Semin Liver Dis 2003; 23(1): 081-088
DOI: 10.1055/s-2003-37584
Copyright © 2002 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Treatment of HBeAg-Negative Chronic Hepatitis B

Stephanos J. Hadziyannis1 , George V. Papatheodoridis2 , Dimitrios Vassilopoulos3
  • 1Professor, Department of Medicine and Hepatology, Henry Dunant Hospital, Athens, Greece
  • 22nd Academic Department of Medicine, Hippokration General Hospital, Athens, Greece
  • 3Department of Medicine and Hepatolog, Henry Dunant Hospital, Athens, Greece
Further Information

Publication History

Publication Date:
03 March 2003 (online)

ABSTRACT

The goals of therapy in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are to abolish or efficiently suppress viral replication, which represents the main determinant of underlying liver necroinflammation and fibrosis. Currently available agents include interferon-alfa (IFN-α), lamivudine, and soon adefovir dipivoxil. A ≥ 12-month course of IFN-α treatment or retreatment achieves sustained biochemical responses in 15 to 25% of patients with eventual hepatitis B surface antigen (HBsAg) loss and anti-HBs development in a proportion of them. Lamivudine induces initial virologic and biochemical responses in 70 to 90%, but breakthroughs due to lamivudine-resistant mutants accumulate with continuation of therapy and thus only one third of patients may remain in remission after the third year of therapy. Adefovir dipivoxil also achieves on-therapy responses in the majority of cases. Adefovir dipivoxil and entecavir appear to be effective against lamivudine-resistant strains. Many other antiviral agents and immunomodulatory approaches are currently evaluated for CHB, but, besides IFN-α, none has yet been convincingly shown to induce sustained off-therapy responses.

