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Hepatology. 2017 Nov;66(5):1444-1453. doi: 10.1002/hep.29320. Epub 2017 Oct 11.

The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B.

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Department of Gastroenterology, Medical School of National and Kapodistrian University of Athens, Laiko General Hospital, Athens, Greece.
Department of Gastroenterology, University of Ankara Medical School, Ankara, Turkey.
Department of Medicine and Research Laboratory of Internal Medicine, University of Thessaly, Larissa, Greece.
Hospital General Universitario Valle Hebron and Ciberehd, Barcelona, Spain.
Department of Gastroenterology & Hepatology, Erasmus MC, University Medical Center, Rotterdam, The Netherlands.
Section of Hepatology, University Clinic Leipzig, Leipzig, Germany.
Hospital U Puerta de Hierro, IDIPHIM CIBERehd, Madrid, Spain.
Department of Hygiene, Epidemiology & Medical Statistics, Medical School of National and Kapodistrian University of Athens, Athens, Greece.
4th Department of Internal Medicine, Αristotle University of Thessaloniki Medical School, Thessaloniki, Greece.
2nd Department of Internal Medicine, Medical School of National and Kapodistrian University of Athens, Hippokratio General Hospital of Athens, Athens, Greece.
"A. M. and A. Migliavacca" Center for Liver Disease, Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.
Humanitas Clinical and Research Centre, Rozzano, Italy.
Liver Clinic, Toronto Western & General Hospital, University Health Network, Toronto, ON, Canada.


Whether there is a change of hepatocellular carcinoma (HCC) incidence in chronic hepatitis B patients under long-term therapy with potent nucleos(t)ide analogues is currently unclear. We therefore assessed the HCC incidence beyond year 5 of entecavir/tenofovir (ETV/TDF) therapy and tried to determine possible factors associated with late HCC occurrence. This European, 10-center, cohort study included 1,951 adult Caucasian chronic hepatitis B patients without HCC at baseline who received ETV/TDF for ≥1 year. Of them, 1,205 (62%) patients without HCC within the first 5 years of therapy have been followed for 5-10 (median, 6.8) years. HCCs have been diagnosed in 101/1,951 (5.2%) patients within the first 5 years and 17/1,205 (1.4%) patients within 5-10 years. The yearly HCC incidence rate was 1.22% within and 0.73% after the first 5 years (P = 0.050). The yearly HCC incidence rate did not differ within and after the first 5 years in patients without cirrhosis (0.49% versus 0.47%, P = 0.931), but it significantly declined in patients with cirrhosis (3.22% versus 1.57%, P = 0.039). All HCCs beyond year 5 developed in patients older than 50 years at ETV/TDF onset. Older age, lower platelets at baseline and year 5, and liver stiffness ≥12 kPa at year 5 were independently associated with more frequent HCC development beyond year 5 in multivariable analysis. No patient with low Platelets, Age, Gender-Hepatitis B score at baseline or year 5 developed HCC.


The HCC risk decreases beyond year 5 of ETV/TDF therapy in Caucasian chronic hepatitis B patients, particularly in those with compensated cirrhosis; older age (especially ≥50 years), lower platelets, and liver stiffness ≥12 kPa at year 5 represent the main risk factors for late HCC development. (Hepatology 2017;66:1444-1453).

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