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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
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