“When we will have the new HCV drugs which are in development, when they will came to market, it will be on us –clinicians, scientists together with the patients- to further optimize also these new tools- tell to me with emphasis Heiner Wedemeyer, managing senior physician and assistant professor in the Department of Gastroenterology, Hepatology and Endocrinology at Hannover Medical School. We are living the beginning of a revolution –the new story of HCV therapy thanks to DAAs, but I would like to start this conversation speaking about the possible “end” of the story: the future of hepatitis C treatment… “I think the future of hepatitis C treatment will be the same as we have today, and this is individualized treatment for each patient. Right now, we are using protease inhibitors in combination with ribavirin. For the first time the labels of these new compounds include already the concept of response-guided therapy, which does mean that in some patients you may have a shorter treatment duration, in others you need a longer treatment duration.
Obviously the benefit is to enhance response rates in each individual patient, also to save costs, to reduce the burden of treatment, to reduce side effects and thereby to optimize treatment in each patient. This concept is now part of the label, but I see that the future of hepatitis C treatment will even further expand this concept of personalized medicine: individualized treatment for each individual subject. Obviously, we would like to have a treatment one-size-fits-all, let’s say for three months one pill a day and we cure all patients. But what we have learned over the last six months and what we have listened during this EASL meeting in Barcelona, is that most likely for some patients this may work but I think that hepatitis C is a disease where we will need to optimize treatment for each individual patient, and this should be possible. The future of HCV treatment can be quite interesting: some patients may be cured with a very short treatment duration, other patients may need a longer treatment duration, and this is based on the compounds we are using, and also this is based on in- dividual patient profiles, including certain their characteristics like, genetics, age and, very importantly for us being hepatologists, liver disease. The stage of liver disease matters. We already know this for interferon-based treatment: patients with more advanced liver disease, liver cirrhosis, fibrosis, they show rather poor response to the current treatment. This also holds true in the context of triple therapy, where interferon/ribavirin is given in combination with the protease inhibitors, so the protease inhibitors are not able to overcome interferon non-responsiveness which is more a problem in patients with advanced liver disease. So, the future will need to show whether the same also holds true when we have more drugs available, but this is on us to investigate.

We are living is a changing paradigm. We should describe this try to figure out how “old words” have now different meanings. For instance, we could start from “naïve” patient…

Well, old words have different meanings indeed, the paradigm will change. We have, let’s say, patients that have been treated with interferon or untreated patients: the response to treatment needs different terminology, the patient characteristics need to be studied in a different context whether the old classical characteristics – old patients, young patients, men, women, different racial backgrounds they also have the same meaning in the context of the new treatments. I think most likely certain characteristics will also be important in the future, while others will be of less importance. The same holds true for patients that may have been exposed already to interferon and ribavirin or the new protease inhibitors, and there an additional player may become important and that is the type of response to this previous treatment.
So, by treating patients we are changing the patients.
First of all, you are changing the virus. A protease inhibitor, if treatment failed, causes resistance: when does this wild-type virus come back? Does this resistant virus somehow is maintained at a higher level and therefore impacts future treatment? In addition, when we are exposing patients to interferon/ribavirin, this may also have consequences for subsequent treatment: again, the virus is changing but also the host is changing when you expose them to such, let’s say, strong treatments for rather long time. The detailed importance of these respective factors, again, have to be studied in the context of the different regimens to be tested in future.

Do you think we need -and is another word- a different “nomenclature” of the drugs?

We have different classes of drugs. We have direct-acting antivirals, which mean that really the virus is targeted specifically by the mode of action of the respective drugs, and then we have drugs which target, for example, host enzymes; then we have drugs that are somehow altering the immune system and are aiming to enhance immunity against HCV. Terminology is important for drugs, but terminology will be also important for assessing treatment response. Currently, we are using in hepatitis C terms like “Rapid Virological Response”: “rapid” is defined by week 4 response, which is quite frankly ridiculous, because a rapid response in these days, in 2012, I consider response much earlier than after 4 weeks, or Early Virological Response, at week 12, which is currently the end of treatment in most treatment regimens.
So, we have proposed a new nomenclature determining treatment response which is more descriptive based on treatment week and the level of virological reduction.
This new terminology should also allow us to compare different trials, to compare different treatment regimens and really to judge whether in the end one treatment is better than the other.

Another word that is critical is “assay”.

We are right now determining in-treatment response by reduction of viral load in these patients and then we have the endpoints or the interim points of suppressing viral replication. Biologically, we have to keep in mind that all these assays that try to detect viral loads have slightly different performances: this may have major impacts in the context of treatment response or response-guided therapy.
For example, if a patient is negative after 4 weeks of treatment, then you can shorten treatment duration according to the current label, but negative may be different between different assays. I think all the clinical investigators, as well as the companies which are providing us with different assays, have really come to a consensus that we do not overtreat some patients. I don’t want to expose patients unnecessarily to another 24 weeks of interferon treatmen,t which really impairs quality of life, simply based on differences in performance of assays.
On the other hand, I don’t want to risk that a patient who has gone through a hard therapy is experiencing a relapse, because I am treating him too short because my assay was not applied in an appropriate way at certain time points during treatment. This is what we also learned during this EASL meeting: that indeed assays matter and that performance matters, but also we as doctors have to learn to read the assays in the right way: it is not only that assays differ, it is on us to understand the assays.

