Journal of Gastroenterology

, Volume 47, Issue 3, pp 334–342 | Cite as

Reducing Peg-IFN doses causes later virologic response or no response in HCV genotype 1 patients treated with Peg-IFN alfa-2b plus ribavirin

  • Tsugiko Oze
  • Naoki Hiramatsu
  • Changho Song
  • Takayuki Yakushijin
  • Sadaharu Iio
  • Yoshinobu Doi
  • Masahide Oshita
  • Hideki Hagiwara
  • Eiji Mita
  • Toshifumi Ito
  • Yoshiaki Inui
  • Taizo Hijioka
  • Shinji Tamura
  • Harumasa Yoshihara
  • Atsuo Inoue
  • Yasuharu Imai
  • Eijiro Hayashi
  • Michio Kato
  • Masanori Miyazaki
  • Atsushi Hosui
  • Takuya Miyagi
  • Yuichi Yoshida
  • Tomohide Tatsumi
  • Shinichi Kiso
  • Tatsuya Kanto
  • Akinori Kasahara
  • Norio Hayashi
  • Tetsuo Takehara
Original Article—Liver, Pancreas, and Biliary Tract
First Online:
Received:
Accepted:

Abstract

Background

The timing to the first undetectable hepatitis C virus (HCV) RNA level is strongly associated with sustained virologic response in pegylated interferon (Peg-IFN) plus ribavirin combination therapy for patients with chronic hepatitis C (CH-C) with genotype 1. This study was conducted to clarify the impact of drug exposure to Peg-IFN on the timing of HCV RNA negativity in Peg-IFN plus ribavirin combination therapy for CH-C patients with genotype 1.

Methods

A total of 1409 patients treated with Peg-IFN alfa-2b plus ribavirin were enrolled and classified into four categories according to the Peg-IFN dosage. Furthermore, 100 patients were extracted from each Peg-IFN dosage category to adjust for characteristic factors, using the propensity score method.

Results

Peg-IFN exposure was dose-dependently associated with the timing of HCV RNA negativity (p ≤ 0.001). The HCV RNA negative rate at week 4 decreased from 12% with a Peg-IFN dose of >1.5 μg/kg/week to 1–3% with a dose of <1.5 μg/kg/week (p ≤ 0.001), and at week 12 the rate had decreased from 44% with a dose of ≥1.2 μg/kg/week to 18% with a dose of <1.2 μg/kg/week (p = 0.001). Treatment failure (patients without a 1-log decrease of HCV RNA at week 4 or a 2-log decrease of HCV RNA at week 12, or positive at week 24) was found in 54–66% of patients given <1.2 μg/kg/week (p ≤ 0.001), and these patients accounted for 64% of the non-responders.

Conclusions

The timing of HCV RNA negativity depends significantly on the Peg-IFN dose. Reducing the Peg-IFN dose can induce a later virologic response or non-response in HCV genotype 1 patients treated with Peg-IFN plus ribavirin.

Keywords

Chronic hepatitis C Pegylated interferon plus ribavirin Drug adherence HCV RNA negativity Propensity score matched study 
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Notes

Acknowledgments

Other institutions and participants in the Osaka Liver Forum are: Osaka Medical Center for Cancer and Cardiovascular Diseases, K Katayama and K Imanaka; Sumitomo Hospital, A Yamada; Itami City Hospital, T Kitada; Toyonaka Municipal Hospital, M Inada; Yao Municipal Hospital, H Fukui; Suita Municipal Hospital, T Nagase; NTT West Osaka Hospital, A Kaneko; National Hospital Organization Minami Wakayama Medical Center, K Fujimoto; Nishinomiya Municipal Central Hospital, H Ogawa; Saiseikai Senri Hospital, K Suzuki; Osaka Kaisei Hospital, N Imaizumi; Kano General Hospital, S Kubota; Saso Hospital, M Nishiuchi; and Meiwa Hospital, Y Hayakawa. This work was supported by a Grant-in-Aid for Research on Hepatitis and BSE from the Ministry of Health, Labour, and Welfare of Japan, and by a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.

Conflict of interest

Professor Tetsuo Takehara received scholarship funds from Merck Sharp & Dohme K. K. Co., Ltd, and Chugai Pharmaceutical Co., Ltd. Dr. Tatsuya Kanto has an affiliation with a donation-funded department from Merck Sharp & Dohme K. K. Co., Ltd.

