Advertisement

Hepatitis B Virus-Associated Hepatocellular Carcinoma

  • Youhua Xie
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1018)

Abstract

Liver cancer is the fifth most common cancer worldwide in men and the ninth in women. It is also the second most common cause of cancer mortality. Hepatocellular carcinoma (HCC) is the most common type of liver cancer. About 350 million people globally are chronically infected with HBV. Chronic hepatitis B virus (HBV) infection accounts for at least 50% cases of HCC worldwide. Other non-HBV factors may increase HCC risk among persons with chronic HBV infection. Both indirect and direct mechanisms are involved in HCC oncogenesis by HBV. HCC-promoting HBV factors include long-lasting infection, high levels of HBV replication, HBV genotype, HBV integration, specific HBV mutants, and HBV-encoded oncoproteins (e.g., HBx and truncated preS2/S proteins). Recurrent liver inflammation caused by host immune responses during chronic HBV infection can lead to liver fibrosis and cirrhosis and accelerate hepatocyte turnover rate and promote accumulation of mutations. Major breakthroughs have been achieved in the prevention of HBV-associated HCC with HBV vaccines and antiviral therapies.

Keywords

Chronic infection Cirrhosis Genotype Hepatitis B virus Hepatocellular carcinoma HBeAg HBsAg HBx Integration Mutation PreS/S 

Notes

Acknowledgments

The author would like to apologize for citing selected papers due to the space limit. This work was supported by the National Key Project for Infectious Diseases of China (2012ZX10002-006, 2012ZX10002012-003), National Basic Research Program of China (2012CB519002), and Natural Science Foundation of China (81472226).

No potential conflict of interest was disclosed.

