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EASL巅峰访谈丨Kennedy教授：“免疫耐受期”慢乙肝患者，应该治疗吗？
发表时间：2018-04-12 访问量：138 标签： 访谈 乙肝 专家访谈 相关搜索： 慢乙肝
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之前称为“免疫耐受”的患者实际并非免疫耐受
到目前为止，我们做的大量研究工作已经表明，之前称为或认为是“免疫耐受”的患者，实际上并非免疫耐受。该点证实了我们已经提议过一段时间的观点，这是基于血清HBV DNA和丙氨酸氨基转移酶（ALT）水平等临床参数的一种临床分类，但是，当我们考虑这些患者的免疫学特征时，称为“免疫耐受”的患者和称为免疫激活的患者相比，并没有任何差异。这一点反对这些患者为免疫耐受期的观点，并且是对之前命名术语进行改变的部分动因。目前，我们将之前称为“免疫耐受”的患者命名为HBeAg阳性慢性HBV感染，我们正在考虑如何治疗和管理这些患者的其他策略。
Dr Kennedy: A lot of our work to-date has shown that when we look at patients who are labeled or considered immune tolerant, they are actually not immunologically tolerant. This confirms what we have been proposing for some time, that this is a clinical categorization based on clinical parameters (HBV DNA, serum ALT), but when we look at these patients immunologically, we don’t see any difference between patients who are labeled immune tolerant from those labeled immune active. This is an argument against the fact that these patients have immune tolerant disease, and part of the driver for the change in terminology. We are now calling these patients formerly labeled as immune tolerant as patients with HBeAg chronic infection. As a consequence of that, we are considering other strategies in terms of their treatment and management.
“免疫耐受”的患者应该接受治疗
如果考虑到研究数据表明这些患者并非真正的免疫耐受，支持对这些患者进行治疗。当然，在面对这种情况时，还需要考虑一些更现实的问题，包括药物花费、患者是否愿意用药、患者对药物治疗的依从性是否良好以及目前应用的治疗药物并不理想，甚至可能欠佳的事实等等。
例如，如果选择应用核苷（酸）类似物（NUCs）治疗，着眼于长期病毒抑制，患者必须维持用药，才能达到这一目标；如果选择应用聚乙二醇干扰素（PegIFN）治疗，Buster等人的重要工作已经表明，PegIFN对真正免疫耐受患者的效果很差。
因此，当我们确定应该治疗“免疫耐受”的患者时，还要认识到并非必须在诊所立即治疗，我们需要更好的生物标志物和其他指标，以特异识别哪些患者通过早期治疗很可能获得更佳的效果。但是，从更长远的角度考虑，这一早期治疗策略将成为主要策略，以避免慢性HBV感染的长期后果，这是一个非常重要的问题。
Dr Kennedy: This is a good question, and a question that comes back time and again. If you take our data for what it shows, it makes an argument for treating these patients. Of course, there are some more real world issues to consider when faced with this scenario. There is the cost of the drug, whether the patients will take the drug, whether patients will be adherent to the drug, and the fact that the treatments we are using at present are not ideal, and probably even suboptimal. If we are using NUCs, for example, we are looking at long-term viral suppression and the patient having to maintain that drug in order to achieve this. For pegylated interferon, in truly immune tolerant patients from seminal work from Buster et al, pegylated interferon works poorly in these patients. So while we are making the case that we should be treating patients who are labeled immune tolerant, we also recognize that this is not something we can necessarily do straight away in the clinic and that we need better biomarkers and identifiers so we can specifically target patients who will probably do better with early treatment, but in the longer run, that this early treatment strategy will become the main strategy to avoid the long-term sequelae of chronic infections. It is a very important subject.
应用PegIFN和NUCs联合或序贯治疗具有一定价值
PegIFN和NUCs都有其局限性：患者对PegIFN治疗的应答率不理想，还有一些药物相关的不良反应，并且仅有部分患者对PegIFN治疗产生应答；另一方面，NUCs的耐受性良好，可以达到病毒抑制，但是，患者必须依从性良好，需要长期药物治疗。考虑到可用治疗与期望达到诸如HBsAg清除等更强的终点存在差距的事实，确实应该考虑应用这些药物联合或序贯治疗。
最近，有一些很好的已发表研究表明，应用PegIFN治疗后，序贯以拉米夫定治疗，患者可以获得更高的HBeAg血清学转换率和HBsAg清除率。这些数据与之前发表的研究结果一致，均表明治疗更年轻的患者可以获得更好的治疗效果，并且也与我们早期的一些研究结果相呼应，应用PegIFN和NUCs序贯治疗，患者可以获得更好的治疗效果。
Dr Kennedy: I have mentioned the limitations of both pegylated interferon and NUCs already. For pegylated interferon, the response rates are not ideal. There are systemic effects associated with the drug. And we know it only works in a proportion of patients. NUCs, on the other hand, are well tolerated. They can achieve viral suppression, but the patient must be adherent to them and must take them for a long time. Given the fact that we have a gap in the therapies that we can give to achieve the more robust endpoints that want, such as HBsAg loss, there is certainly an argument for looking at combinations of some of these drugs and using some of these drugs in sequence. There have been some good recent publications showing the use of pegylated interferon followed by lamivudine in sequence has much greater levels of HBeAg seroconversion and greater levels of HBsAg loss. These data are consistent with previously published data suggesting the same thing, that treating patients younger can lead to better treatment outcomes, and also probably resonate with some of our early data about using pegylated interferon and NUCs in sequence to achieve better treatment outcomes.
期望新的治疗方法
有多种新药处于研发或研发初期，可望作为新的治疗策略。我个人认为，称之为“免疫耐受”的患者应该考虑应用这些新的治疗和参加这些临床试验，因为他们是和其他乙肝患者差不多的适宜治疗者。
困难在于我们尚不清楚这个阶段的最佳治疗以及最有利的治疗方法，能够使患者达到期望的治疗效果，真正期望的治疗目标是HBsAg清除或功能性治愈。能够在相对限定的治疗时间内，使这些患者达到该目标的治疗就是理想的治疗。如果治疗患者达到HBsAg清除，就是很理想的情况，可以降低发生疾病进展和肝细胞癌（HCC）的风险，这是非常明确的。
Dr Kennedy: There are multiple new agents in development and in the development pipeline as potential new treatment strategies. Personally, I think patients labeled as immune tolerant should be considered for those new therapies and considered for those clinical trials, because we see them as treatment candidates as much as other patients with hepatitis B. The difficulty is that we are not clear at this stage what the best therapy will be and what the most advantageous therapy will be in order for them to achieve the treatment outcomes we want. The treatment goal that we really want is HBsAg loss or functional cure. Any therapy that can deliver that in a relatively timely manner will be the ideal therapy for these patients. We think that if we treat patients and achieve HBsAg loss then that is the ideal scenario to reduce the risk of disease progression and reduce the risk of the development of HCC. That is clear. |
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发表于 2018-4-13 14:09
