How to avoid a resistance issue with the first generation protease inhibitors ?
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How to avoid a resistance issue with the first generation protease inhibitors ? O. Lada PHD Service d ’ Hépatologie et INSERM CRB3, AP-HP Hopital Beaujon, Paris, France. [email protected] Progress in the Treatment of Hepatitis C. Direct Acting Antivirals (DAA) drugs targets.

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How to avoid a resistance issue with the first generation protease inhibitors ? O. Lada PHD

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How to avoid a resistance issue with the first generation protease inhibitors ?

O. Lada

PHD

Service d’Hépatologie et INSERM CRB3,

AP-HP Hopital Beaujon, Paris, France.

[email protected]


Progress in the Treatment of Hepatitis C


Direct Acting Antivirals (DAA) drugs targets

Asselah T et al. Liver International 2011


Targets for DAAs

NS5A

Inhibitors

Protease

Inhibitors

Polymerase

Inhibitors

NS3-4A

Protease

NS5A

NS5B

Polymerase

Asselah T et al. Liver International 2012


Resistance 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


Protease inhibitors monotherapy

Telaprevir

7

6

5

Median HCV RNA (Log10 IU/mL)

4

3

2

1

0

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Study Time (days)

Placebo

Telaprevir 450 mg q8h

Telaprevir 750 mg q8h

Telaprevir 1250 mg q12h

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


Factors influencing viral resistance

with DAA

  • 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

Resistance

  • Host Factors

  • Compliance

  • Immune system

  • Replication space

  • Activity of protein kinase

  • Nuceos(t)ide transporters

  • Pharmacological Factors

  • Drug potency

  • Genetic barrier

  • Pharmacokinetic


Emergence of resistance during antiviral therapy

Time

Sensitive variants

Resistant variants

HCV Replication


Emergence of resistance during antiviral therapy

MUTATION(S)

Time

Treatment

Sensitive variants

Resistant variants

HCV Replication


Emergence of resistance during antiviral therapy

Virological breakthrough

Time

Treatment

Sensitive variants

Resistant variants

HCV Replication


HCV protease

Patterns of resistance to PI

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

R155K/T

T54A/S

V36A/M

TELAPREVIR

A156S

A156V/T

R155K/T/Q

V170A

T54A/S

V36A/M

BOCEPREVIR

A156S

V55A

Adapted from Thibault V, GEMHEP_Nov.11


Subtype impacts the genetic barrier to resistance

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

Number of nucleotide substitutions needed according subtype

Genotype 1b

R155K

CGG-AAG

Genotype 1a

2 step

R155K

AGG-AAG

R155K

CGG-CAG

1 step

Resistant variant according to the subtybe in patients treated with boceprevir

Zeuzem et al. EASL 2011, Abst. 9

Thibault-GEMHEP_Nov.11


Resistance and viral fitness

(x43)

(x780)

Resistancelevel (Fold)

Relative Fitness

Boceprevir

Telaprevir

Adapted from Thibault V, GEMHEP_Nov.11

Sarrazin et al. GASTROENTEROLOGY 2007;132:1767–1777

Susser et al. HEPATOLOGY 2009;50:1709-1718.)


Resistance and triple combination therapy

  • 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.


Importance of the lead-in phase

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

Emergence of Resistance accordind to lead-in

SVR rates according to lead-in

% of SVR

68%

31%

<1log

>1log

Reduction in HCV RNA at Week 4

Reduction in HCV RNA at Week 4

Poordad et al. NEJM 2011 364;13, Bacon et al. NEJM 2011,

Vierling et al. AASLD 2011, Abst. 931.

Zeuzem et al. EASL 2011.

Thibault-GEMHEP_Nov.11


Importance of the lead-in phase

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

SVR rates according to previous response

and RNA decline at 4 week

% of SVR

Reduction in HCV RNA at Week 4

Foster et al. EASL 2011, Abst 6A.

Thibault-GEMHEP_Nov.11


Role of IL28B genotype in preventing resistance?


Nature 2009

100%

80%

80%

SVR (%)

60%

40 %

40%

25%

20%

0%

T/T

T/C

C/C


IL28B-genotypes and

triple therapy in naïve patient


SVR Rates by IL28B Genotype and Prior Response

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

Prior relapsers

Prior partial responders

Prior null responders

P=ns

Pooled T12/PR48 (n=134)

Pbo/PR48 (n=33)

Pooled T12/PR48 (n=209)

Pbo/PR48 (n=52)

Pooled T12/PR48 (n=79)

Pbo/PR48 (n=20)

Patients achieving SVR (%)

n/a

TT

TT

TT

CC

CT

CC

CT

CC

CT

n/N=

4/12

100/117

3/10

5/8

1/5

2/10

10/14

4/10

27/92

1/15

51/58

6/30

29/34

33/57

0/5

1/18

10/32

Pol et al. EASL 2011


Conclusions

  • 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


Treatment failure in Phase III trials

Boceprevir trials

Telaprevir trials

Advance

Realize

Sprint-2

Respond-2

T12PR

T8PR

Lead

-in

No lead-in

BOC/RGT

BOC/PR48

BOC/RGT

BOC/PR48

Jacobson et al., AASLD 2010.

Foster et al., AASLD 2010.

Poordard et al., N Eng J Med 2011.

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

Thibault-GEMHEP_Nov.11


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