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EASL专访丨印度Nirupma Trehanpati教授：HBV治疗的新免疫学趋势
—— 作者: 时间:2022-07-05 12:02:56 阅读数:
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慢性乙型肝炎（CHB）抗病毒治疗的最终目标是追求以HBsAg清除为主要特征的“功能性治愈”，但目前可用的治疗策略只能在不到10%的CHB患者中实现“功能性治愈”。增强人体对HBV的免疫力从而获得功能性治愈是CHB治疗的一个非常重要的课题。HBV免疫调节疗法包括HBV中和单克隆抗体、治疗性疫苗、增强T细胞和B细胞功能的免疫工程细胞以及免疫检查点抑制剂，已有很多相关新药处于各期试验阶段。
第57届欧洲肝病研究学会年会（EASL2022）暨2022年国际肝脏大会TM（ILC 2022）上，印度肝胆科学研究所Nirupma Trehanpati教授在“HBV和HDV新疗法概念”论坛，就HBV新免疫疗法做了专题报告，并就乙肝新药研发、免疫调节剂等相关话题接受了《国际肝病》的现场采访，分享了自己的独到见解。
《国际肝病》
目前的抗病毒药物还不能使慢乙肝患者彻底治愈，那么，乙肝新药研发以及新治疗方案探索的进展如何？您认为未来研究的重点和趋势是什么？
Nirupma Trehanpati教授
HBV是一种非常难对付的病毒。它位于细胞核内，药物不能穿透细胞核而触达，所以完全清除HBV是非常困难的。HBV以cccDNA以及与人类基因组整合的形式存在，因此当前出现了很多靶向细胞核、旨在清除cccDNA的新药，但它们进入到临床试验阶段。然而，增强或调节宿主免疫力可能是治疗和清除HBV的更好选择。免疫调节是从细胞中清除HBV感染继而使肝细胞再生的唯一方法。
参考文献：
Prof. Nirupma Trehanpati：HBV is a very difficult virus. It sits in the nucleus, and drugs cannot penetrate to the nucleus to reach it there. So it is very difficult to eliminate HBV completely. There are many drug options coming that are targeting the nucleus, because the virus persists as cccDNA and integrates with the human genome. Treatments are aimed at eliminating cccDNA, but those treatments have not yet reached clinical trials. However, to enhance or modulate the host immunity could be a better option for the treatment of HBV and its elimination. Immune modulation is the only way to eliminate HBV infection from the cells so hepatocytes can regenerate.
《国际肝病》
临床上现有及新型治疗HBV的药物有哪些？各有什么特点？
Nirupma Trehanpati教授
现有HBV抗病毒药物是核苷（酸）类似物（NAs），还有基于聚乙二醇干扰素（PEG IFN）联合治疗和序贯治疗，也可用于调节宿主免疫。正如我前面提到的，免疫调节是从细胞中清除HBV病毒的唯一方法，因此PEG IFN作为免疫调节剂联合或序贯使用，可提高血清学转换和功能性治愈的概率。
参考文献：
Prof. Nirupma Trehanpati：The nucleoside and nucleotide analogs exist for HBV treatment. However, there is combination therapy and sequential therapy with peg-interferon, which can also be used to modulate the host immunity. As I mentioned earlier, immune modulation is the only way to remove the HBV virus from cells, so when peg-interferon is used as an immune modulator in combination or sequentially, there is a better chance of seroconversion and a complete functional cure.
《国际肝病》
随着免疫治疗时代的来临，免疫调节剂成为疾病治疗新兴力量。那么，请您简单介绍一下HBV感染的作用机制有哪些？
Nirupma Trehanpati教授
这很有趣，免疫调节真的有用。免疫调节主要影响T细胞和B细胞，PEG IFN和免疫调节增强了HBV特异性T细胞和B细胞，这无疑强化了针对HBsAg和HBeAg血清学转换的抗病毒免疫效能。
参考文献：
Prof. Nirupma Trehanpati：This is very interesting. I am going to talk about this - that immune modulation really helps. Basically, immune modulation affects the T-cells and B-cells specifically. HBV-specific T-cells and B-cells are potentiated by peg-interferon and immune modulation, which certainly makes the anti-viral immunity stronger for HBsAg and HBeAg seroconversion.
《国际肝病》
目前针对慢性乙型肝炎免疫治疗的策略有哪些？
Nirupma Trehanpati教授
PEG IFNα是一种很好的免疫调节剂，也有一些新的在研药物仍处于不同阶段的试验中，DCR-HBVS和CART细胞是主要的免疫调节疗法。当然可以用多酚和抗氧化剂来增强HBV特异性CD8 T细胞。另一个策略是用治疗性疫苗动员单核细胞。它可能有效，因为这些单核细胞载有其他药物和抗PD-1单抗，但这类方法仍处于研究阶段，尚未在临床实践中应用。所有这些疗法都有可能成为减少和清除HBV的免疫疗法。
参考文献：
Prof. Nirupma Trehanpati：As I mentioned in the previous questions, peg-interferon is a good immunomodulator. However, the latest drugs are still yet to be in trials. HBVS-DCR and CAR T-cells are the main immune modulation therapies. You can certainly potentiate the HBV-specific CD8 T-cells with the polyphenols and antioxidants. Another strategy is mobilizing monocytes with a therapeutic vaccine. It can be useful because those monocytes are drug-loaded and anti-PD-1-loaded, but this is still at the research stage, and not in clinical practice. However, all of these have the potential to become immune therapy for HBV reduction and elimination.
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