[PHC2012]Boceprevir和Telaprevir联合PEG-IFN/RBV治疗应答预测因素——P

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[PHC2012]Boceprevir和Telaprevir联合PEG-IFN/RBV治疗应答预测因素——Prof.Paul Y.Kwo专访            

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来源： 作者：Paul.Y.Kwo 发布时间：2012-3-13 17:50:54   阅读：57

                                    
            　　聚乙二醇干扰素和利巴韦林联合boceprevir或telaprevir的三联疗法可显著提高HCV基因1型的持续应答率，目前我们所能获得的SVR率约70％。
                                               
                                                      

　　Paul Y.Kwo  美国印第安纳大学医学院
　　Hepatology Digest: What are the predictors of response and why are they important?
　　《国际肝病》：请问应答的预测因子是什么，它们为何如此重要？
　　Dr Kwo: The addition of boceprevir and telaprevir to pegylated interferon and ribavirin for genotype 1 has dramatically improved sustained response rates and we are seeing SVR rates now around 70% for genotype 1. However， what we are finding is that because the higher SVR rates are seen it is more difficult to determine what is a predictor of response. What has been determined though is that the improvement over PEG-IFN/RBV remains consistent. Overall， for sustained response rates that we have looked at through the telaprevir study the difference between control and telaprevir groups was 44% versus 75% which went from 46% to 79% once the FDA did their own analysis. The improvement was anywhere from 31-33% over PEG-IFN/RBV. That is the improvement you get. In the Advance Study which was published in the New England Journal where the improvement was 31%， we find that for predictors of response， when you look at subgroup breakout， the SVR rate improvement is preserved. Firstly for telaprevir， in the Advance Study， 75% of the telaprevir group attained SVR and 44% on PEG-IFN/RBV. It is interesting to consider things such as race. Those of black ethnic origin are historically always more difficult to treat and had an SVR rate in the Advance Study of 25% but when telaprevir was added it went up to 62%. Now these are small numbers but it is still a predictor of response in that you get a lower SVR rate. With the addition of telaprevir in this particular case there is a 36% improvement. For Caucasians， there was a 48% SVR rate in Advance for PEG-IFN/RBV and 76% with the addition of telaprevir; so an improvement of 28%. Again， roughly a 30% increment. So in general， with the addition of telaprevir， SVRs appeared to improve around 30%. Even if the predicted SVR is lower on PEG-IFN/RBV it is also going to be lower with the addition of telaprevir or boceprevir but you are still going to gain about 30%. The second predictor is age. If you are a younger person， you have a better chance of achieving sustained response. With respect to age then， if less than age 45， the SVR rate is 52% with PEG-IFN/RBV and if greater than 45 years old， the SVR rate was 38%. With the addition of telaprevir， if less than age 45， the SVR rate was 52% with PEG-IFN/ RBV and if older than 45， the SVR was 38%. If we look at the addition of telaprevir it went from 38% to 70% if you were above 45 with telaprevir and up to 83% if you were less than 45. The thing is there is still the same increment; there will always be an improvement of around 30%. That is also true for high viral load and low viral load. High viral load has always been associated with low SVR rates and indeed with PEG-IFN/RBV， if your virus levels in the Advance Study were greater than 800000， your SVR rate was 36%. That went up to a 74% SVR for that viral load on telaprevir. That’s a huge predictor of response. If you have a low viral load of <800000 from the Advance Study， on PEG-IFN/RBV the SVR was 70% but for PEG-IFN/RBV/telaprevir was 78%; just small numbers but an 8% improvement. So in predicting response， you get a better likelihood with telaprevir of attained SVR and more so with a higher viral load. Genotype is also interesting. Genotype 1a seems to be more difficult to treat than genotype 1b. If you look at a PEG-IFN/RBV control arms in the Advance Study and the Sprint2 Study， the SVR rates were higher for genotype 1b and it was identical with telaprevir. So genotype 1a is harder to treat with PEG-IFN/RBV therefore triple combination therapy is recommended in that case.
