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

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.

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
• 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
• 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
• 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
• 5 Rawal B K, Parida S, Watkins R P et al.. Symptomatic reactivation of hepatitis B in pregnancy.  Lancet. 1991;  337 364
• 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
• 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
• 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
• 9 Wai C-T, Fontana R J. Clinical significance of hepatitis B virus genotypes, variants, and mutants.  Clin Liver Dis. 2004;  8 321-352
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 39 Lok A S, McMahon B J. Chronic hepatitis B: update of recommendations.  Hepatology. 2004;  39 857-861
• 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
• 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
• 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
• 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
• 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
• 45 Marcellin P, Asselah T, Boyer N. Treatment of chronic hepatitis B.  J Viral Hepat. 2005;  12 333-345
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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
• 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