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Early reduction of infected hepatocytes by activated immunity at the time of interferon withdrawal hepatitis followed by lamivudine administration resulted in higher seroconversion in hepatitis Be antigen-positive patients with chronic hepatitis B

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Abstract

Background

It has been found that the efficacy of lamivudine (LAM) therapy can be improved by preceding administration with a short course of corticosteroid that induces a flare of the disease upon its withdrawal. Because of the side effects of corticosteroid, we tested the effect of a short course of interferon (IFN) as the primer instead of prednisolone, which was followed by LAM when the hepatitis flare occurred. The incidence of LAM resistance mutations and the effect of core promoter and precore mutations on the durability of the responses were also studied.

Methods

Patients treated with interferon (IFN)-LAM therapy (n = 73) were compared to those treated with IFN alone (n = 117). The IFN-LAM group received IFN-α MU/day, t.i.w. for a 3-month period. LAM (10mg/day during 1 year) was started when IFN withdrawal hepatitis occurred during 2–10 months after stopping IFN. The LAM-resistant, core promoter, and precore mutations were examined by sequencing.

Results

(1) The IFN-LAM group developed exacerbated hepatitis following IFN withdrawal in 63 patients before starting LAM therapy. The seroconversion (SC) rate was significantly higher in the IFN-LAM group than in the IFN-alone group (61% vs 26%, P = 0.0001). (2) The LAM resistance mutation rate was 31% at 1 year after initiating LAM therapy. (3) In a stepwise discriminant-function analysis, decreased level of HBeAg determined at 4 weeks after LAM administration and increased level of HBeAb before the start of LAM administration contributed significantly on seroconversion to anti-HBe (P = 0.0073 and 0.004, respectively). (4) The reappearance rate of HBeAg within 6 months after the therapy (relapse) was 33% in the IFN-LAM group and 10% in the IFN-alone group. The prevalence of core promoter and precore mutations did not change before and after the therapy, nor did these mutations correlate with the relapse after stopping IFN-LAM therapy.

Conclusions

(1) Our findings suggest that early reduction of infected hepatocytes expressed by HBeAg by LAM may contribute to a high SC rate of IFN-LAM therapy. (2) The emergence of LAM-resistant mutations was similar to the previously reported rate, and neither core promoter nor precore mutations correlated with relapse of seroconverters after IFN-LAM withdrawal.

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References

  1. RP Beasley (1988) ArticleTitleHepatitis B virus: the major etiology of hepatocellular carcinoma Cancer (Phila) 61 1942–56 Occurrence Handle1:STN:280:BieC1MvisVA%3D

    CAS  Google Scholar 

  2. RP Beasley LY Hwang CC Lin CS Chien (1981) ArticleTitleHepatocellular carcinoma and hepatitis B virus Lancet ii 1129–32

    Google Scholar 

  3. CJ Chen MW Yu Y-F Liaw (1997) ArticleTitleEpidemiologic characteristics and risk factors of hepatocellular carcinoma J Gastroenterol Hepatol 12 IssueIDsuppl S294–308 Occurrence Handle1:STN:280:DyaK1c%2FntFansw%3D%3D Occurrence Handle9407350

    CAS  PubMed  Google Scholar 

  4. HS Conjeevaram ASF Lok (2003) ArticleTitleManagement of chronic hepatitis B J Hepatol 38 90–103

    Google Scholar 

  5. C-L Lai M Rosmawati J Lao H Van Vlierberghe FH Anderson T Thomas (2002) ArticleTitleEntecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection Gastroenterology 123 1831–8 Occurrence Handle10.1053/gast.2002.37058 Occurrence Handle1:CAS:528:DC%2BD38Xps1yktbw%3D Occurrence Handle12454840

    Article  CAS  PubMed  Google Scholar 

  6. DK Wong AM Cheung K O'Rourke CD Nayer AS Detsky J Heathcote (1993) ArticleTitleEffect of alpha-interferon treatment in patients with hepatitis B e antigen-positive chronic hepatitis B. A meta-analysis Ann Intern Med 119 IssueID4 312–23 Occurrence Handle1:STN:280:ByyA3MbhvFc%3D Occurrence Handle8328741

