Genética e hepatite C na prática clínica. Qual a real importância do Polimorfismo IL28 na resposta virológica sustentada?

(1)

Genética e hepatite C na prática clínica.

Qual a real importância do Polimorfismo

IL28 na resposta virológica sustentada?

Dr. João Renato Rebello Pinho

Laboratório de Gastroenterologia HepatologiaTropical do Instituto de

MedicinaTropical de São Paulo , Departmento de Gastroenterologia,

Faculdade de Medicina, Universidade de São Paulo

Laboratório de Técnicas Especiais, Albert Einstein Medicina

Diagnóstica

(2)

Genome Wide Association

Studies (GWAS)

• GWAS is the study of genetic variation across the

entire genome that is designed to associate

genetic variations (SNPs) with traits or with the

presence or absence of disease or condition

(3)

Single-nucleotide polymorphism (SNP)

For example, two

sequenced DNA

fragments from

different individuals,

AAGCCTA to

AAGCTTA, contain a

difference in a single

nucleotide.

(4)

effective immune response

ineffective immune response

spontaneous clearance

chronic infection

HCV therapy ineffective

HCV therapy effective

Infected individuals

~30%

_~

70%

~40%

~60%

HCV infection outcomes

(5)

rs12979860 (

C

/

T

)

IL28B

IL28A

IL29

55 kb

Human chromosome 19q13

K70R (A209G)

T112A

Y160H

3 kb

rs8099917 (

G

/

T

)

8 kb

Non risk allelle

(6)

Genome-wide association studies:

Treatment response

Ge D, et al. Nature 2009;461:399-401. rs12979860 (C/T) Sept 17, 2009

Tanaka Y, et al. Nat Genet 2009;41:1105-9. rs8099917 (G/T) e rs12980275 (A/G) Sept 13, 2009

Suppiah V, et al. Nat Genet 2009;41:1100-4. rs8099917 (G/T) etc. Sept 13, 2009

(7)

Nature 2009;

461:399-401.

Illumina

Human610-quad

BeadChip

IDEAL Study

Population

(8)

(9)

The C/C genotype of rs12979860

associates with clearance of hepatitis C

virus

Thomas et al, Nature, 2009

(10)

The allelic distribution of rs12979860

varies across human populations

Thomas et al. Nature. 2009;461:798-801. rs12979860 (T/C)

Sardinians 34 - 52.9%

European-American 92 - 67.4%

Ticuna 62- 20.2%

Karitiana 54 - 82.4%

Surui 47 - 77.7%

Guihiba speakers 12 - 62.5%

Quechua 22 - 63.6%

(11)

Influence of IL28B genotypes

on viral kinetics

Thompson,

GASTRO 2010

(12)

Mangia A, Thompson AJ, Santoro R, Piazzolla V, Tillmann HL, Patel K, Shianna KV,

Mottola L, Petruzzellis D, Bacca D, Carretta V, Minerva N, Goldstein DB,

McHutchison JG.

An IL28B polymorphism determines treatment response of hepatitis C virus

genotype 2 or 3 patients who do not achieve a rapid virologic response.

Gastroenterology. 2010 Sep;139(3):821-7, 827.e1. Epub 2010 Jun 2. PubMed PMID:

20621700.

(13)

Amino Acid Substitution in

Hepatitis C Virus Core Region

and Genetic Variation Near the

Interleukin 28B Gene Predict Viral

Response to Telaprevir with

Peginterferon and Ribavirin

HEPATOLOGY, Vol. 52, No. 2,

(14)

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IL-28 GENE SINGLE NUCLEOTIDE POLYMORPHISMS

(SNPS) GENOTYPING IN INDIVIDUALS INFECTED

WITH HEPATITIS C.

in São Paulo population

(Brazil)

(16)

Study subjects: n=317

 Spontaneous clearance (n=50)

 Sustained virological response (n=70)

 Non-sustained virological response (n=40)

 Healthy controls (n=157)

Objectives:

Compare the genotype frequency of SNPs

rs8099917 and rs12979860 between the groups and

correlates with HCV infection outcome.

(17)

Spontaneous

clearance (n=50)

SVR

(n=70)

Non-SVR*

(n=40)

Healthy controls

(n=157)

0%

6%

3%

16%

17%

66%

31%

84%

83%

28%

66%

GG

GT

TT

rs8099917 genotype (n=317)

Nastri, ACSS et al.

(18)

Spontaneous

clearance (n=50)

SVR

(n=70)

Non-SVR*

(n=40)

Healthy controls

(n=157)

66%

46%

3%

40%

26%

47%

77%

46%

8%

7%

20%

14%

CC

CT

TT

rs12979860 genotype (n=317)

Nastri, ACSS et al.

