Prevention and Surveillance of Hepatitis B Virus-Related Hepatocellular Carcinoma

ABSTRACT

Hepatocellular carcinoma (HCC) is associated with hepatitis B virus (HBV) infection in approximately 50% of cases, although the oncogenic mechanisms of HBV are not well understood. Vaccination for HBV has successfully lowered the rates of both HBV infection and HCC. Once chronic HBV infection is established, the objective of antiviral treatment is to prevent disease progression to liver cirrhosis or HCC, or both. Studies have found HBV DNA level to be a strong predictor for the development of cirrhosis and HCC, irrespective of the status of viral and biochemical factors. This article reviews recent clinical trials evaluating sustained viral suppression with interferon alfa and lamivudine. The results support the need to reduce viral load as an important therapeutic goal. For HCC not prevented by these measures, surveillance using ultrasonography and serum α-fetoprotein assay every 3 to 6 months is able to detect HCC at an earlier stage and allows curative therapy with survival benefit.

HBV vaccine - hepatocellular carcinoma - interferon - lamivudine - liver cirrhosis

REFERENCES

• 1 Parkin D M, Bray F, Ferlay J, Pisani P. Estimating the world cancer burden: Globocan 2000.  Int J Cancer. 2001;  94 153-156
• 2 Chen P J, Chen D S. Hepatitis B virus infection and hepatocellular carcinoma: molecular genetics and clinical perspectives.  Semin Liver Dis. 1999;  19 253-262
• 3 Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures.  J Viral Hepat. 2004;  11 97-107
• 4 Nakamoto Y, Kaneko S, Fan H et al.. Prevention of hepatocellular carcinoma development associated with chronic hepatitis by anti-fas ligand antibody therapy.  J Exp Med. 2002;  196 1105-1111
• 5 Manigold T, Rehermann B. Chronic hepatitis B and hepatocarcinogenesis: does prevention of “collateral damage” bring the cure?.  Hepatology. 2003;  37 707-710
• 6 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
• 7 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
• 8 Liaw Y F, Tai D I, Chu C M et al.. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis: a prospective study.  Gastroenterology. 1986;  90 263-267
• 9 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
• 10 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
• 11 Chen H L, Chang M H, Ni Y H et al.. Seroepidemiology of hepatitis B virus infection in children: ten years of mass vaccination in Taiwan.  JAMA. 1996;  276 906-908
• 12 Ni Y H, Chang M H, Huang L M et al.. Hepatitis B virus infection in children and adolescents in a hyperendemic area: 15 years after mass hepatitis B vaccination.  Ann Intern Med. 2001;  135 796-800
• 13 Chang M H. Decreasing incidence of hepatocellular carcinoma among children following universal hepatitis B immunization.  Liver Int. 2003;  23 309-314
• 14 Chang M H, Chen C J, Lai M S et al.. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group.  N Engl J Med. 1997;  336 1855-1859
• 15 Kane M A. Global control of primary hepatocellular carcinoma with hepatitis B vaccine: the contributions of research in Taiwan.  Cancer Epidemiol Biomarkers Prev. 2003;  12 2-3
• 16 Yu M W, Hsu F C, Sheen I S et al.. Prospective study of hepatocellular carcinoma and liver cirrhosis in asymptomatic chronic hepatitis virus carriers.  Am J Epidemiol. 1997;  145 1039-1047
• 17 Chen C J, Yang H I, Su J et al.. Viral load is a strong predictor of liver cirrhosis risk in people chronically infected with hepatitis B virus regardless of hepatitis B e antigen status.  J Hepatol. 2005;  42 S172 , (abst 476)
• 18 Iloeje U H, Yang H I, Su J et al.. Serum hepatitis B virus DNA level predicts the incidence of liver cirrhosis in persons chronically infected with HBV.  J Hepatol. 2005;  42 S180 , (abst 496)
• 19 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
• 20 Brunetto M R, Oliveri F, Coco B et al.. The outcome of chronic anti-HBe positive chronic hepatitis B in alpha interferon treated and untreated patients: a long term cohort study.  J Hepatol. 2002;  36 263-270
• 21 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
• 22 Yu M W, Yeh S H, Chen P J et al.. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men.  J Natl Cancer Inst. 2005;  97 265-272
• 23 Chen C J, Yang H I, Su J et al.. Elevated serum level hepatitis B virus DNA is an independent risk factor for hepatocellular carcinoma: a long-term follow-up study in Taiwan.  J Hepatol. 2005;  42 16S , (abst 35)
