[DICID2012]决定乙型肝炎病人治疗开始和终止的因素——Nancy W.Y

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[DICID2012]决定乙型肝炎病人治疗开始和终止的因素——Nancy W.Y. Leung教授访谈                    

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                        来源： 作者：N.W.Y. Leung 发布时间：2012-7-20 14:59:48   阅读：24

                    
                                                                I think that the guidelines， the AASLD， EASL， or APASL are fairly similar. Essentially， in the past， we have been looking at patients with more advanced liver disease， but now with blood DNA tests being more widely available， these have become the first indication to look at. Of course， you do not just look at one: the DNA level or even DNA plus ALT.
我认为的指导方针，肝病学会，欧洲肝病学会，或APASL非常相似。从本质上讲，在过去，我们一直在寻找更先进的肝病患者，但现在与血液中的DNA测试是更广泛的应用，这些都成为看的第一个迹象。当然，你不只是看一个：在DNA水平上，甚至DNA加ALT键。

                    
                                                                                       

　　Hepatology Digest: The AASLD and EASL guidelines provide indications for when to start treatment for HBV patients. Is there anything you personally would like to add to these guidelines?
肝病：肝病学会和欧洲肝病学会指引，提供何时开始治疗慢性乙型肝炎患者的迹象。有什么是你个人想补充这些准则？
　　Leung: I think that the guidelines， the AASLD， EASL， or APASL are fairly similar. Essentially， in the past， we have been looking at patients with more advanced liver disease， but now with blood DNA tests being more widely available， these have become the first indication to look at. Of course， you do not just look at one: the DNA level or even DNA plus ALT. I think you have to look at the patient as a whole. I think that is the important thing. The guidelines always say that you have to assess the patient as a whole. That is the guidelines. You have to look at the patient’s age， gender， whether there is a family history of significant liver disease and other similar factors.
梁：我认为的指导方针，肝病学会，欧洲肝病学会，或APASL非常相似。从本质上讲，在过去，我们一直在寻找更先进的肝病患者，但现在与血液中的DNA测试是更广泛的应用，这些都成为看的第一个迹象。当然，你不只是看一个：在DNA水平上，甚至DNA加ALT键。我觉得你有病人作为一个整体来看待。我认为这是最重要的事情。总是说，你必须作为一个整体来评估病人的指引。这是准则。你要看看病人的年龄，性别，是否有家族史显着的肝脏疾病和其他类似的因素。
肝病：您的意见是什么时候来作为标记使用的乙肝表面抗原？
梁：那么作为一个标记表面抗原是新的东西，我认为我们正在学习如何使用它，虽然已在过去两年来的数据是非常有前途的。首先，我认为重要的是要帮助我们使静态疾病的临床诊断，这意味着E-阴性的患者，具有非常低的DNA低于也许，一千IUS相比，在寻找的人究竟是谁E-阴性的活动性疾病。 ALT和DNA的波动，因此，虽然我们说，我们尝试DNA和ALT水平的3倍，每月监控您的病人，我怀疑，如果超过10％的医生正在做的。这是很难得到患者捐血频繁，所以我认为现在我们正在寻找在DNA水平上加表面抗原定量相结合，给我们一些轮廓。量化的过程将在E-阴性的活动性疾病的表面抗原水平高一点。第二大用途是在治疗监测方面。目前，我们只用干扰素或聚乙二醇干扰素治疗的良好指标。核苷，核苷酸类似物，它似乎它归结非常缓慢，因为我们的预期，因此时间会告诉我们。我们可能需要几年看，它来决定是否核苷，核苷类似物治疗，给人一种趋势，可以帮助我们。
　　Hepatology Digest: What would your opinions be when it comes to using the hepatitis B surface antigen as a marker?
肝病：您的意见是什么时候来作为标记使用的乙肝表面抗原？
　　Leung: Well the surface antigen as a marker is something new and I think we are learning to use it， although the data that has come out in the past two years is all very promising. Firstly， I think it is important to help us make the clinical diagnosis of quiescent disease， which means e-negative patients with very low DNA， of below maybe a thousand IUs， as compared to looking at someone who actually has e-negative active disease. The ALT and DNA fluctuates， so， although we say we try to monitor your patients 3-times monthly with DNA and ALT levels， I doubt if more than 10% of the doctors are doing