IL28B polymorphism and SVR
Do IL28B or not do IL28B?
Donald M. Jensen, MD, FACP
Professor of Medicine
Director, Center for Liver Diseases
University of Chicago, USA
Stanislas Pol, MD, PhD
Unité d’Hépatologie, Hôpital Cochin
27 Rue du Faubourg Saint-Jacques
75014
Paris France
IL28B polymorphism
O’Brian TR et al. Nat Genet 2009
Anatomy of the IL28B gene
Ge et al. Nature 2009;461:399-401
IL28B polymorphism
Global prevalence of C/T Alleles at SNP rs 12979860 may explain
recognized geographical variation in SVR rates
Thomas DL, et al. Nature. 2009;461:798-802
Percent of patients achieving spontaneous clearance
IL28B polymorphism and
HCV spontaneous clearance
70
64.2
RR 2.63 (CI: 1.8-3.9)
60
50
p = 4.0*10-8; RR 10.6 (CI: 2.7 – 41.1)
40
30
24.4
p = 5.8*10-78
20
10
RR 2.63
IC: 1.8-3.9
6.1
p = 0.021
0
T/T (n=2/33)
C/T (n=22/90)
C/C (n=43/67)
German anti-D cohort infected with HCV genotype 1 (N=194)
Genetic variation in IL28B (rs 12979860)
Tillmann HL et al. Gastroenterology 2011
IL28B polymorphism and
HCV spontaneous clearance
Predictors of chronic vs. spontaneously cleared HCV infection
1362 individuals
1015 HCV infected
347 who cleared the virus spontaneously
448 HCV/HIV co-infected
Rs 8099917 G-risk allele is associated
with progression to chronicity in either
HCV or HCV/HIV co-infected patients.
Genetic variation in IL28B (rs 8099917)
Rauch A et al. Gastroenterology. 2010;15:1338-1345
IL28B polymorphism and
HCV spontaneous clearance
100
TG
5.6
TG
10.8
GG
3.9
80
60
40
TT
94.4
TT
89.2
20
TG
72.7
GG
TG
TT
TT
23.4
0
Spontaneous
clearance (n=107)
Genetic variation in IL28B (Rs 8099917)
SVR (n=185)
Non response (n=128)
Matsuura K. Abstract 1171. EASL 2010.
IL28B polymorphism and
HCV spontaneous clearance
Practical Implications
• IL28B polymorphism could be used in acute
hepatitis C in order to:
– Select patients who needed to be treated rapidly
(TT or asymptomatic CT rs 12979860 and
GT or GG rs 8099917)
– Follow and delay treatment in patients with
expected high spontaneous clearance
IL28B polymorphism and SVR
Genetic variation in IL28B (rs 12979860)
Ge D et al. Nature 2009
IL28B polymorphism and SVR
Genetic variation in IL28B (rs 12979860)
Ge D et al. Nature 2009
IL28B polymorphism and RVR
IL28B CC genotype predict both RVR and
SVR in Caucasians without RVR
13 %
19 %
TT
CT
CC
56 %
CT
77 %
CC
4%
31 %
RVR=14%
Non-RVR=86%
TT
100%
76%
CT
CC
85%
66%
24%
p>0.25
SVR
Genetic variation in IL28B (rs 12979860)
31%
CC vs. non-CC
p<0.0001
SVR
Thompson AJ et al. AASLD 2009
IL28B polymorphism and SVR
Odds ratio
95% Confidence interval
p-value
CC genotype vs. non-CC
5.2
4.1
6.7
<0.001
VL ≤600,000 IU/mL
3.1
2.3
4.1
<0.001
Caucasian vs. AA ethnicity
2.8
2.0
4.0
<0.001
Hispanic vs. AA ethnicity
2.1
1.3
3.6
0.004
METAVIR F012
2.6
1.8
4.0
<0.001
Fasting blood sugar <5.6 mmol/L
1.7
1.3
2.2
<0.001
•
•
Logistic regression, backward selection
Covariates: rs 12979860 (2-level), ethnicity (4-level), age (>40), gender, BMI (>30), VL (>600,000),
ALT (>ULN), fasting glucose (≥5.6), hepatic steatosis (>0%), fibrosis (METAVIR F34), RBV (≤13
mg/kg/d)
Genetic variation in IL28B (rs 12979860)
Thompson AJ et al. AASLD 2009
IL28B polymorphism and SVR
Genotype 2/3 Patients
SVR: 57% (TT), 75% (CT), 82% (CC); p=0.005
p=0.45
90
p=0.34
88%
79%
75
74% 72%
p=0.0002
87%
84%
73%
67%
SVR %
60
45
29%
30
15
0
TT CT CC
TT CT CC
24 Weeks
(n=68)
12 Weeks
If RVR
(n=122)
Genetic variation in IL28B (rs 12979860)
TT
CT CC
24 Weeks
If no RVR
(n=78)
Mangia A et al. Abstract 126. EASL 2010.
