DAAs: the lexicon of a changing paradigm – Interview with Heiner Wedemeyer

“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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Switching mentality: how “COME” could suggest the way – Interview with Stefano Fagiuoli

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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Hepatitis and stakeholders in Europe – Interview with Markus Peck-Radosavljevic

“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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The future and the present of DAAs against HCV – Interview with Mark Thurz

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.

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…

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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Toxicity vs. tolerance: how pharmacogenomic could help – Interview with Amalio Telenti

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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DAAs drug-drug interaction

Every time we are facing an innovation, we have to be prepare to deal with the issues arising from the novelty. In the pharma field, dealing with complex regimes treating chronic conditions is drug-drug interactions.
In order to define the state of the art of the pharmacological interactions of the new protease inhibitors against HCV I have met David Back, Professor of Pharmacology at the University of Liverpool, one of the leading scientist in this field. Last February professor Back was invited in Rome by the faculty of the Associazione Italiana Studio Fegato for the AISF annual meeting.
The common feeling is that we are at the beginning of a new era also for the drugs against hepatitis C….
“Drug-drug interactions definitely represents a challenge for us, with the new directly-acting antivirals.
We have understanding of telaprevir and boceprevir that there are going to be a number of clear drug interactions that we will have to be watching for. This is because both of those drugs are potent inhibitors of one of the key enzymes for the way that drugs are handled in the body, cytochrome P453A. To a greater or a lesser extent, drugs that are metabolized by that enzyme are going to show drug interaction: that is the area that we are going to be concerned about.

During your speech at the 45th AISF Annual meeting you listed the different drug interactions for the two new drugs we are going to have in the clinical practice. We can start with telaprevir… With telaprevir there are a number of drug interactionstudies which have been done which have shown the potential problems that we face. So, for example, with immunosuppressants, which are key for transplant patients, the magnitude of the interaction with both cyclosporine and tacrolimus is such that we are going to have really careful management of dosing for those particular drugs. In one sense, what we would like to say, where there is a large interaction, is let’s use alternatives, but there are challenges because often there are no clear alternatives that we can use and so, we have to manage those interactions.

From an HIV background, which is where I come from, we are used to managing interactions in HIV. The challenge for hepatologists is to be able to think differently, because with peginterferon and ribavirin there are virtually no clinically relevant drug interactions, one or two at the most. With the DAAs, there are going to be a number, and there are going to be some comeds that are contraindicated, there are going to be some that we will have to be very cautious.
With telaprevir I highlighted some of the key areas that we are concerned about, where there will be contraindications, often with some cardiovascular drugs, and there will be others where we will have to manage those interactions with caution, starting with dose modification and then titrating to effect.

And with boceprevir?

Boceprevir has an additional way that the body gets rid of it. So, there is an enzyme called aldoketoreductase, which also handles boceprevir, metabolizes boceprevir, but it’s not going to rule out drug interactions at all. So, although the magnitude of the interaction with immunosuppressants is slightly less and with midazolam, for example, and with some of the statins, it still means that there are going to be contraindications for boceprevir, and there are going to be the areas that we’ll have to start with a dose, the lowest dose that we can, and gradually titrate to the effect. We are on a steep learning curve, we have a limited number of drug interaction studies done, what we now need to do is to begin to understand those drugs that we can’t do studies with, but we are going to have to use in our patients and that’s where I think pharmacologists, discussing with hepatologists and getting groups of people together to really understand how we can best manage the patients.

Taking into account also the HIV coinfection…

HIV coinfection is a specific issue. So, for example, just two weeks ago Merck issued a statement based on pharmacokinetic data for boceprevir, where the magnitude of the interaction of the HIV drugs with the HCV boceprevir drug meant that the extent of that interaction would rule out, being able to coprescribe atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, key drugs, key protease inhibitors for HIV, with boceprevir. So, what we need to then understand is which HIV drugs can we use in coinfected patients, and at the moment a drug like raltegravir has limited interactions, efavirenz is probably going to be a drug that we can use maybe with some dose modification, which has happened with telaprevir, but again: we are on that steep learning curve, we got new data and we now have to under stand how with the new data we can best use the drugs in coinfected patients.

And there is another issue that covers both drugs that are methadone interactions, because we have a lot of patients with HCV that have a story of intravenous drug use.

