Antiviral Research Volume 121, September 2015, Pages 69–81

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4. Host-targeting antivirals
4.1. Products in clinical development

Five HTAs appear to be in the clinical stage of development (Fig. 4), and two others have recently failed or been discontinued. Of the five still in development, two target host functions used by the virus (Myrcludex B, Brinapant), and the others target the host innate and adaptive immune systems (GS-4774, GS 9620, DV601 & SB9200HBV).

4.1.1. Viral entry inhibitors

Myrcludex B (MycB), a synthetic lipopeptide derived from the LHBs preS1 domain, is an entry inhibitor from Hepatera/Myr-GmbH. Viral entry inhibitors are a relatively new and effective antiviral drugs, with the HIV Trimeris Fuzeon being among the first (Lobritz et al., 2010). Neutralization of virions to prevent their association with target cells by neutralizing antibodies is well established as an approach. For HBV, the only example is Myrcludex B (MycB), a lipopeptide derived from the cell attachment region of the HBV large envelope protein (Gripon et al., 2005, Petersen et al., 2008 and Urban et al., 2014) Myrcludex B requires parenteral administration; this would be a drawback for clinical therapy. In Phase 2a clinical trial studies Myrcludex B demonstrated does dependent decline in the levels of HBV DNA in patients. Myrcludex B also showed promising results in phase 2a trial in patients with chronic hepatitis delta virus (HDV) infection. HDV uses HBV envelope proteins for hepatocyte entry and therefore if Myrcludex B is approved it can be used for treating both HBV and HDV chronic infections. (Hepatera, 2014 and Urban et al., 2014).

4.1.2. Immune enhancers

Four of the HTAs in clinical phase are immune enhancers. The mechanism of liver disease in people with chronic hepatitis B is fundamentally a chronic, but inadequate immunological and inflammatory attack on infected hepatocytes, resulting in liver damage (Ganem and Prince, 2004 and Seeger and Mason, 2000). A DAA alone may therefore not be sufficient; a durable, off-drug, antiviral response is therefore likely to require some type of immunological restoration of the affected individual. While it is hoped that complete suppression of antigenemia, as well as viremia, may unmask or enable an indolent or suppressed immune response (or perhaps “free up” neutralizing antibody that was otherwise complexed with antigen), some type of direct immunologic awakening of the host will be necessary (see review by Durantel and colleagues in this symposium).

Unfortunately, most attempts to stimulate the immune system in chronic HBV carriers to clear HBV have been disappointing, and have failed in human trials or had untoward clinical consequences, such as decompensation in those with advanced fibrosis or cirrhosis. Therefore there has been considerable interest in developing strategies that stimulate the host immune recognition of HBV, in chronic carriers, who usually can recognize the virus, at the cellular and humoral level, without clearing the infection (Bertoletti and Gehring, 2013).

4.1.2.1. YIC

YIC is comprised of HBsAg and HBIG, (anti-HBs Immunoglobulin) complex as a therapeutic agent candidate with alum as the adjuvant (Xu et al., 2008). The candidate reached phase III clinical trials in which the results were found to be unsatisfactory. Overstimulation with YIC was demonstrated to decrease the efficacy of YIC due to immune fatigue (Xu et al., 2013). Its continuation is therefore in doubt, representing a setback and disappointment for these alternative approaches once thought promising.

4.1.2.2. GS 9620

Toll-like receptor (TLR)-7 is a “pathogen recognition receptor” expressed mostly in lysosomal/endosomal compartments of plasmacytoid dendritic cells (pDCs) and B-lymphocytes that recognizes patterns in viral single-stranded RNA (O’Neill et al., 2013). There is a growing body of evidence that pattern recognition receptor activation can directly suppress HBV in infected cells (Chang et al., 2012) (see forthcoming review by Chang and colleagues in this symposium).

