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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PrEP today – Interview with Mark Weinberg

It’s truly a controversial issue: PrEP is a strategy that is able to polarize positions not only between clinicians but also in the community. During a crowded and hot plenary session in Marseille –during the ISHEID conference last May- Mark Weinberg in a nice duel against Mark Nelson supported the idea of PrEP. A that time we know that FDA expert panel had expressed a positive opinion about the approval of truvada in order to prevent HIV transmission. But more time it was expected to be needed in order to get the final decision. The session was really very excited.
In order to be interesting and useful to the audience, such duels on hot issues need open mind duelists, ability to synthesize his own position, no caution in speaking neither diplomacy and a lot of pleasantness. All tool that both Weinberg and Nelson were able to show. We will be back on PREP issue hosting comments and opinions, and the whole story of this strategy.

The following dialogue about me and Mark Weinberg took place in Marseille, at the end of May 2012.

The newest area that you are covering now is the non-conventional use of drugs: I’m referring to PREP…

Well, that’s correct, it’s a very hot area. I addressed this topic I think it’s extremely encouraging that we are now at the stage where we all think that we should be using antiretroviral drugs as part of preventive strategies in addition to using these same compounds as part of therapeutic strategies and you know I think we would all agree that one danger associated with some of these approaches is the potential development of drug resistance. We have to be very careful that we don’t try out these drugs in a preventive way in people who may be infected and don’t know it: for example somebody who is in acute infection. I think ideally we would want to subject people to viral load measurements to be sure that they are not in an acute phase of infection whereby they might be still antibody-negative and viremia-positive and there are tests that we can do to try to ensure that this is the case but one of the problems is that these tests are not easily going to be done in developing-country settings. There is going to be a greater risk that people in developing-country setting and sometimes in fact wind up getting treated with a preventive regimen that will be sub-standard or inadequate in regard to actual therapy and there is where the greatest danger would lie in regard to potential development of drug resistance. But at least we can establish the proof of principle which has already been done through a number of studies, such as the iPrEx study and the Partners PrEP study: antiretroviral drugs do and can play a role in prevention and it’s a fantastic achievement.

Do you can describe the ideal profile of a person that could be eligible for such use of drug?

I think there are a number of categories of individuals who could be ideal candidates for use of antiretroviral drugs in prophylaxis. I think one obvious candidate is the sex worker, someone who is having repeated relations without protection, without condoms with a lot of other people who they may not know very well, that’s I think a very easy example. And, of course, several of the studies that have been done and are being done in regard to pre-exposure prophylaxis are being conducted among gay men and these gay men have volunteered for these studies, they understand what’s at stake and they want to be part of helping to develop strategies that will safely use some of the antiretroviral drugs in prevention. Now, one issue that has come up, and I think it’s an important thing to underline, is that in some setting some people have said “Well, you know, we don’t have drugs available here for treatment, why are you giving people drugs for prevention when we can’t access the same drugs in treatment strategies?” and I think that is a fair point, so I think we should certainly ensure that anybody who needs antiretroviral drugs for treatment should have access and ensuring access should not be in contradiction to following through with prevention strategies.

So, at least you welcome the position from Panel of Food and Drug Administration regarding the use of PrEP?

Yes, I think the future approvation by the Food and Drug Administration of Truvada as a prevention modality is welcome, I think it’s a step in the right direction. You know, it doesn’t mean though that we shouldn’t keep doing studies and I think it’s still important that for certain types of studies that have not yet been validated we should continue to use placebo arms in order to definitely show that PrEP works. One such strategy, for example, would be the idea of intermittent PrEP where people would take pills for prevention in advance of sexual relations and not every day and I think this is an excellent concept that should reduce toxicities associated with drugs because people won’t be taking them every single day, it would also have important ramifications in regard to costs, but the concept needs to be validated in the context of a placebo-controlled trial.

So, at the end, once again we can suggest a combination approach, PrEP can reduce the virus running in the world and fully suppressed people are not infective?

Yes, I think that’s correct, PrEP should prevent new infections, which should over time lead to reduce the viral burden in terms of new infections on the planet and at the same time, of course ,the same drugs should be used as part of key strategies in regard to therapy. Using these drugs therapeutically, if they reduce viral load, the will also lead to diminished rates of transmission. We should look on this as a win-win situation that really will only be complicated in the event that drug resistance develops at far higher than expected levels, because of the potential problem of people going on PrEP without actually realizing that they are infected or not being adherent to a PrEP regimen and becoming infected and then staying on PrEP, because they don’t know that they did get infected by HIV, in which case they would also be very very susceptible to development of drug resistance.

