Pawlotsky jm résist tt hcv 2014
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Transcript of Pawlotsky jm résist tt hcv 2014
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Hépatite C: Résistanceaux Traitements
Prof. Jean-Michel Pawlotsky
CNR des Hépatites B, C et deltaLaboratoire de Virologie & INSERM U635
Hôpital Henri MondorUniversité Paris XII
Créteil
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HCV Resistance
• IFN--ribavirin treatment failure
• HCV resistance to DAAs
• Treatment Failure with the combination of Peg-IFNa, ribavirin and a DAA
• HCV Resistance in All-oral, IFN-free regimens
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I
IFN--Ribavirine TreatmentFailure
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Viral FactorsDisease
Characteristics
HostFactors
TreatmentSchedule
TreatmentFailure
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Genome-Wide Association Studies (GWAS)
A population with distinct clinical
phenotypes
> 3 billion nucleotides> 10 million SNPs
GWAS chip> 500,000 ‘tag’ SNPs> 90% coverage ofcommon genetic
variation
SNP associationBioinformatics to process data and
associate genotype with
phenotype
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SNP and SVR in the IDEAL Trial
IL28B
(Ge et al, Nature, 2009;461:399-401)
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SVR in the IDEAL Trial Accordingto SNP rs12979860 (genotype 1)
(Ge et al., Nature 2009;461:399-401)
0%
20%
40%
60%
80%
100%
TTN=186
CTN=559
CCN=392
Su
stai
ned
vir
olo
gic
al r
esp
on
se (
%)
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Geographic Distribution
(Thomas et al, Nature, 2009;461:798-801)
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Viral Kinetics According to to SNP rs12979860
-3.0
-2.0
-1.0
0
Weeks
Mea
n H
CV
RN
A D
ecre
ase
(Lo
g10 IU
/mL
)
-4.0
-5.0
2 4 120
-6.0
CTTT
CC
p < 0.001
(Thompson et al., Gastroenterology 2010:139;120-9)
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VK on High-Dose Peg-IFNa According to IL28B Genotype
-6
-5
-4
-3
-2
-1
0
0 4 8 12 16 20 24
Weeks of therapyH
CV
RN
A r
edu
ctio
n (
Lo
g10
IU/m
L)
TT
CT
NS
P=0.045
P=0.021
P=0.004
P=0.0005
(Chevaliez S, et al., Gastroenterology 2011;141:119-127)
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SVR Predictors
Odds Ratio 95% CI p-value
rs12979860 CC vs non-CC 5.2 4.1 6.7 <0.0001
HCV RNA ≤ 600,000 IU/mL 3.1 2.3 4.1 <0.0001
Caucasian vs African American 2.8 2.0 4.0 <0.0001
Hispanic vs African American 2.1 1.3 3.6 0.004
METAVIR score ≤F2 2.7 1.8 4.0 <0.0001
Fasting blood sugar < 5.6 mmol/L 1.7 1.3 2.2 <0.0001
(Thompson et al., Gastroenterology 2010;139:1181-9)
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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
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Incidence of Peg-IFN-RibavirinTreatment Failures
2%
0
15
30
45
60 54%48%
58%
24%
16% 18%
Genotype 1 Genotypes 2/3
PEG-IFN-α2a+ribavirin (Fried et al)
PEG-IFN-α2a+ribavirin (Hadziyannis et al)
PEG-IFN-α2b+ribavirin (Manns et al)
(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)
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HCV Kinetics by GenotypeEC-sponsored DITTO-Trial
(Pawlotsky et al., manuscript in preparation)
0
1
2
3
4
5
6
7 HCV RNA (log IU/ml)
0 4 7 8 15 22 291-7-28
Genotype 4
Genotype 1
Genotype 3
* = significant difference, 4 and 1 vs 3
*
*
**
* **
Quantitative assay cutoff
Qualitative assay cutoff
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HCV Kinetics by GenotypeEC-sponsored DITTO-Trial
0
1
2
3
4
5
6
7 HCV RNA (log IU/ml)
0 4 7 8 15 22 291-7-28
Genotype 4
Genotype 1
Genotype 3
* = significant difference, 4 and 1 vs 3
*
*
**
* **
Quantitative assay cutoff
Qualitative assay cutoff
(Pawlotsky et al., manuscript in preparation)
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HCV Kinetics by GenotypeEC-sponsored DITTO-Trial
0
1
2
3
4
5
6
7 HCV RNA (log IU/ml)
