Summit dialogue Prof. Xinxin Zhang VS Prof. Keeffe

Hepatology Digest: The first question today is in regards to nucleocides analogues.  So with nucleocide antiviral drug treatment, what are the clinical criteria for diagnosis of antiviral resistance and how can we detect the antiviral resistant mutations?  Professor Keefe?

Professor Keefe: Well I think the traditional approach has been to have a baseline serum HBV. DNA level and then you have to monitor the patient at some regular interval, probably initially every three months with repeated serum HBV DNA levels.  They will typically fall with all of the oral antiviral agents and then will either become undetectable or will reach some low nadir level.  As the patient is then monitored every three or six months, resistance is defined by so-called “breakthrough” when serum HBV DNA level will increase by more than one log.  Now today in some countries although not everywhere around the world, we have access to actually measure for the resistant viral species through resistance testing.  So that is often performed as a confirmatory test to see if there is a specific mutation to whichever agent is being utilized.  There’s always a differential diagnosis when the serum HBV DNA level rises which is the fact that the patient may not be taking their medication, so in fact there is not a resistance virus they’ve simply become non-compliant for economic or personal reasons and are no longer taking their medication.

Hepatology Digest: Professor Zhang, Professor Keefe mentioned access to tests, can you talk a little bit in China and that testing and access in general.  Can you speak about that?

Professor Zhang: Yes, in China we also have the detection HBV DNA test done regularly about two or three months during the antiviral treatment especially in the big cities.  But in some small cities or small hospitals, DNA commercial detection kits may not be available.  However, detection of the genetic mutation is not very popular in China because of the reagent.  It is too expensive and not very popular but for DNA detection it is quite popular.  So we based it on the breakthrough of DNA to monitor the antiviral therapy and monitor the appearance of mutation.

Professor Keefe: And I think it’s perfectly adequate to do it that way.  There’s a sequence of events that occurs when resistance develops and that is first of all the development of a resistant species that becomes the dominant virus within the patient but then that’s followed by a raise in the serum HBV levels and then later a raise in the ALT level and potential clinical deterioration.  So if one intervenes at the time there’s a rise in the HBV DNA level there is plenty of time to map out a new strategy on how to best manage the patient.  Would you agree?  I think it is perfectly adequate.

Professor Zhang: Yes, and also I would also would like to ask Professor Keefe, in some patients, the patient has the breakthrough of the HBV DNA levels but the genetic mutation is negative so in that case what do you think about this?

Professor Keefe: Well that may be non-compliance or it may be that the fact that the assay that is used is simply not sensitive enough to detect that there is a beginning emergence of a resistant viral species.  It just may not be dominant enough depending on which assay system is utilized.  So I think it is quite reliable, particular it has been recommended that the HBV DNA level be repeated twice so that there is confirmation that it is rising.  And typically it is well more than one log over the lowest levels, typically two or three logs.  So if that is confirmed I think that’s very good evidence that there is fact failure of the drug – provided that the patient says ‘Doctor, I’m taking my pill every day’.

Professor Zhang: But really, we actually meet some – not many – but some patients who have good compliance and we have repeated the HBV DNA assays and we’re sure they have breakthrough but no genetic mutations.  I think even if there is some mutant strain as a minor strain in the serum of the patients, if it is not the dominant strain it could not lead to the breakthrough. 

Professor Keefe: Yeah, you may be right about that.  I don’t think we just have enough experience yet with the use of these tests to know for sure.

Hepatology Digest: We just mentioned in regards to treatment, nucleocides analogues.  It hasn’t taken place yet but there’s going to be a debate here at APASL, a pro and a con, and talking about when and if for stopping nucleocides analogues and discussing the APASL guidelines and other guidelines.  Professor Keefe how do you feel about that, what is your view?

Professor Keefe: Well I answer that according to two different patient populations.  For the patients who are Hepatitis B e-antigen positive I think the stopping rule in most of the international society guidelines has been to have a very low or undetectable HBV DNA on therapy and to have loss of e-antigen and development of e-antibody.  Now if the patient is being monitored every six months and that is detected for the first time, there’s also a common wisdom based on the Lamivudine experience to treat that patient for an additional six or twelve months longer to consolidate in the hopes to reduce to chance of a relapse when therapy is discontinued.  Now for the e-antigen negative patients, the philosophy of most of the international guidelines is long term therapy until we have new information.  And that’s because from all of the prior experience, even if HBV DNA levels becomes undetectable and therapy is discontinued, invariably there is a flare of disease and a rise in HBV DNA levels.

Professor Zhang: Actually, many doctors in China will have this question.  Even if we have the APASL guidelines or even Chinese guidelines but still they have questions about when is the end of treatment, even in the e-antigen positive patients.  Even if we continue the therapy after e-antigen sero conversion for one year we still have some relapse.

Professor Keefe: Yeah there is some relapse for sure.

Professor Zhang: Which is better?  To continue the therapy without stopping, or we stop until the disease relapses and then we treat the disease again.  Which is better?

