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

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

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

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

Genotype Manns MP, et al. Nat Rev Drug Discov. 2007;6:

Impact of IR & DM on hepatitis C HCV-core NS5A Degradation of IRS-1 1. Pazienza V et al. Hepatology 2007;45: Sheikh MY, et al. Hepatology 2008;47: Moucari R et al. Gastroenterology 2008;134: 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: Manolakopoulos S et al. BMC Gastroenterol 2007;7:17. SVR Genotype Viral load IR Obesity Age Steatosis Fibrosis

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

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

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

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

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

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

GWAS in Hepatitis C

IL28B polymorphisms & SVR Ge et al. Nature 2009;

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

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

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

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

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

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

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

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

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

IL28b y Respuesta viral rápida

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

Influencia IL28b en genotipo 2/3 N=488 Genotipo 2 rs 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 rs

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

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

SPRINT-2: SVR by IL28B Polymorphism % SVR Poordad et al. EASL 2011

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:

REALIZE Study Design: Patients with IL28B Genotype Data (n=527) 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

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

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)

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

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%

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

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

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

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

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

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

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

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