Hépatite C_Résistance aux traitements.ppt

Hépatite C: RésistanceHépatite C: Résistanceaux Traitementsaux Traitements

Prof. Jean-Michel PawlotskyProf. Jean-Michel Pawlotsky

CNR des Hépatites B, C et deltaCNR des Hépatites B, C et deltaLaboratoire de Virologie & INSERM U635Laboratoire de Virologie & INSERM U635

HHôpital Henri Mondorôpital Henri MondorUniversité Paris XIIUniversité Paris XII

CréteilCréteil

HCV Resistance

• HCV resistance to IFN- therapy

• HCV resistance to ribavirin ?

• HCV resistance to specific antiviral molecules

I

HCV resistance to IFN-Therapy

Incidence of Peg-IFN-RibavirinTreatment Failures

2%2%

00

1515

3030

4545

606054%54%

48%48%

58%58%

24%24%

16%16% 18%18%

Genotype 1 Genotypes 2/3Genotype 1 Genotypes 2/3

PEG-IFN-PEG-IFN-αα2a+ribavirin 2a+ribavirin (Fried et al)(Fried et al)

PEG-IFN-PEG-IFN-αα2a+ribavirin 2a+ribavirin (Hadziyannis et al)(Hadziyannis et al)

PEG-IFN-PEG-IFN-αα2b+ribavirin 2b+ribavirin (Manns et al)(Manns et al)

(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004) (Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)

TreatmentTreatmentFailureFailure

TreatmentTreatmentScheduleSchedule


HostHostFactorsFactors



DiseaseDiseaseCharacteristicsCharacteristics




Viral FactorsViral FactorsDiseaseDiseaseCharacteristicsCharacteristics




Viral FactorsViral FactorsDiseaseDiseaseCharacteristicsCharacteristics




Viral Resistance

• Intrinsic properties of viral strains that counteract the antiviral action of antiviral drugs

Incidence of Peg-IFN-RibavirinTreatment Failures

2%2%

00

1515

3030

4545

606054%54%

48%48%

58%58%

24%24%

16%16% 18%18%

Genotype 1 Genotypes 2/3Genotype 1 Genotypes 2/3

PEG-IFN-PEG-IFN-αα2a+ribavirin 2a+ribavirin (Fried et al)(Fried et al)

PEG-IFN-PEG-IFN-αα2a+ribavirin 2a+ribavirin (Hadziyannis et al)(Hadziyannis et al)

PEG-IFN-PEG-IFN-αα2b+ribavirin 2b+ribavirin (Manns et al)(Manns et al)

(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004) (Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)

HCV Kinetics by GenotypeEC-sponsored DITTO-Trial

(Pawlotsky et al., manuscript in preparation)

00

11

22

33

44

55

66

77 HCV RNA (log IU/ml)HCV RNA (log IU/ml)

00 44 77 88 1515 2222 292911-7-7-28-28

Genotype 4Genotype 4



** = significant difference, 4 and 1 = significant difference, 4 and 1 vsvs 3 3

**

**

****

** ****

Quantitative assay cutoffQuantitative assay cutoff

Qualitative assay cutoffQualitative assay cutoff


00

11

22

33

44

55

66


00 44 77 88 1515 2222 292911-7-7-28-28





**

**

****

** ****





00

11

22

33

44

55

66


00 44 77 88 1515 2222 292911-7-7-28-28





**

**

****

** ****





00

11

22

33

44

55

66


00 44 77 88 1515 2222 292911-7-7-28-28





**

**

****

** ****




Viral FactorsViral Factors

Antiviral Antiviral resistanceresistance

DelayedDelayedclearanceclearance

LongerLongerhalf-life ofhalf-life of

infected cellsinfected cells

Summary

• HCV resistance to IFN- antiviral effect exists

• Its molecular mechanisms are unknown and probably complex

• It accounts for only a small part of IFN--based treatment failures

SNP and SVR in the IDEAL Trial1 3 5 7 9 11 13 15 17 19 21 X M

2 4 6 8 10 12 14 16 18 20 22 Y

-log10

(P)

0.0

15.0

30.0

-log10(P)

