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Editor Editorial

It is hard to define: if is reality that suggests stories and characters, or if stories could be used to understand realities. As it often happens, the relation is complex to be analized. In some way we could assume a similar approach that underlines the difference between post hoc and propter hoc. And the kingdom of truth –if it is- is complex to be explored. As writes Gilbert K Chesterton in The club of Queer Trades “Truth must necessarily be stranger than fiction, for fiction is the creation of the human mind and therefore congenial to it.” Let’s try to use stories as well as history to approach this end of the year: for two different reason. The first is fictional: we want to remember that in 1993 the film Philadelphia was released. Now, 20 years after, -already 20!- we can guess that a relevant part of the landscape is changed: research, science and interventions were able to set up efficient answers to the question posed by HIV. Indubitably, the answers that have been issued are manly form the science. Unfortunately policies, attitudes, behaviors, beliefs and prejudice stand still against a world fully committed against HIV/AIDS. Some examples? Omophobia, legislation about recreational drugs, women conditions and genders disparities. Stories are important because they are narratives of the emotion and the flavor of the needed engagement in fighting against AIDS. Looking to Philadelphia, we measure and recognize how far we are from the dark and early days of the epidemic. But it is not enough.
Despite the progress we made, the obstacle we are now facing are more hard to overcame, because they are rooted in society and in economy. This is the reason way, together to the analysis of stories that are at the same time shape and construction of health and collective dimension of disease, we need to look at the history of these years in order to make clear that there are persisting as well as emerging challenges that must be addressed. The best way to do this is through the experience of privileged witness of how HIV/AIDS was able to illustrate the “new global vulnerability” we are still living in. The quote is from a key person in the history of HIV/AIDS, Jonathan Mann the scientist and advocate for civil rights who died on Wednesday, September 2, 1998 in the crash of an airplane bound from New York to Geneva, where he was to attend a World Health Organization conference. He was 51. In a visionary preface to “The Coming Plague. Newly Emerging Diseases in a World out of Balance” written by the Pulitzer prize winning Laurie Garrett, Mann writes “We always want to believe that history happened only to “ them”, “in the past”, and that somehow we are outside history, rather than enmeshed within it. Many aspects of history are unanticipated and unforeseen, predictable only in retrospect: the fall of the Berlin Wall is single recent example. Yet in one vital area, the emergence and spread of a new infectious disease, we can already predict the future – and it is threatening and dangerous to us all” (1).
The feeling of momentum and of history inspired any action of Mann, who was the first man to manage the first project on AIDS, in Zaire. It was in January 1984. In the best seller book by Laurie Garret we can have the encyclopedic impressive history of these days. In march 1984 Peter Piot joined Mann in Kinshasa. The personal perspective and the witnessed history of AIDS – through a life in pursuit of deadly viruses- is narrated by Peter Piot in his intense book “No Time to Lose”.
In this issue of our journal we have the privilege to publish a long interview to Peter Piot, that is the director of legendary London School of Hygiene and Tropical Medicine, former undersecretary general of the United Nations and former executive director of UNAIDS. As usual, at the end of the year new geographical atlas are published to fix where we are and how the World goes. This is the reason why we use the book of Piot as a cartography of contemporary AIDS.
Happy new year

Article found in – HAART and correlated pathologies n. 17 –

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Thucydides, HIV and HCV. About the contemporary