Another word that is different is now “clinical trials” because we should now to design them in a different way.

Clinical trials are always a challenge to be designed in the best way for the patients, but also the companies have to fulfill requirements that are set by the Agencies. FDA and EMA have to follow rules, they have their own standards internally, obviously aiming to that only safe drugs are at the end approved and licensed. This agencies have their standards and for hepatitis C. Again, we are right now observing a paradigm shift which is quite fascinat ing. One paradigm shift was over the last two-three years, that we can now test two investigational products at the same time. It was unbelievable three, four, five years ago, we could only test one compound in addition to whatever standard-of-care and now in hepatitis C. Now we are testing two compounds at the same time and I have seen protocol proposals even testing three investigational compounds which have not been licensed at the same time: this is a change in paradigm. The future will need to show whether also we see changes in trial design, in terms of our comparators. Because we have a problem in hepatitis C: sometimes you start a program and you tested against an old comparator which at that time was the standard of care, then in between you have a new standard of care which gets approved and then already the next generation of treatment regimens is in clinical development. So it’s for us quite hard to design the trials and then to go through this, when at the time of finishing your trials your comparator is no longer the current standard of care. We have to think about concepts how to overcome this problem, and obviously finally ,the patients wish that we have fast trials. I don’t want to go for a trial that takes two, three years before everything is analyzed, finalized, etcetera, because obviously this would delay drug developments. I am seeing patients dying from hepatitis C every week and these patients don’t want to wait for long-term trials.There there is a lot of discussion how we can basically speed up drug development without taking too many risks, because also for all the HCV drugs, with all the excitement of the new response rates, of the possibility to cure patients without using interferon, we still have to keep in mind that you have to follow the standard rules. I don’t want to expose my patients to unexpected side effects, I don’t want to expose my patients to unnecessary risks: therefore we have to balance risks but also needs of these patients, which always is something which needs to be discussed, and there is ongoing discussion.

Another word that you anticipated now has now different meaning is “time”.

Time is always an issue. During the old days, we have been treating patients for 48 weeks, sometimes for 72 week. Now we have learned that you may cure HCV in 12 weeks, maybe in 8 weeks, in some patients we have the suggestion that you may even cure chronic hepatitis C infection in 4 weeks, which is I think quite fascinating.
So, the treatment duration will differ between different patients. An other aspect related to time is the time waiting for until the new drugs will become available: does a patient have time to wait or is there not enough time to wait for?. Treating liver diseases, we are quite fortunate: not in every patient, but for many patients we have time, and we should not overtreat patients too early, to expose them to side effects of interferon.In some patients it does not really matter if you start treatment next week, in one year or in two years. On the other hand, there are patients for whom time matters. I don’t want to not treat a patient and then see that this patient will develop hepatocellular carcinoma in one year. Again, it’s time of personalized medicine. It’s individualized treatment: you have to identify the best time point for each patient to initiate treatment, based on the drugs that are available at that specific time point.

Another word with different meaning is “strategy”.

Also treatment strategies will differ in future. We will have completely different strategies, different concepts to treat hepatitis C virus infection. One concept, one strategy is simply to block HCV replication and thereby to cure HCV. A completely different strategy is to use treatment that is based also on enhancing immune responses against the virus. We may even combine these different strategies in the future to further optimize treatment and, finally -I am coming back to this again- I think the strategy of the future will be to individualize treatment of hepatitis C virus infection based on individual patient characteristics, based on specific properties of the respective treatment regimen to be studied.

You open the door to another word of our new lexicon: “safety”….

Safety comes first in drug development. I mentioned this already: we should not expose our patients to unnecessary side effects of the current treatment, and the current treatment has safety issues. As we have learned in the recent months when patients with more advanced liver disease have been treated with a triple therapy of protease inhibitors plus interferon plus ribavirin, if you treat patients with more advanced disease, the likelihood that these patients can experience a severe infection, that they may die from this treatment is obviously higher. We have to select these treatments very carefully, not exposing our patients to unexpected side effects, unexpected safety issues using investigational compounds. Fortunately, so far the safety profile of the new compounds seems to be very good: I think we can give hope to our patients that indeed future treatment will be much easier and will cause less side effects. However, for most of the compounds we are still in Phase II or early Phase III and there are always surprises and some are bad also, this in drug development has been always the case, so before really giving too much hope, before, let’s say, putting the patient into positions where they don’t want to have anything else before the new drugs come, you always have to keep in mind some drugs may not make it to the market: safety comes first.

We are sailing in a crowded sea of choice, how to make “comparison”? That is another word that has now a different meaning.
As I mentioned before, we need to compare treatment responses between different drugs on very clear defini tions. The assays have different performances and the cut-off of responses needs to be defined. Is it that the virus is completely gone by the assays we are using, is it a certain threshold that we measure at certain time points?
This is something which is important during treatment, to compare potency of drugs. However, in the long term it’s easy for us, because we have a very good endpoint and this is cure, the virus is gone, and cure is the same goal for every treatment we will explore: every treatment strategy has only one goal which is cure. How to define cure? Currently, we are measuring HCV RNA 24 weeks after treatment has stopped. During the last year the FDA has approved another endpoint, SVR12, so cure after three months after the end of treatment is acceptable, which is fine. But I think we need to study also for the upcoming new interferon-free treatment regimens whether this holds true for every patient, or whether some patients may not experience a late relapse after 24 or 36 weeks. So, we have to do our homework, we have simply to follow these patients but, once this is achieved, I think all treatment regimens are comparable and the virus needs to be eliminated from the body.

