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

7

3646

7569

0

25

50

75

100

IFN 48 w I+R Peg+Riba T12PR RGT BPR RGT

SVR 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 GenotypeViral loadFibrosis

Metabolic abnormalitiesGenes

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. 2007Fried et al. NEJM 2002 Romero-Gómez et al. Liver Int 2011

Genotype

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

Impact of IR & DM on hepatitis C

HCV-core

NS5A

Degradation of

IRS-1

1. Pazienza V et al. Hepatology 2007;45:11642. Sheikh MY, et al. Hepatology 2008;47:21273. Moucari R et al. Gastroenterology 2008;134:4164. 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.

Insulin resistance and sustained virological response

Eslam M et al (personal communication)

MxA5’-2’-OASPKR

P

INFalfa

JAK-------TyK

IFNAR1 – IFNAR2c

PTPsSOCS

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

responseConfunding factors not

excluded

Mueller T. Hepatology 2003;38:1592Yee 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

(1.31-17.8)]

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

%S

VR

Romero-Gómez et al. Liver Int 2010 (in press)

Meta-analysis association SVR & genotype CC

IL28B POLYMORPHISMS: DISTRIBUTION BY RACE & SVR

Ge et al. Nature 2009;

IL28B mRNA expressionrs8099917

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 2010Gad et al. JBC 2009

Montes-Cano et al. Hepatology 2010

N=731SVC=69CHC= 284Healthy controls: 378

Rauch et al. Gastro 2010; Thomas DL et al. Nature 2009;46:798Tillmann et al. Gastro 2010; Montes-Cano et al. Hepatology 2010

589/1015202/620

48%(917/1916)

68%(590/871)

0

50

100

SVC HEP C

SVCHEP C

P<0.0001

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 8099917

62%64%

0

50

100

TT GT/GG

TT GT/GG

n=25 n=29

SVR in treated acute Hep CN=54

Recent HCV infection

IL28brs8099917

TT

GG/GT

24 w

Peg

Peg

IL28b y Respuesta viral rápida

Influencia del genotipo de la IL28b según RVR Genotipo 1

Thompson A et al. Gastro 2010Mangia A et al. Gastro 2010

Influencia IL28b en genotipo 2/3N=488Genotipo 2rs8099917 p=ns

Yu et al. Hepatology 2011;53:7-13Mangia et al Gastro 2010Montes-Cano et al. Hepatology 2010

% R

VS

N=268Genotipo 2/3rs8099917

Influencia del genotipo de la IL28b según genotipo viral y RVR

Thompson A et al. Gastro 2010Mangia A et al. Gastro 2010

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

SPRINT-2: SVR by IL28B Polymorphism%

SV

R

5064

6377

4455

33116

67103

82115

1037

2342

2644

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: 1195-1206.

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

484 160 128

Weeks

72

T12/PR48Peg-IFN + RBV

TVR + Peg-IFN + RBV

Pbo + Peg-IFN + RBV n=212 Follow-up

SVR assessment

TVR + Peg-IFN + RBV

Peg-IFN + RBVLead-in

T12/PR48

n=210Follow-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

Pat

ien

ts (

%)

n/N=

Pooled T12/PR48

76/422

Pbo/ PR48

17/105

CT TT

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

Pat

ien

ts a

chie

vin

g S

VR

(%

)

n/N=

Pooled T12/PR48

60/76

Pbo/ PR48

5/17

CT TT

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 PriorResponse

Prior relapsers

Pat

ien

ts a

chie

vin

g S

VR

(%

)

Prior partial responders

Prior null responders

CC CT TT CC CT TT CC CT 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 4/12 100/117 6/30 29/34 3/10 5/8 1/5 33/57 2/10 10/14 0/5 4/10 27/92 1/18 10/32 1/15n/N=

n/a

Camino hacia la predicción de respuesta viral sostenida

Stättermayer AF et al. CGH 2011 (in press)Mangia et al. Gastro 2010Romero Gómez et al. Liver Int 2011 (in press)

N=474 (G1/4)N=268 (G2/3)

GenotypeCC

35%

GenotypeCT

50%

GenotypeTT

15%

80%

50%

20%

SVR

28%

25%

3%

56%

Several genetic markers in 19q13.3 (IL28B)

IlluminaAffymetrix

Interaction between IL28B & fibrosis progression%

IL

28b

gen

CC

p=ns

Interaction between IL28B & viral loadV

iral

lo

ad (

log

/ml)

p=ns

Del Campo et al AASLD 2010

P=0.1

P=0.1

P=0.01

P=0.001

P=0.06

Association between IL28B and metabolic disturbancesm

g/d

l

Del Campo et al AASLD 2010

Association between IL28b & lipid and glucose metabolismm

g/d

l

Del Campo et al AASLD 2010

Association between SVR & lipid and glucose metabolismm

g/d

l

Del Campo et al AASLD 2010

New Predictors: IL28B Genotype a Strong Predictor of SVR With PegIFN/RBV

Ge D, et al. Nature. 2009;461:399-401.

Factor Associated With SVR Odds Ratio (95% CI)

Baseline HCV RNA (< vs ≥ 600,000 IU/mL)

1.0 10.00.1

IL28B rs12979860 genotype (CC vs TT)

7.3

Baseline fibrosis (METAVIR F0-F2 vs F3-F4)

Whites (n = 871)

6.1

5.6

Tratamiento convencional con

IFN pegilado y RBV

IP+Peg+RBV

RVR

No RVR