Prise en charge actuelle de l'hépatite C et nouvelles approches thérapeutiques

Transcription

1 Prise en charge actuelle de l'hépatite C et nouvelles approches thérapeutiques Future Complications of Darius Moradpour Service de Gastro-entérologie et d'hépatologie Centre Hospitalier Universitaire Vaudois Darius.Moradpour@hospvd.ch Davis GL et al. Liver Transpl 2003;9: Acute Natural History of Hepatitis C Chronic Cirrhosis 50-80% 4-20% 1-6% / y HCC Based on NIH Consensus Statement. Hepatology 2002;36 (Suppl 1):S2-S20. Progression of Liver Disease Age Gender Alcohol Coinfections (HIV, HBV, Schistosoma) NAFLD Iron overload Diagnosis of Hepatitis C Serologic assays Antibody assays: EIA, RIBA Antigen assays: core antigen Molecular assays HCV RNA Signal amplification assays: bdna Target amplification assays: qualitative or quantitative RT-PCR Genotype determination Risk of Transfusion-Transmitted Hepatitis C 1984 ~ 1 : 100 Surrogate markers Serologic testing Nucleic acid testing 2004 ~ 1 : 2,000,000 Stramer SL et al. N Engl J Med 2004;351:

2 Grading Staging Role of Liver Biopsy Exclusion of other liver diseases Staging Fibrosis Ishak METAVIR None 0 0 Portal fibrosis (some) 1 Portal fibrosis (most) 2 1 Bridging fibrosis (few) 3 2 Bridging fibrosis (many) 4 3 Incomplete cirrhosis 5 Cirrhosis 6 4 Ishak K et al. J Hepatol 1995;22: ; Bedossa P et al. Hepatology 1996;24: Staging of Sampling Error Staging of Noninvasive Fibrosis Predictors Fibrotest Apolipoprotein A1, haptoglobin, a2-macroglobulin, g-gt, bilirubin Imbert-Bismut F et al. Lancet 2001;357: "Forns index" Age, platelets, g-gt, cholesterol Forns X et al. Hepatology 2002;36: AST:platelet ratio index (APRI) Wai C-T et al. Hepatology 2003;38: cm, 1.4 mm: 38% 2.0 cm, 1.4 mm: 94% Colloredo G et al. J Hepatol 2003;39: Fibrosis probability index (FPI) Age, AST, cholesterol, insulin resistance, past alcohol intake Sud A et al. Hepatology 2004;39: Indication for Special Situations All patients with chronic C with an increased risk of developing cirrhosis, i.e. positive HCV RNA necroinflammatory activity significant fibrosis Acute Hepatitis C Persistently normal ALT Advanced liver disease HIV coinfection Recurrence after OLT Active alcohol or drug abuse Chronic renal disease 2

3 Definition of Response Sustained response (SR) Relapse Progress in Treatment of ALT HCV RNA ALT Breakthrough Nonresponse (NR) HCV RNA Months Months Poynard T et al. Lancet 2003;362: Combination PEG-IFN-a + Ribavirin for Hadziyannis S et al. Ann Intern Med 2004;140: Current Early Virological Response Genotype 1 PEG-IFN-a 1 + Ribavirin mg/d for 48 w Genotypes 2 and 3 PEG-IFN-a 1 + Ribavirin 800 mg/d for 24 w 1 PEG-IFN-a2a 180 µg/wk PEG-IFN-a2b 1.5 µg/kg/wk Fried MW et al. N Engl J Med 2002;347:

4 CHRONIC HEPATITIS C HCV genotype determination 2004 GENOTYPE 2 OR 3 GENOTYPE 1 (and 4, 5 or 6) PEG-IFN-a + RBV 800 mg, 24 weeks Liver biopsy HCV RNA detection (sensitive qualitative assay) at the end of treatment and 24 weeks later End-of-treatment virological response Sustained virological response A2 F2 PEG-IFN-a + RBV mg, 48 weeks HCV RNA quantification at baseline and week 12 (genotype 1) A1 F1 No treatment 50% cured by IFN-based therapy 50% resistant to IFN-based therapy 2 log decrease at week 12 HCV RNA detection (sensitive qualitative assay) at the end of treatment and 24 weeks later <2 log decrease at week 12 Stop treatment or continue in order to slow evolution of liver disease Better tolerability: monitoring and tailoring of therapy New antiviral strategies Pawlotsky JM. Hepatology 2002;36:S65-S73 End-of-treatment virological response Sustained virological response Hepatitis C Virus Life Cycle Genetic Organization of HCV Moradpour D and Blum HE. Liver Int 2004;24: Moradpour D et al. Trends Mol Med 2002;8: Structure of the HCV NS3-4A Complex HCV NS3 Serine Protease Inhibitor A C Ki = 150 µm B D Ki = < 1 nm Yao N et al. Structure 1999;7: Tsantrizos YS et al. Angew Chem 2003;42:

5 HCV NS3 Serine Protease Inhibitor BILN 2061 Proof-of-Concept Clinical Studies Hepatitis C Virus Life Cycle HCV RNA (IU/ml) BILN ,000,000 1,000,000 Placebo 100,000 10,000 1, days BILN 2061 Placebo GT 1a GT 1b Lamarre D et al. Nature 2003;426:186 / Hinrichsen H et al. Gastroenterology 2004;127:1347 Receptor antagonists Neutralizing antibodies Novel Antiviral Strategies Antisense strategies Ribozymes RNA interference IRES inhibitors Acute Management of Hepatitis C Chronic Cirrhosis HCC Immunotherapy Protease inhibitors Antiviral therapy a-glucosidase inhibitors Interfering peptides and proteins Polymerase inhibitors Helicase inhibitors OLT Prevention HCC Surveillance Cofactors (alcohol, HAV, HBV, overweight) 5