病毒性肝炎国会2015-病毒性肝炎B和D：临床前和早期临床

StephenW

The Viral Hepatitis Congress 2015, Kap Europa, Frankfurt, Germany
O21 Viral Hepatitis B and D: Preclinical and Early Clinical

O211
What have we learned since the identification of the HBV entry receptor NTCP?

S Urban

Department of Infectious Diseases, Molecular Virology, University Hospital Heidelberg, Heidelberg, Germany

For almost three decades after the discovery of Hepatitis B Virus (HBV) the early events of infection (attachment, receptor binding and fusion) remained entirely unresolved. Although the extraordinary hepatotropism of HBV and its peculiar host specificity were supposed to be linked to specific receptor binding, it remained unclear which domain(s) within the viral envelope protein(s) are essential for mediating virus entry and which cellular receptor(s) are addressed. One reason of this delay of progress was the lack of in vitro cell culture systems. Following the establishment of the first infectable HepaRG cell line in 2002, systematic analyses allowed the identification of a myristoylated preS1-subdomain within the viral L-envelope protein as essential for infection. In 2012 it was shown that this part of the virus specifically binds the sodium taurocholate co-transporting polypeptide (NTCP/SCL10A1) which is exclusively expressed at the basolateral membrane of hepatocytes were it functions in bile salt re-import. The development of (Myrcludex B) as a potent peptidic inhibitor of this receptor opened a novel therapeutic option to treat acute and chronically infected patients. Moreover, the identification of NTCP allowed the establishment of robust cell culture systems, which are currently used to identify novel drugs and cellular factors that can be addressed by possible future therapeutic approaches. In addition, the discovery of NTCP as one of the major host restriction factors for HBV will help to develop immune competent animal models to study pathogenesis of this virus. In my talk, I will discuss the current state of the art of these recent approaches and discuss, if entry inhibition via NTCP-targeting might become important for future therapeutic regiments.

O212
New drug targets for hepatitis B virus and clinical data from phase I/II studies

A Shlomai

The Liver Institute, Rabin Medical Center, Beilinson Hospital, Petah-Tikva, Israel

Chronic hepatitis B virus (HBV) infection is a global health problem affecting more than 350 million people worldwide. Nucleotide/side analogues are currently the main standard of care for chronically infected patients. However, although those drugs efficiently suppress viral replication through inhibition of its polymerase activity, they only seldom cure the patients due to their inability to target the viral episomal DNA (cccDNA). An intensive research for several decades now has advanced our understanding of the HBV life cycle, its interactions with the host and its interplay with the immune system. This provided fertile ground for the development of innovative anti-viral strategies that either target specific steps in the HBV life cycle and/or evoke a more robust immune-mediated anti-viral response to better control the virus. Prominent examples include viral entry inhibitors that bind and block the recently discovered HBV receptor, the bile acid pump NTCP, as well as drugs that interfere with the formation of the viral capsid. Newly introduced genetic-based strategies, such as anti-sense oligonucleotides, ribozymes and RNA interference (RNAi) have shown promise in suppressing viral gene expression thereby provoking a more efficient anti-HBV immune response. Recently, the newly introduced CRISPR/Cas9 system has been shown, albeit so far only in experimental systems, to directly target HBV DNA, as well. Strategies to evoke an effective immune response against the virus are versatile and include activation of the immune response through Toll-like receptors such as TLR-7, reversing T cell exhaustion by blocking co-inhibitory signals and using therapeutic vaccines to restore an effective anti-HBV immune response. There is also renewed interest in activating components of the innate immune system to elicit effective and less cytotoxic anti-viral effect that may promote cccDNA degradation. Some of those innovative strategies have been already translated into drugs that are currently tested in phase I/II clinical trials, giving the hope that a more definitive treatment for chronic HBV infection will be realistic in the foreseen future.

HDV replication and putative drug targets

H Wedemeyer

Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany

Suppression of HDV RNA replication is the primary goal during treatment of hepatitis delta leading usually to normalization of liver enzymes and histological improvement of liver disease. Hepatitis delta infected patients are treated with IFN-α since the mid-1980s; however, similar to HBV monoinfection, sustained virologic response is rarely achieved. Also therapies with a combination of IFN-α and a nucleos(t)ide analogue did not lead to the desired success. Alternative treatment options for hepatitis delta, targeting different steps of the HDV infection and replication cycles, are currently being explored in early clinical trials. The HBV entry inhibitor Myrcludex-B is also being developed for hepatitis delta. Myrcludex-B is a lipopeptide derived from the preS1 domain of the HBV envelope. The molecular target of Myrcludex is the bile acid transporter sodium taurocholate cotransporting peptide (Ni 2013) and it has been shown to prevent HDV in mice models. The compound is also currently being tested in Phase 1 and Phase 2a trials in healthy volunteers and patients with hepatitis B and B/D coinfected patients. The second promising new drug is lonafarnib, a prenylation inhibitor. HDV replication depends on a prenylation step and prenylation inhibitors have already been developed for the treatment of malignancies. First proof-of-concept studies investigating the safety and efficacy of the prenylation inhibitor lonafarnib in patients with hepatitis delta have been completed and showed indeed antiviral efficacy against HDV in patients. Finally, first data are available on another concept investigating nucleic acid polymers in hepatitis delta. Pilot trials showed a marked decline in HBsAg levels within 3–4 months of therapy paralleled by a decline in HDV RNA. More data are needed to investigate long-term response and safety of this strategy. In summary, treatment of hepatitis delta remains a major challenge with very limited options to induce cure from HDV infection but within the last year some promising steps have been done.

