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BIOMARCADORES DE TRATAMIENTO EN LA HEPATITIS C

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BIOMARCADORES DE TRATAMIENTO EN LA HEPATITIS C Madrid, 13 de Mayo de 2011 Manuel Romero-G mez. Unidad M dico-Quir rgica de Enfermedades Digestivas. – PowerPoint PPT presentation

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Title: BIOMARCADORES DE TRATAMIENTO EN LA HEPATITIS C


1
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.

2
Respuesta viral sostenida en genotipo 1
D25 Riba
D10 Peg
D30 RGT
McHutchinson et al. NEJM 1998 Manns et al.
Lancet 2001 Fried et al. NEJM 2002 Hezode et
al. NEJM 2009
3
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
4
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
5
Genotype
Manns MP, et al. Nat Rev Drug Discov.
20076991-1000.
6
Impact of IR DM on hepatitis C
HCV-core NS5A
Impairs SVR
IR
Degradation of IRS-1
Steatosis, Fibrosis Progression and HCC
Improvement of viral fitness
1. Pazienza V et al. Hepatology 2007451164 2.
Sheikh MY, et al. Hepatology 2008472127 3.
Moucari R et al. Gastroenterology 2008134416 4.
Romero-Gómez et al. Gastroenterology 2005128636
Conjeevaram HS et al. Hepatology
20074580-87. Manolakopoulos S et al. BMC
Gastroenterol 2007717.
7
Insulin resistance and sustained virological
response
Eslam M et al (personal communication)
8
Genes and SVR IFN stimulated genes
INFalfa
IFNAR1 IFNAR2c
JAK-------TyK
PTPs SOCS
P
STAT
MxA 5-2-OAS PKR
APO-E4
9
Antiviral proteins MxA, 52-OAS, PKR
Weak associations without multivariate analysis
Knapp S. Genes Immun 20034411.
10
APO-E, IL-10, TGF-b1
N506
  • Il-10 Haplotype extended
  • (108bp)(-2575T)(-2763C)
  • (-1082A)(-819T)(-592A)
  • Allele rare lt 5
  • Associated with sustained response
  • Confunding factors not excluded

Mueller T. Hepatology 2003381592 Yee LJ.
Hepatology 200133708.
11
HLA B 44
N105 (IR) N143 (IFN)
  • HLA B44 is the most prevalente HLA in caucasians
  • Multivariate analysis
  • Genotype non-1 OR2.42 (1.12 5.55)
  • HLA B44 OR4.84 (1.31-17.8)