Professor Keefe: Well I think in a patient that has relatively mild to moderate liver disease I think there’s a reasonable safety to stop there because they’re not likely to deteriorate.  Clinically if there should be a relapse back to e-antigen positivity with a rise in DNA and even a flare in liver disease.  On the other hand, I’ve developed a habit in my practice and I see many of the guidelines suggesting if there’s cirrhosis or advanced fibrosis in a patient who is e-antigen positive that therapy should be continued even after e-antigen sero conversion, and I agree with that.

Professor Zhang: Yes this is sure for the cirrhosis patients.  We will continue this antiviral treatment without stop.  But for others, general chronic Hepatitis D without cirrhosis, some doctors even patients, they think maybe continue with no stopping.

Professor Keefe: Well I don’t think it’s the wrong thing to do, at least from our experience so far somewhere between 60 and 80 percent and maybe even as high as 90 percent with Adefovir, when therapy is discontinued after e-antigen sero conversion that they’ll have quiescent disease on a long term basis.  So I think in my own viewpoint there’s no right or wrong answer here, I think either strategy is probably adequate.

Hepatology Digest: And perhaps it might also come down to considering the individual patients.  I know obviously in the US if we’re lucky we might also have insurance to cover it, you might also want to factor that in as well I’m assuming also as far as financial considerations.  All things considered.

Professor Keefe: Yeah sure absolutely.  And it has been recognized that if HBV negative is not totally undetectable, there is still maybe some residual risk of disease progression.  So it may also make a difference if the patient has not only lost the e-antigen and developed an e-antibody but has had for several years completely undetectable HBV DNA.  To me that provides a greater sense of confidence. Now the other information that has come out lately, although it was first published by Dr. Chu in Taiwan a while back and one of my colleagues at Stanford has also analyzed it is that patients who are e-antigen positive are not homogenous.  They’re quite heterogeneous.  Some of those also have populations of precore and core promotor mutant virus.  So they’re not pure wild type.  That maybe, although I’ve not seen any literature directly studying this, that those that relapse may be those that have a significant population that are precore or core promotor mutant along with the wild type virus.  This is relatively new information, in the last few years.  I think we still need to sort out the implications of this.

Hepatology Digest:  When it comes to quasispecies and HBV there seems to be from what I heard of it a bit of an agreement that HBV quasispecies is the same as an HCV they exist and how Professor Zhang, how do these quasispecies influence the progress of the disease in HBV, can you talk a little about that subject?

Professor Zhang: Well the HBV quasispecies is just like the HCV quasispecies.  It’s not clear what’s the function of these quasispecies.  According to some previous studies, maybe the quasispecies of HBV also play some important roll in the pathogenesis, or it may influence the outcome of the treatment, or even the efficacy of treatment.  For example it has been reported that the evolution of HBV quasi species during the e-antigen sero conversion and the interferon treatment the evolution of quasispecies may influence the efficacy of treatment.  Recently in our study we have looked at the quasispecies of HBV in patients before treatment and four weeks after Lamivudine treatment.  And we found very interesting is that is for these treatment patients actually baseline, the complexity and the diversity of the quasi species for respondants and non-respondances is the same.  No significant difference.  But after 4 weeks of treatment with Lamivudine, the complexity and diversity of the respondents becomes much lower than those of non-respondents.  Even after the HBV DNA is decreased rapidly during the early stage of antiviral treatment that means the patients may be respondent.  I mean he has become HBV DNA negative during the first three months of treatment, but the quasispecies complexity continues to increase not decrease.  Six months after that the patient has a relapse and the mutation appears.  So it is a very interesting phenomenon.  Maybe the quasispecies, the interaction between the different strains in the serum of the patient may influence the antiviral efficacy.  But I still do not know the mechanisms.

Professor Keefe: That’s very interesting, I wasn’t aware of that. 

Professor Zhang: Yes this work has recently been accepted by the Journal of Hepatology.

Hepatology Digest: Perhaps we will have to wait for further research into the actual mechanisms.

Professor Zhang: Yes the actual interaction between the quasi species.

Hepatology Digest:  Regarding the Roadmap Concept.  Some time has passed since the proposal for a Roadmap Concept, have there been any further advances made and Professor  Keefe, can you give your view in general of the roadmap concept?

Professor Keefe: Well the Roadmap Concept was really put forth by myself and my colleagues to draw attention to the fact that the patients who begin antiviral therapy need to be carefully monitored and we that need to look at benchmarks of when therapy has been considered satisfactory or not satisfactory.  Our guidelines that have been published at the time that we proposed the Roadmap Concept didn’t really address so much on treatment management.  They address the concepts of when to begin therapy and when to stop therapy but not really how to manage therapy on treatment.  So that was the goal.  The largest data set that was available when we proposed the concept came from the Globe Trial of Telbivudine versus Lamivudine.  So the Roadmap closely applies to those drugs because we were able to carefully analyze those.  There were prior publications on Lamivudine and predictability of response and there were also a few prior publications on Adefovir.  Adefovir is a little unique because the response rate is a bit slower so decisions regarding adequacy or inadequacy of therapy can probably be deferred six months to one year.  Now if the Roadmap applies and how it might apply to some of newer drugs such as Entecavir and Tenofovir I think are uncertain.  I know my colleagues from industry who are involved in those companies tell me those drugs are so good they can be started and then you can forget about it.  Now I think that’s a little glib, I’ve certainly had patients who have failed on those drugs but it is much less usual to have problems with those drugs because they have high potency and a low rate of resistance.  So again the Roadmap Concept I think doesn’t universally apply and has to be interpreted based on the different drugs which are utilized but it was helpful at least at the time we proposed I think for the existing therapies.