References

  1. 1.
    Manns MP, McHutchison JG, Gordon SC, Rustgi VK, Shiffman M, Reindollar R, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958–65.PubMedCrossRefGoogle Scholar
  2. 2.
    Fried MW, Shiffman ML, Reddy KR, Smith C, Marinos G, Goncales FL Jr, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975–82.PubMedCrossRefGoogle Scholar
  3. 3.
    McHutchison JG, Lawitz EJ, Shiffman ML, Muir AJ, Galler GW, McCone J, et al. Peginterferon alfa-2b or alfa-2a with ribavirin for treatment of hepatitis C infection. N Engl J Med. 2009;361:580–93.PubMedCrossRefGoogle Scholar
  4. 4.
    Jensen DM, Morgan TR, Marcellin P, Pockros PJ, Reddy KR, Hadziyannis SJ, et al. Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy. Hepatology. 2006;43:954–60.PubMedCrossRefGoogle Scholar
  5. 5.
    Mangia A, Minerva N, Bacca D, Cozzolongo R, Ricci GL, Carretta V, et al. Individualized treatment duration for hepatitis C genotype 1 patients: a randomized controlled trial. Hepatology. 2008;47:43–50.PubMedCrossRefGoogle Scholar
  6. 6.
    Yu ML, Dai CY, Huang JF, Chiu CF, Yang YH, Hou NJ, et al. Rapid virological response and treatment duration for chronic hepatitis C genotype 1 patients: a randomized trial. Hepatology. 2008;47:1884–93.PubMedCrossRefGoogle Scholar
  7. 7.
    Berg T, von Wagner M, Nasser S, Sarrazin C, Heintges T, Gerlach T, et al. Extended treatment duration for hepatitis C virus type 1: comparing 48 versus 72 weeks of peginterferon-alfa-2a plus ribavirin. Gastroenterology. 2006;130:1086–97.PubMedCrossRefGoogle Scholar
  8. 8.
    Pearlman BL, Ehleben C, Saifee S. Treatment extension to 72 weeks of peginterferon and ribavirin in hepatitis C genotype 1-infected slow responders. Hepatology. 2007;46:1688–94.PubMedCrossRefGoogle Scholar
  9. 9.
    Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645–52.PubMedCrossRefGoogle Scholar
  10. 10.
    McHutchison JG, Manns M, Patel K, Poynard T, Lindsay KL, Trepo C, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Shiffman ML, Ghany MG, Morgan TR, Wright EC, Everson GT, Lindsay KL, et al. Impact of reducing peginterferon alfa-2a and ribavirin dose during retreatment in patients with chronic hepatitis C. Gastroenterology. 2007;132:103–12.PubMedCrossRefGoogle Scholar
  12. 12.
    Reddy KR, Shiffman ML, Morgan TR, Zeuzem S, Hadziyannis S, Hamzeh FM, et al. Impact of ribavirin dose reductions in hepatitis C virus genotype 1 patients completing peginterferon alfa-2a/ribavirin treatment. Clin Gastroenterol Hepatol. 2007;5:124–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Oze T, Hiramatsu N, Yakushijin T, Kurokawa M, Igura T, Mochizuki K, et al. Pegylated interferon alpha-2b (Peg-IFN alpha-2b) affects early virologic response dose-dependently in patients with chronic hepatitis C genotype 1 during treatment with Peg-IFN alpha-2b plus ribavirin. J Viral Hepat. 2009;16:578–85.PubMedCrossRefGoogle Scholar
  14. 14.
    Hiramatsu N, Oze T, Yakushijin T, Inoue Y, Igura T, Mochizuki K, et al. Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin. J Viral Hepat. 2009;16:586–94.PubMedCrossRefGoogle Scholar
  15. 15.
    Oze T, Hiramatsu N, Yakushijin T, Mochizuki K, Oshita M, Hagiwara H, et al. Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy. J Hepatol. 2011;54:604–11.PubMedCrossRefGoogle Scholar
  16. 16.
    Inoue Y, Hiramatsu N, Oze T, Yakushijin T, Mochizuki K, Hagiwara H, et al. Factors affecting efficacy in patients with genotype 2 chronic hepatitis C treated by pegylated interferon alpha-2b and ribavirin: reducing drug doses has no impact on rapid and sustained virological responses. J Viral Hepat. 2010;17:336–44.PubMedCrossRefGoogle Scholar
  17. 17.
    Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461:399–401.PubMedCrossRefGoogle Scholar
  18. 18.
    Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML, et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–4.PubMedCrossRefGoogle Scholar
  19. 19.
    Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, 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.PubMedCrossRefGoogle Scholar
  20. 20.
    Lindsay KL, Trepo C, Heintges T, Shiffman ML, Gordon SC, Hoefs JC, et al. A randomized, double-blind trial comparing pegylated interferon alfa-2b to interferon alfa-2b as initial treatment for chronic hepatitis C. Hepatology. 2001;34:395–403.PubMedCrossRefGoogle Scholar
  21. 21.
    Fried MW, Jensen DM, Rodriguez-Torres M, Nyberg LM, Di Bisceglie AM, Morgan TR, et al. Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alpha-2a and ribavirin. Hepatology. 2008;48:1033–43.PubMedCrossRefGoogle Scholar
  22. 22.
    Roberts SK, Weltman MD, Crawford DH, McCaughan GW, Sievert W, Cheng WS, et al. Impact of high-dose peginterferon alfa-2A on virological response rates in patients with hepatitis C genotype 1: a randomized controlled trial. Hepatology. 2009;50:1045–55.PubMedCrossRefGoogle Scholar
  23. 23.
    Reddy KR, Shiffman ML, Rodriguez-Torres M, Cheinquer H, Abdurakhmanov D, Bakulin I, et al. Induction pegylated interferon alfa-2a and high dose ribavirin do not increase SVR in heavy patients with HCV genotype 1 and high viral loads. Gastroenterology. 2010;139:1972–83.PubMedCrossRefGoogle Scholar
  24. 24.
    Oze T, Hiramatsu N, Yakushijin T, Mochizuki K, Imanaka K, Yamada A, et al. The efficacy of extended treatment with pegylated interferon plus ribavirin in patients with HCV genotype 1 and slow virologic response in Japan. J Gastroenterol. 2011;46:944–52.PubMedCrossRefGoogle Scholar