Editor Editorial

It could be an unusual mix to put together the greatest Athenian historian, a 30 years old pandemic and hepatitis (mainly HCV infection). But if you have 5 minutes of your time to waste, follow my joke. Because a conceptual link could be found.
I would start with Thucydides. He writes at the beginning of History of the Peloponnesian War: “Thucydides, an Athenian, wrote the history of the war between the Peloponnesians and the Athenians, beginning at the moment that it broke out, and believing that it would be a great war and more worthy of relation than any that had preceded it. This belief was not without its grounds. The preparations of both the combatants were in the last state of perfection; and he could see the rest of the Hellenic race taking sides in the quarrel; those who delayed doing so at once having it in contemplation. Indeed this was the greatest movement yet known in history, not only of the Hellenes, but of a large part of the barbarian world- I had almost said of mankind”.
I want to make clear that I have chosen these lines not because of the war metaphor, but because of the issue of time (and also because it is a such impressive start). In this case the key factor relates to the issue of “time” –the innovation made by Tucydides- is how to deal with the distance between an event and its historical description.
How long do we have to wait, before we can start to describe, understand and interpretate historical events?
Tucydides is the first who gives us an answer. He says that he is “an Athenian” and that he has started to describe, to write, to tell us “the history of the war (…) beginning at the moment that it broke out, and believing that it would be a great war and more worthy of relation than any that had preceded it. This belief was not without its grounds”. Tucydides starts contemporary history, writing as a conscious part of the events he describes -he declares to be “an Athenian”- underlying that he is convinced that the events he was seeing would be “great (…) more worthy of relation than any had preceded them”.
This is what I thought when I received form Amazon my copy of “AIDS at 30. A history”, written by Victoria A. Harden. On the backside cover it is written “current events/ medicine/ medical history”. How is it possible to write the history of an event or a social phenomenon that is still going on? It is quite easy to tell when a story starts but how do we know where and where it stops?
For twenty years Victoria A. Harden was funding director of the Office of NIH History at the National Institutes of Health. In her wonderful book she approaches the virus from a multidiscipline perspective in the history of medical science. It enables her to discuss the process of scientific discovery, scientific evidence and how laboratories identified HIV as the cause of AIDS and developed therapeutic intervention. In addition to that, her study defines AIDS as the first infectious disease to be recognized simultaneously worldwide as a single phenomenon (let’s say so impressive as Peloponnesian War seemed to be for Tucydides).
When the epidemic started society was not prepared for the appearance of a new infectious disease. “After years of believing that vaccines and antibiotics would keep deadly epidemics away, researchers, doctors, patients and the public were forced to abandon the arrogant assumption that they had conquered infectious diseases”. AIDS at 30 illustrates “how medicine identifies and evaluates new infectious disease quickly and what political and cultural factors affect the medical community response”.
How do we define an epilogue for AIDS? We can only say where we are now and where we will be –possibly- in the future. When we see the statistics of death caused by HIV, the rates drop drastically after the introduction of HAART. It happened in 1996 in the northen hemisphere and now we can see a similar trend in the rest of the world. Due to the increase of funding of international donors for diagnosis, treatments and prevention efforts. “Sub-Saharian Africa’s graph shows a similar pattern, with one exception: the number of deaths in the region are measured in millions instead of thousands that characterize the rest of the world”. HIV is a recent discovery: “looking back over the three decades of the HIV/AIDS epidemic, medical science can be pride in how quickly the syndrome was identified, the causative agent found , a diagnostic test prepared and an effective therapy developed”, writes Harden, commenting on Paul Volberding’s quote: “there is probably not anything the equivalent in medicine, apart from may be the development of penicillin, in terms of night and day difference”.
HIV/AIDS is not a classic epidemic like the 1918-19 influenza or a cholera outbreak: “untreated HIV killed 100 per cent of people who developed full blown epidemic AIDS” and “perhaps the most novel development during the first three decades of the epidemic was the consensus during the third decade that HIV/AIDS required a global response because it was a global threat”. This consensus has made it possible to define a new medical discipline called implementation science: “the scientific study of methods to promote the integration of research findings and evidence based intervention into health care policy and practice and hence to improve the quality and effectiveness of health services and care”, according to Peter Piot’s definition.
In my opinion this is the best value of this book, written simultaneously when the events and the consequences are happening contemporarily in front of us, it is like a journey in a new land and the author-traveler is mapping the land where we are. I think that Victoria A. Harden rooted its cultural and historical analysis of HIV/AIDS in the same way that Paul Theroux –the acclaimed author of travel books- did. He explains that “in a sense, the world was once blank. And reason cartography made it visible and glowing with detail was because man believed, and rightly, that maps are a legacy that allows other men and future generations to communicate and trade”.
Speaking about contemporary history, we can say that only time will provide the necessary perspective. Harden suggests that HIV/AIDS epidemic “will be viewed as all others epidemics, as a biological event occurring in a historical time within human social, political, religious and cultural institution”.
In this light, inside our issue of HAART, we decided to cover the Washington International AIDS Conference publishing the opening speech made by Jim Yong Kim, World Bank Group President, about AIDS and poverty, followed by the closing remark made by Francoise Barre-Sinoussi, Nobel laureate and President of International AIDS Society, drawing a possible future scenario from her point of view, being a scientist, a woman and an advocate. In her book Harden claims that “one of the unique characteristic of the HIV/AIDS epidemic has been the vigorous and continuous involvement of people with HIV/AIDS and their supporters, together known colloquially as “AIDS activists”.
