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Semin Liver Dis 2006; 26(2): 116-129
DOI: 10.1055/s-2006-939750
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Hepatitis B e Antigen-Positive Chronic Hepatitis B: Natural History and Treatment

Jordan J. Feld1 , E. Jenny Heathcote2
  • 1Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Disease, National Institutes of Health, Bethesda, Maryland
  • 2University Health Network-Toronto Western Hospital, Toronto, Ontario, Canada
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Publication History

Publication Date:
03 May 2006 (online)

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ABSTRACT

The natural history of hepatitis B e antigen (HBeAg)-positive chronic hepatitis B is very heterogeneous. Age at acquisition is a major factor in determining the natural history of chronic infection. The vigor of the host immune response to the virus, viral factors (genotype, core promoter mutations, and duration of viral replication) as well as exogenous factors (alcohol, immune suppression) all influence the severity of disease. The goal of antiviral therapy is HBeAg seroconversion, and preferably HB surface Ag seroconversion as this latter end-point is associated with sustained immune control and the halting of disease progression. Although peginterferon is now considered as the first line of therapy for HBeAg-positive chronic hepatitis B, in most cases there are circumstances where nucleos(t)ide analogues are indicated (e.g., decompensated liver disease) for those requiring cancer chemotherapy/other immunosuppressive agents and for those with contraindications to interferon. The major challenge for the clinician using these agents is the emergence of antiviral drug resistance. Long-term immune control of viral replication is key to improving patient outcome.

KEYWORDS

Immunotolerant state - HBeAg seroconversion - pegylated interferon - nucleos(t)ide therapies - drug resistance - risk factors - severe hepatitis B

