: In the management of patients with chronic hepatitis B during clinical practice, how to evaluate the host factors that may be related with antiviral response?
Sang hoon AHN教授：遗憾的是，目前我们的前景并不乐观。病毒因素很多，但是很难评估宿主因素。对于使用干扰素治疗，白介素28B基因多态性是最重要的宿主因素，但是，目前还有其他潜在的生物标志物正在研究中。乙型肝炎病毒感染持续时间较长或年龄增加可能与实现功能治愈有更大的相关性。目前，有许多蛋白质组学和基因组学研究正聚焦于寻找有前景的因子及测定方法，以期实现HBsAg的消除，即有效地实现功能性治愈。
Prof. Sang hoon AHN: Unfortunately, we don’t have promising prospects at this moment. There are many viral factors, but it is difficult to evaluate host factors. For the use of interferon as a treatment, interleukin 28B gene polymorphism is the most important host factor, however, there are other potential biomarkers under investigation right now. Maybe a long duration of HBV infection or an age effect may be more related to achievement of a functional cure. Currently, there are many proteomic studies and genomic studies focusing on finding promising factors and assays for achieving HBsAg loss, effectively a functional cure.
: HBsAg (HBV surface antigen) loss is the optimal treatment endpoint for chronic hepatitis B termed ‘functional cure’. What are the major shortcomings of currently available antivirals to achieve the goal of functional cure?
Prof. Sang hoon AHN: Actually, the definition of functional cure is achieving both HBsAg loss and undetectable DNA levels over a prolonged time. This means functional cure may be possible with appropriate treatment. However, this is very difficult with the nucleoside analogs, because the nucleoside analog oral agents are directly targeting reverse transcriptase inhibition, but persistent cccDNA is the reason for persistent HBV infection. Without the elimination of cccDNA is very difficult to achieve a functional cure. It is difficult to target cccDNA directly as drug delivery is difficult, and there is also the chance of carcinogenesis when there is a change in the host genome. There are many new drugs now in development targeting siRNA, capsid inhibitors, immune modulators and entry inhibitors. Some data has shown combining these newer agents rapidly increases HBsAg loss rates, which means achieving a functional cure is not far away. There are many ongoing clinical trials, so there is some hope for a functional cure in the near future.
Sang hoon AHN教授：实际上，功能性治愈的定义是在较长时间内既达到HBsAg消失丢又达到DNA水平无法检测到。这意味着通过适当的治疗可以实现功能性治愈，但是，对于核苷（酸）类似物（NA）来说这是非常困难的。因为NA口服可以直接靶向抑制逆转录酶，但是cccDNA持续性存在才是患者持续性HBV感染的原因所在，如果不消除cccDNA，则很难实现功能性治愈。由于给药困难，直接靶向cccDNA困难，并且当宿主基因组发生变化时，也有致癌的机会。
: Are there any host-targeting or immunotherapeutic agents undergoing clinical trials showing promise in the treatment of hepatitis B? Is it monotherapy or combined with other antiviral drugs?
Dr Ahn: There are many newer drugs targeting viral factors. A promising one is the siRNA and capsid inhibitors. For the host factors, I can introduce some of them. Blocking HBV infection can be achieved with the Myrcludex NTCP inhibitor, or the monoclonal neutralizing antibodies. The other promising one is the HBsAg release inhibitors from Replicor. There is a study combining HBsAg release inhibitors, tenofovir and peg-interferon shows that >50% of patients achieve HBsAg loss, which is quite dramatic. So the combination of HBsAg release inhibitors with peg-interferon may have a role. I am also involved in a clinical trial with a monoclonal antibody against human hepatitis B virus that can block HBV infection as well as neutralizing HBsAg in circulation. We have found in animal studies that many mice models achieved HBsAg loss, and we have progressed to a phase II trial. The phase I trial has been completed and accepted in Clinical Gastroenterology and Hepatology. The other immune modulator might be the TLR agonists. TLR7 and TLR8 are now under investigation. Another very promising agent is inarigivir, a RIG-I, NOD2 inhibitor, which induces type I and type III interferon production, showing a dramatic reduction in HBsAg levels and DNA levels. So in the future, combination therapy with these direct-targeting agents plus immune modulators can cure HBV infections.
Sang hoon AHN教授：有许多针对病毒因素的新型药物，其中siRNA和衣壳抑制剂较有前景。对于宿主因素，我可以介绍一些。可以使用Myrcludex NTCP抑制剂或单克隆中和抗体来阻断HBV感染。另一个有希望的抑制剂是Replicor的HBsAg释放抑制剂。一项结合HBsAg释放抑制剂、替诺福韦和聚乙二醇干扰素的研究表明，>50%的患者会发生HBsAg清除，这是不可思议的。因此，HBsAg释放抑制剂与聚乙二醇干扰素的组合可能发挥作用。
我还参与了针对人类乙型肝炎病毒的单克隆抗体的临床试验，该抗体可以阻断HBV感染并中和循环中的HBsAg。在动物研究中，我们发现许多小鼠模型都达到了HBsAg消失，并且我们已经进入了II期试验。I期临床试验已经完成并被 Clinical Gastroenterology and Hepatology杂志接收。另一个免疫调节剂可能是TLR激动剂。TLR7和TLR8现在正在探索中。另有一个非常有前景的药物是inarigivir（RIG-I、NOD2抑制剂），其可诱导I型和III型干扰素产生，目前已显示出HBsAg水平和DNA水平的显著降低。