GS 9620 is a small-molecule TLR-7 agonist in clinical development ( Roethle et al., 2013). Phase 1b safety studies have been recently reported, showing the drug was safe and achieved expected induction of interferon stimulated genes in peripheral blood cells ( Gane et al., 2015). Indeed, GS-9620 had significant activity in woodchucks and chimps, and would be a “first in class”, to show that pharmacological activation of pattern recognition receptor can have clinical benefit in the management of chronic HBV infection ( Lanford et al., 2013)

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4.1.2.3. SB 9200

HBV replication is suppressed by activation of retinoic acid inducible gene-I (RIG I), which is stimulated by double-stranded RNA and the nucleotide binding oligomerization domain containing protein-2 (NOD-2) (Adam et al., 2002, Mao et al., 2011 and Sato et al., 2015). Agents that can activate RIG-I would therefore provide a new approach. SB 9200 from Spring Bank is reported on their web site to be a small molecule that activates host’s immune system by upregulating RIG-I SB 9200 is currently in Phase 1 clinical trials (Springbank).

4.1.3. Therapeutic vaccines

The concept and current status of therapeutic vaccination for chronic hepatitis B are reviewed in a forthcoming article by Roggendorf and colleagues in this symposium.

DV601 (Dynavax) and GS4774 (Gilead Sciences) are both therapeutic vaccines candidates. GS4774 is a heat-killed vaccine engineered to express a fusion protein containing HBsAg sequences of four major genotypes while DV601 utilizes both core and surface antigens. Vaccine that produce or introduces HBsAg might appear to have limited logic, since people with chronic hepatitis B already have enormous amounts of HBsAg in their circulation. The hypothesis behind this approach is that therapeutic vaccines will induce specific T-cell responses, in the face of presumed T-cell exhaustion due to antigen excess, by either stimulating antigen presentation, or directing antigen presentation from professional antigen presenting cells ( Michel et al., 2015). Some of these challenges are discussed later in this review. As with any immune-enhancing approach, the limitations will most likely relate to toxicity and variable response in different patients.

To date, GS4774, produced from heat-inactivated yeast recombinant HBV antigens, has been evaluated in Phase 1 trials (Gaggar et al., 2014). The Dynavax therapeutic vaccine candidate, which includes phosphorothioate oligonucleotides as well as viral polypeptides, as immunostimulatory adjuvants, has also been shown to be safe and effective as an immunogen in Phase 1 studies (Halperin et al., 2006 and Plotkin and Schaffner, 2013). Since the initial safety trials of DV601, no development has been reported for the vaccine candidate (DYNAVAX, 2011).

4.1.4. Birinapant

Birinapant from Tetralogic Corp, is a small molecule that is believed to mimic second mitochondrial activator of caspases (SMAC) (Seigal et al., 2015). SMAC normally binds to IAP (inhibitor of apoptosis), pushing the cell towards apoptosis (Holohan et al., 2013).

Birinapant has already entered Phase 3 trials for management of myelodysplastic syndrome and colorectal cancer, so there is considerable safety and efficacy information available. The safety information on Birinapant is available from more than 300 patients enrolled in these trials (TetraLogic). For the management of hepatitis B, Birinapant is only in the preclinical phase, but was reported to cause impressive reductions of viremia in the circulation of infected mice (Ebert et al., 2015a, Ebert et al., 2015b and Peters et al., 2004). The mechanism of the antiviral affect was not clear, but it seems that infected cells are selectively eliminated, assuming that they are more sensitive to apoptotic stimuli, compared to the uninfected cells. The strategy is intriguing and the possibility of using such an approach to eliminate remaining infected cell “nests” following the reduction of infected cells with more conventional methods, is very compelling. On the other hand, for obvious reasons, in individuals with a substantial portion of the liver infected, such an approach must be taken cautiously, since the rapid destruction of infected cells can be dangerous.

