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BIOMARCADORES DE TRATAMIENTO EN LA HEPATITIS C

BIOMARCADORES DE TRATAMIENTO EN LA HEPATITIS C. Madrid, 13 de Mayo de 2011. Manuel Romero-Gómez. Unidad Médico-Quirúrgica de Enfermedades Digestivas. Hospital Universitario de Valme. Universidad de Sevilla, Sevilla. Respuesta viral sostenida en genotipo 1. D 25% +Riba. D10 % +Peg.

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BIOMARCADORES DE TRATAMIENTO EN LA HEPATITIS C

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  1. BIOMARCADORES DE TRATAMIENTO EN LA HEPATITIS C Madrid, 13 de Mayo de 2011 Manuel Romero-Gómez. Unidad Médico-Quirúrgica de Enfermedades Digestivas. Hospital Universitario de Valme. Universidad de Sevilla, Sevilla.

  2. Respuesta viral sostenida en genotipo 1 D25% +Riba D10% +Peg D30% +RGT McHutchinson et al. NEJM 1998; Manns et al. Lancet 2001; Fried et al. NEJM 2002; Hezode et al. NEJM 2009

  3. Predictive factors of SVR Viral Genotype Viral load Fibrosis Metabolicabnormalities Genes

  4. Factores predictivos de Respuesta Manns MP, et al. Nat Rev Drug Discov. 2007 Fried et al. NEJM 2002 Romero-Gómez et al. Liver Int 2011

  5. Genotype Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.

  6. Impact of IR & DM on hepatitis C HCV-core NS5A Impairs SVR IR Degradation of IRS-1 Steatosis, Fibrosis Progression and HCC Improvement of viral fitness 1. Pazienza V et al. Hepatology 2007;45:1164 2. Sheikh MY, et al. Hepatology 2008;47:2127 3. Moucari R et al. Gastroenterology 2008;134:416 4. Romero-Gómez et al. Gastroenterology 2005;128:636 Conjeevaram HS et al. Hepatology 2007;45:80-87. Manolakopoulos S et al. BMC Gastroenterol 2007;7:17.

  7. Insulin resistance and sustained virological response Eslam M et al (personal communication)

  8. Genes and SVR: IFN stimulated genes INFalfa IFNAR1 – IFNAR2c JAK-------TyK PTPs SOCS P STAT MxA 5’-2’-OAS PKR APO-E4

  9. Antiviral proteins: MxA, 5’2’-OAS, PKR Weak associations without multivariate analysis Knapp S. Genes Immun 2003;4:411.

  10. APO-E, IL-10, TGF-b1 Il-10: Haplotype extended: (108bp)(-2575T)(-2763C) (-1082A)(-819T)(-592A) Allele rare < 5% Associated with sustained response Confunding factors not excluded N=506 Mueller T. Hepatology 2003;38:1592 Yee LJ. Hepatology 2001;33:708.

  11. HLA B 44 HLA B44 is the most prevalente HLA in caucasians Multivariate analysis: Genotype non-1 [OR=2.42 (1.12 – 5.55)] HLA B44+ [OR=4.84 (1.31-17.8)] N=105 (I+R) N=143 (IFN) Romero Gómez et al. Am J Gastroenterol 2003;98:1621.

  12. GWAS in Hepatitis C

  13. IL28B polymorphisms & SVR Ge et al. Nature 2009;

  14. Influence of IL28b CC genotype on SVR in geno 1 %SVR Ge et al. Nature 2009; Thompson et al. Gastro2010; Rauch et al. Gastro 2010;Tanaka Nature Gen 2009; Suppiah et al. Nature Gen 2009;Montes-Cano et al. Hep2010

  15. Meta-analysis association SVR & genotype CC Romero-Gómez et al. Liver Int 2010 (in press)

  16. IL28B polymorphisms: Distribution by race & SVR Ge et al. Nature 2009;

  17. IL28B mRNA expressionrs8099917 Suppiah et al. Nat Gen 2009;41:1100 Tanaka et al. Nat Gen 2009;41:1105

  18. INF-l3 (IL28B): mechanism of action Asselah et al. J Hepatol 2010 Gad et al. JBC 2009

  19. N=731 SVC=69 CHC= 284 Healthy controls: 378 Montes-Cano et al. Hepatology 2010

  20. IL28b and SPONTANEOUS VIRAL CLEARANCE P<0.0001 202/620 589/1015 Rauch et al. Gastro 2010; Thomas DL et al. Nature 2009;46:798 Tillmann et al. Gastro 2010; Montes-Cano et al. Hepatology 2010

  21. SVR & IL28b IN acute Hepatitis C N=54 n=25 n=29 Grebely et al. Hepatology 2010

  22. IL28b and Spontaneous viral clearance SVR in treated acute Hep C N=54 3/32 15/47 rs 8099917 n=25 n=29 24 w Peg TT Recent HCV infection IL28b rs8099917 Peg GG/GT Gebrely et al. Hepatology 2010

