| [PHC2012] 我们已向HCV清除迈进了一大步，未来我们将走向哪里？——大会主席Patrick Marcellin教授专访 -----
来源： 作者：Patrick.Marcellin 发布时间：2012-3-16 15:37:07 阅读：31
我认为这是一个可以实现的目标。如果看一下近期在联合治疗的最新研究成果，我们会发现现今有大量非常有效的药物，并且非常强效。我们有新的蛋白酶抑制剂，我们有新的聚合酶抑制剂（NUCs和非NUCs的），我们有新的NS5a抑制剂，并且我们指导这些药物组合起来作用会累积，甚至有时起到协同作用。
Hepatology Digest: You made the opening and closing presentations at this year’s Paris Hepatology Conference and you were very optimistic about the potential for a cure and achieving 100% suppression of the hepatitis C virus within five years. Do you think this is really possible?
《国际肝病》：您在今年的巴黎肝病会议的开幕和闭幕演讲中，对五年内实现100％的丙型肝炎病毒抑制保持非常乐观的态度。请问，您觉得这是真的能实现吗?
Prof Marcellin: It is an achievable objective. If we look at the most recent research on combinations of drugs， it is clear that we now have a large number of very efficient and potent drugs. We have the new protease inhibitors， we have the polymerase inhibitors (the NUCs and non-NUCs)， and we have the NS5a inhibitors and now that we know these combinations have an additive effect， even sometimes synergistic， the potency of treatment in the most recent studies has been able to stop viral replication within a few days. So they are very potent combinations of antivirals. I think the concept of the efficacy of these drugs leading to 100% suppression of the virus is now something that is accepted. Secondly， treatment can be shorter. We currently have many drugs and many combinations in phase II trials so I think we will learn a lot about these in the next two or three years. I have said five years but we need to take into account time to register drugs and so on， but I think in terms of the feasibility and efficacy it is realistic that within two years we will have confirmed the efficacy and safety of these drugs. The phase III studies will be conducted more rapidly because it will be possible to have 12 weeks of treatment instead of 48 weeks or 24 weeks. Treatment will become shorter and shorter. I am optimistic that successful use of these drugs seems to be， at this stage， more and more realistic. I will add that two years ago I was thinking that it would take ten years to reach this point. We have made more advances in drug therapy in the last two years than we have in the last ten. Progress is accelerating and offering many good surprises.
Marcellin教授：我认为这是一个可以实现的目标。如果看一下近期在联合治疗的最新研究成果，我们会发现现今有大量非常有效的药物，并且非常强效。我们有新的蛋白酶抑制剂，我们有新的聚合酶抑制剂（NUCs和非NUCs的），我们有新的NS5a抑制剂，并且我们指导这些药物组合起来作用会累积，甚至有时起到协同作用。在最近的一些研究中显示，有些治疗方案能够在数天内就可以显示出抑制病毒复制的能力。因此它们是非常有效的联合抗病毒治疗药物。目前，对于联合治疗能够100%抑制病毒复制的概念已经能够为大家所接受。另外，疗程可以缩短。目前我们有许多药物和组合方案已经进入II期临床试验，因此在未来两年或三年内我们将对这些了解更加深入。我曾经说过需要五年时间，但我们需要考虑到注册药物以及其他情况所花费的时间，但我认为在可行性和有效性方面，2年内我们能够证实这些药物的疗效和安全性。三期临床试验将会开展得更加迅速，因为到时可用12周方案，取代48周或24周方案。疗程将变得越来越短。我乐观地认为，在这个阶段这些药物将取得成功，似乎是越来越现实。而在两年前，我还认为我们还需要10年的时间才能取得这些成就。在过去两年中，我们在药物治疗方面的进步比过去十年取得的还要大。而且这种进步的速度越来越快，将为我们提供更多的惊喜！
Hepatology Digest: The drug getting the most attention right now seems to be PSI-7977. Are your high hopes specifically pinned on this one drug or is your optimism based on the fact that there are so many drugs?