Another hard word is “cost”.

Cost is an issue, my personal opinion is that we all working in the medical health systems have a responsibility to use the resources in the best way. Resources will be limited, there is no way that we can extend treatment cost for whatever and we all have to see that really: we have to pay every price in the end, if is any increase in cost to be justified also in the context of other health burdens.
I have never seen that a new treatment reduced costs, which is unfortunate, but obviously this is something we have to investigate. Just for example, right now we have two options: we have telaprevir or boceprevir in combination with interferon/ribavirin and these drugs have different costs and different treatment groups. I think it’s our responsibility to consider this in treatment decisions.
What the prices will be for the future treatments, we have to see and I think this is a discussion we should start again when these drugs are on the market.

We can say that from the EASL in Barcelona we are going to open the door to the real life for people with hepatitis C.

Well, real life treatments, you mean real using these drugs in real life right now. We can see that we should be very careful in just playing around with the drugs. Here we have to really follow the guidelines. My strong recommendation to all of my colleagues is that we don’t play too much around and if you want to use these new drugs in a safe way, also to use not to waste resources, you really have to follow guidelines. It’s our responsibility as being experts in the field, as being involved in society, to define the rules how these drugs can be safely used in patients with chronic hepatitis C.

When a patient arrives in your clinic, now knowing that there is a lot of future opportunities, how to make the right choice now looking to the next options?

Tthis is obviously a very important question and, as I mentioned earlier, we are now entering the phase of really individualizing treatment, of personalized medicine.
You have to discuss each individual situation with each patient. So, what is the medical need for treatment of this patient? Does this patient need to be treated now to prevent side effects, to prevent decompensation of liver disease?
On the other hand, we also have to consider what are the other circumstances for these patients. So, can they afford being exposed to interferon for 24-48 weeks?
May this have consequence for their profession? Can they still continue work? And, on the other hand, what is the patient wish? How much is the patient suffering from this infection and not necessarily from liver disease? And we are discussing this with each individual patient also considering and keeping in mind that new treatments will be available in three, two, three, four years, which hopefully will have less side effects and which will lead to cure…. We discuss this on an individual basis with each individual patient. This takes time, but this is also fan and this is a great opportunity to really have the best treatment for each individual patient and I think this is our responsibility as being doctors in this field.

Articolo presente in – HAART and correlated pathologies n. 15 –

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During the last EASL meeting, probably it was the study with the highest number of citation, because it was able to define the burden of HCV infection in our world, let’s say in real life. Supported by EpaC – the Italian hepatitis patient based association- the study has as first author Stefano Fagiuoli, director of the Gastroenterology Unit at Ospedali Riuniti, Bergamo.
The name of the study is COME, an acronym that sounds a word that is the Italian for “how”. How is an ad verb that indicate in what way or manner or by what mean something is going to happen; to what extent or degree; in what state or condition; for what reason; to what effect -with what meaning? How is one to interpret his action?- and the manner or way somebody couldn’t figure out how to solve a problem: in this case the problem is HCV infection. I think the name of the study, this acronym, is perfect for your study… “The idea of our study which is the COME study, which means Costs of Hepatic Disease, it’s an Italian acronym, was meant to try to define exactly what was the global cost both in terms of direct cost, indirect cost, medically related cost, liver disease-related cost and anything else that could be necessary to the patient, together with the indirect cost and the quality of life. This is a different approach, because I think that, as physicians, we need to be aware that we probably don’t need or are not obliged to take care only of the specific technical medical condition, but overall take care of the patient as a whole”.
A medical doctor need to be focused on the best way to treat his/her patient: why he should be interested in an evaluation of the cost of a disease?

First of all, I think we have to define what do we mean with cost of the disease. Most of the data available in literature are dealing with direct cost of the drug or hospitalization. I think it’s time to move to a different concept of what costs are. Specifically, cost for a patient means direct cost related to both medical condition, admission, drugs, but also what they usually and routinely spend to reach the hospital, to go and do their testing or to take additional medications or to have somebody taking care of themselves, maybe it’s paid assistance.
We have also indirect costs, which means they have loss due to disease, absenteeism or loss of productivity. Last but not least, we have to consider quality of life, which is a different cost, that patients have to pay for their disease.

From your study, it seem that hepatitis is a luxury that we cannot afford…

We have to consider several issues. First of all, do we know all the patients that are affected by a viral disease? The answer is of course not. So, we need to make them emerge and be aware of having an infection and define if that infection deserves a treatment. Then, the second question is: do we treat all the patients that are infected and have a condition that needs to be treated? And the answer is no, of course not: we are mainly undertreating those patients. As a consequence, this has by definition an evolution of the disease, in terms of cirrhosis, development of hepatocellular carcinoma and need for transplantation. The aim of our study was just to show that you can spend much more money when you are treating early disease, but then you are going to save a huge amount of money if you can avoid development of decompensation in end-stage liver disease.
Of course this is more a political or a socio-economical issue, rather than a medical issue and we are still in the phase in which we are treating a disease. If these data and this information will be confirmed in more advanced studies with a larger population, we may end up realizing that with a more effective drug could be cost-effective treating earlier disease or maybe even the infection but it means switching mentality from seeing the health system as a cost: if you see it as a cost you have to limit access to cure and contain the cost. But if you see it as an investment in health, then it’s an adjunct value to what you are doing. I think we need to have more information to see if we can adjust to a different point of view.

