| [PHC2012]丙型肝炎肝硬化患者的治疗——Prof.Marc Bourliere专访 -----
来源： 作者：Marc.Bourliere 发布时间：2012-3-13 18:16:00 阅读：44
这包括各种感染。肝硬化患者的主要问题是，他们的白细胞计数已经非常低，所以他们的免疫力通常较差，因此感染的风险较大。例如尿路感染。
Hepatology Digest: Your presentation at the PHC 2012 concerned the treatment of HCV for cirrhotics. We hear that interferon-ribavirin therapy tends to yield lower SVR rates for cirrhotics. What do we need to pay attention to when treating patients with cirrhosis?
《国际肝病》：你在初级卫生保健2012年会上进行了有关丙型肝炎肝硬化治疗的演讲。我们注意到肝硬化患者使用干扰素联合利巴韦林治疗，往往SVR率较低。那么我们在肝硬化患者治疗过程中需要注意什么？
Dr Bourliere: It is a fact that treating patients with pegylated interferon and ribavirin gives a lower rate of SVR compared to non-cirrhotic patient on this combination of therapy. However， it is this population of patients who are most in need of treatment. The thing that we need to be aware of is that sometimes side effects like the occurrence of anemia or infectious episodes may be more frequent in this population compared to the overall population of patients with less advanced fibrosis.
Bourliere博士：的确如此，聚乙二醇干扰素联合利巴韦林治疗的肝硬化患者，与非肝硬化患者相比， SVR率是偏低的。然而，这些患者是最需要治疗的。我们需要注意的是，与肝纤维化程度相对较轻的患者相比，某些副作用，例如贫血或感染事件在肝硬化患者中发生率较高。
Hepatology Digest: You mentioned the propensity for anemia and infections. What sort of infections are you referring to?
《国际肝病》：您刚才提到贫血和感染发生的倾向较高。你指的是哪些感染？
Dr Bourliere: This includes all kinds of infections. The problem with cirrhotic patients is that their white blood cell count is already lower so their immune system is more compromised and at greater risk of infection. Urinary infection for example. Infections of ascites (spontaneous bacterial peritonitis) are a special population for which decompensated cirrhosis patients are particularly at risk. For compensated cirrhosis， it is mainly glomerular infections leading to urinary infections and we know that in some cases this will be increased. The situation is that with the interferon-ribavirin strategy， this was only increased in decompensated cirrhosis patients. In the compensated cirrhosis patients， there was more of an increase in side effects due to anemia in cirrhotic patients compared to non-cirrhotic patients. This is when using the interferon and ribavirin combination therapy. When working with DA combinations in triple regimens， with boceprevir and telaprevir for example， in these cases we see an increased incidence of anemia compared to non-cirrhotic patients on this treatment regimen. When dealing with the cirrhotic patients in the clinical setting， in these situations we have observed a slight increase in infection problems usually， as I said， pulmonary infections and urinary infections and even decompensation of cirrhosis with a spontaneous bacterial peritonitis. Using direct-acting antivirals (DAA) in cirrhotic patients， you have an increase in anemia compared to non-cirrhotic patients. As a whole， with triple regimens， you have an increase in anemia. You need to weigh the occurrence of anemia against the standard of care when using pegylated interferon and ribavirin compared to the addition of boceprevir or telaprevir for all populations. When you move from the overall population to the cirrhotic population， when comparing to the non-cirrhotic population there is a slight increase in anemia as per our findings in the phase III trials. In clinical practice we have seen the same thing with the same rate of anemia occurring in cirrhotic patients both in the clinical trials and real life but on top of that we had a small increase also in infectious incidents. There was no significant increase in infections seen in the phase III clinical trial.