《国际肝病》：现在最关注的药物似乎是PSI - 7977。请问您是对这一种药物寄予很大的希望还是乐观认为还有许多其他的药物？
Prof Marcellin: This one is certainly one of the leaders in terms of efficacy. Its profile with respect to safety and resistance is so far very good. I will say though that this is just one of a number of drugs that are very interesting - the NS5a inhibitor from Bristol-Myers Squibb， for instance - and there are many more drugs that are coming. I do not know what the final combination winners will be， but I am convinced that we now have a large number of drugs， many in phase II trials， some of which are less potent than others， but which will shine in combination with others. If we use drugs with different target mechanisms， then these combinations can be very effective. PSI-7977 is one of the leaders. The challenge is not really in finding the single ideal drug; the challenge is finding the right combination.
Marcellin教授：PSI - 7977肯定是最为有效的药物之一，其在安全性和耐药性方面都是迄今为止非常好的。我会说，PSI – 7977仅仅是引人注目的药物中的一种，它是由施贵宝公司研制的一种NS5a抑制剂，就耐药性而言，将会有有更多的药物研制出来。我不知道联合治疗最终的赢家将是什么，但我深信，我们现在有大量的药物在研制，有些还进入II期临床试验，有些虽然抗病毒能力没有其他的强，但是与其他药物组合起来疗效非常好。如果我们用不同作用位点的药物进行组合，那么这些方案将非常有效。?PSI – 7977是其中的佼佼者。目前的挑战是并不是是找到一个单一理想的药物，挑战是找到合适的组合方案。
Hepatology Digest: The interesting thing about PSI-7977 was that trials were being conducted using just ribavirin and PSI-7977 and that was shown to cure 100% of patients (albeit just ten patients) and even you were suggesting in your presentation of moving towards monotherapy within five years time. Do you think the focus needs to be on combinations or on finding the magic bullet?
《国际肝病》：关于PSI -7977非常有意义的是，在一项研究中，使用利巴韦林和PSI – 7977联合治疗，治愈率为100％（尽管只有10例患者）。然而，在您的演讲中提及在未来五年内，将逐步向单一治疗迈进。请问您认为研究的重点是寻找最佳组合还是寻找灵丹妙药？
Prof Marcellin: I would say that combinations， at least as a first step， will be necessary to increase efficacy and to decrease the risk of resistance. I believe that using two or three drugs with different targets is probably the way to go today. It is quite risky to use a single drug at this stage but， as you say， the magic bullet with no resistance and rapid suppression is a possibility. However， I would say that looking at treatment in the next five years， producing an almost 100% cure (100% does not exist in medicine of course) is possible. Look at tenofovir and entecavir in hepatitis B – we would imagine that we could find a drug with the same potency as these drugs that induce an antiviral response in almost all patients. In the meantime， we need to be aiming towards safety in terms of resistance and a more robust action in combinations. Some combinations show very exciting results. At this stage， numbers are still small and there is still the question of safety because in many studies the duration of treatment is relatively short. We will know more by the AASLD meeting at the end of the year. I think 2012 will probably be the year in which things will come together and we will know what the best combinations of drugs are. I believe however that interferon-free treatment is really achievable. There is now no reason to think that we need to continue interferon therapy for years and years and years， so interferon-free treatment is the future. The next question is do we really need ribavirin? That is still not very clear to me.
Marcellin教授：我想说的是为提高疗效，作为初始阶段联合治疗将是必要的，能够减少耐药的风险。我认为联合使用两种或三种不同作用位点的药物将是现阶段可能的方案，使用单一药物是非常危险的。但正如你所讲的，能够快速抑制病毒而无耐药性的灵丹妙药还是有可能的。不过，我认为在未来五年内将能找到治愈率几乎为100％的治疗方案（尽管在医学上在医学上100%并不存在）。从替诺福韦和恩替卡韦治疗乙型肝炎的经验可以看出，我们可以找到具有相同效力的，在广泛人群中适用的抗病毒治疗的药物。在此期间，我们需要对联合治疗的安全性、有效性和耐药性进行深入研究。一些联合治疗方案的结果令人振奋。在现阶段，研究样本量仍然很小，同时存在安全性问题，因为在许多研究中，治疗的时间相对较短。在今年年底的AASLD年会上，我们知道的将会更多。我认为2012年将可能是重要的一年，我们将会知道那些药物是最佳组合。我相信无干扰素治疗时代即将到来，现在我们没有理由认为有必要年复一年地使用干扰素进行治疗。接下来的问题是，我们是否真的需要利巴韦林？这一点我仍不是很清楚。
Hepatology Digest: You also discussed at the conference the topic of genotypes and specifically those patients who were not genotype 1. There has been a lot of progress with telaprevir and boceprevir in treating people with genotype 1， but what do we do now for those with genotypes 2 and 3?
