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Spontaneous reactivation of hepatitis B virus with a frameshift mutation in the precore region in an elderly hepatitis B virus carrier with lifestyle-related diseases

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Abstract

A 76-year-old woman with spontaneous reactivation of hepatitis B virus (HBV) without any immunosuppressants who had been successfully treated with tenofovir alafenamide fumarate (TAF) was reported. The patient was admitted to our hospital because of acute exacerbation of the liver function and jaundice. She had been found to have chronic HBV infection with a normal liver function and had been treated for lifestyle-related diseases, such as diabetes mellitus, dyslipidemia and hypertension, for over 10 years at a local clinic. At admission, her serum HBV DNA was high (7.3 log IU/mL), and anti-hepatitis B core protein immunoglobulin M was slightly elevated (1.47 S/CO). Due to the absence of known risk factors for HBV reactivation, the reactivation was regarded as “spontaneous”. After the initiation of the nucleotide analog TAF, her liver function gradually improved with a decrease in the HBV DNA load. Her HBV genome was typed as subgenotype B1 and possessed a frameshift mutation due to an insertion of T after nucleotide (nt) 1817 and G to A mutations at nt 1896 and nt 1899 (G1896A/G1899A) in the precore region as well as serine to glutamine substitution of amino acid 21 in the core protein. In addition to these viral mutations, aging and complications of lifestyle-related diseases in the present case may have been responsible for the spontaneous HBV reactivation. Careful observation and management of aged HBV carriers with underlying diseases are needed even when persistent HBV infection is free from symptoms and liver dysfunction and no immunosuppressive conditions are involved.

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References

  1. Schweitzer A, Horn J, Mikolajczyk RT, et al. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386:1546–55.

    Article  Google Scholar 

  2. Chang TT, Lai CL, Kew Yoon S, et al. Entecavir treatment for up to 5 years in patients with hepatitis B e antigen-positive chronic hepatitis B. Hepatology. 2010;51:422–30.

    Article  CAS  Google Scholar 

  3. Tenney DJ, Rose RE, Baldick CJ, et al. Long-term monitoring shows hepatitis B virus resistance to entecavir in nucleoside-naïve patients is rare through 5 years of therapy. Hepatology. 2009;49:1503–14.

    Article  CAS  Google Scholar 

  4. Kitrinos KM, Corsa A, Liu Y, et al. No detectable resistance to tenofovir disoproxil fumarate after 6 years of therapy in patients with chronic hepatitis B. Hepatology. 2014;59:434–42.

    Article  CAS  Google Scholar 

  5. Chan HL, Fung S, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of HBeAg-positive chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:185–95.

    Article  Google Scholar 

  6. Buti M, Gane E, Seto WK, et al. Tenofovir alafenamide versus tenofovir disoproxil fumarate for the treatment of patients with HBeAg-negative chronic hepatitis B virus infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet Gastroenterol Hepatol. 2016;1:196–206.

    Article  Google Scholar 

  7. Drafting Committee for Hepatitis Management Guidelines, the Japan Society of Hepatology. Japan Society of Hepatology Guidelines for the Management of Hepatitis B Virus Infection: 2019 update. Hepatol Res. 2020; 50: 892–923.

  8. Tong MJ, Sampliner RE, Govindarajan S, et al. Spontaneous reactivation of hepatitis B in Chinese patients with HBsAg-positive chronic active hepatitis. Hepatology. 1987;7:713–8.

    Article  CAS  Google Scholar 

  9. Kim DH, Kim SB. Hepatic failure by spontaneous reactivation of hepatitis B virus without a trigger factor in a patient with anti-HBs. Case Rep Gastroenterol. 2018;12:286–91.

    Article  CAS  Google Scholar 

  10. Zachou K, Sarantopoulos A, Gatselis NK, et al. Hepatitis B virus reactivation in hepatitis B virus surface antigen negative patients receiving immunosuppression: a hidden threat. World J Hepatol. 2013;5:387–92.

    Article  Google Scholar 

  11. Shouval D, Shibolet O. Immunosuppression and HBV reactivation. Semin Liver Dis. 2013;33:167–77.

    Article  CAS  Google Scholar 

  12. Kamitsukasa H, Iri M, Tanaka A, et al. Spontaneous reactivation of hepatitis B virus (HBV) infection in patients with resolved or occult HBV infection. J Med Virol. 2015;87:589–600.

    Article  CAS  Google Scholar 

  13. Mulyanto, Depamede SN, Surayah K, et al. Identification and characterization of novel hepatitis B virus subgenotype C10 in Nusa Tenggara. Indonesia Arch Virol. 2010;155:705–15.

    Article  CAS  Google Scholar 

  14. Okamoto H, Yotsumoto S, Akahane Y, et al. Hepatitis B viruses with precore region defects prevail in persistently infected hosts along with seroconversion to the antibody against e antigen. J Virol. 1990;64:1298–303.

    Article  CAS  Google Scholar 

  15. Inoue J, Ueno Y, Kawamura K, et al. Association between S21 substitution in the core protein of hepatitis B virus and fulminant hepatitis. J Clin Virol. 2012;55:147–52.