Articolo presente in – HAART and correlated pathologies n. 15

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Routine prescribers? No thanks – Interview with Mark Nelson

“I think we need to start thinking about novel ways of treating patients. I think what is going on is that we have all become rather routine prescribers just writing out our favorite prescription for the majority of patientssays in a very passionate way Mark Nelson, Director for the HIV Directorate and Deputy Director of Research, Chelsea and Westminster Hospital:- so we need to think about the necessity to individualize per patient, that doesn’t mean patients must receive a treatment without HAART, that doesn’t mean the patients need to receive treatment without nucleosides, it means that we need to consider the pros and cons for the individual patient”.
Who is the candidate for a HAART without nukes?
What type of patient may be the type of patient where we think about it? Well, first of all, there are individuals who have multiple resistance to nucleosides but we have kind of just thrown the nucleosides in: the viral load is undetectable, but they may now be experiencing toxicities to those drugs. Potentially, we are aware of a possible association of abacavir with heart disease, tenofovir with kidney and bone disease, as we get older we are more likely to get those: so people may feel safer off the nucleosides, particularly if they are not adding any power to the regimen. There may be individuals who have those toxicities who would prefer to come off and their physician would prefer them to come off those nucleosides.
And at the end, there is the issue of cost, of course. You know, it’s much cheaper potentially to give a single drug as long as that works as well.
So, there are many factors, both patient factors, physician factors, but also population and social problems due to the fact that we are all facing hard times.

We can try to define three big main categories of patients that could take advantage of such simplification, starting from the naïve patients.

Sure. We need to think about several different groups of patients and where the idea of a nucleoside-sparing regimen may actually fit in. It is impor tant to explain what is a nucleoside-sparing regimens.
We are talking about mostly protease inhibitor-based therapy, either a protease inhibitor alone or a protease inhibitor with another class of drugs. So, if we think firstly about the naïve patient, protease inhibitor monotherapy doesn’t work. Two studies, the Monark study and a study of ritonavir and darunavir show that even in patients with low viral loads that start below 100.000, so called easy-to-treat patients, they didn’t do as well as triple therapy. So, it doesn’t seem to be a role of PI monotherapy alone, but there is increasing amount of data on the role of protease inhibitors and non-nucleosides, protease inhibitors and a CCR5 antagonist and protease inhibitors and an integrase inhibitor. The problem: is there really an advantage for the patient there? They are having to take often treatments twice a day because the only integrase inhibitor is raltegravir, they have the issues of protease inhibitor toxicity, so the drugs may actually work just as well as triple therapy in this dual therapy sparing the nucleosides, but is there an advantage? Probably not and there do appear to be some disadvantages. Now, I think there is an interesting study, the NEAT 001 study which is examining Truvada, ritonavir/darunavir vs.
ritonavir/darunavir and raltegravir. I think it’s’ not only about virological success: virological success is likely to be equal, but the issues which are coming out to the patient of twice-daily treatment with raltegravir are: what happens if you fail an integrase-inhibitor containing regimen, etcetera, etcetera. I think there are a lot of issues other than virological success which we need do look at in these large studies.

And for patients that are in a failing regime?

In patients who are virologically failing in resource-rich world, in Europe, I think most people who would start in two nucleosides and a non-nucleoside will go to two nucleosides and a protease inhibitor. But people who are failing, in the resource-poor world the overall situation is different: viral load is not generally available, therefore virological failure is actually found out very late and it tends to be based on drops in CD4 count, clinical progression. So it’s actually quite like they have been on that failing regimen for relatively long time, they have multiple nucleoside resistance. So, I think it’s going to be much more used in failing patients in the resource-poor world and clearly it gets rid of the idea of needing a resistance test. If you are on two nucleosides and a non-nucleoside and you move to two new classes of drugs, no need to do resistance testing, so it may really be something which is very effective in the resource-poor world, but is clearly also something which could be made available in richer parts of this planet.

For patients that are controlled and I want to make an easier option?

I think the big place that we are going to be looking at nucleoside-sparing regimens in the future is switch patients.
I think if you go to a clinic, most clinics would look at success rates of 90, even 95%, one clinic in the UK is reporting 99% of patients with an undetectable viral load. Therefore we can treat the virus, now we need to treat the patient. If the patient is going to be on treatment in the long term, it is likely that the biggest issues are going to be adherence, it’s boring taking treatment, and the toxicities, particularly the long-term toxicities.
So we need to think about simplifying their regimens.
There is an increasing amount of data on the strategy of protease inhibitor monotherapy: just taking a single drug where there is a low rate of failure slightly higher than with triple therapy but not associated with resistance.
Clearly if you take a single drug there is likely to be less toxicity and is going to be a great deal cheaper.
Now, I don’t think we need to go too much about cost, but it’s going to be increasingly important for the clinics in order to give the excellent care that they give to the patient, however that is really going to be an important issue I think of protease inhibitor monotherapy. About the protease inhibitor monotherapy, I think there are physicians who love it, there are physicians who hate it and really we need to actually come together and make a good strategy of when it should be used, how it should be used and in what patients.

In your talk today you said that monotherapy is a strategy.

What do you mean with strategy?
If you look at protease inhibitor monotherapy, if you take patients who are doing very well on treatment and who have full virological suppression, you randomize them to actually take PI monotherapy or to continue their triple therapy, there are more failures with PI monotherapy.
So, that doesn’t look good, but because there is no resistance or the risk of developing resistance is extremely low and certainly not higher than patients failing triple therapy. What we can do is if the patient, if the PI isn’t strong enough by itself, is adding the nucleosides back again. So, it’s the strategy of PI monotherapy with adding in nucleosides if they fail, rather than the treatment that means it’s all finished with.