《国际肝病》：您在会议上还就基因型方面进行了探讨，特别是非基因1型的患者。近来?telaprevir和boceprevir治疗基因1型患者取得重大进展，然而，对于基因型2和3的患者我们该怎么办呢？
Prof Marcellin: Or even genotype 4. I mentioned in my presentation in Paris that we should remember that in many countries， genotype 1 only makes up a small proportion of patients. Genotype 4 is extremely important in the Middle East and Egypt. Genotype 3 is the predominant genotype in India. So there are millions of people infected with non-1 genotypes. What we are seeing in some studies with the polymerase inhibitors (the NUCs)， these drugs are as effective in all genotypes; they are non-genotypic. This is the other big step. If we can develop drugs that are really effective on all genotypes， it will make treatment amenable for more people， more countries and it will also be very simple for clinicians to choose appropriate drugs and even then， maybe one pill containing two or three drugs. I am not sure that one drug is enough， but one pill may be enough. It would not be necessary to check genotype and it would not be necessary to check the virologic response because if a combination is very effective you do not need to prioritize assessment of the viral load. I think treatment will become simpler. The next question raised is， even if we have very effective drugs， what about ensuring diagnosis， treatment and access to these drugs. Presumably the price of these drugs would be very high and could be a limitation in their accessibility to many people. With 170 million patients worldwide， when I say that we could achieve an almost 100% cure in all patients within five years， I am thinking that we will need many years to treat all of the patients who need to be treated in terms of access to therapy. Another side to the story is how this science and progress can be of benefit to the patients. We have good experience of screening patients in France. We started a program of screening many years ago. With screening， we need to be very clear as to why we are screening potential patients. Screening is important if we can give the drugs to the patient. If you diagnose patients but the patient cannot pay for treatment， there is some interest in terms of prevention of further new infections and in terms of epidemiology and for this alone it is important to screen the population， but there remains the issue of who is to pay for treatment. I am confident that because there are many effective drugs becoming available and many companies involved， there will be early access to treatment and an understanding amongst these companies that in some countries， patients will pay and in other countries they will need help. We have seen a similar situation arise in the treatment of HIV in Africa for instance. First we need to achieve the objective of very effective and safe drugs. Then there needs to be an awareness worldwide of this public health problem and then to treat as many patients as we can， hopefully all of the patients who need to be treated.