Yes, so methadone, that’s a key interaction: the good news I think with methadone is that, although there is a change in the exposure of methadone which would initially lead us to think you’d need to modify doses and cause changes in the stable dosing that one would use. In fact, because of some complication of protein binding which I won’t go into in detail, it seems that we don’t need to modify methadone with telaprevir, whether we do with boceprevir at this moment is not clear, but I suspect not. My understanding from the data we have is that methadone we can use pretty much without any dose modification.

As you have already done and established in the HIV field, you are running a website that could be a good help for the clinical practice.

I think it’s critical that we have the information available, so we have set up a website for hepatitis drug interactions which is populated with all the new information that comes from conferences, papers and with an expert editorial board inputting into the website.
What we are going to try to do is to make sure that it is as comprehensive as possible. One of the questions that arose during the discussion after my talk is “can you tell us which drugs we can’t use?”, and what we hope to do with the website is to give clear guidance as to which drugs are not to be used and what alternatives, where there is contraindications, what alternatives can we use in our patients and by doing that we hope that this will be a useful resource for the community. We can’t remember all drug interactions, I work in drug interactions, I can’t remember them, I need help and I need resources.
So, we have a website and from the website you can download for the iPad and for Android resources and iPhone resources, so it’s something that will be useful we hope.

As we said at the beginning of this conversation, we are at the beginning of a new era for hepatitis C treatments, with an impressive pipe line of new drugs.

How can you explain the reason why so many drugs in so small portion of time for hepatitis C? When you look at the pipeline and you see some people quote 60, 70, 80, 90 new drugs in that pipeline, it’s an exciting field to be in. When one considers 170 million people with HCV coinfection, clearly there is a huge potential and we know that we can cure this disease as well. We have started the process with the two new DAAs, we are going to get better drugs, we are going to get drugs that are easier to use. I mean what we are using at the moment, the drugs three time a day in high doses: we want to go to once-daily drugs and potentially then to remove pegylated interferon and ribavirin and those sort of issues are big issues for discussion at the present time and in clinical trial.

The numbers of people affected by this virus maybe is not enough to explain so many drugs because, for instance, for hepatitis B infection affects more people around the world…

Sure. I guess that, I am not from a pharmaceutical background, but when one looks at the pharmaceutical companies and realizes that virtually all the companies now have a big program in HCV with new drugs…we know that some drugs are going to fall by the wayside, that’s the nature of pharmaceutical company development, but I do think it’s an exciting pipeline with an exciting potential for us to really revolutionize the way that we treat hepatitis C. Given the drug interactions which I have described for the two, telaprevir and boceprevir, hopefully we are going to get drugs where we don’t have so many drug interactions and the usefulness would therefore be I think even greater.

Articolo presente in – HAART and correlated pathologies n. 14

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Viral hepatitis public health policies: what we need – From a retrovirus, lessons for future leader commitment

