魏来教授对话Foster教授

Hepatology Digest: I’m here with Prof. Grant Foster and Prof. Lai Wei. Thank you both for joining me today here at APASL， it’s a great honour. The first question I have today， Prof. Foster， can you talk about what is the difference clinically between the two pegylated interferons?

国际肝病：我在这里采访Grant Foster教授和Lai Wei教授，感谢两位接受我的采访，非常荣幸。第一个问题，Foster教授，您能不能谈下两种PEG干扰素在临床上有什么差别？

Prof. Foster: I think we have two pegylated interferons which are currently available. One is the 40 kilodalton branch chain pegylated interferon marketed under the brand name Pegasys， the other is the 12 kilodalton pegylated interferon alpha-2b marketed under the tradename PegIntron. Now there has been a lot of debate over the last few years as to whether those two interferons were identical or whether there were subtle differences. What we have known for a long time is that the 40 kD pegylated interferon lasted a little bit longer in serum than the 12 kD， and that’s led some of us to suggest that perhaps that might have a better efficacy. Now we have seen over the last couple of years some head-to-head comparative trials with the two pegylated interferons and， by and large， those  show that any difference is relatively small. I think there is no doubt that in easy-to-treat patients with genotype 2 and 3 Hepatitis C， both of the pegylated interferons do very well and are probably virtually identical. However when we look at patients with genotype 1 or difficult-to-treat Hepatitis C， there is a very clear trend in all of the studies which favour the bigger， the 40 kD  pegylated alpha-2a. So I think from my own personal view， the 40 kD pegylated has a little bit of superiority in the difficult-to-treat patient population. I think in the easy-to-treat patient population there probably isn’t a difference but it has to be said that the difference seems very small， very difficult to detect and there are plenty of people who think they are  completely the same.

 Foster教授：我们目前有两种聚乙二醇干扰素。一种是40KD的支链聚乙二醇干扰素，商品名为派罗新；另一种是12KD的聚乙二醇干扰素α-2b，商品名为佩乐能。现在有很多关于对过去几年中两种干扰素的作用是否相同，或者是否存在细微差别的争论。就我们所知，40KD干扰素在血清中停留的时间要长于12KD干扰素，这导致我们中有些人认为40KD的干扰素疗效可能会更好一点。目前就过去几年进行的两种干扰素一对一对照试验来看，总体来说，两者差别不大。我认为对较易治疗的基因2型和基因3型的丙肝患者，无疑地，两种PEG干扰素效果都很好，可能实际上是相同的。然而，对基因1型或其他难治性丙肝患者来说，所有的研究都明显趋向于分子量比较大的40KDPEG干扰素α-2a。因此，我个人认为，对难治性患者，40KD的干扰素疗效相对好一些。但相对容易治疗的患者，两种干扰素疗效可能基本上没有差别，也可以说仅有比较细微的难以辨别的差别，大多数人都认为这两种干扰素疗效完全相同。

Prof. Wei: Actually I agree with Dr. Foster’s comments absolutely， and in China we also have the two kinds of pegylated interferons. For the most time and used pegylated interferon just because it is easy for patients to use.   And actually we kind of found lots to do with significant difference between the two kinds of pegylated interferon for the genotype 2 patients.  But for the genotype 1 infected patients maybe just one has a little bit higher efficacy.  And also for some reason the Chinese medical insurance system just covers the pegylated interferons: 50 micrograms of pegylated interferon alpha-2b and 180 micrograms pegylated interferon alpha-2a.  So for the patients covered by the medical insurance， they only use the 180 micrograms pegylated interferon alpha-2a and 50 micrograms pegylated interferon alpha-2b.

