HBV感染的基因治疗——Gish教授访谈

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时间:2008-8-18 10:04:07  

Hepatology Digest: Could you please talk a little bit about the role of gene therapy in HBV?

  《国际肝病》：请您给我们谈一下基因治疗在HBV感染治疗中的应用。

Gish: As you know, currently with hepatitis B, with oral medications most patients will be on therapy indefinitely; we’re using the word lifelong. The treatment that I presented at this meeting may offer the opportunity to stop therapy in patients by clearing s-antigen (HBsAg) and clearing e-antigen (HBeAg). The data I showed here at this meeting shows that this treatment at the first dosing cohort was safe and we’re showing some signals of efficacy. It’s possible with higher doses and repeat treatment we may be able to clear virus in patients and get them off oral therapies.


     Gish教授：目前对于乙型肝炎来说，口服药物治疗疗程不确切，甚至需要终生治疗。基因治疗将给乙肝患者一个清除E抗原与表面抗原以彻底结束治疗的机会。在本次会议上我要向大家展示的就是基因治疗第一次给药后观察的结果，表明该治疗是安全的，并显示了部分有效的迹象。有可能通过加大药物剂量或多次给药可以清除患者体内病毒，使患者摆脱口服药物治疗。



Hepatology Digest: How do you anticipate the timeline for it moving on to the next phase?

《国际肝病》：您预计基因治疗需要多长时间能进行下一阶段的试验？

Gish: Typically, when you enter phase 1B trial to licensing it’s usually a three to five year timeline. I think that’s realistic in this situation with this treatment.

Gish教授：一般来讲进入1B期临床试验需要3到5年时间，对于乙肝的基因治疗来说，这个时间是比较合理的。



Hepatology Digest: The molecular basis of chronic hepatitis B has made great progress in recent years. In your opinion, which pathway or factor would play the most important role in antiviral resistance?

《国际肝病》：近年来，慢乙肝的分子基础研究取得了巨大进展，您认为那种通路或因子在导致抗病毒耐药中起到最重要作用？

Gish: There are two major issues with antiviral resistance. One is how many point mutations are required to establish a viral variant that’s replication fit in the setting of a given medication. With lamivudine it just takes one mutation, with adefovir, one mutation, and the doses of those medicines are modest. The blood levels and tissue levels are modest, therefore they also do not  have a substantial pharmacologic barrier, which is a second component. I think those are balanced. If they have a genetic barrier requiring two, three, or four mutations to impart resistance, such as you see with entecavir，also entecavir has a high pharmacologic barrier, very high tissue levels, very high blood levels. Also it’s potent; the issue of MIC is much lower than other compounds by a factor of 1,000. The other medication that’s emerging is tenofovir. We are not really sure about resistance profile. It looks like one or two resistance mutations might lead to tenofovir resistance, but because the dose is so high it has a very high pharmacologic barrier to resistance. So entecavir has pharmacology behind it and genetic barrier, tenofovir looks like it has a pharmacologic barrier that is substantial. That is exciting because I am expecting long term resistance rates to be in the 1% range with both of these medications.

Gish教授：通常抗HBV耐药主要由两方面因素。即耐药基因屏障与药理学屏障。首先是要看需要多少点突变才能使病毒在药物的压力下正常复制（基因屏障）。拉米夫定需要1个变异位点，阿德福韦酯需要1个。而且两种药物的给药剂量均为中等剂量，血药浓度与组织内药物浓度都为中度，所以这两种药物也不存在一个很好的药理学屏障。有些药物需要两个、三个甚至四个位点变异才能构成耐药，如恩替卡韦，另外恩替卡韦也有一个很好的药理学屏障，它有很高的组织浓度，很高的血药浓度，它的组织内的MIC比其他药物低1000倍。因此它的作用很强。另一个新兴药物是替诺福韦。对于替诺福韦的耐药情况现在还不甚清除，有可能需要一到两个位点变异来导致耐药。但是替诺福韦有很好的药理学屏障。



Hepatology Digest: What would be your approach if, for example, with entecavir or tenofovir if you encountered resistance with either one of those medications? What would your next step be?

