature. 2010;464:405–8.PubMedCrossRef
26.
go back to reference Ochi H, Maekawa T, Abe H, et al. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy-a genome-wide study of Japanese HCV virus patients. Gastroenterology. 2010;139:1190–7.PubMedCrossRef Ochi H, Maekawa T, Abe H, et al. ITPA polymorphism affects ribavirin-induced anemia and outcomes of therapy-a genome-wide study of Japanese HCV virus patients. Gastroenterology. 2010;139:1190–7.PubMedCrossRef
27.
go back to reference Suzuki F, Suzuki Y, Akuta N, et al. Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir. Hepatology. 2011;53:415–21.PubMedCrossRef Suzuki F, Suzuki Y, Akuta N, et al. Influence of ITPA polymorphisms on decreases of hemoglobin during treatment with pegylated interferon, ribavirin, and telaprevir. Hepatology. 2011;53:415–21.PubMedCrossRef
28.
go back to reference Ohnishi Y, Tanaka T, Ozaki K, et al. A high-throughput SNP typing system for genome-wide association studies. J Hum Genet. 2001;46:471–7.PubMedCrossRef Ohnishi Y, Tanaka T, Ozaki K, et al. A high-throughput SNP typing system for genome-wide association studies. J Hum Genet. 2001;46:471–7.PubMedCrossRef
29.
go back to reference Suzuki A, Yamada R, Chang X, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003;34:395–402.PubMedCrossRef Suzuki A, Yamada R, Chang X, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet. 2003;34:395–402.PubMedCrossRef
30.
go back to reference Arase Y, Ikeda K, Suzuki F, et al. Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C. Intervirology. 2007;50:16–23.PubMedCrossRef Arase Y, Ikeda K, Suzuki F, et al. Long-term outcome after interferon therapy in elderly patients with chronic hepatitis C. Intervirology. 2007;50:16–23.PubMedCrossRef
31.
go back to reference Huang CF, Yang JF, Dai CY, et al. Efficacy and safety of pegylated interferon combination with ribavirin for the treatment of older patients with chronic hepatitis C. J Infect Dis. 2010;201:751–9.PubMedCrossRef Huang CF, Yang JF, Dai CY, et al. Efficacy and safety of pegylated interferon combination with ribavirin for the treatment of older patients with chronic hepatitis C. J Infect Dis. 2010;201:751–9.PubMedCrossRef
32.
go back to reference Honda T, Katano Y, Shimizu J, et al. Efficacy of peginterferon-alpha-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C. Liver Int. 2010;30:527–37.PubMedCrossRef Honda T, Katano Y, Shimizu J, et al. Efficacy of peginterferon-alpha-2b plus ribavirin in patients aged 65 years and older with chronic hepatitis C. Liver Int. 2010;30:527–37.PubMedCrossRef
33.
go back to reference Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006;131:997–1002.PubMedCrossRef Reesink HW, Zeuzem S, Weegink CJ, et al. Rapid decline of viral RNA in hepatitis C patients treated with VX-950: a phase Ib, placebo-controlled, randomized study. Gastroenterology. 2006;131:997–1002.PubMedCrossRef
34.
go back to reference Suzuki F, Suzuki Y, Sezaki H, et al. Exploratory study on telaprevir given every 8 h at 500 mg or 750 mg with peginterferon-alpha-2b and ribavirin in hepatitis C patients. Hepatol Res. 2013;43:691–701. doi:10.1111/hepr.12009.PubMedCrossRef Suzuki F, Suzuki Y, Sezaki H, et al. Exploratory study on telaprevir given every 8 h at 500 mg or 750 mg with peginterferon-alpha-2b and ribavirin in hepatitis C patients. Hepatol Res. 2013;43:691–701. doi:10.​1111/​hepr.​12009.PubMedCrossRef
Metadata
Title
Predictive value of the IFNL4 polymorphism on outcome of telaprevir, peginterferon, and ribavirin therapy for older patients with genotype 1b chronic hepatitis C
Authors
Hatsue Fujino
Michio Imamura
Yuko Nagaoki
Yoshiiku Kawakami
Hiromi Abe
C. Nelson Hayes
Hiromi Kan
Takayuki Fukuhara
Tomoki Kobayashi
Keiichi Masaki
Atsushi Ono
Takashi Nakahara
Youji Honda
Noriaki Naeshiro
Ayako Urabe
Satoe Yokoyama
Daisuke Miyaki
Eisuke Murakami
Tomokazu Kawaoka
Nobuhiko Hiraga
Masataka Tsuge
Akira Hiramatsu
Hideyuki Hyogo
Hiroshi Aikata
Shoichi Takahashi
Daiki Miki
Hidenori Ochi
Waka Ohishi
Kazuaki Chayama
Hiroshima Liver Study Group
Publication date
01-12-2014
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 12/2014
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-013-0924-9

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