It is a curious coincidence that in the same box from Amazon came, with “AIDS at 30”, another book: “ Patients as Policy Actors” edited by Beatrix Hoffman; Nancy Tomes, Rachel Grob and Mark Schlesinger. The structure of this strong volume reflects the authors’ determination “to broaden conceptions of patients action and to appreciate the complexity of its influence”.
The book is articulated in 3 sections, each focused on a different type of patient action and voice in health care system. Part 1, titled “Voices of the Silent” examines patients who have been silent or silenced and reflects on the implication of their silence, including the efforts of others to speak for them. Part 2, titled “From Individual to Collective”, looks at patients who speak more directly on their own behalf, both as individuals and as groups (could individuals and collective identities shape patient’s roles as policy actors? Can patients voices constitute a collective action? In which way?). Part 3, “How Patient Matter”, explores situations in which patient influence, both intended and unexpected, succeeded in changing policy. This section is closed by Steven Epstein, providing “a wide-ranging examination of what it means to say that a social movement has achieved success”.
According with the editors, “the desire to understand the role that patients do, can and should have in health care policy making is the driving force behind this book”. Two considerations support this book: first, putting together researcher from different disciplines –those who are studying in patients empowerment and those who are analyzing health care system- the book constitutes an excellent opportunity to pool the different authors/ disciplines insights “into the complex ways that patients interact with health care institutions and influence policy outcomes”. Secondly, it represents the more complete state-of -the-art volume on “wide variety of patients actions and policy arenas”, preferring to use a broader definition of an action in order to represent more accurately “the impact and the potential of the patient-consumer voice in the health care system”. The proposed analysis starts from the fact that “two paradigms – patient-centered medicine and consumer-driven health care- have emerged as road maps to define how patients should exercise greater control over their care” wrote Nancy Thomas and Beatrix Hoffman. “Patient-centered medicine attempts to enhance patients’ involvement in clinical decision making, while consumer-driven health care focuses on economic choice”.
In different ways, but “both paradigms assume that consumers empowered to act on their needs and preferences will change the health care system for better”. Where is the contradiction? Although both approaches have drawn new attention to the role that empowered patient can play in restructuring a dysfunctional heath care system, they tend to put the cart before the horse: they assume that a patient can have a corrective influence on health care trends in the absence of concrete evidence that such a capacity exist”. There are not many in detth analysis that investigate if and how patients and consumers could play a role in transforming doctor-patient relationship, medical institutions, access to care, heath care policy. “Although patient initiative have secured the expansion of some kind of choice and safeguards, especially for the educated and affluent, they have been offset by growing demands for costs containment and marked discipline that have limited both physicians’ and patients’ autonomy”.
In the book there many pages devoted to Hepatitis, but what is happening in our world in these days –let say in the contemporary- with the revolution of Direct Antiviral Agents (DAAs) for HCV infection, create the perfect scenario to read the “Patients as Policy Actors”. Access to drugs, prescription criteria, reimbursement, costcontainment and budget constraint are the key words through which Scientific Societies, health care providers, patients associations and decision makers must define the best inclusive public policy to respond to health needs.
This is the reason why we publish in this book the expert opinion on DAAs by AISF –the most authoritative Italian scientific society on liver disease- and a comment from a member of this society, prof. Calogero Cammà.
This is just the beginning of a debate on DAAs. In the next HAART issue we will host other comments from MDs as well as from patient associations. We will welcome any further comments… I wish you a pleasent reading.

Article found in – HAART and correlated pathologies n. 16 –

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

Editor Interview

“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.

Article found in – HAART and correlated pathologies n. 15 –

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

Editor Interview

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.

Article found in – HAART and correlated pathologies n. 15 –

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

Editor Interview

“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.

Article found in – HAART and correlated pathologies n. 15 –

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

Editor Interview

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

Why is so fascinating thinking about an interferonfree regime?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Not every physician can address this kind of issues…

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

Article found in – HAART and correlated pathologies n. 15 –

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PrEP today – Interview with Mark Weinberg

Editor Special

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?

A:
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.

Article found in – HAART and correlated pathologies n. 15 –

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Routine prescribers? No thanks – Interview with Mark Nelson

Editor Special

“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.

Article found 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

Editor Special

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.

Article found in – HAART and correlated pathologies n. 15 –

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

Editor Special

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.

Article found in – HAART and correlated pathologies n. 15 –

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