References

  1. 1.
    Globocan (2012) Estimated cancer incidence, mortality and prevalence worldwide in 2012. International agency for research on cancer, World Health Organization, http://globocan.iarc.fr
  2. 2.
    Ganem D, Prince AM (2004) Hepatitis B virus infection – natural history and clinical consequences. N Engl J Med 350:1118–1129CrossRefPubMedGoogle Scholar
  3. 3.
    Parkin DM (2006) The global health burden of infection-associated cancers in the year 2002. Int J Cancer 118:3030–3044CrossRefPubMedGoogle Scholar
  4. 4.
    Mittal S, El-Serag HB (2013) Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 47(Suppl):S2–S6CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Sherman M (2010) Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis 30:3–16CrossRefPubMedGoogle Scholar
  6. 6.
    Yuan JM, Ross RK, Stanczyk FZ, Govindarajan S, Gao YT, Henderson BE, Yu MC (1995) A cohort study of serum testosterone and hepatocellular carcinoma in Shanghai, China. Int J Cancer 63:491–493CrossRefPubMedGoogle Scholar
  7. 7.
    Yang JD, Kim WR, Coelho R, Mettler TA, Benson JT, Sanderson SO, Therneau TM, Kim B, Roberts LR (2011) Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. Clin Gastroenterol Hepatol 9:64–70CrossRefPubMedGoogle Scholar
  8. 8.
    El-Serag HB, Tran T, Everhart JE (2004) Diabetes increases the risk of chronic liver disease and hepatocellular carcinoma. Gastroenterology 126:460–468CrossRefPubMedGoogle Scholar
  9. 9.
    Bressac B, Kew M, Wands J, Ozturk M (1991) Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350:429–431CrossRefPubMedGoogle Scholar
  10. 10.
    Marrero JA, Fontana RJ, Fu S, Conjeevaram HS, Su GL, Lok AS (2005) Alcohol, tobacco and obesity are synergistic risk factors for hepatocellular carcinoma. J Hepatol 42:218–224CrossRefPubMedGoogle Scholar
  11. 11.
    Brau N, Fox RK, Xiao P, Marks K, Naqvi Z, Taylor LE, Trikha A, Sherman M, Sulkowski MS, Dieterich DT, Rigsby MO, Wright TL, Hernandez MD, Jain MK, Khatri GK, Sterling RK, Bonacini M, Martyn CA, Aytaman A, Llovet JM, Brown ST, Bini EJ, North American Liver Cancer in HIVSG (2007) Presentation and outcome of hepatocellular carcinoma in HIV-infected patients: a U.S.-Canadian multicenter study. J Hepatol 47:527–537CrossRefPubMedGoogle Scholar
  12. 12.
    Farci P, Niro GA (2012) Clinical features of hepatitis D. Semin Liver Dis 32:228–236CrossRefPubMedGoogle Scholar
  13. 13.
    Wang SH, Yeh SH, Lin WH, Wang HY, Chen DS, Chen PJ (2009) Identification of androgen response elements in the enhancer I of hepatitis B virus: a mechanism for sex disparity in chronic hepatitis B. Hepatology 50:1392–1402CrossRefPubMedGoogle Scholar
  14. 14.
    Naugler WE, Sakurai T, Kim S, Maeda S, Kim K, Elsharkawy AM, Karin M (2007) Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science 317:121–124CrossRefPubMedGoogle Scholar
  15. 15.
    Wang SH, Yeh SH, Lin WH, Yeh KH, Yuan Q, Xia NS, Chen DS, Chen PJ (2012) Estrogen receptor alpha represses transcription of HBV genes via interaction with hepatocyte nuclear factor 4alpha. Gastroenterology 142:989–998. e984CrossRefPubMedGoogle Scholar
  16. 16.
    Qian GS, Ross RK, Yu MC, Yuan JM, Gao YT, Henderson BE, Wogan GN, Groopman JD (1994) A follow-up study of urinary markers of aflatoxin exposure and liver cancer risk in Shanghai, People’s Republic of China. Cancer Epidemiol Biomark Prev 3:3–10Google Scholar
  17. 17.
    Yang HI, Lu SN, Liaw YF, You SL, Sun CA, Wang LY, Hsiao CK, Chen PJ, Chen DS, Chen CJ, Taiwan Community-Based Cancer Screening Project G (2002) Hepatitis B e antigen and the risk of hepatocellular carcinoma. N Engl J Med 347:168–174CrossRefPubMedGoogle Scholar
