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: Vaccines, Hepatitis B, chronic, Therapeutics, Hepatitis B virus
In contrast to most communicable diseases, morbidity and mortality rates related to infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) have increased over the last 20 years. The two different viruses (HCV is an RNA virus belonging to Flaviviridae, while HBV is a DNA virus of the Hepadna-virus family) are both hepatotropic, noncytopathic, and able to establish persistent infections that cause different degrees of hepatic inflammations (chronic hepatitis) leading to the development of liver cirrhosis and hepatocellular carcinoma (HCC).
However, the therapeutic advances in their treatment have been radically different. New therapies for HCV have delivered remarkable results, with more than 90% of patients achieving viral clearance with all-oral treatment with directly acting antivirals. In contrast, therapy options with curative intent for HBV are still a distant future and thus new therapies, targeting either steps of HBV replication or the host immune system, are urgently needed.
Current treatments for chronic HBV infection (CHB) include pegylated-interferon-α (Peg-IFNα) and nucleos(t)ide analogues (NAs), but neither are suitably efficient in providing functional cure, a virological and clinical situation defined by undetectable levels of hepatitis B surface antigen (HBsAg) and HBV DNA in the serum, normality of alanine aminotransferase (ALT) and development of hepatitis B surface antibody (anti-HBs). The term “functional cure” is thus used to define a virological situation in which, like in patients who resolved acute hepatitis B infection, HBV is not fully eliminated and few hepatocytes harbor covalently closed circular DNA (cccDNA) that is maintained under a repressed translational control by innate and adaptive immune mechanisms (NB, for an extended definition of functional cure in HBV we recommend).
Peg-IFNα can achieve sustained off-treatment control, but only in a limited proportion of patients; approximately 10%. NAs therapy suppresses the production of new virions, reduces HBV DNA to undetectable levels in the serum and leads to a normalization of transaminases. However, loss of HBsAg is rarely achieved. Furthermore, since NAs suppress HBV replication by targeting at the level of DNA synthesis only, they are ineffective in their ability to eradicate the cccDNA, the episomal form of HBV from infected cells. Treatment with NAs is thus considered lifelong with the potential risk of long-term toxicity, with limited data on treatment withdrawal, which results in reactivation of HBV in the majority, likely due to a defect on the restoration of anti-HBV immunity.
The rational of immune based approaches to achieve functional cure of HBV infection stems primarily from studies that have analyzed the profile of innate and adaptive immunity during HBV infection, but also from observations derived from HBV-infected patients under immunosuppressive treatment or bone marrow transplantation.
During natural HBV infection the innate immune system is poorly activated, due to an intrinsic ability of the virus to escape recognition. Readers are directed to these recent reviews for in depth description of such mechanism. Note however, that although acute and chronic HBV infections are associated with poor activation of innate immunity, HBV replication is efficiently suppressed by adequate innate immune triggering. Intracellular activation of retinoic acid-inducible gene-I (RIG-I) or apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) pathways in HBV-infected hepatocytes are able to suppress HBV replication. Similarly, different cytokines such as IFNα, IFNγ, tumor necrosis factor-α (TNFα), and interleukin-1β (IL-1β) produced by non-parenchymal cells of the liver can suppress, or even eradicate HBV from infected hepatocytes. The ability of innate cytokines to suppress HBV is also supported by the observation that co-infection with hepatotropic viruses able to activate innate immunity like HCV and hepatitis D virus, causes a drop of HBV replication. Thus, strategies aiming to activate these different components of innate immunity and to obtain for example a localized production of antiviral cytokines in the liver have been sought as possible immunological based therapies for HBV.
The role of natural killer (NK) cells in HBV infection remains controversial with demonstration of a possible protective or pathogenic role. The ability of IFNα therapies to control HBV replication has been linked with activation of NK cells which can be also detected in patients who controlled acute HBV infection. However, at present it is not clear whether NK cells preferentially target HBV-infected hepatocytes or have a regulatory capacity on HBV-specific T cells.
Similarly, even though anti-HBs antibodies have protective capacity and a defective humoral response has been implicated in HBV chronicity, the quantity and functionality of HBV-specific B cell responses during HBV infection is still poorly understood. The reactivation of HBV replication in a proportion of B cell depleted patients treated with rituximab support a role in HBV control and the therapeutic efficacy of anti-HBs antibody has been shown with HBV transgenic mice.
The importance of T cells in establishing a functional cure of chronic HBV infection is instead a very established concept based on data obtained from patients and animal models. In chimpanzees acutely infected with HBV, deletion of CD8 T cells causes the establishment of a chronic HBV infection. Patients with acute HBV infection mount a cellular anti-HBV immune response that is temporally correlated with HBV serum clearance. However, HBV-specific T cells are quantitatively and functionally defective in CHB patients. On the other hand, immunosuppressive treatments targeting cellular immunity in anti-hepatitis B core (anti-HBc) positive subjects often trigger rapid reactivation of HBV. These data therefore indicate that virus specific T cells have the capacity to maintain HBV infection under tight replicative control.
Therapeutic strategies aimed at increasing innate immunity exploit the robust antiviral efficacy demonstrated by distinct cytokines (TNFα, IFNα, IFNγ and IL-1β) mimicking the activation of innate immunity during the early phase of acute HBV infection and inducing a potent maturation of the adaptive immunity.