StephenW

病毒性肝炎国会2015年，金甲欧洲，德国法兰克福

O21病毒性肝炎B和D：临床前和早期临床
O211
由于乙肝病毒进入受体NTCP的鉴定我们学到了什么？

城镇

传染病，分子病毒学，大学医​​院海德堡，德国海德堡系

对于乙肝病毒（HBV）感染（附件，受体结合和融合）的早期事件后发现，几乎三十年仍完全没有得到解决。虽然乙肝病毒和其特有的宿主特异性非凡的嗜肝原本应与特定受体结合，但仍不清楚病毒包膜蛋白（S），在其中域是必不可少的调解病毒进入并细胞受体（S）得到解决。的进展这种延迟的一个原因是缺乏体外细胞培养系统。继建立了第一个可感染HepaRG细胞系在2002年，系统的分析使病毒L-包膜蛋白感染是必不可少内的肉豆蔻前S1子域的标识。在2012年它被示出，这部分的病毒特异性结合的牛磺胆酸钠共转运多肽（NTCP / SCL10A1），其只表达在肝细胞的基底外侧膜是它在胆盐重新导入功能。的（Myrcludex B）作为该受体的强效肽抑制剂的发展开辟了一种新的治疗选择，以治疗急性和慢性感染的患者。此外，NTCP的识别允许建立稳健的细胞培养系统，这是目前用于识别新型药物和细胞因子，可以通过可能的未来的治疗方法来解决的。此外，NTCP的发现为主要宿主的限制因素，HBV之一，将有助于培养免疫能力的动物模型来研究这种病毒的发病机制。在我的谈话中，我将讨论最近这些方法艺术的现状和讨论，如果通过NTCP靶向阻进可能成为未来治疗军团重要的。

O212
乙型肝炎病毒和I / II期临床研究数据的新的药物靶标

一个Shlomai

肝脏研究所，拉宾医学中心，贝林松医院的Petah-Tikva的，以色列

慢性乙型肝炎病毒（HBV）感染是影响全球超过3.5亿人口的全球性健康问题。核苷酸/侧类似物是目前照顾的慢性感染病人的主要标准。然而，尽管这些药物有效地通过抑制其聚合酶活性的抑制病毒的复制，他们只有很少治愈患者因无力为目标的病毒游离DNA（cccDNA的）。一个深入研究了几十年，现在拥有先进的我们对乙肝病毒的生命周期，它与主机及其相互作用与免疫系统相互作用的了解。这提供了沃土创新抗病毒策略的发展，在HBV生命周期或者目标特定步骤和/或唤起更强烈的免疫介导的抗病毒响应，以更好地控制病毒。突出的例子包括结合和阻断最近发现的HBV受体，所述胆汁酸泵NTCP，与病毒衣壳的形成干扰病毒进入抑制剂，以及药物。新引入的遗传基础的策略，例如反义寡核苷酸，核酶和RNA干扰（RNAi）已经显示许在抑制病毒基因表达，从而激起更有效的抗HBV的免疫反应。最近，新引入的CRISPR / Cas9系统已经显示出，尽管至今只在实验系统，直接定位的HBV DNA，以及。策略，以唤起针对病毒的有效免疫反应是通用的，并包括通过激活Toll样受体，例如TLR-7的免疫反应，通过阻断共抑制信号，并使用治疗性疫苗倒车T细胞衰竭，恢复的有效抗乙肝病毒的免疫反应。也有在激活先天免疫系统的组分以引发有效和较少细胞毒性抗病毒效果，可能会促进cccDNA的降解重新产生了兴趣。其中的一些创新策略已经被翻译成在I / II期临床试验目前正在测试的药物，给予希望，更彻底治疗慢性乙型肝炎病毒感染将成为现实，在可预见的未来。

HDV复制和公认的药物靶标

^ h魏德迈

消化内科，肝病及内分泌，汉诺威医学院，汉诺威，德国

抑制HDV RNA复制的是治疗丁型肝炎导致通常到肝酶和肝病的组织学改善的正常化的过程中的主要目标。丁型肝炎感染者与自80年代中期IFN-α治疗;然而，类似的HBV monoinfection，持续病毒学应答很少达到。还治法用IFN-α和一个核苷（酸）的ide类似物的组合没有导致预期的成功。为丁型肝炎替代治疗方案，针对不同步骤的HDV感染和复制周期，目前正在探讨在早期临床试验。在乙肝病毒进入抑制剂Myrcludex-B也正在制定丁型肝炎。 Myrcludex-B是由乙肝病毒包膜的前S1域衍生的脂肽。 Myrcludex的分子靶标是胆汁酸转运牛磺胆酸钠cotransporting肽（镍2013），它已被证明HDV防止在小鼠中的模型。该化合物目前也正在第一阶段和第二阶段2A临床试验在健康志愿者和乙肝患者和B / D合并感染的患者进行测试。第二个有前途的新药lonafarnib，一个异戊烯化抑制剂。 HDV复制取决于一个异戊二烯化步骤和异戊烯化抑制剂已经被开发为恶性肿瘤的治疗。概念验证的首批研究调查的异戊烯抑制剂lonafarnib的安全性和有效性的患者丁型肝炎已建成并表明对HDV的患者的确是抗病毒疗效。最后，第一数据可在另一个概念调查丁型肝炎核酸聚合物。先导试验表明，3-4个月的治疗在HDV RNA的下降平行内明显下滑HBsAg水平。需要更多的数据来研究这一战略的长期的应对和安全性。总之，治疗肝炎的三角洲仍非常有限的选择是一个重大挑战，从HDV感染，但去年一些有希望的步骤已经完成内诱导治疗。

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