health, everywhere. Thanks to some all-night efforts” said Dr Margaret Chan, WHO Director-General at the closing ceremony of the Sixtythird World Health Assembly, which brought together Health Ministers and senior health officials from the World Health Organization (WHO) Member States. It was 21st May 2010, and the delegates adopted resolutions on a variety of global health issues including the most relevant to us: a resolution on viral hepatitis “as a global public health problem”, with the goal “to stimulate the strengthening of preventive and control measures of this disease in Member States”. A report on hepatitis was performed by patients’ based organizations together with clinicians and scientific society and it was presented to the World Health Assembly: member States accepted the report and adopted a resolution including the celebration of World Hepatitis Day on 28 July. Viral hepatitis (i.e. hepatitis A, B, C, D and E), a combination of diseases that are estimated to kill over 1 million people each year and an estimated 1 in 12 persons are currently infected and have to face a life with liver disease if unrecognized.
This endorsement by Member States calls for WHO to develop a comprehensive approach to the prevention and control of these diseases. But the declaration makes pressure on member states in order to define policies that address such a global threat and social burden. The approved document provides a list of conceptual actions that includes: the implementation and/or improvement of “epidemiological surveillance systems in order to generate reliable information for guiding prevention and control measures”; “to use national and international resources, either human or financial, to provide technical support to strengthen health systems in order to adequately provide local populations with the most cost-effective and affordable interventions that suit the needs of local epidemiological situations”.
The celebration of World Hepatitis Day represent a call for action, and for the first time it happened officially last July 28.
Because of all these considerations, in order to provide an example of how is it possible to mark a difference in setting up policies to address viral hepatitis, we publish here two document.
One is the US Presidential Proclamation on Viral Hepatitis Day 2011 issued by Barack Obama: it is impressive to see that the leader of the most powerful State decided to pay attention on viral hepatitis, and we hope it will be an example to be followed for the leaders all over the world.
The second document we decide to publish here is an article written by Ronald O. Valdiserri, Deputy Assistant Secretary for Health, Infectious Diseases, U.S. Department of Health and Human Services, who posted it on the blog of the White House (on the website of the White House you can find also the Obama’s proclamation). Many reasons suggested us to include this document in the last 2011 issue of HAART. The first is that Valdisserri gave his speech about the US strategy against viral hepatitis during the Liver Meeting in San Francisco, and the talk was an extended release of the conceptual frame expressed in the document we are publishing. The second is that Valdiserri was a key person in fighting against AIDS and in order to put the experience of AIDS crisis in perspective, in 2003 he edited a book: “Dawning Answers: how the HIV/AIDS Epidemic has Helped to Strengthen Public Health”. The central premise of this book “is that among the many consequences of the HIV/AIDS epidemic have been substantial and ongoing changes in public health theory and practice –both domestically and internationally”. Other authors have underlined the need to put HIV epidemic in historical perspective. In a book published in 1993 Virginia Berridge listed at least three functions of “historical policy writing”: ‘policy relevant’ history feeding in to current policies or used in forecasting future developments; ‘recreating the past’ for its own sake, academic ‘voyeurism’ or journalism; and “policy analysis”, the understanding of past events according to particular theoretical models and empirical understanding, analysis the past without specific current policy intent (although the insights provided may feed into perceptions of the present). I want to underline that when Berridge wrote this was in 1993, in a pre-HAART era, during the deep dark AIDS crisis. As stated by Valdiserri in his book, he adopts the first function described by Berridge as predominant, because the goal is “to describe and place in context a variety of changes in public health theory and practice that are related, either wholly or in a large part, to unfolding HIV/AIDS epidemic and to exemplify and extrapolate their application to other public health problem”. Valdiserri and the others authors in the book declare to assume the Institute of Medicine’s definition of public health’s mission as “fulfilling society’s interest in assuring condition in which people can be healthy”. The core functions included in this definition are the assessment of the health of communities and population at risk, the setup of policies that address health threats and the assurance that all population have access to the needed health care and prevention services.
A recent stories support these consideration, considering the emergence that “the silent epidemic” represents for public health. A study that was presented at The Liver Meeting 2011, the annual meeting of the American Association for the Study of Liver Diseases last November shows that deaths associated with hepatitis C have overtaken deaths caused by HIV. By examining multiple-cause death records, researchers from the Centers for Disease Control and Prevention have determined that deaths from viral hepatitis are insufficiently appreciated and by 2007 were exceeding reported deaths caused by HIV.
Approximately 218 million records were included in the study. Those records were examined for mention of hepatitis B or C and for HIV.
For the period of 1999 to 2007, deaths associated with hepatitis B remained constant, HIV declined, and hepatitis C increased –- significantly.
Almost three-quarters of HCV-related deaths occurred in the 45-64 year-old age group.
HIV was one of the comorbidities associated with viral hepatitis, as were chronic liver disease, other hepatitis virus, and alcohol-related conditions. Scott Holmberg, MD, the study’s presenter at the Liver Meeting in San Francisco spoke directly to the conclusion of his team’s study, which states a change in policy direction to improve detection and access to care for patients with hepatitis is required to decrease mortality associated with hepatitis, “without reducing allocation of resources that have diminished HIV deaths, we think a commitment to detect and treat chronic HCV will markedly improve the growing wave of disability and death from this under-appreciated viral infection”.
“HIV/AIDS has proven to be an unprecedented catalyst to the development of important scientific, technical and policy advances” writes Valdiserri. Dealing with HIV has enabled community and scientists to store information that “can be applied for the benefit of future generations in combating this epidemic and other, related challenges to health around the globe”: the experience gained is susceptible to be applied to other public health problems “in the development of new approaches to assessment, policy development and assurance”.
Let us add now, as we need it to be done for the hepatitis.

