using genetic markers in clinical practice david thomas advisor: merck clinical trial: gilead and...

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