Achieving a Cure: The Next Frontier in Hepatitis B Treatment

Abstract

Since the discovery of the hepatitis B virus (HBV) by Blumberg et al. in 1965, significant progress has been made in understanding the pathogenesis of the virus and creating an effective vaccine. In the past two decades, several antiviral therapies have reduced the incidence of HBV-related hepatocellular carcinoma. The nucleos(t)ide analogues have succeeded in decreasing the viral load to undetectable levels but have been unable to eradicate the virus due to the persistence of covalently closed circular DNA in the hepatocyte nucleus. Despite being on successful antiviral therapy for multiple years, patients are still at risk of developing hepatocellular carcinoma. Recently, a number of different drug targets have been identified that intervene on the viral replication cycle or host immune system. This chapter discusses the immunopathogenesis of the virus, the effectiveness of nucleos(t)ide analogues, and recent therapeutic developments. In light of robust progress achieved in antiviral therapy, the cure for hepatitis B is likely on the horizon.

Review of Related Factors for Persistent Risk of Hepatitis B Virus-Associated Hepatocellular Carcinoma

“…The Liver Disease Prevention Center, Division of Gastroenterology and Hepatology at Thomas Jefferson University Hospital, has observed several HBV positive patients develop HCC even after 10 or more years of successful viral suppression [106]. Specifically, in our observational cohort, 17 patients developed HCC despite having noted undetectable HBV DNA for up to 12 years and on treatment for up to 19 years (Table 1) [107]. Currently, this is among the longest known follow-up studies on the development of HCC in patients on HBV treatment.…”

“…Development of HCC in patients with cirrhosis on long-term antiviral therapy. Sourced from Boortalary et al[107].…”

Model‐based meta‐analysis to quantify the effects of short interfering RNA therapeutics on hepatitis B surface antigen turnover in hepatitis B‐infected mice

“…Pharmacological treatment of chronic HBV includes life‐long nucleos(t)ide analog (NA) therapy, that is, daily oral entecavir, tenofovir disoproxil fumarate, or tenofovir alafenamide therapy. Such treatments do not allow for “complete HBV” cure, defined as eradication and sterilization of HBV, due to the persistence of covalently closed circular DNA (cccDNA) and HBV DNA integration in the host genome 10 . Both sources serve as templates for the vast production and secretion of viral proteins such as hepatitis B surface antigen (HBsAg) in the circulation.…”

“…Such treatments do not allow for “complete HBV” cure, defined as eradication and sterilization of HBV, due to the persistence of covalently closed circular DNA (cccDNA) and HBV DNA integration in the host genome. 10 Both sources serve as templates for the vast production and secretion of viral proteins such as hepatitis B surface antigen (HBsAg) in the circulation. High‐serum HBsAg concentrations for prolonged periods of time establish a persistent inflammatory state, leading to progressive T‐cell exhaustion.…”