魏来教授：实际上，我非常同意Foster博士的观点，在中国我们也有这两种干扰素。大多数时候，我们都用PEG干扰素，因为这种干扰素更容易应用于患者。实际上我们发现这两种干扰素在对基因2型患者的治疗上存在很明显的差别。对基因1型患者，它们可能是仅有的一种能提高疗效的干扰素。还有一些其他原因，中国的医疗保险恰恰包括PEG干扰素：50ug的PEG干扰素α-2b和180ug的PEG干扰素α-2a。所以对有医疗保险的患者，他们只会选择这两种干扰素。

Hepatology Digest: The treatment guidelines don’t differentiate between the two， now with these new studies， like in your presentation you mentioned IDEAL and some other studies， do you think now that we have these more head-to-head comparisons， do you see that that might influence the guidelines， Prof. Foster?

国际肝病：治疗指南中没有对两种药物加以区分，现在有了这些新研究，就像您刚才提到的IDEAL和一些其他研究，现在我们有了更多的一对一对照试验，您认为这些研究结果可能会对指南产生什么影响，Foster教授？

Prof. Foster: No， I don’t think they should. I think that the best opportunity for patients is to have a choice of treatment. I think the best opportunity for clinicians is to have a choice of drugs because there are undoubtedly circumstances where you may want to use one or the other interferon depending on circumstances. My own view is that it is to the best advantage to the patient that clinicians have access to both interferons and they can make their own personal choices based on the data they have seen in their own patient population. So I would be very opposed to a restriction of the prescribing of pegylated interferons. They are my personal views. Other clinicians have slightly different personal opinions and I think it is important that doctors are allowed to choose and the patient should have a choice. Do you agree?

Foster教授：不，我不认为会对指南有影响。我认为对患者来说最好的是能选择治疗方法。对临床医生来说，最好有机会选择药物，因为环境不可改变，无论选择哪种干扰素要依据具体情况。我个人认为，对患者最有利的是临床医生有权使用两种干扰素，并且根据患者各自的具体资料做出个体化的选择。因此我不赞同限定使用哪种干扰素。当然，这仅代表我个人的观点。其他的医生看法可能会略有不同。我认为重要的是允许医生做选择，患者应该有选择。您同意吗？

Prof. Wei: Yes， I agree.

魏来教授：是的，我同意。

Hepatology Digest: So how about in the case again for Hepatitis C treatment with interferon and Riboviron， perhaps some older patients can’t tolerate the therapy so what would be your approach for treating older patients and should we detect or test their HCV antigen more frequently perhaps than younger patients?

国际肝病：那么，对丙肝患者进行干扰素和利巴韦林治疗的病例呢，如果某些年老的患者不能耐受，您会采取什么治疗方法？对他们进行丙肝病毒抗原检测的频率应该比年轻人更频繁一些吗？

Prof. Foster: I think the patients have to be individualised. I don’t think there is a correct answer for every patient. If you have an elderly patient， you have firstly to look at the extent of their liver damage and you then have to look at their general health. If you have someone who is elderly with heart problems， with lung problems， then perhaps their liver is not the priority for treatment. On the other hand， if you treat a fit healthy 80 year old with hepatitis C because they have got bad fibrosis in their liver， so I think you have to personalise the therapy. You can’t go on the actual age of the patient， you’ve got to go on  how the patient behaves. If you have an 80 year old patient who is behaving like a 60 year old， he’s got bad liver fibrosis， may well get cancer and die from their Hepatitis C then I think you are justified in treating them quite aggressively. But if you have got a 60 year old patient who has got a bad heart， who has bad chest problems， not a lot of scarring on their liver biopsy then I personally don’t think those patients should be treated.

