The document summarizes research on hepatitis C virus (HCV) resistance to treatments. It discusses three key points:
1. HCV can develop resistance to interferon-alpha and ribavirin treatment, as well as direct-acting antivirals (DAAs). Resistance is caused by genetic mutations in the virus.
2. Certain genetic variants of the host, particularly near the IL28B gene, influence treatment response by affecting interferon signaling and HCV kinetics.
3. New DAAs target various stages of the HCV life cycle including the NS3/4A protease, NS5B polymerase, and NS5A protein. While some DAAs have a low barrier to resistance,
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Pawlotsky jm résist tt hcv 2014
1. Hépatite C: Résistance
aux Traitements
Prof. Jean-Michel Pawlotsky
CNR des Hépatites B, C et delta
Laboratoire de Virologie & INSERM U635
Hôpital Henri Mondor
Université Paris XII
Créteil
2. HCV Resistance
• IFN--ribavirin treatment failure
• HCV resistance to DAAs
• Treatment Failure with the combination
of Peg-IFN, ribavirin and a DAA
• HCV Resistance in All-oral,
IFN-free regimens
5. 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 of
common genetic
variation
Bioinformatics to
process data and
associate
genotype with
phenotype
SNP association
6. SNP and SVR in the IDEAL Trial
IL28B
(Ge et al, Nature, 2009;461:399-401)
7. Sustained virological response (%)
SVR in the IDEAL Trial According
to SNP rs12979860 (genotype 1)
100%
80%
60%
40%
20%
0%
(Ge et al., Nature 2009;461:399-401)
TT
N=186
CT
N=559
CC
N=392
9. Viral Kinetics According to
to SNP rs12979860
Mean HCV RNA Decrease
(Log10 IU/mL)
0
-1.0
-2.0
-3.0
TT
CT
-4.0
p < 0.001
-5.0
CC
-6.0
0
2
4
12
Weeks
(Thompson et al., Gastroenterology 2010:139;120-9)
10. VK on High-Dose Peg-IFN
According to IL28B Genotype
Weeks of therapy
0
4
8
12
16
20
24
HCV RNA reduction (Log10 IU/mL)
0
-1
NS
P=0.045
-2
P=0.021
TT
-3
-4
CT
P=0.004
-5
-6
(Chevaliez S, et al., Gastroenterology 2011;141:119-127)
P=0.0005
11. 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)
12. 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
13. Incidence of Peg-IFN-Ribavirin
Treatment Failures
60
58%
54%
PEG-IFN-α2a+ribavirin (Fried et al)
48%
PEG-IFN-α2a+ribavirin (Hadziyannis et al)
PEG-IFN-α2b+ribavirin (Manns et al)
45
30
24%
16%
15
18%
2%
0
Genotype 1
Genotypes 2/3
(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)
18. 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
43. Nucleoside/Nucleotide Analogue
Inhibitors of HCV RdRp
Phase
Dose
Duration
Median/mean log
HCV 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
Drug
44. HCV Resistance to 2’-C-Methyl
Nucleoside Inhibitors
2’C-Me-ATP in the catalytic site
(Migliaccio et al., J Biol Chem 2003;278:49164-70)
45. 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)
47. Non-Nucleoside Inhibitors
of HCV RdRp (NNIs)
Phase
Dose
Duration
Median/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
Drug
48. Non-Nucleoside Inhibitors (NNI)
Thumb I
Deleobuvir (BI207127)
BMS-791325
TMC647055
Palm I
Setrobuvir
ABT-333
ABT-072
A
B
C
D
Thumb II
Filibuvir
Lomibuvir (VX-222)
GS-9669
Palm II
Tegobuvir
49. HCV NNI Resistance Mutations
95
142
Thumb
A
C
495
499
496
423
419
411
96
451
448
316
365
201
Palm
D
(courtesy of Isabel Najera, Roche)
176
414
482
B
282
Fingers
50. NS5A Protein
Required for HCV RNA
replication
NS5A Dimer
Domain III
Domain II
Domain I
Cytosol
Required for HCV viral
particle assembly
ER membrane
ER lumen
May be involved in the
release of HCV particles
51. NS5A Inhibitors
Phase
Dose
Duration
Median/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
Drug
52. NS5A Inhibitor Resistance
Effect of NS5A Domain I Mutations on
Replication and Daclatasvir Potency
Mutation
Fold Resistance
Replication Level, %a
Wild-type
1
100
F28S
7735
125 49
L31M
141
83 37
C92R
98
10 8
Y93H
749
NS5A Dimer, Domain I
81 21
Means standard deviations from transient-transfection assays with
luciferase reporter replicon.
Primary and secondary mutation sites
(Fridell et al., Hepatology 2011;54:1924; Aghemo & De Francesco Hepatology 2013;58:428)
61. Treatment Failures on Triple
Combination with a DAA
• Due to an inadequate response to PegIFN and ribavirin
• Results in uncontrolled outgrowth of
resistant HCV variants selected by the
protease inhibitor
(Pawlotsky JM. Hepatology 2011;53:1742-51)
62. SVR According to Lead-in
(SPRINT-2, non-black)
100
% of patients with SVR
90
82%
82%
80
70
60
<1 log HCV RNA
decrease
50
39%
40
30
≥1 log HCV RNA
decrease
29%
20
10
0
BOC/RGT
(Poordad et al., N Engl J Med 2011;364:1185-206)
BOC/PR48
64. Probability of TelaprevirResistant Variant Detection
1.0
0.9
Median time to wild-type by population
sequencing =7 months (95% CI: 5-8)
0.8
Probability
0.7
0.6
median
0.5
0.4
0.3
0.2
0.1
0.0
0
2
4
6
8
10
12
14
16
Time after treatment failure (months)
(Sullivan et al., EASL 2011)
18
66. 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
67. 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)
69. P + R + Simeprevir-QUEST-1/2
Phase III, Treatment-naive, Gen 1
Simeprevir + PR
(RGT 12+12)
100
90
SVR24 rate (%)
80
Placebo + PR
81%
80%
70
60
50%
50%
50
40
30
20
10
0
N=264
N=130
QUEST-1
(Jacobson et al., EASL 2013; Manns et al., EASL 2013)
N=257
N=134
QUEST-2
70. P + R + Simeprevir-QUEST-1/2
Role 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%
(Jacobson et al., AASLD 2013; Choe et al., AASLD 2013; FDA AVDAC, Oct 24, 2013)
71. 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)
73. P + R + Sofosbuvir-NEUTRINO
Phase III, 12 weeks, Gen 1-4-5-6,
Treatment-naive
100
96%
100%
90%
89%
N=327
N=292
N=28
N=7
TOTAL
Genotype 1
(89%)
Genotype 4
(9%)
Genotype 5, 6
(2%)
90
SVR12 rate (%)
80
70
60
50
40
30
20
10
0
(Lawitz et al., N Engl J Med 2013;368:1878-87)
74. 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
92. Conclusions
• In the real life, 5-15% of patients receiving alloral, 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