Summit dialogue Prof. Guiqiang Wang VS Prof. Edward J. Gane

Hepatology Digest:Professor Gane, in your talk today 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? 

Dr. Gane: When we are talking about re-treating patients with established anti-viral 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 to 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. 

Hepatology Digest: And Professor Wang, can you give us some of your views on that?

Dr. Wang :Yes, Yes, we have the same ideas.  After the Lamivudine or Telbivudine with the roadmap concept we can add the 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. 

Hepatology Digest : So professor Gane, in that case would you say the same add-on: in the absence of Tenofovir add on Adefovir?  Would that be…?

Dr. Gane : For Lamivudine resistance? 

Hepatology Digest: Ah, right.

Hepatology Digest : You mentioned in your talk about partial responders; how can we finally really work 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?

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 to Entecavir resistance.  In one of my slides I suggested that 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 potent drug, or Telbivudine, a potent drug, may be preferable to add-on purely for the cost aspects.

Hepatology Digest: I have a question for you…
 
Dr. Gane: Yes.

Hepatology Digest: If all these drugs are first-line treatment, what is your priority for Lamivudine or Telbivudine or Entecavir in patients?  Which is your choice, in general?

Dr. Gane: I think it depends on a lot of baseline factors including whether the patient is e-antigen positive, in which case you are looking at trying to achieve e- antigen sero-conversion and therefore a finite course of therapy.  Compared to e-antigen negative patients where usually you start treatment you are committed to long-term therapy.  I think if you are treating an e-antigen positive patient with an oral antiviral, you’d be looking at using an agent which may have a higher rate of e-antigen sero-conversion.  In that situation, of course, Telbivudine would seem an attractive agent.  Realizing that Telbivudine does have a higher rate of resistance than Tenofovir or Entecavir, if you are going to use Telbivudine as a first-line agent in the hope that you will achieve a higher rate of e-antigen sero-conversion -- and therefore shorter duration of therapy – then that would be the ideal agent in which to use such a roadmap concept.  So, use that 24 week response to determine whether that patient should continue on Telbivudine alone or should be thinking of adding a second agent. 

Dr. Wang: OK, yeah… I agree with you

Hepatology Digest :How about in the case of – perhaps I’ll ask you professor Wang – what about an agent like pegylated interferon or other agents: can we apply the roadmap concept to an agent such as that?

Dr. Wang: Yeah, sure.  All the drug should have a set of roadmaps, but until now for interferon it is not yet established.  There are some data and literatures showing that 12 weeks or 24 weeks may be the point for evaluation for prediction, but, there is not enough data to support the use clinically.  But in my hands in China, we use a similar roadmap of interferon.  If we treat patients with interferon alpha 2b or 2a with half a year of non response, then we just change the nucleotide analogs.

Dr. Gane: Right.

Hepatology Digest: Would you say the same as well professor Gane?

Dr. Gane : When we do use pegylated interferon we tend to use a finite course.  There is not as much data on HBV DNA as being a predictor; there was one small study in e-antigen negative patients.  I think people that interesting in looking at other sign-posts for predicting -- such as quantitative e-antigen, surface antigen – I think we need more data.

Hepatology Digest: Some time has passed since the original proposal of the roadmap concept.

 Dr. Gane: Yes.

Hepatology Digest: So, professor Gane, what advances have been made on it, and perhaps at some of the meetings since: what has been changed if any, and with outlook on it?

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 Navada (Navata? Nevada? (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. 

Dr. Wang: Yes.  The road map is good.  In China we also think about the roadmap as practice guidelines.

Dr. Gane: Yes. 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 ????...
 
Dr. Gane: So what is the cutoff for that? The cut off is: the liner reach is from 10 to 3 to 10 to 8.

Dr. Gane: Right.

Yeah.  After 10 to 8 it is not exactly dependable. 

Dr. Gane: Yes. So, the roadmap is based on clinical trials of Telbivudine, but in China it should be more defined.  It will take time, I think.

Dr. Gane: Yes. It is a problem for Chinese doctors. 

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

Dr. Gane : Well, 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 predictability will not be as great.   

Hepatology Digest : I’m curious again professor Wang, and this is regarding fibrosis, when we are talking about current liver fibrosis markers…

Dr. Wang: Yeah… When reflecting the liver function or degree of fibrosis, we know that they are not liver-specific.  So from your experience, could we get more sensitive or more specific diagnosis through a combination of these markers?

Dr.Wang : Yes, we are dealing with non invasive fibrosis assessment.

