Jessica Parkinson assisted in the preparation of the article. Kristin Stephan, PhD, provided article and editorial coordination support. Jonathan Kirk provided graphical design support. All are employees/stockholders of Vertex Pharmaceuticals Inc. All authors were either employed by Vertex Pharmaceuticals Inc. (V.G., J.E.L., K.A., P.N., and X.L.) or Tibotec (R.v.H.) at the time of the study. J.E.L. is currently employed by the U.S. Food and Drug Administration, Silver Spring, MD. Her contribution to this article was based on her prior employment

and the content of the work does not necessarily reflect any position of the Food and Drug Administration. NVP-AUY922 clinical trial “
“Pegylated interferon-α (PEG-IFN-α) forms an integral part of the current treatment for hepatitis C virus (HCV) infection. PEG-IFN-α suppresses HCV production by augmenting the innate antiviral immune response. Recent studies have reported the induction of hepcidin, the iron regulatory hormone, by IFN-α in vitro. As hepcidin plays an important Everolimus in vivo role in innate immunity,

we hypothesized that this finding may be of clinical relevance to HCV and investigated the changes in iron homeostasis during the first 24 hours of treatment. Blood samples were obtained from HCV patients immediately prior to and 6, 12, and 24 hours following the first dose of PEG-IFN-α/ribavirin (RBV). Samples were 上海皓元 analyzed for hepcidin, cytokine, iron levels, and HCV viral load, and hepcidin messenger RNA (mRNA) expression was quantified in peripheral blood mononuclear cells. Hepcidin induction by IFN-α was further analyzed in cell culture. In HCV patients a single dose of PEG-IFN-α/RBV resulted in a

significant increase in serum hepcidin, peaking at 12 hours, coinciding with a 50% reduction in serum iron and transferrin saturation over the 24-hour period. Patients with a ≥2 log decline in HCV viral load over the first 24 hours had significantly lower SI and TS levels at 12 and 24 hours. Moreover, 24-hour SI levels were an independent predictor of the immediate HCV viral decline, an indicator of ultimate treatment outcome. In cell culture, a direct induction of hepcidin by IFN-α was seen, controlled by the STAT3 transcription factor. Conclusion: Hepcidin induction occurs following the initiation of PEG-IFN-α treatment for HCV, and is mediated by way of STAT3 signaling. The subsequent hypoferremia was greatest in those with the most significant decline in viral load, identifying systemic iron withdrawal as a marker of immediate interferon-α efficacy in HCV patients. (HEPATOLOGY 2012) Chronic hepatitis C virus (HCV) infection is a leading cause of endstage liver disease worldwide.1 Current therapy involves pegylated interferon alpha (PEG-IFN-α) in combination with the nucleoside analog ribavirin (RBV).