Jean-Michel Pawlotsky on His important Breakthrough in Therapy of Chronic HCV Infection
New Hot Paper Commentary, July 2010
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Article: Telaprevir and Peginterferon with or without Ribavirin for Chronic HCV Infection
Authors: Hezode, C;Forestier, N;Dusheiko, G;Ferenci, P;Pol,
S;Goeser, T;Bronowicki, JP;Bourliere, M;Gharakhanian,
S;Bengtsson, L;McNair, L;George, S;Kieffer, T;Kwong,
A;Kauffman, RS;Alam, J;Pawlotsky,
JM;Zeuzem, S;PROVE2 Study Team |
Jean-Michel Pawlotsky talks with ScienceWatch.com and answers a few questions about this month's New Hot Papers paper in the field of Clinical Medicine.
Why do you think your paper is highly
cited?
Over 170 million individuals are infected with hepatitis C virus (HCV) worldwide. Chronic HCV infection is a leading cause of cirrhosis, end-stage liver disease, and primary liver cancer, and accounts for up to 500,000 deaths per year.
For the past 10 years, we have been living with a treatment based on the combination of pegylated interferon alpha and ribavirin. This treatment cured infection in approximately half of treated patients, but there are still many contraindications to this therapy, especially in the most severe cases, and we had nothing to offer in case of failure.
Our paper represents the most important breakthrough in therapy of this major infectious threat in the past 10 years. It is indeed a phase II trial of a combination of pegylated interferon and ribavirin with a novel, potent, direct-acting antiviral inhibitor of HCV protease. Research on direct acting antivirals has been very active over the past three to five years, thanks to our better knowledge of the HCV life cycle and to the development of new tools and technological approaches for drug design.
Our paper represents the first successful clinical application of these concepts and opens the way to the introduction of such therapies in clinical practice. With infection cure rates on the order of 70% in a rather difficult-to-treat population (patients infected with HCV genotype 1) with a shorter treatment duration than current standard of care, the benefit for the patients is obvious.
Does it describe a new discovery, methodology, or
synthesis of knowledge?
The paper describes the first clinical application of a new discovery, namely direct-acting antiviral molecules that inhibit the enzymatic function of the HCV protease, an enzyme that ensures maturation of viral proteins. The trial was a classical Phase II trial where this drug, called telaprevir and developed jointly by Vertex in the United States and Tibotec in Europe, was used in combination with the current standard treatment of hepatitis C: pegylated interferon and ribavirin.
"...the World Health Organization General Assembly very recently passed a resolution recognizing chronic viral hepatitis (B and C) as a major infectious threat and a priority for health. We believe that our contribution to research in this field will be useful."
The reason for using this combination is that telaprevir monotherapy is associated with the emergence of resistant strains and does not lead to a cure of infection. The combination of both approaches ensures better inhibition of viral replication and prevention of viral resistance in the absence of any cross-resistance.
Would you summarize the significance of your paper
in layman's terms?
This is a major breakthrough in the curative treatment of patients with chronic hepatitis C, who are 170 million worldwide, as this Phase II trial has shown that the combination of the current treatment, interferon alpha and ribavirin, with a specific inhibitor of HCV yields cure rates of the order of 70% in patients infected with HCV genotype 1, a difficult to eradicate virus.
How did you become involved in this research, and how would you describe the particular challenges, setbacks, and successes that you've encountered along the way?
I was trained as a clinical hepatologist and gastroenterologist. HCV was discovered in 1989. In 1990, my mentor suggested that I get interested in this new virus and be trained in molecular virology. I thus became a viral hepatologist or a liver virologist!
I subsequently had the opportunity to build a true translational research team on viral hepatitis, with three complementary and intricate groups: a clinical group doing clinical and epidemiological research and clinical trials; a clinical virology group which has acquired a worldwide recognized expertise in viral hepatitis testing and monitoring tools; and a basic research group.
This latter group has developed research activities in two directions: HCV therapy (mechanisms of treatment failure and success, resistance, new drug design), and pathophysiology of HCV-related liver disease (virus-induced carcinogenesis, mechanisms of liver fibrosis and HCV-related metabolic perturbations).
In this context, I was involved as one of the two Principal Investigators of this Phase II multicenter European trial involving clinical teams from France, Germany, the UK, and Austria. The trial and collaboration was a success and I believe this paper, together with the American Phase II trial published in the same issue of the New England Journal of Medicine, represent a true breakthrough in the way we treat hepatitis C. It has indeed led to the initiation of three Phase III trials that are ongoing and are likely to change the face of HCV therapy within the next two years.
Where do you see your research leading in the
future?
"Over 170 million individuals are infected with hepatitis C virus (HCV) worldwide."
There remains major challenges we want to address in the future. The main ones are treatment failures with new HCV therapies and the major challenge of the increasing incidence of HCV-related liver cancers in the Western world. We are currently extending our research capacity, especially in the lab, in these two directions.
More precisely, we are interested in the mechanisms of action of the drugs, in the molecular mechanisms of drug resistance and in the discovery of new lead compounds that could find applications not only in the treatment of HCV infection, but also in infections related to other members of the same viral family, Flaviviridae, such as dengue, yellow fever or animal pestiviruses.
On the other hand, we are interested in unraveling the molecular mechanisms underlying the intrinsic carcinogenic properties of HCV, which has now become the first cause of primary liver cancers in most industrialized areas.
Do you foresee any social or political
implications for your research?
Participating in the discovery and development of new therapies that may help control a major infectious disease known to be associated with considerable morbidity and mortality obviously has major social and political implications.
In this respect, the World Health Organization General Assembly very
recently passed a resolution recognizing chronic viral hepatitis (B and C)
as a major infectious threat and a priority for health. We believe that our
contribution to research in this field will be useful.
Prof. Jean-Michel Pawlotsky, M.D., Ph.D.
National Reference Center for
Viral Hepatitis B, C and Delta, Department of Virology & INSERM
U955
Henri Mondor Hospital, University of
East-Paris
Créteil, France
KEYWORDS: TELEPREVIR, PEGINTERFERON, RIBAVIRIN, CHRONIC HCV INFECTION, HEPATITIS C VIRUS GENOTYPE 1, VIROLOGIC RESPONSE, PHASE 2 CONTROLLED RANDOMIZED TRIAL, PROVE2 STUDY TEAM, PRURITUS, RASH, ANEMIA, RESPONSE RATES.