Marcellin教授：包括基因4型的患者。我在巴黎的演讲中提到，在许多国家，基因1型只占极少的一部分患者。基因?4型在中东和埃及是非常重要的。?基因3型是印度的主要基因型。因此，有数百万人为非-1基因型。我们注意到在聚合酶抑制剂（NUCs）的一些研究中，这些药物对所有基因型均是有效的，它们是非基因型特异性的。这是一大进步，如果我们能开发出对所有基因型均有效的药物，那么对所有国家、所有患者均有效，临床医生选择合适的药物将变得非常简单，甚至我们可以研制出含有两种或三种药物的复方制剂。我不清楚一种药物是不是足够，但是一片复方制剂可能是足够的。如果一个组合非常有效，你并不需要去检测基因型，甚至没有必要去检测病毒应答，你甚至没有必要去检测病毒载量。我认为治疗将变得更简单。接下来的问题就是，即使我们拥有非常有效的药物，如何确保诊断、治疗以及得到这些药物。假定这些药物的价格非常昂贵，对于大众而言仍然是可望而不可及的。在全世界大约有1.7亿患者，即使我说过在5年内在所有患者达到100%的治愈率，但是我们需要多少年才能对需要治疗的患者进行治疗。另外的问题是，科学和进步如何为患者谋求利益。在法国，我们筛选病人有良好的经验。很多年前，我们开始了筛选方案。通过筛选，我们需要很清楚的是为什么我们筛选潜在患者。如果我们能够给患者药物治疗，那么筛选病人将非常重要。如果你诊断了一个患者，但是无力支付治疗，监测对于预防更多的新发感染以及流行病学方面有重大的意义。我深信，因为有许多有效的药物可以获得，并且有许多公司参与，在某些国家，可能能更早地接受治疗，并且在公司之间取得谅解。在一些国家，病人将支付治疗费用，而在另外一些国家，他们将需要得到公司的帮助。我们已经看到了类似的情况出现，例如在非洲的艾滋病毒治疗。首先，我们的目标是找到非常有效和安全的药物。然后需要重视这一全球公共卫生问题，治疗尽可能多的患者，期望可以治疗所有需要治疗的患者。
Hepatology Digest: What do we do right now though? In America， even with the protease inhibitors working across genotypes， they are only approved for genotype 1. What is our approach to a patient with genotype 2， 3 or 4?
《国际肝病》：那么我们现在应该做些什么呢？在美国，即使蛋白酶抑制剂抗病毒效果是跨基因型的，但是他们只批准基因1型的。那么对于2，3或4基因型的病人，我们该怎么办呢?
Prof Marcellin: We still use the standard treatment of PEG-IFN/RBV. Boceprevir and telaprevir are the first generation of the protease inhibitor and are not effective or have little effectiveness in all of the genotypes so there is a high risk of developing resistance. It is recommended to use them only in genotype 1 which is why I think the new drugs are very important overall. In addition to better efficacy and safety， more and more drugs are effective against all of these genotypes. So today， these pioneering drugs， boceprevir and telaprevir are a big step and progress only for a section of the patient population. In France， genotype 1 makes up 50% of cases. So 50% of patients are still treated with PEG-IFN/RBV. We need to accelerate this process of developing new drugs and particularly the PSI-7977 and the NUCs. The NUCs have this interesting property of being effective on all genotypes. The first generation of protease inhibitors are very specific for genotype 1. The new protease inhibitors could be more active on the other genotypes but the key is still to be using combinations.
Marcellin教授：我们目前仍然使用标准PEG-IFN/RBV进行治疗。?Boceprevir和telaprevir作为第一代的蛋白酶抑制剂，对于所有的基因型的患者而言，疗效并不理想，并且耐药的风险较高。我们推荐只在基因1型的患者中使用，这一点非常重要。因此，虽然Boceprevir和telaprevir取得巨大成绩，但这只是针对一小部分患者而言是有效的。在法国，基因1型的患者只占50%的患者。因此，剩余的50%的患者仍然需要使用PEG-IFN/RBV治疗。我们需要加快开发新药，特别是PSI-7977和NUCs。?NUCs似乎对所有基因型的患者均有效，而第一代的蛋白酶抑制剂只对基因1型的患者有效。新的蛋白酶抑制剂可能对其他的基因型更有效，但是仍然需要联合用药。
Hepatology Digest: There was a debate at the conference as to whether or not to do IL28B testing. One of the reasons not to do IL28B testing was because we are getting drugs very soon that will bypass the necessity to know if a patient will respond to interferon. In those countries that cannot afford or use these new drugs for quite some time， what will be the approach there?
