慢乙肝路线图的应用和肝纤维化的无创检测—Gane教授 vs. 王贵强教授

Edward J. Gane  新西兰肝移植中心

王贵强  北京大学第一临床医院

Hepatology Digest: Some time has passed since the original proposal of the roadmap concept. So， Professor Gane， what advances have been made on it， and perhaps at some of the meetings since: what changes have been made， if any， and what is the outlook on it?

《国际肝病》：路线图概念从最初提出到现在已经有一段时间了。那么Gane教授，路线图概念有何进展，是否有会议提出修订，您对这方面的展望是什么？

Dr. Gane: I think one issue is that， until now， there have not been any good prospective studies to fully evaluate the roadmap model.  As I pointed out in my presentation: there are studies now， registration studies， where patients have been switched arbitrarily at the end of one year， and that is regardless of the early virological response. And the current study， the Novartis’ study which has started looking at the addition of tenofovir to patients who are partial responders to telbivudine I think is probably the first real study designed prospectively to test the roadmap. We heard from Patrick Marcellin on some interesting data， but very preliminary data on patents switching from tenofovir to Truvada - which of course is a combination of tenofovir and emtricitabine - suggesting that， in a small number of patients， you didn’t appear to achieve increased viral suppression. I think that needs to be proven with subsequent studies. 

Gane博士：我认为问题是，到目前为止，仍没有相对较好的前瞻性研究来充分评估路线图模型。就如我在演讲中提到的，在有些药物注册的相关研究中，患者在1年的治疗后被武断地换用药物，无视患者早期的病毒学应答。目前有研究考虑对替比夫定部分应答患者加用替诺福韦进行治疗，我认为这可能是第一个真正的检测路线图的前瞻性研究。我们从Patrick Marcellin那里得到了一些有趣的数据，是关于将替诺福韦换为Truvada（含恩曲他滨/替诺福韦）的初期数据。数据显示，有一小部分患者的病毒抑制并未增加。我认为这需要后续研究来证实。

Prof.Wang: Yes. The roadmap is good. In China we also think about the roadmap as a practice guideline. But there is a problem in China， you know.  The HBV DNA quantitave is not sensitive in China. We use the domestic reagent and the methods. So， the roadmap is based on clinical trials of telbivudine， but in China it should be more defined. It will take time， I think. It is a problem for Chinese doctors.

王贵强教授：是的。路线图概念很好，在中国也被作为临床参考。问题是，在中国我们用的是国产试剂和方法，HBV DNA定量并不是很敏感。路线图是根据替比夫定的临床试验制定的，它在中国还要被更精准的定义。这需要时间，我想这确实是中国医生的问题。

Hepatology Digest: So do you think this really makes it more difficult for them to apply the roadmap concept， professor， is this a real stumbling block?

《国际肝病》：那么您是否认为这会导致路线图概念的应用变得更加困难？这是否是个障碍？

Dr. Gane: I think the data from GLOBE， which was a very large study - including a large number of patients from China - looked at different cutoffs. It looked at level of detectability. It looked from 300 to 1000 copies per milliliter， from 1000 to 10 000 and greater 10 000.  So you just need to look at making a split of the data at 1000 copies per milliliter， if that is the sensitivity of the local assay and reexamine that.  There is no doubt that the roadmap concept will still be predictive: it will still predict who will have a higher rate of achieving good long term outcomes， but the predictive value will not be as great.   

Gane博士：从GLOBE的数据来看——这是个非常大型的研究，也包括很多中国患者，要考虑不同的停药标准。要考虑到不同的检测水准问题。标准可以从300到1000 copies/mL，从1000到10 000 copies/mL以及10 000 copies/mL以上。因此你可以考虑以1000 copies/mL作为分界，如果当地的化验在这个水平上比较敏感的话，可以反复进行这种检查。无疑，路线图概念还是有预测性的，它可以预测哪类患者可以对长期临床取得更好的疗效，但预测能力并不是很强。

Hepatology Digest: Professor Gane， in your talk you gave us some new insights into the roadmap concept. It appears that this approach is unlikely to be suitable for previously treated patients. So， how should we monitor the drug resistance of these patients and could it be possible to propose an early predictive method like the roadmap in this particular situation? 

