Cyclophilin inhibitors: a novel class of promising host-targeting anti-HCV agents
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Cyclophilin inhibitors: a novel class of promising host-targeting anti-HCV agents Philippe A. Gallay
Published online: 15 December 2011 Ó Springer Science+Business Media, LLC 2011
Abstract With the approval in 2011 of the protease inhibitors Victrelis and Incivek, direct-acting antivirals have begun to revolutionize HCV treatment. Although the addition of Incivek or Victrelis to PEGylated IFNa and ribavarin (pIFNa/RBV) may improve cure rates and shorten the treatment duration of the ‘‘old’’ standard of care (SOC), this triple therapy will not be suitable for patients intolerant to pIFNa or RBV. The efficacy of this triple therapy will also certainly be attenuated in pIFNa/RBV non-responders. As Incivek is inactive against genotype 3 (GT3) combined with the fact that all protease inhibitors and most of the non-nucleoside polymerase inhibitors in development are active primarily against GT1, pIFNa/RBV will remain the SOC for non-GT1 until new classes of inhibitors enter into clinical practice. GT1 patients who do not respond to this new triple therapy will have developed resistance to protease inhibitors that will limit future treatment options. There is thus an important need for the identification of new potent HCV agents. A novel class of HCV inhibitors that have great potential for the treatment for HCV has recently emerged: the host-targeting antivirals cyclophilin inhibitors. Keywords HCV Treatment Cyclophilins Cyclophilin inhibitors Host-targeting antiviral
P. A. Gallay (&) Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA e-mail: [email protected]
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Introduction Hepatitis C HCV is the major causative agent of acute and chronic liver diseases [1]. Primary infection is often asymptomatic or associated with mild symptoms, whereas persistently infected individuals exhibit a high risk of chronic liver diseases, such as hepatocellular carcinoma and cirrhosis [1]. Nearly 200 million people worldwide (3% of the population), including 4–5 million in the United States, are chronically infected with HCV and 4 million new infections occur every year [2, 3]. In the developed world, HCV accounts for two-thirds of all cases of liver cancer and transplants [4], and in the United States, approximately 12,000 people are estimated to die from HCV each year [5]. The ‘‘old’’ standard of care The introduction of interferon alpha (IFNa) and the nucleoside analog RBV greatly improved the percentage of chronically HCV-infected patients able to reach a sustained antiviral response (SVR) [6, 7]. SVR is defined by undetectable HCV RNA levels 24 weeks following completion of therapy and long-lasting viral clearance. Yet, the ‘‘old’’ standard pIFNa/RBV therapy has a low success rate of approximately 50% in patients with GT1 [8, 9] and causes severe side effects (i.e., sustained flu-like symptoms, anemia and depression) [10]. Not only is GT1 the most prevalent HCV genotype in Europe, North and South America, China and Japan, it is also the mo
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