4.1.5. Zadaxin

Zadaxin is a 28-amino-acid peptide based on thymosin-α, a natural polypeptide from the thymus (Tsai et al., 2003). It was reported to initially show promise, but there are studies demonstrating both favorable and unfavorable results (Wu et al., 2015). A randomized clinical trial conducted in China demonstrated that Zadaxin is safe, well tolerated and is effective in inhibiting HBV replication. Patients treated with Zadaxin had much higher rate of seroconversion as compared to the patients treated with IFN-α (You et al., 2001). In another clinical trial, HBeAg negative patients treated with Zadaxin in combination with IFN-α had much robust virological and biochemical response as compared to the patients treated with combination of lamivudine and IFN-α or IFN-α alone (Saruc et al., 2003). In contrast, Zadaxin in combination with lamivudine was not found to be any better than lamivudine alone (Lee et al., 2008). Thymosin-α also did not have any clear benefits when used in combination with IFN-α in another clinical trial (Yang et al., 2008). Subsequent studies showed that, in combination with lamivudine or interferon, Zadaxin added little to detectable benefit in chronically infected HBeAg-positive patients, on the grounds of antiviral efficacy, and interest has waned (Kim et al., 2012).

4.2. HTAs in the preclinical stage

4.2.1. Immune checkpoint inhibitors (PD-1)

Recent advancements in our understanding of immune exhaustion is generating a new hope for the immunological or host-targeted therapeutic strategies. We now have a greater understanding of the mechanisms by which some viral antigens, in chronic infection, are presented to the immune system that can result in the failure of the immune system to clear the virus. There are now several known pathways that lead to T-cell exhaustion and these pathways could be blocked to enhance T-cell responses.

For example, the programmed cell death (PD-1)/PD-1 ligand pathway plays critical role in antigen-mediated exhaustion of T-cells in several chronic infections, including HIV and hepatitis C (Bertoletti and Gehring, 2007, Bertoletti and Gehring, 2013, Bertoletti and Kennedy, 2014, Day et al., 2006 and Peng et al., 2008). In the hydrodynamic tail vein injection model system for HBV expression in C57BL mice (Tzeng et al., 2012), it was demonstrated that a PD-1/PD-L1 pathway inhibition with monoclonal antibody could reverse immune dysfunction and HBV viral persistence. PD-1 expression levels in HBV-infected patients have also been studied, and it was demonstrated that 70% of the circulating HBV-specific T-cells were PD-1 positive (Zhang et al., 2013).

Anti-PD-1 antibody has now been used effectively in human cancer therapy, and in trials for the management of chronic hepatitis C (Gardiner et al., 2013). However, there is no ongoing clinical trial involving PD-1 for the management of chronic HBV infection. This may be due to concerns about adverse effects of autoimmune type reactions. Thus, despite the theoretical appeal, and strong experimental evidence, PD-1-derived therapies for chronic hepatitis B may take some time to develop. However, other members of the PD-1-like superfamily of coreceptors may be important in regulating chronicity, and ultimately prove better therapeutic targets (Xing and Hogquist, 2012).

4.2.2. Therapeutic vaccines

Therapeutic vaccines have received a considerable amount of attention, and the clinical stage therapeutic vaccines for HBV have been discussed (above). Here we describe leading examples of preclinical technologies and their development status, when it could be confirmed.

4.2.2.1. Altravax DNA vaccine

Altravax’s therapeutic vaccine approach is to construct a chimera of wild-type and xenogenic HBs surface peptides, and subsequent inclusion of HBc peptides. This approach is based upon the hypothesis that the chimera will result in the presentation of novel epitopes by antigen presenting cells. These novel epitopes will beneficially stimulate the immune response in chronic HBV infection. C57BL/6 mice were immunized with the vaccine, and the T-cell responses elicited by the vaccine were reported to meet the expectations by the investigators (Altravax).

4.2.2.2. INO-1800

INO-1800 is a recombinant DNA vaccine from Inovio that encodes consensus sequence of HBV core antigen, which has induced antigen-specific strong T-cell responses and high antibody titers in preclinical trials (Obeng-Adjei et al., 2012). The vaccine also demonstrated strong cytotoxic T-cell response to kill target cells without causing considerable liver injury (Obeng-Adjei et al., 2012). The company has just initiated Phase1 trials for the vaccine (Inovio, 2015).