《国际肝病》：如果您在临床上遇到恩替卡韦或替诺福韦耐药的患者，您会如何处理？

Gish: I would add the other medicine, the alternate medicine, because they can work together. There’s probably additive effects, additive antiviral effects, probably even synergy using entecavir and tenofovir together. So it’s actually a very good partnership.

Gish教授：我会加用其他的药物，其他不同类型的药物，这样他们能协同作用，甚至可能联合恩替卡韦与替诺福韦，这两种药物将会是很好的组合。



Hepatology Digest: You talked about compliance and it’s been talked about at the conference. It appears there is a bit of a difference between compliance issues in the east and the west. How would you approach it in this case if you suspect a compliance issue, from a western perspective?

《国际肝病》：本次会议上也涉及到抗HBV治疗用药依从性的问题。似乎东西方在依从性问题的认识上存在一定差异。您能从西方的角度给我们介绍一下吗？

Gish: I think the difference is not as substantial as some people are proposing right now. I think if you look across many licensing studies, non-compliance ranges from 10 to 30% depending on the complexity of the medications that somebody is taking. So, I think if a patient has a flat response to a therapy, they’re not clearing virus, or the virus has started to increase upon doing surveillance testing, I would do resistance testing at that point. If they have resistant mutations I would add a second therapy, but if they don’t I would reinforce compliance and reassess them in 1 to 3 months.

    Gish教授：我认为中西方对依从性认识的差异不像部分学者介绍的那么大。如果你仔细回顾一下几个大型注册临床试验，你会发现不依从的比例在10%~30%，与治疗方案的复杂程度有关。因此，对于我来说，如果患者治疗后应答不佳，未能清除病毒或出现了病毒的反弹，我会给患者进行耐药检测。如果发现了耐药变异，会给患者加用别的药物，如果未发现变异，我会加强患者依从性，过1~3个月后再进行评估。



Hepatology Digest: How do the various antiviral options differ in resistance profile? Does this difference translate to the choice of treatment for patients?

《国际肝病》：抗病毒药物之间的耐药情况有何不同，这些差异会影响到治疗药物选择吗？

Gish: I think one of the main issues we need to review is the rate of resistance. With lamivudine, long term rates of resistance are in the 60% to 100% range, depending on the study and the patient profile. Even with lamivudine, you may have high rates of e-antigen seroconversion, but many of these patients have now emerged with e-negative disease and resistance. So lamivudine’s got the highest resistance rate; we have a lot of data to support that. That’s why with lamivudine if the patient has not cleared virus within 1 to 3 months, you must commit to add on therapy with adefovir or tenofovir. Tenofovir is better, but harder to access in many countries. Telbivudine is just behind lamivudine, it also has a substantial resistance rate. The published data is 9% and 20%, but that’s got limited definitions. I think it’s higher than that long term. So, with telbivudine, if someone is not negative at 6 months or less, they need also to have add-on adefovir or tenofovir. So the roadmap is complicated with lamivudine and telbivudine because you have to add on adefovir or tenofovir at an early time point. With entecavir I am willing to wait 2, 3, or 4 years because the potency is substantial, PCR negativity is high, and resistance is low; but if somebody has lamivudine resistance and was switched to entecavir they need to have a very profound early suppression or I am going to add on adefovir or tenofovir in that setting. Adefovir is relatively weak and has a relatively high resistance rate so I am going to make a decision at one year or less. If a patient’s not negative at one year or less, I am going to switch or add on another therapy depending on resistance profile. If you’re on adefovir and you have resistance, especially with the 181, if you change to tenofovir you may fail in up to 50% of patients to clear virus at one year. That was published by Van Bommel at EASL recently. So, it’s complicated; you have to know your medication, have monitoring with DNA, use the simplest pathway starting with some medication like entecavir, and I am thinking tenofovir depending on the long term data. This makes it much simpler to manage the patient; probably cheaper to manage the patient, because surveillance is less frequent, there’s less concern about resistance, death, progression, and urgent transplant.