that. It is difficult to get patients to give blood that frequently， so I think now we are looking at the combination of the DNA level plus the surface antigen quantification to give us some outline. The quantification of course will have a bit higher surface antigen level in the e-negative active disease. The second big use is in terms of the therapeutic monitoring. Currently， we only get good indicators with interferon or pegylated-interferon treatment. With nucleoside， nucleotide analogues， it seems that it comes down very slowly， as we expect， so time will tell us. We will probably need to look at it in a few years to decide whether or not the nucleoside， nucleotide analogue therapy gives a trend that helps us.
梁：那么作为一个标记表面抗原是新的东西，我认为我们正在学习如何使用它，虽然已在过去两年来的数据是非常有前途的。首先，我认为重要的是要帮助我们使静态疾病的临床诊断，这意味着E-阴性的患者，具有非常低的DNA低于也许，一千IUS相比，在寻找的人究竟是谁E-阴性的活动性疾病。 ALT和DNA的波动，因此，虽然我们说，我们尝试DNA和ALT水平的3倍，每月监控您的病人，我怀疑，如果超过10％的医生正在做的。这是很难得到患者捐血频繁，所以我认为现在我们正在寻找在DNA水平上加表面抗原定量相结合，给我们一些轮廓。量化的过程将在E-阴性的活动性疾病的表面抗原水平高一点。第二大用途是在治疗监测方面。目前，我们只用干扰素或聚乙二醇干扰素治疗的良好指标。核苷，核苷酸类似物，它似乎它归结非常缓慢，因为我们的预期，因此时间会告诉我们。我们可能需要几年看，它来决定是否核苷，核苷类似物治疗，给人一种趋势，可以帮助我们。
　　Hepatology Digest: The newly updated EASL guidelines recommend sustained off-therapy response， what is your opinion on this development?
肝病：欧洲肝病学会最新更新的指引建议持续治疗外响应，你这方面的发展的看法是什么？
　　Leung: Sustained off-therapy response is a type of a virological response that we use across all diseases， so of course we would like to see that if the patient is on nucleoside， nucleotide analogue， the end of treatment DNA is PCR negative. If you are purist， then you do not even want to see the DNA come back to 100 or 150. However， if we know and look at the whole spectrum of chronic hepatitis B patients， as I said， maybe 70% of them clear the virus themselves and have a very inactive disease， though their DNA level is not undetectable. The majority of them have a DNA count of less than 1000 or less than 10000 IUs. At that level， you do not have ALT abnormality or liver inflammation. I think that， in terms of defining a sustained response of treatment， maybe we should define it as an upper limit rather than undetectable.
梁：持续了治疗的反应是，我们在所有疾病中使用的病毒学应答的类型，所以我们当然想看到，如果病人是核苷，核苷酸类似物，治疗DNA年底PCR阴性。如果你是纯粹的，那么你甚至不希望看到的DNA回来到100或150。然而，如果我们知道，看在慢性乙型肝炎患者的全谱，我说，也许70％的清除病毒，并有一个非常无效的疾病，但他们的DNA水平是不是不到。他们中的大多数有DNA小于1000或大于10000 IUS计数。在这个水平，你没有ALT异常或肝脏炎症。我认为，在定义一个疗程的持续反应，也许我们应该定义为上限，而不是检测不到它。
　　Hepatology Digest: Interferon treatment is more likely to result with a patient off-therapy， but when it comes to nucleoside， nucleotide analogue treatments， there is a higher risk reoccurrence. Could you please discuss which analogues have the greatest potential for sustained， off-therapy treatment?
肝病：干扰素治疗，更可能导致病人的治疗，但是当谈到核苷，核苷类似物治疗，有较高的风险复发。能否请您谈谈这类似物持续关疗法的最大潜力？
　　Leung: Well， you ask a very good question. I think that in this day and age， we want evidenced-based medicine; we want good， randomized-controlled trials with significant numbers; we want the trial to be conducted very well to give us the answer. Unfortunately， the question you pose to me on which nucleoside or nucleotide analogue has the best off-treatment sustained response cannot be answered at this time. Those data have not be gathered in the past few years， because all of the pivot trials for the new