CurrentandFutureTreatmentofChronicHepatitisC.ppt

Current and Future Treatment of Chronic Hepatitis C John Scott, MD, MSc University of Washington Case 43 yo Asian woman w/ chronic Hep C, GT 1, HCV RNA level of 2 million IU/ml ALT 53, INR 1.0, Albumin 4.1 Liver biopsy: grade 2 inflammation, stage 2 fibrosis HTN What to do next? Treat now or wait? Outline Epidemiology Natural History Current Therapy -Efficacy -Side effects -Mechanism of action -Kinetics Future Therapy Epidemiology 3.9-4.1 million Americans are HCV Ab+ May be as high as 7 million 2.7-3.2 million are chronically infected Highest prevalence in 30-54 yo Highest prevalence in African Americans and Hispanics Risk Factors for HCV Injection drug use (60%) Blood transfusion before 1992 Multiple sex partners Iatrogenic (hemodialysis, re-use of vials, etc) Intranasal cocaine Piercing, tattooing, scarification Unknown (10%) Evolution of therapy for HCV What is Pegylation? Covalent attachment of polyethelene glycol to peptide Increases hydrodynamic size Prolonged circulation, delayed renal clearance PegIntron (12kd, Schering), Pegasys (40kd, Roche) Enzon pharmaceutical Adenosine deaminase Others: Neulasta (GCSF), doxorubicin Side Effects of PegIFN/Ribavirin The importance of viral kinetics Kinetics and SVRGT 1 (Pegasys + RVN) Mechanism of Action: Interferon Effect of IFN-?/Ribavirin Ribavirin Prevention of Relapse Ribavirin’s Antiviral Mechanisms Direct inhibition of HCV RNA-dependent RNA polymerase ? Depletion of intracellular GTP pools via IMPDH inhibition ? RNA mutagenesis leading to error catastrophe ? Ribavirin Antiviral Mechanisms Future Therapies Coming soon! (2011?) Potent Rapid antiviral resistance if used by itself More side effects HCV Life Cycle: Key Features Multiple proteins mediate HCV entry: CD81, Scavenger Receptor B1, Claudin 1, Occludin, Very Low Density Lipoprotein Receptor Input HCV RNA is translated, a polyprotein is formed, and individual viral proteins are released from polyprotein by cellular and viral proteases HCV proteins a