You said early treatment, in the natural history of hepatitis C the infection may be complicated in order to establish what means early.

That is exactly why I am trying to put the discussion to an extreme and discussing about treating disease or treating the infection. We know that most of the infection will lead to a chronic liver disease but not all of this chronic disease will lead to an end-stage liver disease, but we have to consider that times are changing, as always, and metabolic disease and alcohol consumption are actually re-increasing in our society, especially in the Western society, so this may actually imply that having co-factors adding on the same issue, which is viral hepatitis, you may actually see an even more important evolution of the end-stage liver disease. So, my point is if we have effective drugs then we can consider dealing with this disease treating more patients to avoid evolution.
Up until now, we didn’t have effective enough drugs to achieve this goal and so there was no point in treating everybody having less than 50% success, but if you can reach a higher success rate, then it gets costeffective to treat everybody and of course it’s an investment in health which probably is very difficult to get accepted in this economical period.
The results, some results of the studies presented here claim that a sustained viral response at 12 could be a measure but we have also 4 weeks of sustained viral response, that means thanks to this different evaluation and the new drugs we can reduce the time and drugs and have a more good economic outcome?

Of course, the issue is very simple in that way, if you have a short treatment which is very effective, and we are very close to this because with hepatitis B we can achieve almost 100% success but we have to treat lifelong.
Hepatitis C, which was the worst condition because we could achieve success in less than 50% of the overall population, now seems to be aiming towards a situation in which in 4 or maximum 8 or 12 weeks in a few years there will be available drugs that will let us treat a larger number of patients with success. This will change the picture in terms of cost-effectiveness of the treatment because it will cost less and will be more effective and of course we could not afford to treat now for 12 months with these costs all these people, so it needs to be adjusted, of course.

As we said, the name of the study sounds “come” that in Italian means “how”, can now you describe the study?

It is a very simple study. We enrolled all consecutive patients admitted in our unit for any condition related to liver disease and with any kind of admission, which could be hospitalization, daily admission or outpatient clinic. At the enrollment patients were asked to fill up an assisted questionnaire -there was a physician assisting them in filling the questionnaire- which was basically building up the 6 previous months history of their liver-related disease and taking into account any possible direct and indirect cost, like we were saying. Then, they were asked to fill up a EQ-5D questionnaire for the quality of life and then to fill up a questionnaire dealing with what was their feeling about their wellbeing, and this was done for a period of about 8 months.
We collected more than 1,000 patients and we built a sort of a trend in expense according to chronic hepatitis, cirrhosis, hepatocellular carcinoma and liver transplantation, according to etiology of the disease and being successfully treated or being under treatment. What comes out from the study is that the management of chronic hepatitis who is being treated and is a full time responder to treatment ranges around 3 to 400 Euros, however if you aim at treating a patient which is already transplanted the cost for this patient is going to be 5- or 6-fold higher, so these are the numbers that came out from the study.

This is a policy maker issue. But decision makers need to be advised by expert. There is a study published on Plus One (1) that evaluated the method that politicians or decision makers decide or define the expert to be enrolled in commissions and very often the greatest part of the experts enrolled by politicians are not chosen on scientific evidence, for instance by the number of papers published and so on, but only through direct contact. In your opinion, how could expert be enrolled in the process of decision making? A study like your study –scientifically founded and supported by EpaC, the main community based organization in this fieldcould be a good tool in order to define where we should to go…

Well, I think it’s quite a complicated matter, I don’t want to put myself in a bad position, but the habit usually: if you are put by somebody in a position, then you become an expert for that. In an ideal world, you have shown that you have some expertise, then you should be in that position, that is the way it should work. I think what we should choose centers that are dealing with these patients and audit those centers to see who is appropriate in diagnosis, treatment and management.
Then when you have done this, combined with people that are publishing results or producing results in that field, then you can select a sort of a population of experts, but that’s the ideal world…

In Italy, we are in some way lucky because the Italian Association for the Study of Liver published an expert opinion paper (2) on the direct antiviral agent.

Yes, we are lucky but at the same time it’s a little bit confusing the situation, for a very simple reason. If you are dealing with viral hepatitis in any European country, Spain, France, England, Germany, you have a very restricted number of experts which are dealing with that issue. When you are dealing with Italy, you have dozens of experts and that’s not a good thing, but is our problem I believe.

Too much is not enough.

Exactly. I mean, in Lombardy, in my Region, we have 91 prescriptor centers for viral hepatitis, so that’s not the right way to do it, it should have hub-and-spoke centers to deal with this, if you have a thousand of prescribing centers you can’t control quality.

Articolo presente in – HAART and correlated pathologies n. 15 –

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“We are considering the stakeholders that are involved in the management of the clinical condition of hepatitis”: well said Markus Peck-Radosavljevic, Associate Professor of Medicine at the Department of Gastroenterology and Hepatology at the Medizinische Universität Wien, Austria, in the speech he gave during EASL meeting in Barcellona, where I met him.
A medical doctor usually works on patients or on scientific perspectives directly related to an agent that causes the disease. Why is it important to think about stakeholders, when you are speaking about hepatitis?
As a medical doctor, my main interest is my patient but, as a official of a scientific organization that is engaging not only in science, but also in political action and lobbying for a certain disease, like in our case liver disease, for me it also important to talk about the other stakeholders. This is the reason why EASL is becoming more and more interested also in things like epidemiology and therefore we are interested in public action, in political action and in also teaming up with other people involved in the field like patients organizations.

