how to avoid a resistance issue with the first generation protease inhibitors ? o. lada phd service...
TRANSCRIPT
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]
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