4.2.2.3. VLP

VLP Biotech is developing a virus-like particle (VLP) (Schickli et al., 2015), based on the HBV core antigen, modified and designed to elicit neutralizing antibodies to PreS1 (Whitacre et al., 2009).

4.2.2.4. Chimigen HBV/NU500

This investigational agent from Akshaya Bio (Canada) is a chimeric polypeptide comprised of regions of the core and surface antigen proteins and the Fc-binding domain of IgG. The hypothesis is that the Fc component will direct the chimeric protein to dendritic antigen presenting cells, and there will be enhanced presentation of HBV antigen. The concept is compelling, and in vitro and in vivo studies reported at professional conferences, suggest that this approach can induce robust immunological responses to the HBV antigens, in mice ( George, 2014). However, successful production and presentation of viral antigens may be insufficient to restore a meaningful host immunological response to HBV, since there may be an “afferent” defect in the immunologic response in all individuals with chronic hepatitis B, known as “immunological exhaustion”. As mentioned earlier, immune exhaustion due to the pathways such as PD-1/PD-1L might undermine the effects of enhanced antigen presentation.

4.2.2.5. Editopes

A novel method by which a small molecule can induce production of an HBsAg peptide bearing a novel epitope has been described (Norton et al., 2010). Briefly, imino sugar glucosidase inhibitors such as N-butyldeoxynojirimycin, which inhibit alpha-glucosidase 1, prevent the glycan processing of HBsAg (M) polypeptides, causing them to misfold and be degraded in the proteasomes (Norton et al., 2010 and Simsek et al., 2009). Prior to their degradation, the N-glycans on the HBsAg are removed from the polypeptide backbone by the action of PNgase, which hydrolyzes the asparagine linked to the N-glycan, resulting in its conversion into an aspartic acid. The proteolytic fragment of the HBsAg thus contains a CTL epitope that is not encoded by the HBV gene. Since this amino acid resides within a major CTL epitope, the new epitope, called an editope, contains an aspartic acid in place of an asparagine.

This suggests that animals (and presumably, humans) could be treated with the imino sugar, and immunized with the novel CTL epitope (editopes), and, ideally, would develop CTL responses that would attack the infected cells. The hypothesis was evaluated in woodchucks chronically infected with woodchuck hepatitis virus (WHV), and it was demonstrated that selective lymphocytic responses to the aspartic acid containing editope could be induced in a pharmacologically dependent manner (Norton et al., 2010). However, there was no detectable effect on viremia or antigenemia. Thus, despite an immunological proof of principle, this approach has not progressed further.

4.2.3. Epigenetic modifiers

Small-molecule histone deacetylase (HDAC) inhibitors have been shown to suppress cccDNA transcription in tissue culture, under non-cytotoxic conditions (Liu et al., 2013). At the same time, transcription from HBV DNA integrated into the host genome was enhanced, demonstrating that transcription from cccDNA is regulated differently than the transcription from the integrated genome. These results are particularly compelling, since there are several HDAC inhibitors in Phase 3 clinical studies for other diseases, and two are already approved for refractory cutaneous and peripheral T cell lymphoma (Khan and La Thangue, 2012 and West and Johnstone, 2014). The positive results of the use of HDAC inhibitors for suppressing cccDNA is therefore exciting, since two of them have already been approved for other indications, but of course, as with any host targeting agent, human use may pose risks.

4.2.4. Dimethylxanthenone STING agonists

The Stimulator of Interferon Genes (STING) is an adaptor polypeptide for several cytoplasmic DNA-sensing receptors, as well as a bacterial cyclic di-nucleotide second messenger and an intracellular moderator of innate immune responses (Cai et al., 2014). Stimulation of STING with small-molecule flavonoids effectively suppressed HBV replication in mouse hepatocytes. It was demonstrated that STING stimulation mainly induced type-1 IFN response, unlike the TLR agonist that induced inflammatory cytokines response (Guo et al., 2015). Importantly, it has been demonstrated that after less than 24 h of infection, STING agonists reduced the amount of HBV DNA in the blood of infected mice in a hydrodynamic tail-vein injection model (Guo et al., 2015).