Numbers and figures about viral hepatitis are absolutely impressive. We need to understand the facts that are beyond these figures…

The numbers are fairly high but the numbers are also highly variable, even within Europe and especially globally. If we concentrate on Europe you will find countries where you have not such a high burden of viral hepatitis, especially, with incidences or preva where the prevalence is 10%. Some countries are just ahead in the management of those diseases, and this has historic reasons.

EASL puts emphasis on societal liver disease burden in Europe. What it means?

If we refer to numbers and figures, the two most important clinical condition related to liver are alcoholic liver disease and viral hepatitis, and the third most common is probably non-alcoholic fatty liver disease.
Those are the three diseases that make up the vast majority of patients with liver disease in Europe. We feel that we really have to work for all of them, but especially in viral hepatitis there is also other parties who are very active, like the industry and the patients organizations. In other areas, like in alcohol and nonalcoholic fatty liver disease, there is not so much interest from other stakeholders and for that reason we are very actively engaged in those areas.

Speaking about viral hepatitis, what kind of dimensions are evaluated in order to define the societal burden?
On the one hand the problem is that we don’t have a clear idea how many patients are really affected by viral hepatitis. On the other hand, viral hepatitis, as opposed to other causes of liver disease, is fairly easy to detect because screening just works with a little blood, as opposed to alcoholic liver disease and nonalcoholic liver disease, where you don’t have a simple test. So, that means actually if you want to start a screening and an early detection effort, viral hepatitis is actually an ideal candidate because we have a very good and easy, not very expensive test and with that we could find probably most of the patients if we would try.

We know that now we are treating only the peak of an iceberg. One hundred years ago the Titanic crashed because of an iceberg, now we are in the condition to treat, thanks to the new drugs, people with hepatitis C but the risk is that the financial crisis and the cost of the drugs cause a crash for public health…

Well, there is some danger but I don’t think there is immediate danger and, for one very important thing: not every patient with viral hepatitis needs treatment.
It’s estimated that only 20 to 30% of those patients actually will ever suffer any harm from their liver disease. The problem at the moment is that it’s not so easy to define who will actually run into problems and who will not. Of course the search is also on for other markers, to better define patients at risk vs. patients not at risk, but this is something also for the future. For the moment, at the present, it would be already very good to detect all the patients and then we can consider whom we want to treat. I really want to point out that actually by an Italian study that has been featured here at the Conference it was clearly shown that most of the cost that comes from treating patients with liver disease, more than half of them comes from hospitalizations, and hospitalizations always occur late in the disease stage. That means yes, it’s going to be more expensive if you find more patients and treat them early, but you will also save significant cost because you will have a lot less patients with advanced-stage liver disease, so in the long run I think it will really pay off to do this.

Efforts of researcher are focusing on the possibility to define markers that could shorten the period in order to define as early as possible the results of the efficacy of the therapy…

Well, you know, everybody is trying to shorten treatment, because all these treatments cause side effects.
If you have them for shorter periods of time, it’s much more easy to take for the patients. Shortening the follow-up has also an advantage for drug development, because if your follow-up is shorter you get your results earlier and that means you can move on with drug development much faster. So, the combination of shortened treatment durations plus shortened follow-up will help us a lot in finding out which of all these new substances are actually really good treatments and which of these substances are not worth pursuing.

Now we are speaking about 4 weeks…

Yes. think this has to be validated, I mean you have to compare the outcome of SVR4 with SVR12 and with SVR24, but I think there is a good indication that for the direct-acting antiviral drugs SVR4 could also be a good time plan and, if this holds true, it will be great.

The problem we have now is there is a lot of population still in need of therapy are not elegible to these drugs, or at least we don’t have enough data…I am thinking about patients co-infected with HIV or transplant patients or people that are in advancedstage of the disease.

Yes. For those patients the problem are the drugdrug interactions, so this has to be rigorously tested, so we understand that there is a great need and we really would like to treat those patients, however it has to be done safely. As we know for the two drugs that are protease inhibitors that are in the market right now, especially for one of them, it has a lot of drug-drug interactions, so it’s really important to check out what can be really used for treatment of these patients. But as treatments durations will get shorter, for example for the co-infected cohort, you could also think about like stopping your antiretroviral treatment for 3 months treating hepatitis C and then continue with the antiretroviral treatments.
This approach is feasible, at least for the co-infected cohort. Of course, in liver transplantation you need your immunosuppression: you cannot stop that for three months, at least not without significant risks.
For those patients we really have to define which substances can be combined with which, but there is actually very active research ongoing in this area as well.

Three year ago we were at EASL in Vienna the day before of the declaration by the World Health Organization that hepatitis is a global problem and emergency for public health. In the last three years we had witnessed big changes, WHO hepatitis, two DAAs in the market, many new compound are coming and we are thinking about a therapy without interferon. From your point of view, how can you explain all these shifts in a such short time?

