Management and Treatment of Patients with Chronic Hepatitis B: Towards Personalized Medicine

Abstract

The currently available antiviral treatments (Peg-Interferon-α and Nucleos(t)ide Analogues, NA) for chronic hepatitis B (CHB) achieve a functional cure (serum HBsAg and HDV-DNA clearance) of HBV infection in a limited number of patients. Nevertheless, the continuous pharmacological suppression of viral replication by NA halts liver disease progression lowering the risk of HCC development and improving the survival. In the near future, to fully exploit the potential of old and new drugs for HBV treatment a personalized approach to the patients will be required according to an accurate definition of their virologic, immunologic and clinical profile.

Keywords: HBV; HBV functional cure; Interferon-α; antiviral treatment; chronic hepatitis B; nucleos(t)ide analogues.

Figure 1

HBV replicative cycle and targets of the drugs under development to cure chronic hepatitis B patients. Description of their mode of action at the different steps of the HBV cycle or according to their modulation of immune response: (1) inhibition of viral entry by Na-Taurocholate Cotransporting Polypeptide (NTCP) receptor inhibitors or by neutralizing antibodies targeting the Pre-S1 domain of the HBsAg (b); (2) destabilization/degradation of the nuclear covalently closed circular DNA (cccDNA) or inhibition of its transcription; (3) inhibition of viral proteins synthesis by targeting viral mRNAs coding for HBx, small, middle and large (S, M and L) HBs, Core and Polymerase (Pol) proteins; (4) interference with Core protein assembly and (5) HBcAg-mediated cccDNA replenishment; (6) inhibition of viral and subviral particles HBsAg release; (a) modulation of innate immunity by Toll Like Receptors (TLR) agonists, which can activate Plasmacytoid Dendritic Cells (PDC), Natural Killer (NK) cells, or Interferon (IFN) Sensitive Genes (ISGs) response, which increase the production of several IFN Response Factors (IRFs) with broad-spectrum antiviral activity, similar to that of 2′-5′-oligoadenylate synthetase (OASs) and RNase L; (b) modulation of the adaptive immunity, by check point inhibitors acting on the Programmed Death 1 (PD-1) receptor of viral antigen-specific T cells exhausted because of the antigen overload, thus improving Cytotoxic T Lymphocytes (CTL) activity. Alternative approaches to increase recognition and elimination of HBV infected cells include genetically engineered T cells and therapeutic vaccines.

Figure 2

Interferon-α (IFN-α) has been shown to target different steps of HBV cycle either by generic antiviral mechanisms (1), via activation of the IFN Sensitive Genes (ISGs), or by specific blocking (2) and degrading (3) replication competent core particles, as well as pre-genomic-RNA (4) and nuclear covalently closed circular DNA (cccDNA), or by inhibition of cccDNA transcription (5). The main immune-modulatory activity of IFN-α consists in boosting the innate immune response (6) by stimulating Natural Killer (NK) cells, whereas IFN-α appears unable to restore the effector function of the HBV specific cytotoxic T cells (CTLs). Nevertheless, a late improvement of the adaptive immune responses (7), involving the functions of Kupfer Cells (KC), T Helper lymphocytes and Plasmacytoid Dendritic Cells (PDC), is observed in responder patients.

Figure 3

Virologic and clinical characteristics, that should guide the therapeutic choice in chronic hepatitis B patients to grant a personalized approach with both the currently available and the new drugs. The functional cure with a finite treatment should be pursued primarily in young patients with chronic hepatitis, whereas in older patients with cirrhosis the persistent inhibition of both viral replication and disease activity is a reasonable goal of antiviral therapy, as it was shown to stop/reduce the progression to end stage liver disease complications. An accurate characterization of the HBV infection profile and of its evolution overtime, together with the treatment history of the patient will further guide the selection for each patient of the most appropriate treatment strategy, particularly when new antiviral and immune modulatory drugs will be available.