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Current treatment for chronic hepatitis B in Japan

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Abstract

To standardize diagnosis, treatment, and management of chronic hepatitis B, updated treatment guidelines in Japan have been formulated by a research team of the Japanese Ministry of Health, Labor and Welfare (MHLW)’s study project “Research on standardization of treatment for viral liver diseases including liver cirrhosis.” The guidelines recommend first that chronic hepatitis B patients characterized by ALT levels of at least 31 IU/l, with HBe antigen (HBeAg)-positive patients having HBV DNA levels of at least 5 log copies/ml and HBeAg-negative patients with HBV DNA levels of at least 4 log copies/ml, be targeted for treatment. Patients indicated for treatment intervention, for whom are suggested such basic treatments as entecavir therapy, long-term interferon (IFN) therapy, and sequential therapy, are divided into age groups comprising young patients (less than 35 years of age) and middle-aged/elderly patients (35 years and older), HBeAg-positive and HBe-negative patients, and patients with HBV DNA levels of at least 7 log copies/ml and those of less than 7 log copies/ml. As for switching to entecavir for chronic hepatitis B patients currently undergoing lamivudine therapy, the guidelines suggest specific therapies for different groups, dividing patients into those undergoing lamivudine therapy for less than 3 years and those treated for 3 years or longer, as well as those having HBV DNA levels of less than 1.8 log copies/ml and those of 1.8 log copies/ml or more. Formulated on the basis of consideration of chronic hepatitis B patient age, ALT level, HBeAg status, HBV DNA level, and liver disease severity, these guidelines are considered useful for the understanding and implementation of chronic hepatitis B infection diagnosis and treatment, which in recent years have advanced markedly and grown ever more diverse.

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References

  1. Lee WM. Hepatitis B virus infection. N Engl J Med. 1997;337:1733–45.

    Article  CAS  PubMed  Google Scholar 

  2. Kumada H (Principal investigator). Research on standardization of treatment for viral liver diseases including liver cirrhosis. FY2008 MHLW-supported found report; 2009.

  3. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2007;45:507–39.

    Article  CAS  PubMed  Google Scholar 

  4. Fattovich G. Natural history of hepatitis B. J Hepatol. 2003;39(Suppl 1):S50–8.

    Article  PubMed  Google Scholar 

  5. Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology. 2000;119:172–80.

    Article  CAS  PubMed  Google Scholar 

  6. Lok AS, Lai CL, Leung N, Yao GB, Cui ZY, Schiff ER, et al. Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology. 2003;125:1714–22.

    Article  CAS  PubMed  Google Scholar 

  7. Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med. 2005;352:2673–81.

    Article  CAS  PubMed  Google Scholar 

  8. Brook MG, Karayiannis P, Thomas HC. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors. Hepatology. 1989;10:761–3.

    Article  CAS  PubMed  Google Scholar 

  9. Perrillo RP, Schiff ER, Davis GL, Bodenheimer HC Jr, Lindsay K, Payne J, et al. A randomized, controlled trial of interferon alfa-2b alone and after prednisone withdrawal for the treatment of chronic hepatitis B. The Hepatitis Interventional Therapy Group. N Engl J Med. 1990;323:295–301.

    CAS  PubMed  Google Scholar 

  10. Lok AS, Wu PC, Lai CL, Lau JY, Leung EK, Wong LS, et al. A controlled trial of interferon with or without prednisone priming for chronic hepatitis B. Gastroenterology. 1992;102:2091–7.

    CAS  PubMed  Google Scholar 

  11. Suzuki F, Arase Y, Akuta N, Tsubota A, Suzuki Y, Sezaki H, et al. Efficacy of 6-month interferon therapy in chronic hepatitis B virus infection in Japan. J Gastroenterol. 2004;39:969–74.

