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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 Triple Combination of Peg-IFNa, Ribavirin and Telaprevir or Boceprevir
• HCV Resistance in All-oral, IFN-free regimens
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I
IFN--Ribavirine TreatmentFailure
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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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Viral FactorsDisease
Characteristics
HostFactors
TreatmentSchedule
TreatmentFailure
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Viral FactorsDisease
Characteristics
HostFactors
TreatmentSchedule
TreatmentFailure
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Viral Resistance
• Intrinsic properties of viral strains that counteract the antiviral action of antiviral drugs
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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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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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rs12979860 Allele Frequency
12%
39%
49%
37%
16%
47%
C/C C/T T/T
Caucasianancestry
n=871
African Americanancestry
n=191
(Ge et al, Nature, 2009;461:399-401)
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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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Δ H
CV
RN
A (
Lo
g10 I
U/m
L)
CTTT
-3.0
-2.0
-1.0
0
Weeks
-4.0
-5.0
2 4 120
-6.0
CC
Effect on HCV Kinetics(African Americans)
(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)
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IL28B vs RVR to Predict SVR
Sensitivity (%) Specificity (%) PPV (%) NPV (%)
Caucasian
CC vs non CC 56 (52-60) 79 (76-82) 69 (65-74) 68 (65-71)
RVR vs non RVR 25 (21-29) 96 (94-97) 84 (77-89) 59 (56-62)
(Thompson et al., Gastroenterology 2010;139:1181-9)
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89%79%
64%
24%48%
20%0%
50%
100%
< 600 pg/ml > 600 pg/ml TTCT
CC
serum IP-10IL28B genotype
(Darling et al., Hepatology 2010;53:14-22)
Improvement in SVR Prediction by Combining IL28B and IP-10
N=272
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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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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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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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Antiviral Efficacy of 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
TMC435 (Janssen) III 200 mg qd 7 days -4.1
Danoprevir (RG7227, Roche) II 200 mg q8h 14 days -3.8
Vaniprevir (MK-7009, Merck) II 700 mg bid 8 days -4.7
BI201335 (BI) II 240 mg qd 14 days -4.0
Narlaprevir (Merck) II 400 mg bid 7 days -4.2
BMS-650032 (BMS) II 300 mg bid 3 days -3.3
ABT-450/r (Abbott) II 200 mg qd 3 days -4.1
GS-9451 (Gilead) I 400 mg qd 3 days -3.5
MK-5172 (Merck) I 400 mg qd 7 days -5.4
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NS3/4A Protease Inhibitors
(Raney et al., J Biol Chem 2010:285:22725-31)
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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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Resistance and Fitness
In vivo
fitness
Resistance
(Kieffer T, et al. Hepatology 2007;46:631-9)
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(Reesink HW, et al. Gastroenterology 2006;131:997-1002)
Telaprevir Resistance
-5
-4
-3
-2
-1
0
1
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Study Time (Days)
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)
Placebo VX-950 450 mg q8h VX-950 1250 mg q12h
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wt
R155K
A156T
A156V
D168Y
MK-5
172
Vanip
revi
r
0
100
200
300
400
500
600
700
EC
50 [
nM
]
Vaniprevir
MK-5172 Resistance Profile
MK-5172
(Merck, unpublished data)
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Drug Phase Dose DurationMedian/mean logHCV RNA level
reduction
Mericitabine (RG7128, Roche) II 1500 mg bid 14 days -2.7
IDX184 (Idenix) II 100 mg qd 3 days -0.7
PSI-7977 (Pharmasset) II 400 mg qd 3 days -1.9
PSI-938 (Pharmasset) II 300 mg qd 7 days -3.9
INX-189 (Inhibitex) Ib 100 mg qd 7 days -2.5
PSI-879 (Pharmasset) I - - -
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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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
Filibuvir (Pfizer) II 300 mg bid 8 days -2.1
ANA598 (Anadys) II 800 mg bid 3 days -2.9
BI207127 (BI) II 800 mg q8h 3 days -3.1
ABT-333 (Abbott) II 600 mg bid 2 days -1.5
VX-222 (Vertex) Ib 750 mg bid 3 days -3.7
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RdRp Resistance Mutations
(courtesy of Isabel Najera, Roche)
FingersThumb
Palm
A
B
C
D
pol
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Filibuvir (Pfizer) Resistance in IFN Null-Responders
(Mori et al., EASL 2010)
Thumb 2 domainM423
Filibuvir
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Antiviral Efficacy of NS5A Inhibitors
Drug Phase Dose DurationMedian/mean log
HCV RNA reduction
BMS790052 II 10 mg qd 1 day -3.2
AZD7295 Ib 233 mg q8h 6 days -2.1 (only 1b)
PPI-461 Ib 100 mg qd 3 days -3.7
GS-5885 Ib 30 mg qd 3 days -3.3
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BMS-790052 Resistance in vitro
Subtype Sustitution EC50 Fold-changeReplication level (% wt)
1b replicon
wt 2.6±0.3 1 100
L31V 61±15 24 144±47
Y93H 49±13 19 20±7
wt 5.9±3.7 1 100
1a replicon
M28T 4,100±360 360 31±23
Q30H 8,700±1,900 1,900 75±31
Q30R 7,300±1,100 1,100 41±16
L31M 2,100±610 610 55±15
L31V 20,000±6,000 6,000 117±29
Y93C 11,000±4,000 4,000 11±7