0 4 7 8 15 22 291-7-28
Genotype 4
Genotype 1
Genotype 3
* = significant difference, 4 and 1 vs 3
*
*
**
* **
Quantitative assay cutoff
Qualitative assay cutoff
(Pawlotsky et al., manuscript in preparation)
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HCV Kinetics by GenotypeEC-sponsored DITTO-Trial
0
1
2
3
4
5
6
7 HCV RNA (log IU/ml)
0 4 7 8 15 22 291-7-28
Genotype 4
Genotype 1
Genotype 3
* = significant difference, 4 and 1 vs 3
*
*
**
* **
Quantitative assay cutoff
Qualitative assay cutoff
(Pawlotsky et al., manuscript in preparation)
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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
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II
HCV resistance to DAAs
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HCV Quasispecies
Major viral population
Intermediate viral populations
Minor viral populations
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Mechanisms of resistance
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sensitive
resistant
Mechanisms of Resistance
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sensitive
resistant
Drug
Mechanisms of Resistance
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sensitive
resistant
Drug
resistant
Mechanisms of Resistance
sensitive
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sensitive
resistant
Drug Stop drug
resistant
Mechanisms of Resistance
sensitive
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sensitive
resistant
sensitive
resistant
Drug Stop drug
resistant
Mechanisms of Resistance
sensitive
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sensitive
resistant
sensitive
resistant + fit
Drug Stop drug
resistant
Mechanisms of Resistance
sensitive
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sensitive
resistant
Drug Stop drug
resistant
Mechanisms of Resistance
sensitive
resistant + very fit
sensitive
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Chronic HCV infection is curable
by therapy
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sensitive
resistant
Mechanisms of Resistance
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sensitive
resistant
Drug
resistant
Mechanisms of Resistance
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sensitive
resistant
Drug Stop drug
resistant
Mechanisms of Resistance
resistant
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HCV resistance to DAAs
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HCV Life Cycle
(Popescu & Dubuisson, Biol Cell 2009;102:63-74)
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Barrier to Resistance
Low-barrier drug High-barrier drug
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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
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NS3/4A Protease Inhibitors
(Raney et al., J Biol Chem 2010:285:22725-31)
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NS3/4A Protease Inhibitors
Drug Phase Dose DurationMedian/mean log HCV RNA
reduction
Telaprevir (Janssen) Approved 750 mg q8h 14 days -4.4
Boceprevir (Merck) Approved 400 mg tid 7 days -1.6
Simeprevir (Janssen) III 200 mg qd 7 days -4.1
Faldaprevir (BI) III 240 mg qd 14 days -4.0
Asunaprevir (BMS) III 300 mg bid 3 days -3.3
ABT-450/r (AbbVie) III 200 mg qd 3 days -4.1
Danoprevir/r (Roche) II 200 mg q8h 14 days -3.8
Sovaprevir (Achillion) II 600 mg qd 5 days -3.8
GS-9451 (Gilead) II 400 mg qd 3 days -3.5
IDX320 (Idenix) II 400 mg qd 3 days -3.3
Vaniprevir (Merck) Japan 700 mg bid 8 days -4.7
MK-5172 (2nd-gen, Merck) II 400 mg qd 7 days -5.4
ACH-2684 (2nd-gen, Achillion) Ib 400 mg qd 3 days -4.0
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Asp168
Ala156
Arg155
Thr54
Val36
(Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219)
Amino Acid Substitutions Associated with PI Resistance
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MK-5172 and Boceprevir Resistance-Associated Variants
