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III CURSO PARA RESIDENTES SOBRE DIAGNSTICO Y TRATAMIENTO DE LAS ENFERMEDADES HEPTICAS Barcelona, 11-12 de noviembre de 2011Tratamiento de la hepatitis crnica C

Javier Garca-Samaniego Unidad de HepatologaHospital Carlos III. CIBERehd MadridObjetivos del tratamientoObjetivo primario = curarEliminar el virus1Detener la progresin(necrosis/fibrosis)Aliviar los sntomasObjetivos secundarios

Reducir la progresin de la fibrosis1 Reducir la evolucin a cirrosis2 Evitar descompensaciones Evitar el CHC21. Worman. Hepatitis C: Sourcebook 2002. 2. Peters et al. Medscape HIV/AIDS eJournal. 2002;8(1). Host DNAHepatitis C differs from HIV and HBV No long-term or latent reservoir HBVHIVHCVcccDNAProviral DNAViral RNATREATMENTTREATMENTTREATMENTLong-term suppression of viral replicationLong-term suppression of viral replicationViral Eradication = CureEvolucin del tratamiento de la hepatitis CDescubrimiento del genoma del VHCLa combinacin IFN + RBV mejora la respuestaPeg-IFN alfa ms RBV terapia de referenciaTratamiento con IFN alfa 3 veces/sem durante 24 o 48 sem. Resultados pobres Desarrollo de Peg-IFN en monoterapia20111989Terapia basada en la respuesta viralDesarrollo de nuevos antivirales Evolucin de la tasa de respuesta0102030405060701009080RVS (%)66%19%41%39%6%200571998 48 sem219981,2200031997 24 s1 1. McHutchison J, et al. N Engl J Med 1998; 339: 1485 2. Poynard T, et al. Lancet 1998; 352: 14263. Zeuzem S, et al. N Engl J Med 2000; 343: 1666 4. Lindsay K, et al. Hepatology 2001; 34: 395 5. Manns M, et al. Lancet 2001; 358: 958 6. Fried M, et al. N Engl J Med 2002; 347: 975 7. Zeuzem S, et al. J Hepatol 2005; 43: 25054%20015Todos los genotipos23%56%2001420026Peg-IFN-2b + RBV Peg-IFN-2 a + RBV Peg-IFN-2b Peg-IFN -2aIFN + RBVIFNEASL 2011 HCV Guidelines: PegIFN/RBV RegimensCraxi A, et al. J Hepatology. 2011;[Epub ahead of print].Genotype 1/4PegIFN alfa-2aPegIFN alfa-2bPegIFN dose (weekly)180 g1.5 g/kgRBV dose (daily)15 mg/kg15 mg/kgPlanned duration*48 wks48 wksGenotype 2/3PegIFN alfa-2aPegIFN alfa-2bPegIFN dose (weekly)180 g1.5 g/kgRBV dose (daily)800 mg800 mgIf low responsiveness anticipated15 mg/kg15 mg/kgPlanned duration24 wks24 wks*24 wks of therapy can be considered in patients with low HCV RNA (< 400,000-800,000 IU/mL) who achieve RVR.12-16 wks can be considered in patients who achieve RVR.Hepatitis C: escenario en 2011Tratamiento con pegIFN + RBV en pacientes con genotipos 2, 3 y 4 Aprobacin de los primeros DAAs: telaprevir y boceprevirIncremento de la RVS hasta el 75% con terapia triple en pacientes naves G1Problemas potenciales con el uso de estos nuevos frmacos:Seleccin adecuada de los pacientesControl y monitorizacin inapropiadosManejo de los efectos adversosResistenciasInteracciones farmacolgicas