REFERENCES

  • 1 Prince A M. Relation of Australia SH antigens.  Lancet. 1968;  2 462-463
    PubMedGoogle Scholar
  • 2 Milich D R, Jones J E, Hughes J L et al.. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?.  Proc Natl Acad Sci USA. 1990;  87 6599-6603
    PubMedGoogle Scholar
  • 3 Chen M, Sallberg M, Hughes J et al.. Immune tolerance split between hepatitis B virus precore and core proteins.  J Virol. 2005;  79 3016-3027
    CrossrefPubMedGoogle Scholar
  • 4 Esteve M, Saro C, Gonzalez-Huix F et al.. Chronic hepatitis B reactivation following infliximab therapy in Crohn's disease patients: need for primary prophylaxis.  Gut. 2004;  53 1363-1365
    CrossrefPubMedGoogle Scholar
  • 5 Rawal B K, Parida S, Watkins R P et al.. Symptomatic reactivation of hepatitis B in pregnancy.  Lancet. 1991;  337 364
    CrossrefPubMedGoogle Scholar
  • 6 Aroldi A, Lampertico P, Montagnino G et al.. Natural history of hepatitis B and C in renal allograft recipients.  Transplantation. 2005;  79 1132-1136
    CrossrefPubMedGoogle Scholar
  • 7 Thursz M R, Kwiatkowski D, Allsopp C E et al.. Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia.  N Engl J Med. 1995;  332 1065-1069
    CrossrefPubMedGoogle Scholar
  • 8 Evans A A, O'Connell A P, Pugh J C et al.. Geographic variation in viral load among hepatitis B carriers with differing risks of hepatocellular carcinoma.  Cancer Epidemiol Biomarkers Prev. 1998;  7 559-565
    PubMedGoogle Scholar
  • 9 Wai C-T, Fontana R J. Clinical significance of hepatitis B virus genotypes, variants, and mutants.  Clin Liver Dis. 2004;  8 321-352
    CrossrefPubMedGoogle Scholar
  • 10 Tanaka H, Tsukuma H, Yamano H et al.. Prospective study on the risk of hepatocellular carcinoma among hepatitis C virus-positive blood donors focusing on demographic factors, alanine aminotransferase level at donation and interaction with hepatitis B virus.  Int J Cancer. 2004;  112 1075-1080
    CrossrefPubMedGoogle Scholar
  • 11 Colin J-F, Cazals-Hatem D, Loriot M A et al.. Influence of human immunodeficiency virus infection on chronic hepatitis B in homosexual men.  Hepatology. 1999;  29 1306-1310
    CrossrefPubMedGoogle Scholar
  • 12 Di Martino V, Thevenot T, Colin J F et al.. Influence of HIV infection on the response to interferon therapy and the long-term outcome of chronic hepatitis B.  Gastroenterology. 2002;  123 1812-1822
    CrossrefPubMedGoogle Scholar
  • 13 Zanati S A, Locarnini S A, Dowling J P et al.. Hepatic failure due to fibrosing cholestatic hepatitis in a patient with pre-surface mutant hepatitis B virus and mixed connective tissue disease treated with prednisolone and chloroquine.  J Clin Virol. 2004;  31 53-57
    CrossrefPubMedGoogle Scholar
  • 14 Donato F, Tagger A, Gelatti U et al.. Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women.  Am J Epidemiol. 2002;  155 323-331
    CrossrefPubMedGoogle Scholar
  • 15 Gu D, Reynolds K, Wu X InterASIA Collaborative Group et al.. Prevalence of the metabolic syndrome and overweight among adults in China.  Lancet. 2005;  365 1398-1405
    CrossrefPubMedGoogle Scholar
  • 16 Gordon A, McLean C A, Pedersen J S et al.. Hepatic steatosis in chronic hepatitis B and C: predictors, distribution and effect on fibrosis.  J Hepatol. 2005;  43 38-44
    CrossrefPubMedGoogle Scholar
  • 17 Bortolotti F, Cadrobbi P, Crivellaro C et al.. Long-term outcome of chronic type B hepatitis in patients who acquire hepatitis B virus infection in childhood.  Gastroenterology. 1990;  99 805-810
    PubMedGoogle Scholar
  • 18 Niederau C, Heintges T, Lange S et al.. Long-term follow-up of HBeAg-positive patients treated with interferon alfa for chronic hepatitis B.  N Engl J Med. 1996;  334 1422-1427
    CrossrefPubMedGoogle Scholar
  • 19 Lin S-M, Sheen I-S, Chien R-N et al.. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.  Hepatology. 1999;  29 971-975
    CrossrefPubMedGoogle Scholar
  • 20 Hsu Y-S, Chien R-N, Yeh C-T et al.. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.  Hepatology. 2002;  35 1522-1527
    CrossrefPubMedGoogle Scholar
  • 21 Chu C-M, Hung S-J, Lin J et al.. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.  Am J Med. 2004;  116 829-834
    CrossrefPubMedGoogle Scholar
  • 22 Marx G, Martin S R. Long-term follow-up of chronic hepatitis B virus infection in children of different ethnic origins.  J Infect Dis. 2002;  186 295-301
    CrossrefPubMedGoogle Scholar
