HAART and correlated pathologies N. 18


La rivista presenta i seguenti articoli:

Hiv & bone metabolism
Autore/i: Davide Gibellini; Fabio Vescini; Paolo Bonfanti; Stefano Mora; Antonio Di Biagio; Tiziana Quirino; Marco Borderi.
Much cheaper, almost as good treatment: a possible approach to guarantee sustainability of HIV care?
Autore/i: Enrico Girardi; Claudio Angeletti.
The PrEP Failures at CROI 2013
Autore/i: Giuseppina Liuzzi.
How to monitor bone disease in HIV infection
Autore/i: Marco Borderi; Pierluigi Viale.

Anno: 2013
Formato: Brossurato – Colore
Pubblicato il: 01/03/2013
Dimensioni: 21 cm x 29,7 cm x 0,8 cm
Pagine: 48
ISSN: 1974-3246

Management of invasive fungal Infections in non-neutropenic patients


Invasive fungal infections (IFIs) are documented in critically ill, non-neutropenic patients, in intensive care units (ICUs) and surgical wards, but also in non critical patients cared for in medical wards.
Candida spp. infections mainly occur in patients undergone to major abdominal surgery, receiving broad spectrum antibiotic therapy and after a long ICU stay. A more favorable outcome is reported for fungemia due to C. parapsilosis; the worse prognosis is associated with C. tropicalis infections.
Any delay in starting an appropriate antifungal treatment is associated with an increase in mortality rate of candidemia. When used as empirical therapy, fluconazole did not show any superiority to placebo and was inferior to anidulafungin in the treatment of documented candidemia/invasive candidiasis. ECCMID guidelines emphasize the role of echinocandins and, as a reliable alternative, suggest the use of liposomal Amphotericin B. Although with more nephrotoxicity with respect to echinocandins, Amphotericin B showed a systematic fungicidal and anti-biofilm activity against C. albicans and non-albicans species.
Invasive Aspergillosis have been also reported in non neutropenic patients with chronic obstructive pulmonary disorders receiving steroid therapy for respiratory failure, in pts with severe liver failure and in solid organ transplant patients. Treatment of choice for Invasive Aspergillosis is represented by Voriconazole, but liposomal Amphotericin B represents a reliable alternative when azole use is contraindicated.

Articolo presente in – HAART and correlated pathologies n. 17

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HIV regimens de-intensification with PI monotherapy: one size does not fit all


The 2008-2011 aids&mobility project aimed to improve health literacy and awareness among the immigrant population of HIV and the health service availability by training young migrants as certified transcultural mediators to promote health and prevention in their communities.
The project established its activities and target population on included a systematic literature review of the scientific literature. The literature wes also the frame of reference for the evaluation and publication of results.
Evaluation was based on the folllowing:
– Outcomes of the HIV health promotion activities and drug-related programs aimed at increasing access to counselling, testing and treatment;
– Method used to measure outocoms;
– Method used to calculate effectiveness calculated and whether comparable to economic modelling; eventual “social accounting”;
– Policy recommendations to ensure program sustainability;
The review describes the results of the analysis of relevant research articles identified through a systematic database search.

Articolo presente in – HAART and correlated pathologies n. 17

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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

Articolo presente in – HAART and correlated pathologies n. 17

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HAART and correlated pathologies N. 17


La rivista presenta i seguenti articoli:

Autore/i: Andrea Tomasini.
No time to lose
Autore/i: Andrea Tomasini.
HIV regimens de-intensification with PI monotherapy: one size does not fit all
Authore/i: Diego Ripamonti.
Management of invasive fungal Infections in non-neutropenic patients
Autore/i: Francesco Menichetti; Enrico Tagliaferri.

On the verge of getting a much better treatment
Autore/i: Andrea Tomasini.

Anno: 2012
Formato: Brossurato – Colore
Pubblicato il: 01/12/2012
Dimensioni: 21 cm x 29,7 cm x 0,8 cm
Pagine: 48
ISSN: 1974-3246

Thucydides, HIV and HCV. About the contemporary

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.

Articolo presente in – HAART and correlated pathologies n. 16

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HAART and correlated pathologies N. 16


La rivista presenta i seguenti articoli:

Thucydides, HIV and HCV. About the contemporary
Autore/i: Andrea Tomasini.
First-generation Hcv protease inhibitors: A sustainable innovative Technology?
Autore/i: Calogero Cammà.
The Invader(s) Images, maps, essays and the outbreak narratives
Autore/i: Andrea Tomasini.
Ending AIDS and Poverty
Autore/i: Jim Yong Kim.
On Being scientist, advocate, woman
Autore/i: Françoise Barré-Sinoussi.
Microbial translocation and novel therapeutic interventions to reduce induced immune activation
Autore/i: Jason Brenchley.