4.2.5. Cyclophilin inhibitors

Cyclophilin inhibitors have been shown to have broad antiviral affects in clinical trials for hepatitis C (Membreno et al., 2013). The mechanism of action appears to involve an affect upon host protein-folding chaperones used in viral polypeptide function.

The cyclophilin inhibitors Alisporivir (formerly Debio 025) and Novartis compound NIM811 have both been reported to have inhibitory activity against HBV in tissue culture (Phillips et al., 2015). Oncore-Tekmira is now developing a cyclophilin inhibitor (OCB-030/NVPO19) for the management of chronic hepatitis B. Cyclosporin A, a chemical inhibitor of cyclophilin that binds and inhibits cyclophilin without any immunosuppressive effects, may also be important for inhibiting entry in hepatocytes (Nkongolo et al., 2014).

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5. Conclusions
It has been 50 years since the discovery of the Australia antigen, but therapies that cure chronic HBV infection are still not available. In contrast, 25 years after the discovery of the hepatitis C virus, virtually all cases of chronic hepatitis C can now be cured through a short course of antiviral therapy (Ward, 2014). This dramatic success with hepatitis C has created excitement about the possibility of a cure for chronic hepatitis B, and many scientists are now moving to hepatitis B research. Coupled with the growing prominence of antiviral research in China and the rest of South Asia, where hepatitis B is prevalent (El-Serag, 2012), this has created a momentum of innovation in hepatitis B therapeutic strategies.

As discussed in this review, investigational agents currently in the advanced stages of clinical development are the prodrugs that have promise to improve upon the existing therapies by increasing efficacy and decreasing the side-effects. Investigational agents such as siRNA, HBsAg inhibitors and capsid inhibitors that have reached clinical trials, have different mechanism of action as compared to the current therapies. The new delivery technologies such as lipid nanoparticles have breathed new life into the siRNA approach. New technologies for discovery, screening and profiling, have also made possible the development of many investigational agents in the pre-clinical phase of development that use novel and previously unexplored areas of HBV biology. These include entry inhibitors, use of novel chimeric epitopes, selective killing of infected hepatocytes and novel therapeutic vaccines. There is a hope that these investigational agents that use novel mechanisms for inhibiting HBV replication, used alone or in combination with the existing therapies would help in better management of chronic hepatitis. The great challenge is to decrease intrahepatic viral DNA levels and to eliminate cccDNA. Candidate therapies such as siRNA hold promise to do that by eliminating HBV transcripts, eventually leading to loss of cccDNA, over a period of time, and therefore the results from the clinical trials are awaited. In addition to the DAAs, it is thought that agents that can boost the immune response against the virus can play an important role in sustained off drug virological responses. Therefore new HTAs in development, such as therapeutic vaccines, PD-1/PD-1ligand pathway inhibitors, novel chimeric antigens, enhancement of antigen presentation, might be beneficial.

That said, to date there are still only two families of drugs to treat chronic hepatitis B, the interferons and the polymerase inhibitors. But this is clearly going to change. Based on some of the investigational agents in the pipeline that we describe in this review, we predict that within five years there will be at least two new drugs approved for management of chronic hepatitis B, and within ten years, there should be functional cures.

Conflicts of Interest
Timothy Block receives research support from Oncore-Tekmira and is on the board of Contravir. Carol Brosgart is a member of the board of Tobira Therapeutics and of Contravir, and is a consultant for Dynavax. Siddhartha Rawat reports no conflicts.

Acknowledgements
The preparation of this manuscript was supported in part by funding from NIH grant RO1 AI104636, by the Baruch S. Blumberg Institute and by the Commonwealth of Pennsylvania.