  • 23 Lok A SF, Lai C-L. A longitudinal follow-up of asymptomatic hepatitis B surface antigen-positive Chinese children.  Hepatology. 1988;  8 1130-1133
    CrossrefPubMedGoogle Scholar
  • 24 Evans A A, Fine M, London W T. Spontaneous seroconversion in hepatitis B e antigen-positive chronic hepatitis B: implication for interferon therapy.  J Infect Dis. 1997;  176 845-850
    PubMedGoogle Scholar
  • 25 Bell S J, Lau A, Thompson A et al.. Chronic hepatitis B: recommendations for therapy based on the natural history of disease in Australian patients.  J Clin Virol. 2005;  32 122-127
    CrossrefPubMedGoogle Scholar
  • 26 Liaw Y-F, Tai D-I, Chu C-M et al.. Acute exacerbation in chronic type B hepatitis: comparison between HBeAg and antibody-positive patients.  Hepatology. 1987;  7 20-23
    PubMedGoogle Scholar
  • 27 Lok A SF, Lai C-L. Acute exacerbations in Chinese Patients with chronic hepatitis B virus (HBV) infection.  J Hepatol. 1990;  10 29-34
    CrossrefPubMedGoogle Scholar
  • 28 Perrillo R P. Acute flares in chronic hepatitis B: the natural and unnatural history of an immunologically mediated liver disease.  Gastroenterology. 2001;  120 1009-1022
    CrossrefPubMedGoogle Scholar
  • 29 Kao J-H, Chen P-J, Lai M-Y et al.. Acute exacerbations of chronic hepatitis B are rarely associated with superinfection of hepatitis B virus.  Hepatology. 2001;  34 817-823
    CrossrefPubMedGoogle Scholar
  • 30 Yang H-I, Lu S-N, Liaw Y-F et al.. Hepatitis B e antigen and the risk of hepatocellular carcinoma.  N Engl J Med. 2002;  347 168-174
    PubMedGoogle Scholar
  • 31 Kao J-H, Chen P-J, Lai M-Y et al.. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.  Gastroenterology. 2000;  118 554-559
    CrossrefPubMedGoogle Scholar
  • 32 Tsubota A, Arase Y, Ren F et al.. Genotype may correlate with liver carcinogenesis and tumor characteristics in cirrhotic patients infected with hepatitis B virus subtype adw.  J Med Virol. 2001;  65 257-265
    CrossrefPubMedGoogle Scholar
  • 33 Chan HL-Y, Hui A Y, Wong M L et al.. Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma.  Gut. 2004;  53 1494-1498
    CrossrefPubMedGoogle Scholar
  • 34 Chu C-J, Hussain M, Lok A SF. Hepatitis B virus genotype B is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C. .  Gastroenterology. 2002;  122 1756-1762
    CrossrefPubMedGoogle Scholar
  • 35 Ito K, Tanaka Y, Orito E et al.. T1653 mutation in the box alpha increases the risk of hepatocellular carcinoma in patients with chronic hepatitis B virus genotype C infection.  Clin Infect Dis. 2006;  42 1-7
    CrossrefPubMedGoogle Scholar
  • 36 Sánchez-Tapias J M, Costa J, Mas A et al.. Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients.  Gastroenterology. 2002;  123 1848-1856
    CrossrefPubMedGoogle Scholar
  • 37 Chu C-J, Keeffe E B, Han S-H and the US HBV Epidemiology Study Group et al.. Hepatitis B Virus genotypes in the United States: results of a nationwide study.  Gastroenterology. 2003;  125 444-451
    CrossrefPubMedGoogle Scholar
  • 38 Keeffe E B, Dieterich D T, Han S H et al.. A treatment algorithm for the management of chronic hepatitis B virus infection in the United States.  Clin Gastroenterol Hepatol. 2004;  2 87-106
    PubMedGoogle Scholar
  • 39 Lok A S, McMahon B J. Chronic hepatitis B: update of recommendations.  Hepatology. 2004;  39 857-861
    CrossrefPubMedGoogle Scholar
  • 40 Perrillo R P, Lai C L, Liaw Y F et al.. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B.  Hepatology. 2002;  36 186-194
    CrossrefPubMedGoogle Scholar
  • 41 Lau G K, Piratvisuth T, Luo K X et al.. Peginterferon alfa-2a, lamivudine, and the combination for HBeAg-positive chronic hepatitis B.  N Engl J Med. 2005;  352 2682-2695
    CrossrefPubMedGoogle Scholar
  • 42 Yuen M-F, Yuan H-J, Wong DK-H et al.. Prognostic determinants for chronic hepatitis B in Asians: therapeutic implications.  Gut. 2005;  54 1610-1614
    CrossrefPubMedGoogle Scholar
  • 43 Yao F Y, Terrault N A, Freise C et al.. Lamivudine treatment is beneficial in patients with severely decompensated cirrhosis and actively replicating hepatitis B infection awaiting liver transplantation: a comparative study using a matched, untreated cohort.  Hepatology. 2001;  34 411-416
    CrossrefPubMedGoogle Scholar
  • 44 van Zonneveld M, Honkoop P, Hansen B E et al.. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.  Hepatology. 2004;  39 804-810