《国际肝病》：Gane教授，您的演讲提出了一些关于路线图概念中的新观点。似乎这一方法并不适用于既往治疗过的患者。那么对这类患者，我们如何监测耐药的发生？在这种特殊情况下，能否提出一种类似于路线图中的早期预测方法？

Dr. Gane: When we are talking about re-treating patients with established antiviral resistance， I think we will really look at approaches. For example， lamivudine resistance， when we add in adefovir we find it far more effective than switching to adefovir.  So I think that already we have moved to combination therapy for most cases of established lamivudine resistance.  We know that simply switching from lamivudine to adefovir in that situation will lead to a significant risk of adefovir resistance over the ensuing years.  So I think we have already gone beyond the roadmap in that concept for treating patients with established resistance， and that if affordable and available we are adding in a second drug.  It is important that that second drug has a different mode of action so that there is no cross resistance. 

Gane博士：谈到对已确定发生耐药的患者进行复治的问题，我想我们的确需要注重方法。例如，我们发现，对拉米夫定发生耐药的患者加用阿德福韦酯，要比换用阿德福韦酯有效得多。因此对大多数已被证实有拉米夫定耐药的病例，我们都采用联合治疗。我们知道，在这种情况下，如果只是简单地把拉米夫定换成阿德福韦酯，那么在接下来的几年中，对阿德福韦酯发生耐药的风险也会增高。所以我认为在对已被证实发生耐药的患者进行治疗时，是否可以找到这样一种可以加用的能负担起的药物，这个概念上已经超出了路线图。重要的是，这种药物要有不同的作用模式，这样才不会发生交叉耐药。

Prof. Wang: Yes，  we have the same ideas. After the lamivudine or telbivudine with the roadmap concept we can add  adefovir - we have no tenofovir. I think you have tenofovir， we have none， but we just add-on adefovir as the native treatment to reduce the resistance and promote the therapy.

王贵强教授：是的，我们的观点相同。在依照路线图应用拉米夫定和替比夫定后，我们会加用阿德福韦酯——现在我们还没有替诺福韦。你们有替诺福韦，而我们没有。我们只是加用阿德福韦酯作为替代疗法来降低耐药率，提高治疗效果。

Hepatology Digest: Dr. Gane， you mentioned in your talk about partial responders; how can we finally really make out in which cases it would be advantageous and for which agents - you had mentioned there are some new agents - in which cases that we would add-on and in which that it might be preferable to switch?  I know you talked a little bit about that and can you explain a little bit?

《国际肝病》：Gane博士，您的演讲中提到了部分应答者，最终我们如何真正分辨出在哪些病例哪种药物有效——您提到了一些新药物；在哪些病例我们应该加用药物，哪些病例应该换用药物？能否谈一下这方面的问题，并稍作解释？

Dr. Gane: Sure. I think that if you are looking at an agent such as lamivudine and you have a partial response， in that situation if available you would like to add-on a second drug.  That second drug may be adefovir early on， or you may chose to switch to a different drug. What we don’t know is whether switching to a drug such as entecavir in a patient who has had a suboptimal response to lamivudine may increase the risk of entecavir resistance. One of the arguments for add-on rather than switch with lamivudine partial responders is the worry that you have very low levels of lamivudine resistance species already in your blood at 24 weeks after starting lamivudine and in that situation you would increase the rate of entecavir resistance. Now I should say that as of yet， there is no strong data to support that. And some people would argue that changing form lamivudine to entecavir， a more potent drug， or telbivudine， a more potent drug， may be preferable to add-on purely for the cost aspects.

Gane博士：当然。我认为如果患者对一些药物，如对拉米夫定产生部分应答，在这种情况下，如果有可用的药物当然愿意加用第二种药物。早期加用的这种药物或许是阿德福韦酯，或者可以选择换用其他不同的药物。我们不确定对拉米夫定产生部分应答的患者，如果换用如恩替卡韦这类药物后是否会增加其对恩替卡韦耐药的风险。对拉米夫定发生部分应答的患者加用而不换用药物的另一个考虑是，担心在开始应用拉米夫定治疗24周以后，部分应答者的血中已经存在很低水平的拉米夫定耐药株，在这种情况下，恩替卡韦的耐药率也会增加。目前还没有强有力的证据支持这一点。也有一些观点认为，从经济角度来考虑，将拉米夫定换成强效药物如恩替卡韦或者替比夫定，或许比加用药物更合适。

Hepatology Digest: What about an agent like pegylated interferon or other agents: can we apply the roadmap concept to an agent such as that?

《国际肝病》：PEG-IFN或者其他一些药物效果如何，我们是否可以将路线图概念应用于这类药物？

Prof.Wang: Yes， sure. All the drugs should have a set of roadmap