I think there were two very important findings that helped this. First of all, hepatitis C research is really tremendously benefitting from HIV research because a lot of what is known about viral kinetics and so on was learned from the HIV community.
The second and really major breakthrough for hepatitis C research was the so-called “replicon system” at the turn of the century, developed in 1999 actually. Before that it was not able to grow the virus in culture, so it was not able to test targeted agents in a culture system which made drug development incredibly difficult because you could only grow the virus in chimpanzees outside the human beings. Now, with the replicon system, out of a sudden you could test drugs in a petri dish and that’s what started the revolution because the companies were starting to employ a rational drug design to develop all these drugs against the different components of the virus and that’s when it started off and from then on it’s just a blast.

Articolo presente in – HAART and correlated pathologies n. 15 –

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So, my name is Mark Thursz and I am the Secretary General of the European Association for the Study of the Liver and we are here now at the 47th International Liver Congress in Barcelona and one of the most exciting things that we have seen this year presented at the meeting is a series of presentations on interferon-free regimes…”.
It is not only the beginning of a press press conference, it seems to the beginning of a new era, the era of a different and possible therapy for people affected by chronic hepatitis C.
Prof Thursz, it seems that time is going to run faster than we expected… Last year we saw for the first time a proof-of-concept study, a very small study from BMS presented by Anna Lok at this meeting showing that it was possible to cure a patient with chronic hepatitis C without the use of pegylated interferon and ribavirin. That was really exciting but none of us expected how quickly those results would be consolidated with other drugs and other regimens and different groups of patients, so it’s been wonderful in many ways to see but it has made it really difficult for us to understand where the field is going to go over the next couple of years.
What we’d really like to see is that an all-oral drug regimen goes into clinical practice within two years.

Why is so fascinating thinking about an interferonfree regime?

The problem with interferon is it has side effects, similarly so does ribavirin have side effects, and in certain circumstances this limits the efficacy of the medication, so that side effects mean either dose reductions or termination of therapy. In some cases, patients can get very depresses, very tired, it also affects their ability to work or their family lives, it suppresses the bone marrow and that means in some cases they become susceptible to infection or susceptible to bleeding and so, and the ribavirin causes anemia, so it would be much better if can treat patients without these, without the drugs that cause all of these complications.

In a very short time we have a very complex pipeline, different classes and new direct antiviral agents.
Before to describe these molecules, can you explain why it was possible in so short time to have a so huge pipeline for hepatitis C instead of other clinical conditions or infections?

Obviously that is an interesting question because we don’t know why after many years of research, suddenly, so many of the pharmaceutical companies now have drugs that are so potent and so effective.
I can’t really give you an explanation for that, there has perhaps been a general move away from protease inhibitors. The protease inhibitors we know are good, we have two already available for use in Europa, telaprevir and boceprevir, but they are not particularly easy to use and they have to be used with the pegylated interferon. So, moving away from those, people have targeted the polymerase of the protein, the polymerase enzyme and particularly with nucleoside or nucleotide analogues these are affective across all genotypes, which again is a benefit, and resistance doesn’t seem to be a major issue. The other target that people have been working on is the NS5A and I guess we as a community were slow to recognize the importance of this particular viral enzyme because nobody knew exactly what it does, we know it’s involved in the replication of the virus but not exactly the specific function. What is clear now is that if you inhibit NS5A you end up with a very potent antiviral and what we have seen perhaps most effective is a combination of a nucleoside/nucleotide polymerase inhibitor along with a NS5A inhibitor and these seem to be very powerful.

Is going to change the landscape also of some established concept, for instance naïve patients having a protease inhibitors at the beginning and when we spoke about naïve patients we thought naïve to PI, a different way to define naïve patient.

Oh, yes, that is absolutely true. We will need one group of naïve to pegylated interferon and ribavirin and then we will be talking about a different group that are naïve in terms of their exposure to previous direct antivirals. Conceptually, one of the issues here is the emergence of resistance to direct antivirals which could present a problem in your selection of future direct-acting agents. One thing that is perhaps reassuring here is that we have learned that the viral variants that emerge and the suboptimal inhibition tend to disappear within 12 or 18 months, so probably developing resistance to one of these new agents is probably not long-lasting because the variants are not archived anywhere within the liver cells. The other important concept to understand is that with pegylated interferon previous treatment we defined a group of patients called non-responders, there are people where the virus really never was suppressed with pegylated interferon and ribavirin and we recognized those as being a very difficult-totreat group.

Do you think that when we are going to establish clinical trials in order to evaluate direct antiviral agents without interferon background means that we have to evaluate vs. placebo?

I think the era of a placebo-controlled trial is well and truly over, so frankly is the era of pegylated interferon and ribavirin-controlled trial because I don’t really consider that any longer to be standard of care in genotype-1-infected patients, perhaps it remains in place for genotypes 2, 3 and 4 but not for long.
What about the opportunity and the possibility to combine different direct antiviral agents? Here were presented many studies about this.

There are a couple of issues here obviously because some of the best-in-class are being developed by different companies. We can’t quite control the situation that we get combinations of best-in-class all the time in the drug development era. Inevitably what will happen is, once these drugs are licensed and we know something about their safety profiles, as well as their efficacy profiles, then obviously the hepatological community of physicians will start experimenting with different regimes, which may be obviously that you may need different combinations depending on which group of patients you are looking at.

We have a lot of results and data regarding genotype 1 and what about the other genotypes of HCV?

