Semin Liver Dis 2006; 26(2): 142-152
DOI: 10.1055/s-2006-939752
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662.

Hepatitis B Virus-Related Cirrhosis: Natural History and Treatment

Chia-Ming Chu1 , Yun-Fan Liaw1
  • 1Liver Research Unit, Chang Gung Memorial Hospital and Chang Gung University, Taipei, Taiwan
Further Information

Publication History

Publication Date:
03 May 2006 (online)

ABSTRACT

In patients with compensated hepatitis B virus (HBV) cirrhosis, active viral replication correlates significantly with the risk of hepatic flare, decompensation, and the development of hepatocellular carcinoma (HCC). The 5-year survival of patients with compensated cirrhosis was reported to be 80 to 85%, and is significantly lower in patients with replicative HBV. Both interferon and maintenance lamivudine therapy have been shown to reduce the risk of decompensation or HCC and prolong survival in responders. A finite course of interferon is recommended as the first-line agent. For patients who had a contraindication for or who have failed interferon therapy, direct antiviral(s) can be considered for long-term treatment. Once decompensation occurs, mortality increases remarkably. Early treatment with nucleoside analogues should be instituted. Lamivudine therapy is associated with rapid viral suppression, improvement in Child-Pugh scores, and improved survival, but drug resistance is a major problem and is associated directly with a poor clinical outcome. Adefovir or entecavir is preferred in patients with decompensated cirrhosis who require long duration of treatment, due to the lower rate of development of resistance.