HCV Treatment: A Lexicon of Acronyms DAAs: direct acting antivirals IL28B: IL28B polymorphism (rs12979860) genotype test NA: nucleoside analog polymerase inhibitors NNI: nonnucleoside polymerase inhibitors PI: protease inhibitors MV: minority variants UDPS: ultradeep pyrosequencing vBT: viral breakthrough RGT: response-guided therapyeRVR: extended rapid virological responseDRM: drug-resistant mutations New predictors: Genetic markers associated with SVR to PEG plus RBV in genotype 1 HCV patients**Ge D, et al. Nature.2009;461:399-401.Factor Associated With SVROdds Ratio (95% CI)Baseline HCV RNA (< vs 600,000 IU/mL)1.010.00.1IL28B rs12979860 genotype (CC vs TT)7.3Baseline fibrosis (METAVIR F0-F2 vs F3-F4)Whites (n = 871)Blacks (n = 191)Hispanics (n = 75)4.23.06.15.11.15.62.44.1Genetics Predict Response: IL28B C/C Associated With Higher SVR Rate in Gt 1

SVR (%)European-AmericansAfrican-AmericansHispanicsCombinedT/TT/CC/CT/CT/CT/CT/TC/CT/TC/CT/TC/C102336703014261863924339135559n =P = 1.06 x 10-25P = 2.06 x 10-3P = 4.39 x 10-3P = 1.37 x 10-28Genotype of rs12979860 on chromosome 19. Ge D et al. Nature. 2009;461:399-401.Select DAAs in Clinical DevelopmentPhase IPhase IIPhase IIIProtease InhibitorsABT-450ACH-1625GS 9451MK-5172VX-985

BMS-650032-AsuprenavirCTS-1027DanoprevirGS 9256IDX320VaniprevirBI 201335Boceprevir (approved)Telaprevir (approved)TMC435Nonnucleoside polymerase inhibitorsBI 207127IDX375ABT-333ABT-072ANA598BMS-791325FilibuvirTegobuvirVX-759VX-222Nucleoside polymerase inhibitorsIDX184PSI-7977RG7128-MericitabineNS5A inhibitorsA-831PPI-461

BMS-790052-DaclatasvirBMS-824393CF102Pre ClinicPhase IPhase IIPhase IIICyclo sporine analogueSCY-635 (Scynexis)Cyclo sporine analogueAlisporivir (Novartis)Cyclo sporine analogueNIM-811 ( Novartis)Entree inhibitorPRO-206 (Progenics) Cyclo sporine analogueJTK-652 (Amsterdam) TLR agonistANA 773 (Anadys)Cyclo sporine analogueEP-CyP282 (Enanta)Anti-HCV drugs in developmentNTelapreviroBoceprevirRibavirinaPegIFN-Standard of care en 2012Boceprevir and TelaprevirBoceprevir, a potent inhibitor of HCV NS3/4A proteaseTelaprevir, a potent inhibitor of HCV NS3/4A proteaseBoth being tested in combination with standard-of-care pegIFN alfa-2/RBV in phase III studies in chronic HCV infectionBoceprevirSPRINT-2: naive GT1 patientsRESPOND-2: nonresponder GT1 patients (partial responders and relapsers)TelaprevirADVANCE: naive GT1 patientsILLUMINATE: response-guided therapy in naive GT1 paitentsREALIZE: nonresponder GT1 patients (null responders, partial responders, relapsers)Phase III ADVANCE: Telaprevir + PegIFN/RBV in GT 1 Tx-Nave PatientsTreatment-naive patients with GT 1 HCV

(N = 1088)Wk 12TVR + PR*(n = 364)TVR + PR*(n = 363)PR*(n = 361)eRVR: PR*Wk 72Wk 48Wk 8Follow-upFollow-upFollow-up*TVR 750 mg q8h; pegIFN alfa-2a 180 g/wk; weight-based RBV 1000-1200 mg/day. eRVR = undetectable HCV RNA at Wks 4 and 12.Jacobson I, et al. N Engl J Med 2011;364:2405-2416.Wk 24PR*eRVR: PR*PR*Follow-upFollow-upRandomized, placebo-controlled trialADVANCE: SVR ratesSVR756944P