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Liver-related events after direct-acting antiviral therapy in patients with hepatitis C virus-associated cirrhosis

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

Background

Direct-acting antiviral (DAA) therapy enables a high rate of sustained virologic response (SVR) in patients with hepatitis C virus associated cirrhosis. However, the impact of DAA therapy on liver-related events in patients with cirrhosis is unclear.

Methods

A total of 350 patients with compensated and decompensated cirrhosis administered DAA therapy at 29 Japanese hospitals were enrolled (Child–Pugh class A [CP-A]: 195 patients, CP-B: 131 patients and CP-C: 24 patients).

Results

The SVR rates of patients with CP-A, CP-B and CP-C were 96.9%, 93.1% and 83.3%, respectively (p = 0.006). Seventy patients developed hepatocellular carcinoma (HCC), and male sex, previous HCC treatment, platelet counts < 10.0 × 104/µl, alpha-fetoprotein levels ≥ 5.0 ng/ml and CP-C were identified as significant factors in the multivariate analysis. The cumulative HCC occurrence/recurrence rates at 1 year were 6.6%/45.2%. The cumulative rate of decompensated cirrhotic events requiring hospital admission at 1 year was 9.1%. In the multivariate analysis, CP-B and CP-C were identified as significant factors. During the median observation period of 14.9 months, 13 patients died and one patient received liver transplant. The overall survival rates at 1 year were 98.4% in patients with CP-A, 96.4% in those with CP-B and 85.6% in those with CP-C (CP-A vs. CP-B: p = 0.759, CP-A vs. CP-C: p = 0.001 and CP-B vs. CP-C: p = 0.005).

Conclusions

HCC development and mortality in patients with CP-B were not different from those with CP-A. On the other hand, in patients with CP-C, the development of HCC and decompensated cirrhotic events requiring hospital admission, and death were frequent.

Trial registration

University Hospital Medical Information Network (UMIN000036150).

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Abbreviations

HCV:

Hepatitis C virus

DAA:

Direct-acting antiviral

SVR:

Sustained virologic response

HCC:

Hepatocellular carcinoma

SOF:

Sofosbuvir

VEL:

Velpatasvir

RBV:

Ribavirin

MELD:

Model for end-stage liver disease

CP:

Child–Pugh

GLE:

Glecaprevir

PIB:

Pibrentasvir

EBR:

Elbasvir

GZR:

Grazoprevir

LDV:

Ledipasvir

EOT:

End of treatment

SBP:

Spontaneous bacterial peritonitis

INR:

International normalization ratio

ALT:

Alanine aminotransferase

AFP:

Alpha-fetoprotein

HR:

Hazard ratio

HVPG:

Hepatic venous pressure gradient

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Acknowledgements

The authors thank Yoshito Uchida (Department of Gastroenterology and Hepatology, Saitama Medical University), Shinnya Maekawa (First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi), Sawako Uchida (Department of Hepatology, Graduate School of Medicine, Osaka City University), Shun Kaneko (Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital), Kotaro Kumagai (Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medicine and Dental Sciences), Hiroaki Takatani (Department of Gastroenterology, Nara Medical University), Hidekatsu Kuroda (Division of Hepatology, Deportment of Internal Medicine, Iwate Medical University), Yohei Koizumi (Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine), Masanori Fukushima (Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences), Masato Nakamura (Department of Gastroenterology, Graduate School of Medicine, Chiba University), Kazuo Okumoto (Department of Gastroenterology, Faculty of Medicine, Yamagata University), Kazumasa Tajima (Clinical Research Center, National Hospital Organization Nagasaki Medical Center), Yuya Seko (Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine), Tatsuya Minami (Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo), Takuro Hisanaga (Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine), Tatsushi Naito (Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui), Miyako Murakawa (Department of Gastroenterology and Hepatology, Department of Liver Disease Control, Tokyo Medical and Dental University), Yosuke Osawa (The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine), Atsunori Tsuchiya (Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University) and Tatsunori Hanai (Department of Gastroenterology/Internal Medicine Gifu University Graduate School of Medicine) for data collection and Rina Okada (Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine) and Hiroyuki Araki (Osaka University Graduate School of Medicine Department of Biostatistics and Data Science) for data management.

