using genetic markers in clinical practice david thomas advisor: merck clinical trial: gilead and...
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Using genetic markers in clinical practice
David Thomas
Advisor: MerckClinical trial: Gilead and Merck
Using genetic markers in clinical practice
• IL28b test for chronic genotype 1 hepatitis C
• IL28b test for chronic genotype 2/3 hepatitis C
• IL28b for acute hepatitis C• Future use of IL28b testing with DAA
Recovery Persistence
Ge, Nature, 2009; Thomas, Nature 2009; Rauch Gastroenterology 2010
Seven SNPs within a 17-kb region around IL28B gene are associated with HCV recovery
Seven SNPs within a 17-kb region around IL28B gene are associated with HCV recovery
Ge, Nature, 2009
C allele associated with PegIFN and RBV in IDEAL
Clark Am J Gastro
IL28b genotyping helps predict SVR in Caucasians
Clark Am J Gastro
IL28b genotyping helps predict SVR in African Americans
Independent replication of the effect of genetic variation in SNPs near IL28B and
SVR
Ge et al Tanaka et al Suppiah et al Rauch et al
Race Americans: European; African; Hispanic
Japanese European; Australian
European
SNP rs8099917;1.72 x 10-26
rs8099917;2.68 x 10-32
rs8099917;9.25 x 10-9
rs8099917;5.7 x 10-8
rs1297860;1.37 x 10-28
Gene IL28B IL28B IL28B IL28B
Adjusted odds ratio of failure by rs8099917 carriage
5.6, Hispanic6.1, African7.3, Caucasian
12.1 1.98 5.2
Ge D, et al. Nature 2009;461:399-401. Tanaka Y, et al. Nat Genet 2009;41:1105-9. Suppiah V, et al. Nat Genet 2009;41:1100-4. Rauch A, et al. Gastroenterology 2010; Jan 7.
Kinetics of HCV RNA decline differ early in IL28b haplotypes
Genotype 1 Caucasian patients
IL28b haplotype predicts SVR in HIV/HCV coinfected patients
Rallon AIDS 2010 (Pineda CID 2010, Medrano CID 2010)
Using genetic markers in clinical practice
• IL28b test for chronic genotype 1 hepatitis C
• IL28b test for chronic genotype 2/3 hepatitis C
• IL28b for acute hepatitis C• Future use of IL28b testing with DAA
Mangia Gastro 2010
Effect of unfavorable IL28b genotype is less in Caucasian genotype 2/3 HCV infection
Genotype 2, N=213; Genotype 3, N=55
Favorable IL28b genotype may be associated with relapse of genotype
3 HCV infection • 281 genotype
3, Scandinavian, >11wks Rx
• RVR, 14 wks peg/R no RVR, 24 wks
• Overall SVR 80%
• CC relapse:o 13/64 (20%)
14wko 7/43 (16%) 24
wk
Moghaddam Hepatology 2011
Both donor and recipient IL28 status are important for outcome of IFN treatment after liver
transplant
Charlton Hepatology 2011
Using genetic markers in clinical practice
• IL28b test for chronic genotype 1 hepatitis C
• IL28b test for chronic genotype 2/3 hepatitis C
• IL28b for acute hepatitis C• Future use of IL28b testing with DAA
C allele associates with higher probability of spontaneous clearance of
HCV
Thomas Nature 2009; Grebely Hepatology 2010; Rauch Gastro 2010
Persons with acute hepatitis C and unfavorable IL28b genotype should be
treated sooner • With genotype 1, interferon alfa
sensitivity diminishes with time from acute infection
• Interferon alfa sensitivity diminishes most with genotype 1
• Prioritize early treatment for T allele• May not be case for HIV/HCV
coinfected1
1Nattermann JID 2011
Using genetic markers in clinical practice
• IL28b test for chronic genotype 1 hepatitis C
• IL28b test for chronic genotype 2/3 hepatitis C
• IL28b for acute hepatitis C• Future use of IL28b testing with DAA
EOT and SVR according to rs12979860 genotype
72 patients Telaprevir/PegIFN/RBV for total duration of 12 or 24 weeks
Akuta N et al. Hepatology 2010
SPRINT-2 Treatment-Naïve Patients
Stopping Rule
Weeks 12 24 28 48 72
Follow-up24 wks
TW 8-24 Undetectable
Follow-up
24 wks
TW 8-24 Detectable
Follow-up24 wks
8
Placebo + P/R
44 wks
P/R4 wks
Follow-up24 wks
BOC + P/R
24 wks
P/R4 wks
Follow-up44 wks
Placebo + P/R 20 wks
BOC + P/R
44 wks
P/R4 wks
Decision point for long vs. short therapy
Arm 1PR48
Control
Arm 2BOCRGT
Arm 3BOC/PR48
Lead-in
RESPOND-2 Previous Treatment Failure
Stopping Rule
Weeks 12 24 48 72
Placebo + P/R
44 wks
P/R4 wks
Follow-up24 wks
Arm 1PR48
Control
TW 8 Undetectable
BOC + P/R
32 wks
P/R4 wks
Follow-up36 wks
Placebo + P/R12 wks
Follow-up
24 wks
TW 8 Detectable
Arm 2BOCRGT
BOC + P/R
44 wks
P/R4 wks
Follow-up24 wks
Arm 3BOC/PR48
8 36
Decision point for long vs. short therapy
Lead-in
consented to testing and who received ≥1 dose BOC or placebo (63%)
Distribution of IL-28B Polymorphisms
RESPOND 266%
(259/394)
SPRINT 262%
(653/1048)
TT (15%)CC
(24%)
CT (61%)
TT (19%)
CC (30%)
CT (51%)
SPRINT 2 team: Poordad EASL 2011