0.0

15.0

30.0

-log10

(P)

0.0

15.0

30.0

Chromosome 19 ideogram

0 M 10 M 20 M 30 M 40 M 50 M 60 M

39,623 K 39,666 K 39,708 K 39,750 K 39,793 K 39,835K

PAK4 SYCN IL28B IL29 LRFN1NCCRP1 AC011445.6IL28A GMFG

IL28B IL28AAC011445.6

39,711 K 39,721 K 39,732 K 39,743 K 39,753 K 39,764K

rs12979860P=1.37 _10-28

1 3 5 7 9 11 13 15 17 19 21 X M2 4 6 8 10 12 14 16 18 20 22 Y

-log10

(P)

0.0

15.0

30.0

-log10(P)

0.0

15.0

30.0

-log10

(P)

0.0

15.0

30.0

Chromosome 19 ideogram

0 M 10 M 20 M 30 M 40 M 50 M 60 M

39,623 K 39,666 K 39,708 K 39,750 K 39,793 K 39,835K

PAK4 SYCN IL28B IL29 LRFN1NCCRP1 AC011445.6IL28A GMFG

IL28B IL28AAC011445.6

39,711 K 39,721 K 39,732 K 39,743 K 39,753 K 39,764K

rs12979860P=1.37 _10-28

IL28B

(Ge et al, Nature, 2009;461:399-401)(Ge et al, Nature, 2009;461:399-401)

rs12979860 Allele and SVR


rs12979860 Allele Frequency

12%12%

39%39%

49%49%

37%37%

16%16%

47%47%

C/CC/C C/TC/T T/TT/T

CaucasianCaucasianancestryancestry

n=871n=871

African AmericanAfrican Americanancestryancestry

n=191n=191


Geographic Distribution

(Thomas et al, Nature, 2009;461:798-801)(Thomas et al, Nature, 2009;461:798-801)

Effect on HCV Kinetics (Caucasians)

ΔΔ H

CV

RN

A (

Lo

gH

CV

RN

A (

Lo

g101

0

IU/m

L)

IU/m

L)

CT

TT-3.0

-2.0

-1.0

0

Weeks

-4.0

-5.0

2 4 120

-6.0 CC

(Thompson et al, AASLD 2009) (Thompson et al, AASLD 2009)

ΔΔ H

CV

RN

A (

Lo

gH

CV

RN

A (

Lo

g101

0

IU/m

L)

IU/m

L) CT

TT

-3.0

-2.0

-1.0

0

Weeks

-4.0

-5.0

2 4 120

-6.0

CC

Effect on HCV Kinetics(African Americans)


-5-5

-4-4

-3-3

-2-2

-1-1

00

00 44 88 1212 1616 2020 2424Weeks of therapyWeeks of therapy

HC

V R

NA

red

uct

ion

(L

og

HC

V R

NA

red

uct

ion

(L

og

1010 I

U/m

L)

IU

/mL

)

TT

CT

NSNS

P=0.045P=0.045

P=0.021P=0.021

P=0.004P=0.004

P=0.0005P=0.0005

VK on High-Dose Peg IFNAccording to IL28B

Genotype

(Chevaliez et al, AASLD 2010) (Chevaliez et al, AASLD 2010)

SVR Predictors

Odds RatioOdds Ratio 95% CI95% CI p-valuep-value

rs12979860 CC vs non-CCrs12979860 CC vs non-CC 5.25.2 4.14.1 6.76.7 <0.0001<0.0001

HCV RNA ≤ 600,000 IU/mLHCV RNA ≤ 600,000 IU/mL 3.13.1 2.32.3 4.14.1 <0.0001<0.0001

Caucasian vs African AmericanCaucasian vs African American 2.82.8 2.02.0 4.04.0 <0.0001<0.0001

Hispanic vs African AmericanHispanic vs African American 2.12.1 1.31.3 3.63.6 0.0040.004

METAVIR score ≤F2 METAVIR score ≤F2 2.72.7 1.81.8 4.04.0 <0.0001<0.0001

Fasting blood sugar < 5.6 mmol/LFasting blood sugar < 5.6 mmol/L 1.71.7 1.31.3 2.22.2 <0.0001<0.0001


Summary

• In patients infected with HCV genotype 1, the rs12979860 genotype:

• Is strongly associated with the SVR

• Explains 60% of the ethnic influence on SVR

• Influences HCV kinetics on therapy

• Is probably a marker of patient cell “resistance“ to the effect of IFN- through mechanisms that remain to be elucidated

II

HCV Resistance to Ribavirin ?

