Skip to main content

Advertisement

SpringerLink
Log in

Nationwide prospective and retrospective surveys for hepatitis B virus reactivation during immunosuppressive therapies

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

The significance of HBV reactivation during immunosuppressive therapy was evaluated in three nationwide cohorts including patients with previously resolved HBV (prHBV) infection.

Methods

The clinical features of 1061 patients with acute liver failure (ALF) or late-onset hepatic failure (LOHF) were retrospectively examined, focusing on those who experienced HBV reactivation. Additionally, 420 patients with prHBV infection were prospectively enrolled: 203 received immunosuppressive therapies immediately after enrollment, while the remaining 217 were enrolled after having received immunosuppressive therapies without the occurrence of HBV reactivation. The serum HBV-DNA levels were prospectively monitored every month, and the incidences of HBV reactivation, defined as a serum HBV-DNA level of 1.3 log IU/ml or more, were evaluated.

Results

In the retrospective study, persistent HBV infection was found in 90 patients, and HBV reactivation was responsible for liver injuries in 50 patients including 23 receiving immunosuppressive therapies (26 with HBs-antigen positivity, 7 with prHBV infection). None of seven patients with prHBV infection were rescued. In the prospective studies, HBV reactivation occurred in ten patients, but preemptive entecavir administration prevented liver injury. The cumulative reactivation rate was 3.2 % at 6 months, and the increase of the rate compared to that at 6 months was +1.5 % at 48 months.

Conclusions

HBV reactivation during immunosuppression was responsible for liver injuries in a quarter of the ALF/LOHF patients with persistent HBV infection. Early serum HBV-DNA monitoring may improve patient prognosis, since HBV reactivation typically occurs within 6 months of the start of immunosuppressive therapies in patients with prHBV infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. World Health Organization. Hepatitis: fact sheet N°204, July 2015. www.who.int/mediacentre/factsheets/fs204/en/.

  2. Perz JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer world wide. J Hepatol. 2006;45:529–38.

    Article  PubMed  Google Scholar 

  3. Tanaka J, Kumagai J, Katayama K, et al. Sex- and age-specific carriers of hepatitis B and C virus in Japan estimated by the prevalence in the 3,485,648 first-time blood donors during 1995–2000. Intervirol. 2004;47:32–40.

    Article  Google Scholar 

  4. Kusumoto S, Tanaka Y, Mizokami M, et al. Reactivation of hepatitis B virus following systemic chemotherapy for malignant lymphoma. Int J Hematol. 2009;90:13–23.

    Article  CAS  PubMed  Google Scholar 

  5. Wands JR, Chura CM, Roll FJ, et al. Serial studies of hepatitis-associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders. Gastroenterology. 1975;68:105–12.

    CAS  PubMed  Google Scholar 

  6. Lok AS, Liang RH, Chiu EK, et al. Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology. 1991;100:182–8.

    Article  CAS  PubMed  Google Scholar 

  7. Uemoto S, Sugiyama K, Marusawa H, et al. Transmission of hepatitis B virus from hepatitis B core antibody-positive donors in living related liver transplants. Transplantation. 1998;65:494–9.

    Article  CAS  PubMed  Google Scholar 

  8. Dervite I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab. N Engl J Med. 2001;344:68–9.

    Article  CAS  PubMed  Google Scholar 

  9. Barone M, Notarnicola A, Lopalco G, et al. Safety of long-term biologic therapy in rheumatologic patients with a previously resolved hepatitis B viral infection. Hepatology. 2015;62:40–6.

    Article  CAS  PubMed  Google Scholar 

  10. Urata Y, Uesato R, Tanaka D, et al. Prevalence of reactivation of hepatitis B virus replication in rheumatoid arthritis patients. Mod Rheumatol. 2011;21:16–23.

    Article  CAS  PubMed  Google Scholar 

  11. Mori S. Past hepatitis B infection in rheumatoid arthritis patients receiving biologic and/or nonbiologic disease-modifying antirheumatic drugs. Mod Rheumatol. 2011;21:621–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tamori A, Koike T, Goto H, et al. Prospective study of reactivation of hepatitis B in patients with rheumatoid arthritis who received immunosuppressive therapy: evaluation of both HBsAg-positive and HBsAg-negative cohorts. J Gastroenterol. 2011;46:556–64.

    Article  CAS  PubMed  Google Scholar 

  13. Oketani M, Ido A, Uto H, et al. Prevention of hepatitis B virus reactivation in patients receiving immunosuppressive therapy or chemotherapy. Hepatol Res. 2012;42:627–36.

