Geoffrey McCaughan 教授访谈

Hepatology Digest ：I am here with Professor Geoffrey McCaughan at APASL 2009, thank you for joining us today, professor.

国际肝病：我现在在2009年APASL年会采访McCaughan教授，感谢您接受我们的采访。

Pro.McCaughan: It’s a pleasure to be here.

McCaughan教授：很高兴来到这里。

Hepatology Digest ：One of your lectures here at APASL 2009 was on the management of hepatitis B in Liver transplantation, could you introduce, perhaps, a couple of the key points in that, in the management of hepatitis B in transplantation.

国际肝病：您在2009年APASL年会上的一个演讲主题是乙肝的肝移植治疗，您能不能介绍一下这方面的几个关键问题？

Pro.McCaughan :Ok.  I think the first big thing is that there has been a dramatic change in transplantation for hepatitis B in the last 10 years.  Essentially 10 years ago this was associated with very, very poor outcomes and the recurrence of the virus after transplantation.  And now, 10 years later, all countries throughout the world are using strategic new drugs to prevent recurrence.  We’ve been able to virtually get recurrence of hepatitis-B down after transplant to less than 5 percent.  And that’s now resulted, in effect, in exactly the opposite result from 10 years ago: that hepatitis B now has the best outcomes from liver transplant than any disease at all.  So, I think that has been the big change.  There are nuances about how to use these antiviral drugs – particularly the new ones.  But that’s the big message, I think.

McCaughan教授：好的。我想最重要的一点是，在近10年中，乙肝的肝移植治疗已经有了显著的变化。从本质上说，在10年前，肝移植的效果非常差，而移植后复发率非常高。而10年后的今天，世界上所有国家都在使用具有重要意义的新药来防止复发。实际上，我们已经可以使移植后的乙肝复发率降到5%以下。确切地说，这种结果已经和10年前截然相反了：目前，乙肝已经成为进行肝移植后预后最好的一类疾病了。因此，我认为变化是非常大的。如何应用这些抗病毒药物，尤其是新药物，还是个比较微妙的问题。但我认为，这是个很重要的信息。

Hepatology Digest ：And what are some of the ones that are still some of the poorer outcomes?  I would say if we make progress with the hepatitis B patients, what are some of the other ones that might have a poorer outcome?

国际肝病：那么哪类患者预后仍旧会较差呢？我的意思是，我们对乙肝患者的治疗取得了进展，而其他哪些患者的效果会较差呢？

Pro.McCaughan: Well, the biggest challenge in liver transplantation on the planet is hepatitis C infection, because hepatitis C infection is not quite as bad as hepatitis B infection was 10 years ago, but recurrence always occurs, virtually universally.  The drugs we have only clear the virus in about 25 percent of patients after transplant.   Although grafts are not lost all that quickly, as were transplanted and the follow-up have gotten longer, the results of hepatitis C – particularly beyond five years, five to ten years – are now looking not as good as we had hoped.  So, in liver transplantation the prevention of hepatitis C recurrence and the effective treatment when it does recur is a great challenge that we have not met at all yet, really. 

McCaughan 教授：在世界上，对肝移植效果威胁最大的是HCV感染。虽然HCV感染不像10年前HBV感染那么严重，但实际上，复发是经常性而且是普遍性的。对移植后病毒感染复发的患者，药物清除病毒的有效率大约在25%左右。虽然移植肝不会在刚移植后就迅速衰竭——实际上，疗效持续的时间已经比过去延长了，但HCV感染的防治结果——尤其是超过5年、5~10年期疗效，并不如我们希望的那样好。因此，在肝移植治疗中，预防丙肝的复发以及丙肝复发后的有效治疗是一个极大的挑战。实际上，我们还没有真正的开始迎接这个挑战。

Hepatology Digest ：And again regarding transplantation, liver transplantation with living donors is being carried out, probably, say really more and more because of the shortage of cadaver livers and donors.  So, what are some of the, perhaps, you know, advantages and disadvantages of using living donor liver transplantation?

国际肝病：目前由于尸肝和供者的短缺，活体肝移植的施行正在越来越普遍。那么，使用活体肝移植都有那些利弊？

Pro.McCaughan: Well, certainly the Asian region is the strongest region in the world now for living donor transplantation.  Japan particularly had led the field a decade ago, but other countries have now developed good live donor programs. The major advantage of this to the recipient, if a suitable donor is available they are guaranteed a transplant and they are not going to wait for a cadaveric donor. Waiting for a cadaveric donor in most, even in the Western countries which have significant reasonable rates of cadaveric donation, there is up to 20 percent mortality while waiting.  So that doesn’t occur.  That is particularly important in liver cancer, where liver cancer patients can’t wait because the cancer grows and cancer is becoming a major need for liver transplantation. 