    Article  CAS  Google Scholar 

  16. Nakao R, Yatsuhashi H, Myoji M, et al. Discrimination between acute hepatitis B and acute exacerbations of chronic hepatitis B by measurement of IgM class antibody to hepatitis B core antigen by CLIA method. Kanzo. 2006;47:279–82 ((In Japanese)).

    Article  CAS  Google Scholar 

  17. Hou J, Wang Z, Cheng J, et al. Prevalence of naturally occurring surface gene variants of hepatitis B virus in nonimmunized surface antigen-negative Chinese carriers. Hepatology. 2001;34:1027–34.

    Article  CAS  Google Scholar 

  18. Raheel M, Choga WT, Blackard JT. The distribution of hepatitis B virus surface antigen polymorphisms at positions associated with vaccine escape. J Med Virol. 2020. https://doi.org/10.1002/jmv.25730.

    Article  PubMed  Google Scholar 

  19. Pei R, Grund S, Verheyen J, et al. Spontaneous reactivation of hepatitis B virus replication in an HIV coinfected patient with isolated anti-Hepatitis B core antibodies. Virol J. 2014;11:9.

    Article  Google Scholar 

  20. Chen PM, Yao NS, Wu CM, et al. Detection of reactivation and genetic mutations of the hepatitis B virus in patients with chronic hepatitis B infections receiving hematopoietic stem cell transplantation. Transplantation. 2002;74:182–8.

    Article  Google Scholar 

  21. 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  Google Scholar 

  22. Ozasa A, Tanaka Y, Orito E, et al. Influence of genotypes and precore mutations on fulminant or chronic outcome of acute hepatitis B virus infection. Hepatology. 2006;44:326–34.

    Article  CAS  Google Scholar 

  23. Imamura T, Yokosuka O, Kurihara T, et al. Distribution of hepatitis B viral genotypes and mutations in the core promoter and precore regions in acute forms of liver disease in patients from Chiba. Japan Gut. 2003;52:1630–7.

    Article  CAS  Google Scholar 

  24. Kusakabe A, Tanaka Y, Mochida S, et al. Case-control study for the identification of virological factors associated with fulminant hepatitis B. Hepatol Res. 2009;39:648–56.

    Article  CAS  Google Scholar 

  25. Koumbi L, Pollicino T, Raimondo G, et al. Hepatitis B virus basal core promoter mutations show lower replication fitness associated with cccDNA acetylation status. Virus Res. 2016;220:150–60.

    Article  CAS  Google Scholar 

  26. Lizzano RA, Yang B, Clippinger AJ, et al. The C-terminal region of the hepatitis B virus X protein is essential for its stability and function. Virus Res. 2011;155:231–9.

    Article  CAS  Google Scholar 

  27. Luo N, Cai Y, Zhang J, Tang W, et al. The C-terminal region of the hepatitis B virus X protein is required for its stimulation of HBV replication in primary mouse hepatocytes. Virus Res. 2012;165:170–8.

    Article  CAS  Google Scholar 

  28. Li H, Chi CY, Lee S, Andrisani OM. The mitogenic function of hepatitis B virus X protein resides within amino acids 51 to 140 and is modulated by N- and C-terminal regulatory regions. J Virol. 2006;80:10554–64.

    Article  CAS  Google Scholar 

  29. Liu X, Wang L, Zhang S, et al. Mutations in the C-terminus of the X protein of hepatitis B virus regulate Wnt-5 expression in hepatoma Huh7 cells: cDNA microarray and proteomic analyses. Carcinogenesis. 2008;29:1207–14.

    Article  Google Scholar 

  30. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL. Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;2017(67):370–98.

    Google Scholar 

  31. Terrault NA, Lok ASF, McMahon BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–99.

    Article  Google Scholar 

  32. Hara T, Oka K, Iwai N, et al. Hepatitis B virus reactivation 55 months following chemotherapy including rituximab and autologous peripheral blood stem cell transplantation for malignant lymphoma. Intern Med. 2021;60:417–21.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Kusunoki Hospital, 607-22, Fujioka, Gunma, 375-0024, Japan

    Satoshi Takakusagi, Hitoshi Takagi, Yozo Yokoyama, Kazuko Kizawa, Kyoko Marubashi & Takashi Kosone

  2. Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine, 3311-1 Yakushiji, Shimotsuke, Tochigi, 329-0498, Japan

    Shigeo Nagashima, Masaharu Takahashi, Kazumoto Murata & Hiroaki Okamoto

Authors
  1. Satoshi Takakusagi
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  2. Hitoshi Takagi
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  3. Yozo Yokoyama
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  4. Kazuko Kizawa
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Correspondence to Hitoshi Takagi.

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Takakusagi, S., Takagi, H., Yokoyama, Y. et al. Spontaneous reactivation of hepatitis B virus with a frameshift mutation in the precore region in an elderly hepatitis B virus carrier with lifestyle-related diseases. Clin J Gastroenterol 14, 1202–1210 (2021). https://doi.org/10.1007/s12328-021-01423-5

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  • DOI: https://doi.org/10.1007/s12328-021-01423-5

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