The suppressive effect of nucleos(t)ide analogue treatment on the incidence of hepatocellular carcinoma in chronic hepatitis B patients.

The development of nucleos(t)ide analogues (NA) has influenced hepatitis B virus management. However, the annual incidence rate during NA treatment has been reported to be 0.3-1.2% in non-cirrhosis cases and 1.8-6.0% in cirrhosis cases, indicating that the suppressive effect of NA treatment on hepatocellular carcinoma (HCC) would be insufficient. Past studies, including one randomized control trial that compared lamivudine treatment with placebo, have revealed that NA treatment could suppress the incidence of HCC in patients with advanced fibrosis. However, it remains unknown whether NA treatment can suppress the incidence of HCC in chronic hepatitis patients without advanced fibrosis. The HCC incidence in patients treated with entecavir was similar to that of those treated with lamivudine, although entecavir exhibits a stronger viral suppression than lamivudine. The following risk factors related to the incidence of HCC during NA treatment have been identified: older age, male gender, pre-existing cirrhosis, a family clustering of hepatitis B virus, lower platelet counts, and higher hepatitis B core-related antigens as baseline factors and higher alpha fetoprotein levels as an on-treatment factor. Conversely, the loss of the hepatitis B surface antigen (HBsAg) by interferon or NA was correlated with a lower HCC incidence rate. Because interferon treatment has much more effects on reducing HBsAg levels compared with NA treatment, a combination treatment with NA and pegylated interferon can bring additional reduction of HBsAg levels compared with NA monotherapy. Further study is needed to clarify this.