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BIOMARCADORES DE BIOMARCADORES DE BIOMARCADORES DE BIOMARCADORES DE TRATAMIENTO EN LA TRATAMIENTO EN LA TRATAMIENTO EN LA TRATAMIENTO EN LA
HEPATITIS CHEPATITIS CHEPATITIS CHEPATITIS CMadrid, 13 de Mayo de 2011
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
756975
100
SVR genotipo 1
∆∆∆∆25% +Riba ∆10∆10∆10∆10% +Peg ∆30∆30∆30∆30% +RGT
7
36
46
0
25
50
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
Viral GenotypeViral loadFibrosis
CV baja
SI
Fib leve
Gen 2/3
50% FibrosisMetabolic abnormalities
Genes
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
Impact of IR & DM on hepatitis C
HCV-core
NS5A Impairs SVR SVR
Genotype
Viral load
IRObesity
AgeSteatosis
Fibrosis
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
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 .
INFalfa
JAK-------TyK
IFNAR1 – IFNAR2c
PTPsSOCS
Genes and SVR: IFN stimulated genes
MxA5’-2’-OASPKR
PSOCS
APO-E4
STAT
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%
N=506
Allele rare < 5%Associated with sustained
responseConfunding factors not
excluded
Mueller T. Hepatology 2003;38:1592Yee LJ. Hepatology 2001;33:708.
HLA B 44
HLA B44 is the most prevalente HLA in caucasians
N=105 (I+R)N=143 (IFN)
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.
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
IL28B mRNA expressionrs8099917
Tanaka et al. Nat Gen 2009;41:1105 Suppiah et al. Nat Gen 2009;41:1100
48%
(917/1916)
68%
(590/871)
50
100
SVC
P<0.0001
IL28b and SPONTANEOUS VIRAL CLEARANCE
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
(917/1916)
0
50
SVC HEP C
SVC
HEP C
IL28b and Spontaneous viral clearance
3/32
15/47
62%64%
100
TT GT/GG
SVR in treated acute Hep CN=54
Gebrely et al. Hepatology 2010
rs 8099917
0
50
TT GT/GG
n=25 n=29
Recent HCV infection
IL28brs8099917
TT
GG/GT
24 w
Peg
Peg
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
N=268Genotipo 2/3rs8099917
Yu et al. Hepatology 2011;53:7-13Mangia et al Gastro 2010Montes-Cano et al. Hepatology 2010
% R
VS
Influencia del genotipo de la IL28b según
genotipo viral y RVR
78% 80%
96%
86%
77%70%
88%
100%
71%
100
26%28%
33%
0
50
G1 G2/3 G1 RVR G2/3 RVR G1 no-RVR G2/3 NON-RVR
CC CT TTThompson A et al. Gastro 2010Mangia A et al. Gastro 2010
SPRINT-2: SVR by IL28B Polymorphism
7882
65
55
80
71
5960
70
80
90
100PR48 BOC RGT BOC/PR48
% S
VR
28 27
55
0
10
20
30
40
50
60
CC CT TT
% S
VR
5064
6377
4455
33116
67103
82115
1037
2342
2644
Poordad et al. EASL 2011
52
86
31
82
29
89
37
82
39
91
4340
60
80
100
Triple terapia con boceprevir. SPRINT-2: RVS en función PCR w 4 y 8.
5
3129
0
20
40
Caída PCR >1 log w4
Caída PCR < 1 log w4
PCR - w8 PCR + w8
Grupo control Triple guiada 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 IL28BGenotype Data (n=527)
T12/PR48Peg-IFN + RBV
TVR + Peg-IFN + RBV
Pbo + Peg-IFN + RBV n=212 Follow-up
TVR + Peg-IFN + RBV
Peg-IFN + RBVLead-in
T12/PR48
n=210Follow-up
Pbo + Peg-IFN + RBV
484 160 128
Weeks
72
SVR assessment
Pbo/PR48
(control ) Pbo + Peg-IFN + RBV
Peg-IFN + RBVn=105
Follow-up
Data from T12/PR48 and LI T12/PR48 arms were pooled since no differences were observed between TVR arm s. Randomization was stratified by viral load and prior response. St opping rules were applied for TVR (Weeks 4, 6, 8 fo r T12/PR48, Weeks 8, 10,
12 for LI T12/PR48) and PR (Weeks 12, 24, 36 for T1 2/PR48, Weeks 16, 24, 36 for LI T12/PR48 )
Peg-IFN: Peg-IFN alfa-2a = 180 µg/week; RBV = 1000–1200mg/day TVR = 750mg every 8 hours; Pbo = placebo
Overall Baseline IL28B Genotype Distribution
63
5560
80CC
Pat
ient
s (%
)
CT TT
18 1916
29
0
20
40
Pat
ient
s (%
)
n/N=
Pooled T12/PR48
76/422
Pbo/ PR48
17/105
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
ient
s ac
hiev
ing
SV
R (
%)
CT TT
Pat
ient
s ac
hiev
ing
SV
R (
%)
n/N=
Pooled T12/PR48
60/76
Pbo/ PR48
5/17
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 H CV 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
88 85 85
7180
100
Prior relapsers
Pat
ient
s ac
hiev
ing
SV
R (
%)
Prior partial responders
Prior null responders
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)
63
4033
20
58
2920 20
6
71
3130
07
0
20
40
60
80
Pat
ient
s ac
hiev
ing
SV
R (
%)
CC CT TT CC CT TT CC CT TT51/58 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
Selección de Variables:
Genotipo
Carga viral
Fibrosis
Alt. metabólicas
RVRTipo de tratamiento:
P+R
T12PR
BPR
POSIBILIDADES DE CURACIÓN
N=474 (G1/4)N=268 (G2/3)
50%
86%
91%
59%
40%
73%
82%
29%
0 50 100
S
E
VPP
VPN
G2/3 G1/4
Stättermayer AF et al. CGH 2011 (in press)Mangia et al. Gastro 2010Romero Gómez et al. Liver Int 2011 (in press)
GenotypeCC
35%
GenotypeCT
50%
GenotypeTT
15%
80%
50%
20%
SVR
28%
25%
3%
56%
Several genetic markers in 19q13.3 (IL28B)
rs12997860rs8099917rs8105790rs11881222rs7248668rs8103142
rs48032219
IlluminaAffymetrix
Interaction between IL28B & viral loadV
iral l
oad
(log/
ml)
p=nsV
iral l
oad
(log/
ml)
Del Campo et al AASLD 2010
P=0.1
P=0.01
P=0.001
P=0.06
Association between IL28B and metabolic disturbance sm
g/dl
P=0.1mg/
dl
Del Campo et al AASLD 2010
New Predictors: IL28B Genotype a Strong Predictor of SVR With PegIFN/RBV
Factor Associated With SVR Odds Ratio (95% CI)
IL28B rs12979860 genotype (CC vs TT)
7.3
Whites (n = 871)
Ge D, et al. Nature. 2009;461:399-401.
Baseline HCV RNA (< vs ≥ 600,000 IU/mL)
1.0 10.00.1
genotype (CC vs TT)
Baseline fibrosis (METAVIR F0-F2 vs F3-F4)
6.1
5.6
Hepatitis C
Genotipo 1
Valorar factores predictivos de respuesta:
Carga viral, fibrosis, resistencia a la insulina
Genotipo no-1
Valorar factores predictivos de RVS
IL28B
CC
CT/TTTratamiento
convencional con
IFN pegilado y RBV
IP+Peg+RBV
RVR
No
RVR