(Gao et al., Nature 2010;465:96-100)
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Antiviral Efficacy of Cyclophylin Inhibitors
Drug Phase Dose DurationMedian/mean log HCV RNA
reduction
Alisporivir(DEBIO-025) II 1200 mg bid 14 days -3.6
SCY-465 Ib 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 Telaprevir or Boceprevir
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Pre-existence of PI-resistant HCV variants
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Mathematical Modeling
• “…all possible single and double mutants are predicted to be generated multiple times each day“
• “…all viable single and double mutants that confer drug resistance preexist and may compete with the wild-type virus during therapy“
• “[triple mutants] can be selected by sequential mutations when single or double mutants replicate“
(Rong et al., Sci Transl Med 2010;2:30ra32)
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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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Summary
• Viruses with amino acid substitutions known to confer resistance to HCV protease inhibitors pre-exist, generally (but not always) as minor viral populations, in 100% of HCV-infected patients
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Resistance and PI monotherapy
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(Reesink HW, et al. Gastroenterology 2006;131:997-1002)
Telaprevir Resistance
-5
-4
-3
-2
-1
0
1
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Study Time (Days)
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)
Placebo VX-950 450 mg q8h VX-950 1250 mg q12h
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DAA Resistance
(Pawlotsky JM. Hepatology 2011;53:1742-51)
-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)
![Page 66: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/66.jpg)
-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)DAA Resistance
(Pawlotsky JM. Hepatology 2011;53:1742-51)
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-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Resistant HCV
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)DAA Resistance
(Pawlotsky JM. Hepatology 2011;53:1742-51)
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Summary
• The administration of a protease inhibitor alone selects pre-existing resistant viral variant populations, which grow exponentially until they become dominant if treatment is continued
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Triple Combination Treatment Failure
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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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SVR According to Lead-in (RESPOND-2, non-black)
33% 34%
79%
% o
f p
atie
nts
wit
h S
VR
0
10
20
30
40
50
60
70
80
90
100
BOC/RGT BOC/PR48
73%
<1 log HCV RNA decrease
≥1 log HCV RNAdecrease
(Bacon et al., N Engl J Med 2011;364:1207-17)
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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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-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Resistant HCV
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)DAA Resistance
(Pawlotsky JM. Hepatology 2011;53:1742-51)
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-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
![Page 76: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/76.jpg)
-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Potent IFN-ribavirin effect
![Page 77: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/77.jpg)
-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Potent IFN-ribavirin effect
![Page 78: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/78.jpg)
-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Resistant HCV
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Potent IFN-ribavirin effect
![Page 79: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/79.jpg)
-5
-4
-3
-2
-1
0
1
Wild-type, sensitive HCV
Resistant HCV
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Potent IFN-ribavirin effect
CURED
![Page 80: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/80.jpg)
-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Moderate IFN-ribavirin effect
![Page 81: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/81.jpg)
-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Moderate IFN-ribavirin effect
Wild-type, sensitive HCV
![Page 82: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/82.jpg)
-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Moderate IFN-ribavirin effect
Wild-type, sensitive HCV
Resistant HCV
![Page 83: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/83.jpg)
-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Moderate IFN-ribavirin effect
Wild-type, sensitive HCV
Resistant HCV
CUREDor
RELAPSE with RESISTANT VIRUS
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-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Modest or null IFN-ribavirin effect
![Page 85: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/85.jpg)
-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Modest or null IFN-ribavirin effect
Wild-type, sensitive HCV
![Page 86: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/86.jpg)
-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Modest or null IFN-ribavirin effect
Wild-type, sensitive HCV
Resistant HCV
![Page 87: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/87.jpg)
-5
-4
-3
-2
-1
0
1
Study Time
Med
ian
HC
V R
NA
Ch
ang
e f
rom
Bas
elin
e (L
og
10 IU
/mL
)Triple Combo Failure
Modest or null IFN-ribavirin effect
Wild-type, sensitive HCV
Resistant HCVRELAPSE or BREAKTHROUGH