(Lahser et al., AASLD 2012)
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MK-5172 Resistance Profile
1a W
T
1a_V
36M
1a_R
155K
1a_T
54S
1a_A
156S
1a D
168A
1a_V
36M
_R15
5K
1a_T
54S_R
155K
1a R
155K
/D16
8N
1b W
T
1b A
156S
1b A
156T
1b D
168Y
0.1
1.0
10.0
100.0
1000.0
10000.0
MK-5172BMS-032
simeprevirGS-9551
boceprevirtelaprevir
MK-5172 BMS-032 simeprevir GS-9551 boceprevir telaprevir
Re
plic
on
EC
90
(n
M)
(Lahser et al., AASLD 2012)
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CatalyticSite
Nucleoside/Nucleotide Analogue Inhibitors of HCV RdRp
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Drug Phase Dose DurationMedian/mean logHCV RNA level
reduction
Sofosbuvir (Gilead) III 400 mg qd 3 days -3.7
VX-135 (ALS-2200, Vertex) II 200 mg qd 7 days -4.5
Mericitabine (Roche) II 1500 mg bid 14 days -2.7
Nucleoside/Nucleotide Analogue Inhibitors of HCV RdRp
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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
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Sofosbuvir Resistance
• Sofosbuvir binds to the highly conserved catalytic site of the HCV RdRp
• S282T• Is the only known aa substitution conferring phenotypic
resistance to sofosbuvir• Is associated with low-level resistance (<20-fold) in vitro• Results in a severe reduction of replication capacity in
vitro and in vivo
• No S282T variants found at baseline by population sequencing (n=1992) or deep sequencing (n=576)
(Gilead, data on file)
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Non-Nucleoside Inhibitors (NNI)
Thumb I
Thumb II
Palm I
Palm II
A
BC
D
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Non-Nucleoside Inhibitors of HCV RdRp (NNIs)
Drug Phase Dose DurationMedian/mean log
HCV RNA reduction
Tegobuvir (Gilead) II 40 mg bid 8 days -1.4
Setrobuvir (Roche) II 800 mg bid 3 days -2.9
Deleobuvir (BI207127, BI) II 800 mg q8h 3 days -3.1
ABT-333 (AbbVie) III 600 mg bid 2 days -1.5
ABT-072 (AbbVie) III 600 mg qd 3 days -1.6
Lomibuvir (VX-222, Vertex) II 750 mg bid 3 days -3.7
GS-9669 (Gilead) II 500 mg qd 3 days -3.1
BMS-791325 (BMS) II ? ? ?
TMC647055 (Janssen) Ib 1000 mg bid 6 days -3.4
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Non-Nucleoside Inhibitors (NNI)
Thumb IDeleobuvir (BI207127)
BMS-791325 TMC647055
Thumb IIFilibuvir
Lomibuvir (VX-222)GS-9669
Palm ISetrobuvirABT-333ABT-072
Palm IITegobuvir
A
BC
D
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HCV NNI Resistance Mutations
(courtesy of Isabel Najera, Roche)
FingersThumb
Palm
A
B
C
D
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NS5A Protein
Domain III
Domain II
Domain I
Required for HCV RNA replication
Required for HCV viral particle assembly
May be involved in the release of HCV particles
NS5A Dimer
ER membrane
Cytosol
ER lumen
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NS5A Inhibitors
Drug Phase Dose DurationMedian/mean log
HCV RNA reduction
Daclatasvir (BMS) III 10 mg qd 1 day -3.2
Ledipasvir (GS-5885, Gilead) III 30 mg qd 3 days -3.3
PPI-461 (Presidio) II 100 mg qd 3 days -3.7
PPI-668 (Presidio) II 240 mg qd 3 days -3.7
ACH-2928 (Achillion) II 60 mg qd 3 days -3.7
ABT-267 (AbbVie) III 200 mg qd 3 days -3.1
GSK2336805 (GSK) II 60 mg qd 1 day -3.0
BMS824393 (BMS) II 50 mg qd 3 days -3.9
Samatasvir (IDX719, Idenix) II 50 mg qd 3 days -3.7
MK-8742 (2nd-gen, Merck) Ib 50 mg qd 5 days -4.1
ACH-3102 (2nd-gen, Achillion) Ib 50 mg qd 1 day -3.8
GS-5816 (2nd-gen, Gilead) Ib 50 mg qd 3 days -4.0
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NS5A Inhibitor Resistance
Primary and secondary mutation sites
NS5A Dimer, Domain I
Mutation Fold Resistance Replication Level, %a
Wild-type 1 100
F28S 7735 125 49
L31M 141 83 37
C92R 98 10 8
Y93H 749 81 21
Effect of NS5A Domain I Mutations on Replication and Daclatasvir Potency
Means standard deviations from transient-transfection assays with luciferase reporter replicon.
