How to avoid a

resistance issue with the

first generation protease

inhibitors ?

O. Lada

PHDService d’Hépatologie et INSERM CRB3,

AP-HP Hopital Beaujon, Paris, France.Olivier.lada@inserm.fr

Progress in the Treatment of Hepatitis C

PEGPEG--IFNIFN IFN+RBVIFN+RBV

6 16%6 16%18 23%18 23%

47% 63%47% 63%

35 43%35 43%

PEGPEG--IFN+RBVIFN+RBV

19891989 20102010 2011 2011 --20..20..

IFNIFN

70% 90 %70% 90 %

DAAsDAAs

HBV HIV HCV

Genome DNA RNA RNA

Mutation rate +++ + +++

Daily viral production 1013 1010 1012

Viral Reservoir cccDNA Integrated c DNA None

Therapeutic strategy Single Multiple Multiple

recovery No No Yes

Direct Acting Antivirals (DAA) drugs Direct Acting Antivirals (DAA) drugs targetstargets

Asselah T et al. Liver International 2011Asselah T et al. Liver International 2011

NS3-4A Protease NS5B

Polymerase

NS5A

Protease Inhibitors

Polymerase Inhibitors

NS5A Inhibitors

Asselah T et al. Liver International 2012

Targets for DAAs

Resistance to specific HCV inhibitorsResistance to specific HCV inhibitors

Selection of viral variants bearing amino acid

substitutions that alter the drug target and thereby confer

reduced susceptibility to the drug

Placebo Telaprevir 450 mg q8h Telaprevir 750 mg q8h Telaprevir 1250 mg q12h

1

2

3

4

5

6

7

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Study Time (days)

Me

dia

n H

CV

RN

A (

Lo

g1

0 IU

/mL

)Telaprevir

Reesink HW, et al. Hepatology. 2005;42:234A.

Protease inhibitors monotherapyProtease inhibitors monotherapy

Pharmacological Factors• Drug potency• Genetic barrier• Pharmacokinetic

Viral Factors

• Level of viral replication (1012/day)• Low fidelity of polymerase• Impact of mutations on fitness• Viral quasi-species• Half-life of infected hepatocytes

Host Factors• Compliance• Immune system• Replication space• Activity of protein kinase• Nuceos(t)ide transporters

Factors influencing viral resistance Factors influencing viral resistance with DAAwith DAA

Resistance

Time

HC

V R

eplic

atio

n

Sensitive variants

Emergence of resistance during antiviral Emergence of resistance during antiviral therapytherapy

Resistant variants

Time

HC

V R

eplic

atio

n

Sensitive variants

Resistant variants

TreatmentTreatment

MUTATION(S)

Emergence of resistance during antiviral Emergence of resistance during antiviral therapytherapy

Time

HC

V R

eplic

atio

n

Sensitive variants

Resistant variants

Virological breakthrough

TreatmentTreatment

Emergence of resistance during antiviral Emergence of resistance during antiviral therapytherapy

Adapted from Thibault V, GEMHEP_Nov.11

Les RAVS... (Variants associés à la résistance)

V36A/M T54A/S R155K/T/Q

A156S

V170A

BOCEPREVIRV55A

Patterns of resistance to PIPatterns of resistance to PI

V36A/M T54A/S R155K/T

A156SA156V/T

TELAPREVIR

Thibault-GEMHEP_Nov.11

Nombre de changements de nucléotides pour modifier un résidu en "RAV"

Zeuzem et al. EASL 2011, Abst. 9

Subtype impacts the genetic barrier to resistance

Number of nucleotide substitutions needed according subtype

R155K

AGG-AAG

R155K

AGG-AAG

1 step R155K

CGG-CAG

R155K

CGG-CAG

R155K

CGG-AAG

R155K

CGG-AAG2 step

Genotype 1a

Genotype 1b

Resistant variant according to the subtybe in patients treated with boceprevir

0

2

4

6

8

10

12

14

16

18

20

0

10

20

30

40

50

60

70

80

90

100

Rel

ativ

e F

itnes

s

Adapted from Thibault V, GEMHEP_Nov.11Sarrazin et al. GASTROENTEROLOGY 2007;132:1767–1777Susser et al. HEPATOLOGY 2009;50:1709-1718.)