    Article  CAS  PubMed  Google Scholar 

  14. Drafting Committee for Hepatitis Management Guidelines and the Japan Society of Hepatology. JSH guidelines for the management of hepatitis B virus infection. Hepatol Res. 2014;44(Suppl S1):1–58.

    Article  Google Scholar 

  15. Mochida S, Takikawa Y, Nakayama N, et al. Diagnostic criteria of acute liver failure: a report by the intractable hepato-biliary diseases study group of Japan. Hepatol Res. 2011;41:805–12.

    Article  PubMed  Google Scholar 

  16. Sugawara K, Nakayama N, Mochida S. Acute liver failure in Japan: definition, classification, and prediction of the outcome. J Gastroenterol. 2012;47:849–61.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Mochida S, Takikawa Y, Nakayama N, et al. Classification of the etiologies of acute liver failure in Japan: a report by the intractable hepato-biliary diseases study group of Japan. Hepatol Res. 2014;44:365–7.

    Article  PubMed  Google Scholar 

  18. Allice T, Cerutti F, Pittaluga F, et al. COBAS AmpliPrep-COBAS TaqMan hepatitis B virus (HBV) test: a novel automated real-time PCR assay for quantification of HBV DNA in plasma. J Clin Microbiol. 2007;45:828–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Fujiwara K, Mochida S, Matsui A, et al. Intractable liver diseases study group of Japan. Fulminant hepatitis and late onset hepatic failure in Japan: summary of 698 patients between 1998 and 2003 analyzed by the annual nationwide survey. Hepatol Res. 2008;38:646–57.

    Article  PubMed  Google Scholar 

  20. Oketani M, Ide A, Nakayama N, et al. Etiology and prognosis of fulminant hepatitis and late-onset hepatic failure in Japan: summary of the annual nationwide survey between 2004 and 2009. Hepatol Res. 2013;43:97–105.

    Article  PubMed  Google Scholar 

  21. Reddy KR, Beavers KL, Hammond SP, et al. American gastroenterological association institute guideline on the prevention and treatment of hepatitis B virus reactivation during immunosuppressive drug therapy. Gastroenterology. 2015;148:215–9.

    Article  CAS  PubMed  Google Scholar 

  22. Dickson RC, Terrault NA, Ishitani M, et al. Protective antibody levels and dose requirements for IV 5 % Nabi hepatitis B immune globulin combined with lamivudine in liver transplantation for hepatitis B-induced end stage liver disease. Liver Transpl. 2006;12:124–33.

    Article  PubMed  Google Scholar 

  23. Knöll A, Boehm S, Hahn J, et al. Long-term surveillance of haematopoietic stem cell recipients with resolved hepatitis B: high risk of viral reactivation even in a recipient with a vaccinated donor. J Viral Hepat. 2007;14:478–83.

    Article  PubMed  Google Scholar 

  24. Nakamoto S, Kanda T, Nakaseko C, et al. Reactivation of hepatitis B virus in hematopoietic stem cell transplant recipients in Japan: efficacy of nucleos(t)ide analogues for prevention and treatment. Int J Mol Sci. 2014;15:21455–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kusumoto S, Tanaka Y, Suzuki R, et al. Monitoring of hepatitis B virus (HBV) DNA and risk of HBV reactivation in B-Cell lymphoma: a prospective observational study. Clin Infect Dis. 2015;61:719–29.

    Article  PubMed  Google Scholar 

  26. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661–2.

    Article  PubMed  Google Scholar 

  27. European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol. 2012;57:399–420.

    Article  Google Scholar 

Download references

Acknowledgments

We thank the doctors for their cooperation in enrolling patients to Parts 2 and 3 (Supplementary Table). This study was performed with the support of the Ministry of Health, Labour and Welfare as an official project by the Intractable Hepato-biliary Diseases Study Group of Japan and by the Research on Hepatitis and BSE.