(19)

DESENVOLVIMENTO DE UM

SISTEMA ORIGINAL

SIMPLIFICADO PARA A

ANÁLISE DE POLIMORFISMOS

RELACIONADOS AO GENE

IL28B.

Dissertação de Mestrado apresentada como requisito final

para obtenção do título de Mestre no Programa de

Pós-Graduação em Saúde e Meio Ambiente.

Mestranda: Simone Moreira

Orientador: Prof. Dr. Mauro de Souza Leite Pinho

Co-orientador: Prof. Dr. Paulo Henrique Condeixa de França

Joinville/2012

(20)

Menor

frequência

genotípica, G/G

do polimorfismo

rs8099917

(6,7%)*

Número mínimo

estimado para se

encontrar um

caso

correspondente

ao genótipo G/G

15 Número de

amostras

analisadas

75 Estimativa de amostras

*Disponível em: http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=8099917. Acesso em:

10/07/2010.

METODOLO

GIA

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Frequência genotípica encontrada

n=75

rs12979860

Genótipo

Frequência (%)

CC

52 CT

40 TT

8 rs8099917

Genótipo

Frequência (%)

TT

70,7

TG

25,3

GG

4 RESULTADOS

(22)

IL28B polymorphisms are markers of therapy response and are influenced by

genetic ancestry in chronic hepatitis C patients from an admixed population.

Lourianne Nascimento Cavalcante

1,5

_{, Kiyoko Abe-Sandes}

2,4

_{, Ana Luiza Dias Angelo}

2 _,

Taisa Manuela B. Machado

2 _{, Denise C. Lemaire}

2,3

_{, Carlos Maurício Cardeal Mendes}

6 _,

João Renato Pinho

7 _{, Fernanda Malta}

7 _{, Luiz G C.Lyra}

1,5

_{& André Castro Lyra}

1,5

_.

1Federal University of Bahia (UFBA), Salvador, Bahia, Brazil

2 Laboratory of Immunology – Health Sciences Institute (ICS) – Federal University of

Bahia (UFBA),

Salvador, Bahia, Brazil.

3 Bahiana School of Medicine and Public Health (EBMSP), Salvador, Bahia, Brazil

4 State University of Bahia (UNEB), Department of Life Sciences, Salvador, Bahia,

Brazil

5 Gastro-Hepatology Service - Hospital São Rafael - Monte Tabor, Salvador, Bahia,

Brazil.

6 Fima Lifshitz Research Center, Federal University of Bahia, Bahia, Brazil.

7 Medicine Tropical Institution - Faculty of Medicine,University of São Paul

(23)

(24)

Figure 1. IL28B rs12979860 according to therapy response

A. Analysis considering IL28B genotypes separately

B. Analysis considering C/T and T/T genotypes together versus C/C.

(25)

Figure 2. IL28B rs8099917 according to therapy response.

A. Analysis considering IL28B genotypes separately.

B. Analysis considering G/G and G/T genotypes together versus T/T.

(26)

Will IL28B polymorphism remain relevant in the era of direct

acting antiviral agents for HCV?

A.J.Thompson (1,2,3) , J.G. McHutchison (4)

1 - Gastroenterology Department, St. Vincent’s Hospital, Melbourne,

Victoria, Australia

2 - Victorian Infectious Diseases Reference Laboratory, Melbourne,

Victoria, Australia

3 – Duke Clinical Research Institute, Duke University Medical Center,

Durham, North Carolina, USA

4 - Gilead Sciences, Inc, Foster City, California, USA

A.J.T and J.G.M are co-inventors of a patent related to the IL28B

discovery. A.J.T has received research support from Merck, Roche

and Gilead Sciences; has served as a consultant for Merck, Roche

and Janssen-Cilag; and has served on speaker bureaus for Merck.

J.G.M. is an employee of Gilead Sciences.

(27)

Treatment-naïve patients

Boceprevir

Boceprevir attenuated the association between IL28B genotype and

treatment outcome, relative to the PR control arm. IL28B genotype

(28)

Lead-in period:

Naïve and experienced patient populations

Boceprevir

• major benefit of boceprevir in the C/C population might be to allow short treatment

duration. 97% of C/C patients in the SPRINT-2 / RESPOND-2 studies achieved a 1

log reduction in HCV RNA by week 4.