    CAS  PubMed  Google Scholar 

  7. InstitutionalAuthorNameAsia Hepatitis Lamivudine Study Group (2000) ArticleTitleEffects of extended lamivudine therapy in Asian patients with chronic hepatitis B Gastroenterology 119 172

    Google Scholar 

  8. P Mercellin TT Chang SG Lim MJ Tong W Sievert M Shiffman et al. (2001) ArticleTitleGS-98-437. A double blind, randomized, placebo-controlled study of adefovir depivoxil (ADV) for the treatment of patients with HBeAg chronic hepatitis B infection: 48 week results (abstract) Hepatology 34 340A

    Google Scholar 

  9. O Yokosuka (2004) ArticleTitleEvents occurring at the time of breakthrough hepatitis during lamibudine treatment for chronic hepatitis B J Gastroenterol 39 813–4 Occurrence Handle10.1007/s00535-004-1415-9 Occurrence Handle15338383

    Article  PubMed  Google Scholar 

  10. G Barbaro F Zechnini AM Pellicelli (2001) ArticleTitleLong-term efficacy of interferon alpha 2b and lamibudine in combination compared to lamibudine monotherapy in patients with chronic hepatitis B. An Italian multicenter, randomized trial J Hepatol 35 406–11 Occurrence Handle10.1016/S0168-8278(01)00145-3 Occurrence Handle1:CAS:528:DC%2BD3MXnslKrsbk%3D Occurrence Handle11592603

    Article  CAS  PubMed  Google Scholar 

  11. J Tavis (1996) ArticleTitleThe replication strategy of the Hepadanaviruses Viral Hepatitis Rev 2 205–18

    Google Scholar 

  12. Y-F Liaw S-L Tsai R-N Chen C-T Yeh C-M Chu (2000) ArticleTitlePrednisolone priming enhances Th1 response and efficacy of subsequent lamivudine therapy in patients with chronic hepatitis B Hepatology 32 604–9 Occurrence Handle10.1053/jhep.2000.9717 Occurrence Handle1:CAS:528:DC%2BD3cXmsF2mu7w%3D Occurrence Handle10960456

    Article  CAS  PubMed  Google Scholar 

  13. RP Perrillo (2000) ArticleTitleShort-term corticosteroid therapy combination with lamivudine: a case of déjà vu? Hepatology 32 663–5 Occurrence Handle1:STN:280:DC%2BD3cvislyrug%3D%3D Occurrence Handle10960466

    CAS  PubMed  Google Scholar 

  14. BC Song DJ Sus HC Lee YH Chung YS Lee (2000) ArticleTitleHepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea Hepatology 32 803–806 Occurrence Handle10.1053/jhep.2000.16665 Occurrence Handle1:CAS:528:DC%2BD3cXnslemsbg%3D Occurrence Handle11003626

    Article  CAS  PubMed  Google Scholar 

  15. RN Chien YF Liaw SL Tsai CT Yeh CM Chu (2002) ArticleTitleHBV genotype is the major factor for durability of HBeAg responses to lamivudine therapy Gastroenterol J Taiwan 19 65

    Google Scholar 

  16. M Shindo K Hamada K Nishioji A Muramatsu Y Oda T Okuno (2004) ArticleTitleThe predictive value of liver fibrosis in determining the effectiveness of interferon and lamivudine therapies for chronic hepatitis B J Gastroenterol 39 260–7 Occurrence Handle10.1007/s00535-003-1293-6 Occurrence Handle1:CAS:528:DC%2BD2cXivVaqs74%3D Occurrence Handle15065004

    Article  CAS  PubMed  Google Scholar 

  17. M Shindo K Hamada S Koya Y Sokawa T Okuno (1999) ArticleTitleThe clinical significance of core promoter and precore mutations during the natural course and interferon therapy in patients with chronic hepatitis B Am J Gastroenterol 94 2237–45 Occurrence Handle10.1111/j.1572-0241.1999.01299.x Occurrence Handle1:CAS:528:DyaK1MXlsFWntLY%3D Occurrence Handle10445556