(Fridell et al., Hepatology 2011;54:1924; Aghemo & De Francesco Hepatology 2013;58:428)
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MK-8742 Resistance Profile
(Merck, unpublished data)
1a WT
1a_M28V
1a_Q30R
1a_L31V
1a_L31F
1a_Y93H
1a_Y93N
1b WT
1b_Y93H
1b_L31V
0.001
0.01
0.1
1
10
100
1000
MK-8742
Daclatasver
GS-5885
MK-8742 Daclatasver GS-5885
Rep
lico
n E
C90
(n
M)
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GS-5816, a 2nd-GenerationNS5A Inhibitor
(Gilead, data on file)
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Cyclophilins
Cyclophilin A
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Antiviral Efficacy of Cyclophylin Inhibitors
Drug Phase Dose DurationMedian/mean log HCV RNA
reduction
Alisporivir (DEBIO-025) III 1200 mg bid 14 days -3.6
SCY-465 II 900 mg qd 15 days -2.2
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Alisporivir Resistance in vitro
3’UTRNS3 NS4
A BNS5A
ANS5B5’UTR neo
HCV
IRES
EMCV
IRES
Domain I Domain II Domain III
36 213 250 342 356 447
R262Q R318WA241P D320E
A241P + R262Q
A241P + R318W
R262Q + R318W
R318W + D320E
A241P + R262Q + R318W
A241P + R262Q + R318W +
D320E
Fold-changevs wt
1.02 1.58 1.37 3.67 1.72 3.89
(Coelmont et al., EASL 2009)
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III
Treatment Failure with the Triple Combination of Peg-IFNa, Ribavirin and a DAA
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Treatment failure on telaprevir or boceprevir triple combo
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Pre-existing HCV Resistant Variants by UDPS
PatientIL28B
genotype
HCV subtype
pegIFN
RBV
TVR
Response
V36A/M
T54A/S V55A Q80
R/KR155K/T/Q
A156S/T/V
D168A/V/T/H
I170A/T
Pt-1 CT 1a NR - 90.0% - - 0.1% 0.4% 0.1% 0.5%Pt-2 CT 1a NR - - - - 0.1% 1.1% - 0.2%Pt-3 CT 1b RR - - - - 0.5% 0.5% - 0.2%Pt-4 TT 1b RR - 29.4% - - - 1.3% - 0.1%Pt-5 CT 1a RR - - - - 0.1% 2.9% 0.1% -Pt-6 CT 1b RR 4.2% - - - 0.1% 0.1% 0.1% 0.1%Pt-7 CT 1a SVR - 11.1% - 0.7% - 0.3% - 0.3%Pt-8 CT 1a SVR - - - - 0.1% 0.5% 0.1% -Pt-9 CC 1a SVR - - - - 0.6% 1.8% - -
Pt-10 CC 1a SVR - - - - 0.6% - - 0.1%Pt-11 TT 1a RR - - 100.0% 0.1% 6.0% 3.2% 0.1% 0.3%Pt-12 CT 1b SVR - - - - - 0.3% - 0.1%Pt-13 CT 1b SVR - - - - 0.2% 0.2% - 0.8%Pt-14 TT 1b NR - - - - 0.1% 0.2% - 0.1%Pt-15 CT 1b SVR - - - - 0.4% 0.2% 0.1% 0.1%Pt-16 CT 1a SVR - - 1.3% 0.5% 7.8% 0.2% 0.1% 0.1%Pt-17 CT 1a SVR - 47.4% - - 0.1% 0.4% 0.1% 0.1%Pt-18 CT 1b SVR - 20.0% - - 0.1% 0.4% 0.1% 0.1%
*SNP rs12979860
(Chevaliez S., et al. EASL 2011)
SVR: sustained virological response; RR: response-relapse; NR: non-response
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Treatment Failures on Triple Combination with a DAA
• Due to an inadequate response to Peg-IFN and ribavirin
• Results in uncontrolled outgrowth of resistant HCV variants selected by the protease inhibitor
(Pawlotsky JM. Hepatology 2011;53:1742-51)
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SVR According to Lead-in (SPRINT-2, non-black)
29%
39%
82%
% o
f p
atie
nts
wit
h S
VR
0
10
20
30
40
50
60
70
80
90
100
BOC/RGT BOC/PR48
82%
<1 log HCV RNA decrease
≥1 log HCV RNAdecrease
(Poordad et al., N Engl J Med 2011;364:1185-206)