REFERENCES

  • 1 Hadziyannis S J. Hepatitis B e antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment.  Viral Hepat Rev . 1995;  1 7-36
  • 2 Lok A S, Heathcote E J, Hoofnagle J H. Management of hepatitis B: 2000-summary of a workshop.  Gastroenterology . 2001;  120 1828-1853
  • 3 Hadziyannis S J, Vassilopoulos D. Hepatitis B e antigen- negative chronic hepatitis B.  Hepatology . 2001;  34 617-624
  • 4 Carman W F, Jacyna M R, Hadziyannis S. Mutation preventing formation of 'hepatitis B e antigen' in patients with chronic hepatitis B infection.  Lancet . 1989;  2 588-590
  • 5 Hunt C M, McGill J M, Allen M L, Condreay L D. Clinical relevance of hepatitis B virus mutations.  Hepatology . 2000;  31 1037-1044
  • 6 Papatheodoridis G V, Hadziyannis S J. Diagnosis and management of pre-core mutant chronic hepatitis B.  J Viral Hepat . 2001;  8 311-321
  • 7 Lok A SF, McMahon B J. Chronic hepatitis B.  Hepatology . 2001;  34 1225-1241
  • 8 Manesis E K, Papatheodoridis G V, Hadziyannis S J. Serum HBV-DNA levels in inactive hepatitis B virus carriers.  Gastroenterology . 2002;  122 2092-2093
  • 9 Korenman J, Baker B, Waggoner J. Long-term remission of chronic hepatitis B after alpha-interferon therapy.  Ann Intern Med . 1991;  114 629-634
  • 10 Gerken G, Gomez J, Lambertico P. Clinical evaluation and applications of the Amplicor HBV Monitor test, a quantitative HBV DNA PCR assay.  J Virol Methods . 1998;  74 155-165
  • 11 Pawlotsky J-M. Molecular diagnosis of viral hepatitis.  Gastroenterology . 2002;  122 1554-1568
  • 12 Niederau C, Heintges T, Lange S. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.  N Engl J Med . 1996;  334 1422-1427
  • 13 Lin S-M, Sheen I-S, Chien R-N, Chu C-M, Liaw Y-F. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.  Hepatology . 1999;  29 971-975
  • 14 Brunetto M R, Oliveri F, Colombatto P. Treatment of chronic anti-HBe-positive hepatitis B with interferon-alpha.  J Hepatol . 1995;  22 42-44
  • 15 Manesis E K, Hadziyannis S J. Interferon-alpha treatment and retreatment of hepatitis B e antigen-negative chronic hepatitis B.  Gastroenterology . 2001;  121 91-100
  • 16 Papatheodoridis G V, Manesis E, Hadziyannis S J. The long-term outcome of interferon-α treated and untreated patients with HBeAg-negative chronic hepatitis B.  J Hepatol . 2001;  34 306-313
  • 17 Brunetto M R, Oliveri F, Rocca G. Natural course and response to interferon of chronic hepatitis B accompanied by antibody to hepatitis B e antigen.  Hepatology . 1989;  10 198-202
  • 18 Hadziyannis S, Bramou T, Makris A. Interferon alfa-2b treatment of HBeAg negative/serum HBV DNA positive chronic active hepatitis B.  J Hepatol . 1990;  11(Suppl) S133-S136
  • 19 Pastore G, Santantonio T, Milella M. Anti-HBe- positive chronic hepatitis B with HBV-DNA in the serum: response to a 6-month course of lymphoblastoid interferon.  J Hepatol . 1992;  14 221-225
  • 20 Oliveri F, Santantonio T, Bellati G. Long term response to therapy of chronic anti-HBe-positive hepatitis B is poor independent of type and schedule of interferon.  Am J Gastroenterol . 1999;  94 1366-1372
  • 21 Lampertico P, Del Ninno E, Manzin A. A randomized, controlled trial of a 24-month course of interferon alfa 2b in patients with chronic hepatitis B who had hepatitis B virus DNA without hepatitis B e antigen in serum.  Hepatology . 1997;  26 1621-1625
  • 22 Vinayek R, Shakil O. Adverse events associated with interferon-alfa therapy in patients with chronic viral hepatitis.  Viral Hep Rev . 1997;  3 167-177
  • 23 Jarvis B, Faulds D. Lamivudine. A review of its therapeutic potential in chronic hepatitis B.  Drugs . 1999;  58 101-141
  • 24 Lok A SF. Hepatitis B infection: pathogenesis and management.  J Hepatol . 2000;  32(Suppl 1) 89-97
  • 25 Tassopoulos N C, Volpes R, Pastore G. Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B.  Hepatology . 1999;  29 889-896
  • 26 Santantonio T, Mazzola M, Iacovazzi T. Long-term follow-up of patients with anti-HBe/HBV DNA-positive chronic hepatitis B treated for 12 months with lamivudine.  J Hepatol . 2000;  32 300-306
  • 27 Hadziyannis S J, Papatheodoridis G V, Dimou E, Laras A, Papaioannou C. Efficacy of long-term lamivudine monotherapy in patients with HBeAg negative chronic hepatitis B.  Hepatology . 2000;  32 847-851
  • 28 Papatheodoridis G V, Dimou E, Laras A, Papadimitropoulos V, Hadziyannis S J. Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease.  Hepatology . 2002;  36 219-226
  • 29 Tassopoulos N C, Volpes R, Pastore G. Post lamivudine treatment follow up of patients with HBeAg negative chronic hepatitis B.  J Hepatol . 1999;  30(Suppl 1) 117
  • 30 Papatheodoridis G V, Dimou E, Papadimitropoulos V. Nucleoside analogues for chronic hepatitis B: antiviral efficacy and viral resistance.  Am J Gastroenterol . 2002;  97 1618-1628
  • 31 Lok A SF, Hussain M, Cursano C. Evolution of hepatitis B virus polymerase gene mutations in hepatitis B e antigen-negative patients receiving lamivudine therapy.  Hepatology . 2000;  32 1145-1153
  • 32 Cundy K C. Clinical pharmacokinetics of the antiviral nucleotide analogues cidofovir and adefovir.  Clin Pharmacokinet . 1999;  36 127-143
  • 33 Marcellin P, Chang T-T, Lim S G. GS-98-437 A double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) for the treatment of patients with HBeAg+ chronic hepatitis B infection: 48 weeks results.  Hepatology . 2001;  34 340A
  • 34 Hadziyannis S, Tassopoulos N, Heathcote E. GS-98-438 A double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) for presumed precore mutant chronic hepatitis B: 48 weeks results.  J Hepatol . 2002;  36(Suppl 1) 4