It is also an option for people that are aging older because it could be reduced polypharmacy?

Yes, I think that PI monotherapy is something that the people who are taking multiple drugs may like. There are clearly other strategies as well. It’s about the individual patient: if someone is taking 20 tablets three times a day, reducing their HIV tablets by two or three makes no difference, but for some individuals who are struggling to take all their drugs it may be an advantage.
This advantage, of course, is that would mean taking ritonavir, ritonavir does have a lot of drug interactions, it’s very important again, but it’s a balanced approach and we don’t just jump in without thinking.

To plan a therapy for a chronic condition in other therapeutic areas it is used an approach called induction and maintenance. Is it feasible in HIV field?

I think that the idea of induction/maintenance is something which has been explored several times within HIV and will be explored further in the future. I think what’s happening as regards simplification and PI monotherapy is that at the moment it’s a very reactive approach, so it’s an approach if something is happening to that individual as regards toxicity or adherence. It’s not something that in clinic we are thinking about doing something routinely. Induction/maintenance will only come to the fore if we get clinical research backing it up as approach and secondly if we are much more proactive of thinking about simplification of therapy. A patient who is on triple therapy and doing well with no side effects is unlikely to change to monotherapy, we find in clinical practice, because he says “Look, I am doing well, why would I want to switch?” and so it’s a big discussion that has to go on about the possible advantages and disadvantages of such an approach.

You said it’s a big discussion: it means that listen to the patient is the key anyway?

I think it’s about explaining to the patient, I think… It’s like many things that doctors can do.Iit’s really about saying to the patient look, we don’t know what is the right approach, this is a moving field, we know what a wrong approach is, but what is the correct approach, this is the advantages of such an approach, these are the disadvantages of such approach…. The problem is within the clinic there are more and more patients because they are doing well, they want to get out of that clinic and it has become a consultation of “your CD4 count is normal, your viral load is undetectable, see you in six months”. I think we need to take a step back and look at the long-term effects of these drugs, the long-term effects of HIV and continue to rationalize different treatments for different people.

Articolo presente in – HAART and correlated pathologies n. 15

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The old and the new: lessons learned for the future – Interview with Mark Weinberg

Sometime old words hide new concepts. It happends when in a changed environment arrive new opportunities.
Its seems to me it is the case of terms like “monotherapy” or “dual therapy”. Being involved in HIV field since the beginning of the story, about these topics I looked for an expert opinion of another old guy, Mark Weinberg, who is in seek the Director of the McGill University AIDS Centre at the Montreal Jewish General Hospital and Professor of Medicine and of Microbiology at McGill University.

“I think a lot of the ideas that we had previously dismissed may come back and I don’t think we are going to be using monotherapy very much in the future, even an excellent drug like darunavir, boosted darunavir which some people have suggested could be used as a kind of monotherapy. I don’t think is going to be sustainable, I don’t think it’s a good idea. I think that over the long term it will lead to a lot of treatment failure and resistance against all of the PI drugs, so I would not be in favor of this. I think I might be willing to give more of a chance to dual therapy with some of the newer agents coming forward. I think that some of them are really very very encouraging and, you know, the one new drug class that we have, notably the integrase inhibitors, are very much underexploited and we really need to fully consider how the integrase inhibitor class of drugs may make a real difference in regard perhaps to paving the road toward dual therapy and, you know, we may be in for some very pleasant surprises, we need to do the clinical trials but we have to be optimistic.

We have a lot of toxicity now on the floor, we have kidney, bone, muscle, mitochondrial myopathy, co-infection, we have to plan a long-term therapy, a chronic therapy. How can we deal with this toxicity?

Toxicity is part of the problem in regard to developing any really good triple strategy. There is no question that we learn more and more about toxicity as time goes by. We should be positive and remember though that we have at least four drugs that don’t seem to have any major toxicities at all, maybe five drugs. One of them is certainly raltegravir, it’s a very clean safe drug, another is 3TC, a third drug is FTC and I think a fourth drug that is approved that falls into the same category is maraviroc. None of these drugs really shows any kind of long-term toxicity, in contrast probably with all of the others that are associated with some form of side effect. The newest drug that is now in clinical trials, dolutegravir, from what we see so far is also a very clean drug in terms of its toxicity profiles. So, again, I think we have to be optimistic.
So many drugs, but we haven’t still resolved the first step: when we start?

Oh, I think we have resolved the first step of when we start. I think there is a growing consensus that we should start as soon as somebody is diagnosed as being HIV positive. Now, this is not always possible, we sometimes wait way too long before making a diagnosis of HIV positivity, but as far as I am concerned, and I think as far as other key opinion leaders like Stefano Vella are concerned, we really should start the moment somebody receives an HIV diagnosis, assuming, of course, that the person is going to be willing to take their drugs in a fully adherent way and that we will be using good drugs on this person. You know, there is so much evidence that allowing the virus to continue to replicate has the potential to do irreparable damage to the immune system.
Why would anybody want to let that happen?