Foster教授：我认为对患者进行个体化治疗。没有能针对每个患者都正确的答案。如果患者年龄较大，首先要看患者肝损伤的程度，然后再看患者的一般健康状况。如果患者年龄较大并有心肺方面的疾患，那么可能他们的肝脏问题不是首要解决的对象。另一方面，如果对一个80岁的伴有严重肝纤维化的HCV患者，健康状况尚可，那么我认为需要个体化治疗方案。不能根据患者的实际年龄来选择治疗方案，而要根据患者的健康状况来选择。如果患者80岁但健康状况如同60岁患者，但有严重的肝纤维化，那么其患肝癌并死于丙肝的可能性比较大，所以我们就应该考虑更积极一点的治疗方案。但是如果一个60岁的患者，有严重的心肺问题，但肝活检显示没有太多的瘢痕形成，从个人角度，我不认为应该对这些患者进行治疗。

Prof. Wei: Actually for some of the older patients， older than 60 years old， it seems the efficacy is in a lower order and I think sometimes it depends on the stage of the disease and in some of the old patients they were often infected very young.  Then they have time to get to the end stage of liver disease.  Then it is difficult to predict.  So for these patients， I think we should stage a bit earlier.  If we can do some biopsy on someone old then you can know what time and what stage the patient location is.  Then you can give the patient more appropriate treatment.  And otherwise if the patient has very slow developments then you do not worry about it.  You can do something and give the patient some detectors.  As for the HCV antigens， sometimes， actually commonly we just use the HCV-RNA detector because HCV-antigen detecting is not approved at all in China.  And so maybe sometime you can change and switch the HCV-RNA detecting to the HCV-antigen detectors because if you use the antigen detecting it may be easier.  But right now because of sensitivity of the HCV-antigen， detecting is quite low.  And so for some low viral load patients， we cannot detect anything using the antigen assay so we don’t administer it at all.  So in answering this question， I think because there is no data that indicates the relationship between HCV and viral load or the thesis directly， therefore I think we cannot use HCV-RNA to be sure to locate the patients status.  What we need to do is a biopsy. 

魏来教授：实际上，对一些年老的患者，比如超过60岁，看起来疗效会比较差。我认为这有时也要取决于疾病的阶段。有一些患者年轻时就被感染，随着时间的发展逐渐进展为终末期肝病。这很难预见。所以对这类患者，我认为应该采取措施使疾病停留在早期阶段。如果对年老患者进行肝活检，那么就可以了解疾病所处的时间和阶段，可能对患者做出更恰当的治疗。反之如果患者病情进展很慢，也可以不用为此担心。你可以对患者做一些检测。谈到HCV抗原检测，有时我们经常检测HCV-RNA，因为在中国，HCV抗原的检测不被认可。所以有时或许要改变或换用HCV-RNA的检测来代替HCV抗原检测，这样或许更容易些。现在由于HCV抗原的敏感性，检出率非常低。对一些病毒载量低的患者，我们不能用检测抗原的方法检出，所以我们对这种方法不认可。因此，对这个问题的回答，我想没有数据或直接学说可以表明HCV 与病毒载量的关系，我认为不能根据HCV-RNA对患者做出肯定定位。我们需要做肝活检。

Hepatology Digest: Do you agree， Prof. Foster?

国际肝病：您同意吗，Foster教授？

Prof. Foster: I agree entirely that it’s the right approach for the personalised case.

Foster教授：我完全同意，个体化治疗是非常正确的。

Hepatology Digest: How about in the case of the treatment of relapse of Hepatitis C Professor， how is the efficacy and would you treat with peg. Interferon alpha-2a and Riboviron and what maybe special things would you consider in that case?

国际肝病：对丙肝复发患者的治疗呢，效果如何？您是否会用PEG干扰素α-2a和利巴韦林治疗？在这种情况下，您认为哪些特殊因素需要被关注？

Prof. Wei: Actually， sometimes for the relapse for the breakthrough and for maybe all the different basis that use interferon.  In China we still use some conventional interferon so the relapse prediction is higher for these patients.  For these patients we can switch them to the pegylated interferons and also for the pegylated interferon if the patient has a breakthrough or relapse maybe what you can do is to identify which factor that has affected the HCV species.  And some patients have a relapsed after the treatment so we switch to other interferons such as for genotype 3 type we show that if we use the pegylated interferon alpha-2b maybe we can have a little bit higher efficacy for this patients.  Also to my knowledge and to my experience， if most of the patient is relapsed you can also switch to pegylated interferon alpha-2a then you also can have a little higher efficacy for these patients but I have to say the efficacy for these patients – I mean the VSR for these patients is the lower than that of the other patients. 