  23. IL28b y Respuesta viral rápida

  24. Influencia del genotipo de la IL28b según RVR Genotipo 1 Thompson A et al. Gastro 2010 Mangia A et al. Gastro 2010

  25. N=268 Genotipo 2/3 rs8099917 N=488 Genotipo 2 rs8099917 Influencia IL28b en genotipo 2/3 p=ns % RVS Yu et al. Hepatology 2011;53:7-13 Mangia et al Gastro 2010 Montes-Cano et al. Hepatology 2010

  26. Influencia del genotipo de la IL28b según genotipo viral y RVR Thompson A et al. Gastro 2010 Mangia A et al. Gastro 2010

  27. IL28b en pacientes tratados con triple terapia: IP + Peg + Riba

  28. SPRINT-2: SVR by IL28B Polymorphism % SVR 50 64 63 77 44 55 33 116 67 103 82 115 10 37 23 42 26 44 Poordad et al. EASL 2011

  29. Triple terapia con boceprevir. SPRINT-2: RVS en función PCR w 4 y 8. Estos resultados incluyen exclusivamente pacientes raza no negra. Poordad F, et al. Boceprevir for Untreated Chronic HCV Genotype 1 Infection. NEJM 2011; 364: 1195-1206.

  30. REALIZE Study Design: Patients with IL28B Genotype Data (n=527) T12/PR48 TVR + Peg-IFN + RBV Pbo + Peg-IFN + RBV Peg-IFN + RBV Follow-up n=212 Lead-in T12/PR48 Pbo + Peg-IFN + RBV TVR + Peg-IFN + RBV Peg-IFN + RBV Follow-up n=210 Pbo/PR48(control) Pbo + Peg-IFN + RBV Peg-IFN + RBV Follow-up n=105 72 4 0 12 16 48 8 Weeks SVR assessment Peg-IFN: Peg-IFN alfa-2a = 180μg/week; RBV = 1000–1200mg/day TVR = 750mg every 8 hours; Pbo = placebo Data from T12/PR48 and LI T12/PR48 arms were pooled since no differences were observed between TVR arms. Randomization was stratified by viral load and prior response. Stopping rules were applied for TVR (Weeks 4, 6, 8 for T12/PR48, Weeks 8, 10, 12 for LI T12/PR48) and PR (Weeks 12, 24, 36 for T12/PR48, Weeks 16, 24, 36 for LI T12/PR48)

  31. Overall Baseline IL28B Genotype Distribution CC CT TT Patients (%) Pooled T12/PR4880/422 Pbo/ PR48 30/105 Pooled T12/PR4876/422 Pbo/ PR4817/105 Pooled T12/PR48266/422 Pbo/ PR4858/105 n/N=

  32. Overall SVR Rates by IL28B Genotype CC CT TT Patients achieving SVR (%) Pooled T12/PR48 60/76 Pbo/ PR48 5/17 Pooled T12/PR48 49/80 Pbo/ PR48 4/30 Pooled T12/PR48 160/266 Pbo/ PR48 9/58 n/N= In a 2-step multivariate analysis exploring factors including: treatment group, IL28B genotype, prior response category, treatment/prior response interaction and other baseline characteristics including baseline HCV RNA, IL28B genotype did not have a significant impact on SVR (p=0.169 for CC, p=0.792 for TT)

  33. SVR Rates by IL28B Genotype and PriorResponse Prior relapsers Prior partial responders Prior null responders Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Patients achieving SVR (%) n/a TT TT TT CC CT CC CT CC CT n/N= 4/12 100/117 3/10 5/8 1/5 2/10 10/14 4/10 27/92 1/15 51/58 6/30 29/34 33/57 0/5 1/18 10/32

  34. Camino hacia la predicción de respuesta viral sostenida SVR 28% Genotype CC 35% 80% N=474 (G1/4) N=268 (G2/3) 56% Genotype CT 50% 25% 50% Genotype TT 15% 3% 20% Stättermayer AF et al. CGH 2011 (in press) Mangia et al. Gastro 2010 Romero Gómez et al. Liver Int 2011 (in press)

  35. Several genetic markers in 19q13.3 (IL28B) Illumina Affymetrix

  36. Interaction between IL28B & fibrosis progression p=ns % IL28b gen CC

  37. Interaction between IL28B & viral load p=ns Viral load (log/ml) Del Campo et al AASLD 2010

  38. Association between IL28B and metabolic disturbances P=0.001 P=0.1 P=0.01 P=0.06 mg/dl P=0.1 Del Campo et al AASLD 2010

  39. Association between IL28b & lipid and glucose metabolism mg/dl Del Campo et al AASLD 2010

  40. Association between SVR & lipid and glucose metabolism mg/dl Del Campo et al AASLD 2010

  41. New Predictors: IL28B Genotype a Strong Predictor of SVR With PegIFN/RBV Whites (n = 871) Factor Associated With SVR Odds Ratio (95% CI) IL28B rs12979860 genotype (CC vs TT) 7.3 Baseline HCV RNA (< vs ≥ 600,000 IU/mL) 6.1 5.6 Baseline fibrosis (METAVIR F0-F2 vs F3-F4) 0.1 1.0 10.0 Ge D, et al. Nature. 2009;461:399-401.

  42. No RVR IP+Peg+RBV RVR Tratamiento convencional con IFN pegilado y RBV

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