How to plan a chronic therapy, simplifying the puzzle?

I think we have to be willing to try some new approaches such as reducing viral load to undetectable levels by using three excellent drugs that should I believe include maraviroc, which I think is an excellent drug and one that is very much underutilized in the current spectrum of antiretroviral therapy. Once we do succeed in reducing viral load to undetectable levels, perhaps then simplification strategy could be contemplated in which we use drugs that are virtually non-toxic in a context of perhaps reducing the numbers of drugs sometimes and look forward to long-term success. Again, patients have to be fully adherent: we don’t have that many drugs that really have a fantastic safety profile, so we want to, therefore, and we need to preserve the drugs that have a fantastic safety profile for as long a period of time as possible. Patients need to understand this, so that they don’t wind up being non-adherent and therefore develop resistance to some of these compounds which will then wind up only compromising their future therapy, and will result in them needing to take drugs perhaps that won’t have as clean profiles in regard to toxicity as some of the other choices that might be available.

In your opinion, is possible to use an approach like induction and maintenance in chronic therapy for HIV infection?

Yes, I think induction/maintenance could be a very positive strategy, there is some clinical trials now underway to evaluate this hypothesis. You know, one of the worries, of course, that we would have is whether or not removing a drug as part of the simplification strategy could sometimes perhaps lead to more immune activation, so even if you don’t immediately wind up with more viral load, are you going to wind up with more immune activation or are you going to wind up potentially causing long-term problems. I think this is a very important issue that needs to be evaluated very seriously.

Another aspect related to immune activation is aging: aging because we have patients that are getting older with HIV/AIDS and aging because there is an immune senescence caused by the replication and inflammation of HIV.

Yes, I completely agree, aging is a problem and I think that there is no question that some of the side effects that we associate with drugs are now showing up in the aging population, so it makes it very important to really think about using drugs that have the cleanest possible profiles as part of an antiretroviral regimen. If we assume that a cure is very far off, eradication is very far off and even the type of minimal cure that we would hope for whereby perhaps we would be able to never completely eradicate but still not have viral replication come back. Even for that kind of situation I think we would want to have a drug regimen that is as clean as possible and right now what we are seeing is that some of the very good drugs that are currently being prescribed as part of triple therapy do seem to be having side effects in the aging population, perhaps because people have been treated over such a long period of time and it’s taking a lot of years for some of these side effects to show up. We have to be cognizant of this, absolutely.

The last aspect I actually want to cover together is the central nervous system problems. It’s related to premature aging in some way and is related to the immune activation caused by the virus? Well, of course, central nervous system aspects are extremely important. We know that some people who are HIV-positive who respond well to antiretroviral drugs may nonetheless wind up having problems of dementia.

In some cases we think that it may be attributable to the fact that not all of the drugs that they may be on penetrate into brain tissue and central nervous system tissue as well as might happen for other drugs and there is apparently considerable inter-patient variability in regard to ability of drugs to penetrate the blood brain barrier.
It’s still on ongoing area of investigation, it needs more attention and hopefully we may be able to rely at some point on genomics. Certain genetic tests that may be able to tell us who can be safely treated with drugs that ostensibly don’t seem to relate well to penetration of the blood brain barrier, some people may be able to get away with these drugs and other people may not. Its’ an ongoing area of research.

Articolo presente in – HAART and correlated pathologies n. 15

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Opulence vs. Austerity: how to deal with innovation? – Interview with Josè Gatell

In HIV field we have so many drug and different classes of drugs that could potentially change paradigms of established way of thinking about therapy of HIV infection.
I’m referring to dual or to mono therapy, -for instance- but we are experiencing increasing warning on costs. How to deal with innovation and simplification in this our hard time? The question is for Josè Gatell, Senior Consultant & Head of Infectious Diseases & AIDS Units at the Hospital Clinic and Professor of Medicine at the University of Barcelona.

“I have two considerations on that: first of all, you point that every time some new drugs or new families are introduced, almost everything changessay to me “That has been true for a number of years but now a new theme that will have to be introduced is the economic problem, is the cost of the drugs and so for a new drug to be considered in the initial therapy they will have to demonstrate a big and a very evident advantage over the old regimes unless the company prices these drugs at the same level of the old drugs, so that the issues of cost and cost efficacy is going to be strongly considered in the year 2012 and in the forthcoming years when we decide what to start with. That is one point and the second point in terms of a strategy. I think for the moment the only attempt that has been made to use monotherapy as initial therapy it failed, so that I don’t think monotherapy is going to be considered for initial therapy. Conversely, the issue of combination of two drugs, like a protease inhibitor plus an integrase inhibitor, this may well work and may have some advantages. However, again, this type of therapy for the moment is substantially more expensive than, for example, a triple and they will have to show a really big advantage to be considered in practice for initial therapy.

