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Ayoub et al.                                                                                                                                    Nucleos(t)ide therapy for hepatitis B impacts HCC incidence

           studies, the reduction of HCC incidence was not the   Disease. Management of hepatocellular carcinoma: an update.
           primary outcome measured. Despite these limitations,   Hepatology 2011;53:1020-2.
           results from medium-length follow up studies with   2.   Chang MH, You SL, Chen CJ, Liu CJ, Lai MW, Wu TC, Wu SF, Lee
           entecavir and tenofovir and analyses of registration   CM, Yang SS, Chu HC, Wang TE, Chen BW, Chuang WL, Soon
                                                                 MS, Lin CY, Chiou ST, Kuo HS, Chen DS; Taiwan Hepatoma Study
           trials already suggest that treatment with these NAs   Group. Long-term effects of hepatitis B immunization of infants in
           have chemopreventive effects and reduce risk of HCC.   preventing liver cancer. Gastroenterology 2016;151:472-80.e1.
                                                              3.   Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, Tanwandee
           Continued viral suppression is critical to minimize   T, Tao QM, Shue K, Keene ON, Dixon JS, Gray DF, Sabbat J;
           the risk of HCC development, although achieving       Cirrhosis Asian Lamivudine Multicentre Study Group. Lamivudine
           viral suppression will not eliminate the risk of HCC,   for patients with chronic hepatitis B and advanced liver disease. N
           specifically  in  high-risk  patients  with  advanced   4.   Engl J Med 2004;351:1521-31.
                                                                 Vlachogiannakos J, Papatheodoridis G. Hepatocellular carcinoma
           fibrosis or cirrhosis. In these situations, continuous   in chronic hepatitis B patients under antiviral therapy. World J
           surveillance for HCC is essential. Prospective studies   Gastroenterol 2013;19:8822-30.
           which address the confounding factors such as      5.   Kao JH, Liu CJ, Jow GM, Chen PJ, Chen DS, Chen BF. Fine
           gender, age, fibrosis stage. Finally, HCC screening   mapping of hepatitis B virus pre-S deletion and its association with
           algorithms are necessary to better elucidate the impact   hepatocellular carcinoma. Liver Int 2012;32:1373-81.
           of chemoprevention on HCC development in HBV       6.   Tseng TC, Liu CJ, Yang HC, Su TH, Wang CC, Chen CL, Kuo SF, Liu
           patients treated with the newer nucleos(t)ide agents.   CH, Chen PJ, Chen DS, Kao JH. High levels of hepatitis B surface
                                                                 antigen increase risk of hepatocellular carcinoma in patients with low
                                                                 HBV load. Gastroenterology 2012;142:1140-9.e3; quiz e13-4.
           In summary, treatment of hepatitis B leads to      7.   Moon JC, Kim SH, Kim IH, Lee CH, Kim SW, Lee SO, Lee ST, Kim
           decreased incidence of hepatocellular carcinoma in    DG. Disease progression in chronic hepatitis B patients under long-
           Asians and Caucasians regardless of the nucleos(t)ide   term antiviral therapy. Gut Liver 2015;9:395-404.
           used. Also, decreasing the HBV viral load, regardless   8.   Fattovich G, Bortolotti F, Donato F. Natural history of chronic
           of achieving seroconversion, results in decreased     hepatitis B: special emphasis on disease progression and prognostic
           HCC incidence. Despite this reduction in HCC          factors. J Hepatol 2008;48:335-52.
           incidence, patients treated with nucleos(t)ides still   9.   Raffetti E, Fattovich G, Donato F. Incidence of hepatocellular
                                                                 carcinoma in untreated subjects with chronic hepatitis B: a systematic
           need to undergo liver cancer screening. Several HCC   review and meta-analysis. Liver Int 2016;36:1239-51.
           predictor models have been developed, but as of now,   10.  Marcellin P, Buti M, Krastev Z, de Man RA, Zeuzem S, Lou L,
           there are limitations in applicability.               Gaggar A, Flaherty JF, Massetto B, Lin L, Dinh P, Subramanian GM,
                                                                 McHutchison JG, Flisiak R, Gurel S, Dusheiko GM, Heathcote EJ.
           DECLARATIONS                                          Kinetics of hepatitis B surface antigen loss in patients with HBeAg-
                                                                 positive chronic hepatitis B treated with tenofovir disoproxil fumarate.
                                                                 J Hepatol 2014;61:1228-37.
           Authors’ contributions                             11.  Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology
           Project conception: W.S. Ayoub, P. Martin, P.D. Jones  2009;50:661-2.
           Literature review, manuscript drafting and critical   12.  Gish RG, Chang TT, Lai CL, de Man R, Gadano A, Poordad F, Yang
           revision: W.S. Ayoub, F. Dailey, P. Martin, P.D. Jones   J, Brett-Smith H, Tamez R. Loss of HBsAg antigen during treatment
                                                                 with entecavir or lamivudine in nucleoside-naive HBeAg-positive
                                                                 patients with chronic hepatitis B. J Viral Hepat 2010;17:16-22.
           Financial support and sponsorship                  13.  Ayoub WS, Keeffe EB. Review article: current antiviral therapy of
           None.                                                 chronic hepatitis B. Aliment Pharmacol Ther 2011;34:1145-58.
                                                              14.  Triolo M, Della Corte C, Colombo M. Impact of HBV therapy on the
           Conflicts of interest                                 incidence of hepatocellular carcinoma. Liver Int 2014;34 Suppl 1:139-
           Walid S. Ayoub, Francis Dailey, Paul Martin, Patricia D.   45.
           Jones declare that they have no conflicts of interest.  15.  Liu F, Wang XW, Chen L, Hu P, Ren H, Hu HD. Systematic review
                                                                 with meta-analysis: development of hepatocellular carcinoma
                                                                 in chronic hepatitis B patients with hepatitis B surface antigen
           Patient consent                                       seroclearance. Aliment Pharmacol Ther 2016;43:1253-61.
           Not applicable.                                    16.  Sung JJ, Tsoi KK, Wong VW, Li KC, Chan HL. Meta-analysis:
                                                                 treatment of hepatitis B infection reduces risk of hepatocellular
           Ethics approval                                       carcinoma. Aliment Pharmacol Ther 2008;28:1067-77.
           This article does not contain any studies with human   17.  Papatheodoridis GV, Lampertico P, Manolakopoulos S, Lok A.
           or animal subjects performed by any of the authors.   Incidence of hepatocellular carcinoma in chronic hepatitis B patients
                                                                 receiving nucleos(t)ide therapy: a systematic review. J Hepatol
                                                                 2010;53:348-56.
           REFERENCES                                         18.  Singal AK, Salameh H, Kuo YF, Fontana RJ. Meta-analysis: the
                                                                 impact of oral anti-viral agents on the incidence of hepatocellular
                                                                 carcinoma in  chronic hepatitis B. Aliment Pharmacol  Ther
           1.   Bruix J, Sherman M; American Association for the Study of Liver   2013;38:98-106.

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