• Direct inhibition of HCV RNA-dependent RNA polymerase ?

• Depletion of intracellular GTP pools via IMPDH inhibition ?

• RNA mutagenesis leading to "error catastrophe" ?

• Enhancement of IFN-induced responses in the liver ?

Ribavirin’s Antiviral Mechanisms

Ribavirin’s Antiviral Effect

(Pawlotsky et al., Gastroenterology 2004;126:703-14)

-1.0-1.0

-0.5-0.5

0.00.0

0.50.5

00 22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626 2828

Mean HCV RNA decrease (log IU/ml)Mean HCV RNA decrease (log IU/ml)

Time (days)Time (days)

ControlsControls

RibavirinRibavirinmonotherapymonotherapy

-1.5-1.5

-1.0-1.0

-0.5-0.5

0.00.0

+0.5+0.5

00 22 44 66 88 1010 1212 1414

DaysDays

HCV RNA changes (log IU/ml)HCV RNA changes (log IU/ml)

-1.5-1.5

-1.0-1.0

-0.5-0.5

0.00.0

+0.5+0.5

00 22 44 66 88 1010 1212 1414

DaysDays


-1.5-1.5

-1.0-1.0

-0.5-0.5

0.00.0

+0.5+0.5

00 22 44 66 88 1010 1212 1414

DaysDays


-1.5-1.5

-1.0-1.0

-0.5-0.5

0.00.0

+0.5+0.5

00 22 44 66 88 1010 1212 1414

DaysDays


(Pawlotsky et al., Gastroenterology 2004;126:703-14)

Ribavirin’s Antiviral Effect

Summary

• Ribavirin mechanisms of action in chronic hepatitis C remain unknown

• Ribavirin direct antiviral effect is modest and transient

• Long-term ribavirin administration does not select for specific resistance substitutions

III

HCV Resistance to Direct Acting Antivirals

HCV ResistanceHCV Resistance

• Definition Selection of viral variants bearing amino acid

substitutions that alter the drug target and thereby confer reduced susceptibility to the drug

• Resistant variants are pre-existing at baseline as minor viral populations All single mutants ~10% of double mutants

(Pawlotsky JM, Ther Adv Gastroenterol 2009;2:205-219; Perelson AS, unpublished data) (Pawlotsky JM, Ther Adv Gastroenterol 2009;2:205-219; Perelson AS, unpublished data)

sensitivesensitive

resistantresistant

Mechanisms of Resistance

sensitivesensitive

resistantresistant

DrugDrug


sensitivesensitive

resistantresistant

DrugDrug

resistantresistant


sensitivesensitive

sensitivesensitive

resistantresistant

DrugDrug Stop drugStop drug

resistantresistant


sensitivesensitive

sensitivesensitive

resistantresistant

sensitivesensitive

resistantresistant


resistantresistant


sensitivesensitive

sensitivesensitive

resistantresistant

sensitivesensitive

resistant + fitresistant + fit


resistantresistant


sensitivesensitive

sensitivesensitive

resistantresistant


resistantresistant


sensitivesensitive

resistant + very fitresistant + very fit

sensitivesensitive

Chronic HCV infection is curable

by therapy

sensitivesensitive

resistantresistant


sensitivesensitive

resistantresistant

DrugDrug

resistantresistant


sensitivesensitive

resistantresistant


resistantresistant


resistantresistant

HCV Life Cycle

(Popescu & Dubuisson, Biol Cell 2009;102:63-74)

DAAs in Development

• NS3/4A protease inhibitors

• Inhibitors of HCV replication• Nucleoside/nucleotide analogue inhibitors

of RdRp• Non-nucleoside inhibitors of RdRp (NNIs)• NS5A inhibitors• Cyclophylin inhibitors