Articolo presente in – HAART and correlated pathologies n. 13

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HBV: a global threat, bus with less attention paid – Interview with Robert Perrillo

Robert Perrillo is the Associate Director of Hepatology at Baylor University Medical Center at Dallas and Director of the Hepatology Fellowship Program. Dr. Perrillo is internationally recognized for his work on antiviral therapy of chronic hepatitis B and the scientist that AASLD suggested me in order to have a talk about hepatitis B. I met him in San Francisco during the Liver meeting.

This 2011 seems to be the year of hepatitis. There is a lot effort in order to increase awareness about hepatitis C and hepatitis B all over the world. Here, during the Liver meeting i there were two sessions devoted to the global program against hepatitis, one driven by CDC and the other one together with NIAID. But many of the noise rased is realted to HCV. About hepatitis B, where we are?

Well, hepatitis B is a condition that afflicts 400 million people worldwide and I think that the United Stated has been considered traditionally as a low-incidence area, a low-risk geographic region. But now we all of the practicing physicians who see such patients are noticing that we are seeing a lot more patients who are of the immigrant populations to the United States, not just Asian Americans, but also those from the continent of Africa and also those from the Eastern European nations, who have immigrated here and have brought hepatitis B with them. So, the prevalence for hepatitis B in the United States has been traditionally underestimated: it is probably above 2 million people. Now, that pales in comparison to hepatitis C where we think it’s more like 4 million people, but both of these conditions are very significant. Hepatitis B, like hepatitis C, can establish a chronic carrier state and can lead to cirrhosis and liver cancer and actually is a leading cause of death in people that have the affliction of hepatitis B from early in their life, where 15% or more of adult, generally younger males in their middle ages can have a decompensating form of liver disease or liver cancer, so it must be taken seriously. The two major types of therapeutic agents that we have available to treat it are an injectable material called interferon, which is also currently being used as part of a triple therapy regimen for hepatitis C. Interferon has been a license for hepatitis B for approximately 18 years now, and it tends to be not utilized, because of some adverse events. Into the past five years, we had availability of nucleoside analogues or nucleotide analogues: pills that can be taken orally, once a day, and they inhibit and suppress hepatitis B virus. Interferon, unlike the oral drugs, actually augments cell-mediated immunity against hepatitis B and therefore the state of the art is moving towards a direction of looking at combination therapy, where we are using interferon to stimulate immune responses against the virus in conjunction with a potent suppressive agent that can be taken orally. First past studies, five-six years ago, looked at interferon with a less than completely effective nucleotide analogue and so these studies where not definitive by their very nature. We now have oral drugs, such as tenofovir and entecavir, that can be taken with a very slight risk of developing drug resistance, then had stymied us in the past and prevented us looking at monotherapy as a long-term kind of beneficial way of treating the infection. Unfortunately, the problem with the nucleosides still remains: they are only effective as long as you take them. So, there is indefinite treatment needed, sometimes you could conceive of this as being in excess of six or ten years while waiting for the markers to change sufficiently that you would be able to stop therapy, so we don’t really know when we can stop in many patients. The combination of interferon and a nucleoside offers the option to come up with a higherquality response, perhaps getting down to even minute levels of virus remaining in the liver tissue and for all intents and purposes coming as close to a clinical cure of the disease as we come.

This is the reason why we need the new drugs? Yes, we need new drugs all the time.

The biggest gap of what we really need is a drug that like interferon can stimulate the immune response against the virus, get to a greater state of viral elimination and yet not have the unpleasant side effects. So, the magic bullet for the future will be an immunostimulatory compound that doesn’t have a lot of side effects.

Notwithstanding, until we come up with such a drug, the combination of interferon and nucleoside analogue therapy can be an effective tool that we hope will bear fruit.
There are many studies ongoing now to look at this, sometimes these studies use the drugs simultaneously, sometimes there is a leadin with the interferon to induce an immune active state before you add on the viral suppressive agent. In some studies they are looking at people that have been on the oral pills for a while and haven’t come to a complete satisfactory response where you’d feel comfortable stopping: so they had interferon on the trailing edge of that therapy to see if they can come to a higher-quality response where you can lose the hepatitis B surface antigen, which is the outside envelope of the virus, at which point you can be pretty sure you that are going to have a long-term response if you stop the therapy. I think the field is exciting, there aren’t as many new drugs being developed as in hepatitis C, but we are coming to a far better understanding of how to use the existing drugs for hepatitis B.

