Chronic Hepatitis B and Hepatocellular Carcinoma: Novel Therapeutic Concepts

Abstract

Hepatitis B virus (HBV) is a partially double-stranded hepatotropic DNA virus that currently infects about 4% of the population worldwide (ca. 296 million people) with the highest prevalence in Asia and Africa and more than half a million deaths annually. Clinically, HBV infection can be asymptomatic with normal or near normal aminotransferase levels or with elevated alanine aminotransferase levels, significant necroinflammation and eventually progression to advanced liver cirrhosis and hepatocellular carcinoma. Indications for treatment of chronic hepatitis B are HBV DNA levels >2000 IU per milliliter and liver cirrhosis. Different from the now available curative oral therapies of chronic hepatitis C by direct-acting antiviral agents (DAAs), to date there exists no curative therapeutic strategy for chronic hepatitis B. Therefore, multiple new investigational therapeutic antiviral concepts are currently explored. Globally, HCC is the sixth most diagnosed cancer and the third leading cancer-related death in 2020. The management of HCC is complex and depends on the stage of the disease at the time of diagnosis. HCC is largely chemotherapy-resistant and no systemic treatments improved survival until recently. In the early 2000s HCC treatment was revolutionized by sorafenib, a modestly effective orally available tyrosine kinase inhibitor (TKI). In 2018 levantinib was also approved as first-line treatment, followed by several antiangiogenic agents, including among others regorafinib, ramucirumab, and cabozantinib as second-line treatments. Unfortunately, 5-year overall survival of advanced or metastatic disease is still <10%. Therefore, numerous clinical trials are ongoing, assessing immune checkpoint inhibitors (ICIs) in combination with each other or with targeted agents in the treatment of HCCs. Further, ICI incorporation into the treatment of very early-stage HCC by resection or ablation may lower recurrence rate or even cure these patients.