Resistance level (F

old)

Boceprevir

Telaprevir

(x43) (x780)

Resistance and viral fitnessResistance and viral fitness

Resistance and triple combination Resistance and triple combination therapytherapy

Treatment failure with the triple combination of Peg-IFN,

Ribavirin and a protease inhibitor is principally due to an

insufficient antiviral response to Peg-IFN and ribavirin.

This poor response favors the growth of resistant virus

selected by telaprevir or boceprevir.

68% 31%

Emergence of Resistance accordind to lead-in

<1log >1log

Reduction in HCV RNA at Week 4Reduction in HCV RNA at Week 4

Zeuzem et al. EASL 2011.Thibault-GEMHEP_Nov.11Poordad et al. NEJM 2011 364;13, Bacon et al. NEJM 2011, Vierling et al. AASLD 2011, Abst. 931.

SVR rates according to lead-in

Pooled data from SPRINT-2, RESPOND-2 and PROVIDE trial (Boceprevir)

Importance of the lead-in phase Importance of the lead-in phase %

of

SV

R

% o

f S

VR

Reduction in HCV RNA at Week 4Reduction in HCV RNA at Week 4

Thibault-GEMHEP_Nov.11Foster et al. EASL 2011, Abst 6A.

SVR rates according to previous response and RNA decline at 4 week

Data from the 4 weeks lead-in arm of the REALIZE trial (Telaprevir)

Importance of the lead-in phaseImportance of the lead-in phase

% o

f S

VR

% o

f S

VR

Reduction in HCV RNA at Week 4Reduction in HCV RNA at Week 4

Role of IL28B genotype in preventing resistance?

Nature 2009

25%

80%

0%

20%

40%

60%

80%

100%

SV

R (

%)

T/T C/C

40 %

T/C

IL28B-genotypes and IL28B-genotypes and triple therapy in naïve patienttriple therapy in naïve patient

64%

90%

73%80%

67%

82%

25%

71%

28%

68%

26%

50%

0%

20%

40%

60%

80%

100%

PR T12PR PR BOC/PR48 PR IFN-lambda

IL28B-CC IL28B-nonCC

Telaprevir Bocepravir IFN-l

Jacobson et al, EASL 2011; Poordad et al, EASL 2011; Zeuzem et al, EASL 2011

cEVR

SVR Rates by IL28B Genotype and Prior Response

88

63

4033

20

85

58

2920 20

6

85

71

3130

07

0

20

40

60

80

100

Prior relapsers

Pat

ien

ts a

chie

vin

g S

VR

(%

)

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 4/12 100/117 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

SVR Rates by IL28B Genotype and Prior SVR Rates by IL28B Genotype and Prior Response (Telaprevir regimens) Response (Telaprevir regimens)

P=ns

• Importance of adherence

• Cross resistance between telaprevir and boceprevir

• Impact of subtype (1a/1b) on genetic barrier

• Treatment failure to triple therapy is mainly due to a poor response to Peg-IFN and ribavirin.

• Lead-in period could be useful

• IL28B status is not significant to predict SVR in treatment-experienced patients

Conclusions

Thibault-GEMHEP_Nov.11

Jacobson et al., AASLD 2010.Foster et al., AASLD 2010.

Treatment failure in Phase III trialsTreatment failure in Phase III trials

Advance Realize Sprint-2 Respond-2

T12PR T8PR Lead-in

No lead-in

BOC/RGT

BOC/PR48

BOC/RGT

BOC/PR48

Poordard et al., N Eng J Med 2011.Bacon et al., , N Eng J Med 2011.

Telaprevir trials Boceprevir trials