The Impact of Currently Licensed Therapies on Viral and Immune Responses in Chronic Hepatitis B

Considerations for Future Novel Therapeutics

Upkar S. Gill; Patrick T. F. Kennedy

Disclosures

J Viral Hepat. 2019;26(1):4-15. 

In This Article

Novel Pipeline Therapies for HBV

Multiple therapeutic approaches for HBV, targeting steps of HBV replication and restoring the host immune response are in development. Even with the advent of new therapies, currently licensed therapies are likely to remain a backbone of HBV management in the short to medium term, especially the employment of NAs for viral suppression. Novel drug targets are entering clinical trials to determine efficacy and are discussed at length elsewhere.[103–106] Here, we outline a selection of novel agents and their potential role in combination with currently licensed therapies.

Viral Targets

The identification of the cellular receptor for HBV entry, NTCP, along with an improved understanding of cccDNA formation, degradation and its epigenetic control and targets for viral entry have provided significant impetus to the field. The entry inhibitor Myrcludex B has shown promise in preclinical trials of HBV and hepatitis delta virus (HDV) and is being tested in clinical trials with and without Peg-IFNα.[107] Targets against cccDNA include antiviral cytokines (IFNα, IFNγ, TNFα and lymphotoxin-β receptor agonists),[108] and technologies such as CRISP-R/Cas9 are being utilized to eliminate cccDNA along with the use of histone deacetylase (HDAC) inhibitors.[109,110] It will be important to establish if these agents are best deployed in combination with NA's and/or immune modulating agents (Figure 2; potential effects of therapies). Secretion inhibitors, such as nucleic acid polymers (NAPs), have shown promise in inhibiting HBsAg release. Clinical trials of molecules REP-2044 and REP-2139 used as monotherapy or in combination with Peg-IFNα induced rapid declines of HBsAg. In addition, TDF with Peg-IFNα in combination with REP-2139 and REP-2165 has also generated promising results.[111] The core/HBc/Cp proteins have emerged as promising DAA targets (core allosteric modulators [CpAM]). These agents allow for inhibition of nucleocapsid assembly leading to the inability of pgRNA enscapsidation or capsid formation with arrest of the neosynthesis of viral rcDNA.[112] Whether these will show increased potency in combination with current NAs and/or Peg-IFNα remains to be seen. Silencing RNA using RNA interference (RNAi) to prevent HBV replication is also being investigated. Preliminary results of a phase II trial showed that a single dose of ARC-520 in combination with ETV resulted in rapid decreases in HBV DNA in HBeAg-positive and HBeAg-negative patients, but only showed a decline in HBsAg in HBeAg-positive patients.[113] It will also be interesting to see if viral targets also induce beneficial effects on the host immune response as has been shown with DAAs in HCV[114]

Figure 2.

Diagram depicting the viral and immune responses with nucleos(t)ide analogue- and pegylated interferon-based therapies, and potential viral and immune outcome with novel therapies indicated (used in isolation or in combinations) with a view to achieving functional cure in hepatitis B virus

Immune Targets

Immune therapies include molecules directing innate responses within HBV infected hepatocytes triggering antiviral mechanisms (cytokine production, direct killing) of liver nonparenchymal cells. Checkpoint modulators, therapeutic vaccines and targeted T cell therapies are also being investigated.

Agents for immune stimulation include pathogen recognition receptor (PRR) agonists, the TLR-7 agonist GS-9620, which was shown to induce strong anti-HBV activity,[115] but a trial in CHB patients did not show any effect on viral replication/HBsAg levels. However, GS-9620 used as add-on therapy in patients virally suppressed with NAs demonstrated increased levels of T cell effector cytokines compared to NAs alone. NK cell activation and function increased after the addition of GS-9620, which signalled via the IFN-type I pathway, while the ability of NK cells to delete T cells was diminished, indicating the importance of type I IFN signalling.[116] The use of TLR-8 and TLR-9 agonists may provide more promise, potentially in combination with NAs. Other potential targets for immune stimulation include TLR-1/2, RIG-I and stimulator of interferon genes (STING).[117] These agents induce direct HBV inhibition in infected hepatocytes, and SB9200, an oral molecule activating RIG-I, is able to decrease HBV DNA and HBsAg levels in the WHV, with early clinical trials showing promise in humans.[118] Innate immune therapies have been designed which activate intrahepatic NK/NK-T cell responses, with antibody-blocking inhibitory NK cell receptors[119] or via NK cell triggering cytokines such as IL-12, IL-18[120] or with classical IFNα, utilized alone or conjugated with antibodies for selective delivery.[121] Modulation of innate-adaptive interactions could also hold therapeutic promise, for example targeting the regulatory role of NK cells and MDSC's to improve HBV-specific T cell immunity.[82,122] Cytokines such as TNF-α, IL-2 and IL-12 have been shown to inhibit HBV replication in vitro and thus could potentially be used with NAs[123] However, these molecules have not yet been successfully used in clinical trials.[103]

Hepatitis B virus-specific T cells are exhausted, overexpressing inhibitory checkpoint molecules such as PD-1 and CTLA-4.[124–126] Blockade of these molecules has shown potential in vitro, with promising data emerging in HBV-related HCC with the anti-PD1 agent, nivolumab.[127] Anti-PD1/PDL-1 blockade can partially restore exhausted HBV-specific T cells in CHB patients,[126,128] and it will be important to determine whether these agents are more efficacious in combination with NAs. Therapeutic vaccines such as GS-4774 and TG-1050 are being investigated in clinical trials.[129,130] These have been designed to boost quantity and function of antiviral T cells through HBV-specific stimulation.[131] Initial trials of vaccines showed suboptimal results,[132,133] but new formulations or combination therapies with NAs have demonstrated some effect in selected trials.[134] Increasing the number of HBV-specific T cells by autologous infusion of T cells expressing chimeric antigen receptors or by engineering T cells to overexpress HLA-restricted HBV-specific TCRs has been used in human studies and show some promise.[135,136] Design and expansion of engineered HBV-specific T cells for adoptive transfer is feasible,[137,138] and data in animal models[139] or selected clinical situations[136] have been encouraging, but further investigation is required and how best to employ these options in patients remains to be seen.

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