Tolerance could be one of the key issues in this landscape? Well, tolerance can be one of the key issues and when we talk about tolerance or side effects I think we need to differentiate between what we may call short-term or acute side effects and long-term side effects. Of course, if one drug is very clearly associated with long-term side effects, that is going to be deleted from our armamentarium and this is what happened in the past for example with d4T or with AZT that is no longer in use. In terms of the acute toxicity…I mean it’s true that this is important, however we need to take into account that shortterm or acute toxicity for the drugs we are now using, this kind of toxicities are never very severe. People who pay for antiretroviral regimes they may say that well, you can start with the less costly regimes and if your patient develops some kind of toxicity, don’t worry: just feel free to change. But they may not allow us to start with more expensive antiretroviral regimes simply because there is a little bit less short-term toxicity, mostly if this shortterm toxicity is not a very severe one and it is something that you can solve simply by changing the regime.

The therapy of HIV infection is now, is a chronic therapy, that means that we have to plan for the future. Do you think that an approach like induction and maintenance could work?

Theoretically, it could and this is what in fact what we are doing with all of our simplification trials. The problem is that all the two or three trials along the history that have addressed the issue of induction simplification, they have failed. They have failed probably because the period of time of undetectable viral load was too short, so the simplification trials they work because we recruit or include patients that had been undetectable for a number of years and the longer you have been undetectable, the higher the likelihood of succeeding in a simplification trial. Conversely, the induction and maintenance trials, in general you go to the maintenance regime, to the less or to the most simple maintenance regimen very quickly after the patients reach undetectable viral load and probably this may be the explanation why some of these trials they have failed in the past.

What kind of strategies now we have available to simplification?

Well, I am going to address this issue in a symposium one hour from now. I mean, there are several strategies addressed to simplification and all these strategies in general they are focusing on trying to solve or in trying to overcome one issue. For example, you may wish not to have a patient long-life on a boosted protease inhibitor, so you may address the question of whether you can replace a boosted protease inhibitor with a non-nucleoside or with raltegravir, for example, or maybe in the future with elvitegravir or with dolutegravir. You may try to focus on how to address the question, to focus on the question of long-term potential kidney and bone toxicity of tenofovir and then you may try to jump to a simplification regime free of nucleosides, and this may mean monotherapy with boosted PI or PI plus raltegravir: So, I think there are a number of strategies that have proved to be successful and the strategy you may use for simplification is going to be depending on what is the problem or the hurdle you would like to overcome.

One problem that we try to overcome is aging and that it is related together to long-term strategy of therapy.

I think to overcome the problem of aging, we need to pray and ask God to bless us (laughing).

At a lower level, I am referring how to deal with the drugs.

Having said that, we may try to help God a little bit.

Well, I think the issue of accelerated aging is not associated particularly to any type of drug or combination, is probably more associated with residual inflammation or with chronic inflammation and also with chronic immune activation.This is something that for the moment it happens or is a problem associated with any of the antiretroviral regimes we are using at that moment. So, in this regard, trying to address this problem, probably what we are going to need is to explore the possibility of whether residual viral replication can be shut down by intensifying antiretroviral treatment, or by using some drugs that have a better access to the GALT or to the lymphatic tissue and, at the end of the day, also trying to focus on the possibility of a functional cure or of an eradication of the HIV. But this is for the moment a domain of the research, not a domain of the clinical arena: I mean it’s probably nothing that we are going to be able to solve in the next couple of years.

But we can address the problem of polypharmacy in this kind of patient.

Yes and no. No, I am saying yes and no, I mean… We can try to address and we have been successful and I am sure we’ll be even more successful in the future in addressing the issue of antiretroviral therapy, of compressing the antiretroviral therapy in a few number of pills and, even better, in a single pill. The problem is that the more the patients are getting older, antiretroviral therapy is simply one of the components of the treatment our patients are receiving. I mean, our patients are receiving salicylate or statins for primary cardiovascular prevention, our patients are receiving drugs to help them sleeping better, they are receiving anti-inflammatory drugs for hip or for knee arthrosis, they are maybe receiving painkillers for whatever and so we are not going to be able to put all of that in a single pill. Just saying that we are treating our HIV patient in a single pill it’s true and it’s not true, it’s true in terms of antiretroviral therapy but it’s not true in the terms of the whole treatment these patients are receiving.

One aspect related to immune activation is also the CNS problem.

Well, despite many years of research on antiretroviral therapy, the issue of CNS is not totally solved. First of all, the vast majority of our patients who have an undetectable viral load in plasma, they also have an undetectable viral load in the CSF. If we are able to achieve an undetectable viral load in the CSF, it’s hard to think about what else can we do in these patients in terms of antiretroviral therapy. It’s true that a small percentage of patients, despite having an undetectable viral load in the plasma, they still may have a detectable viral load in the CSF and in that case, I mean in that case we may try to change the antiretroviral therapy or to intensify the antiretroviral therapy or to choose drugs with a better CSF penetration and this may improve the situation.
The problem is how to detect that, because this would mean that we may need to do a CSF extraction: we may need to obtain CSF in all our patients who are undetectable and that is something that is not yet in the routine clinical. I am not sure that I have to do a lumbar tap in all my patients just to check whether or not the viral load in the CSF is undetectable, but it may well be a recommendation in the near future. If you think about, for example, some kinds of leukemias, they get a lumbar tap just to check whether the leukemic cells have been cleared from the CSF and so that is something that is not today a formal recommendation but it may well be a recommendation in the near future saying that, well, if you have a patient that has been undetectable for more than one year or for more than two years and is doing well, just at least once in your life make sure that the virus has also been cleared at least from the CSF.