Romero Gómez et al. Am J Gastroenterol
2003981621.
12
RVS
SLC11A1
HFE
TNF
NRAMP2
MxA
PKR
52-OAS
20210PT
HLA-B44
TGF-b1
APO-E
CCR5
13
GWAS in Hepatitis C
14
IL28B polymorphisms SVR
Ge et al. Nature 2009
15
Influence of IL28b CC genotype on SVR in geno 1
SVR
Ge et al. Nature 2009 Thompson et al.
Gastro2010 Rauch et al. Gastro 2010Tanaka
Nature Gen 2009 Suppiah et al. Nature Gen
2009Montes-Cano et al. Hep2010
16
Meta-analysis association SVR genotype CC
Romero-Gómez et al. Liver Int 2010 (in press)
17
IL28B polymorphisms Distribution by race SVR
Ge et al. Nature 2009
18
IL28B mRNA expressionrs8099917
Suppiah et al. Nat Gen 2009411100
Tanaka et al. Nat Gen 2009411105
19
INF-l3 (IL28B) mechanism of action
Asselah et al. J Hepatol 2010 Gad et al. JBC 2009
20
N731 SVC69 CHC 284 Healthy controls 378
Montes-Cano et al. Hepatology 2010
21
IL28b and SPONTANEOUS VIRAL CLEARANCE
Plt0.0001
589/1015
202/620
Rauch et al. Gastro 2010 Thomas DL et al. Nature
200946798 Tillmann et al. Gastro 2010
Montes-Cano et al. Hepatology 2010
22
SVR IL28b IN acute Hepatitis C
N54
n25
n29
Grebely et al. Hepatology 2010
23
IL28b and Spontaneous viral clearance
SVR in treated acute Hep C N54
3/32
15/47
rs 8099917
n25
n29
24 w
Peg
TT
Recent HCV infection
IL28b rs8099917
Peg
GG/GT
Gebrely et al. Hepatology 2010
24
IL28b y Respuesta viral rápida
25
Influencia del genotipo de la IL28b según RVR
Genotipo 1
Thompson A et al. Gastro 2010 Mangia A et al.
Gastro 2010
26
Influencia IL28b en genotipo 2/3
N488 Genotipo 2 rs8099917
N268 Genotipo 2/3 rs8099917
pns
RVS
Yu et al. Hepatology 2011537-13 Mangia et al
Gastro 2010 Montes-Cano et al. Hepatology 2010
27
Influencia del genotipo de la IL28b según
genotipo viral y RVR
Thompson A et al. Gastro 2010 Mangia A et al.
Gastro 2010
28
IL28b en pacientes tratados con triple terapia
IP Peg Riba
29
SPRINT-2 SVR by IL28B Polymorphism
SVR
50 64
63 77
44 55
33 116
67 103
82 115
10 37
23 42
26 44
Poordad et al. EASL 2011
30
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.
31
REALIZE Study Design Patients with IL28B
Genotype Data (n527)
4
72
48
16
0
12
8
Weeks
SVR assessment
Peg-IFN Peg-IFN alfa-2a 180µg/week RBV
10001200mg/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)
32
Overall Baseline IL28B Genotype Distribution
CC
CT
TT
Patients ()
Pooled T12/PR4880/422
Pbo/ PR48 30/105
Pooled T12/PR4876/422
Pbo/ PR48 17/105
Pooled T12/PR48266/422
Pbo/ PR48 58/105
n/N
33
Overall SVR Rates by IL28B Genotype
CC
CT
TT
Patients achieving SVR ()
Pooled T12/PR48 60/76
Pbo/ PR48 5/17
Pooled T12/PR48 49/80
Pbo/ PR48 4/30
Pooled T12/PR48 160/266
Pbo/ PR48 9/58
n/N
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 (p0.169 for CC, p0.792 for TT)
34
SVR Rates by IL28B Genotype and PriorResponse
Prior relapsers
Prior partial responders
Prior null responders
Pooled T12/PR48 (n134) Pbo/PR48 (n33)
Pooled T12/PR48 (n209) Pbo/PR48 (n52)
Pooled T12/PR48 (n79) Pbo/PR48 (n20)
Patients achieving SVR ()
n/a
CC
CT
TT
CC
CT
TT
CC
CT
TT
n/N
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
1/15
35
Camino hacia la predicción de respuesta viral
sostenida
N474 (G1/4) N268 (G2/3)
Stättermayer AF et al. CGH 2011 (in press) Mangia
et al. Gastro 2010 Romero Gómez et al. Liver Int
2011 (in press)
36
Several genetic markers in 19q13.3 (IL28B)
Illumina Affymetrix
37
Interaction between IL28B fibrosis progression
pns
IL28b gen CC
38
Interaction between IL28B viral load
pns
Viral load (log/ml)
Del Campo et al AASLD 2010
39
Association between IL28B and metabolic
disturbances
P0.001
P0.1
P0.01
P0.06
mg/dl
P0.1
Del Campo et al AASLD 2010
40
Association between IL28b lipid and glucose
metabolism
mg/dl
Del Campo et al AASLD 2010
41
Association between SVR lipid and glucose
metabolism
mg/dl
Del Campo et al AASLD 2010
42
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 (lt vs 600,000 IU/mL)
6.1
5.6
Baseline fibrosis (METAVIR F0-F2 vs F3-F4)
1.0
10.0
0.1
Ge D, et al. Nature. 2009461399-401.
43
No RVR
IPPegRBV
RVR
Tratamiento convencional con IFN pegilado y RBV
44
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