魏来教授：实际上，对复发、突破和所有不同基础情况都用干扰素。在中国，我们仍然应用一些常规干扰素，这些患者复发预测值可能会高些。对这些患者我们可以换用PEG干扰素，对PEG干扰素来说，如果患者发生突破或复发，我们所做的就是判别哪些因素可能对HCV病毒株造成影响。一些患者在治疗后复发，这种情况下我们可以换用其他干扰素，比如通过研究发现，对基因3型患者应用PEG干扰素a-2b疗效会更高一些。就我的所掌握的资料和经验来看，对复发大多数患者，换用PEG干扰素α-2 a可以取得更高的疗效，但是，这些患者的疗效，我是说患者所取得的持续病毒学应答要比其他患者差一些。

Prof. Foster: I would agree. I think you are absolutely right. The sustained response rate is much lower in this patient population and you have got to personalise treatment: you have to look at the first course of treatment; decide how they responded first time round; look at the extent of fibrosis in their liver biopsy and then make a decision with the patient as to whether the benefits of the treatment are worth the very considerable inconvenience and the very considerable expense.

Foster教授：我非常同意您的观点。这类患者的持续应答率要低得多，所以要对他们进行个体化治疗：首先要看治疗的第一个疗程，判定患者第一轮应答的情况，通过肝活检观察纤维化的程度，从患者的受益程度和治疗花费方面考虑并作出决定，是否值得进行这种麻烦而又昂贵的治疗。

Hepatology Digest: Obviously with genotype 1 patients， it is very difficult in that， I believe the numbers are 40 to 50 percent， that can achieve SVR. I am sure there is not a simple answer to this Prof. Foster， but what is your personal approach in treating these genotype 1 patients and your advise?

国际肝病：显然基因1型患者比较难治疗，我想只有40%～50%的患者能达到持续病毒学应答。Foster教授，对于治疗基因1型患者的治疗，您的个人经验和建议是什么？我知道这不是给简单的问题。

Prof. Foster: Well I think the evidence at the moment is that if you treat these patients early you have much better response rates， so I am a great advocate for catching patients at an early stage of disease and getting them on treatment. For genotype 1， we do however know that we have some new drugs in development. There are a lot of small molecules being tested at the moment， and I think we have every chance that one or two of those will start to come through over the next three or four years. So my view at the moment is to discuss the choice with the patient， talk about the benefits of early treatment， talk about the potential benefits of delaying treatment while the new drugs become available， and that’s not a risk-free procedure as of course if the new drugs don’t pan out then we may find we’ve missed an opportunity to treat. So I think you have to personalise the treatment， talk to the patient about the choices and then try to pick what’s right for them.

Foster教授：我认为，目前证据显示，治疗越早，应答率也越高。因此，我积极倡导在病程早期对患者进行治疗。对基因1型患者，我知道确实有一些新药在开发。目前有一些小分子药物正在检测中，我认为我们有这样的机会，那就是其中的1～2种药物有望在接下来3～4年内研发出来。因此，目前我的看法是，在和患者讨论治疗的选择时，谈谈早期治疗的益处，也谈谈将来上市的新药对延期治疗的潜在益处，但等待这些药物的过程并不是没有风险的，如果新药未成功，我们就丧失了这个治疗时机。因此，我认为要对患者进行个体化治疗，和患者一起探讨治疗方案的选择，尽可能找到最适合他们的方案。

Prof. Wei:  Except in HCV drugs maybe some patients you can extend the treatment.  You can use the long term treatment for these patients except for some patients they have the either older viral response or slow response for these patients and you can’t extend the treatment， say two weeks treatment.  Then you have higher SVR with these patients.  And also in China you have some patients – very difficult patients， the viral load is in fact reduced very very slowly.  For the patients who have been waiting for two years or three years for treatment then they become candidates for early treatment.