There is an increased also use of neuroimaging in order to determine if there are some lesions in the brain…

The neuroimaging technology is something that is fascinating, and it may help to differentiate between what it is normal and what is not normal. However many of this technologies are not able to translate in a meaningful clinical interpretation so quite often: I don’t think that a neuroimaging procedure may help us to discriminate between what patients need a lumbar tap, as opposed to those patients who don’t need it. If someone would find a correlation in one of these non-traumatic neuroimaging technologies, it can be used as a screening procedure to avoid a lumbar tap, that would be welcomed.

Articolo presente in – HAART and correlated pathologies n. 15

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HIV pharmacology: How to get data quickly to decide – Interview with David Back

“I think the issue that we always want to address is risk benefit of any therapy, be it a single drug or a regimen, and a major principle is that you want the benefit to clearly outweigh the risk- states David Back, Professor of Pharmacology, Department of Molecular & Clinical Pharmacology at the University of Liverpool, starting our conversation about new possible paradigms in HIV therapy. Every time we have new drugs in the market we start to think how to change or innovate: we have to save the way towards innovation as well as the way towards standard therapy. In any case tolerability remains the main issue… We know that there are adverse effects, we have seen adverse effects, if we go back through the development, for example, of the nucleoside analogues, the D drugs were always drugs that concerned us about mitochondrial toxicity, which then linked through to lipodystrophy, so we have got better, I think at understanding some of the key areas. We then had abacavir hypersensitivity of course with the nuke, and we understood the basis of abacavir hypersensitivity brought in the HLAB* 5701 testing. When you look at the other classes of drugs, I think now we are more concerned about long-term toxicity, so that we think of tenofovir and what are the implications of small changes which are seen in renal function and the odd case report of Fanconi syndrome… We are concerned long term and we have new drugs, so that the tenofovir GS-7340, which is the new form of tenofovir, if you like, which is a pro-drug looks an exciting drug but we have a lot to learn. I think we have learned but we are learning and we need to continue to learn.
In these periods there is lot of noise about dual therapy and monotherapy…
Yes. So, the basic principle has always been that you have to have enough drugs in the regimen to suppress the virus and we learned very early on that combination therapy clearly was the way forward. What I think has now gradually emerged is that, once you suppress the virus, the question then is can you maintain the suppression of the viral load by reducing the number of drugs in their regimen, if you really need to have three drugs, what about two drugs and even then… Of course, we have monotherapy studies with one drug.
It’s an area that has caused a degree of polarization of views, not everyone has agreed that this is the way that we need to proceed, but we clearly have data which suggests that there are certain areas that we can use, maybe reduced numbers of drugs.

What kind of parameters we have to consider in order to make therapy easier and simply?

As far as dose simplification is concerned, one is looking all the time to make a regimen as simple as possible for the patient so that patient will be adherent to the therapy, that’s a key, adherence to therapy, and to maintain a reduced impact of any adverse effects. So, simplification of therapy, which is why with Atripla, for example, one pill once a day, with the new Quad which will emerge is one pill once a day, and fixed-dose combinations being the simplest type of regimen. In a sense, if you got a fixed dose at one pill once a day, you could argue it doesn’t matter whether there are three drugs in that one pill or whether there is only one drug in that one pill because you got a simpler regimen which is much easier for the patient to take, as long as you haven’t got adverse effects and intolerability issues. We know that tolerability issues have revolved to a large extent around certain drugs: ritonavir has always been a tolerability question mark in people’s minds because of the diarrhea, the gastrointestinal effects, etcetera. Will cobicistat, the new booster, be any better? I think time will tell, there is always an excitement around a new drug but then there is always the realization that at this moment in time there is no perfect drug: every drug has got its benefits and we have to work out what the issues are around some of the side effects.

In planning a chronic therapy, in oncology it’s used a concept of induction and maintenance, do you think that also in the HIV field we should use a similar approach?

Logically, that should work in my view. If you can induce and make sure the patient’s virus is suppressed, can you then suppress it with less drug or less numbers of drugs.
Clearly the clinical data will always be the key that we rely on, it’s not just a theory, it’s got to be shown in practice in long-term, three-year, five-year trials. You can really suppress the viral load with, if you are going to reduce the number of drugs in that regimen you really got to make sure that is true, but there are data to suggest that we can do that under certain circumstances, but it’s not, you have to define which patients will benefit by that strategy.