Funding

This work was partially supported by Gilead Sciences, Inc. and a Grant-in-Aid for Research from the Japan Agency for Medical Research and Development (JP20fk0210058).

Author information

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, Hayato Hikita, Ryotaro Sakamori, Ryoko Yamada, Takahiro Kodama, Tomohide Tatsumi & Tetsuo Takehara

  2. Department of Gastroenterology and Hepatology, Saitama Medical University, Saitama, Japan

    Satoshi Mochida

  3. First Department of Internal Medicine, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan

    Nobuyuki Enomoto

  4. Department of Hepatology, Graduate School of Medicine, Osaka City University, Osaka, Japan

    Norifumi Kawada

  5. Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan

    Masayuki Kurosaki

  6. Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, Japan

    Akio Ido

  7. Department of Gastroenterology and Metabolism, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan

    Daiki Miki

  8. Department of Gastroenterology, Nara Medical University, Nara, Japan

    Hitoshi Yoshiji

  9. Division of Hepatology, Department of Internal Medicine, Iwate Medical University, Iwate, Japan

    Yasuhiro Takikawa

  10. Department of Gastroenterology and Metabology, Ehime University Graduate School of Medicine, Ehime, Japan

    Yoichi Hiasa

  11. Department of Gastroenterology and Hepatology, Nagasaki University of Graduate School of Biomedical Sciences, Nagasaki, Japan

    Kazuhiko Nakao

  12. Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Naoya Kato

  13. Department of Gastroenterology, Faculty of Medicine, Yamagata University, Yamagata, Japan

    Yoshiyuki Ueno

  14. Clinical Research Center, National Hospital Organization Nagasaki Medical Center, Nagasaki, Japan

    Hiroshi Yatsuhashi

  15. Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Yoshito Itoh

  16. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    Ryosuke Tateishi

  17. Department of Gastroenterology and Hepatology, Graduate School of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan

    Goki Suda

  18. Department of Gastroenterology and Hepatology, Yamaguchi University Graduate School of Medicine, Ube, Yamaguchi, Japan

    Taro Takami

  19. Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Fukui, Japan

    Yasunari Nakamoto

  20. Department of Gastroenterology and Hepatology, Department of Liver Disease Control, Tokyo Medical and Dental University, Tokyo, Japan

    Yasuhiro Asahina

  21. Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Kentaro Matsuura

  22. Department of General Medicine, Kanazawa University Hospital, Kanazawa, Japan

    Taro Yamashita

  23. The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Chiba, Japan

    Tatsuya Kanto

  24. Department of Hepatology, Toranomon Hospital, Tokyo, Japan

    Norio Akuta

  25. Division of Gastroenterology and Hepatology, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, Japan

    Shuji Terai

  26. Department of Gastroenterology/Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan

    Masahito Shimizu

  27. Department of Gastroenterology, Kasugai Municipal Hospital, Kasugai, Japan

    Satoshi Sobue

  28. Department of Gastroenterology, Toyokawa City Hospital, Toyokawa, Japan

    Tomokatsu Miyaki

  29. Department of Gastroenterology, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan

    Akihiro Moriuchi

  30. Department of Medical Innovation, Osaka University Hospital, Suita, Osaka, Japan

    Tomomi Yamada

Authors
  1. Yuki Tahata
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  2. Hayato Hikita
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  3. Satoshi Mochida
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Contributions

Yuki Tahata, Hayato Hikita and Tetsuo Takehara contributed to the study concept and design, interpretation of the data and drafting of the manuscript. Yuki Tahata and Tomomi Yamada contributed to data analysis. All authors contributed to data collection and approved the final version of the manuscript.

Corresponding author

Correspondence to Tetsuo Takehara.