  18. 18.
    Sun HC, Zhang W, Qin LX, Zhang BH, Ye QH, Wang L, Ren N, Zhuang PY, Zhu XD, Fan J, Tang ZY (2007) Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol 47:684–690CrossRefPubMedGoogle Scholar
  19. 19.
    Chen CJ, Yang HI, Su J, Jen CL, You SL, Lu SN, Huang GT, Iloeje UH, Group R-HS (2006) Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level. JAMA 295:65–73CrossRefPubMedGoogle Scholar
  20. 20.
    Chen CJ, Yang HI, Iloeje UH, Group R-HS (2009) Hepatitis B virus DNA levels and outcomes in chronic hepatitis B. Hepatology 49:S72–S84CrossRefPubMedGoogle Scholar
  21. 21.
    Chan HL, Tse CH, Mo F, Koh J, Wong VW, Wong GL, Lam Chan S, Yeo W, Sung JJ, Mok TS (2008) High viral load and hepatitis B virus subgenotype ce are associated with increased risk of hepatocellular carcinoma. J Clin Oncol 26:177–182CrossRefPubMedGoogle Scholar
  22. 22.
    Lin CL, Kao JH (2011) The clinical implications of hepatitis B virus genotype: recent advances. J Gastroenterol Hepatol 26(Suppl 1):123–130CrossRefPubMedGoogle Scholar
  23. 23.
    Kao JH, Chen PJ, Lai MY, Chen DS (2000) Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B. Gastroenterology 118:554–559CrossRefPubMedGoogle Scholar
  24. 24.
    Chan HL, Hui AY, Wong ML, Tse AM, Hung LC, Wong VW, Sung JJ (2004) Genotype C hepatitis B virus infection is associated with an increased risk of hepatocellular carcinoma. Gut 53:1494–1498CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Ni YH, Chang MH, Wang KJ, Hsu HY, Chen HL, Kao JH, Yeh SH, Jeng YM, Tsai KS, Chen DS (2004) Clinical relevance of hepatitis B virus genotype in children with chronic infection and hepatocellular carcinoma. Gastroenterology 127:1733–1738CrossRefPubMedGoogle Scholar
  26. 26.
    Sanchez-Tapias JM, Costa J, Mas A, Bruguera M, Rodes J (2002) Influence of hepatitis B virus genotype on the long-term outcome of chronic hepatitis B in western patients. Gastroenterology 123:1848–1856CrossRefPubMedGoogle Scholar
  27. 27.
    Brechot C, Gozuacik D, Murakami Y, Paterlini-Brechot P (2000) Molecular bases for the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Semin Cancer Biol 10:211–231CrossRefPubMedGoogle Scholar
  28. 28.
    Minami M, Daimon Y, Mori K, Takashima H, Nakajima T, Itoh Y, Okanoue T (2005) Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis. Oncogene 24:4340–4348CrossRefPubMedGoogle Scholar
  29. 29.
    Murakami Y, Saigo K, Takashima H, Minami M, Okanoue T, Brechot C, Paterlini-Brechot P (2005) Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas. Gut 54:1162–1168CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Sung WK, Zheng H, Li S, Chen R, Liu X, Li Y, Lee NP, Lee WH, Ariyaratne PN, Tennakoon C, Mulawadi FH, Wong KF, Liu AM, Poon RT, Fan ST, Chan KL, Gong Z, Hu Y, Lin Z, Wang G, Zhang Q, Barber TD, Chou WC, Aggarwal A, Hao K, Zhou W, Zhang C, Hardwick J, Buser C, Xu J, Kan Z, Dai H, Mao M, Reinhard C, Wang J, Luk JM (2012) Genome-wide survey of recurrent HBV integration in hepatocellular carcinoma. Nat Genet 44:765–769CrossRefPubMedGoogle Scholar
  31. 31.
    Ding D, Lou X, Hua D, Yu W, Li L, Wang J, Gao F, Zhao N, Ren G, Li L, Lin B (2012) Recurrent targeted genes of hepatitis B virus in the liver cancer genomes identified by a next-generation sequencing-based approach. PLoS Genet 8:e1003065CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Ferber MJ, Montoya DP, Yu C, Aderca I, McGee A, Thorland EC, Nagorney DM, Gostout BS, Burgart LJ, Boix L, Bruix J, McMahon BJ, Cheung TH, Chung TK, Wong YF, Smith DI, Roberts LR (2003) Integrations of the hepatitis B virus (HBV) and human papillomavirus (HPV) into the human telomerase reverse transcriptase (hTERT) gene in liver and cervical cancers. Oncogene 22:3813–3820CrossRefPubMedGoogle Scholar