The simplification approach is a good tool in order to deal with the aging process caused by HV and occurring as overall effect in HIV/AIDS people that – because of HAART- are living longer…

Aging is a real challenge as well because there are so many changes taking place with aging. There are changes in the way that the body handles the drugs, the body responds to the drugs, the implication of maybe increased adverse reactions to the drugs, there are all the co-morbidities that are been treated as well, so one has to think as patients get older of strategies to maintain the optimum management.
From my clinical pharmacological background, it is always optimize the management of the patient who is in front of you: it is not just looking at patients as a group, it’s always to say can we do better for an individual patient and I think that is the way that we have to look.

In this context, also polypharmacy is a key issue.

Sure, polypharmacy is a key issue. We did a survey recently with a Swiss cohort of over 50s and under 50s in terms of the number of co-medications and, unsurprisingly, if you are over 50 you are on more other medications for co-morbidities, particularly around cardiovascular disease, so in terms of high blood pressure treatment, in terms of lipid lowering agents, there were clear differences between the under 50s and the over 50s. In that context, you have to think about the co-morbidities being treated and what drugs can you use, what drugs would be unadvisable to use because of drug-drug interactions, which is still an area that we have to manage well and manage better with all drug interactions: indeed, aging is an issue.

Last question is related to CNS. We don’t have so many drugs that are able to reach the HIV everywhere where is replicating.

No, that is true. It’s clear, the data that we have comes from CSF, so that we look at penetration into the CSF and then the debate is “is a drug in the CSF necessarily the same as a drug actually in brain tissue” and all the different considerations that we need to think about because we know that some drugs can penetrate into the CSF, other drugs don’t seem to penetrate so well into the CSF. But we have to then think about all the drugs in a regimen: do you need all three drugs or maybe you can have less in terms of the regimen as long as you have got really effective drugs, because you got low viral replication.
Again: I think there is a lot we don’t know and we sometimes tend to extrapolate beyond what we do know. The challenge is going to be, particularly with the new drugs coming through, of getting the data quickly, which will enable us to understand better and CNS penetration is one major issue. I think that is an issue which for CNS penetration is: is that one drug going to penetrate into the CNS, and it’s not just the CNS, it is to all sites where there potentially is virus. For example, there is a recent study looking at GALT biopsies, where apparently atazanavir didn’t seem to penetrate into the GALT tissue. So, there is ongoing studies where I think, as long as we can look at the virology and the pharmacology together, we will get a greater understanding of tissue penetration and tissue localization of drugs.

Articolo presente in – HAART and correlated pathologies n. 15

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In a crowded sea, sailing toward a brave new (HIV/AIDS) land

The great number of antiretrovirals available to set up a potent end durable therapy poses many questions in terms of decision. We are not referring to solutions as defined by guidelines, that usually define a sort of “standard way to deal with”. We are more interested to explore strategies of innovation that could arise from different approaches that take into account which drugs we could use in a different way, taking into account the main issues we are facing in these hard days. On one side we have financial constraint –it’s true-, but on the other side we are sitting on a great success: HIV/AIDS is now a chronic condition; the therapeutic armamentarium is crowded and neither potency neither efficacy are still on discussion. On stage, there are key issues like compartmentalization, simplification, future options and –mainly- safety.
In order to address these issues we met four experts in order to speculate –on the ground on the present data- which could be the spaces for different, may be future, options in terms of strategies dealing with HIV as chronic infection and HAART as chronic therapy.
We chose the experts from different fields (and persona attitude) in order to draw the picture as complete as possible: David Back because he is the leading expert in terms of HIV/AIDS pharmacology applied to clinical decision; José Gatell, because he is a clinicians who worked in HIV/AIDS since the beginning; Mark Weinberg because he is a basic science researcher working on translational approach, also adopting radical positions: he was one of the first to claim for microbiocides and now –once again- he is supporting a non-traditional use of antiretrovirals like PREP (as you can read in the box, pag x); Mark Nelson, a real provocative clinician who seek to define innovative way to deal with ARV, lying in the tradition –as only an English man can do.
The following pages aim to be an open door to the possible and to the future: a door that could be used by anyone of our readers, who wants to say something and adding his/her opinion about these topics.
Closing this issue of HAART FDA decided to approve the first drug to prevent HIV infection.
We had already decided to put a box on this “non conventional use of ARV”. We will be back on this topic for many reasons, not only medical but also sociological and cultural.
Everyone who would send us his/her comment on PREP and FDA approval to join the forum will be welcome.

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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Editorial Renaissance and/or Baroque?