McCaughan 教授：当然，亚洲地区目前是世界上活体肝移植技术力量最强大的地区。尤其是日本，十年前在这个领域就处于领先地位，而现在其他国家活体肝移植技术也已经成熟。这对受者最大的好处就是，如果有合适的供者，受者的肝移植手术会有保证，而他们不需要等待合适的尸肝。即使在尸肝捐献率较高的西方国家，在等待合适的尸肝期间，患者的死亡率也高达20%。因此，我们不能只等待尸肝捐献，这对肝癌患者尤其重要。肝癌患者没有时间等待，因为肿瘤在生长。癌症正逐渐成为肝移植的主要需求。

Hepatology Digest ：Sure.  And what are some of the factors that can influence response to treatment in patients with chronic hepatitis B?

国际肝病：是的。那么什么因素会影响慢性乙肝患者的治疗效果呢？

Pro.McCaughan: Just generally?

McCaughan 教授：通常来说么？

Hepatology Digest: Just general, sure.

国际肝病：是的。

Pro.McCaughan: In general, well, the major issue is the level of virus before you start treatment is very important.  In what we call e antigen positive disease, the level of liver inflammation, actually we can not counter intuitively, but the more liver inflammation you have, with a raised liver enzyme – the higher your enzyme – the more likely you are to respond to treatment.  And that’s because to clear the hepatitis B virus properly, and get it right under control, immune responses are probably necessary.  So the drugs we have, if they come in and an immune response is already happening – particularly in e antigen positive disease – that actually enhance treatment outcomes. 

McCaughan 教授：通常来说，开始治疗前的病毒载量是主要影响因素。在所谓的HBeAg阳性的患者，我们虽然不能直接量化他们肝脏的炎性反应程度，但转氨酶的水平可以代表肝脏炎性反应的程度。转氨酶越高，患者对治疗产生应答的可能性就越大。这可能与HBV的清除相关，而要良好的控制感染，免疫应答是必要的。因此，如果我们应用的药物引发了免疫应答，特别是在HBeAg阳性的患者，那么就能提高疗效。

Hepatology Digest: And what is about the role of pegylated interferon in the treatment of hepatitis B? Now that, obviously, there are a lot of agents. What do you feel the role is?

国际肝病：那么聚乙二醇干扰素的应用在乙肝治疗中处于怎样的地位呢，显然，目前这类药物有很多，您觉得他们的应用情况怎样呢？

Pro.McCaughan: Well I think it got a very important role in younger people, certainly without cirrhosis, but particularly women who wish to be, at child bearing age, and want to have children, because it is a fixed course of 12 months – which means you’ve got about a 30 percent chance in e antigen positive disease of getting a response. And if you get that response then you don’t need to have any more treatment.  The oral antivirus agents suppress the virus much better, and in the long term much better, but there is some advice not to use them in pregnancy. There is also accumulating data of successful early e antigen clearance with pegylated interferon may be associated with increasing loss of surface antigen in the long term that may take up to five years or even longer. There was preliminary data on this, or small data on this, many, many years ago with conventional interferon, but there is emerging data that surface antigen many be lost.  And if surface antigen is lost that means viral replication is really, really, really low and virtually stopped all together. And no new traces of hepatitis B left in the body if surface antigen disappears. If that data emerges and looks solid then people may start to use pegylated interferon more than they are using it now. The patients prefer to take a tablet a day – even if they have to take it for the rest of their lives – than have an injection once a week for year. 

McCaughan 教授：我认为它对未合并肝硬化的年轻患者的治疗非常重要，尤其是有生育需求的育龄妇女，因为它的疗程固定为12个月，而有30% HBeAg阳性患者能够对治疗产生应答。如果产生了应答，患者就可以停止治疗。口服抗病毒药物抑制病毒的疗效很好，长期服用效果会更好，但对怀孕的妇女不推荐使用。有累积数据表明，如果应用聚乙二醇干扰素早期成功清除HBeAg,并能保持很长一段时间——5年甚至更长，那么可以提高HBsAg的转阴率。在很多年前，就有少数关于应用常规干扰素治疗后HBsAg转阴方面的初步数据。现在有越来越多的HBsAg转阴的数据。如果HBsAg消失，意味着病毒极少复制，实际上可以说是停止复制，体内也基本上没有HBV残存。如果这些数据真实可靠，那么聚乙二醇干扰素的应用或许要比现在广泛。患者更愿意每天口服药片，即使他们可能不得不终生服用药物，他们也不愿意接受每周注射一次、为期一年的治疗。

Hepatology Digest: And you mentioned surface antigen.  So, what’s your opinion of taking hepatitis B surface antigen seroconversion at the end of therapy? 