Dr Bourliere: 这包括各种感染。肝硬化患者的主要问题是，他们的白细胞计数已经非常低，所以他们的免疫力通常较差，因此感染的风险较大。例如尿路感染。对于失代偿期肝硬化患者而言，腹水感染（自发性细菌性腹膜炎）较为常见。对于代偿性肝硬化患者，主要是继发于尿路感染的肾小球感染，在某些患者，感染发生几率将会增加。例如，干扰素联合利巴韦林的策略，会增加失代偿期肝硬化患者感染的几率。对于代偿性肝硬化患者中，存在肝硬化的患者由于贫血导致的副作用发生率较肝硬化患者增加。当使用干扰素和利巴韦林联合治疗时是这样的。当使用三联疗法进行治疗时，也即与boceprevir和telaprevir联合治疗时，与非肝硬化患者相比，对于肝硬化患者而言，贫血的发病率是增加的。
在治疗肝硬化患者时，我们发现感染的问题略有增加，正如我所说，肺部感染和泌尿系统感染，甚??至肝硬化失代偿期患者的自发性细菌性腹膜炎。
在肝硬化患者中使用的直接作用抗病毒药物（DAA），与非肝硬化患者相比，贫血的发生率明显增加。三联疗法，作为一个整体，贫血发生率是增加的。当使用聚乙二醇干扰素和利巴韦林标准治疗，或者使用boceprevir或telaprevir治疗时，你需要权衡贫血的风险。
当眼目光从整个人群转移到肝硬化患者时，与非肝硬化患者相比，贫血的发生率轻微升高的，这一点我??们在第三期临床试验中已经得到证实。
在临床实践中，我们在临床试验和现实生活中均发现肝硬化患者贫血发生率升高，但最重要的是，我们同时也发现感染的发生率也有小幅增长。
在三期临床试验中并没有发现感染有显着增加。
Hepatology Digest: This observed increase in anemia and infections applies to both decompensated and compensated cirrhosis or one more than the other?
《国际肝病》：贫血和感染发生率增加是在失代偿和代偿性肝硬化患者中均存在还是其中某些人群更多？
Dr Bourliere: That is what we are not able to answer yet. In the real life studies we have performed， we enrolled patients who were not able to be enrolled into phase III trials because they had other comorbidities or complications and we have not yet looked into that and are not able to answer at this point whether these infection episodes occur in patients who were， for example， in decompensated cirrhosis.
Dr Bourliere：到目前为止，尚无肯定回答。在我们已经完成的研究中，我们入选的患者都是那些因为有其他合并症或并发症无法参加三期临床试验的人群，但是我们尚未进行详细研究，并且到目前为止尚不能回答这些患者，例如失代偿期肝硬化患者，是否感染的发生率是增加的。
Hepatology Digest: If there are a significant number of side effects even using just interferon and ribavirin therapy， what can be done for patients who have decompensated cirrhosis or compensated cirrhosis and who need to be treated? What extra precautions need to be taken?
《国际肝病》：如果使用干扰素和利巴韦林治疗发生显著的副作用，对于失代偿期肝硬化和代偿期肝硬化患者有何好的治疗方法？需要采取额外的预防措施吗？
Dr Bourliere: We need to be cautious of these kinds of episodes. In terms of cirrhosis， we need to be a little more cautious and advise patients to visit more frequently and spend more time with these patients. For cirrhotic patients， we need to look at them very closely. What we have shown in our study is that treatment with a triple regimen is feasible. We can do it. But we need to be aware that we have an increased rate of anemia in cirrhotic patients and that we need to take this anemia into account early， reduce the dose of ribavirin more dramatically to avoid transfusions and to be more reactive in the way that we manage anemia in these patients.
Dr Bourliere：对于这些情况，我们需要谨慎处理。对于肝硬化患者而言，我们需要更加谨慎，提醒他们勤随访，并在他们身上都花些时间。我们的研究显示，三联疗法治疗是可行的。我们可以做到这一点。但我们需要注意的是，肝硬化患者贫血发生率是增加的，所以我们要注意到贫血的情况，减少利巴韦林的剂量，以避免输血，并且对于这些患者的贫血管理更加积极。
Hepatology Digest: So the approach here is to reduce the dose and prolong the therapy rather than trying to treat the side effects?
《国际肝病》：那么是不是靠减少剂量和延长治疗来达到疗效，而不是试图治疗副作用？
Dr Bourliere: Regarding the anemia， it is not only due to the direct-acting compound， but also due to ribavirin and partly due to interferon. The key point is that when we manage anemia we try to reduce the use of ribavirin， but if we do so too deeply， we are going to lose SVR. So at this point， we aim to reach a balance between the reduction in ribavirin and the management of anemia. When working with a triple regimen， the problem is a little bit different because in these cases we have very potent antiviral efficacy. In these cases the viral load decreases very rapidly and in most patients become undetectable quite early. If you were to reduce the ribavirin dosage there would be no loss of SVR. This is a different way of managing anemia than what we were doing before.
Dr Bourliere：至于贫血，不仅与直接抗病毒药物有关，但也可能与利巴韦林和干扰素有关。关键的一点是，当我们治疗贫血时需要减少利巴韦林的剂量，但是如果我们将利巴韦林的剂量减得过低，SVR将减少。因此，在这一点上，我们必须在减少利巴韦林剂量和贫血治疗之间找到平衡。当使用三联治疗时，这个问题有点不同，因为在这些情况下，抗病毒疗效非常好。在这些患者中，病毒载量下降非常迅速，大多数患者在早期病毒载量就不能检出。如果减少利巴韦林剂量，SVR不会降低。这一点，与我们既往治疗贫血时是有所不同的。
Hepatology Digest: What are your thoughts on the future treatment of hepatitis C and cirrhosis?