Hepatology Digest:  Your thoughts Professor Zhang?

Professor Zhang: I just wondered what do you think about why for some patients after antiviral therapy with nucleocide analogues, at the beginning almost all the patients have a decrease in HBV DNA.  For example from ten to seven or eight, or ten to five or ten to four.  At that stage it stops at that stage.  What do you think about the reason for this phenomenon?

Professor Keefe: Yeah I’ve thought about that long and hard as well.  I really don’t know, I have no idea.  And we often use the term “a sub-optimal response” to apply to a patient like that. Now in the early days when antiviral therapies first became available, we were quite excited if we could use a drug like Lamividine, which was the first drug we had access to, and drive the viral load down from ten to the 9th, or 10 to the 5th or 4th.  We though that was terrific, we thought we’d done a very good job for our patient.  Well we learned later that that was not  really wasn’t fully adequate because thought there was benefit initially that resistance had a high likelihood of occurring with some loss of the benefit.  But why that occurs that’s a long answer to your short question, I really don’t know.

Hepatology Digest: This next question is a bit, I’m not sure, but I’d like to ask anyway.  When choosing antiviral drugs for women of childbearing age, should we consider the value of HB surface antigen more seriously or more strenuously, either one is it an issue?

Professor Keefe: Well I think its one of our challenges on a day to day practice is how to best manage the young woman who has Hepatitis B meets treatment criteria based on elevated HBV DNA levels and elevated ALT levels but who wishes to be begin a family.  I mean there are a number of options  One is to use pegylated interferon which you alluded to as a potential, defer beginning childbearing for a year or two and see if there can be achieved a sero conversion from e-antigen to e-antibody.  The other option is to make use of a liver biopsy or non-invasive testing to confirm that there’s relatively little liver damage so the woman can go ahead and defer therapy for a couple of years while she initiates a family.  And then there other complicated factor is that does the woman want to have one child or four children?  That’s less than an issue in China I understand but in having one child I think is a bit easier because many people can have therapy deferred for a couple of years.  So we know that some of our drugs are available, Telbivudine and Tenofovir are pregnancy category B so there’s a greater safety threshold for our patients.  But most young women would prefer to avoid any drug while they’re pregnant, just to avoid any potential risk to their child.  So there’s no easy answer, I struggle nearly every day with the best approach.  I don’t know if you have any insights for me on how you manage this in China?

Professor Zhang: Yes I think it is a difficult situation.

Hepatology Digest: It’s always going to be an issue I’m sure.  One final question I had today, what about as far as Hepatitis B and C and comparing the progression of the disease and the natural history, and between those two Professor Zhang, can you talk a little bit about the natural history?

Pro Zhang: Yes, it’s different between Hepatitis B and C.  Because after the HBV infection, only 5% patients when if infected during the adult age will evolved into a chronic or even cirrhosis.  But for Hepatitis C, it’s about more than 50% or even 70% will evolve to chronic. Actually in Chinese clinics we meet many many hepatitis B not hepatitis C.  So my impression is we talk a lot about hepatitis C but in clinical, in china, we don’t meet so many patients, but for hepatitis B yes. This very reason maybe because in hepatitis B there’s vertical transmission in China. If the infection occurs during the natal age, many many immuno tolerances can lead to the chronicity. 

Professor Keefe:  Another point I’d like to make about the natural history, is that Hepatitis C when it comes chronic after infection, tends to have a relatively linear progression that’s slow over time, like hepatitis B.  it may accelerate a little bit with older age pass the age of fifty-five or sixty.  On the other hand Hepatitis B may have a more variable natural history because there is immunotolerance phase when there’s no active disease and then there’s a period of disease activity during the immuno clearance phase sometimes around the age of thirty or forty or so that may be brief or may be prolonged then there is a period of quiescence, the inactive carrier, but then there may be reactivation.  So Hepatitis B is considerably more complex in natural history for those reasons compared to Hepatitis C.

Hepatology Digest: Professor Zhang you just mentioned the vertical transmission.  How are the efforts progressing in China to prevent and what’s being done to help prevent that?

Professor Zhang: I think its the vaccination.  Yes, we vaccinate all the babies since 1992.  The prevalence of HBV infection has decreased remarkably during the past ten years, more than 10 years.

Professor Keefe: We’ll be out of a job in a generation.