  33. 33.
    Liang HW, Wang N, Wang Y, Wang F, Fu Z, Yan X, Zhu H, Diao W, Ding Y, Chen X, Zhang CY, Zen K (2016) Hepatitis B virus-human chimeric transcript HBx-LINE1 promotes hepatic injury via sequestering cellular microRNA-122. J Hepatol 64:278–291CrossRefPubMedGoogle Scholar
  34. 34.
    Lau CC, Sun T, Ching AK, He M, Li JW, Wong AM, Co NN, Chan AW, Li PS, Lung RW, Tong JH, Lai PB, Chan HL, To KF, Chan TF, Wong N (2014) Viral-human chimeric transcript predisposes risk to liver cancer development and progression. Cancer Cell 25:335–349CrossRefPubMedGoogle Scholar
  35. 35.
    Baptista M, Kramvis A, Kew MC (1999) High prevalence of 1762(T) 1764(A) mutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers. Hepatology 29:946–953CrossRefPubMedGoogle Scholar
  36. 36.
    Kuang SY, Jackson PE, Wang JB, Lu PX, Munoz A, Qian GS, Kensler TW, Groopman JD (2004) Specific mutations of hepatitis B virus in plasma predict liver cancer development. Proc Natl Acad Sci U S A 101:3575–3580CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Yang HI, Yeh SH, Chen PJ, Iloeje UH, Jen CL, Su J, Wang LY, Lu SN, You SL, Chen DS, Liaw YF, Chen CJ, Group R-HS (2008) Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma. J Natl Cancer Inst 100:1134–1143CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Liu S, Zhang H, Gu C, Yin J, He Y, Xie J, Cao G (2009) Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma: a meta-analysis. J Natl Cancer Inst 101:1066–1082CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Pollicino T, Cacciola I, Saffioti F, Raimondo G (2014) Hepatitis B virus PreS/S gene variants: pathobiology and clinical implications. J Hepatol 61:408–417CrossRefPubMedGoogle Scholar
  40. 40.
    Chen BF, Liu CJ, Jow GM, Chen PJ, Kao JH, Chen DS (2006) High prevalence and mapping of pre-S deletion in hepatitis B virus carriers with progressive liver diseases. Gastroenterology 130:1153–1168CrossRefPubMedGoogle Scholar
  41. 41.
    Hsieh YH, Su IJ, Wang HC, Chang WW, Lei HY, Lai MD, Chang WT, Huang W (2004) Pre-S mutant surface antigens in chronic hepatitis B virus infection induce oxidative stress and DNA damage. Carcinogenesis 25:2023–2032CrossRefPubMedGoogle Scholar
  42. 42.
    Wang HC, Huang W, Lai MD, Su IJ (2006) Hepatitis B virus pre-S mutants, endoplasmic reticulum stress and hepatocarcinogenesis. Cancer Sci 97:683–688CrossRefPubMedGoogle Scholar
  43. 43.
    Lucifora J, Arzberger S, Durantel D, Belloni L, Strubin M, Levrero M, Zoulim F, Hantz O, Protzer U (2011) Hepatitis B virus X protein is essential to initiate and maintain virus replication after infection. J Hepatol 55:996–1003CrossRefPubMedGoogle Scholar
  44. 44.
    Forgues M, Difilippantonio MJ, Linke SP, Ried T, Nagashima K, Feden J, Valerie K, Fukasawa K, Wang XW (2003) Involvement of Crm1 in hepatitis B virus X protein-induced aberrant centriole replication and abnormal mitotic spindles. Mol Cell Biol 23:5282–5292CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Wen Y, Golubkov VS, Strongin AY, Jiang W, Reed JC (2008) Interaction of hepatitis B viral oncoprotein with cellular target HBXIP dysregulates centrosome dynamics and mitotic spindle formation. J Biol Chem 283:2793–2803CrossRefPubMedGoogle Scholar
  46. 46.
    Martin-Lluesma S, Schaeffer C, Robert EI, van Breugel PC, Leupin O, Hantz O, Strubin M (2008) Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1. Hepatology 48:1467–1476CrossRefPubMedGoogle Scholar
  47. 47.