• useful for risk stratification: 68% of non-C/C patients in the boceprevir-treatment

arms achieved a ≥ 1 log10 IU/mL reduction in HCV RNA at week. The SVR rate in

these patients was 75 – 82% 5. Among non-C/C patients, with a HCV RNA

(29)

IFN-experienced patient populations

Boceprevir

The clinical utility of IL28B genotyping for these treatment experienced patients is

therefore not to predict treatment outcome, but rather to predict the likelihood of short

duration therapy. IL28B genotype was strongly associated with virological response

during the lead-in phase (OR 4.5, 1.5 - 13.7, P=0.007).

(30)

Treatment-naïve patients

Telaprevir

(31)

IFN-experienced patient populations

Telaprevir

(32)

Other DAAs in development

INFORM-1

Mericitabine(RG7128) + Danoprevir (RG7227)

+Ribarivirine

(33)

Oth

er DAAs i

n develo

pment

18 SILEN-C143 (naïve) SVR24 BI201335 240mg + PR (n=70) PR (n=40) 100% 82% 71% 41% SOUND-C223 (naïve)

cEVR BI201335 120mg +BI207127 600mg TID

+ RBV (HCV-1A, n = 86) (HCV-1B, n = 118) BI201335 120mg +BI207127 600mg BD + RBV (HCV-1A, n = 29) (HCV- 1B, n = 47)

BI201335 120mg +BI207127 600mg TID (HCV-1A, n = 12) (HCV-1B, n = 27) HCV-1A 88% HCV-1B 92% HCV-1A 86% HCV-1B 91% HCV-1A 100% HCV-1B 100% 64% 86% 45% 89% 22% 65% ATLAS44 (naïve) SVR24 Danoprevir 300mg + PR (n=51) Danoprevir 600mg + PR (n=57) Danoprevir 900mg + PR (n=38) PR (n=24) 81% 95% 85% 88% 63% 79% 68% 25% ESSENTIAL16 (Naïve) SVR24 Alisporivir + PR, 24 weeks (n=72) Alisporivir + PR, 48 weeks (n=72) Alisporivir + PR, RGT (n=71) 71% 100% 100% 33% 62% 73% 18 SILEN-C143 (naïve) SVR24 BI201335 240mg + PR (n=70) PR (n=40) 100% 82% 71% 41% SOUND-C223 (naïve)

BI201335 120mg +BI207127 600mg TID (HCV-1A, n = 12) (HCV-1B, n = 27) HCV-1A 88% HCV-1B 92% HCV-1A 86% HCV-1B 91% HCV-1A 100% HCV-1B 100% 64% 86% 45% 89% 22% 65% ATLAS44 (naïve) SVR24 Danoprevir 300mg + PR (n=51) Danoprevir 600mg + PR (n=57) Danoprevir 900mg + PR (n=38) PR (n=24) 81% 95% 85% 88% 63% 79% 68% 25% ESSENTIAL16 (Naïve) SVR24 Alisporivir + PR, 24 weeks (n=72) Alisporivir + PR, 48 weeks (n=72) Alisporivir + PR, RGT (n=71) 71% 100% 100% 33% 62% 73%

(34)

Other DAA

s

in development

SOUND-C2 Interim Results: High Efficacy, Good Safety

Profile of IFN-Free BI 201335, BI 207127, and RBV

Combination Therapy in Treatment-Naive Patients With

Genotype 1 HCV

• Response rates highest (up to 82%) in patients with

genotype 1b HCV (regardless of IL28B genotype)

and those with genotype 1a, IL28B genotype CC

HCV

• Data support further evaluation of BI 201335, BI

207127, and RBV as IFN-free regimen for patients

with genotype 1b HCV or genotype 1a, IL28B CC

HCV

(35)