IL28B polymorphism and SVR
164 HCV/HIV co-Infected
patients treated by PR
CC genotype is associated with SVR only in genotype 1/4 patients.
Genetic variation in IL28B (rs 12979860)
Rallon NI, et al. AIDS. 2010;15:F23-29
IL28B polymorphism and viral kinetics
African Americans
Caucasians
0
0
-2.0
-2.0
TT
CT
TT
-4.0
CT
-6.0
CC
4
2
4
12
Weeks
-4.0
CC
-6.0
4
2
4
12 Weeks
Hispanics
0
-2.0
TT
-4.0
CT
CC
Reduction of viral load is independently
associated with IL28B genotypes and
ethnicity (p<0.0001).
-6.0
4
2
4
12
Weeks
Genetic variation in IL28B (rs 12979860)
Thompson AJ et al. AASLD 2009
IL28B polymorphism and hepatic ISG
•
•
•
•
•
91 patients, gene expression
profile in the liver
Expression of IFN stimulated
gene (ISG) in relation to IL28B
(Rs 8099917)
Patients with up-regulated ISGs
are associated with NR.
IL28B polymorphisms are
strongly associated with SVR
(TT: 86% vs. GG: 65%; p<0.001)
Hepatic ISGs were strongly
associated with IL28B
polymorphism; its expression
was higher in patients with
minor genotypes (TG or GG)
• The different expression of
hepatic ISGs before
treatment may be due to
polymorphisms in IL28B
Genetic variation in IL28B (rs 8099917)
Honda M, et al. Gastroenterology 2010
IL28B polymorphism and SVR
Practical Implications
• Dual vs. Triple therapy
• Duration of therapy
IL28B polymorphism and SVR
Practical Implications
• Dual vs. Triple therapy
• Duration of therapy
Impact of IL28B on SVR with DAAs
CC patients with non extensive fibrosis (F0-2) and RVR
have the same rate of SVR with dual vs. triple therapy
CC
100
80
78
82
CT
80
65
RVS (%)
TT
71
55
60
40
28
59
27
20
0
PR48
BOC BOC44/ PR48 BOC BOC44/ PR48
RGT PR48
RGT PR48
BOC BOC44/
RGT PR48
n/N= 50/64
63/77 44/55 33/116 67/103 82/115 10/37
23/42
26/44
SPRINT-2
Poordad F, et al. N Engl J Med 2011;364:1195-206
Impact of IL28B on SVR with DAAs
CC patients with non extensive fibrosis (F0-2) and RVR
have the same rate of SVR with dual vs. triple therapy
% SVR
All the patients (cohort 1 and cohort 2)
SPRINT-2
Vierling JM. et al. EASL 2011. (abstract 481)
IL28B polymorphism and SVR
Practical Implications
• Dual vs. Triple therapy
• Duration of therapy
Impact of IL28B on SVR
•
Retrospective analysis of randomized comparing PEG-IFNα-2a 180 μg/w. + RBV
1000-1200 mg/j 24 w. vs 48 w. in Taïwan
662 genotype 1-infected patients
100
% SVR if RVR
•
p = 0.21
99
95
80
p < 0.001
97
24 w.