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Conflict of interest

Satoshi Mochida received research grants from Janssen Pharmaceutical K. K., EA Pharma Co, Ltd., MIC Medical Corp., AbbVie GK, EPS International Holdings Co., Ltd. and Gilead Sciences, Inc. and scholarship grants from Toray Industries Inc, AbbVie GK, ASKA Pharmaceutical Co., Ltd, Eisai Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd and EA Pharma Co., Ltd. and is on the speakers’ bureau for MSD K. K, Gilead Sciences, Inc, Toray Industries Inc, AbbVie GK, Sumitomo Dainippon Pharma Co., Ltd, Eisai Co., Ltd, Otsuka Pharmaceutical Co., Ltd and ASKA Pharmaceutical., Ltd. Norifumi Kawada received research grants from Takeda Pharmaceutical Company Limited, Chugai Pharmaceutical Co., Ltd, AstraZeneca plc, MSD co., Ltd, Gilead Sciences, Inc, GlaxoSmithKline plc and Bristol Myers Squibb. and scholarship grants from AbbVie GK, Otsuka Pharmaceutical Co., Ltd and Eisai Co., Ltd. and is on the speakers’ bureau for AbbVie GK, MSD Co., Ltd and Gilead Sciences, Inc. Masayuki Kurosaki is on the speakers’ bureau for Gilead Sciences, Inc and AbbVie GK. Hitoshi Yoshiji received research grants from AbbVie GK, Otsuka Pharmaceutical Co., Ltd and Asuka Pharmaceutical Co., Ltd. and is on the speakers’ bureau for Gilead Sciences, Inc, Otsuka Pharmaceutical Co., Ltd, Sumitomo Dainippon Pharma Co., Ltd, Asuka Pharmaceutical Co., Ltd and AbbVie GK. Naoya Kato received scholarship grants from Gilead Sciences, Inc. and is on the speakers’ bureau for Gilead Sciences, Inc. Yoshiyuki Ueno received scholarship grants from AbbVie GK, EA Pharma and Otsuka Pharmatheutical and is on the speakers’ bureau for EA Pharma, AbbVie GK. and Otsuka Pharmaceutical. Hiroshi Yatsuhashi received research grants from AbbVie GK. Yoshito Itoh received research grants from MSD, Gilead Sciences Inc and Bristol-Myers Squibb Company and scholarship grants from Bristol-Myers Squibb Company, AbbVie GK and MSD and is on the speakers’ bureau for AbbVie GK, Gilead Sciences, Inc. and MSD. Goki Suda received research grants from Gilead Sciences, Inc. Taro Takami belongs to a donation-funded department funded by SHIBUYA Corporation. Yasuhiro Asahina belongs to a donation-funded department funded by Gilead Sciences, Inc., AbbVie GK, Toray Industries Inc and Fujirebio Inc. Tatsuya Kanto is on the speakers’ bureau for Gilead Sciences, Inc.and AbbVie GK. Norio Akuta is on the speakers’ bureau for AbbVie GK, Gilead Sciences, Inc. and Mitsubishi Tanabe Pharma Corporation. Shuji Terai received research grants from Intersterm Routo, Asuka, Tsumura, Abbot, Toso, Sysmex, Kowa, Stemrim, Towa, Gilead, Chiome, Shionogi, Niohonseiyaku, Kyowa and BioMimetics Sympathies and scholarship grants from AbbVie, Dainipponsumitomo, Aasakikasei, Niohokkayaku, Eisai, EA pharma, Boston and Takeda and is on the speakers’ bureau for Otsuka, Gilead, Takeda, Asuka, MSD and DaiichiSankyo. Tetsuo Takehara received research grants from Gilead Sciences, Inc., MSD, AbbVie GK. and Chugai Pharmaceutical Co., Ltd. and is on the speakers’ bureau for Gilead Sciences, Inc., AbbVie GK and MSD. All other authors declare that they have no conflicts of interest to disclose.

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535_2021_1845_MOESM2_ESM.tif

Supplementary Fig. 1. Treatment completion rates and SVR rates according to Child–Pugh class. A Treatment completion rates. B SVR rates. The Cochran-Armitage test was used to analyze treatment completion rates and SVR rates according to CP class. Abbreviations: CP, Child–Pugh; SVR, sustained virologic response (TIF 867 KB)

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Tahata, Y., Hikita, H., Mochida, S. et al. Liver-related events after direct-acting antiviral therapy in patients with hepatitis C virus-associated cirrhosis. J Gastroenterol 57, 120–132 (2022). https://doi.org/10.1007/s00535-021-01845-5

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