Improvement in SVR in naïve patients with boceprevir is greater
with T allele
SPRINT 2 team: Poordad EASL 2011
Improvement in SVR in retreated patients with boceprevir is greater
with T allele
RESPOND 2 team: Poordad EASL 2011
IL-28B CC polymorphism is a strong predictor of TW8
response*
% Patients with undetectable HCV-RNA by TW8
CC
CT + TT
SPRINT-2 RESPOND-2
*Decision point for short vs. long treatment duration with RGT
4150
80156
118132
158304
Early Interferon Response (Lead-In) Further Defines Likelihood of Success For Non-CC
Patients
02
23
24
5675
83102
5872
127 19
512045
37117
83111
109133
120 6
251025
1326
2328
2634
CC CT TT≥ ≥ ≥
SPRINT-2 and RESPOND-2 combined
Design of the ADVANCE Study of Telaprevir in Treatment Naïve HCV
genotype 1 Patients
Differences between ADVANCE cohort and those typed
Improvement in SVR in Caucasian naive patients with telaprevir is greater with T
allele
ADVANCE TEAM, Jacobson EASL 2011
REALIZE (retreatment) Study Design
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 Pbo +
Peg-IFN + RBV Peg-IFN + RBV
n=105Follow-up
SVR Rates by IL28B Genotype and Prior
ResponsePrior
relapsers
Patients achieving SVR (%)
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 4/12100/117 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
Pol et al EASL 2011
Viral Breakthrough Rates by IL28B Genotype and Prior Response
Viral breakthrough defined as confirmed HCV RNA increase >1 log10 from the lowest level during a considered treatment phase, or confirmed HCV RNA >100 IU/mL in patients who previously reached <25 IU/mL during the considered treatment phase
Patients with viral breakthrough (%)
Prior relapsers 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)
1/58 0/12 2/117 4/30 0/34 0/10 1/8 1/5 9/57 1/10 1/14 0/5 5/10 44/92 2/18 16/32 1/15n/N=
n/a
Relapse Rates by IL28B Genotype and
Prior Response
Patients with viral relapse (%)
Prior relapsers
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)
2/56 6/10 8/112 12/18 2/33 2/5 1/7 0/1 10/44 0/2 3/13 0/5 11/40 2/3 4/14 1/2n/N=
Relapse was defined as having confirmed detectable HCV RNA levels during the entire follow-up period (relapse Week 72)
n/an/a
IL28b C allele use is even less clear beyond boceprevir and
telaprevir
• May play a role with IFN sparing DAA o HCV protease may inhibit and its inhibition
may have larger effect with C allele• More potent regimens will mask the
IL28b difference
More potent HCV regimens will overwhelm IL28b C allele
advantage
Pilar investigators Aerssens EASL 2011
Clinical Applications of IL28b Testing in HCV genotype 1
infection• IL28b testing provides information that
is useful for estimating treatment response but not generally necessary for care of HCV infected persons
• IL28b genotype discriminates less as treatment potency improves and will someday be unhelpful
Clinical Applications of IL28b Testing in HCV genotype 1
infection• Timing of treatment of acute infection
o Start sooner for unfavorable genotype• Timing of treatment for chronic
infection o Delay for unfavorable genotype and low
disease stage• Not to withhold HCV protease inhibitor• Staging (CC noninvasive to detect
cirrhosis)• Transplant: ?? IL28b favorable liver for
IL28b unfavorable recipient
SNPs on chromosome 20 strongly associated with Hb
decline at week 4• Hemoglobin change at week 4 of
PegIFN/RBV: > 3 g/dL and < 10 g/dL
• Anemia occurred in 9.1 – 11% of the population
• Among European Americans – rs6051702 had genome wide significance; P = 10-45
o Weaker among African and Hispanic Americans
• Inosine triphosphatase (ITPA) gene o 2 gene mutation cause ITPA
deficiency
Predicted ITPA deficiency is associated with less Hb decline at treatment week 4
Population Frequency of ITPA deficiency
Protective mechanism of ITPA deficiency is not known but does not
impact SVR• RBV metabolism
differs in nucleated and non-nucleated cells
• RBV-TP accumulates → deplete ATP → hemolysis
• Potential mechanism(s)o Accumulation of
ITP modifies the ratio of RBV-TP and ATP
↓ Inosine-MP↓
phosphate
Page T; Connor JD. Int J Biochem; 1990;22:379; Homma et al Clin Gastro Hepatol 2004;2:337; Bierau J et al. Future medicine 2007;8:1221
SNP at ribavirin transporter gene influences SVR post pegIFN and
ribavirin
Morello JID 2010
Clinical application of ITPA testing
• Not commercially available in USA• Might inform RBV dose• Might inform patient counseling• Might inform timing of rEPO
Personalized Medicine for Hepatitis C
• IL28b gives important information on likelihood of spontaneous clearance and SVR
• Future applications of ITPA and other discoveries are changing