Dr. Gane: Right. We just try to use FibroTest from France.  Yes. In chronic hep-B, because most of the chemical markers or panels are based on HCV infection, not HBV infection – only a few studies have done HBV.  So, we tried FibroTest in Chinese patients and it seems to have worked to assess the liver fibrosis in chronic hep-B.  But not as good as ???? in hep-C because the sensitivity is a little bit lower.  So now there are some other biochemical markers, panels, generated by Chinese doctors:  including our department to generate a new one; and from Beijing Friendship Hospital, professor Jia’s group; and also from Shanghai, professor Zhang’s group – all to generate Chinese models based on Chinese patients.  It seems to work on chronic hep-B – the sensitivity and specificity – but we still need to do some further study, to do more multicenter motivation (????) work.  I think the combination with the biochemical marker and Fibroscan is best.  Some reports show that Fibroscan and FibroTest combined can promote accuracy.  

Hepatology Digest : What about the accuracy, professor Gane, I mean, what do you think about this approach and do you have anything new…?

Dr.Gane : I think it is important to try to develop noninvasive methods of assessing the severity of liver disease, in particular whether a patient may have cirrhosis or not.  Because that very much determines how you monitor the patient, especially with complications such as hepatocellular carcinoma.  I don’t personally have any experience with FibroTest, but I am aware of the lot of the data, and as I pointed out a lot of that data is in alcohol and hepatitis C. The Firbroscan data looks very interesting.  The data in chronic hepatitis B appears to be very good, provided the patients are not having acute flares of hepatitis B. 

Dr. Wang: Yeah, sure, sure.

Hepatology Digest: Do you have any experiences with Fibroscan?

Dr. Wang : Yeah, yeah, right.  Recently there was a clinical trial in China. It was a multicenter clinical trial for Fibroscan conducted by professor Ji-Dong Jia.  In it in a total 260 patients are included by now.  It seems it is good for the assessment of liver fibrosis in chronic hep-B.  But it is influenced by many factors, as just mentioned by Edward:  acute hepatitis, elevated – very high – ALT levels, ????,

Dr. Gane: Yes. Obesity and even high bilirubin can influence the result of fiber scan. So, it seems Fibroscan has limitations. 

Hepatology Digest : And one final question today, Professor Gane, obviously this year APASL is in Hong Kong and next year in Beijing; how have you seen -- what are some of the things you have seen as far as the research coming out of China? I’m just curious about your general opinion and what you think, perhaps is the future in cooperation with courtiers such as Australia and New Zealand and some of the research that is coming out of China, maybe in chronic hepatitis B or in other areas in… 

Dr. Gage : I think certainly the growth of clinical trials within China has been very important, and the amount of data which China can supply to the world – really, I think,  with large numbers of patients, new strategies of treatment  with new agents – it is going to be very, very important for the future.  And certainly over last decade the numbers of good, high quality studies coming out of China have risen exponentially.  Now I think that China has a lot to offer the rest of the world when it comes to the management of hepatitis B and other aspects of herpetology such as hepatocellular carcinoma. Some of the new data of Chinese studies of comparing different forms of oblation in combination with hepatocellular carcinoma I think are very important data.  I would hope in the future that the Chinese herpetology community will contribute to the advancement and knowledge of hepatitis C given the large numbers of hepatitis C also in China. 

Dr. Wang : Sure.  There are many patients both with HBV and HCV infections.  Especially we have very much emphasized the HBV infection. In fact we neglected HCV infection.  The epidemiology data from 1992 has shown me that there 3.2% HCV in China.  But now we don’t know how much.  But from the clinical practice we have not seen a lot of HCV patents.  But patients with HCV patients always have cirrhosis ???? disease.   I think the screening system needs to be promoted.  Just screening the HCV antibody to find the patients, then they can be treated and monitored and to do something for them. The government has given a big grant for HCV infection in China.

Dr. Gane: Yes. We have many plans, including the combination treatment trials and the individualized treatment.  Also some studies on the natural history of Chinese patients and imuno-???? treatment.  So I hope in the future that Chinese doctors can contribute more.

Dr. Gane: Xie xie. But I suppose we need the support from all over the world. 

Hepatology Digest : Certainly over the last decade China has become the major force within this Asian Pacific Association, and I certainly hope that the small countries – such as New Zealand and Australia – are able to collaborate with China in the future. 

Dr. Wang: Sure. More and more.

Hepatology Digest: Thank you both for joining us today, it was a real pleasure

Dr.Gage:  Thank you