nucleoside， nucleotide analogues， unlike in the lamivudine trial days， just ask patients to continue treatment. As a result， we do not have a very good， organized trial to look at for treatment response. However， all these will be coming， because lots of hepatologists， my colleagues， have treated patients for so long already. They just need to switch the mindset away from worrying about rebound and not daring to stop treatment. This can be guided by the quantitative surface antigen and when you have a group of patients who are off-treatment， with undetectable DNA after one or two years and a quantitative surface antigen count of less than 100. I think， soon， we’ll have those answers.
梁：嗯，你问了一个很好的问题。我认为在这个时代，我们希望医学证据为基础;我们想好，随机控制，具有显著的数字试验;我们要进行的试验很好，给我们的答案。不幸的是，你对我的问题核苷或核苷酸类似物具有最佳的治疗持续应答不能在这个时候回答。这些数据没有被收集在过去的几年中，因为所有的支点试验新的核苷，核苷酸类似物，不同于拉米夫定审判日，只是要求病人继续接受治疗。因此，我们没有一个很好的，有组织的试验，以寻找治疗的反应。然而，所有这些将到来，因为有很多治疗肝病，我的同事，所以已久的患者。他们只需要切换的心态，从担心反弹，不敢停止治疗。这可以指导定量表面抗原，当你有一组患者治疗外，不到一年或两年后DNA的定量表面抗原数少于100。很快，我认为，我们将这些问题的答案。
　　Hepatology Digest: Could you recommend some trials for us to watch?
肝病：你能推荐一些试验中，我们看呢？
　　Leung: Currently， there are a lot of clinical trials going on， as discussed in the meeting， about trying to attain a better virological response or sustained response with combination therapy. I personally know that entecavir and pegylated-interferon trials are ongoing. I always feel that with the trial， the inclusion and exclusion criteria are very important. If you use pegylated-interferon， for a trial， or even a nucleoside analogue， we know that if you have a lot e-positive patients with ALT between 2 and 5 times normal， your results are bound to be very good. I also remember that because recruitment is so low and because those patients are difficult to come by， we lower our threshold for ALT to just above normal. So the trial results are not so good. That is why I think it comes to the point at the end of that discussion just now: if we go back to 20 years ago， we could use sterile withdrawal (7:28) as a way to stimulate the host immune system， to give them a little ALT flare. But now， we do not dare do that， because as we gain experience， we found that some patients flare rapidly. I think that a lot of the studies going on are not so much multinational， pharmaceutical sponsored trials， these are individual hospital trials. I know that in Prince of Wales Hospital， together with my previous hospital， we have a host of patients that have been on entecavir， for example， and their DNA has been undetectable for a couple of years. They are doing a very structured， off-treatment observation and monitoring. This， together with surface antigen quantification， will allow us to see at what level treatment should be stopped.
梁：目前，有很多正在进行的临床试验，在会议讨论的努力，以达到更好的联合治疗的持续病毒学应答或响应。我个人知道，恩替卡韦和聚乙二醇干扰素试验正在进行中。我始终觉得，审判，纳入和排除标准是非常重要的。如果您使用干扰素，干扰素，为审判，甚至是一种核苷类似物，我们知道，如果你有很多e抗原阳性患者与正常人的2倍和5倍之间ALT，结果必然是非常好的。我还记得，因为招聘是如此之低，因为这些患者是很难得的，我们的门槛降低为ALT高于正常。因此，试验结果是不那么好。这就是为什么我认为它是在讨论结束时，刚才点：如果我们回到20年前，我们可以使用无菌撤离（19:28）的方式来刺激宿主的免疫系统，给他们一点点的ALT耀斑。但现在，我们也不敢这样做，因为我们获得的经验，我们发现，一些患者的耀斑迅速。我认为，很多研究都没有这么多的跨国公司，制药赞助的试验，这些都是个别医院试验。我知道，在威尔斯亲王医院，连同我以前的医院，我们有一个病人已经对恩替卡韦，例如，它们的DNA已检测不到一两年的主机。他们正在做一个很有条理，处理过的观测和监测。这一点，连同表面抗原定量，将让我们看到了什么水平，应停止治疗。
                                                