《国际肝病》：请您展望一下未来治疗丙型肝炎和肝硬化可能会有哪些进展？
Dr Bourliere: We know now that using a triple regimen with first generation protease inhibitors， PEG-IFN and RBV we can cure nearly 100% of treatment- experienced genotype 1 patients. Actually we are doing a new trial now in which we demonstrate about the same results and will present those at the EASL meeting. But again， with very few cirrhotic patients so the next step will be to try and treat these cirrhotic patients with these new regimens to see what the cure rates will be. We are also developing a new combination therapy with DAAs without interferon and with or without ribavirin. We have to wait for the results of those trials but if we are able to demonstrate that first in non-cirrhotic patients we are able to cure a high number of patients (over 80-90%)， it will be very interesting to move on to cirrhotic patients. The advantage of using DA combination therapy without interferon is， as you would imagine， we can move towards treating more advanced cirrhotic patients. This is another thing we need to look at. You will be aware of a compound from Pharmasset which is now a Gilead compound， GS7977. If we are able to use this compound in combination with other potent protease inhibitors or other potent NS5A inhibitors in a triple regimen with or without ribavirin， it could be interesting even in cirrhotic patients. We know that because of the way the compound GS7977 is metabolized， not within the liver but more renal metabolism， we can expect to use it in more advanced cirrhosis patients. So by using different associations of potent DA compounds， we can imagine that in five or ten years we will be able to be in the situation we are now with hepatitis B patients. Because of the use of entecavir and tenofovir， it is now possible to ‘cure’ advanced cirrhosis patients and to avoid transplantation in hepatitis patients and obtain very good results. That is the way in which we need to go and that depends on how effective this compound will be. If we have no safety issue and no drug interaction issues， we can imagine that we will be able to cure a larger number of cirrhotic patients and a larger number of patients worldwide. The dream would be that in HCV we would reach the situation we are in now with HIV where we will be using combinations of drugs in a single pill like Atripla for HIV. In this case， by using potent combination therapy we can expect to have the solution and key to hepatitis C. I hope that dream is reality in the very near future.
Dr Bourliere：现在我们知道，使用与第一代蛋白酶抑制剂、PEG-干扰素和利巴韦林的三联疗法，基因1型的患者治愈率接近100％。目前我们正在进行一项新的研究，得出的结论相同，这一结论将发表在欧洲肝病学会上。但是同样，肝硬化患者很少，因此下一步将对这些肝硬化患者进行研究，了解他们的治愈率将是多少。我们也正在开发一个新的无干扰素治疗的方案，即DAAS和/或利巴韦林。我们必须等待这些试验的结果，如果能够证明在非肝硬化患者有效（占80-90％以上的患者），那么我们就可以将其应用到肝硬化患者。使用无干扰素的DA联合疗法的优点是，你可以想象到，我们可以治疗更多的进展期肝硬化患者。这是我们需要另外关注的一点。你可能注意到，Pharmasset近期开发出一种新的化合物GS7977。如果我们能够将这种化合物与其他蛋白酶抑制剂或则其有效的NS5A抑制剂联合使用，组成一个含有或者不含有利巴韦林的三联治疗方案，这对于肝硬化患者来讲可能很有意义。我们知道，GS7977的代谢方式不是在肝脏内，而是在的肾脏代谢，因此期望能在进展期肝硬化患者中使用。
因此，使用有效的直接抗病毒药物进行联合治疗，我们可以想像在五年或十年后，我们的情况可能和现今乙肝患者的情况相同。由于使用恩替卡韦和替诺福韦，现在可以“治愈”晚期肝硬化患者，以避免肝移植，取得了非常好的效果。
这是我们必须经过的道路，取决于这种化合物的疗效。
如果不存在安全问题，同时也没有药物的相互作用，可以想像，我们将能够治愈世界各地更多的肝硬化患者。我们的理想是，在丙型肝炎抗病毒治疗过程中，我们会达到艾滋病抗病毒治疗的那样，使用像Atripla那样的单一药片就可以治疗。因此，我们可以通过有效地联合治疗，来治疗丙型肝炎。我希望在不久的将来这个梦想可以实现。
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发表于 2012-3-17 13:58
