The impact of nucleos(t)ide analog therapy in hepatitis B on the incidence of hepatocellular carcinoma: an update including recent literature findings

Abstract

Worldwide, hepatocellular carcinoma (HCC) is a significant cause of morbidity and mortality. In men, it is the fifth most common cancer and seventh most common in women; HCC is the second highest cause of cancer-related death worldwide. It is less prevalent in the USA and Northern Europe and more prevalent in Eastern and South-Eastern Asia. Over 700,000 cases are diagnosed each year - half of which occur in China - and result in roughly the same number of deaths per year. HCC significantly impairs quality of life and is associated with great costs to society. It is estimated that half of the deaths from HCC are associated with hepatitis B virus (HBV). Fortunately, HBV vaccination and antiviral therapy have shown excellent efficacy in decreasing the incidence of HCC. We will discuss the relationship of HBV to HCC, address available treatments for HBV and the impact of treatment on the development of HCC.

Keywords

Liver cancer / hepatocellular carcinoma / hepatitis B / nucleos(t)ides / entecavir / tenofovir / lamivudine

References

[1] Bruix J.Management of hepatocellular carcinoma: an update..Hepatology2011;53:1020-2 PMCID:PMC3084991

[2] Chang MH,Chen CJ,Lai MW,Wu SF,Yang SS,Wang TE,Chuang WL,Lin CY,Kuo HS.Long-term effects of hepatitis B immunization of infants in preventing liver cancer..Gastroenterology2016;151:472-80.e1

[3] Liaw YF,Chow WC,Lee CZ,Tanwandee T,Shue K,Dixon JS,Sabbat J.Lamivudine for patients with chronic hepatitis B and advanced liver disease..N Engl J Med2004;351:1521-31

[4] Vlachogiannakos J.Hepatocellular carcinoma in chronic hepatitis B patients under antiviral therapy..World J Gastroenterol2013;19:8822-30 PMCID:PMC3870533

[5] Kao JH,Jow GM,Chen DS.Fine mapping of hepatitis B virus pre-S deletion and its association with hepatocellular carcinoma..Liver Int2012;32:1373-81

[6] Tseng TC,Yang HC,Wang CC,Kuo SF,Chen PJ,Kao JH.High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load..Gastroenterology2012;142:1140-9.e3; quiz e13-4

[7] Moon JC,Kim IH,Kim SW,Lee ST.Disease progression in chronic hepatitis B patients under long-term antiviral therapy..Gut Liver2015;9:395-404 PMCID:PMC4413974

[8] Fattovich G,Donato F.Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors..J Hepatol2008;48:335-52

[9] Raffetti E,Donato F.Incidence of hepatocellular carcinoma in untreated subjects with chronic hepatitis B: a systematic review and meta-analysis..Liver Int2016;36:1239-51

[10] Marcellin P,Krastev Z,Zeuzem S,Gaggar A,Massetto B,Dinh P,McHutchison JG,Gurel S,Heathcote EJ.Kinetics of hepatitis B surface antigen loss in patients with HBeAg-positive chronic hepatitis B treated with tenofovir disoproxil fumarate..J Hepatol2014;61:1228-37

[11] Lok AS.Chronic hepatitis B: update 2009..Hepatology2009;50:661-2

[12] Gish RG,Lai CL,Gadano A,Yang J,Tamez R.Loss of HBsAg antigen during treatment with entecavir or lamivudine in nucleoside-naive HBeAg-positive patients with chronic hepatitis B..J Viral Hepat2010;17:16-22

[13] Ayoub WS.Review article: current antiviral therapy of chronic hepatitis B..Aliment Pharmacol Ther2011;34:1145-58

[14] Triolo M,Colombo M.Impact of HBV therapy on the incidence of hepatocellular carcinoma..Liver Int2014;34 Suppl 1:139-45

[15] Liu F,Chen L,Ren H.Systematic review with meta-analysis: development of hepatocellular carcinoma in chronic hepatitis B patients with hepatitis B surface antigen seroclearance..Aliment Pharmacol Ther2016;43:1253-61

[16] Sung JJ,Wong VW,Chan HL.Meta-analysis: treatment of hepatitis B infection reduces risk of hepatocellular carcinoma..Aliment Pharmacol Ther2008;28:1067-77

[17] Papatheodoridis GV,Manolakopoulos S.Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review..J Hepatol2010;53:348-56

[18] Singal AK,Kuo YF.Meta-analysis: the impact of oral anti-viral agents on the incidence of hepatocellular carcinoma in chronic hepatitis B..Aliment Pharmacol Ther2013;38:98-106

[19] Hosaka T,Kobayashi M,Kawamura Y,Akuta N,Saitoh S,Ikeda K,Kumada H.Long-term entecavir treatment reduces hepatocellular carcinoma incidence in patients with hepatitis B virus infection..Hepatology2013;58:98-107

[20] Wong GL,Mak CW,Ip ZM,Iu HW,Lai JW,Chan HY.Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients with liver cirrhosis..Hepatology2013;58:1537-47

[21] Su TH,Chen CY,Chuang WL,Wang CC,Chen MY,Chien RN,Wang HY,Yang SS,Mo LR,Tseng KC,Suk FM,Bair MJ,Lei YC,Chen CL.Four-year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients..Liver Int2016;36:1755-64

[22] Kumada T,Tada T,Tanikawa M,Kanamori A,Yasuda S,Yamamoto K.Effect of nucleos(t)ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients: a propensity score analysis..J Hepatol2013;58:427-33