    Article  CAS  PubMed  Google Scholar 

  12. Marcellin P, Lau GK, Bonino F, Farci P, Hadziyannis S, Jin R, et al. Peginterferon alfa-2a alone, lamivudine alone, and the two in combination in patients with HBeAg-negative chronic hepatitis B. N Engl J Med. 2004;351:1206–17.

    Article  CAS  PubMed  Google Scholar 

  13. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology. 2001;34:1225–41.

    Article  CAS  PubMed  Google Scholar 

  14. Wong DK, Cheung AM, O’Rourke K, Naylor CD, Detsky AS, Heathcote J. Effect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis. Ann Intern Med. 1993;119:312–23.

    CAS  PubMed  Google Scholar 

  15. Chayama K, Suzuki Y, Kobayashi M, Kobayashi M, Tsubota A, Hashimoto M, et al. Emergence and takeover of YMDD motif mutant hepatitis B virus during long-term lamivudine therapy and re-takeover by wild type after cessation of therapy. Hepatology. 1998;27:1711–6.

    Article  CAS  PubMed  Google Scholar 

  16. Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, et al. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. Gastroenterology. 2000;119:172–80.

    Article  CAS  PubMed  Google Scholar 

  17. Perrillo R, Hann HW, Mutimer D, Willems B, Leung N, Lee WM, et al. Adefovir dipivoxil added to ongoing lamivudine in chronic hepatitis B with YMDD mutant hepatitis B virus. Gastroenterology. 2004;126:81–90.

    Article  CAS  PubMed  Google Scholar 

  18. Rapti I, Dimou E, Mitsoula P, Hadziyannis SJ. Adding-on versus switching-to adefovir therapy in lamivudine-resistant HBeAg-negative chronic hepatitis B. Hepatology. 2007;45:307–13.

    Article  CAS  PubMed  Google Scholar 

  19. Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw YF, Cianciara J, et al. Entecavir for treatment of lamivudine-refractory, HBeAg-positive chronic hepatitis B. Gastroenterology. 2006;130:2039–49.

    Article  CAS  PubMed  Google Scholar 

  20. Hoofnagle JH, Doo E, Liang TJ, Fleischer R, Lok AS. Management of hepatitis B: summary of a clinical research workshop. Hepatology. 2007;45:1056–75.

    Article  CAS  PubMed  Google Scholar 

  21. Ha NB, Ha NB, Garcia RT, Trinh HN, Vu AA, Nguyen HA, et al. Renal dysfunction in chronic hepatitis B patients treated with adefovir dipivoxil. Hepatology. 2009; Epub ahead of print.

  22. Leung N, Peng CY, Hann HW, Sollano J, Lao-Tan J, Hsu CW, et al. Early hepatitis B virus DNA reduction in hepatitis B e antigen-positive patients with chronic hepatitis B: A randomized international study of entecavir versus adefovir. Hepatology. 2009;49:72–9.

    Article  CAS  PubMed  Google Scholar 

  23. Keeffe EB, Marcellin P. New and emerging treatment of chronic hepatitis B. Clin Gastroenterol Hepatol. 2007;5:285–94.

    Article  CAS  PubMed  Google Scholar 

  24. Locarnini S, Mason WS. Cellular and virological mechanisms of HBV drug resistance. J Hepatol. 2006;44:422–31.

    Article  CAS  PubMed  Google Scholar 

  25. Tenney DJ, Rose RE, Baldick CJ, Pokornowski KA, Eggers BJ, Fang J, 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  PubMed  Google Scholar 

  26. McMahon MA, Jilek BL, Brennan TP, Shen L, Zhou Y, Wind-Rotolo M, et al. The HBV drug entecavir—effects on HIV-1 replication and resistance. N Engl J Med. 2007;356:2614–21.

    Article  CAS  PubMed  Google Scholar 

  27. Sasadeusz J, Audsley J, Mijch A, Baden R, Caro J, Hunter H, et al. The anti-HIV activity of entecavir: a multicentre evaluation of lamivudine-experienced and lamivudine-naive patients. AIDS. 2008;11(22):947–55.