REFERENCES

  • 1 Liaw Y F, Tai D I, Chu C M, Chen T J. The development of cirrhosis in patients with chronic type B hepatitis: a prospective study.  Hepatology. 1988;  8 493-496
  • 2 Fattovich G, Brollo L, Giustina G et al.. Natural history and prognostic factors for chronic hepatitis type B.  Gut. 1991;  32 294-298
  • 3 Sumi H, Yokosuka O, Seki N et al.. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease.  Hepatology. 2003;  37 19-26
  • 4 Liaw Y F, Chen Y C, Sheen I S et al.. Impact of acute hepatitis C virus superinfection in patients with chronic hepatitis B virus infection.  Gastroenterology. 2004;  126 1024-1029
  • 5 Liaw Y F, Lin D Y, Chen T J, Chu C M. Natural course after the development of cirrhosis in patients with chronic type B hepatitis: a prospective study.  Liver. 1989;  9 235-241
  • 6 Tsai S L, Yang P M, Lai M Y et al.. Natural history of hepatitis B surface antigen-positive cirrhosis in Taiwan: a clinicopathological study.  J Gastroenterol Hepatol. 1988;  3 583-592
  • 7 Realdi G, Fattovich G, Hadziyannis S et al.. Survival and prognostic factors in 366 patients with compensated cirrhosis type B: a multicenter study. The Investigators of the European Concerted Action on Viral Hepatitis (EUROHEP).  J Hepatol. 1994;  21 656-666
  • 8 de Jongh F E, Janssen H L, de Man R A et al.. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver.  Gastroenterology. 1992;  103 1630-1635
  • 9 Chu C M, Liaw Y F, Sheen I S, Lin D Y, Huang M J. Sex difference in chronic hepatitis B virus infection: an appraisal based on the status of hepatitis B e antigen and antibody.  Hepatology. 1983;  3 947-950
  • 10 Chu C M, Hung S J, Lin J, Tai D I, Liaw Y F. Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels.  Am J Med. 2004;  116 829-834
  • 11 Liaw Y F, Chen J J, Chen T J. Acute exacerbation in patients with liver cirrhosis: a clinicopathological study.  Liver. 1990;  10 177-184
  • 12 Fattovich G, Giustina G, Realdi G, Corrocher R, Schalm S W. Long-term outcome of hepatitis B e antigen-positive patients with compensated cirrhosis treated with interferon alfa. European Concerted Action on Viral Hepatitis (EUROHEP).  Hepatology. 1997;  26 1338-1342
  • 13 Liaw Y F, Pao C C, Chu C M, Sheen I S, Huang M J. Changes of serum HBV-DNA in two types of clinical events preceding spontaneous HBeAg seroconversion in chronic type B hepatitis.  Hepatology. 1987;  7 1-3
  • 14 Liaw Y F, Sheen I S, Chen T J, Chu C M, Pao C C. Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: a prospective study.  Hepatology. 1991;  13 627-631
  • 15 Chung H T, Lai C L, Lok A S. Pathogenic role of hepatitis B virus in hepatitis B surface antigen-negative decompensated cirrhosis.  Hepatology. 1995;  22 25-29
  • 16 Fattovich G, Giustina G, Schalm S W et al.. Occurrence of hepatocellular carcinoma and decompensation in western European patients with cirrhosis type B. The EUROHEP Study Group on Hepatitis B Virus and Cirrhosis.  Hepatology. 1995;  21 77-82
  • 17 Fattovich G, Pantalena M, Zagni I et al.. Effect of hepatitis B and C virus infections on the natural history of compensated cirrhosis: a cohort study of 297 patients.  Am J Gastroenterol. 2002;  97 2886-2895
  • 18 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
  • 19 Chen Y C, Sheen I S, Chu C M, Liaw Y F. Prognosis following spontaneous HBsAg seroclearance in chronic hepatitis B patients with or without concurrent infection.  Gastroenterology. 2002;  123 1084-1089
  • 20 Fattovich G, Stroffolini T, Zagni I, Donato F. Hepatocellular carcinoma in cirrhosis: incidence and risk factors.  Gastroenterology. 2004;  127(5 suppl 1) S35-S50
  • 21 Kato Y, Nakata K, Omagari K et al.. Risk of hepatocellular carcinoma in patients with cirrhosis in Japan. Analysis of infectious hepatitis viruses.  Cancer. 1994;  74 2234-2238
  • 22 Ikeda K, Saitoh S, Suzuki Y et al.. Interferon decreases hepatocellular carcinogenesis in patients with cirrhosis caused by the hepatitis B virus: a pilot study.  Cancer. 1998;  82 827-835
  • 23 Chiaramonte M, Stroffolini T, Vian A et al.. Rate of incidence of hepatocellular carcinoma in patients with compensated viral cirrhosis.  Cancer. 1999;  85 2132-2137
  • 24 Ikeda K, Arase Y, Kobayashi M et al.. Consistently low hepatitis B virus DNA saves patients from hepatocellular carcinogenesis in HBV-related cirrhosis. A nested case-control study using 96 untreated patients.  Intervirology. 2003;  46 96-104
  • 25 Mahmood S, Niiyama G, Kamei A et al.. Influence of viral load and genotype in the progression of hepatitis B-associated liver cirrhosis to hepatocellular carcinoma.  Liver Int. 2005;  25 220-225
  • 26 Di Marco V, Lo Iacono O, Camma C et al.. The long-term course of chronic hepatitis B.  Hepatology. 1999;  30 257-264
  • 27 Hui A Y, Chan H L, Leung N W et al.. Survival and prognostic indicators in patients with hepatitis B virus-related cirrhosis after onset of hepatic decompensation.  J Clin Gastroenterol. 2002;  34 569-572
  • 28 Fattovich G, Giustina G, Sanchez-Tapias J et al.. Delayed clearance of serum HBsAg in compensated cirrhosis B: relation to interferon alpha therapy and disease prognosis. European Concerted Action on Viral Hepatitis (EUROHEP).  Am J Gastroenterol. 1998;  93 896-900
  • 29 Liaw Y F. Prevention and surveillance of hepatitis B virus-related hepatocellular carcinoma.  Semin Liver Dis. 2005;  25(suppl 1) 40-47
  • 30 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
  • 31 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
  • 32 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
  • 33 Lin S M, Tai D I, Chien R N et al.. Comparison of long-term effects of lymphoblastoid interferon alpha and recombinant interferon alpha-2a therapy in patients with chronic hepatitis B.  J Viral Hepat. 2004;  11 349-357