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0
20
40
60
80
100
Pat
ien
ts W
ith
Un
det
ecta
ble
HC
V
RN
A (
%)
Priornull-response
Prior partialresponse
Priorrelapse
(Foster et al., EASL 2011)
REALIZERx-experienced, Gen 1, Telaprevir
62%
94%
56%59%
15%
54%
<1 log decrease
≥1 log decrease
Overall
33%
82%
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Median time to wild-type by population sequencing =7 months (95% CI: 5-8)
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
bab
ility
0 2 4 6 8 10 12 14 16 18
Time after treatment failure (months)
median
Probability of Telaprevir-Resistant Variant Detection
(Sullivan et al., EASL 2011)
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Genotype 1b
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Time after treatment failure (years)
0 0.5 1 1.5 2
T54AT54SAll
Genotype 1a
% r
esis
tan
t vi
ral v
aria
nts
det
ecte
d
2
Time after treatment failure (years)
0.5 1 1.5 0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
V36M
T54SR155K
All
0
(Barnard et al., CROI 2011)
% V
aria
nt
vir
al r
ésis
tan
t d
étec
té
Post-Failure Follow-up (Boceprevir)
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Practical Recommendations
• Prior to therapy:
• All patients should be considered as harboring minor viral populations that are resistant to telaprevir and boceprevir
• There is no indication for resistance testing at baseline
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Practical Recommendations
• In case of treatment failure:
• Protease inhibitor-resistant viral populations have been enriched in every patient treated with telaprevir or boceprevir who did not clear infection
• There is no indication for resistance testing during and after therapy, as the result will have no impact on treatment decisions
• Resistance testing is required in clinical trials and global surveillance studies (research setting)
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Treatment failure on simeprevir triple combo
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(Jacobson et al., EASL 2013; Manns et al., EASL 2013)
80%
50%
SV
R24
rat
e (%
)
0
10
20
30
40
50
60
70
80
90
100
QUEST-1 QUEST-2
N=264 N=130
81%
50%
N=257 N=134
Placebo + PRSimeprevir + PR(RGT 12+12)
P + R + Simeprevir-QUEST-1/2Phase III, Treatment-naive, Gen 1
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(Jacobson et al., AASLD 2013; Choe et al., AASLD 2013; FDA AVDAC, Oct 24, 2013)
P + R + Simeprevir-QUEST-1/2Role of HCV subtype and Q80K substitution
*Q80K prevalence in 1500 clinical specimens sent to an US commercial lab• GT 1a: 32.5%• GT 1b: 0.1%
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Summary of Simeprevir Resistance Data
• Baseline Q80K polymorphism • Present in 41% of patients with genotype 1a infection
• Associated with lower SVR12 rate in QUEST-1
• Selection of NS3 protease substitutions in >90% of patients without SVR
• Genotype 1a: R155K alone, with mutations at positions 80 and/or 168;
• Genotype 1b: most common substitutions: D168V, Q80R+D168E
(Jacobson et al., EASL 2013; Manns et al., EASL 2013)
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Treatment failure on sofosbuvir triple combo