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Faculty of Medicine, Saitama Medical University, 38 Morohongo, Moroyama-cho, Iruma-gun, Saitama, 350-0495, Japan

    Satoshi Mochida, Masamitsu Nakao, Nobuaki Nakayama, Yoshihito Uchida & Sumiko Nagoshi

  2. Department of Digestive and Lifestyle Related Diseases, Human and Enviromental Sciences, Health Research, Kagoshima University Graduate School of Medicine and Dental Sciences, Kagoshima, Japan

    Akio Ido & Hirohito Tsubouchi

  3. Department of Rheumatology and Applied Immunology, Faculty of Medicine, Saitama Medical University, Saitama, Japan

    Toshihide Mimura

  4. Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

    Masayoshi Harigai

  5. Division of Rheumatic Diseases, National Center for Global Health and Medicine, Tokyo, Japan

    Hiroshi Kaneko

  6. Department of Gastroenterology and Rheumatology, School of Medicine, Fukushima Medical University, Fukushima, Japan

    Hiroko Kobayashi

  7. Department of Dermatology, Saitama Medical University, Saitama, Japan

    Tetsuya Tsuchida

  8. Department of Nephrology, Saitama Medical University, Saitama, Japan

    Hiromichi Suzuki

  9. Department of Nephrology, Teine Keijinkai Hospital, Sapporo, Japan

    Nobuyuki Ura

  10. Department of Hematology, Saitama Medical University, Saitama, Japan

    Yuichi Nakamura & Masami Bessho

  11. Department of Hematology, Nippon Medical School, Tokyo, Japan

    Kazuo Dan

  12. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Science, Nagoya, Japan

    Shigeru Kusumoto

  13. Department of Medical Oncology, International Medical Cnter/Comprehensive Cancer Center, Saitama Medical University, Saitama, Japan

    Yasutsuna Sasaki

  14. Department of Clinical Oncology, Jichi Medical University, Shimotsuke, Japan

    Hirofumi Fujii

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

    Fumitaka Suzuki & Kenji Ikeda

  16. Department of Allergy and Pheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

    Kazuhiko Yamamoto

  17. Department of Medicine, Teikyo University of School of Medicine, Tokyo, Japan

    Hajime Takikawa

  18. The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Japan

    Masashi Mizokami

Authors
  1. Satoshi Mochida
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masamitsu Nakao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Nobuaki Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshihito Uchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sumiko Nagoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Akio Ido
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Toshihide Mimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Masayoshi Harigai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Hiroshi Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hiroko Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Tetsuya Tsuchida
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Hiromichi Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Nobuyuki Ura
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Yuichi Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Masami Bessho
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Kazuo Dan
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Shigeru Kusumoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Yasutsuna Sasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  19. Hirofumi Fujii
    View author publications

    You can also search for this author in PubMed Google Scholar

  20. Fumitaka Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  21. Kenji Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  22. Kazuhiko Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  23. Hajime Takikawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  24. Hirohito Tsubouchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  25. Masashi Mizokami
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Satoshi Mochida.

Ethics declarations

Conflict of interest

Satoshi Mochida has received research grants, speaking fees, or honoraria from Bristol Myers Squibb, Chugai Pharmaceutical Co. Ltd., Dainippon, Mitsubishi Tanabe Pharma Co., MSD K.K., Toray Medical Co. Ltd., Ajinomoto Pharmaceuticals Co. Ltd., and Eisai Co. Ltd. Satoshi Mochida and Yoshihito Uchida have received patent royalties from SRL Inc. Masayoshi Harigai has received research grants from Abbvie Japan Co. Ltd., Astellas Pharma Inc., Chugai Pharmaceutical Co. Ltd., Eisai Co. Ltd., Mitsubishi Tanabe Pharma Co., Ono Pharmaceuticals, Takeda Pharmaceutical Co. Ltd., and UCB Japan. Kenji Ikeda has received speaking fees or honoraria from Sumitomo Dainippon Pharma Co. Ltd. and Eisai Co. Ltd. Masamitsu Nakao, Nobuaki Nakayama, Sumiko Nagoshi, Akio Ido, Toshihide Mimura, Hiroshi Kaneko, Tetsuya Tsuchida, Hiromichi Suzuki, Nobuyuki Ura, Yuichi Nakamura, Masami Bessho, Kazuo Dan, Shigeo Kusumoto, Yasutsuna Sasaki, Hirofumi Fujii, Fumitaka Suzuki, Hiroko Kobayashi, Kazuhiko Yamamoto, Hajime Takikawa, and Hirohito Tsubouchi have no conflict of interest directly relevant to the content of this article.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 28 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mochida, S., Nakao, M., Nakayama, N. et al. Nationwide prospective and retrospective surveys for hepatitis B virus reactivation during immunosuppressive therapies. J Gastroenterol 51, 999–1010 (2016). https://doi.org/10.1007/s00535-016-1168-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-016-1168-2

Keywords

Search

Navigation