New Approaches to the Treatment of Chronic Hepatitis B

Abstract

The currently recommended treatment for chronic hepatitis B virus (HBV) infection achieves only viral suppression whilst on therapy, but rarely hepatitis B surface antigen (HBsAg) loss. The ultimate therapeutic endpoint is the combination of HBsAg loss, inhibition of new hepatocyte infection, elimination of the covalently closed circular DNA (cccDNA) pool, and restoration of immune function in order to achieve virus control. This review concentrates on new antiviral drugs that target different stages of the HBV life cycle (direct acting antivirals) and others that enhance both innate and adaptive immunity against HBV (immunotherapy). Drugs that block HBV hepatocyte entry, compounds that silence or deplete the cccDNA pool, others that affect core assembly, agents that degrade RNase-H, interfering RNA molecules, and nucleic acid polymers are likely interventions in the viral life cycle. In the immunotherapy category, molecules that activate the innate immune response such as Toll-like-receptors, Retinoic acid Inducible Gene-1 (RIG-1) and stimulator of interferon genes (STING) agonists or checkpoint inhibitors, and modulation of the adaptive immunity by therapeutic vaccines, vector-based vaccines, or adoptive transfer of genetically-engineered T cells aim towards the restoration of T cell function. Future therapeutic trends would likely be a combination of one or more of the aforementioned drugs that target the viral life cycle and at least one immunomodulator.

Early Steps of Hepatitis B Life Cycle: From Capsid Nuclear Import to cccDNA Formation

“…Moreover, an understanding of the mechanisms that govern capsid translocation and rcDNA release, as well as the identification of cellular factors that interact with rcDNA during these early steps, may help to understand why HBV is not sensed by the innate immunity. The restoration of an antiviral response may help to eliminate HBV, in combination with additional antiviral treatments [ 107 ]. To date, several drugs are under development that directly target different stages of the HBV life cycle or modulate the innate or adaptative cellular antiviral response.…”

“…However, the consensus in the field is that drugs will have to be used in combination in order to achieve an HBV cure. New therapeutic approaches and the results of preclinical/clinicals trials have been discussed in recent reviews [ 107 , 109 , 110 ].…”

From hepatitis A to E: A critical review of viral hepatitis

“…Another potential target is at the level of capsid assembly, where core assembly modulators have been found to disrupt the assembly by producing abnormal capsid proteins (Type I) or virions without DNA (Type II)[ 73 ]. In vitro evaluation of infected hepatocytes showed a decrease in HBV DNA with different investigational molecules such as JNJ-6379, RO7049389, EDP 514, GLS4 and BAY 41-4109.…”

Novel vectors and approaches for gene therapy in liver diseases

“…63 Recently, a phase II clinical trial has been completed based on the inhibition of HBV replication using LNPs containing 3 chemically modified siRNAs that inhibit HBV antigen expression and replication in preclinical HBV infection models. 64 Additionally, LNPs are now being used for the delivery of gene editing molecules such as ZFNs and Cas9 mRNA together with a single guide (sg)RNA. mRNA encoding ZFNs formulated into LNP have enabled >90%…”