The issues you have mention explain why adherence is a key issue in the management of a patient with HBV…

Adherence will always be an issue, whether you are taking one pill or four pills a day, because of the human character. Hepatitis B and C are often asymptomatic or minimally symptomatic, so it’s hard to stay with a relatively costly drug therapy for an indefinite period, which is what we often do with hepatitis B, hepatitis C has more time-defined therapy, so we have side effects but we hope to get the patients through before the side effects become limiting. With hepatitis B, with the oral drugs that we have, we don’t have side effects, we do have cost, we do have an asymptomatic condition.
Unfortunately, there is an undeserved stigma from having hepatitis B. Many people who are in the immigrant populations who have it would rather not have it and cause concern for their family members, as well as the cost of care. In fact, the sad truth is that in hepatitis B we estimate that at least 50% of the people in the US are foreign born who have it and these are people that don’t always have the greatest access to care, so as a result we can’t reach the net out there, the health net to treat these people very effectively, there are cultural barriers against seeing doctors for this condition. Diabetes, hypertension and high cholesterol get more attention that hepatitis B which can be life threatening over a long period of time.

Articolo presente in – HAART and correlated pathologies n. 13

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A future without interferon? – Interview with Jaen-Michel Pawlotsky

“I would say major scientific progress, modest humankind progress”, said to me Jaen- Michel Pawlotsky, Department Head of Virology at the Hospital Henri Mondor, Cretteil, in France: this could be the synthesis of the gap between the social burden of hepatitis and the outcomes of medical advances in this field. It is a realistic statement and it underlines that sometimes science and research go faster that social consciousness and policies. This year World Health Organization celebrated the first Hepatitis World Day, and it was after a deep lobby activity started some years ago together by the international scientific societies -EASLD and AASLD- and the patient based organization World Hepatitis Alliance. Now there is a WHO resolution that recognize viral hepatitis as global threat, a public health concern. I had the opportunity to met prof. Pawlotsky during last Liver meeting in San Francisco, immediately after the speech he gave to the conference.
“Well, things have changed a lot scientifically. In terms of making priorities and improving screening and access to care things are going much slower and I think this is a kind of dissociation we are seeing in this field right now. The science is evolving very rapidly, we will probably discuss a number of advances that have been made, progresses are made in terms of new drugs coming, interferon-free regimen, etcetera, etcetera. Now, the global awareness of the problem, the knowledge that 130 million people are infected with HCV, active campaign for screening and ensuring access to care to these patients with the old drugs and eventually with the new drugs in future is something that I think is going very slowly and very late”.

How we can describe the global burden of viral hepatitis?

Currently we estimate that 130 million people are infected with the hepatitis C virus worldwide, 350 million people are infected with the hepatitis B virus worldwide. Not everybody has access to therapy, for those who have access to therapy it’s easy to control hepatitis B, you don’t cure hepatitis B but you can control it with the drugs we have, entecavir, tenofovir.

We see better and better treatments with hepatitis C and a lot of new data with very high cure rates but, again, I would like to insist on the fact that access to care, screening, active campaigns for screening and identifying patients and giving them the opportunity to have their disease controlled is going very slow and there are areas of the world where virtually nothing is done and I think that’s a major issue that our community, the viral hepatitis hepatology community will have to tackle in the future.

Having a vaccine for the hepatitis B means that it is feasible the idea to eradicate hepatitis B virus from the world?

Yes, the vaccine is a very active one, it’s very safe, it’s something which works very well, the problem is that you have two steps. If you start vaccinating newborns, which is done in many areas of the world, you really decrease the burden of the disease and this is what is happening in China right now, they have been able through their vaccination campaign to reduce the burden of HBV infections in young people tremendously, but you still have the old ones who are infected. So, your approach must be a double approach: you must obviously improve vaccination coverage all over the world, but you must also take care of the patients who have acquired the infection, are chronically infected and may need therapy. And this is a little bit of a challenge, vaccination is generally relatively cheap and very cost effective as a strategy, antiviral therapy is costly and this does not work everywhere and different countries have adopted different approaches for that.

For hepatitis C, we don’t have any vaccine, but we are staring to have so many drugs..

