Immunotherapy for Chronic Hepatitis B Virus Infection

Abstract

While new therapies for chronic hepatitis C virus infection have delivered remarkable cure rates, curative therapies for chronic hepatitis B virus (HBV) infection remain a distant goal. Although current direct antiviral therapies are very efficient in controlling viral replication and limiting the progression to cirrhosis, these treatments require lifelong administration due to the frequent viral rebound upon treatment cessation, and immune modulation with interferon is only effective in a subgroup of patients. Specific immunotherapies can offer the possibility of eliminating or at least stably maintaining low levels of HBV replication under the control of a functional host antiviral response. Here, we review the development of immune cell therapy for HBV, highlighting the potential antiviral efficiency and potential toxicities in different groups of chronically infected HBV patients. We also discuss the chronic hepatitis B patient populations that best benefit from therapeutic immune interventions.

Keywords: Hepatitis B virus; Hepatitis B, chronic; Therapeutics; Vaccines.

Fig. 1

Immune therapeutic approaches to achieve a functional cure of hepatitis B virus (HBV). (A) Schematic representation of immune responses and viral load in chronic and resolved HBV infection. Chronic HBV infection is characterized by the loss or functional exhaustion of HBV-specific CD8 T cells and elevated HBV load in infected hepatocytes. Resolved HBV infection is characterized by the presence of functional HBV-specific T cells, antibodies blocking new infection and few hepatocytes harboring HBV. (B) Schematic representation of different immunotherapeutic strategies able to boost innate or adaptive immunity to suppress HBV replication. TLR, Toll-like receptor; RIG-I, retinoic acid-inducible gene-I; NKT, natural killer T; TCR, T cell receptor; APC, antigen-presenting cell; PD-1, programmed cell death-1; HBsAg, hepatitis B surface antigen.

Fig. 2

Therapeutic strategies designed to restore hepatitis B virus (HBV)-specific T cell responses in chronic hepatitis B patients. Vaccine therapy aims to induce and boost new HBV-specific T cells and check point inhibitors (anti-PD-1/anti-PD-L1) to restore the functionality of existing exhausted HBV-specific T cells. T cell engineering aims to produce new HBV-specific T cells through the introduction of genetic information (DNA or messenger RNA) encoding HBV-specific T cell receptors into the patients’ T cells. APC, antigen-presenting cells; TCR, T cell receptor; CAR, chimeric antigen receptor.

Fig. 3

Pathogenesis of liver damage during chronic hepatitis B virus (HBV) infection. Increased levels of alanine aminotransferase (ALT) are not proportional to the quantity of HBV-specific CD8 T cells. Liver damage is mediated by the intrahepatic recruitment of inflammatory cells. Similar frequencies of HBV-specific CD8 T cells can trigger different inflammatory outcomes depending on the changes in the liver microenvironment.