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89%
SV
R12
rat
e (%
)
0
10
20
30
40
50
60
70
80
90
100
Genotype 1(89%)
96%
100%
TOTAL
90%
P + R + Sofosbuvir-NEUTRINOPhase III, 12 weeks, Gen 1-4-5-6,
Treatment-naive
Genotype 5, 6(2%)
Genotype 4 (9%)
N=327 N=28N=292
(Lawitz et al., N Engl J Med 2013;368:1878-87)
N=7
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Sofosbuvir Resistance in Phase III Trials
• S282T identified as primary mutation in all replicon genotypes (1–6)
• No genotypic or phenotypic resistance to sofosbuvir observed
• L159F identified in 3% of relapse patients with no phenotypic shift
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IV
HCV Resistance in All-oral, IFN-free regimens
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Principles
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Barrier to Resistance
Low-barrier drug High-barrier drug
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• Low barrier to resistance• First-generation protease inhibitors• Non-nucleoside inhibitors of RdRp• NS5A inhibitors (subtype 1a)
• High barrier to resistance• Nucleoside/nucleotide analogues• Cyclophylin inhibitors• NS5A inhibitors (subtypes other than 1a)• 2nd-generation protease and NS5A inhibitors
Barrier to Resistance
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GS-9256 (PI) + Tegobuvir (NNI)
0 7 14 21 280
1
2
3
4
5
6
7
8
(<25 IU/mL)HC
V R
NA
IU
/mL
(L
og
)
Days
GS-9256 + tegobuvir
(Zeuzem et al., Hepatology 2012;55:749-58)
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Danoprevir (PI) + Mericitabine (NI)INFORM-1 Trial
Days DaysDays
Danoprevir, 900 mg bid + RG7128Danoprevir, 900 mg bid + pegIFNand ribavirin Increasing doses of danoprevir and RG7128
(Gane et al., Lancet 2010;376:1467-757)
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(Suzuki et al., EASL 2012)
Daclatasvir (NS5A)/Asunaprevir (PI)HCV Genotype 1b
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IFN-free treatment failures
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IFN-Free Combination OptionsNI PI NS5A NNI RBV
Nucleos(t)ide analogue-based strategies
Gilead Sofosbuvir Ledipasvir GS-9669 ±
Vertex/others VX-135 Simeprevir Daclatasvir ±
Roche Mericitabine Danoprevir/r Setrobuvir ±
Nucleoside-free triple combo strategies
Abbvie ABT-350/r ABT-267 ABT-333 ±
BMS Asunaprevir Daclatasvir BMS791325 ±
BI/Presidio Faldaprevir PPI-668 Deleobuvir ±
Janssen/GSK Simeprevir GSK2336805 TMC647055 ±
Nucleoside-free, second-generation double combo strategies
Merck MK-5172 MK-8742 ±
Achillion ACH-2684 ACH-3102 ±
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12 wkCirrhosis
83%
N=12
SV
R12
rat
e (%
)
0
10
20
30
40
50
60
70
80
90
100
12 wkNo cirrhosis
97%
Sofosbuvir + RBV in Gen 2Phase III, 12 weeks, cirrhosis vs no cirrhosis
FISSION (Rx-naïve)
(FDA hearings, October 25, 2013)
N=61
92%
16 wk12 wk
90%
FUSION (Rx-experienced)
N=29 N=26
78%
16 wk12 wk
60%
N=10 N=9
No cirrhosis Cirrhosis
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Sofosbuvir + RBV in Gen 3Phase III, Treatment-experienced
(Jacobson et al., N Engl J Med 2013;368:1867-77; Zeuzem et al., AASLD 2013; FDA hearings, October 25, 2013)