Gish教授：首先，我们需要回顾一下不同药物的耐药发生率。对于拉米夫定来说，视患者与研究项目不同，长期耐药发生率约在60%~100%。但是应用拉米夫定的患者，仍有相当比例出现了E抗原血清学转换，不过这些患者也可出现E抗原阴性的慢乙肝与耐药。所以现有药物当中，拉米夫定耐药发生率最高，这也是为什么应用拉米夫定1~3个月仍未清除病毒的患者要加用阿德福韦酯或替诺福韦。替诺福韦要好一些，但是目前在多个国家还很难评价。替比夫定仅次于拉米夫定，也有相当的耐药发生率。文献报道的耐药发生率为9%与20%，但是在对耐药的定义上有一些问题。我认为长期用药的耐药发生率还要高。因此，对于替比夫定，如果用药6个月或更短时间患者HBV DNA仍未转阴，也需要加用阿德福韦酯或替诺福韦。对于恩替卡韦来说，我会观察2~4年来决定是否换药，因为恩替卡韦抗病毒作用强、HBV DNA低于检测下限患者比例高，耐药发生率低。但是如果患者拉米夫定耐药后换用恩替卡韦，那就需要早期加用阿德福韦酯或替诺福韦了。阿德福韦酯抗病毒作用相对较弱，耐药发生率相对较高，所以我会在治疗1年或更短时间进行评估并考虑调整方案。但是在2008年EASL年会上，Bommel等报道了，阿德福韦酯耐药患者，尤其是rt181为耐药患者，换用替诺福韦有高达50%患者治疗一年仍不能使HBV DNA低于检测下限。因此抗病毒治疗是很复杂的，需要医生对药物有相当地把握。从最简单的方案入手，如恩替卡韦，另外从长期考虑，也可选择替诺福韦。这就使患者管理更加简单，因为监测不需那么频繁，而对于耐药、死亡、疾病进展以及紧急肝移植的忧虑也会相应下降。



Hepatology Digest: You have talked about surveillance and so when you are talking about cost that’s obviously a factor; not to have the patient just look at the cost of the medication. So, do you figure that in when you are doing patient education?

《国际肝病》：您刚才讲到了治疗监测的问题，实际上监测时检查的费用也是患者除药物费用之外的花费的一个重要组成，您会在患者宣教中谈到这些吗？

Gish: That’s a great question, and let’s look at this simply. If you use lamivudine, you know that at less than 5 years 70% of patients will be on combination therapy and you will have spent a substantial amount of money every 3 months doing DNA testing. Lamivudine plus adefovir is the same price as entecavir. If you add in testing, I think it’s going to be more expensive because you have to do more frequent surveillance. So entecavir is at least equal, maybe cheaper when you are looking at long term treatment, which is what we have now in 80+% of our patients. It’s really indefinite therapy.

Gish教授：这个问题很好，简单的讲，如果患者选择拉米夫定，不到5年耐药发生率达70%，所以你需要每3个月对患者进行HBV DNA检测并且一旦发生耐药还需要联合治疗。拉米夫定联合阿德福韦酯的费用与恩替卡韦费用相当。所以，加上检查的费用，拉米夫定治疗的费用可能还会比恩替卡韦要高。所以考虑到长期治疗，恩替卡韦治疗费用与拉米夫定相当甚至低于拉米夫定。这也是为什么我们有超过80%患者选择恩替卡韦的原因。

坚强胜利

Gish教授：一般来讲进入1B期临床试验需要3到5年时间，对于乙肝的基因治疗来说，这个时间是比较合理的。

一期都需要3～5年啊，等吧！