• 24 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
• 25 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
• 26 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
• 27 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
• 28 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
• 29 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
• 30 Lampertico P, Del Ninno E, Vigano M et al.. Long-term suppression of hepatitis B e antigen-negative chronic hepatitis B by 24-month interferon therapy.  Hepatology. 2003;  37 756-763
• 31 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
• 32 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
• 33 Yuen M F, Hui C K, Cheng C C et al.. Long-term follow-up of interferon alfa treatment in Chinese patients with chronic hepatitis B infection: the effect on hepatitis B e antigen seroconversion and the development of cirrhosis-related complications.  Hepatology. 2001;  34 139-145
• 34 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
• 35 Lin S M, Yu M L, Lee C M et al.. Interferon therapy improves prognosis in patients with chronic hepatitis B.  J Hepatol. 2005;  42 S149 , (abst 406)
• 36 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
• 37 Camma C, Giunta M, Andreone P, Craxi A. Interferon and prevention of hepatocellular carcinoma in viral cirrhosis: an evidence-based approach.  J Hepatol. 2001;  34 593-602
• 38 Leung N. Liver disease-significant improvement with lamivudine.  J Med Virol. 2000;  61 380-385
• 39 Goodman Z, Dhillon A P, Wu P C et al.. Lamivudine treatment reduces progression to cirrhosis in patients with chronic hepatitis B.  J Hepatol. 1999;  30(suppl 1) , 59 (abst)
• 40 Dienstag J L, Goldin R D, Heathcote E J et al.. Histological outcome during long-term lamivudine therapy.  Gastroenterology. 2003;  124 105-117
• 41 Tennant B C. Animal models of hepadnavirus-associated hepatocellular carcinoma.  Clin Liver Dis. 2001;  5 43-68
• 42 Peek S F, Toshkov I A, Erb H N et al.. 3′-Thiacytidine (3TC) delays development of hepatocellular carcinoma (HCC) in woodchucks with experimentally induced chronic woodchuck hepatitis virus (WHV) infection. Preliminary results of a lifetime study.  Hepatology. 1997;  26(suppl) 368A
• 43 Colonno R J, Genovesi E V, Medina I et al.. Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection.  J Infect Dis. 2001;  184 1236-1245
• 44 Korba B E, Cote P J, Menne S et al.. Clevudine therapy with vaccine inhibits progression of chronic hepatitis and delays onset of hepatocellular carcinoma in chronic woodchuck hepatitis virus infection.  Antivir Ther. 2004;  9 937-952
• 45 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
• 46 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
• 47 Peters M G, Hann Hw H, Martin P et al.. Adefovir dipivoxil alone or in combination with lamivudine in patients with lamivudine-resistant chronic hepatitis B.  Gastroenterology. 2004;  126 91-101
• 48 Shaw T, Locarnini S. Entecavir for the treatment of chronic hepatitis B.  Expert Rev Anti Infect Ther. 2004;  2 853-871
• 49 Lin D Y, Lin S M, Liaw Y F. Non-surgical treatment of hepatocellualr carcinoma.  J Gastroenterol Hepatol. 1997;  12(suppl) S319-S328
• 50 Lin D Y, Liaw Y F. Optimal surveillance of hepatocellular carcinoma in patients with chronic viral hepatitis.  J Gastroenterol Hepatol. 2001;  16 715-717
• 51 Bolondi L. Screening for hepatocellular carcinoma in cirrhosis.  J Hepatol. 2003;  39 1076-1084
• 52 Sheu J C, Sung J L, Chen D S et al.. Growth rate of asymptomatic hepatocellular carcinoma and its clinical implications.  Gastroenterology. 1985;  89 259-266
• 53 Sherman M, Peltekian K M, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population.  Hepatology. 1995;  22 432-438
• 54 Yu M W, Chang H C, Liaw Y F et al.. Familial risk of hepatocellular carcinoma among chronic hepatitis B carriers and their relatives.  J Natl Cancer Inst. 2000;  92 1159-1164
• 55 Sangiovanni A, Del Ninno E, Fasani P et al.. Increased survival of cirrhotic patients with a hepatocellular carcinoma detected during surveillance.  Gastroenterology. 2004;  126 1005-1014
• 56 Kim D Y, Han K-H, Ahn S H et al.. Long-term clinical results of 280 patients with hepatocellular carcinoma detected during surveillance: a 10-year follow-up study.  J Hepatol. 2005;  42 95S , (abst)