I think what we have learned over the past few months, or weeks or even days here at this meeting, that it’s very easy to cure infection, but we didn’t have the right drugs to do that so far. Now these drugs are coming and we see that with good drugs. What is a good drug? It’s a drug that is potent and has a high barrier to resistance, if you can sustain inhibition of viral replication for a few weeks, two months, you’ll get to a cure. So, it’s an easy-to-cure infection, the issue of vaccination is a different one. The point is that it’s very difficult to develop a vaccine for this virus because of the immunology of this virus, the fact that it is highly variable, that infection does not protect against a new infection and there are other issues which is it has not become apparent to the vaccine industry that a vaccine for HCV was something important. I think it is still something important, I think in many areas of the world a vaccine would be useful, especially because for the same reason we discussed for hepatitis B, you have to treat the patients that have the disease but you also have to prevent new infections and protect the population, but right now this has not appeared as an obvious need and I would say that research and funding for vaccine research is very limited.

For HCV the standard of care is interferon plus ribavirin. Starting form this year we can add a protease inhibitor…

Yes, the new standard of care for genotype 1 is a triple combination of interferon, ribavirin and a protease inhibitor, either telaprevir or boceprevir. I think these two drugs are a progress but it’s still interferon alpha-based and there are some issues and especially issues with tolerance of these combinations. But new new drugs are coming as well new combinations, as we learned at this meeting, previous meetings as well, but here in San Francisco the evidence is very compelling: we can treat and cure hepatitis C pretty easily without interferon. I think the next step will really be the interferon-free era and the question is which drugs, which duration, which patient and this is really we are entering maybe the final step of our quest for the “Holy Grail” of HEP C cure and this one will be which is the best overall interferon-free regimen for all patients infected with HCV. Then we have done that, the same problem we discussed earlier will remain: how do we ensure that access to care is possible for everybody? We have great treatments, they are very expensive, how can we treat everybody? So, it’s the beginning of the end of the story, maybe.

In you speech you presented here in San Francisco a study Phase II that demonstrates the possibility to treat hepatitis C without interferon with a new compound. Can you describe the study?

It’s a study which has been done in patients infected with genotype 2 and 3, they are relatively easy-to-cure patients and the study was based on the use of a cyclophilin inhibitor1, it’s a drug that targets host proteins involved in the HCV replication cycle. This drug was used either alone or in combination with ribavirin without interferon. The patients had the possibility of using interferon if they did not achieve an RVR, rapid virological response, undetectable HCV-RNA at week 4. I think the interesting result there is that with ribavirin and a reasonable dose of alisporivir without interferon, 50% of the patients were able to achieve a rapid virological response on treatment at week 6. We demonstrated that ribavirin added to this, if it’s better to use alisporivir plus ribavirin than alisporivir alone, also demonstrated that some patients who did not have an undetectable HCV/RNA at week 4 got to an undetectable HCV/RNA at week 6 and now, this was interim analysis, we are waiting for the final results of the study and see if these patients will relapse or will achieve a sustained viral response. I am pretty optimistic they will achieve a sustained viral response without interferon, but this will be presented I hope at the next EASL meeting.

And what about the safety profile of this new compound?

The comparison of interferon-containing arms and non-interferon-containing arms gave an obvious advantage for the non-interferon-containing arms. The two major side effects have been associated with the use of alisporivir more frequent than in the non-alisporivir arms were, number one, nausea, which was a little bit more frequent, and, number two, hyperbilirubinemia, which is well-known effect of alisporivir. With the doses that were used in the trial, the elevation in bilirubin levels were pretty acceptable, very few patients did more than 3 times the upper limit of normal and no patient more than 5 times the upper limit of normal. So, on average, it was a modest increase of bilirubin that was dose-dependent and more important in the presence of ribavirin, no other major side effects to report.

So, we will meet in Barcelona to discuss the new results of the study..

I hope that in Barcelona we will be able to show you the sustained viral response results, but I am sure there will be many other studies show in Barcelona and we will probably have a lot to discuss them.

Articolo presente in – HAART and correlated pathologies n. 13

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Hepatitis C: the changing landscape – Interview with Gary Davis

Gary Davis, is the Director of the Division of Hepatology, at Baylor University Medical Center in Dallas and Chair of AASLD’s special interest group on hepatitis C.
I thought that Professor Davis could be in the right position to summarize how the hepatitis C landscape is changed and fast moving. I met him last November, during The Liver Meeting in San Francisco.

In 1991, we were using only one drug, interferon, in fighting against hepatitis C, and it seems we were entering in the future. Now, after twenty years, we have a lot of choices, most of them shortly available. Can you summarize the story of the therapeutics in hepatitis C?

