Research ArticleIncidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir
Graphical abstract
Introduction
Over the last 15 years, the outcome of chronic hepatitis B virus (HBV) infection has dramatically improved due to the development of effective treatment options [1]. In particular, long-term monotherapy with one of the current first-line nucleos(t)ide analogues (NAs), entecavir (ETV) or tenofovir disoproxil fumarate (TDF), results in maintained virological remission in >95% of patients, often achieves regression of the histological lesions of cirrhosis and prevents or reverses hepatic decompensation [1], [2], [3], [4]. However, hepatocellular carcinoma (HCC) may still develop in chronic hepatitis B (CHB) patients, particularly those with cirrhosis, even when they achieve maintained virological remission under long-term therapy with NA(s) [5], [6]. Most of the HCC data in chronic HBV patients come from cohorts of patients treated with lamivudine and/or adefovir [5], [6], [7], two drugs with a weaker antiviral potency and a higher risk of resistance, while strong HCC data in ETV and particularly TDF-treated patients are missing [7].
Since HCC remains the major complication of chronic HBV patients, the identification of cases at high or increased risk for HCC is mandatory. Recently, three risk scores (GAG-HCC, CU-HCC, and REACH-B) for predicting the development of HCC in untreated CHB patients have been reported [8], [9], [10] and their predictability was subsequently confirmed in patients treated with entecavir [11]. However, all these scores were derived from and confirmed in cohorts of CHB patients from East Asia and have not been validated in patients of other ethnicities and geographical origin [7]. The aim of this large, multicentre, cohort study was to evaluate the incidence and the predictors of HCC as well as the accuracy of the existing HCC risk scores in Caucasian CHB patients, receiving the currently recommended oral antiviral agents ETV and/or TDF.
Section snippets
Patient population
All patients with CHB, followed in the liver clinics of the seven participating centres up to September 2012, were retrospectively included in this study if they were adults (⩾16 years old) Caucasians and had received treatment with ETV or TDF for at least 6 months. The participating centres were in Greece (Athens, Larissa, Thessaloniki), Italy (Milano), Spain (Barcelona), The Netherlands (Rotterdam) and Turkey (Ankara). Patients with or without cirrhosis of any severity as well as
Results
In total, 1756 CHB patients with or without cirrhosis started therapy with ETV and/or TDF in the 7 participating centres during the period of this study. Ninety (5%) patients were excluded because they were not Caucasians (n = 34) or had short (<6 months) follow-up under ETV/TDF without development of HCC (n = 56). The main baseline characteristics at the onset of ETV or TDF of the 1666 patients who were included in this study are presented in Table 1. Most of the patients were HBeAg negative (85%)
Discussion
The findings of this large multicentre retrospective study in Caucasian patients with CHB indicate that HCC may still develop under effective long-term ETV or TDF therapy, with the HCC risk being higher in patients with more advanced liver disease. The 5-year cumulative HCC rates of 3.7% in CHB patients without cirrhosis, 17.5% in patients with compensated cirrhosis and 36.3% in patients with decompensated cirrhosis, or the estimated mean annual HCC rates of 0.7%, 3.5%, and 7.3% respectively,
Conflict of interest
G.V. Papatheodoridis: advisor/lecturer for Abbott/AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Janssen, Merck, Novartis, Roche; research grants AbbVie, Bristol-Meier Squibb, Gilead, Janssen, Roche; consultant for Roche; Data Safety Management Board for Gilead. G.N. Dalekos: advisor/lecturer for AbbVie, Bristol-Myers Squibb, Gilead, Novartis, Bayer, Roche; grant support from Bristol-Myers Squibb, Gilead, Roche. C. Yurdaydin: speaker’s bureau and/or advisor for
Authors’ contributions
G.V. Papatheodoridis: Conception and design of the study; assembly, analysis and interpretation of data; drafting of the manuscript; approval of the final version of the manuscript. G.N. Dalekos: Design of the study; interpretation of data; revision of the manuscript; approval of the final version of the manuscript. C. Yurdaydin: Design of the study; interpretation of data; revision of the manuscript; approval of the final version of the manuscript. M. Buti: Conception and design of the study;
References (19)
EASL Clinical Practice Guidelines: management of chronic hepatitis B virus infection
J Hepatol
(2012)- et al.
Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study
Lancet
(2013) - et al.
Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy: a systematic review
J Hepatol
(2010) - et al.
Independent risk factors and predictive score for the development of hepatocellular carcinoma in chronic hepatitis B
J Hepatol
(2009) - et al.
Risk estimation for hepatocellular carcinoma in chronic hepatitis B (REACH-B): development and validation of a predictive score
Lancet Oncol
(2011) - et al.
Accuracy of risk scores for patients with chronic hepatitis B receiving entecavir treatment
Gastroenterology
(2013) - et al.
Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors
J Hepatol
(2008) - et al.
Effect of nucleos(t)ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients: a propensity score analysis
J Hepatol
(2013) - et al.
Efficacy and safety of entecavir versus adefovir in chronic hepatitis B patients with hepatic decompensation: a randomized, open-label study
Hepatology
(2011)
Cited by (137)
Immunotherapeutic treatments in hepatocellular carcinoma; achievements, challenges and future prospects
2021, International ImmunopharmacologyHepatocellular Carcinoma Prediction Models in Chronic Hepatitis B: A Systematic Review of 14 Models and External Validation
2021, Clinical Gastroenterology and HepatologyControversies in the Management of Hepatitis B: Hepatocellular Carcinoma
2021, Clinics in Liver DiseaseHistological features of chronic hepatitis B patients with normal alanine aminotransferase according to different criteria
2024, Hepatology CommunicationsA prediction nomogram for hepatitis B virus-associated hepatocellular carcinoma
2024, Scandinavian Journal of Gastroenterology