    CrossrefPubMedGoogle Scholar
  • 45 Marcellin P, Asselah T, Boyer N. Treatment of chronic hepatitis B.  J Viral Hepat. 2005;  12 333-345
    CrossrefPubMedGoogle Scholar
  • 46 Lau D T, Everhart J, Kleiner D E et al.. Long-term follow-up of patients with chronic hepatitis B treated with interferon alfa.  Gastroenterology. 1997;  113 1660-1667
    PubMedGoogle Scholar
  • 47 Song B C, Suh D J, Lee H C et al.. Hepatitis B e antigen seroconversion after lamivudine therapy is not durable in patients with chronic hepatitis B in Korea.  Hepatology. 2000;  32 803-806
    CrossrefPubMedGoogle Scholar
  • 48 van Nunen A B, Hansen B E, Suh D J et al.. Durability of HBeAg seroconversion following antiviral therapy for chronic hepatitis B: relation to type of therapy and pretreatment serum hepatitis B virus DNA and alanine aminotransferase.  Gut. 2003;  52 420-424
    CrossrefPubMedGoogle Scholar
  • 49 Chien R N, Yeh C T, Tsai S L et al.. Determinants for sustained HBeAg response to lamivudine therapy.  Hepatology. 2003;  38 1267-1273
    CrossrefPubMedGoogle Scholar
  • 50 Lee C M, Ong G Y, Lu S N et al.. Durability of lamivudine-induced HBeAg seroconversion for chronic hepatitis B patients with acute exacerbation.  J Hepatol. 2002;  37 669-674
    CrossrefPubMedGoogle Scholar
  • 51 Ryu S H, Chung Y H, Choi M H et al.. Long-term additional lamivudine therapy enhances durability of lamivudine-induced HBeAg loss: a prospective study.  J Hepatol. 2003;  39 614-619
    CrossrefPubMedGoogle Scholar
  • 52 Kagawa T, Watanabe N, Kanouda H et al.. Fatal liver failure due to reactivation of lamivudine-resistant HBV mutant.  World J Gastroenterol. 2004;  10 1686-1687
    PubMedGoogle Scholar
  • 53 Chan H L, Leung N W, Hui A Y et al.. A randomized, controlled trial of combination therapy for chronic hepatitis B: comparing pegylated interferon-alpha2b and lamivudine with lamivudine alone.  Ann Intern Med. 2005;  142 240-250
    CrossrefPubMedGoogle Scholar
  • 54 Brook M G, Karayiannis P, Thomas H C. Which patients with chronic hepatitis B virus infection will respond to alpha-interferon therapy? A statistical analysis of predictive factors.  Hepatology. 1989;  10 761-763
    PubMedGoogle Scholar
  • 55 Erhardt A, Blondin D, Hauck K et al.. Response to interferon alfa is hepatitis B virus genotype dependent: genotype A is more sensitive to interferon than genotype D.  Gut. 2005;  54 1009-1013
    CrossrefPubMedGoogle Scholar
  • 56 Wai C T, Chu C J, Hussain M, Lok A S. HBV genotype B is associated with better response to interferon therapy in HBeAg(+) chronic hepatitis than genotype C.  Hepatology. 2002;  36 1425-1430
    CrossrefPubMedGoogle Scholar
  • 57 Kao J H, Wu N H, Chen P J et al.. Hepatitis B genotypes and the response to interferon therapy.  J Hepatol. 2000;  33 998-1002
    CrossrefPubMedGoogle Scholar
  • 58 Chow W C, Manns M, Paik S W et al.. Effect of ethnicity, genotype, gender, age and bodyweight on sustained response in a large, randomised study of peginterferon alfa-2a (40KD) (Pegasys) +/- lamivudine versus lamivudine alone for HBeAg-positive chronic hepatitis B.  Hepatology. 2005;  42(suppl 1) 567A
    PubMedGoogle Scholar
  • 59 Moskovitz D N, Osiowy C, Giles E et al.. Response to long-term lamivudine treatment (up to 5 years) in patients with severe chronic hepatitis B, role of genotype and drug resistance.  J Viral Hepat. 2005;  12 398-404
    CrossrefPubMedGoogle Scholar
  • 60 Yuen M F, Wong D K, Sablon E et al.. Hepatitis B virus genotypes B and C do not affect the antiviral response to lamivudine.  Antivir Ther. 2003;  8 531-534
    PubMedGoogle Scholar
  • 61 Westland C, Delaney W, Yang H et al.. Hepatitis B virus genotypes and virologic response in 694 patients in phase III studies of adefovir dipivoxil.  Gastroenterology. 2003;  125 107-116
    CrossrefPubMedGoogle Scholar
  • 62 ter Borg M J, Flink H J, Janssen H L et al.. Delayed viral decline is associated with highest sustained response rate during peginterfon treatment for HBeAg-positive chronic hepatitis B.  Hepatology. 2005;  42(suppl 1) 575A
    PubMedGoogle Scholar
  • 63 Flink H J, Sprengers D, Hansen B E et al.. Flares in chronic hepatitis B patients induced by the host or the virus? Relation to treatment response during Peg-interferon α-2b therapy.  Gut. 2005;  54 1604-1609
    CrossrefPubMedGoogle Scholar