Let’s say that this issue of HAART is on drugs and how to use drugs at the best. It is for HIV infection as well as for HCV.
We know that every virus tells its story, but some similarities could be found, especially if you think about the process of drug discovery and the knowledge spread about it use. The impact of having efficient drugs in HIV and HCV is similar: we have to face epidemics on a global scale, to prevent the contagious, to reduce the burden to the disease and to cure the infection. Ideally, we would end the epidemic.
All of this needs drugs and we do have antivirals: we call HAART the combination of them to treat HIV infection; we call DAA the new compounds that address directly HCV the process of replication. It is a impressive condition that was unthinkable only some years ago, making improvements day by day. Drug are thought as the main surrogate of health, “the” solution to restore a condition that is not balanced, the answer you can swallow in order to face a threat.
A substance becomes a drug when there is a person who intake it for some expected effect that the above mentioned substance should have –either if it’s supposed to have, either it has demonstrated to have. A substance without a person cannot be a drug. It remains a powerful substance, but not a drug. Drugs –pharmaceuticals- are at the heart of the story of HIV infection. Drugs, the quest for an antiretroviral was the first question that was made by people that were in need. Because to our culture drug –a pill- could be the answer: it reflects a specific cultural approach to formulate and to think a problem a in a specific way that includes -at some extent- in itself the answer. If we understands how it works, then we can built the solution. HIV was the first big challenge to this. I’m referring, for instance, to the too much optimistic statement made during a memorable press conference in April 1984 by Margaret Heckler, US Health and Human Services Secretary, after -may be- having had a conversation with the virus’s co-discoverer Robert Gallo: “We hope to have a vaccine ready for testing in about two years”. Now, 30 year after, we don’t have any licensed vaccine (we have only some people claiming that have got it). But we have drugs and HAART, and it impact on prevention.
As said last year during the IAS conference in Rome the director of the US National Institute of Allergy and Infectious Diseases (NIAID) Anthony Fauci “I’ve never seen something explode like this”, commenting the results of HPTN052: earlier ARV treatment of HIV-infected individuals leads to a dramatic 96% decrease in HIV transmission. And the results of Partners PrEP and TDF2 showed that pre-exposure prophylaxis (PrEP)— ARVs to HIV-uninfected individuals— resulted in a 62%-73% reduction in HIV transmission among heterosexual men and women. Also without a vaccine we could stop the epidemic, may be, but Adherence appears to be a critical factor for PrEP protection against HIV.
How we were able to be here? We cannot forget the tremendous role played by activist on making pressure on R&D department in Pharma as well as in public health sectors. At the very beginning of the epidemic we have seen a contradictory behavior: those who were afraid by toxicity and by the medicalisation –including anxieties for the growingup role of pharmaceutical companies-, saying that there is any link between medical sciences and society, and those who were claiming -writing it on their panels- “make tomorrow happen today” and “drugs into our body”, a sort of utopist republic of anti HIV drugs.
Pharmaceutical drugs represent a unique opportunity to study the relationship between symbol and political economy considering drugs as commodities with their distinctive biographies – considering in this case biography as metaphor: “people give these substance a history. As powerful technical devices and status symbols, medicine acquire a status and force in society” (2). “Following the transaction of these object reveals biographical order –and a gendered technical order- to their social life. Pharmaceuticals may profoundly transform social relations, thus rendering useful a consideration of politics –understood as various struggles shaped by power and its operations” (3).
HIV field with its antiretroviral access programs – especially in middle income countries- considering aspects like adherence to treatments and perspective for the future, point to innovative forms of socio-political identification and participation focused on the concept of the therapeutic or biological citizenship (including the right to health care) (4).
We know that every virus tell us a different story, but the history of HIV and the history of drugs development could be useful for those who are working in Hepatitis field –both for physicians and activists. As explanation of the reason why we have a huge number of compound that are now in the HCV pipe line, Markus Peck-Radosavljevic, associate professor of medicine at the Department of Gastroenterology and Hepatology at the Medizinische Universität Wien, told us that “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 and that was very difficult. Now, with the replicon system, out of a sudden you could test drugs in a petri dish and that’s what started the revolution”. (see his interview at pag XX).
We have getting solution for HCV infection, in a short period also without interferon. And In HIV field we are in the privileged position to define new strategy, because we have so many efficient ARVs. “I think we need to start thinking about novel ways of treating patients. I think what is going on is that we have all become rather routine prescribers just writing out our favorite prescription for the majority of patients- says in a very passionate way Mark Nelson, Director for the HIV Directorate and Deputy Director of Research, Chelsea and Westminster Hospital:- so we need to think about the necessity to individualize per patient: we need to consider the pros and cons for the individual patient”. (see his interview at pag XX).
Now a fully trust on drugs now arise also from some of those who were critics against the “republic of Pharma”. And at the same time we can listen that people who were in favour of early use of drugs are now claiming against PrEP. It is all too new in order to solve the puzzle, in which stands the FDA decision to approve the first drug to prevent HIV infection.
We need to the bate all these issues related to the non conventional use of ARV.
Somebody suggested that we are living may be in a sort of antiviral Renaissance. I think it could be a nice definition of the very recent period, until now. With the PrEP revolution we are entering a in new phase, may be: let’s call the Baroque. If Renaissance means in art and philosophy the use of the geometrical perspective and the human being as measure of everything, fully trust in human mind and its ability, Baroque –that comes against Reform as the need to reaffirm the supremacy of Catholic Church as prescriptive core behavior and values- means emphasis for “decoration” and expression of the power. Today it’s seem that the (wonderful) power of the drugs is founding a new one-way rationality of behavior, that must be based on adherence. Let’s ask in a provocative way: is it the beginning of the era in which pharmacopeia will represent the only accepted manners and etiquette? We are open to publish all the answers you have.

Articolo presente in – HAART and correlated pathologies n. 15

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