国际肝病：您提到了HBsAg，那么您对于在疗程结束的时候取得乙肝HBsAg血清转换怎么看呢？

Pro.McCaughan: Well that’s obviously an ideal, and we have not really concentrated on it all that much because we haven’t been able to achieve it.  So, we need to be realistic about setting our goal to high.  But we’ve always recognized the importance of patients loosing surface antigen. And we know that happens spontaneously. We’ve all have had long-standing patients who have had infections for 50 years and some of them slowly lose their surface antigen.  They still have traces of hepatitis B in their body.  And we know if tragedy happens to those persons and they become an organ donor, even if they are surface antigen negative, they transmit hepatitis B into a naive, non hepatitis B patient.  So they still have traces of virus.  But it’s probably not hogenic at that stage it’s certainly not causing any liver inflammation.  

McCaughan 教授：这当然是一种理想状态，我们目前还没有把主要精力集中在这方面，因为我们还不能达到这一点。我们有远大的理想，但也需要现实一些。不过，我们一直都充分认识到了患者HBsAg转阴的重要性。我们也知道这种现象是自发产生的。感染病史超过50年的某些患者的HBsAg会慢慢消失，但他们体内还有HBV的残存。而我们知道，如果这些患者发生不幸，并成为器官捐献者，即使他们的HBsAg是阴性的，他们也会将HBV传染给那些体内原本没有HBV的患者。所以这些患者体内还是有病毒残存的。不过这些病毒在这种状态下可能是非致病性的，当然也不会造成任何肝脏炎性反应。

Hepatology Digest:Sure.  What would be the more recent advances, if any, in treatment for hepatitis B, hepatitis C co-infection?

国际肝病：是的。那么在HBV/HCV混合感染患者的治疗上，近期有什么进展么？

Pro.McCaughan:Well, this is where pegylated interferon does have a significant role, particularly if there is hepatitis C viral replication because the pegylated interferon can be used to treat both viruses in that situation. Well, the hepatitis C requires an additional ribavirin.  So, that’s probably the major issue.  The co-infection of both viruses is quite interesting in many, many aspects. It’s a much more pathopoiesis process than mono-infection. But there’s often this paradigm that both viruses don’t replicate together at the same time. They do in some patients, and that’s mainly because if you get hepatitis C viral replication going on that you have a lot of what are called th1 cytokines being produced in the liver. And th1 cytokines suppress hepatitis B viral replication quite well.  So often a hepatitis C infected patient will have will have low levels of hepatitis B viral replication.  And then patients like – with the hepatictis B -- that will respond better to pegylated interferon.  So, treating those viruses at the one time, I don’t see major problems with that.

McCaughan教授：我们认为聚乙二醇干扰素在治疗中确实有重要作用，特别是对有HCV复制的患者，因为在这种情况下聚乙二醇干扰素对两种病毒都起作用。而HCV感染的治疗还需要联用利巴韦林。这可能才是主要问题。两种病毒混合感染在许多方面都是很有意思的，这种感染要比单一感染更有致病性。但通常在这种感染模式下，两种病毒并不会同时进行复制。在一些患者，情况确实是这样的，这主要是因为HCV的持续复制会诱导机体产生Th1类细胞因子。Th1类细胞因子能很好地抑制HBV的复制。所以通常同时感染了HCV的乙肝患者，其体内HBV复制水平比较低。而这类乙肝患者对聚乙二醇干扰素治疗的应答相对较好。所以，同时治疗这些混合感染，在我看来不是很大的困难。

Hepatology Digest:And how about the choice of the two commonly available, commercially available pegylated interferons – I mean the alpha 2a and 2b; do you feel any difference in that case, or in general?

国际肝病：那么对于目前市场上常见的两种聚乙二醇干扰素——我是说α2a和α2b这两种，我们应该如何选择呢？您认为这两种干扰素是否有不同么，在这种情况下或者从整体上来说？

Pro. McCaughan:  Is that hepatitis B or hepatitis C?

McCaughan：对乙肝或者丙肝的治疗来说么？

Hepatology Digest: Well, in co-infection, or in either/or hepatitis B, C or co-infection, between those two…

国际肝病：对混合感染，或者HBV、HCV单一感染，或者单一感染与混合感染之间。

Pro. McCaughan: I’m a bit of a nealist about the two forms of pegylated interferon.  So, I think they’re likely to have similar results. They’ve been shown in what is known as the IDEAL study in Hepatitis C to have identical SVR rates.  

McCaughan 教授：对这两种干扰素的看法，我比较倾向于现实主义。因此，我认为其实它们的效果差不多。IDEAL研究结果显示，它们在针对丙肝的治疗中取得的持续病毒学应答率相差不多。

Hepatology Digest: There’s a slight difference at the end of treatment numbers I believe, right?