Anno: 2012
Formato: Brossurato – Colore
Pubblicato il: 02/09/2012
Dimensioni: 21 cm x 29,7 cm x 0,8 cm
Pagine: 48
ISSN: 1974-3246

HOT TOPICS IN HIV - Allegato a HAART and correlated pathologies N. 16

HOT TOPICS IN HIV – Allegato a HAART N. 16

La rivista presenta i seguenti articoli:

Autore/i Andrea Tomasini.
Tossicità a lungo termine – Introduzione
Autore/i Andrea Tomasini.
La tollerabilità dei regimi non contenenti nucleosidici in terapia antiretrovirale
Autore/i Antonio Di Biagio.
Insufficienza renale e nefrotossicità correlate alla HAART
Autore/i Paolo Maggi.
Tossicità ossea della terapia antiretrovirale
Autore/i Paolo Bonfanti.
HAART e tossicità muscolare
Autore/i Giordano Madeddu.
Ruolo e limiti della terapia HAART nella coinfezione da virus epatitici: quali i problemi alla luce delle nuove terapie
Autore/i Tiziana Quirino.
Focus on: la tossicità a lungo termine nelle Linee Guida
Autore/i Marco Borderi.
Monoterapia – Introduzione
Autore/i Andrea Tomasini.
Nuove scelte terapeutiche: le ragioni della monoterapia
Autore/i Teresa Bini.
Revisione critica dell’uso dei diversi PI negli studi di monoterapia
Autore/i Mauro Zaccarelli.
Fattori predittivi del fallimento della monoterapia con inibitori delle proteasi (PI/r) come terapia di semplificazione nei pazienti con meno di 50 copie/ml di HIV RNA
Autore/i Nicola Gianotti.
I rischi associati al fallimento virologico in corso di monoterapia con IP/r
Autore/i Diego Ripamonti.
Regimi di monoterapia: quali vantaggi?
Autore/i Cristina Gervasoni.
Monoterapia: un confronto con Linee Guida
Autore/i Simona Di Giambenedetto.
Induzione, mantenimento e semplificazione – Introduzione
Autore/i Andrea Tomasini.
Il trattamento del paziente naïve: Linee Guida e pratica clinica
Autore/i Cristina Mussini.
La semplificazione terapeutica: cosa dicono le Linee Guida Italiane
Autore/i Sergio Lo Caputo.
Il paziente con soppressione virologica mantenuta: nuovi scenari virologici, farmacologici e nuovi switch terapeutici
Autore/i Stefano Rusconi; Stefano Bonora.
Paradigma induzione-mantenimento: progettare una terapia cronica
Autore/i Renato Maserati.
Ageing – Introduzione
Autore/i Andrea Tomasini.
Etiopatogenesi e diagnosi del paziente anziano con infezione da HIV ed invecchiamento precoce: un confronto con le Linee Guida
Autore/i Benedetto Maurizio Celesia.
Ageing, infezione virologica persistente e immunosenescenza
Autore/i Carlo Torti.
Il fenotipo fragile nella caratterizzazione clinica del paziente con infezione da HIV
Autore/i Giovanni Guaraldi.
Asymmetric dimethylarginine – ADMA, un nuovo marcatore di danno endoteliale nei pazienti con infezione da HIV – Hot topic from CROI 2012
Autore/i Emanuele Nicastri.
Insulino-resistenza, diabete e infezione da HIV: update 2012
Autore/i Antonella Castagna.
SNC – Introduzione
Autore/i Andrea Tomasini.
Epidemiologia e stadiazione del danno neurologico
Autore/i Andrea Gori.
Cerebrospinal Fluid escape in corso di HAART
Autore/i Paola Cinque.
Neuroefficacia e neurotossicità della HAART
Autore/i Andrea De Luca.
Lo screening e la neurodiagnostica nella pratica clinica
Autore/i Valerio Tozzi.
Le nuove prospettive del Neuroimaging nel paziente HIV
Autore/i Amedeo Capetti.
Il confronto con le Linee Guida per il management del deficit neurocognitivo HIV-correlato
Autore/i Giustino Parruti.

Anno: 2012
Formato: Brossurato – Colore
Pubblicato il: 01/09/2012
Dimensioni: 21 cm x 29,7 cm x 0,8 cm
Pagine: 80
ISSN: 1974-3246

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

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

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

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

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

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

Another word that is critical is “assay”.

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

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

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

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

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

Another word with different meaning is “strategy”.

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

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

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

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

Another hard word is “cost”.

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

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

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

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

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

Articolo presente in – HAART and correlated pathologies n. 15

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Too much is not enough.

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

Articolo presente in – HAART and correlated pathologies n. 15

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