魏来教授：除了用HCV药物外，对一些患者可以延长治疗。对缓慢病毒应答患者不能采用延长治疗的方法，我说的是2周的治疗，除此之外的患者，可以采用长期治疗，这样可以达到高效持续病毒学应答。在中国，也有些非常难治的患者，实际病毒载量降低非常缓慢。对这类患者，我们需要治疗2年或者3年来巩固早期治疗。

Hepatology Digest: Just now Professor Foster mentioned some of the new agents being developed， how about from your experience and what’s your view， perhaps for the future and how soon we may see some new agents and such?

国际肝病：Foster教授刚才提到了一些正在开发的新药，能否谈谈您的经验和观点，经过多长时间才能看到这些新药呢？

Prof. Wei:  Yeah after all the new data has showed us that the combined surface interferon and new agents improved SVR in some difficult to treat patients such as genotype 1 or patients with high viral load and patients who relapse and so on.  All these treatments were needed for treatment resistant patients.  So in the future we have to find the new drugs and also patient uses it and the HCV resistant drugs could be given to the patient.  And therefore a necessary step， is maybe combining drugs and bypass difficult treatment.

魏来教授：好的。毕竟现在的一些最新研究数据表明，对一些难治性患者，比如基因1型患者或高病毒载量的患者，还有一些复发患者等，联合现有的干扰素和一些新药可以提高持续病毒学应答。所有的治疗方法都应是针对耐药患者的治疗。所以在将来，我们发现致力于发现一种新药，不仅适用于普通患者，对HCV耐药患者也适用。因此，这是一个必要阶段，可以通过药物联合避免复杂困难的治疗。

Prof. Foster: I agree with that. I think we still don’t know enough about these new drugs to be able to predict which patients are going to need them. I think we are all hopeful that by 2011 we are going to start to see the first licensing of these new agents. How expensive they will be， which patients they will work  with， we still don’t know. So there is a lot of interesting data to come but I think it is a little early to start predicting who is going to benefit and who isn’t.

Foster教授：我同意，我认为我们对这些新药还不够了解，无法预测那类患者需要它们。我想很可能到2011年就能够看到这些新药开始陆续上市。这些药物价格多昂贵，哪类患者可以使用，我们对这些还不了解。因此，会有很多令人感兴趣的数据发表，但预测哪类患者会受益，哪类患者不会受益还为时尚早。

Hepatology Digest: With these new agents will there again still be a combination approach?

国际肝病：这些新药也可以联合应用吗？

Prof. Foster: I’m sure the first few years will be a combination of pegylated interferon， Riboviron and the new small molecule. Then as we get more small molecules then maybe we will start to change. It is going to be a combination to begin with.

Foster教授：我敢肯定，在最初的几年，应该是联合应用PEG干扰素、利巴韦林和新的小分子药物。然后，当小分子药物越来越多的时候，联合应用疗法的药物可能会改变。可能会重新开始联合。

Prof. Wei: I agree.

魏来教授：我同意。

Hepatology Digest:  Finally， obviously there are differences between your experience in the West and the East， how about some special local conditions that you might encounter in China that perhaps some of your western colleagues don’t see? Are there any special problems that you see in China that perhaps you would like to talk about?

