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
SVR genotipo 1
100
D25% +Riba
D10% +Peg
D30% +RGT
75
75
69
46
50
36
25
7
0
IFN 48 w
I+R
Peg+Riba
T12PR RGT
BPR RGT
McHutchinson et al. NEJM 1998; Manns et al. Lancet 2001;
Fried et al. NEJM 2002; Hezode et al. NEJM 2009
Predictive factors of SVR
CV baja
SI
Fib leve
Gen 2/3
50%
CV alta
RI
Fib av
Gen 1/4
Viral Genotype
Viral load
Fibrosis
Metabolic abnormalities
Genes
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
Genotype
Manns MP, et al. Nat Rev Drug Discov. 2007;6:991-1000.
Impact of IR & DM on hepatitis C
Genotype
HCV-core
NS5A
Impairs SVR
Fibrosis
SVR
Viral
load
IR
Obesity
Age
Steatosis
Degradation
of
IRS-1
IR
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
Steatosis,
Fibrosis
Progression and HCC
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)
Genes and SVR: IFN stimulated genes
INFalfa
IFNAR1 – IFNAR2c
JAK-------TyK
P
PTPs
SOCS
STAT
MxA
5’-2’-OAS
PKR
APO-E4
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
N=506
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.
HLA B 44
N=105 (I+R)
N=143 (IFN)
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.
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;
%SVR
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
Meta-analysis association SVR & genotype CC
Romero-Gómez et al. Liver Int 2010 (in press)
IL28B POLYMORPHISMS: DISTRIBUTION BY RACE
& SVR
Ge et al. Nature 2009;
IL28B mRNA expression
rs8099917
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
N=731
SVC=69
CHC= 284
Healthy controls: 378
Montes-Cano et al. Hepatology 2010
IL28b and SPONTANEOUS VIRAL CLEARANCE
P<0.0001
100
68%
(590/871)
48%
(917/1916)
50
SVC
HEP C
0
202/620
SVC
HEP C
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
SVR & IL28b IN acute Hepatitis C
N=54
n=25
Grebely et al. Hepatology 2010
n=29
IL28b and Spontaneous viral clearance
SVR in treated acute Hep C
N=54
3/32
TT
GT/GG
100
15/47
64%
62%
n=25
n=29
50
rs 8099917
0
TT
GT/GG
24 w
Peg
TT
Recent HCV
infection
IL28b
rs8099917
GG/GT
Peg
Gebrely et al. Hepatology 2010
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
p=ns
N=268
Genotipo 2/3
rs8099917
% RVS
N=488
Genotipo 2
rs8099917
Yu et al. Hepatology 2011;53:7-13
Mangia et al Gastro 2010
Montes-Cano et al. Hepatology 2010
Influencia del genotipo de la IL28b según
genotipo viral y RVR
96%
100
100%
88%
86%
80%
78%
71%
77%
70%
50
28%
26%
33%
0
G1
G2/3
G1 RVR
CC
G2/3 RVR
CT
TT
G1 no-RVR
G2/3 NON-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
PR48
BOC RGT
BOC/PR48
100
90
80
78
82
80
71
65
% SVR
70
55
60
59
50
40
30
28
27
33 67
82
116 103 115
10
37
20
10
0
50
64
63
77
CC
44
55
CT
23
42
26
44
TT
Poordad et al. EASL 2011
Triple terapia con boceprevir.
SPRINT-2: RVS en función PCR w 4 y 8.
100
91
86 89
82 82
80
60
52
39
40
31
29
37
43
20
5
0
Caída PCR >1 log Caída PCR < 1 log
w4
w4
Grupo control
PCR - w8
Triple guiada
PCR + w8
Triple 48 w
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)
T12/PR48
TVR +
Peg-IFN + RBV
n=212
Lead-in
T12/PR48
n=210
Pbo +
Peg-IFN
+ RBV
Pbo +
Peg-IFN
+ RBV
TVR +
Peg-IFN + RBV
Peg-IFN + RBV
Follow-up
Peg-IFN + RBV
Follow-up
Peg-IFN + RBV
Follow-up
Pbo/PR48
Pbo +
Peg-IFN + RBV
(control)
n=105
0
4
8
12
16
48
Weeks
72
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)
Overall Baseline IL28B Genotype Distribution
CC
CT
TT
80
Patients (%)
63
60
55
40
29
20
0
n/N=
19
18
16
Pooled
T12/PR48
Pbo/
PR48
Pooled
T12/PR48
Pbo/
PR48
Pooled
T12/PR48
Pbo/
PR48
76/422
17/105
266/422
58/105
80/422
30/105
Overall SVR Rates by IL28B Genotype
CT
TT
Patients achieving SVR (%)
CC
n/N=
Pooled
T12/PR48
Pbo/
PR48
Pooled
T12/PR48
Pbo/
PR48
Pooled
T12/PR48
Pbo/
PR48
60/76
5/17
160/266
9/58
49/80
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
Prior partial
responders
Prior null
responders
Pooled T12/PR48 (n=209)
Pooled T12/PR48 (n=79)
Pooled T12/PR48 (n=134)
Pbo/PR48 (n=52)
Pbo/PR48 (n=20)
Pbo/PR48 (n=33)
Patients achieving SVR (%)
100
88
85
85
80
71
63
58
60
40
40
33
n/N=
20
20
51/58
CT
4/12 100/117 6/30
TT
29/34
3/10
CC
5/8
1/5
CT
33/57
2/10
TT
10/14
CC
0/5
4/10
7
6
n/a
0
CC
31
29
20
20
0
30
CT
27/92
1/18
TT
10/32
1/15
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
N=474 (G1/4)
N=268 (G2/3)
G2/3
G1/4
29%
VPN
SVR
59%
82%
91%
VPP
73%
E
Genotype
CC
35%
80%
28%
Genotype
CT
50%
50%
25%
20%
3%
56%
86%
Genotype
TT
15%
40%
50%
S
0
50
100
Stättermayer AF et al. CGH 2011 (in press)
Mangia et al. Gastro 2010
Romero Gómez et al. Liver Int 2011 (in press)
Several genetic markers in 19q13.3 (IL28B)
rs12997860
rs8099917
rs8105790
rs11881222
rs7248668
rs8103142
rs48032219
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
Association between IL28B and metabolic disturbances
P=0.001
P=0.1
P=0.01
mg/dl
P=0.06
P=0.1
Del Campo et al AASLD 2010
mg/dl
Association between IL28b & lipid and
glucose metabolism
Del Campo et al AASLD 2010
mg/dl
Association between SVR & lipid and
glucose metabolism
Del Campo et al AASLD 2010
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
Ge D, et al. Nature. 2009;461:399-401.
1.0
10.0
Hepatitis C
Genotipo no-1
Genotipo 1
Valorar factores predictivos
de respuesta:
Valorar factores
predictivos de RVS
Carga viral, fibrosis,
resistencia a la insulina
IL28B
CT/TT
CC
No
RVR
RVR
IP+Peg+RBV
Tratamiento
convencional con
IFN pegilado y RBV