Oth

er DAAs i

n develo

pment

18 SILEN-C143 (naïve) SVR24 BI201335 240mg + PR (n=70) PR (n=40) 100% 82% 71% 41% SOUND-C223 (naïve)

BI201335 120mg +BI207127 600mg TID (HCV-1A, n = 12) (HCV-1B, n = 27) HCV-1A 88% HCV-1B 92% HCV-1A 86% HCV-1B 91% HCV-1A 100% HCV-1B 100% 64% 86% 45% 89% 22% 65% ATLAS44 (naïve) SVR24 Danoprevir 300mg + PR (n=51) Danoprevir 600mg + PR (n=57) Danoprevir 900mg + PR (n=38) PR (n=24) 81% 95% 85% 88% 63% 79% 68% 25% ESSENTIAL16 (Naïve) SVR24 Alisporivir + PR, 24 weeks (n=72) Alisporivir + PR, 48 weeks (n=72) Alisporivir + PR, RGT (n=71) 71% 100% 100% 33% 62% 73% 19 PR (n=73) 73% 17% PROTON45 (naïve) SVR12 PSI-7977 200mg + PR (n=48) (SVR12 = 88%) PSI-7977 400mg + PR (n=47) (SVR12 = 91%) PR (n=26) N/A N/A N/A }T/T = 13/13 } N/A JUMP-C 13 (Naïve) SVR12 Mericitabine + PR (n=33) PR (n=85) 80% N/A 72% N/A 15 cEVR ANA-598 200mg + PR (n=21) ANA-598 400mg + PR (n=30) PR (n=24) 100% 86% 82% 76% 65% 46% AI44401046 (naïve) cEVR BMS-790052 20mg + PR (n=80) BMS-790052 60mg + PR (n=78) PR (n=10) 73% 68% 18% C/T = 44% T/T = 47% C/T = 49% T/T = 44% C/T = 17% T/T (n=0) 24 (null responder) SVR24 BMS-790052 + BMS-650032 2/2** 8/8** 11 (null responder) SVR24 BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PR 1/1 1/1 4/10*** 9/9 19 PR (n=73) 73% 17% PROTON45 (naïve) SVR12 PSI-7977 200mg + PR (n=48) (SVR12 = 88%) PSI-7977 400mg + PR (n=47) (SVR12 = 91%) PR (n=26) N/A N/A N/A }T/T = 13/13 } N/A JUMP-C 13 (Naïve) SVR12 Mericitabine + PR (n=33) PR (n=85) 80% N/A 72% N/A 15 _cEVR _{ANA-598 200mg + PR (n=21)} ANA-598 400mg + PR (n=30) PR (n=24) 100% 86% 82% 76% 65% 46% AI44401046 (naïve) cEVR BMS-790052 20mg + PR (n=80) BMS-790052 60mg + PR (n=78) PR (n=10) 73% 68% 18% C/T = 44% T/T = 47% C/T = 49% T/T = 44% C/T = 17% T/T (n=0) 24 (null responder) SVR24 BMS-790052 + BMS-650032 2/2** 8/8** 11 (null responder) SVR24 BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PR 1/1 1/1 4/10*** 9/9

(36)

Oth

er DAAs i

n develo

pment

19 PR (n=73) 73% 17% PROTON45 (naïve) SVR12 PSI-7977 200mg + PR (n=48) (SVR12 = 88%) PSI-7977 400mg + PR (n=47) (SVR12 = 91%) PR (n=26) N/A N/A N/A }T/T = 13/13 } N/A JUMP-C 13 (Naïve) SVR12 Mericitabine + PR (n=33) PR (n=85) 80% N/A 72% N/A 15 _cEVR _{ANA-598 200mg + PR (n=21)} ANA-598 400mg + PR (n=30) PR (n=24) 100% 86% 82% 76% 65% 46% AI44401046 (naïve) cEVR BMS-790052 20mg + PR (n=80) BMS-790052 60mg + PR (n=78) PR (n=10) 73% 68% 18% C/T = 44% T/T = 47% C/T = 49% T/T = 44% C/T = 17% T/T (n=0) 24 (null responder) SVR24 BMS-790052 + BMS-650032 2/2** 8/8** 11 (null responder) SVR24 BMS-790052 + BMS-650032 BMS-790052 + BMS-650032 + PR 1/1 1/1 4/10*** 9/9

(37)

How will IL28B genotyping be incorporated into the boceprevir

/ telaprevir treatment paradigms in treatment-naïve patients?

1 - Shorten treatment duration; 2 - Include only patients who fail

PEG/RIBA therapy; 3 -Include only non RVR patients identified

by a lead-in period

(38)

How will IL28B genotyping be incorporated into the boceprevir

/ telaprevir treatment paradigms in treatment-naïve patients?

In patients carrying the poor response IL28B genotypes, telaprevir / boceprevir

regimens offer a large increment in SVR; the lead-in stratifies patient for likelihood

of SVR and the risk of selection of NS3 variants associated with resistance.

(39)

How will IL28B genotyping be incorporated into the boceprevir

/ telaprevir treatment paradigms in treatment-naïve patients?

Hypothetical future strategies for the use of DAAs +/- IFN according to IL28B

genotype. PR = peginterferon plus ribavirin; RBV = ribavirin; DAA = direct

(40)

What is the most cost-effective strategy for the

introduction of DAA-based therapy for genotype 1

HCV?

The whole sale acquisition cost (WAC)

of a 48 week course of pegIFN and RBV

in the US is approximately $US30,000.

The current pricing schedule for

boceprevir will be $US1,100 per week,

translating to $US26,400 for 24 weeks,

$US35,200 for 32 weeks and $US48,400

for 44 weeks of treatment.

Telaprevir has a $US49,200 WAC price

for 12 weeks.

(41)