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The impact of an inosine triphosphate pyrophosphatase genotype on bilirubin increase in chronic hepatitis C patients treated with simeprevir, pegylated interferon plus ribavirin

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

Hyperbilirubinemia, mild or moderate, is a commonly observed laboratory abnormality in chronic hepatitis C patients treated with simeprevir with pegylated interferon (Peg-IFN) plus ribavirin. In this prospective, multicenter study, we aimed to investigate the clinical features and factors associated with bilirubin increases during the therapy.

Methods

A total of 192 patients with chronic hepatitis C who were treated with simeprevir with Peg-IFN plus ribavirin were analyzed.

Results

The mean serum bilirubin level increased significantly during the initial 12 weeks of simeprevir administration and peaked at 2 weeks after the administration. Hyperbilirubinemia of more than 2 mg/dl developed in 18 % of the patients; in 85 % of those patients, the bilirubin levels peaked within 6 weeks and gradually decreased thereafter. A univariable analysis revealed that an increase in serum total bilirubin of 1.0 mg/dl or more from baseline was significantly associated with the sex, red blood cell count, serum hemoglobin level, serum alanine aminotransferase level, serum creatinine level and inosine triphosphate pyrophosphatase (ITPA) genotype. In the multivariable analysis, the ITPA genotype (CC odds ratio 4.990, p = 0.011) was found to be the only independent factor. Consistent with this result, there was a significant correlation between hyperbilirubinemia and the degree of hemolytic anemia.

Conclusions

Hyperbilirubinemia develops at early time points after simeprevir administration in most cases and is dependent on the ITPA genotype. Careful attention should be paid to hyperbilirubinemia, which occurs at later time points or in patients with an ITPA non-CC genotype so that a diagnosis of liver damage with hyperbilirubinemia is not missed.

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Abbreviations

SMV:

Simeprevir

HCV:

Hepatitis C virus

Peg-IFN:

Pegylated interferon

RBV:

Ribavirin

CH-C:

Chronic hepatitis C

Plt:

Platelet

WBC:

White blood cell

Hb:

Hemoglobin

IL-28B:

Interleukin-28B

ITPA:

Inosine triphosphate pyrophosphatase

ALT:

Alanine aminotransferase

BMI:

Body mass index

RBC:

Red blood cell

OR:

Odds ratio

SVR:

Sustained virologic response

SOF:

Sofosbuvir

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Acknowledgments

Other institutions and participants in the Osaka Liver Forum include the following: Kinki Central Hospital of Mutual Aid Association of Public School Teachers, E. Hayashi; Yao Municipal Hospital, H. Fukui; NTT West Osaka Hospital, A. Kaneko; Osaka Police Hospital, M. Oshita; Sumitomo Hospital, A. Yamada; Higashi Osaka General Hospital, S. Iio; Itami city Hospital, Y. Saji; Saiseikai Senri Hosptial, K. Suzuki; Hyogo Prefectural Nishinomiya Hospital, Y. Inui; Otemae Hospital, Y. Doi; Suita Municipal Hospital, T. Nagase; Ashiya Municipal Hospital, A. Takeda; Nishinomiya Municipal Central Hospital, H. Ogawa; Izumiotsu Municipal Hospital, S. Yamagata; 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 from the Ministry of Health Labor and Welfare of Japan and Scientific Research from the Ministry of Education, Science, and Culture of Japan.

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    Authors and Affiliations

    1. Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

      Yuki Tahata, Naoki Hiramatsu, Tsugiko Oze, Naoki Morishita, Naoki Harada, Ryoko Yamada, Takayuki Yakushijin, Hayato Hikita, Ryotaro Sakamori, Takuya Miyagi, Yuichi Yoshida, Tomohide Tatsumi & Tetsuo Takehara

    2. National Hospital Organization Osaka National Hospital, Osaka, Osaka, Japan

      Eiji Mita

    3. Kansai Rousai Hospital, Amagasaki, Hyogo, Japan

      Hideki Hagiwara & Norio Hayashi

    4. Kaizuka City Hospital, Kaizuka, Osaka, Japan

      Yukinori Yamada

    5. Japan Community Health Care Organization Osaka Hospital, Osaka, Osaka, Japan

      Toshifumi Ito

    6. National Hospital Organization Osaka Minami Medical Center, Kawachinagano, Osaka, Japan

      Taizo Hijioka

    7. Toyonaka Municipal Hospital, Toyonaka, Osaka, Japan

      Masami Inada

    8. Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Osaka, Japan

      Kazuhiro Katayama

    9. Minoh City Hospital, Minoh, Osaka, Japan

      Shinji Tamura

    10. Osaka Rousai Hospital, Sakai, Osaka, Japan

      Harumasa Yoshihara

    11. Osaka General Medical Center, Osaka, Osaka, Japan

      Atsuo Inoue

    12. Ikeda Municipal Hospital, Ikeda, Osaka, Japan

      Yasuharu Imai & Keiko Irishio

    13. National Hospital Organization Minami Wakayama Medical Center, Tanabe, Wakayama, Japan

      Michio Kato

    14. Department of Innovative Clinical Trials and Data Science, Osaka University Graduate School of Medicine, Suita, Osaka, Japan

      Toshimitsu Hamasaki

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    1. Yuki Tahata
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    Corresponding author

    Correspondence to Naoki Hiramatsu.

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    Conflict of interest

    Prof. Tetsuo Takehara received a research grant from Janssen Pharmaceutical K.K., Merck Sharp & Dohme K.K. Co., Ltd. and Chugai Pharmaceutical Co., Ltd.

    Additional information

    Y. Tahata and N. Hiramatsu contributed equally to this work and share first authorship.

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    Tahata, Y., Hiramatsu, N., Oze, T. et al. The impact of an inosine triphosphate pyrophosphatase genotype on bilirubin increase in chronic hepatitis C patients treated with simeprevir, pegylated interferon plus ribavirin. J Gastroenterol 51, 252–259 (2016). https://doi.org/10.1007/s00535-015-1105-9

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    • DOI: https://doi.org/10.1007/s00535-015-1105-9

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