  • 35 Knight W, Hayashi S, Benhamou Y. Dosing guidelines for adefovir dipivoxil in the treatment of HBV infected patients with renal or hepatic impairment.  J Hepatol . 2002;  36(Suppl 1) 136
  • 36 Heathcote E, Jeffers L, Perrillo R. Sustained antiviral response and lack of viral resistance with long term adefovir dipivoxil (ADV) therapy in chronic HBV infection.  J Hepatol . 2002;  36(Suppl 1) 110
  • 37 Yang H, Westland C E, Delaney IV E W. Resistance monitoring in chronic hepatitis B patients exposed to adefovir dipivoxil for 72 to 136 weeks.  Hepatology . 2001;  34 316A
  • 38 Torresi J, Locarnini S. Antiviral chemotherapy for the treatment of hepatitis B virus infections.  Gastroenterology . 2000;  118(Suppl) S83-S103
  • 39 Peters M. Mechanisms of action of interferons.  Semin Liver Dis . 1989;  9 235-239
  • 40 Honkoop P, de Man A R, Niesters H GM, Zondervan P E, Schalm S W. Acute exacerbation of chronic hepatitis B virus infection after withdrawal of lamivudine therapy.  Hepatology . 2000;  32 635-639
  • 41 Lau D TY, Khokhar M F, Doo E. Long-term therapy of chronic hepatitis B with lamivudine.  Hepatology . 2000;  32 828-834
  • 42 Ono-Nita S K, Kato N, Shiratori Y. Influence of B domain mutation (L528M) of the hepatitis B virus polymerase on replication ability and resistance to nucleoside analogues.  Hepatology . 2000;  32(Suppl) 393A
  • 43 Xiong X, Flores C, Yang H, Toole J J, Gibbs C S. Mutations in hepatitis B DNA polymerase associated with resistance to lamivudine do not confer resistance to adefovir in vitro.  Hepatology . 1998;  28 1669-1673
  • 44 Perrillo R, Schiff E, Yoshida E. Adefovir dipivoxil for the treatment of lamivudine-resistant hepatitis B mutants.  Hepatology . 2000;  32 129-134
  • 45 Ahmad J, Dodson S F, Balan V. Adefovir dipivoxil suppresses lamivudine resistant hepatitis B virus in liver transplant recipients.  Hepatology . 2000;  32(Suppl) 292A
  • 46 Perrillo R, Schiff E, Hann H-WL. The addition of adefovir dipivoxil to lamivudine in decompensated chronic hepatitis B patients with YMDD variant HBV and reduced response to lamivudine-preliminary 24 week results.  Hepatology . 2001;  34 349A
  • 47 Schiff E, Neuhaus P, Tillmann H. Adefovir dipivoxil (ADV) for the treatment of lamivudine resistant HBV (LAM-R) in patients post liver transplant (post-OLT) patients.  J Hepatol . 2002;  36(Suppl 1) 32
  • 48 Westland C E, Yang H, Namimi H. Comparison of anti-HBV activity of adefovir against different lamivudine-resistant HBV strains in vitro and in liver transplant patients.  Hepatology . 2001;  34 446A
  • 49 Peters M, Hann H W, Martin P. Adefovir dipivoxil (ADV) alone and in combination with lamivudine (LAM) suppresses LAM-resistant hepatitis B virus (HBV) replication: 16 week interim analysis.  J Hepatol . 2002;  36(Suppl 1) 6
  • 50 Yamanaka G, Wilson T, Innaimo S. Metabolic studies on BMS-200475, a new antiviral compound active against hepatitis B virus.  Antimicrob Agents Chemother . 1999;  43 190-193
  • 51 Nevens F, de Man A R, Chua D. Effectiveness of a low dose of entecavir in treating recurrent viremia in chronic hepatitis B.  Hepatology . 2000;  32(Suppl) 377A
  • 52 Lai C, Rosmawati M, Lao J. A phase II study of entecavir vs lamivudine in adults with chronic hepatitis B.  J Hepatol . 2001;  34(Suppl 1) 24
  • 53 de Man R, Wolters L, Nevens F. A study of oral entecavir given for 28 days in both treatment-naive and pre-treated subjects with chronic hepatitis.  Hepatology . 2000;  32(Suppl) 376A
  • 54 Tassopoulos N, Hadziyannis S, Cianciara J. Entecavir is effective in treating patients with chronic hepatitis B who have failed lamivudine therapy.  Hepatology . 2001;  34 340A
  • 55 Hadziyannis S J, Manesis E K, Papakonstantinou A. Oral ganciclovir treatment in chronic hepatitis B virus infection: a pilot study.  J Hepatol . 1999;  31 210-214
  • 56 Tassopoulos N, Hadziyannis S, Ideo G. Famciclovir treatment of anti-HBe+ chronic hepatitis B: results of a randomized, placebo-controlled study.  J Hepatol . 2000;  32(Suppl 2) 102
  • 57 Wang C, Correy L, Leung N. Antiviral activity of 48 weeks of emtricitabine (FTC) treatment in patients with HBeAg negative/HBV DNA positive chronic hepatitis B (CHB).  Hepatology . 2001;  34 323A
  • 58 Marcellin P, Sereni D, Sacks S. Anti-HBV activity and tolerability of clevudine, a novel nucleoside analogue: initial results of a phase I/II 28-day study.  Hepatology . 2001;  34 320A
  • 59 Lai C-L, Myers M W, Pow D M. Safe and potent suppression of hepatitis B virus (HBV) with L-deoxythymidine (LDT): results of a dose-escalation trial.  Hepatology . 2001;  34 321A
  • 60 Shaw T, Locarnini S. Combination chemotherapy for hepatitis B virus: the final solution?.  Hepatology . 2000;  32 430-432
  • 61 Lau G K, Tsiang M, Hou J. Combination therapy with lamivudine and famciclovir for chronic hepatitis B-infected Chinese patients: a viral dynamics study.  Hepatology . 2000;  32 394-399
  • 62 Marques A R, Lau D T, McKenzie R, Straus S E, Hoofnagle J H. Combination therapy with famciclovir and interferon-alpha for the treatment of chronic hepatitis B.  J Infect Dis . 1998;  178 1483-1487
  • 63 Schalm S W, Heathcote J, Cianciara J. Lamivudine and alpha interferon combination treatment of patients with chronic hepatitis B infection: a randomised trial.  Gut . 2000;  46 562-568
  • 64 Santantonio T, Anna N G, Sinisi E. Lamivudine/interferon combination therapy in anti-HBe positive chronic hepatitis B patients: a controlled pilot study.  J Hepatol . 2002;  36 799-804
  • 65 Hadziyannis S, Alexopoulou A, Papakonstantinou A, Petraki K, Manesis E. Interferon treatment with or without oral ganciclovir in HBeAg-negative chronic hepatitis B: a randomized study.  J Viral Hepat . 2000;  7 235-240