[23] Chang TT,Wu SS,Han KH,Safadi R,Halota W,Chi YC,Hindes R,Beebe S.Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B..Hepatology2010;52:886-93

[24] Wu CY,Ho HJ,Lee TY,Wu C.Association of nucleos(t)ide analogue therapy with reduced risk of hepatocellular carcinoma in patients with chronic hepatitis B: a nationwide cohort study..Gastroenterology2014;147:143-51.e5

[25] Coffin CS,Pang JX,Klein P,Myers RP.The incidence of hepatocellular carcinoma is reduced in patients with chronic hepatitis B on long-term nucleos(t)ide analogue therapy..Aliment Pharmacol Ther2014;40:1262-9

[26] Gordon SC,Rupp LB,Holmberg SD,Spradling PR,Vijayadeva V,Henkle EM,Lu M.Antiviral therapy for chronic hepatitis B virus infection and development of hepatocellular carcinoma in a US population..Clin Gastroenterol Hepatol2014;12:885-93 PMCID:PMC5719871

[27] Marcellin P,Buti M,Sievert W,Washington MK,Flaherty JF,Bornstein JD,Subramanian GM,Heathcote EJ.Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study..Lancet2013;381:468-75

[28] Kim W,Loomba R,Dinh P,Martins E,Gurel S.Long term tenofovir disoproxil fumarate (TDF) therapy and the risk of hepatocellular carcinoma..J Hepatol2013;58:S19

[29] Wang HM,Lee CM,Wang JH,Kee KM,Tseng PL,Chen CH.Three-year efficacy and safety of tenofovir in nucleos(t)ide analog-naive and nucleos(t)ide analog-experienced chronic hepatitis B patients..J Gastroenterol Hepatol2016;31:1307-14

[30] Sinn DH,Goo J,Gwak GY,Choi MS,Koh KC,Paik SW.Hepatocellular carcinoma risk in chronic hepatitis B virus-infected compensated cirrhosis patients with low viral load..Hepatology2015;62:694-701

[31] Lin D,Nguyen N,Kim Y,Le A,Nguyen V,Li J,Hsing A,Nguyen MH.Reduction of chronic hepatitis B-related hepatocellular carcinoma with anti-viral therapy, including low risk patients..Aliment Pharmacol Ther2016;44:846-55

[32] Koklu S,Gulsen MT,Koksal AS,Aygun C,Ozdil K,Akin E,Yuksel I,Ibis M,Nadir I,Akbal E,Basar O,Baykal O.Long-term efficacy and safety of lamivudine, entecavir, and tenofovir for treatment of hepatitis B virus-related cirrhosis..Clin Gastroenterol Hepatol2013;11:88-94

[33] Idilman R,Koruk M,Meral CE,Elhan AH,Yurdaydin C.Long-term entecavir or tenofovir disoproxil fumarate therapy in treatment-naive chronic hepatitis B patients in the real-world setting..J Viral Hepat2015;22:504-10

[34] Papatheodoridis GV,Yurdaydin C,Goulis J,Sypsa V,Mangia G,Keskin O,Hansen BE,Galanis K,Colombo M,Janssen HL.Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir..J Hepatol2015;62:363-70

[35] Papatheodoridis GV,Hansen BE,Lampertico P.Risk of hepatocellular carcinoma in chronic hepatitis B: assessment and modification with current antiviral therapy..J Hepatol2015;62:956-67

[36] Papatheodoridis GV,Touloumi G,Raptopoulou-Gigi M,Vafiadis-Zouboulis I,Chouta A,Drakoulis C,Ketikoglou I,Mela M,Dalekos GN.Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet.Greece cohort..J Viral Hepat2015;22:120-7

[37] Wang JP,Wu CY,Chao Y,Li CP.Nucleos(t)ide analogues associated with a reduced risk of hepatocellular carcinoma in hepatitis B patients: a population-based cohort study..Cancer2015;121:1446-55

[38] Huang G,Wang ZG,Yuan SX,Zhou WP.Antiviral therapy improves postoperative survival in patients with hepatocellular carcinoma: a randomized controlled trial..Ann Surg2015;261:56-66

[39] Yin J,Han Y,Deng Y,Guo W,Wang H,Cao G.Effect of antiviral treatment with nucleotide/nucleoside analogs on postoperative prognosis of hepatitis B virus-related hepatocellular carcinoma: a two-stage longitudinal clinical study..J Clin Oncol2013;31:3647-55

[40] Wu CY,Ho HJ,Kuo KN,Lin JT.Association between nucleoside analogues and risk of hepatitis B virus-related hepatocellular carcinoma recurrence following liver resection..JAMA2012;308:1906-14

[41] Zhou Y,Zhao Y,Li B.Antiviral therapy decreases recurrence of hepatitis B virus-related hepatocellular carcinoma after curative resection: a meta-analysis..World J Surg2014;38:2395-402

[42] Wong VW,Mo F,Loong HH,Lui YY,Sung JJ,Chan HL.Clinical scoring system to predict hepatocellular carcinoma in chronic hepatitis B carriers..J Clin Oncol2010;28:1660-5

[43] Yuen MF,Fong DY,Wong DK,But DY,Wong BC,Lai CL.Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B..J Hepatol2009;50:80-8

[44] Abu-Amara M,Malhi G,Yim C,Wong DK,Feld JJ.The applicability of hepatocellular carcinoma risk prediction scores in a North American patient population with chronic hepatitis B infection..Gut2016;65:1347-58