　　Dr Kwo：聚乙二醇干扰素和利巴韦林联合boceprevir或telaprevir的三联疗法可显著提高HCV基因1型的持续应答率，目前我们所能获得的SVR率约70％。然而，目前的临床试验显示三联疗法已经获得了很高的SVR率，反而使得确定应答的预测因子相对更困难。虽然已确定的是相对PEG-IFN/RBV应答率的提高是保持一致的。总体而言，对于持续应答率，我们通过telaprevir研究发现对照组和telaprevir组之间的差异为44％和75％，美国FDA自己的分析显示为46％至79％。相对PEG-IFN/RBV提高了31-33％。在新英格兰医学杂志发表的Advance研究中，应答率提高31％，我们发现对于应答的预测因子，即使在对亚组病毒学突破进行分析时，SVR率的提高仍然存在。首先对于telaprevir，在Advance研究中，telaprevir治疗组SVR达到75％，而PEG-IFN/RBV组为44％。考虑其中一些因素如种族是很有趣的。黑色人种一般更难治疗，在Advance研究中PEG-IFN/RBV治疗的SVR率为25％，但联合telaprevir治疗时提高到62％。现在，尽管数据量并不大，但它仍是应答的一个预测因子，可预测较低的的SVR率。在这种特殊情况下联合telaprevir会有36％的提高。而对于白种人，在Advance研究中PEG-IFN/RBV治疗的SVR率为48％，联合telaprevir治疗时为76％，提高了28%。大约也是提高了30％。所以一般来说，加上telaprevir后SVR率提高30％左右。即使PEG-IFN/RBV治疗预测的SVR较低，同样联合telaprevir或boceprevir治疗也相对较低，但仍然可获得30％左右的提高。第二个预测因子是年龄。如果你是一个年轻人，那么你将更有机会获得持续应答。如果小于45岁，PEG-IFN/RBV治疗的 SVR率是52%，如果大于45岁，SVR率为38％。当加上telaprevir时，如果45岁以上，SVR率将从38％提高到70％，如果小于45，则提高到83％。事实上增量是相同的，总体上会有30％左右的提高。对于高病毒载量和低病毒载量也是这样的。高病毒载量常与低的SVR率有关。 PEG-IFN/RBV治疗确实是这样，在Advance研究中，如果病毒水平大于800000， SVR率为36％。联合 telaprevir治疗后升高到74％。这是一个重要的预测因子。如果病毒载量小于800000， PEG-IFN/RBV的SVR率为70％，而PEG-IFN/RBV/telaprevir为 78％，提高并不多，只有8％的增加。因此，在预测应答方面，高病毒载量在联合telaprevir治疗后获得SVR的可能性更高。基因型也很有趣。基因型1a似乎比基因型1b更难治疗。如果你看一下Advance研究和Sprint2研究中PEG-IFN/RBV对照组，基因型1b的SVR率较高的，和联合telaprevir治疗时相同。所以PEG-IFN/RBV治疗基因型1a更难，因此，在这种情况下，建议采用三联疗法。
　　Hepatology Digest: So from what you have said， it would seem that there are no new predictors for whether triple therapy is going to work other than if you have a low viral load?
　　《国际肝病》：根据您所说，如果是低病毒载量，对于三联疗法能否起作用没有新的预测因子？
　　Dr Kwo: Right. That is a fact. If you have a low viral load， you still do better if you add telaprevir but you get the same percentage SVR as on PEG-IFN/RBV. The interesting situation was the polymorphism IL28B which is the marker of PEG-IFN/RBV responsiveness. What I hope will be the advantage to using telaprevir is the ability to go short， i.e. the ability to treat for six months if you have a favorable genotype. IL28CC was extremely high on telaprevir. The problem with the Advance Study as well as the Sprint2 Study was that this IL28b was not discovered at the time the studies were initiated so we had to do retrospective analyses. Confirmed IL28B genotypes made up 42% of the cohort. The retrospective analysis looked at the database and telaprevir improved SVR across all genotypes but with IL28CC the chance of achieving SVR in six months was very high. That is what IL28CC seems to predict. All the factors that I have just described were also true for boceprevir. If you have low viral load， there is a 76% sustained response rate with PEG-IFN/RBV/boceprevir versus PEG-IFN/RBV at 64%. So again it is very high. If you have a high viral load， you picked up an extra 30% over the PEG-IFN/RBV control similar to telaprevir. Looking at genotype 1a and 1b， there is an identical pattern. Let’s look at fibrosis and advanced fibrosis response rates with PEG-IFN/RBV/telaprevir are better than the control. And finally with both of them， on-treatment viral response correlates closely with SVR. If you achieve a complete early viral response on telaprevir and clear of virus by week 12 your opportunity for SVR is good. Now with more potent therapies， the trend has been to truncate therapy as early as possibly while maintaining a sustained response. Those who are less likely candidates to have a truncated course of therapy are those with advanced fibrosis and cirrhosis. At least for now， they still require at least 48 weeks of therapy but other subgroups can be truncated at 24 weeks of therapy and maybe in the future， even shorter.
