Lower Observed Hepatocellular Carcinoma Incidence in Chronic Hepatitis B Patients Treated With Entecavir: Results of the ENUMERATE Study

Abstract

OBJECTIVES:Data from the United States are lacking regarding the impact of entecavir (ETV) on the risk of hepatocellular carcinoma (HCC). Our aim is to determine whether treatment with ETV is associated with a reduced HCC risk by calculating the expected HCC incidence based on the Risk Estimation for Hepatocellular Carcinoma in Chronic Hepatitis B (REACH-B) model and comparing it with the observed HCC incidence. METHODS:The incidence of HCC in US patients treated with ETV between 2005 and 2013 in a retrospective cohort was obtained. The predicted HCC incidence was calculated using the REACH-B model. The standardized incidence ratios (SIRs) were calculated as a ratio of observed over predicted HCC cases. RESULTS:Of 841 patients, 646 (65% male, 84% Asian, median age 47 years, 36% hepatitis B e antigen positive, 9.4% with cirrhosis) met the inclusion criteria. Over a median follow-up of 4 years, 17 (2.6%) cases of HCC were diagnosed, including 8 out of 61 (13.1%) patients with cirrhosis and 9 out of 585 (1.5%) without cirrhosis. Compared with those without HCC, the 17 patients with HCC were older at 53 years vs. 47 years and more likely to have cirrhosis at 47.1% vs. 8.4%. Among patients without cirrhosis, the observed HCC incidence was signifi cantly lower than predicted by the fourth year (SIR, 0.37; 95% confi dence interval: 0.166-0.82). A sensitivity analysis that comprised all patients, including those with cirrhosis, showed that at the maximum follow-up time of 8.2 years, a signifi cantly lower than predicted HCC incidence was noted with an SIR of 0.56 (95% confi dence interval: 0.35-0.905).CONCLUSIONS: Based on the REACH-B model, long-term ETV therapy was associated with a lower than predicted HCC incidence. However, the risk of HCC persisted, and careful HCC surveillance remains warranted despite the anti-viral treatment.SUPPLEMENTARY MATERIAL is linked to the online version of the paper at

A large real‐world cohort study examining the effects of long‐term entecavir on hepatocellular carcinoma and HBsAg seroclearance

“…In their study, only 30% of the population were Asians, and predicted cases with respective SIR were only determined at the time of each incident HCC instead of using a yearly estimate. Another American study with 841 entecavir‐treated patients followed up to 8.2 years also showed similar findings . The majority (84%) of the subjects were Asians.…”

Four‐year entecavir therapy reduces hepatocellular carcinoma, cirrhotic events and mortality in chronic hepatitis B patients

“…Several studies have demonstrated that antiviral therapy might reduce the risk of HCC. (Table ) Their limitations include studying a small proportion of patients with cirrhosis (9%‐33% of all patients) and a relatively short duration of antiviral therapy. The indications and regimens for NUC therapy and the patient populations were heterogeneous and thus not comparable.…”

“…In the current study, the 5‐year cumulative incidence of HCC was 26.4% in the untreated cohort and 11.3% in the entecavir cohort. Several European and American studies using the HCC risk scores (REACH‐B, CU‐HCC and GAG‐HCC) for comparison because of unavailable control groups . Unexpectedly, the benefit of NUC therapy were found only in non‐cirrhotic rather than cirrhotic subgroups, probably because of small number of cirrhotic patients and these HCC risk scores might not be a good reference in cirrhotic patients undergoing NUC therapy.…”

“…In this study, we confirmed that PAGE‐B score>/=18 (vs <18) could predict the development of HCC (log‐rank P <.0001) in Asian patients (Figure S1). In addition, some studies include HCC development within the 1st year of NUC therapy, which might reduce the protective effect of NUC therapy.…”

Low‐level viremia in hepatitis b patients on antiviral treatment: Can we ignore it?

“…With the goal of antiviral treatment being to decrease the morbidity and mortality associated with chronic hepatitis B (CHB), the first‐line antiviral agents recommended for treating CHB patients by the American Association for the Study of Liver Diseases (AASLD) include pegylated interferon, entecavir, and tenofovir . With their easy tolerability and efficacy in suppressing viral replication associated with high genetic barrier to resistance, many patients with HBV worldwide were treated with either oral agent, often achieving reversal of cirrhosis and reduced incidence of HCC …”