NS3/4A Protease Active Site

Antiviral Efficacy of NS3/4A PIs

Drug Phase Dose DurationMedian/mean log

HCV RNA reduction

Telaprevir III 750 mg q8h 14 days -4.4

Boceprevir III 400 mg tid 7 days -1.6

TMC435 II 200 mg qd 7 days -4.1

Danoprevir (RG7227) II 200 mg q8h 14 days -3.8

Vaniprevir (MK-7009) II 700 mg bid 8 days -4.7

BI201335 II 240 mg qd 14 days -4.0

Narlaprevir II 400 mg bid 7 days -4.2

BMS-650032 Ib 300 mg bid 3 days -3.3

ACH-1625 Ib 600 mg bid 4.5 days -3.9

GS-9256 Ib 200 mg bid 3 days -2.8

Asp168

Ala156

Arg155

Thr54

Val36

(Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219) (Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219)

Amino Acid Substitutions Amino Acid Substitutions Associated with PI ResistanceAssociated with PI Resistance

Amino Acid Substitutions Amino Acid Substitutions Associated with PI ResistanceAssociated with PI Resistance

Resistance and Fitness

In vivoIn vivo

fitnessfitness

ResistanceResistance

(Kieffer T, et al. Hepatology 2007;46:631-9)(Kieffer T, et al. Hepatology 2007;46:631-9)

(Reesink HW, et al. Gastroenterology 2006;131:997-1002)(Reesink HW, et al. Gastroenterology 2006;131:997-1002)

Telaprevir Resistance

-5-5

-4-4

-3-3

-2-2

-1-1

00

11

00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414

Study Time (Days)Study Time (Days)

Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)

Placebo VX-950 450 mg q8h VX-950 1250 mg q12h

0

1

2

3

4

5

6

7

0 10 20 30 40 50 60 70 80 90

HC

V R

NA

(L

og

HC

V R

NA

(L

og

1 010

I U/ m

L)

IU/m

L)

WeeksWeeks

WTWT

AABB CC DD

EE FF

AA BB CC

DD EER155K/NR155K/NV36L/MV36L/MWTWT

A40TA40TV36L/M + A40TV36L/M + A40TR155K/N + A40TR155K/N + A40TV36L/M + R155K/NV36L/M + R155K/NV36L/M + R155K/N + A40TV36L/M + R155K/N + A40T

TVR-Peg-IFNTVR-Peg-IFN

Telaprevir Resistance (PROVE2)

(Chevaliez S, et al., EASL 2009)(Chevaliez S, et al., EASL 2009)

Telaprevir Resistance (PROVE2)H

CV

RN

A (

Lo

gH

CV

RN

A (

Lo

g1 01

0 I U

/ mL

) IU

/mL

)

WeeksWeeks

WTWT

AABB

CC

DD

EE

R155K/E + T42SR155K/E + T42SWTWT

AA BBWTWT

CC DD EE

TVR-Peg-IFNTVR-Peg-IFN

SOCSOC

00

11

22

33

44

55

66

77

00 88 1616 2424 3232 4040 4848 5656 6464 7272

(Chevaliez S, et al., EASL 2009)(Chevaliez S, et al., EASL 2009)

Antiviral Efficacy of NUCs


HCV RNA reduction

R7128 II 1500 mg bid 14 days -2.7

IDX184 II 100 mg qd 3 days -0.7

2’C-Me-ATP in the catalytic site

(Migliaccio et al., J Biol Chem 2003;278:49164-70)

HCV Resistance to 2’-C-Methyl Nucleoside Inhibitors

Antiviral Efficacy of NNIs


HCV RNA reduction

GS-9190 II 40 mg bid 8 days -1.4

Filibuvir II 300 mg bid 8 days -2.1

ANA598 II 800 mg bid 3 days -2.9

BI207127 II 800 mg q8h 3 days -3.1

VCH-759 II 400 mg tid 10 days -1.7

ABT-333 II 600 mg bid 2 days -1.5

VX-222 Ib 750 mg bid 3 days -3.2

MK-3281 Ib 800 mg bid 7 days -1.3 (1a), -3.8 (1b)