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http://www.hepb.org/

阳光醉人

4。宿主靶向抗病毒药物
4.1。产品在临床开发
五卫生技术评估是开发的临床阶段（图4），和另外两个最近失败或已停产。的五个仍在发展中，两个目标主机功能使用的病毒（Myrcludex B，brinapant），和其他目标主机的先天和适应性免疫系统（gs-4774，GS 9620，dv601 sb9200hbv）。
4.1.1。病毒进入抑制剂
Myrcludex B（mycB），从LHBs preS1域衍生的合成肽，是进入抑制剂Hepatera / myr-gmbh.病毒进入抑制剂是一个相对较新的和有效的抗病毒药物，HIV trimeris FUZEON之间第一（lobritz等人。，2010年）。病毒以防止其与靶细胞的中和抗体是公认的一种方法。乙型肝炎病毒（HBV），唯一的例子是Myrcludex B（mycB），脂肽来自细胞附着区的乙肝病毒外膜大蛋白（格里蓬等人。，2005年，彼得森等人。，2008年城市等人。，2014年）Myrcludex B需要胃肠外给药；这将是一个缺点，为临床治疗。2A期临床试验研究证明Myrcludex乙患者HBV DNA水平下降不依赖。Myrcludex B也显示出可喜的成果，在2A期试验在慢性丁型肝炎病毒（HDV）感染。HDV采用HBV包膜蛋白肝细胞进入，因此如果Myrcludex B被批准可用于治疗乙型肝炎和丁型肝炎病毒的慢性感染。（Hepatera，2014城市等人。，2014）。
4.1.2。免疫增强剂
在临床阶段的HTA四免疫增强剂。慢性乙型肝炎患者肝脏疾病的机制是从根本上一个慢性，但不足免疫和炎症攻击感染的肝细胞，导致肝损伤（Ganem和王子，2004年，西格和梅森，2000）。一天可能因此不充分；持久，停药后，抗病毒反应，因此可能需要某种类型的受影响的个体的免疫恢复。虽然它是希望，完全抑制抗原，以及病毒血症，可能揭露或使一个懒惰或抑制免疫反应（或也许“自由”中和抗体，否则复合抗原），某些类型的直接免疫觉醒的主机将是必要的（见审查durantel和他的同事们在本次研讨会）。
不幸的是，大多数尝试刺激免疫系统在慢性HBV携带者清除HBV有令人失望，并在人体试验失败或有不良临床后果，如那些与先进的肝纤维化或肝硬化失代偿。因此就有了相当大的兴趣，发展战略，促进宿主的免疫识别HBV，慢性携带者，他们通常能识别病毒，在细胞和体液免疫水平，没有清除感染（贝托列提，Gehring，2013年）。
4.1.2.1。盐
盐是由HBsAg和乙肝免疫球蛋白，（抗-HBs免疫球蛋白）复合物作为一种治疗剂有明矾作为佐剂（Xu等人。，2008）。候选人达到第三阶段的临床试验，结果被认为是不能令人满意的。过度的刺激与YIC表明降低盐由于免疫疲劳的功效（Xu等人。，2013）。因此，它的延续无疑是一个挫折和失望，因为这些替代方法曾经认为有前途的。
4.1.2.2。GS 9620
Toll样受体（TLR）- 7是一个“病原体识别受体表示“大多在溶酶体/胞内舱的浆细胞样树突状细胞（pDCs）和B淋巴细胞，识别模式病毒单股RNA（奥尼尔et al。，2013年）。有越来越多的证据表明，模式识别受体的激活可以直接抑制乙肝病毒在感染的细胞（如2012）（见即将发表的评论，在本次研讨会中的常和同事）。
GS 9620是一种小分子激动剂临床发展TLR-7（roethle等人。，2013）。1B期安全性研究最近报道，显示该药是安全的，达到了预期的诱导干扰素刺激基因在外周血细胞（Gane等人。，2015）。的确，GS - 9620有旱獭和黑猩猩的重大活动，和将是一个“第一在班”，表明模式识别受体的药理学活性可以有临床效益管理慢性HBV感染（兰福德等人。，2013年）