　　Dr Kwo：对。这是一个事实。如果你病毒载量低，联合telaprevir治疗将获得和PEG-IFN/RBV治疗相同比例的SVR。有趣的是， IL28B多态性是PEG-IFN/RBV应答的一个标志。我所希望的是telaprevir治疗具有疗程更短的优势，如果是一个预后较好的基因型，三联疗法能够治疗6个月就获得较高的SVR。 telaprevir治疗IL28CC时SVR极高。Advance研究以及Sprint2研究的问题是，在开始进行研究时IL28B未被发现，所以我们不得不做回顾性分析。结果证实IL28B基因型患者高达42％。回顾性分析发现，telaprevir治疗可提高所有基因型SVR，而IL28CC在6个月实现的SVR的几率是非常高的。看起来IL28CC可作为预测因子。我刚才所描述的所有因素在boceprevir也是如此。如果你病毒载量低，PEG-IFN/RBV/boceprevir治疗的SVR为76%，而PEG-IFN/RBV的SVR率为64％。因此，这又是非常高的。如果你病毒载量高，相比PEG-IFN/RBV可获得30％的提高，这与telaprevir相似。基因型1a和1b有一个相同的模式。另外，肝纤维化和晚期肝纤维化PEG-IFN/RBV/telaprevir应答率优于对照。最好，治疗的病毒应答与SVR密切相关。如果telaprevir实现早期病毒学完全应答并在12周清除病毒，获得SVR的机会还是不错的。现在有了更有效的疗法，今后的趋势是尽可能早的缩短治疗并且同时保持持续应答。那些不太可能缩短疗程的患者包括晚期肝纤维化和肝硬化。至少现在，他们仍然需要至少48周的治疗，但其他亚组在将来可能被缩短为24周疗程，甚至更短。
　　Hepatology Digest: Is the reason that you cannot truncate treatment for patients with advanced fibrosis and cirrhosis because if the virus relapses you can’t risk the increased inflammation and ALT levels?
　　《国际肝病》：不能缩短晚期肝纤维化和肝硬化患者治疗的原因是我们不能冒如果病毒复发导致炎症和ALT水平增加的风险？
　　Dr Kwo: Those relapses are usually well-tolerated. The issue is that cirrhotics are less PEG-IFN/RBV responsive and no one really knows why but conceptually it is harder to eradicate the hepatitis C virus from fibrotic liver than those without fibrosis. In the advanced fibrosis group and with the advent of the direct-acting antiviral agents we will be striving to answer the question whether or not you can clear viral loads with shorter periods of therapy， particularly if you can eliminate the virus very quickly. We generally treat for 48 weeks right now if you have cirrhosis. The improvement again is about 30% over PEG-IFN/RBV and this is what these drugs seem to be able to achieve over PEG-IFN/RBV but with slightly increased side effects. So there are more side effects but better SVR rates. The future of therapy for hepatitis C is entering the area of response-guided therapy where we will use the rate of clearance of the hepatitis virus from the serum as a marker of the duration of therapy that will be required to achieve the same response.
　　Dr Kwo：那些复发通常耐受性良好。问题是肝硬化对PEG-IFN/RBV应答低，尽管没有人真正知道为什么，但概念上认为从肝纤维化的肝脏清除丙肝病毒比没有肝纤维化困难。在晚期肝纤维化组随着直接作用的抗病毒药物的问世，我们将努力回答是否可以用更短的时间来清除病毒载量的问题，特别是如何很快清除病毒。如果有肝硬化，我们一般治疗48周。其SVR率相比PEG-IFN/RBV提高30%，而副作用略有增加。因此，副作用更多，但SVR率更好。 未来丙肝治疗将进入应答指导治疗的时代，届时我们将使用血清肝炎病毒清除率作为要达到同样应答需要的治疗疗程的一个标志。
　　Hepatology Digest: We have heard that there may be some virus strains that are developing resistance to boceprevir and telaprevir. Are you aware of any studies where this has happened?
