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Scientists at Inserm and Institut Pasteur have performed biomarker discovery on patients being treated for chronic hepatitis C infection. Their work, published in The Journal of Clinical Investigation, demonstrates that the plasma levels of the protein IP-10 predict, prior to treatment initiation, the efficacy of treatment with pegylated-interferon and ribavirin. Based on these results, the scientists have developed a prognostic test. Commercialization is anticipated in 2011, and will help inform physicians of the chances that patients will respond to standard treatment or if instead they will require new therapeutic cocktails (e.g., inclusion of protease inhibitors).
Importantly, hepatitis C is the leading cause of primary liver cancer (hepatocellular carcinoma) and it remains an important cause of liver failure due to fibrosis and cirrhosis. This infectious disease represents a major public health problem, with greater than 170 million cases worldwide. The World Health Organization estimates 3 to 4 million new cases per year and considers the virus a “ viral time bomb” due to the long term sequella of infection.
Currently, there is no approved vaccine available and approximately 80% of individuals infected by the virus develop chronic disease, a risk factor for cirrhosis, liver failure, liver cancer as well as other medical complications (e.g., diabetes).
For the past ten years, treatment has been based on the use of type I interferon given in combination with the anti-viral ribavirin. While effective, it results in a cure for only 50% of patients. Moreover, treatment is long (24 – 48 weeks), and it results in severe side effects (e.g., depression, anemia).
It is in this context that the Inserm and Institut Pasteur sponsored research lab of Dr. Matthew Albert, in close collaboration with the Liver Disease Unit headed by Prof. Stanislas Pol, evaluated plasma biomarkers to define predictors for patients’ response to treatment.
With the help of the Centre for Human Immunology at Institut Pasteur, the investigators involved have performed a prospective study. They identified the protein IP-10 as a prognostic biomarker – elevated in those patients for whom treatment was ineffective. This observation was paradoxical as IP-10 is considered a pro-inflammatory molecule, which should have facilitated migration of activated T cells to the liver, the exact cell types responsible for viral immunity. In fact, what was discovered is that the IP-10 had been catabolized and it was a truncated form present in the HCV patients. Strikingly, the short form of IP-10 is an antagonist and inhibits T cell recruitment. Thus, it is suggested that the antagonist form of IP-10 is responsible for the failure to respond to treatment in the 50% of patients who do not benefit from pegylated-interferon / ribavirin treatment.
The investigators worked in close collaboration with an American company, Rules Based Medicine, Inc., who will develop a diagnostic test to distinguish the different forms of IP-10 as a simple blood test. This test will be a significant step towards the improved management of patients with HCV as well as other chronic inflammatory diseases.
This scientific work was conducted under the direction of Matthew L. Albert, MD PhD, Mixed Institut Pasteur / Inserm Research Unit; and Stanislas Pol, MD PhD, Univerisity of Paris, Descartes and Institut Cochin. Financial support was provided by the ANRS and promotion of the study was taken by Inserm Medical.
Evidence for chemokine antagonisms in human infected chronically with Hepatitis C Virus, Journal of Clinical Investigation, XXXX.
Armanda Casrouge, Jérémie Decalf, Mina Ahloulay, Cyril Lababidi, Hala Mansour, Anaïs Vallet-Pichard, Vincent Mallet, Estelle Mottez, James Mapes, Arnaud Fontanet, Stanislas Pol and Matthew L. Albert
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