    Article  Google Scholar 

  28. Keeffe EB, Dieterich DT, Han SH, Jacobson IM, Martin P, Schiff ER, et al. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States: 2008 update. Clin Gastroenterol Hepatol. 2008;6:1315–41.

    Article  CAS  PubMed  Google Scholar 

  29. Sarin SK, Kumar M, Kumar R, Kazim SN, Guptan RC, Sakhuja P, et al. Higher efficacy of sequential therapy with interferon-alpha and lamivudine combination compared to lamivudine monotherapy in HBeAg positive chronic hepatitis B patients. Am J Gastroenterol. 2005;100:2463–71.

    Article  CAS  PubMed  Google Scholar 

  30. Minami M, Okanoue T. Management of HBV infection in Japan. Hepatol Res. 2007;37:S79–82.

    Article  CAS  PubMed  Google Scholar 

  31. Ohishi W, Shirakawa H, Kawakami Y, Kimura S, Kamiyasu M, Tazuma S, et al. Identification of rare polymerase variants of hepatitis B virus using a two-stage PCR with peptide nucleic acid clamping. J Med Virol. 2004;72:558–65.

    Article  CAS  PubMed  Google Scholar 

  32. Niederau C, Heintges T, Lange S, Goldmann G, Niederau CM, Mohr L, et al. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B. N Engl J Med. 1996;334:1422–7.

    Article  CAS  PubMed  Google Scholar 

  33. Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA. 2006;295:65–73.

    Article  CAS  PubMed  Google Scholar 

  34. Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ, et al. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology. 2006;130:678–86.

    Article  PubMed  Google Scholar 

  35. Tsang PS, Trinh H, Garcia RT, Phan JT, Ha NB, Nguyen H, et al. Significant prevalence of histologic disease in patients with chronic hepatitis B and mildly elevated serum alanine aminotransferase levels. Clin Gastroenterol Hepatol. 2008;6:569–74.

    Article  PubMed  Google Scholar 

  36. Sorrell MF, Belongia EA, Costa J, Gareen IF, Grem JL, Inadomi JM, et al. National Institutes of Health Consensus Development Conference Statement: management of hepatitis B. Ann Intern Med. 2009;150:104–10.

    PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan

    Waka Ohishi

  2. Department of Medicine and Molecular Science, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551, Japan

    Waka Ohishi & Kazuaki Chayama

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  1. Waka Ohishi
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  2. Kazuaki Chayama
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Correspondence to Kazuaki Chayama.

Appendix: Supplement to guidelines

Appendix: Supplement to guidelines

  • Efficacy of hepatitis B treatment varies depending on HBV genotype, making it desirable to consider such genotype information when treatment methods are determined. In particular, because IFN therapy for genotypes A and B even in those aged 35 years and older is highly effective, IFN therapy is desirable as the first treatment option.

  • The IFN treatment period is generally 24 weeks, but for responders (decrease in HBV DNA levels and/or normalization of ALT levels), 48-week treatment is recommended.

  • In the many patients when mother-to-child hepatitis B infection is IFN resistant, sequential entecavir and IFN therapy is considered one option.

  • Patients with liver cirrhosis and/or HCC post-curative also can be treated with nucleoside analogues.

  • For patients aged 35 years or older with normal ALT levels, and in whom viral replication is persistent, antiviral therapy is applicable. However, for patients in whom administration of antiviral therapy proves difficult, such as in the elderly or in HBeAg-negative patients, liver supporting therapy over time is an option.

  • Even for patients in whom HBV DNA levels are low and ALT levels are normal, immunosuppressive drugs and anti-cancer drug administration can lead to increased HBV DNA levels and severe hepatic damage [37], requiring great caution.

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Ohishi, W., Chayama, K. Current treatment for chronic hepatitis B in Japan. Clin J Gastroenterol 2, 325–330 (2009). https://doi.org/10.1007/s12328-009-0100-1

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