48 w.
70
60
40
20
0
IL28B rs8099917 TT
ARN < 600 000 UI/ml
IL28B rs8099917 TT
ARN > 600 000 UI/ml
Liu CH et al. AASLD 2011, Abs. 414
Impact of IL28B on SVR with DAAs
Higher rate of SVR in CC vs. CT/TT
CC
80
78
82
CT
CC
CT
90
80
71
55
60
40
100
TT
80
65
RVS (%)
TT
28
59
27
60
40
25
20
73
71
64
RVS (%)
100
23
20
0
0
PR48
BOC BOC44/ PR48 BOC BOC44/ PR48
RGT PR48
RGT PR48
BOC BOC44/
RGT PR48
n/N= 50/64
63/77 44/55 33/116 67/103 82/115 10/37
23/42
26/44
PR48
T12PR
PR48
T12PR
PR48
T12PR
n/N= 35/55
45/50
20/80
48/68
6/26
16/22
Poordad F, et al. N Engl J Med 2011;364:1195-206;
Jacobson IM, et al. N Engl J Med 2011;364:240516
Impact of IL28B on SVR with DAAs
Higher rate of SVR in CC vs. CT/TT
PILLAR study with TMC435
97
100
100
84
% SVR
78
73
80
60
50
40
20
0
n=
31
35
12
CC
TMC435 75 mg
78
72
34
CT/TT
TMC435 150 mg
P/R
Fried MW et al. AASLD 2011, Abs. LB5
Impact of IL28B on SVR with DAAs
Higher rate of « short » treatments in CC vs. CT/TT :
~ 80 % of CC naïve patients are eligible
PR48
100
90
80
78
82
BOC TGR
80
65
70
RVS (%)
BOC/PR48
71
55
60
59
50
40
30
20
10
0
50
50
64
54
63
77
CC
44
55
28
27
33 67 82
116 103 115
10
37
CT
23
42
26
44
TT
(SPRINT-2: Boceprevir in naïve patients)
Poordad F, et al. N Engl J Med 2011;364:1195-206
Impact of IL28B on SVR with DAAs
Higher rate of « short » treatments in CC vs. CT/TT :
~ 80 % of CC experienced patients are eligible
100
PR48
BOC TGR
BOC/PR48
90
79
80
77
73
RVS (%)
70
72
61
60
50
50
46
55
40
30
17
20
10
6
13
22
28
17
22
5
29
38
62
48
66
5
10
6
11
13
18
0
CC
CT
TT
(RESPOND-2: Boceprevir in experienced patients)
Bacon BR et al. N Engl J Med 2011;364:1207-17
Impact of IL28B on SVR with DAAs
SVR Rates by IL28B Genotype and Prior Response
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 (%)
Prior
relapsers
CC
n/N=
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
0/5
CC
4/10
0/0
CT
27/92
1/18
TT
10/32
1/15
Pol S, et al. EASL 2011
Impact of IL28B on SVR with DAAs
Prove 2 sub-analysis
•
Phase II, randomized controlled trial in genotype 1 naïve patients in 323 patients
•
Telaprevir (TVR) 750 mg/8 h, PEG-IFN 180 µg/w, RBV 1 000-1 200 mg/d
PR48 (n = 82)
T12/PR24
(n = 81)
T12/PR12
(n = 82)
T12/P12
(n = 78)
Placebo + PEG-IFNα-2a + ribavirin (RBV)
TVR + PEG-IFNα-2a
+ RBV
PEG-IFNα-2a + RBV
TVR + PEG-IFNα-2a
+ RBV
TVR + PEG-IFNα-2a
Hezode C et al. NEJM 2009
Impact of IL28B on SVR with DAAs
Prove 2 sub-analysis
Relapse (%)
Virologic Response after treatment
SVR
%
80
60
p = 0.01* p = 0.08*
RVS 12
68
62
48
20
0
48
40
NS*
29
30
36
40
%
50
20
20
14
10
39/82
55/81
51/82
28/78
9/45
8/56
18/63
22/46
0
PR48
T12/PR24
T12/PR12T12/P12
(No RBV)
PR48 T12/PR24
T12/PR12 T12/P12
(No RBV)
* vs PR48
Hezode C et al. NEJM 2009
Impact of IL28B on SVR with DAAs
Prove 2 sub-analysis
Virologic Response after treatment
SVR
%
80
60
RVS 12
p = 0.01* p = 0.08*
68
62
36
40
20
0
NS*
48
TPR 12w : 100% CC SVR
< 50% CT/TT
39/82
PR48
55/81
T12/PR24
51/82
28/78
T12/PR12T12/P12