    Kim S, Park SY, Yong H, Famulski JK, Chae S, Lee JH, Kang CM, Saya H, Chan GK, Cho H (2008) HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint. Oncogene 27:3457–3464CrossRefPubMedGoogle Scholar
  48. 48.
    Knoll S, Furst K, Thomas S, Villanueva Baselga S, Stoll A, Schaefer S, Putzer BM (2011) Dissection of cell context-dependent interactions between HBx and p53 family members in regulation of apoptosis: a role for HBV-induced HCC. Cell Cycle 10:3554–3565CrossRefPubMedGoogle Scholar
  49. 49.
    Ahn JY, Jung EY, Kwun HJ, Lee CW, Sung YC, Jang KL (2002) Dual effects of hepatitis B virus X protein on the regulation of cell-cycle control depending on the status of cellular p53. J Gen Virol 83:2765–2772CrossRefPubMedGoogle Scholar
  50. 50.
    Liu H, Shi W, Luan F, Xu S, Yang F, Sun W, Liu J, Ma C (2010) Hepatitis B virus X protein upregulates transcriptional activation of human telomerase reverse transcriptase. Virus Genes 40:174–182CrossRefPubMedGoogle Scholar
  51. 51.
    Kojima H, Kaita KD, Xu Z, Ou JH, Gong Y, Zhang M, Minuk GY (2003) The absence of up-regulation of telomerase activity during regeneration after partial hepatectomy in hepatitis B virus X gene transgenic mice. J Hepatol 39:262–268CrossRefPubMedGoogle Scholar
  52. 52.
    Cougot D, Wu Y, Cairo S, Caramel J, Renard CA, Levy L, Buendia MA, Neuveut C (2007) The hepatitis B virus X protein functionally interacts with CREB-binding protein/p300 in the regulation of CREB-mediated transcription. J Biol Chem 282:4277–4287CrossRefPubMedGoogle Scholar
  53. 53.
    Cougot D, Allemand E, Riviere L, Benhenda S, Duroure K, Levillayer F, Muchardt C, Buendia MA, Neuveut C (2012) Inhibition of PP1 phosphatase activity by HBx: a mechanism for the activation of hepatitis B virus transcription. Sci Signal 5:ra1CrossRefPubMedGoogle Scholar
  54. 54.
    Park SH, Jung JK, Lim JS, Tiwari I, Jang KL (2011) Hepatitis B virus X protein overcomes all-trans retinoic acid-induced cellular senescence by downregulating levels of p16 and p21 via DNA methylation. J Gen Virol 92:1309–1317CrossRefPubMedGoogle Scholar
  55. 55.
    Chung TW, Lee YC, Kim CH (2004) Hepatitis B viral HBx induces matrix metalloproteinase-9 gene expression through activation of ERK and PI-3K/AKT pathways: involvement of invasive potential. FASEB J 18:1123–1125CrossRefPubMedGoogle Scholar
  56. 56.
    Yu FL, Liu HJ, Lee JW, Liao MH, Shih WL (2005) Hepatitis B virus X protein promotes cell migration by inducing matrix metalloproteinase-3. J Hepatol 42:520–527CrossRefPubMedGoogle Scholar
  57. 57.
    Arzumanyan A, Friedman T, Kotei E, Ng IO, Lian Z, Feitelson MA (2012) Epigenetic repression of E-cadherin expression by hepatitis B virus x antigen in liver cancer. Oncogene 31:563–572PubMedGoogle Scholar
  58. 58.
    Pan J, Lian Z, Wallett S, Feitelson MA (2007) The hepatitis B x antigen effector, URG7, blocks tumour necrosis factor alpha-mediated apoptosis by activation of phosphoinositol 3-kinase and beta-catenin. J Gen Virol 88:3275–3285CrossRefPubMedGoogle Scholar
  59. 59.
    Rahmani Z, Huh KW, Lasher R, Siddiqui A (2000) Hepatitis B virus X protein colocalizes to mitochondria with a human voltage-dependent anion channel, HVDAC3, and alters its transmembrane potential. J Virol 74:2840–2846CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Yang B, Bouchard MJ (2012) The hepatitis B virus X protein elevates cytosolic calcium signals by modulating mitochondrial calcium uptake. J Virol 86:313–327CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Arzumanyan A, Friedman T, Ng IO, Clayton MM, Lian Z, Feitelson MA (2011) Does the hepatitis B antigen HBx promote the appearance of liver cancer stem cells? Cancer Res 71:3701–3708CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Yoo YG, Oh SH, Park ES, Cho H, Lee N, Park H, Kim DK, Yu DY, Seong JK, Lee MO (2003) Hepatitis B virus X protein enhances transcriptional activity of hypoxia-inducible factor-1alpha through activation of mitogen-activated protein kinase pathway. J Biol Chem 278:39076–39084CrossRefPubMedGoogle Scholar
