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Review
. 2015 Apr 1;5(4):a021501.
doi: 10.1101/cshperspect.a021501.

Antiviral therapies and prospects for a cure of chronic hepatitis B

Fabien Zoulim  1 , David Durantel  1
Affiliations
Review

Antiviral therapies and prospects for a cure of chronic hepatitis B

Fabien Zoulim et al. Cold Spring Harb Perspect Med. .

Abstract

Current therapies of chronic hepatitis B (CHB) remain limited to either pegylated interferon-α (Peg-IFN-α), or one of the five approved nucleoside analog (NA) treatments. Although viral suppression can be achieved in the majority of patients with high-barrier-to-resistance new-generation NAs (i.e., entecavir and tenofovir), HBsAg loss is achieved in only 10% of patients with both classes of drugs after a follow-up of 5 years. Attempts to improve the response by administering two different NAs or a combination of NA and Peg-IFN-α have been unsuccessful. Therefore, there is a renewed interest to investigate a number of steps in the hepatitis B virus (HBV) replication cycle and specific virus-host cell interactions as potential targets for new antivirals. Novel targets and compounds could readily be evaluated using both relevant in vitro and newly developed in vivo models of HBV infection. The addition of one or several new drugs to current regimens should offer the prospect of markedly improving the response to therapy, thus reducing the burden of drug resistance, as well as the incidence of cirrhosis and hepatocellular carcinoma (HCC).

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Figures

Figure 1.
Figure 1.
Schematic of interferon (IFN)-α and nucleoside analog (NA) modes of action. NAs block the synthesis of relaxed circular DNA (rcDNA) into neosynthesized nucleocapsids by acting as chain terminator for hepatitis B virus (HBV) polymerase. IFN-α has both direct and indirect actions on HBV replication in vivo. It can either (1) stimulate professional immunity cells (e.g., natural killer (NK)/natural killer T cell (NKT) and CD8+ cells) to enhance their dual mode of action, which is either noncytolytic clearance of HBV replication via the action of cytokines (e.g., IFN-γ) or cytolysis of infected cells, or (2) induce the expression of interferon-stimulated genes (ISG) and proteins, which can bear antiviral properties, such as APOBEC3A/B or MxA. cccDNA, covalently closed circular DNA; ER, endoplasmic reticulum; hNTCP, human sodium taurocholate cotransporting polypeptide; pgRNA, pregenomic RNA.
Figure 2.
Figure 2.
Position of resistance mutations within hepatitis B virus (HBV) polymerase. Mutations conferring resistance to the five approved nucleoside analogs (NAs) are located within the subdomains A, B, C, and D of HBV polymerase. Some mutations confer resistance to different NAs; this cross-resistance profile is to be taken into consideration for the clinical management of patients. ADV, Adefovir dipivoxil; ETV, entecavir; LdT, telbivudine; LMV, lamivudine; POL/RT, reverse transcriptase domain of HBV polymerase; TFV, tenofovir.
Figure 3.
Figure 3.
Schematic representation of various classes of anti-HBV molecules on the Hepatitis B virus (HBV) life cycle. Compounds in development for chronic hepatitis B can be seen at www.hepb.org/professionals/hbf_drug_watch.htm. cccDNA, covalently closed circular DNA; ER, endoplasmic reticulum; hNTCP, human sodium taurocholate cotransporting polypeptide; pgRNA, pregenomic RNA; rcDNA; relaxed circular DNA.
See this image and copyright information in PMC

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