(No RBV)
* vs PR48
By courtesy of J-P. Bronowicki
IL28B polymorphism
Practical Implications
The “Pro” summary
• Early treatment of acute hepatitis
• Dual vs. Triple therapy: PR vs. BOC/TVR PR
• Duration of therapy: 12w/24w/36 w or 48w
IL28B in the Era of DAA Therapy:
What’s not to like?
• Can we avoid the toxicity of DAAs and use
dual therapy in IL28B CC patients?
• Is knowledge of IL28B CC status helpful in
encouraging patients to be treated with the
hope of eRVR+ RGT?
• Can we use IL28B TT or CT information in
patients with “mild” disease to wait for newer
therapies with better outcomes?
Dual versus Triple Therapy
• The argument: Dual therapy for IL28B CC is
more cost-effective than triple therapy:
– For patients with IL28B CC: SVR rates (~90%) are
about the same with P/R as if T/P/R was used right
from the start
– It is more cost-effective to treat IL28B CC subjects
initially with PEG/RBV and reserve TVR-based triple
therapy to those who do not respond.
Gellad et al: AASLD 2011
Dual versus Triple Therapy
• However,….
– This two step strategy means that at least 36% of patients
will require a subsequent course of triple therapy
– It assumes that 100% of P/R failures will undergo retreatment - not supported by clinical experience data.
– Evolution of therapy may demonstrate that these uniquely
responsive patients may achieve a comparably high rate of
SVR with only 12 weeks of triple therapy without the need
for a PEG/RBV tail (trial in progress)
– Finally, patients may refuse a non-DAA containing therapy
Duration of Therapy: 24 vs 48 weeks
• The argument: Those with geno-1, IL28B CC
are more likely to have an eRVR and qualify for
24 weeks (RGT) therapy.
• However,….
– Regardless of IL28B status, an eRVR still requires
actual measurement of undetectable HCV RNA at
weeks 4 and 12
– Therefore, it’s on-treatment virologic responses
that really matter, not pre-treatment dispositions
Selecting Candidates for Therapy
• Argument: IL28B CT or TT with ‘mild disease’
may be able to wait for future therapies
However,…
– How do we define ‘mild’? What is the accuracy?
• E.g. Liver bx: 25-30% may miss cirrhosis
– Should all ‘mild’ cases be deferred given the
toxicity of DAA triple therapy?
– When is IFN-free therapy anticipated?
Selecting Candidates for Therapy
• Argument: IL28B may identify a cohort of
uniquely sensitive subjects for short course
IFN-free therapy
However,….
– As therapies become more effective (>90% SVR),
the role of IL28B will decline as a predictor (e.g.
PILLAR)
– In the absence of IFN, is there even a role for lIFN responsiveness? (e.g. PROTON)
Summary
• How will IL28B be utilized in the era of DAA
triple therapy?
– Predict shorter treatment duration
– Identify patients who may benefit from dual
therapy
However,…
– True utilization may depend upon real life clinical
experience with triple therapy and retrospective
analysis of IL28B
Ten years too late????