  63. 63.
    Sanz-Cameno P, Martin-Vilchez S, Lara-Pezzi E, Borque MJ, Salmeron J, Munoz de Rueda P, Solis JA, Lopez-Cabrera M, Moreno-Otero R (2006) Hepatitis B virus promotes angiopoietin-2 expression in liver tissue: role of HBV x protein. Am J Pathol 169:1215–1222CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Chisari FV, Klopchin K, Moriyama T, Pasquinelli C, Dunsford HA, Sell S, Pinkert CA, Brinster RL, Palmiter RD (1989) Molecular pathogenesis of hepatocellular carcinoma in hepatitis B virus transgenic mice. Cell 59:1145–1156CrossRefPubMedGoogle Scholar
  65. 65.
    Wang HC, Chang WT, Chang WW, Wu HC, Huang W, Lei HY, Lai MD, Fausto N, Su IJ (2005) Hepatitis B virus pre-S2 mutant upregulates cyclin A expression and induces nodular proliferation of hepatocytes. Hepatology 41:761–770CrossRefPubMedGoogle Scholar
  66. 66.
    Wang LH, Huang W, Lai MD, Su IJ (2012) Aberrant cyclin A expression and centrosome overduplication induced by hepatitis B virus pre-S2 mutants and its implication in hepatocarcinogenesis. Carcinogenesis 33:466–472CrossRefPubMedGoogle Scholar
  67. 67.
    Luan F, Liu H, Gao L, Liu J, Sun Z, Ju Y, Hou N, Guo C, Liang X, Zhang L, Sun W, Ma C (2009) Hepatitis B virus protein preS2 potentially promotes HCC development via its transcriptional activation of hTERT. Gut 58:1528–1537CrossRefPubMedGoogle Scholar
  68. 68.
    Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS, Liang DC, Shau WY, Chen DS (1997) Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Child Hepatoma Study Group New England J Med 336:1855–1859Google Scholar
  69. 69.
    Greenberg DP (1993) Pediatric experience with recombinant hepatitis B vaccines and relevant safety and immunogenicity studies. Pediatr Infect Dis J 12:438–445CrossRefPubMedGoogle Scholar
  70. 70.
    Greenup AJ, Tan PK, Nguyen V, Glass A, Davison S, Chatterjee U, Holdaway S, Samarasinghe D, Jackson K, Locarnini SA, Levy MT (2014) Efficacy and safety of tenofovir disoproxil fumarate in pregnancy to prevent perinatal transmission of hepatitis B virus. J Hepatol 61:502–507CrossRefPubMedGoogle Scholar
  71. 71.
    Pan CQ, Duan Z, Dai E, Zhang S, Han G, Wang Y, Zhang H, Zou H, Zhu B, Zhao W, Jiang H, China Study Group for the Mother-to-Child Transmission of Hepatitis B (2016) Tenofovir to prevent hepatitis B transmission in mothers with high viral load. N Engl J Med 374:2324–2334CrossRefPubMedGoogle Scholar
  72. 72.
    Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J, Cirrhosis Asian Lamivudine Multicentre Study G (2004) Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 351:1521–1531CrossRefPubMedGoogle Scholar
  73. 73.
    Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A (2010) Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review. J Hepatol 53:348–356CrossRefPubMedGoogle Scholar
  74. 74.
    Papatheodoridis GV, Chan HL, Hansen BE, Janssen HL, Lampertico P (2015) Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy. J Hepatol 62:956–967CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2017

Authors and Affiliations

  1. 1.Key Laboratory of Medical Molecular Virology (Ministries of Education and Health), Shanghai Medical CollegeFudan UniversityShanghaiPeople’s Republic of China

Personalised recommendations