Series10
20
40
60
80
100
37
6385
19
6160
12 wks 16 wks 24 wks 12 wks 16 wks 24 wks
SV
R1
2, %
No cirrhosis Cirrhosis
FUSION (12 wk) FUSION (16 wk) VALENCE (24 wk)
N=38 N=40 N=100 N=26 N=23 N=45
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96.4%
SV
R12
rat
e (%
)
0
10
20
30
40
50
60
70
80
90
100
SOF/LDV+RBV
99.1%
99.1%
SOF/LDV
93.6%
SOF/LDV+RBVSOF/LDV
12 weeks 24 weeks(Gilead press release, December 18, 2013)
N=109 N=111 N=109 N=111
Sofosbuvir/Ledipasvir FDC ± RBVION-2-Phase III, Gen 1, Rx-experienced, 20% cirrhosis
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Sofosbuvir/Ledipasvir FDC ± RBVRelapse Pt with multidrug resistance
(Lawitz et al., AASLD 2013)
0
2
3
4
5
6
7
NS5B: No RAVsNS5A: L31M (25.5%)
NS5B: S282T (91.2%)NS5A: Q30L (4.5%)
L31M (>99%)Y93H (96.7%)
NS5B: S282T (8.0%)NS5A: Q30L (3.5%)
L31M (94.4%)L31V (4.7%)Y93H (98.2%)
LLOQ-TDLLOQ-TNDH
CV
RN
A (
log
10 IU
/mL
)
SOF/LDV 8 Weeks
Re-treatment:SOF/LDV + RBV
24 Weeks
Post-Treatment
Post-Treatment
SVR12
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IFN-Free Combination OptionsNI PI NS5A NNI RBV
Nucleos(t)ide analogue-based strategies
Gilead Sofosbuvir Ledipasvir GS-9669 ±
Vertex/others VX-135 Simeprevir Daclatasvir ±
Roche Mericitabine Danoprevir/r Setrobuvir ±
Nucleoside-free triple combo strategies
Abbvie ABT-350/r ABT-267 ABT-333 ±
BMS Asunaprevir Daclatasvir BMS791325 ±
BI/Presidio Faldaprevir PPI-668 Deleobuvir ±
Janssen/GSK Simeprevir GSK2336805 TMC647055 ±
Nucleoside-free, second-generation double combo strategies
Merck MK-5172 MK-8742 ±
Achillion ACH-2684 ACH-3102 ±
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96%
SV
R12
rat
e (%
)
0
10
20
30
40
50
60
70
80
90
100
All genotypes 1
95%
Subtype 1a
98%
Subtype 1b
ABT-450/r (PI) ± ABT-267 (NS5A) ± ABT-333 (NNI)SAPPHIRE I-Phase III, Genotype 1, Rx-naïve, N=631
(Abbvie press release, November 18, 2013)
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IFN-Free Combination OptionsNI PI NS5A NNI RBV
Nucleos(t)ide analogue-based strategies
Gilead Sofosbuvir Ledipasvir GS-9669 ±
Vertex/others VX-135 Simeprevir Daclatasvir ±
Roche Mericitabine Danoprevir/r Setrobuvir ±
Nucleoside-free triple combo strategies
Abbvie ABT-350/r ABT-267 ABT-333 ±
BMS Asunaprevir Daclatasvir BMS791325 ±
BI/Presidio Faldaprevir PPI-668 Deleobuvir ±
Janssen/GSK Simeprevir GSK2336805 TMC647055 ±
Nucleoside-free, second-generation double combo strategies
Merck MK-5172 MK-8742 ±
Achillion ACH-2684 ACH-3102 ±
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(Lawitz et al., EASL 2013)
MK-5172 (2nd-gen PI) + MK-8742 (2nd-gen NS5A)C-WORTHY, Gen 1, Rx-naive, noncirrhotic, 12 wks
5172+ 8742 20 mg
+ RBV
96%
SV
R12
rat
e (%
)
0
10
20
30
40
50
60
70
80
90
100
N=24
89%
N=27
100%
N=12
5172+ 8742 50 mg
+ RBV
5172+ 8742 50 mg
No RBV
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Conclusions
• In the real life, 5-15% of patients receiving all-oral, IFN-free regimens may fail to eradicate HCV
• In most cases, treatment failures will be associated with/due to multidrug resistant viruses
• Retreatment strategies will need to be well defined in this patients