　　《国际肝病》：我们已经听说可能会有一些病毒株发生boceprevir和telaprevir耐药。您知道这方面的研究吗？
　　Dr Kwo: That is correct. The hepatitis virus does not replicate very efficiently and indeed these NS3-NS4 protease inhibitors such as telaprevir and boceprevir， when you add them you generate variants and you generate them immediately. The difference is that PEG-IFN/RBV further affects their replication. If you add PEG-IFN/RBV to boceprevir and telaprevir， the viral load immediately goes down and you generate resistant variants but with PEG-IFN/RBV onboard， those resistant variants don’t continue to replicate. If an individual is less PEG-IFN/RBV responsive， then it is in these individuals where the variants breakthrough. A lack of PEG-IFN/RBV responsiveness is what allows the resistant variants to breakthrough. Again， with boceprevir for instance， there is a lead-in period with four weeks of PEG-IFN/RBV which we can use as a predictor of response. If you have a one month introduction with PEG-IFN and RBV as a lead-in before adding boceprevir， the opportunity for an SVR is very high and can be used as a predictor of response on-treatment. That is mostly what we are striving for as the potency of these drugs improves and the combinations improve， to find the most potent combination of these drugs to drive the virus out. Pre-treatment predictors are probably going to become less important.
　　Dr Kwo：这是正确的。肝炎病毒复制效率并不高，对于NS3-NS4蛋白酶抑制剂如telaprevir和boceprevir，确实加上这些药物时同时也产生了变异株。不同的是，PEG-IFN/RBV进一步影响其复制。如果将PEG-IFN/RBV联合 boceprevir或telaprevir治疗，病毒载量会很快下降，并产生耐药变异株，但在PEG-IFN/RBV存在的情况下，这些变异株不会继续复制。如果患者PEG-IFN/RBV应答低，那么变异株将发生突破。PEG-IFN/RBV应答不足导致耐药变异株突破。再以boceprevir为例，有4周PEG-IFN/RBV诱导期，我们可以作为应答预测因子。如果加入boceprevir前PEG-IFN/RBV诱导期为1个月， SVR的机会是非常高的，可作为治疗应答的预测因子。我们正在努力寻找这些药物的有效组合来强有力清除病毒。治疗前的预测因子可能会变得不那么重要。
　　Hepatology Digest: What happens if during those first four weeks before introducing boceprevir， we don’t see the requisite decrease in virus?
　　《国际肝病》：如果在增加boceprevir前最初4周，我们没有看到病毒载量的必要性下降，将会发生什么问题？
　　Dr Kwo: If there is less than a robust response then the opportunity for a sustained response is lower and probably in the range of 30-35%. You are then looking to have to discuss options with the patient. If you have advanced fibrosis， a 30% or 35% opportunity for SVR is actually something that is maybe quite desirable if you are trying to avoid decompensation or a liver transplant. If you have minimum scarring and you have less virus reduction， less PEG-IFN/RBV responsiveness then maybe you don’t need to be treating right now. The patient may be doing fine， stage 0-1 fibrosis; let’s wait. Very useful.
　　Dr Kwo：如果没有很强的应答，那么获得持续应答的机会较低，大概在30-35％的范围内。那么就需要与患者讨论治疗方法的选择。如果患者有晚期肝纤维化，如果想要避免失代偿或肝移植，30％或35％的机会获得SVR也许是非常可取的。如果肝损伤较轻，病毒水平下降少， PEG-IFN/RBV应答低，那么，也许你现在并不需要治疗。肝纤维化0-1期患者可能会很好，让我们等一等是非常有用的。
　　Hepatology Digest: We wait until new or better drugs become available?
　　《国际肝病》：我们可以等待新的或更好的药物？
　　Dr Kwo: Yes. And they are certainly on the horizon right now. We can all confidently say right now that we can see the horizon. They are not here yet but the horizon is well within our visual field.
　　Dr Kwo：是的。现在它们正在研发中。我们可以理直气壮地说这是很有希望的。尽管现在还没有，但在我们可以预见的将来会有。