国际肝病：最后，现在西方和东方的经验有明显的差异，在中国您是否遇到什么特殊的地域因素，而这些正是您的西方同行们没有遇到过的？能否谈一下中国存在什么特殊的问题？

Prof. Wei: Firstly in China， in some provinces， medical insurance does not cover interferon in medical assistance system covers the pegylated interferon and in some provinces it does not cover the pegylated interferon.  Therefore for in these provinces they have to use the conventional interferon.  So this is the first challenge.  And so we had to present the new medical data and action statements to the government and medical insurance office so they can know and understand the data and maybe change the policy so more and more people can use the standard treatment.  The second issue is we should have some older age patients， old age patients infected in the 1980s or earlier than the 1990s.  Therefore because these patient have now history of more than eight years， so most of these patients are in the end stage of liver disease.  So for these patients sometimes there are a lot of side effects with the pegylated interferon.  So we have to find from the drugs， maybe do some trials of using low dose interferon to see if we can obtain some stall， prevent， or even delay the disease progression.  That is the second reason.  The third is if we have increase instances of cirrhosis in China， then we also have some patients who is core instance is the C and the cirrhosis.  So for these patients we have to combine the treatment for the cirrhosis and the HCV infection so therefore we really need some balance in the drugs and some decisions for the important actions.

魏来教授：首先，在中国某些省份，干扰素还没有纳入到医保报销范围，也有一些省份没有常规干扰素。这是第一个挑战。所以我们通过发表最新医学数据和举办学术活动向政府和医疗保险机构传达这些信息，以便于他们能够了解并理解，在政策上做出调整，使越来越多的人能享受这种标准治疗。第二个问题是，对一些年龄偏大的患者，他们感染的时间可能在八十年代或九十年代初。因为现在这些患者病史已经超过八年，很多患者处于终末期肝病阶段，所以对这类患者应用PEG干扰素治疗可能存在很多副作用。因此，我们需要进行一些药物试验，观察用小剂量的干扰素治疗是否可以抑制、预防、甚至延缓病情进展。这是第二个原因。第三个问题是，在中国，如果肝硬化患者逐渐增多，那么我们面对的主要就是肝硬化和HCV患者。对这些肝硬化和HCV感染的患者，我们必须采用联合治疗的方法，因此，我们确实需要在药物和一些重要活动的抉择间达成平衡。

Prof. Foster: I think you make a very interesting point about the costs of treatment， and I think as the western world’s markets go into decline， we are going to have to learn some lessons here to help economise on our drugs budget. So I think it will be a very challenging time for all of us.

Foster教授：我认为你所提的治疗花费问题很有意思，随着西方经济的下滑，我们应该从您这里吸取更多的经验来节约我们的医疗开支。我想这是一个非常具有挑战性的时刻。

Hepatology Digest:  Thank you both for joining me here today at APASL.

国际肝病：感谢二位接受我们的采访。

Prof. Wei: Excuse me.  For China， I want to add one more thing.  In China we also use the domestic reagents.  This just means that IRP is made in China.  So the sensitivity is sometimes not as good as TaqMan.  Therefore it seems that what time you can identify the IVR and the EVR actually we would identify the IVR and the EVR that means we need to use the sensitive reagents.  Actually in China， TaqMan is not approved at all though maybe in the near future it will be approved.  But before that， it is difficult for dcotors to use IVR because we don’t have the exact IVR in China.  Therefore we have to keep them one year of treatment for these patients.

魏来教授：打扰一下。我还需要补充一点。在中国，我们也应用一些国产试剂。IRP是由中国生产的，虽然有时它的敏感性不如TaqMan那么好。看起来好像能分辨快速病毒学应答和早期病毒学应答的时间，实际上我们需要敏感的试剂来辨别快速病毒学应答和早期病毒学应答的时间。在中国，实际上，TaqMan并没有证明具有很好的敏感性，但将来可能会被证实。在这之前，临床医生很难辨别快速病毒学应答，因为在中国没有真正的快速病毒学应答。因此，我们需要对这类患者治疗一年。

Hepatology Digest:  Thank you both. It was a pleasure and I hope to see you next year.

国际肝病：感谢二位，非常高兴，希望明年再次见面。