RdRp Resistance Mutations

(courtesy of Isabel Najera, Roche)

499

495

496

316

365

201

482

423

419

95

176

451

414

411448

142 96

282

499

495

496

316

365

201

482

423

419

95

176

451

414

411448

142 96

282

499

495

496

316

365

201

482

423

419

95

176

451

414

411448

142 96

282

FingersThumb

Palm

AA

BB

CC

DD

polpol

Filibuvir (Pfizer) Resistance in IFN Null-Responders

(Mori et al., EASL 2010)

Thumb 2 domainM423

Filibuvir

Antiviral Efficacy of NS5A Inhibitors


HCV RNA reduction

BMS790052 II 10 mg qd 1 day -3.2

AZD7295 Ib 233 mg q8h 5 days -2.1 (only 1b)

BMS-790052 Resistance in vitro

SubtypeSubtype SustitutionSustitution EC50EC50 Fold-changeFold-change Replication Replication level (% wt)level (% wt)

1b replicon1b replicon

wtwt 2.6±0.32.6±0.3 11 100100

L31VL31V 61±1561±15 2424 144±47144±47

Y93HY93H 49±1349±13 1919 20±720±7

wtwt 5.9±3.75.9±3.7 11 100100

1a replicon1a replicon

M28TM28T 4,100±3604,100±360 360360 31±2331±23

Q30HQ30H 8,700±1,9008,700±1,900 1,9001,900 75±3175±31

Q30RQ30R 7,300±1,1007,300±1,100 1,1001,100 41±1641±16

L31ML31M 2,100±6102,100±610 610610 55±1555±15

L31VL31V 20,000±6,00020,000±6,000 6,0006,000 117±29117±29

Y93CY93C 11,000±4,00011,000±4,000 4,0004,000 11±711±7

(Gao et al., Nature 2010;465:96-100)

Antiviral Efficacy of Cyclophylin Inhibitors


HCV RNA reduction

Alisporivir(DEBIO-025)

II 1200 mg bid 14 days -3.6

SCY-465 Ib 900 mg qd 15 days -2.2

NIM 811 II 600 mg bid 14 days None

Alisporivir Resistance in vitro

3’UTRNS3 NS4

A BNS5A

ANS5B5’UTR neo

HCV

IRES

EMCV

IRES

Domain IDomain I Domain IIDomain II Domain IIIDomain III

3636 213213 250250 342342 356356 447447

R262QR262Q R318WR318WA241PA241P D320ED320E

A241P + A241P + R262QR262Q

A241P + A241P + R318WR318W

R262Q + R262Q + R318WR318W

R318W + R318W + D320ED320E

A241P + A241P + R262Q + R262Q + R318WR318W

A241P + A241P + R262Q + R262Q + R318W + R318W +

D320ED320E

Fold-Fold-changechangevs vs wtwt

1.021.02 1.581.58 1.371.37 3.673.67 1.721.72 3.893.89

(Coelmont et al., EASL 2009)

IV

Triple Combination Treatment Failure

DAADAA

Prevention of DAA Resistance

DAADAA

RibavirinRibavirinPegylated Pegylated IFN-IFN-

++

Prevention of DAA Resistance

Treatment Failures on Triple Combination with a DAA

• Treatment-Naïve: 20-30%

• Treatment-experienced: 40-50%

Expected Higher Failure Ratesin Difficult-to-Treat Patients

• Advanced liver disease

• Liver transplant

• HIV coinfected

• Hemodialysis

• Immunosuppressed patients

• African Americans

• etc…


• Insufficient response to Peg-IFN and ribavirin

• Growth of uncontrolled DAA-resistant HCV variants

7171 76767070

27273333

1717

00 00

00

2020

4040

6060

8080

100100

<0.5<0.5

LogLog1010 HCV RNA level at week 4 (Lead-in phase) HCV RNA level at week 4 (Lead-in phase)