  • 64 Nair S, Perrillo R P. Serum alanine aminotransferase flares during interferon treatment of chronic hepatitis B: is sustained clearance of HBV DNA dependent on levels of pretreatment viremia?.  Hepatology. 2001;  34 1021-1026
    CrossrefPubMedGoogle Scholar
  • 65 Fried M W, Liaw Y F, Luo K X et al.. Role of baseline and on-treatment quantitative HBeAg in predicting response to peginterferon alfa-2a (40KD) (pegasys) monotherapy in a large, multinational trial of patients with chronic hepatitis B.  Hepatology. 2005;  42(suppl 1) 268A
    PubMedGoogle Scholar
  • 66 Janssen H L, van Zonneveld M, Senturk H et al.. Pegylated interferon alfa-2b alone or in combination with lamivudine for HBeAg-positive chronic hepatitis B: a randomised trial.  Lancet. 2005;  365 123-129
    CrossrefPubMedGoogle Scholar
  • 67 Kanwal F, Gralnek I M, Martin P, Dulai G S, Farid M, Spiegel B M. Treatment alternatives for chronic hepatitis B virus infection: a cost-effectiveness analysis.  Ann Intern Med. 2005;  142 821-831
    PubMedGoogle Scholar
  • 68 Stephan C, Berger A, Carlebach A et al.. Impact of tenofovir-containing antiretroviral therapy on chronic hepatitis B in a cohort co-infected with human immunodeficiency virus.  J Antimicrob Chemother. 2005;  56 1087-1093
    CrossrefPubMedGoogle Scholar
  • 69 Bessesen M, Ives D, Condreay L et al.. Chronic active hepatitis B exacerbations in human immunodeficiency virus-infected patients following development of resistance to or withdrawal of lamivudine.  Clin Infect Dis. 1999;  28 1032-1035
    CrossrefPubMedGoogle Scholar
  • 70 Liaw Y F, Sung J J, Chow W C et al.. Lamivudine for patients with chronic hepatitis B and advanced liver disease.  N Engl J Med. 2004;  351 1521-1531
    CrossrefPubMedGoogle Scholar
  • 71 Lau G K, Yiu H H, Fong D Y et al.. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy.  Gastroenterology. 2003;  125 1742-1749
    CrossrefPubMedGoogle Scholar
  • 72 Liaw Y F. Impact of YMDD mutations during lamivudine therapy in patients with chronic hepatitis B.  Antivir Chem Chemother. 2001;  12(suppl 1) 67-71
    PubMedGoogle Scholar
  • 73 Nafa S, Ahmed S, Tavan D et al.. Early detection of viral resistance by determination of hepatitis B virus polymerase mutations in patients treated by lamivudine for chronic hepatitis B.  Hepatology. 2000;  32 1078-1088
    CrossrefPubMedGoogle Scholar
  • 74 Liaw Y F, Chien R N, Yeh C T et al.. Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.  Hepatology. 1999;  30 567-572
    CrossrefPubMedGoogle Scholar
  • 75 Lampertico P, Vigano M, Manenti E et al.. Adefovir rapidly suppresses hepatitis B in HBeAg-negative patients developing genotypic resistance to lamivudine.  Hepatology. 2005;  42 1414-1419
    CrossrefPubMedGoogle Scholar
  • 76 Wong V W, Chan H L, Wong M L et al.. Clinical course after stopping lamivudine in chronic hepatitis B patients with lamivudine-resistant mutants.  Aliment Pharmacol Ther. 2004;  19 323-329
    CrossrefPubMedGoogle Scholar
  • 77 Fung S K, Andreone P, Han S H et al.. Adefovir-resistant hepatitis B can be associated with viral rebound and hepatic decompensation.  J Hepatol. 2005;  43 937-943
    CrossrefPubMedGoogle Scholar
  • 78 Osiowy C, Heathcote E J, Zoulim F et al.. Resistance to adefovir dipivoxil in patiens with lamivudine-resistant chronic hepatitis B.  Hepatology. 2005;  42(suppl 1) 586A
    PubMedGoogle Scholar
  • 79 Brunelle M N, Jacquard A C, Pichoud C et al.. Susceptibility to antivirals of a human HBV strain with mutations conferring resistance to both lamivudine and adefovir.  Hepatology. 2005;  41 1391-1398
    CrossrefPubMedGoogle Scholar
  • 80 Marcellin P, Chang T T, Lim S G et al.. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B.  N Engl J Med. 2003;  348 808-816
    CrossrefPubMedGoogle Scholar
  • 81 Sung J JY, Lai J Y, Zeusem S et al.. A randomised double-blind phase II study of lamivudine (LAM) compared to lamivudine plus adefovir dipivoxil (ADV) for treatment naive patients with chronic hepatitis B (CHB): week 52 analysis.  J Hepatol. 2003;  38(suppl 2) 69
    PubMedGoogle Scholar
  • 82 Ghany M, Lutchman G, Kleiner D et al.. Lamvudine and adefovir versus adefovir alone for HBeAg-positive chronic hepatitis B.  Hepatology. 2005;  42(suppl 1) 591A
    PubMedGoogle Scholar

E. Jenny HeathcoteM.D. 

Toronto Western Hospital, University Health Network, 399 Bathurst Street

6B Fell Pavilion, Room 154, Toronto, Ontario, Canada M5T 2S8

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