Elsevier

Journal of Hepatology

Volume 62, Issue 2, February 2015, Pages 363-370
Journal of Hepatology

Research Article
Incidence and predictors of hepatocellular carcinoma in Caucasian chronic hepatitis B patients receiving entecavir or tenofovir

https://doi.org/10.1016/j.jhep.2014.08.045Get rights and content

Background & Aims

The risk of hepatocellular carcinoma (HCC) in Caucasian patients with chronic hepatitis B (CHB), treated with entecavir (ETV) or tenofovir (TDF), is unclear. We evaluated the incidence and predictors of HCC and the accuracy of existing HCC risk scores in Caucasian CHB patients receiving ETV/TDF.

Methods

This large, multicentre, retrospective cohort study included 1666 adult Caucasian CHB patients under ETV/TDF for 39 months. CHB without cirrhosis, compensated and decompensated cirrhosis were present in 67%, 39%, and 3% of patients, respectively. The predictability of baseline parameters and three risk scores (GAG-HCC, CU-HCC, and REACH-B), developed in Asian patients, was assessed.

Results

The cumulative probability of HCC was 1.3%, 3.4%, and 8.7% at year-1, year-3, and year-5 after ETV/TDF onset. Older age and lower platelets were strong independent HCC predictors in the total population and in the subgroups of cirrhotic and non-cirrhotic patients, while liver disease severity was an independent HCC predictor in the total population and in the cirrhotics. GAG-HCC, CU-HCC, and REACH-B risk scores were associated with HCC development only in the univariable but not in the multivariable analyses and offered poor to modest predictability.

Conclusions

HCC can still develop in Caucasian CHB patients treated with ETV/TDF. Besides the well-known predictors of HCC, such as older age, male gender and more advanced liver disease, lower platelets represent an independent factor of higher HCC risk. The applicability and predictability of HCC risk scores developed in Asian patients are poor or modest in Caucasian CHB patients, for whom different risk scores are required.

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;

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