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.
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.
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?
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.
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.
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?
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.
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.
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?
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.