I think for the first time we are beginning to see drugs coming through that have efficacy against genotypes 2, 3 and 4, as well as genotype 1. So, a lot of the new drugs are not genotype-restricted, the classes such as the nucleotide analogues, they are not restricted to just one genotype, similarly NS5A inhibitors, they work across the board.

There are also some concerns regarding the assay that were used in clinical studies. I am referring to different sensibility of Abbot and Roche assays, could you comment about this?
Obviously, in these studies, the new drug development studies where we are really keen to know whether the virus has gone, then the sensitivity of the assay is absolutely critical, but we are now working at the limit of both assays capabilities and I think it will actually emerge over the next few months what is the best way of measuring, what are the key time points to measure, but at the moment I agree, there is some confusion that needs to be resolved.

Q:
Clinical trials enroll selected people. There are some populations within HCV that are in some way in a hurry because they have a different condition, a disease more progressed, they are transplant people or co-infected people, we haven’t any data regarding the treatment with currently available protease inhibitors?

Well, at the meeting actually there have been two studies that have helped us along in this way. One in co-infected patients showing that it is feasible to use protease inhibitors in patients with HIV. Obviously, drug-drug interactions need to be carefully managed, but what the study tells us is that is entirely feasible and that when protease inhibitors are used in combination with Peg/ Riba in this patient group it can be very effective, it certainly improves the sustained virological response rates or it’s expected to.
Similarly, it is possible to manage drug-drug interactions in patients who are on CNI drugs, tacrolimus or cyclosporine, posttransplantation.
We are going beyond that, there are other groups that the new regimes may benefit, so we have not really been able to treat patients who have end-stage liver disease decompensated cirrhosis because they can’t tolerate pegylated interferon and ribavirin. We now know that here are regimens available that will allow those patients to access drugs and I know that protocols are currently in development for those patients.

Cost about new drugs is a central issue, but here there was presented also a study related to the disease burden.
Can you comment how to manage the amount of money we have to spend now for a possible cure vs. the disease burden of hepatitis C in Europe?

It’s true, of course the burden of viral hepatitis in Europe is high and potentially the cost of treating patients is one of the reasons why Health Agencies and Governments have perhaps not been taking the epidemic so seriously, but we all know that if you fail to take action now the cost in the future will be much higher, so in the long term if you take a longer time horizon, it’s more effective to get on and treat patients at the point in which they got chronic hepatitis because studies from Italy show that by the time you get to cirrhosis, transplantation and hepatocellular carcinoma, there is an exponential rise in the cost of managing these patients. We don’t know what the cost of the new drug regimes are going to be but there is no doubt at all that the cost of treating a patient with chronic hepatitis is definitely going to outweigh the concept of delaying until the patient has symptomatic disease.

It’s difficult to define what means in hepatitis C early treatment?

The early treatment has perhaps two concepts. There is those patients who have recently been exposed to hepatitis C or present with symptomatic hepatitis C infection, so you could say those are acute infections, early treatment seems to be pretty effective in that group and they actually respond extremely well in the early phases. The other concept transposes early in the stage of disease in patients who have chronic infection, so that would be the phase before they get to fibrosis scores of 3 or 4 on a Metavir scale.

Thanks to direct antiviral agents we are going to define the 12 week sustained viral response, now we are speaking also about 4 week as we are, that means that we have a tool in order to reduce the costs?

So, being able to monitor the point at which you know confidently that a patient has been cured, this is clearly important, so for the last few years we have used SVR24, 24 weeks after the end of treatment we measure whether a patient has the virus or not. We are now confident that SVR12 is just as informative as SVR24. SVR4 probably overestimates the success of a treatment regime in many cases, but SVR4 gives a very good indication of what the outcome is going to be for the trial. So I am not sure that licensing agencies necessarily are going to take SVR4 on board, but I have no doubt that SVR4 data is not going to really be regarded as interim but is going to be very indicative of SVR12 result.

Speaking about real life. Imagine a patient arriving in your clinic now. You know that he/she could be treated with the new drugs now available, but these drugs could have some noisy side effects. You know that a lot of new drugs are coming probably in few years with a better safety profile. What do you suggest to your patient?

This is a really good point actually because if you have advanced disease, so you have got cirrhosis already as a patient, then there is no doubt we need to get on and treat you, but for pretty much every other patient, well, if it was me, I would choose to wait at the moment because in two or three years’ time there is a treatment option that is easier to take, it’s shorter duration, probably far less side effects and more effective and it’s going to be quite difficult to recommend anything other than waiting for most patients.

So many DAAs will pone –shortly- the problem of the comparison between them, in order to decide which one should be used first. EASL is the most authoritative scientific society, now how can you approach the story? This is a very crowded world…

A:
So, this is an issue I alluded to earlier on that probably the combinations of direct antivirals that get licensed may not necessarily be the optimal combinations for patients. So, we have seen what happened in HIV that, after combinations were licensed, then the community set about resolving some of these issues with clinical trials. EASL of course doesn’t have the funds to run these trials by itself, I think EASL’s role here is to make sure that people are extremely well educated and for us also to lobby at the European agencies, the DG Research, as well as Member State funding bodies, for trials to be funded so we can get to the bottom of this.

Last question. In the future may be that, having so many choices, tailoring therapy will be the right way to address hepatitis C?