《国际肝病》：在本次会议上，有一个关于是否进行IL28B检测的辩论。支持不需要进行IL28B检测的理由之一就是在不久的将来，我们将有更新的药物可以不考虑患者对于干扰素的疗效。然而，对于那些不能负担或者暂时还没有新药的国家，是否需要进行该项检测呢？
Prof Marcellin: IL28 is a strong predictor of response if interferon is being used. So these days it is important if you do not have access to the genotype 1 protease inhibitors. In many countries， these drugs are difficult to obtain or even not registered so IL28 can help give an idea of the degree of response as it is the strongest predictor of response. But in the future when we use interferon-free treatments， IL28 will no longer be useful because it is not a predictor of response to the direct-acting antiviral agents. IL28 is a predictor of response to interferon but it is not a predictor of response to interferon-free treatment. In terms of cost benefit with standard of care and with a large proportion of patients worldwide still treated with interferon plus ribavirin， IL28 is something that can be cost-effective to select the right patients who have a high likelihood of a cure. In some strategies and in some countries it should be used. It is a simple test and can be done on a PCR with a serum sample and assists in making the decision whether to treat or not. One of the roles of the PHC is to analyze the best way to optimize treatment according to the different situations that exist in different countries. I don’t think the management of patients with hepatitis C is the same in United States as it is in China or in India or in Africa. We have to think in terms of the priorities of public health， in terms of available resources and how to achieve the best efficacy and best strategy with what is available. This concept will be followed at the next meeting of the PHC in January 2013 (they will now be held every year) where we will be discussing hepatitis B and hepatitis C (this meeting was just hepatitis C obviously because hepatitis C was a very hot topic). In the next meeting we will return to hepatitis B because it is the biggest public health issue and particularly in China where it is a huge problem. I mentioned that advances in hepatitis C are accelerating and in hepatitis B now there are similar advances that need an annual review of the state of the art and there will be many important debates. I am sure that next year we will have a lot of new results and data and the controversies and debates will continue. The concept of this meeting I arrange each year is to discuss different treatment strategies according to different regions of the world. The patients are different; the resources are different; and the management is different. The challenge for the future will be to allow access to treatment to all patients who need treatment. Maybe not all patients need to be treated; we will need to treat the most serious patients and we have to come up with strategies on how to use these tools and weapons against hepatitis C in the best way.
Marcellin教授：IL28是干扰素治疗效果高效预测因子之一。因此，在还没有基因1型蛋白酶抑制剂的国家，进行该项检测还是非常重要的。在许多国家，这些药物非常难以获得，或者还未进行注册，IL28检测可以帮助预测干扰素治疗效果。 但是在将来，我们如果使用无干扰素治疗方案时，IL28检测将不再有益，因为它并不是直接抗病毒治疗药物疗效的预测因子。就标准治疗方案成本效益方面进行分析，因为全球仍有大部分患者仍然在使用干扰素联合利巴韦林治疗，IL28对于筛选合适的患者非常有益，因为能够提高治愈率。在某些治疗策略和某些国家，进行该项检测，还是有一定帮助的。它只需进行一个简单的试验，通过对血清样品进行PCR分析就可以决定是否需要进行治疗。初级卫生保健的一个原则就是通过分析不同国家存在的不同情况，对不同的状况进行优化治疗。对于丙型肝炎患者的治疗，我并不认为美国的治疗方案和中国、印度或者非洲等国家的治疗方案是相同的。我们必须依据国情、可获得的资源条件来做出最好的策略以期获得最佳治疗效果。这个观点将在2013年召开的初级卫生保健论坛（以后将每年举办一次）中进一步加以阐述，到那时我们将要讨论的乙型肝炎和丙型肝炎（本次会议主要是丙型肝炎，因为丙型肝炎是一个热点话题）。在下次会议中，我们将着重讨论乙型肝炎，因为它仍然是最大的公众健康问题，尤其是在中国。我曾经提到，在丙型肝炎方面进展非常迅速，同时异性肝炎也取得同样的进步，因此非常有必要每年对最新的进展进行回顾，将会有许多重要的辩论。我相信，明年我们将有很多新的研究结果和数据发表，争鸣将会得以继续下去。每年，我们会议的主题就是对不同国家和地区的治疗策略进行讨论。在不用的地区，患者不同，资源也不同，因此治疗策略也应不同。也许，并不是所有的患者均需要进行治疗，我们需要治疗病情更严重的患者，我们必须对如何更好利用现有的资源有清醒的认识，以便找到治疗丙型肝炎的最佳策略。
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发表于 2012-3-17 13:55