with RESISTANT VIRUS
![Page 88: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/88.jpg)
Summary
• Treatment failure (i.e. the failure to eradicate HCV infection) with the triple combination of Peg-IFNa, ribavirin and a protease inhibitor is due to an inadequate response to IFNa and ribavirin
• The outgrowth of viral populations resistant to the protease inhibitor is the consequence of treatment failure, not its cause
![Page 89: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/89.jpg)
Treatment failure and resistance in Phase III trials
![Page 90: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/90.jpg)
Dominant virus atthe time of failure
Total n=342*
9743
117
38
32
15
0
50
100
150
200
250
300
Pat
ien
ts,
n
1a 1b
No sequence available
Dominant resistant virus
Dominant wild-type virus
(Zeuzem S., et al., EASL 2011)
Boceprevir Resistance in Patients with Treatment Failure
![Page 91: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/91.jpg)
Frequency and distribution of resistancesubstitutions according to the subtype
(% substitutions detected by subtype)
3
61
60 0
19
3 1
68
8 5 4 07
0 1 1 0 03 3
42
3 3
37
24
0 3 0
26
3 5 5
32
0 0 3 5
0
10
20
30
40
50
60
70
80
90
100
V36A
V36M
T54A
T54C
T54G
T54S
V55A
V55I
R155K
R155T
A156S
A156T
A156V
V158I
V170A
I170
FI1
70T
V170T
M17
5L
Var
ian
ts, %
Subtype 1a
Subtype 1b
(Zeuzem S., et al., EASL 2011)
Boceprevir Resistance in Patients with Treatment Failure
![Page 92: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/92.jpg)
(Chevaliez S., et al., EASL 2011)
0
57
0%
20%
40%
60%
80%
100%
H28Q+R155K
H28Q+R155K+S54T+Y52C
H28Q+R155K+S54T+Y52C+V36M+H57L+P96H
0
2
4
6
8
Days of therapy
% o
f var
iant
s in
the
quas
ispe
cies
*PyroLink®
TVR + PegIFN
HCV
RN
A(Lo
g 10 IU
/mL)
Viral populations
Treatment Failure-PROVE2
![Page 93: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/93.jpg)
Summary
• In Phase III trials, approximately half of the patients who failed to eradicate HCV were infected by dominant viral populations that were resistant to telaprevir or boceprevir at the time of viral escape, depending on the ability of therapy to clear wild-type, sensitive viruses at the time of failure
![Page 94: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/94.jpg)
Post-treatment failure outcome
![Page 95: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/95.jpg)
Long-Term Follow-Up After Treatment Failure (EXTEND)
100 100
Overall 36 155 156 36+15554
NS3 variant positions
9288 8589
0
20
40
60
80
100
% o
f sa
mp
les
wit
h n
o d
etec
tab
le
vari
ant
at e
nd
of
follo
w-u
p
Median follow-up 22 months (range 5-35)
(Zeuzem et al., AASLD 2010)
![Page 96: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/96.jpg)
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)
![Page 97: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/97.jpg)
0.6
Pro
bab
ility
Time after failure (months)
0.0
0.1
0.2
0.3
0.4
0.5
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18
median
Probability of Telaprevir-Resistant Variant Detection
(Sullivan et al., EASL 2011)
1a
1b
![Page 98: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/98.jpg)
(Chevaliez S., et al., EASL 2011)H
CV R
NA
(Log
10 IU
/mL)
0
2
4
6
8
Days of treatment
% o
f mut
ation
s in
the
who
le q
uasi
spec
ies
*PyroLink®
0
29
57
85
182
595
686
903
0%
20%
40%
60%
80%
100% H28Q+R155K
H28Q+R155K+S54T+Y52C
H28Q+R155K+S54T+Y52C+V36M+H57L+P96H
V36M+R155K+H57L
R155K
% o
f var
iant
s in
the
quas
ispe
cies
Days of therapy
HCV
RN
A (L
og10
IU/m
L)
Viral populations
Treatment Failure-PROVE2
![Page 99: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/99.jpg)
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)
![Page 100: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/100.jpg)
Summary
• The decrease of telaprevir- or boceprevir-resistant viral populations starts immediately after administration of the protease inhibitor is stopped
• This decrease is slow and leads, after a few months to years, to their replacement by a wild-type (i.e. protease inhibitor-sensitive) dominant population, which coexists with minor populations made of resistant viruses, i.e. a situation similar to the pretherapeutic one
![Page 101: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/101.jpg)
Practical role of HCV resistance testing
![Page 102: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/102.jpg)
Viral Sequence Analysis Tools
Population (direct) sequencingReverse hybridization
Reverse hybridizationCloning/sequencing
Next-generation sequencing (UDPS)
![Page 103: Pawlotsky du 2012 hepatites-resistance](https://reader038.vdocuments.net/reader038/viewer/2022103115/556ea132d8b42afe778b4789/html5/thumbnails/103.jpg)
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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IV
HCV Resistance in All-oral, IFN-free regimens
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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
(Zeuzem et al., AASLD 2010)
GS-9256 + tegobuvir
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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)
Days
(Zeuzem et al., AASLD 2010)
HC
V R
NA
IU
/mL
(L
og
)
GS-9256 + tegobuvir
GS-9256 + tegobuvir + ribavirin
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BMS-650032 (PI) + BMS-790052 (NS5A)
0 1 2 3 4 6 8 10 121
2
3
4
5
6
7
0 1 2 3 4 6 8 10 12
1
2
3
4
5
6
7
Weeks
HC
V R
NA
(lo
g10
)H
CV
RN
A (
log
10)
No Peg/ribavirin
+Peg/ribavirin
Weeks
(Lok et al., AASLD 2010)
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Danoprevir + RG7128 ComboINFORM-1 Trial
(Gane et al., Lancet 2010; published online)
Days DaysDays
Danoprevir, 900 mg bid + RG7128Danoprevir, 900 mg bid + pegIFNand ribavirin Increasing doses of danoprevir and RG7128