0.5 0.5 –– <1.0

<1.0

1.0 1.0 –– <1.5

<1.5

1.5 1.5 –– <2.0

<2.0

2.0 2.0 –– <3.0

<3.0

3.0 3.0 –– <4.0

<4.0≥≥4.04.0

Undetectable

Undetectable

N=7N=7 N=21N=21 N=10N=10 N=11N=11 N=21N=21 N=12N=12 N=11N=11 N=3N=3

Tre

atm

ent

failu

res

(%)

Tre

atm

ent

failu

res

(%)

(Kwo et al., AASLD 2009) (Kwo et al., AASLD 2009)

Treatment Failures in SPRINT-1Treatment Failures in SPRINT-1Failures according to lead-in, 28wkFailures according to lead-in, 28wk

00

2020

4040

6060

8080

100100

<0.5<0.5

LogLog1010 HCV RNA level at week 4 (Lead-in phase) HCV RNA level at week 4 (Lead-in phase)

0.5 0.5 –– <1.0

<1.0

1.0 1.0 –– <1.5

<1.5

1.5 1.5 –– <2.0

<2.0

2.0 2.0 –– <3.0

<3.0

3.0 3.0 –– <4.0

<4.0≥≥4.04.0

Undetectable

Undetectable

N=9N=9 N=13N=13 N=17N=17 N=10N=10 N=14N=14 N=17N=17 N=12N=12 N=9N=9

(Kwo et al., AASLD 2009) (Kwo et al., AASLD 2009)

5656

3838 3535

2020 21211818

88 00

Treatment Failures in SPRINT-1Treatment Failures in SPRINT-1Failures according to lead-in, 48wkFailures according to lead-in, 48wk

Tre

atm

ent

failu

res

(%)

Tre

atm

ent

failu

res

(%)

SVR According to Lead-in (SPRINT-2, non-black)

29%29%29%29%

39%39%39%39%

82%82%82%82%

% o

f p

atie

nts

w

ith

SV

R%

of

pat

ien

ts

wit

h S

VR

% o

f p

atie

nts

w

ith

SV

R%

of

pat

ien

ts

wit

h S

VR

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

BOC/RGTBOC/RGT BOC/PR48BOC/PR48

(Poordad et al., AASLD 2010)(Poordad et al., AASLD 2010)

82%82%82%82%

<1 log HCV RNA <1 log HCV RNA decreasedecrease<1 log HCV RNA <1 log HCV RNA decreasedecrease

≥≥1 log HCV RNA1 log HCV RNAdecreasedecrease≥≥1 log HCV RNA1 log HCV RNAdecreasedecrease

SVR According to Lead-in (RESPOND-2, non-black)

33%33%33%33% 34%34%34%34%

79%79%79%79%

% o

f p

atie

nts

w

ith

SV

R%

of

pat

ien

ts

wit

h S

VR

% o

f p

atie

nts

w

ith

SV

R%

of

pat

ien

ts

wit

h S

VR

00

1010

2020

3030

4040

5050

6060

7070

8080

9090

100100

BOC/RGTBOC/RGT BOC/PR48BOC/PR48

(Bacon et al., AASLD 2010)(Bacon et al., AASLD 2010)

73%73%73%73%

<1 log HCV RNA <1 log HCV RNA decreasedecrease<1 log HCV RNA <1 log HCV RNA decreasedecrease

≥≥1 log HCV RNA1 log HCV RNAdecreasedecrease≥≥1 log HCV RNA1 log HCV RNAdecreasedecrease

Telaprevir Rollover Study 107

0

20

40

60

80

100

37%

55%

75%

97%

59%

Pat

ien

ts W

ith

Un

det

ecta

ble

H

CV

RN

A (

%)

TOTALN=117

Priornull-response

N=51

Prior partialresponse

N=29

Priorbreakthrough

N=8

PriorrelapseN=29

(Berg et al., EASL 2010) (Berg et al., EASL 2010)

REALIZE Trial-Telaprevir Arms

0

20

40

60

80

100

31%

57%

86%

65%

Pat

ien

ts W

ith

Un

det

ecta

ble

H

CV

RN

A (

%)