    Article  CAS  PubMed  Google Scholar 

  18. VJ Desmet M Gerber JH Hoofnagle M Manns PJ Scheuer (1994) ArticleTitleClassification of chronic hepatitis: diagnosis, grading and staging Hepatology 19 1513–20 Occurrence Handle10.1016/0270-9139(94)90250-X Occurrence Handle1:STN:280:ByuB2crhtFU%3D Occurrence Handle8188183

    Article  CAS  PubMed  Google Scholar 

  19. PJ Sheuer (1991) ArticleTitleClassification of chronic viral hepatitis: a need for reassessment J Hepatol 13 372–4

    Google Scholar 

  20. P Bedossa T Poynard InstitutionalAuthorNamethe METAVIR Cooperative Group (1994) ArticleTitleInter- and intra-observer variations in the assessment of liver biopsy of chronic hepatitis C Hepatology 20 15–20

    Google Scholar 

  21. P Bedossa T Poynard (1996) ArticleTitleThe METAVIR Cooperative Study Group Hepatology 24 289–93 Occurrence Handle1:STN:280:BymA3Mbks1w%3D Occurrence Handle8690394

    CAS  PubMed  Google Scholar 

  22. LMM Wolters BE Hansen HGM Niesters RS Levi-Drummer AU Neuman SW Schalm et al. (2002) ArticleTitleThe influence of baseline characteristics on viral dynamics parameters in chronic hepatitis B patients treated with lamivudine J Hepatol 37 253–8 Occurrence Handle1:CAS:528:DC%2BD38XlsVKjsrk%3D Occurrence Handle12127431

    CAS  PubMed  Google Scholar 

  23. S Saab M Kim TL Wright SHB Han P Martin RW Busttil (2001) ArticleTitleSuccessful orthotopic liver transplantation for lamivudine-associated YMDD mutant hepatitis B virus Gastroenterology 119 1382–4

    Google Scholar 

  24. NW Leung YF Liaw TT Chang R Guan C-M Lee K-Y Ng et al. (2001) ArticleTitleDurable HBeAg response in Chinese patients with Lamivudine Hepatology 34 348A

    Google Scholar 

  25. T Laskus J Rakela DH Persing (1995) ArticleTitleNucleotide sequence analysis of precore and proximal core regions in patients with chronic hepatitis B treated with interferon Dig Dis Sci 40 271–9 Occurrence Handle10.1007/BF02063933

    Article  Google Scholar 

  26. R Perrillo E Schiff E Yoshida A Statler K Hirsch T Wright et al. (2000) ArticleTitleAdefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants Hepatology 32 129 Occurrence Handle1:CAS:528:DC%2BD3cXltFWgs7c%3D Occurrence Handle10869300

    CAS  PubMed  Google Scholar 

  27. S Levine D Hernandez G Yamanaka S Zhang R Rose S Weinheimer RJ Colonbo (2002) ArticleTitleEfficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerase in vitro Antimicrob Agents Chemother 46 2525 Occurrence Handle10.1128/AAC.46.8.2525-2532.2002 Occurrence Handle1:CAS:528:DC%2BD38XlsFGit70%3D Occurrence Handle12121928

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Liver Diseases Section, Akashi Municipal Hospital, 1-33 Takashoumachi, Akashi, 673-8501, Japan

    Michiko Shindo, Akira Muramatsu, Teruhisa Morikawa & Tadao Okuno

  2. Kyoto Institutes for Technology, Kyoto, Japan

    Kazushige Hamada

Authors
  1. Michiko Shindo
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  2. Kazushige Hamada
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  3. Akira Muramatsu
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  4. Teruhisa Morikawa
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  5. Tadao Okuno
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Shindo, M., Hamada, K., Muramatsu, A. et al. Early reduction of infected hepatocytes by activated immunity at the time of interferon withdrawal hepatitis followed by lamivudine administration resulted in higher seroconversion in hepatitis Be antigen-positive patients with chronic hepatitis B. J Gastroenterol 41, 151–157 (2006). https://doi.org/10.1007/s00535-005-1734-5

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  • DOI: https://doi.org/10.1007/s00535-005-1734-5

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