In 1991, we were using standard interferon, which was three times a week. The chance of eradicating the virus was, in retrospect, about 6%. We didn’t know that when we did those studies, we had only ALT levels to go by. We later added pegylated interferon and ribavirin, which improved these responses significantly and then, this last year, we have had the introduction of direct-acting antiviral agents, specifically protease inhibitors, which have allowed us to increase the responses to therapy significantly to the point where we have about 70% of patients who are able to eradicate the infection, that’s cured of the infection.

The landscape of hepatitis C is going to change: how is easy to use these drugs?

Every time we add a drug, we add side effects, we add cost, so it increases the complexity of managing your patients. The payback, of course, of that is that you have greater chance of getting a treatment response and curing your patient, preventing them from getting progressive liver disease.

This Conference is hosting many studies related to costs. How is relevant this kind of issue in the management of hepatitis C?

Cost is very relevant. It’s relevant to the individual patient, it’s probably even more relevant to society. There are abstracts at this meeting talking about ways to better screen for patients, 75% of the patients with hepatitis C don’t know they have it. If we screen better and identify those patients, we bring, in this country, the US, more than a million new patients into physicians’ offices to treat. The cost of doing that, both in personnel, as well as the cost of buying drugs, is phenomenal and we have no way of knowing how we are going to pay for that. So, cost is a real societal issue and access to care is a societal issue and these are becoming as big a challenge as is developing new therapies now.

We know the efficacy of the new drugs that are now approved. What about their safety profile and side effects?

The two protease inhibitors that have just come out in the market, the major side effects are anemia and rash, with one of the drugs, these are problems to manage.
Probably, the most bothersome thing that we have to deal with is drug-drug interactions.
As the infectious disease physicians have been dealing with for years in HIV therapy, these specific antiviral agents go through a complex drug metabolism and they can interfere with the metabolism of other drugs, so that makes management of them very difficult.

In comparison with the HIV field we have a more complex situation, considering that we have to deal with a lot of virus genotypes and with different answers from the virus and the host, regarding these new drugs.

Fortunately, with genotypes 2 and 3, which are the other common genotypes of this infection, we are able to have pretty good responses with interferon and ribavirin themselves. A lot of the new agents are more pan-genotypic, meaning they don’t just work in genotype 1 but they can work in other viral genotypes as well and we expect, as this field develops, that we’ll have more agents that work across genotypes and will improve the responses in all genotypes of hepatitis C.

The patient schedule is going to become more complex: we have to add new pills to the combination interferon plus ribavirin. In this Conference, there are some studies related to the adherence. Many of them are studies related to adherence regarding interferon or standard therapy. We know that interferon produces mood disturbances, depression and other kinds of problems: how is relevant adherence considering the new drugs?

The currently available proteases have to be given every eight hours, that’s difficult for the best patient to be compliant with or adherent with and the new drugs that are in development may not offer a big efficacy advantage, they may not increase the number of patients who clear the virus, but the advantage is they can be taken once a day or twice a day, which is much easier to be adherent to. Hopefully, as we get away from interferon-based therapy, we’ll have less side effects, better tolerated therapies, perhaps taken all by mouth and that should improve adherence as well.
There were presented some studies related to a possible future therapy without interferon…

We hope so. We are not there yet but it’s very encouraging, some of the early results shown at this meeting and the last European study at the Liver Disease meeting were very encouraging that we are going to be able to achieve this. We know we can achieve it in a proportion now with these therapies that are in trial, we need to achieve it in a 100%.
There are many new drugs that are coming, can you list the most hopefully drugs that are arriving?

There are two protease inhibitors that are in Phase III trial in the United States and they should, if all goes well, possibly be approved by the FDA in 2014. There are some drugs right behind that, there is a replicase complex inhibitor, cyclophilin inhibitor, so 2014 and after we’ll see another wave of new agents start to come out, there are many right on the heels of that, so, a lot of drugs coming in the next few years.

It’s interesting that here, in San Francisco, we see downtown, on the buses and trains panel “a new hope, a new era of hepatitis”: when a disease arrives on such display on buses and trains, it means that the story is changing?

Oh, yes, the story is changing a lot. For somebody who has been working in the field for thirty-five years or so, this is very exciting to see the discovery of a virus and within your own career see the potential to eradicate the infection.

Articolo presente in – HAART and correlated pathologies n. 13

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