TOTAL Priornull-response

Prior partialresponse

Priorrelapse

(Vertex press release, Sept 7, 2010) (Vertex press release, Sept 7, 2010)


• Insufficient response to Peg-IFN and ribavirin

• Growth of uncontrolled DAA-resistant HCV variants

Incidence of HCV resistanceIncidence of HCV resistance

(Hézode et al., N Engl J Med 2009;360:1839-50) (Hézode et al., N Engl J Med 2009;360:1839-50)

ArmArm EventEvent NN VL <LODVL <LOD Wild-typeWild-type Low-levelLow-levelresistanceresistance

High-levelHigh-levelresistanceresistance

T12PR24T12PR24BreakthroughBreakthrough 44 -- -- -- 44

RelapseRelapse 88 -- 11 44 33

T12PR12T12PR12BreakthroughBreakthrough 11 -- 11 -- --

RelapseRelapse 1919 33 11 1313 22

T12P12T12P12BreakthroughBreakthrough 1919 22 -- 99 88

RelapseRelapse 2222 44 -- 1616 22

-5-5

-4-4

-3-3

-2-2

-1-1

00

11

Study TimeStudy Time

Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)

DAA Resistance

-5-5

-4-4

-3-3

-2-2

-1-1

00

11

Wild-type, sensitive HCVWild-type, sensitive HCV


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)

DAA Resistance

-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Resistant HCVResistant HCV


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)

DAA Resistance

-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)

Triple Combo Failure

-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)

Triple Combo FailurePotent IFNPotent IFN-ribavirin effect-ribavirin effect

-5-5

-4-4

-3-3

-2-2

-1-1

00

11



Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)


-5-5

-4-4

-3-3

-2-2

-1-1

00

11




Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)


-5-5

-4-4

-3-3

-2-2

-1-1

00

11




Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)


CUREDCURED

-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)

Triple Combo FailureModerate IFNModerate IFN-ribavirin effect-ribavirin effect

-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)



-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)




-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)




CUREDCUREDoror

RELAPSE with RESISTANT VIRUSRELAPSE with RESISTANT VIRUS

-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)

Triple Combo FailureModest or null IFNModest or null IFN-ribavirin effect-ribavirin effect

-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)



-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)




-5-5

-4-4

-3-3

-2-2

-1-1

00

11


Med

ian

HC

V R

NA

Ch

ang

eM

edia

n H

CV

RN

A C

han

ge

fro

m B

asel

ine

(Lo

gfr

om

Bas

elin

e (L

og

1010

IU/m

L)

IU/m

L)



Resistant HCVResistant HCVRELAPSE or BREAKTHROUGHRELAPSE or BREAKTHROUGH

with RESISTANT VIRUSwith RESISTANT VIRUS

V

Prevention of Treatment Failures

Prevention of Treatment Failure

• Prediction of treatment failure (assessment of IFN-ribavirin responsiveness)

• Prevention of treatment failure in poor IFN responders

Weeks on therapyWeeks on therapy

363600 24241212 4848

SPRINT-2 TrialBoceprevir, Naïve, Genotype 1

6060 7272

*RVR = undetectable HCV RNA at week 4 of boceprevir treatment (i.e. at week 8)*RVR = undetectable HCV RNA at week 4 of boceprevir treatment (i.e. at week 8)

Boceprevir Boceprevir 800 mg tid 800 mg tid

+ + Peg-IFNPeg-IFN2b 2b + RBV+ RBV

Follow-upFollow-upPeg-IFNPeg-IFN2b 2b + RBV+ RBV

Peg-Peg-IFNIFN2b 2b + RBV+ RBV

Follow-upFollow-up

44

Peg-IFNPeg-IFN2b 2b + RBV+ RBV

Follow-upFollow-up

Peg-IFNPeg-IFN2b2b+ RBV+ RBV Follow-upFollow-up

no

RV

Rn

o R

VR

Boceprevir Boceprevir 800 mg tid 800 mg tid

+ + Peg-IFNPeg-IFN2b 2b + RBV+ RBV

Peg-Peg-IFNIFN2b 2b + RBV+ RBV

RV

RR

VR

2828

N >

100

0N

> 1

000

Weeks on therapyWeeks on therapy

363600 24241212 4848

REALIZE TrialTelaprevir, Nonresponders, Genotype 1

6060 7272

*eRVR = undetectable HCV RNA at week 4 and week 12*eRVR = undetectable HCV RNA at week 4 and week 12