Copyright information

© Springer 2011

Authors and Affiliations

  • Tsugiko Oze
    • 1
  • Naoki Hiramatsu
    • 1
  • Changho Song
    • 1
  • Takayuki Yakushijin
    • 1
  • Sadaharu Iio
    • 2
  • Yoshinobu Doi
    • 3
  • Masahide Oshita
    • 4
  • Hideki Hagiwara
    • 5
  • Eiji Mita
    • 6
  • Toshifumi Ito
    • 7
  • Yoshiaki Inui
    • 8
  • Taizo Hijioka
    • 9
  • Shinji Tamura
    • 10
  • Harumasa Yoshihara
    • 11
  • Atsuo Inoue
    • 12
  • Yasuharu Imai
    • 13
  • Eijiro Hayashi
    • 14
  • Michio Kato
    • 15
  • Masanori Miyazaki
    • 1
  • Atsushi Hosui
    • 1
  • Takuya Miyagi
    • 1
  • Yuichi Yoshida
    • 1
  • Tomohide Tatsumi
    • 1
  • Shinichi Kiso
    • 1
  • Tatsuya Kanto
    • 1
  • Akinori Kasahara
    • 1
  • Norio Hayashi
    • 5
  • Tetsuo Takehara
    • 1
  1. 1.Department of Gastroenterology and HepatologyOsaka University Graduate School of MedicineSuitaJapan
  2. 2.Higashiosaka City Central HospitalHigashiosakaJapan
  3. 3.Otemae HospitalOsakaJapan
  4. 4.Osaka Police HospitalOsakaJapan
  5. 5.Kansai Rosai HospitalAmagasakiJapan
  6. 6.National Hospital Organization Osaka National HospitalOsakaJapan
  7. 7.Osaka Koseinenkin HospitalOsakaJapan
  8. 8.Hyogo Prefectural Nishinomiya HospitalNishinomiyaJapan
  9. 9.National Hospital Organization Osaka Minami Medical CenterKawachinaganoJapan
  10. 10.Minoh City HospitalMinohJapan
  11. 11.Osaka Rosai HospitalSakaiJapan
  12. 12.Osaka General Medical CenterOsakaJapan
  13. 13.Ikeda Municipal HospitalIkedaJapan
  14. 14.Kinki Central Hospital of Mutual Aid Association of Public School TeachersItamiJapan
  15. 15.National Hospital Organization Minami Wakayama Medical CenterTanabeJapan

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