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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, [email protected]
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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
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Direct Acting Antivirals (DAA) drugs Direct Acting Antivirals (DAA) drugs targetstargets
Asselah T et al. Liver International 2011Asselah T et al. Liver International 2011
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NS3-4A Protease NS5B
Polymerase
NS5A
Protease Inhibitors
Polymerase Inhibitors
NS5A Inhibitors
Asselah T et al. Liver International 2012
Targets for DAAs
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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
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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
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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
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Time
HC
V R
eplic
atio
n
Sensitive variants
Emergence of resistance during antiviral Emergence of resistance during antiviral therapytherapy
Resistant variants
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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
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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
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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
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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
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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
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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.
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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
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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
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Role of IL28B genotype in preventing resistance?
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Nature 2009
25%
80%
0%
20%
40%
60%
80%
100%
SV
R (
%)
T/T C/C
40 %
T/C
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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
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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
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• 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
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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