Telaprevir Telaprevir 750 mg q8h 750 mg q8h

+ + Peg-IFNPeg-IFN2a 2a + RBV+ RBV

Follow-upFollow-upPeg-IFNPeg-IFN2a 2a + RBV+ RBV

Peg-Peg-IFNIFN2a 2a + RBV+ RBV

Peg-IFNPeg-IFN2a 2a + RBV+ RBV

Follow-upFollow-up

282844

Peg-IFNPeg-IFN2a 2a + RBV+ RBV Follow-upFollow-up

Telaprevir Telaprevir 750 mg q8h 750 mg q8h

+ + Peg-IFNPeg-IFN2a 2a + RBV+ RBV

N = 260N = 260

N = 260N = 260

N = 130N = 130

Prevention of Treatment Failure

• High-dose pegylated IFN and/or ribavirin in combination with protease inhibitors

• Quadruple therapy in order to increase the barrier to resistance of DAAs in combination with pegylated IFN and ribavirin

• IFN-free regimens with multiple DAAs

55%

26%

34%39%

21%

11%6%

53% 55%

0%

10%

20%

30%

40%

50%

60%

70%

W4 W12 W24

< 1 log10 HCV-RNA decrease

1 to 2 log10 HCV-RNA decrease

≥≥ 2 log10 HCV-RNA decrease

Undetectable HCV-RNA (<15 IU/mL)

1% 8%

22%

(Hézode et al., AASLD 2010)

High-Dose Pegylated IFN- and Ribavirin in Non-Responders

GS-9256 (PI) + Tegobuvir (NNI)

0 7 14 21 280

1

2

3

4

5

6

7

8

((<<2255 IIUU//mmLL))HC

V R

NA

IU

/mL

(L

og

)

Days

(Zeuzem et al., AASLD 2010)

GS-9256 + tegobuvir

GS-9256 (PI) + Tegobuvir (NNI)

0 7 14 21 280

1

2

3

4

5

6

7

8

((<<2255 IIUU//mmLL))

Days

(Zeuzem et al., AASLD 2010)

HC

V R

NA

IU

/mL

(L

og

)

GS-9256 + tegobuvir

GS-9256 + tegobuvir + ribavirin

BMS-650032 (PI) + BMS-790052 (NS5A)

0 1 2 3 4 6 8 10 121

2

3

4

5

6

7

0 1 2 3 4 6 8 10 12

1

2

3

4

5

6

7

Weeks

HC

V R

NA

(lo

g10

)H

CV

RN

A (

log

10)

No Peg/ribavirin

+Peg/ribavirin

Weeks

(Lok et al., AASLD 2010)

Danoprevir + RG7128 ComboINFORM-1 Trial

(Gane et al., Lancet 2010; published online)

Days DaysDays

Danoprevir, 900 mg bid + RG7128Danoprevir, 900 mg bid + pegIFNand ribavirin Increasing doses of danoprevir and RG7128

Conclusions

Conclusions

• The administration of DAAs is always associated with the selection of resistant HCV variants

• In combination regimens, the antiviral effect of pegylated IFN and ribavirin prevents the growth of DAA-resistant variants and leads to viral eradication

• Treatment failure with the triple combination of pegylated IFN, ribavirin and a DAA is due to an insufficient antiviral response to IFN and ribavirin

• Treatment failure is characterized by the growth of DAA-resistant HCV variants, as a result of virtual monotherapy with the DAA

• Prevention of treatment failure in patients with an insufficient response to pegylated IFN and ribavirin is based on:

• An accurate assessment of IFN responsiveness (lead-in phase, baseline parameters)

• Alternative options for true IFN null responders that must be assessed in prospective clinical trials

Conclusions

Documents

Hépatite C_Résistance aux traitements.ppt