国际肝病：在治疗的最终结果上还是稍有不同的，对么？

Pro.McCaughan:  Different, yeah, higher end of treatment responses with PEGSYS, I think, but more relapse.  So they all come out equal.  That relapse issue is actually very interesting between the two agents: it seems as though if you continue with PEGASYS, you continue to get loss of virus as you go though treatment.

McCaughan 教授：是有些不同，应用派罗欣组的治疗应答要高一些，但复发率也要高一些。所以，它们的最终疗效相同。实际上，两种药物在复发问题上是很有意思的：似乎如果继续应用派罗欣，仍然能继续清除病毒。

Pro. McCaughan:  This was on treatment for a year. During the year that you are on treatment with pegasys your PCR negativity sort of increases as you go on – even with, that happens naturally, but it looks differently to PegIntron. So consequently because of that, if you go for 12 months there’s a subsection of patients on pegasys who have only been PCR negative – this applies to genotype one – for a relatively short period of time, not for the full 12 months , or 9 months.  Maybe only for 5 months, so there is a subgroup of patients.  And they are the patients that relax because they have not been PCR negative for quite as long and that probably explains the increased relapse rate.  But in the end, you know, for a patient, it doesn’t really… who cares? The SVR is what’s important.

McCaughan 教授：这是治疗1年以后的情况。用派罗欣治疗的1年中，即使PCR阴性率有一定的增加——这种情况的发生很自然，但这种治疗结果也和应用佩乐能的结果有所不同。因此，治疗1年以后，有一小部分应用派罗欣的患者——这里指基因1型患者，其PCR阴性持续的时间要相对短一点，可能达不到12个月或者9个月，可能只能持续5个月。这一部分患者可能比较放松，因为他们达不到PCR阴性标准已经有一段时间了，而这或许可以解释为什么复发率会增加。但最终，你知道，对患者来说，谁在乎呢，持续病毒学应答才是真正重要的。

Hepatology Digest:Sure, sure. And one final question: the incidence of non-alcoholic fatty liver disease in the Asia Pacific is on the rise.  So what impact will this have on the treatment and outcome of viral hepatitis? 

国际肝病：是的。最后一个问题是，在亚太地区，非酒精性脂肪性肝病的发病率正在增加，那么这对病毒性肝炎的治疗和预后有什么影响么？

Pro. McCaughan: Well the outcome is that it seems as though these syndromes are… non alcoholic fatty liver disease is part of what we call a metabolic syndrome.  It’s an insulin resistance type illness which is associated with diabetes and vascular disease and heart disease and obesity and fatty liver and hypertension and high uric acids.  And that syndrome – whether it is with hepatitis B or hepatitis C -- is associated with worse outcomes, there is no question about that.  So we were one of the first to show that insulin resistance is, in fact were the first to show that insulin resistance associated with worse fibrosis in hepatitis C.  But there is increasing data now in hepatitis B that there’s a similar affect.  What’s interesting is that in the hepatitis，well as far as I know there is no data whether that affects treatment outcomes for hepatitis B.  Presumably people will start to look at that, but it does affect treatment outcomes for hepatitis C. If you have the insulin resistance and the full-blown metabolic syndrome, then your responses to antiviral therapy:  pegylated interferon and ribavirin are significan tly poorer.  And so there’s an approach to try to fix those issues up before you start treatment with antivirals, but, that’s more easily said than done (laugh).

McCaughan 教授：非酒精性脂肪性肝病是所谓的代谢综合征的一部分，它是一类胰岛素抵抗型疾病，与糖尿病、心血管疾病、肥胖症、脂肪肝、高血压、高尿酸血症等疾病相关。不论是否患有乙肝或者丙肝，患有这类综合征的患者都预后不佳，这是毫无疑问的。因此，我们首先要说明的是，胰岛素抵抗意味着丙肝患者的肝纤维化程度会更严重。但有越来越多的数据表明，乙肝患者也有类似的问题。有意思的是，在肝炎就我所知，没有数据表明这是否会影响乙肝患者的治疗效果。患者开始治疗的时候，可能都要做这些检查，而这也确实会影响丙肝患者的治疗效果。如果患者有胰岛素抵抗、代谢综合征也很严重，那么他们对抗病毒疗法——聚乙二醇干扰素、利巴韦林的治疗应答会非常不理想。因此，有一种疗法是在开始进行抗病毒治疗前改善患者代谢综合征方面的症状，但这说来容易，做起来却很难。

Hepatology Digest: Sure. Well, um, thank you for joining us here today professor, it was a great honor having the chance to meet you and speak with you today. Thank you. 

国际肝病：是的，感谢您今天接受我们的采访，很高兴和您交谈，谢谢。

Pro.  McCaughan:  Thank you.  Its great pleasure and I’ve enjoyed coming up to Hong Kong again and going to this terrific meeting here.  Thank you.

McCaughan 教授：谢谢，这也是我的荣幸，同时，很高兴来香港参加这次盛会。