                    

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来源：国际肝病作者：Nancy W.Y. Leung发布时间：2009-2-13阅读：1816文章导读：In summary, there is a strong case for treating CHB patients with low ALT, when there are options of effective and safe therapy. However, it must be emphasized that the recommendation to treat CHB patients with low ALT does not supersede a proper full assessment of the patient. Other factors that should prompt clinician to treat are the male gender, older age group, family history of serious liver disease or hepatocellular carcinoma, high serum HBV DNA levels, histological grading and staging or imaging suggesting coarse liver echo texture or cirrhosis. Nancy W.Y. Leung  Alice Ho Miu Ling Nethersole Hospital, Hong Kong SAR, China

Serum alanine aminotrans-ferase (ALT) has been used as a surrogate marker for the degree of inflammation in liver diseases.  It is a simple, readily available, and cheap blood test that can be repeated serially for monitoring disease progression.  It has good correlation with the histological grading and staging of chronic hepatitis B (CHB).  In the development of therapy for CHB, the main endpoint was initially targeted at the normalization of abnormal ALT.  In recent years, FDA added histological and viral response to ALT normalization as combined endpoints for assessing efficacy of treatment in clinical trials.

Almost all pivotal clinical trials on HBV therapy required raised ALT in the protocol inclusion criteria.  Results from these trials formed the backbone for developing HBV consensus and guidelines such as AASLD, EASL, and APASL.  This is evidence-based medicine.  There is very little published controlled data on therapy for low or normal ALT among CHB patients.  However, there are many good reasons to treat patients with low ALT.

1.ALT may fluctuate, some may have recurrent short ALT elevation or even flares.  Higher levels are easily missed in usual clinical practice when ALT is monitored at 3 to 6 monthly interval.

2.The “normal” ALT used in different laboratories is above the new suggested normal of 30 IU/L for males and 19 IU/L for females.

3.Many recent research and studies indicate patients with “persistent” low or normal ALT have significant liver diseases that require therapy.

4.A percentage of CHB patients are in immune tolerant stage and have very high viral load but normal ALT.  Antiviral therapy is not generally recommended for these patients, especially if they are young.  However, many are in their fourth, fifth and even sixth decade of life.  Evidence suggests that this prolonged duration of viraemia exposes them to higher risk of fibrosis progression and hepatocelluar carcinoma development.

5.In HBeAg-negative CHB, the ALT may be even more difficult to monitor.  These patients are older and despite lower serum HBV DNA, have a higher probability of significant liver disease.

6.In patients with advance fibrosis or cirrhosis, even low rate of disease progression reflected by low ALT level may indicate insidious progression.  Withholding therapy in these patients will hasten decompensation and death in short duration.

In summary, there is a strong case for treating CHB patients with low ALT, when there are options of effective and safe therapy.  However, it must be emphasized that the recommendation to treat CHB patients with low ALT does not supersede a proper full assessment of the patient.  Other factors that should prompt clinician to treat are the male gender, older age group, family history of serious liver disease or hepatocellular carcinoma, high serum HBV DNA levels, histological grading and staging or imaging suggesting coarse liver echo texture or cirrhosis.
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