  • 34 Papatheodoridis G V, Manesis E, Hadziyannis S J. The long-term outcome of interferon-alpha treated and untreated patients with HBeAg-negative chronic hepatitis B.  J Hepatol. 2001;  34 306-313
  • 35 Brunetto M R, Oliveri F, Coco B et al.. Outcome of anti-HBe positive chronic hepatitis B in alpha-interferon treated and untreated patients: a long term cohort study.  J Hepatol. 2002;  36 263-270
  • 36 Oon C J. Long-term survival following treatment of hepatocellular carcinoma in Singapore: evaluation of Wellferon in the prophylaxis of high-risk pre-cancerous conditions.  Cancer Chemother Pharmacol. 1992;  31(suppl) S137-S142
  • 37 Mazzella G, Accogli E, Sottili S et al.. Alpha interferon treatment may prevent hepatocellular carcinoma in HCV-related liver cirrhosis.  J Hepatol. 1996;  24 141-147
  • 38 Benvegnu L, Chemello L, Noventa F et al.. Retrospective analysis of the effect of interferon therapy on the clinical outcome of patients with viral cirrhosis.  Cancer. 1998;  83 901-909
  • 39 International Interferon-α Hepatocellular Carcinoma Study Group . Effect of interferon-α on progression of cirrhosis to hepatocellular carcinoma: a retrospective cohort study.  Lancet. 1998;  351 1535-1539
  • 40 Cooksley W G, Piratvisuth T, Lee S D et al.. Peginterferon alpha-2a (40 kDa): an advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B.  J Viral Hepat. 2003;  10 298-305
  • 41 Marcellin P, Lau G K, Bonino F 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 1206-1217
  • 42 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
  • 43 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
  • 44 Dienstag J, Goldin R, Heathcote E J et al.. Histological outcome during long-term lamivusine therapy.  Gastroenterology. 2003;  124 105-117
  • 45 Di Marco V, Marzano A, Lampertico P et al.. Clinical outcome of HBeAg-negative chronic hepatitis B in relation to virological response to lamivudine.  Hepatology. 2004;  40 883-891
  • 46 Papatheodoridis G V, Dimou E, Dimakopoulos K et al.. Outcome of hepatitis B e antigen-negative chronic hepatitis B on long-term nucleos(t)ide analog therapy starting with lamivudine.  Hepatology. 2005;  42 121-129
  • 47 Hadziyannis S J, Tassopoulos N C, Heathcote E J et al.. Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B.  N Engl J Med. 2005;  352 2673-2681
  • 48 Chien R N, Lin C H, Liaw Y F. The effect of lamivudine therapy in hepatic decompensation during acute exacerbation of chronic hepatitis B.  J Hepatol. 2003;  38 322-327
  • 49 Hoofnagle J H, Di Bisceglie A M, Waggoner J G, Park Y. Interferon alfa for patients with clinically apparent cirrhosis due to chronic hepatitis B.  Gastroenterology. 1993;  104 1116-1121
  • 50 Perrillo R, Tamburro C, Regenstein F et al.. Low-dose, titratable interferon alfa in decompensated liver disease caused by chronic infection with hepatitis B virus.  Gastroenterology. 1995;  109 908-916
  • 51 Villeneuve J P, Condreay L D, Willems B et al.. Lamivudine treatment for decompensated cirrhosis resulting from chronic hepatitis B.  Hepatology. 2000;  31 207-210
  • 52 Kapoor D, Guptan R C, Wakil S M et al.. Beneficial effects of lamivudine in hepatitis B virus-related decompensated cirrhosis.  J Hepatol. 2000;  33 308-312
  • 53 Yao F Y, Bass N M. Lamivudine treatment in patients with severely decompensated cirrhosis due to replicating hepatitis B infection.  J Hepatol. 2000;  33 301-307
  • 54 Yao F Y, Terrault N A, Freise C, Maslow L, Bass N M. 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
  • 55 Perrillo R P, Wright T, Rakela J et al.. A multicenter United States-Canadian trial to assess lamivudine monotherapy before and after liver transplantation for chronic hepatitis B.  Hepatology. 2001;  33 424-432
  • 56 Andreone P, Biselli M, Gramenzi A et al.. Efficacy of lamivudine therapy for advanced liver disease in patients with precore mutant hepatitis B virus infection awaiting liver transplantation.  Transplantation. 2002;  74 1119-1124
  • 57 Fontana R J, Keeffe E B, Carey W et al.. Effect of lamivudine treatment on survival of 309 North American patients awaiting liver transplantation for chronic hepatitis B.  Liver Transpl. 2002;  8 433-439
  • 58 Fontana R J, Hann H W, Perrillo R P et al.. Determinants of early mortality in patients with decompensated chronic hepatitis B treated with antiviral therapy.  Gastroenterology. 2002;  123 719-727
  • 59 Hann H W, Fontana R J, Wright T et al.. A United States compassionate use study of lamivudine treatment in nontransplantation candidates with decompensated hepatitis B virus-related cirrhosis.  Liver Transpl. 2003;  9 49-56
  • 60 Manolakopoulos S, Karatapanis S, Elefsiniotis J et al.. Clinical course of lamivudine monotherapy in patients with decompensated cirrhosis due to HBeAg negative chronic HBV infection.  Am J Gastroenterol. 2004;  99 57-63
  • 61 Bae S H, Yoon S K, Choi J Y et al.. Timing of lamivudine administration according to Child class in patients with decompensated cirrhosis.  J Gastroenterol Hepatol. 2005;  20 1527-1532
  • 62 Schiff E R, Lai C L, Hadziyannis S et al.. Adefovir dipivoxil therapy for lamivudine-resistant hepatitis B in pre- and post-liver transplantation patients.  Hepatology. 2003;  38 1419-1427
  • 63 Kim K M, Choi W B, Lim Y S et al.. Adefovir dipivoxil alone or in combination with ongoing lamivudine in patients with decompensated liver disease and lamivudine-resistant hepatitis B virus.  J Korean Med Sci. 2005;  20 821-828
  • 64 Liaw Y F, Lee C M, Chien R N, Yeh C T. Switching to adefovir monotherapy after emergence of lamivudine resistant mutations in patients with liver cirrhosis.  J Viral Hepat. 2006;  13 250-255

 Professor
Yun-Fan LiawM.D. 

Liver Research Unit, Chang Gung Memorial Hospital

199, Tung Hwa North Road, Taipei 105, Taiwan