There is no doubt about it that a patient with endstage genotype 4 is unlikely to need the same treatment as a naïve patient with early disease and genotype 1. So, yes, tailoring will be critical, we are not quite sure at this point in time how important ontreatment virological monitoring is going to be, but that may also be part of the complexity of managing these patients in the future.

Not every physician can address this kind of issues…

Well, it’s interesting, we could conceive now of simple straightforward regimens that might be applied in primary care settings rather than in big hospitals’ specialist units in the future. The specialist units will then be left dealing with the more complicated patients with resistance issues, advanced disease and that sort of thing.

Articolo presente in – HAART and correlated pathologies n. 15 –

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This is the crude statement that could summarize my talk with Amalio Telenti, professor of Medical Virology at University Hospital and University of Lausanne, in Switzerland. This year he had the opportunity to draw the state of the art of genomics research in HIV/AIDS during the CROI in Seattle and after during the ISHEID conference in Marseille, where he accepted to answer to my questions. Despite progress and relevant amount of publications the use of genomic tools to make easier decision and simplify the daily life of a person dealing with his/her own therapy, in your talk said that genetics is everywhere except in the clinic Yes, I think that was the common motive to my talk. It is to express how as much as it comes out of daily press and there is lots of hopes and there is a lot of interest also outside of the medical environment, surprisingly we are not seeing much of it coming to us, either because it’s not ready or because there is something wrong in the way we are bringing those tools into our help.

In the HIV field, you started working on genomics since 2005. I remember during the IAS conference in Rio you told me the future of this approach. Now, 7 years later, you have lot of new data you have presented in your talk, focusing on individual answer to every specific drug… I think we have to think that, as much as we are all different, we are also different in terms of how we metabolize drugs, how we develop toxicities and some of it is coded and it can be traced back with the new technology to particular genes. Some of the genes are very good at predicting, almost black and white: a particular problem like for example the famous abacavir hypersensitivity and a type of HLA.Some of the genes contribute a small information, but information could be useful.

For example your patient may develop diabetes, if you put him on this drug. It’s very hard to re-educate all the medical community on how to use a large number of new tools, new tests and which one is very good, which one is a bit informative. I think the challenge will be this new generation of physicians that will probably have to slowly integrate predictors in their clinics.

In your talk, you discussed the position of pharmaceutical companies and the perception of the medical doctors vs. the perception of patients.
I think there are important issues to be discussed in our community – doctors, healthcare workers, patients – in what is acceptable toxicity and this can be what the doctors look for. Big things: you don’t want to do harm to a patient, but then when we go away from the big things, we stop listening to the patient, we don’t want the patient to be whining because they don’t sleep well or because they get sad or because they say that their body is changing. Why? Because, of course, accepting those minor complaints will force us to consider new therapies, change therapies, so we just push it away. Now, when you observe the behavior of patients in retrospect, you will realize that if they are given the choice they will drop drugs not because of major toxicity, but just because it doesn’t feel well. In my opinion this is a field where pharmacogenetics could help. Companies don’t want to hear about it because they don’t want their drugs to be pushed aside just by what they call minor adverse events. Doctors don’t want to be busy changing drugs for what they also consider as a kind of minor problems of a therapy, that otherwise works wonderfully against the virus. So, the whole system is built to ignore that therapy may not be well tolerated and that there could be alternatives.

It’s interesting the concept “toxicity vs. tolerance” you have used in your talk…

I think I hope that we think about that: toxicity is what is in the doctor’s head, tolerance is what is in the patient’s head and these two worlds have to reconcile.

The Food and Drug Administration recommends some kind of genetic tests in order to start a therapy with some drugs, the NIAID has said that it could be useful if everybody enrolled in clinical trials will give informed consent about to storage their DNA. Why it’s so difficult to obtain this?
I think because there is still this deep-rooted feeling that genetics is a violation of our last level of privacy and therefore either ethics commissions, patients, countries will oppose what is required, that means a storage, long-term storage and large-scale screening, it makes no sense to ask permission to analyze one gene, it makes sense to ask permission to analyze a whole genome.
Therefore, somehow people say I am exposing myself excessively and this is a risk, or perceived risk, insurance, etcetera. The idea is to try to convince society that when you spend half a billion or one billion to put a drug in the market, the minimum that you can do is already from the beginning try to identify those people that may pay a heavy price from receiving that drug because they will die of a hypersensitivity reaction or a toxicity of the liver or they will accumulate a particular distressing syndrome or will not respond. Now, this is a change in mentality. A clinical trial should attempt to understand the origin and basis of failure or of toxicity from the start, not five years later. Academic groups like ours will try to catch up and try to figure out in retrospect why people were getting a particular problem. This has to be built into the system and, as I mentioned in my talk, there are excellent examples, like for example IL28b, the interferon lambda, and interferon response excellent exemple of successful use of clinical trial materials to find something that is very important for people: am I going to respond to interferon or not? Is it worth to start a costly treatment for something where I know already I will not respond?
It’s a way to maintain the promise of less drugs more efficient.

This is a war of the movements where the pharmaceutical companies have not decided: are we asking pharmaceutical companies to produce drugs for everybody?
Are we asking them to produce effective drugs for some people? Of course, these are two competing economic models and eventually somebody will have to figure out what makes sense in terms of society or economically. Is it cheaper to pay for toxicities or is it cheaper to pay for individualization?

Articolo presente in – HAART and correlated pathologies n. 15 –

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