BIOMARCADORES DE TRATAMIENTO EN LA HEPATITIS C Manuel Romero-Gómez. Unidad Médico-Quirúrgica de Enfermedades Digestivas. Hospital Universitario de Valme.

Presentación del tema: "BIOMARCADORES DE TRATAMIENTO EN LA HEPATITIS C Manuel Romero-Gómez. Unidad Médico-Quirúrgica de Enfermedades Digestivas. Hospital Universitario de Valme."— Transcripción de la presentación:

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

2 Respuesta viral sostenida en genotipo 1  25% +Riba McHutchinson et al. NEJM 1998; Manns et al. Lancet 2001; Fried et al. NEJM 2002; Hezode et al. NEJM 2009  % +Peg  % +RGT

3 Predictive factors of SVR Viral Genotype Viral load Fibrosis Metabolic abnormalities Genes CV baja SI Fib leve Gen 2/3 50% CV alta RI Fib av Gen 1/4

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 Degradation of IRS-1 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 IR Impairs SVR Steatosis, Fibrosis Progression and HCC Improvement of viral fitness Conjeevaram HS et al. Hepatology 2007;45:80-87. Manolakopoulos S et al. BMC Gastroenterol 2007;7:17. SVR Genotype Viral load IR Obesity Age Steatosis Fibrosis

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

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

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 Mueller T. Hepatology 2003;38:1592 Yee LJ. Hepatology 2001;33:708. N=506

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)] Romero Gómez et al. Am J Gastroenterol 2003;98:1621. N=105 (I+R) N=143 (IFN)

12 RVS SLC11A1 HFE TNF NRAMP2 MxA PKR 5´2-OAS 20210PT HLA-B44 TGF-b1 APO-E CCR5

13 GWAS in Hepatitis C

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

15 Influence of IL28b CC genotype on SVR in geno 1 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 %SVR

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

17 IL28B POLYMORPHISMS : D ISTRIBUTION BY RACE & SVR Ge et al. Nature 2009;

18 IL28B mRNA expression rs8099917 Tanaka et al. Nat Gen 2009;41:1105 Suppiah et al. Nat Gen 2009;41:1100

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

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

21 Rauch et al. Gastro 2010; Thomas DL et al. Nature 2009;46:798 Tillmann et al. Gastro 2010; Montes-Cano et al. Hepatology 2010 589/1015202/620 P<0.0001 IL28b and SPONTANEOUS VIRAL CLEARANCE

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

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

24 IL28b y Respuesta viral rápida

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

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

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

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

29 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

30 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.

31 REALIZE Study Design: Patients with IL28B Genotype Data (n=527) 48 4 16012 8 Weeks 72 T12/PR48 Peg-IFN + RBV TVR + Peg-IFN + RBV Pbo + Peg-IFN + RBV n=212 Follow-up SVR assessment TVR + Peg-IFN + RBV Peg-IFN + RBV Lead-in T12/PR48 n=210 Follow-up Pbo + Peg-IFN + RBV Pbo/PR48 ( control ) Pbo + Peg-IFN + RBV Peg-IFN + RBV n=105 Follow-up 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) Peg-IFN: Peg-IFN alfa-2a = 180μg/week; RBV = 1000–1200mg/day TVR = 750mg every 8 hours; Pbo = placebo

32 Overall Baseline IL28B Genotype Distribution CC Patients (%) n/N= Pooled T12/PR48 76/422 Pbo/ PR48 17/105 CTTT Pooled T12/PR48 266/422 Pbo/ PR48 58/105 Pooled T12/PR48 80/422 Pbo/ PR48 30/105

33 Overall SVR Rates by IL28B Genotype CC Patients achieving SVR (%) n/N= Pooled T12/PR48 60/76 Pbo/ PR48 5/17 CTTT Pooled T12/PR48 160/266 Pbo/ PR48 9/58 Pooled T12/PR48 49/80 Pbo/ PR48 4/30 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)

34 SVR Rates by IL28B Genotype and Prior Response Prior relapsers Patients achieving SVR (%) Prior partial responders Prior null responders CCCT TT CCCT TT CCCT TT Pooled T12/PR48 (n=209) Pbo/PR48 (n=52) Pooled T12/PR48 (n=79) Pbo/PR48 (n=20) Pooled T12/PR48 (n=134) Pbo/PR48 (n=33) 51/58 4/12100/117 6/3029/34 3/105/81/5 33/57 2/1010/14 0/5 4/1027/92 1/1810/32 1/15 n/N= n/a

35 Camino hacia la predicción de respuesta viral sostenida Selección de Variables: Genotipo Carga viral Fibrosis Alt. metabólicas RVR Tipo de tratamiento: P+R T12PR BPR POSIBILIDADES DE CURACIÓN Stättermayer AF et al. CGH 2011 (in press) Mangia et al. Gastro 2010 Romero Gómez et al. Liver Int 2011 (in press) N=474 (G1/4) N=268 (G2/3) Genotype CC 35% Genotype CT 50% Genotype TT 15% 80% 50% 20% SVR 28% 25% 3% 56%

36 Several genetic markers in 19q13.3 (IL28B) rs12997860 rs8099917rs8105790rs11881222 rs7248668 rs8103142rs48032219 Illumina Affymetrix

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

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

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

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

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

42 New Predictors: IL28B Genotype a Strong Predictor of SVR With PegIFN/RBV Ge D, et al. Nature. 2009;461:399-401. Factor Associated With SVROdds Ratio (95% CI) Baseline HCV RNA (< vs ≥ 600,000 IU/mL) 1.010.00.1 IL28B rs12979860 genotype (CC vs TT) 7.3 Baseline fibrosis (METAVIR F0-F2 vs F3-F4) Whites (n = 871) 6.1 5.6

43 Hepatitis C Genotipo 1 Valorar factores predictivos de respuesta: Carga viral, fibrosis, resistencia a la insulina IL28B CC CT/TT Genotipo no-1 Valorar factores predictivos de RVS Tratamiento convencional con IFN pegilado y RBV IP+Peg+RBV RVR No RVR

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