Herbicide Resistance. Discussion Topics What is resistance? What causes resistance?
NS5A Resistance
Transcript of NS5A Resistance
NS5A Resistance: What we Know
and What we Think we Know
Prof. Jean-Michel Pawlotsky, MD, PhD
National Reference Center for Viral
Hepatitis B, C and delta
Department of Virology & INSERM U955
Henri Mondor Hospital
University of Paris-Est
Créteil, France
Available HCV DAA Classes
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
NS3/4A protease
inhibitors Nucleotide
analogues
Non-nucleoside
inhibitors
NS5A
inhibitors
NS5A
inhibitors
NS5A RAVs
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
NS5A Inhibitor Resistance Low barrier to resistance
(Lontok et al., Hepatology 2015;62:1623-32)
Prevalence of Baseline NS5A RAVs
Prevalence of NS5A RAVs
(Zeuzem et al., AASLD 2015)
Deep sequencing, 1% cutoff
Influence of Baseline RAVs on
IFN-Free Treatment Outcomes
92%
Any
RAV
N=318
97%
No
RAVs
N=1629
SVR According to Baseline NS5A RAVs ION-1/2/3- Sofosbuvir/Ledipasvir ± RBV
(Dvory-Sobol et al., International Workshop on Antiviral Drug Resistance, June 2014)
SV
R12 r
ate
(%
)
0
10
20
30
40
50
60
70
80
90
100
92%
Any
RAV
N=318
97%
No
RAVs
N=1629
SVR According to Baseline NS5A RAVs ION-1/2/3- Sofosbuvir/Ledipasvir ± RBV
(Dvory-Sobol et al., International Workshop on Antiviral Drug Resistance, June 2014)
97%
SV
R12 r
ate
(%
)
0
10
20
30
40
50
60
70
80
90
100
K24R
86%
M28T
94%
Q30H
82%
Q30R
91%
L31M
92%
Y93H
N=68 N=28 N=80 N=89 N=29 N=48
SVR to Sofosbuvir/Ledipasvir According
to NS5A RAVs (513 cirrhotic patients)
(Sarrazin et al., EASL 2015)
Influence of NS5A RAVs Sofosbuvir-Ledipasvir
0
20
40
60
80
100
SV
R12
(%
)
LDV/SOF 8 wk
TN <6M
With RAVs
98
No RAVs
99 99 99 90
99
LDV/SOF 12 wk
TN
LDV/SOF 12 wk
TE
30
32 107
108
187
189 504
509
79
88
298
300
(Zeuzem et al., AASLD 2015)
0
20
40
60
80
100
SV
R12
(%
)
LDV/SOF + RBV
12 weeks
89 96
87
100
LDV/SOF
24 weeks
59
66
206
214
13
15 84
84
No cirrhosis Cirrhosis
Grazoprevir + Elbasvir C-EDGE TN– Phase III, Rx-naïve, Gt 1, w/o cirrhosis, 12 weeks
89%
SV
R12 r
ate
(%
)
0
10
20
30
40
50
60
70
80
90
100
Bs
NS3
RAVs
97%
N=86 N=65 N=25 N=104
100% 96%
N=19 N=135
99%
58%
N=18 N=112
100% 94%
No Bs
NS3
RAVs
Bs
NS3
RAVs
No Bs
NS3
RAVs
Bs
NS5A
RAVs
No Bs
NS5A
RAVs
Bs
NS5A
RAVs
No Bs
NS5A
RAVs
GT 1a GT 1b GT 1a GT 1b
(Zeuzem et al., Ann Intern Med 2015; epub ahead of print)
0
20
40
60
80
100
SV
R12 (
%)
No Baseline NS5A RAVs
99% 100%
12 weeks RBV, 16 weeks
1% (5XRAV)
20% (5XRAV)
20% (Position 30, 31, 58)
NGS Sensitivity Threshold
98% 100% 99% 100%
307
311
45
45
326
331
50
50
330
335
51
51 0
20
40
60
80
100
SV
R12 (
%)
With Baseline NS5A RAVs
64%
100%
1% (5XRAV)
20% (5XRAV)
20% (Position 30, 31, 58)
NGS Sensitivity Threshold
38%
100%
25%
100%
28
44
9
9
9
24
4
4
5
20
3
3
Influence of NS5A RAVs Grazoprevir-Elbasvir
(Jacobson et al., AASLD 2015)
Selection of RAVs in Patients
who Fail to Achieve an SVR
Selection of RAVs in Patients
who Failed after LDV (no SOF)
16% (12/76)
84% (64/76)
Before LDV Treatment
99% (72/73)
1%
At Virologic Failure With LDV Treatment
Patients without NS5A RAVs
Patients with NS5A RAVs
Patients who failed after a ledipasvir-containing treatment
(without sofosbuvir)
(Dvory-Sobol et al., EASL 2015)
Treatment Failures in SAPPHIRE-2 Genotype 1, Rx-experienced, 3D ± Ribavirin
Virologic failure in 7/297 patients (2.4%)
(Zeuzem et al., N Engl J Med 2014;370:1604-1614)
Post-treatment RAV Persistence
in Patients who Fail to Achieve an SVR
(Lenz et al., EASL 2014)
Replacement of PI-Resistant
Viruses by Wild-Type Viruses
Persistence of RAVs in Patients
who Failed after LDV (no SOF)
98% 100% 98% 100% 95%
82%
0
20
40
60
80
100
VFParentStudy
Baseline FU-12 FU-24 FU-48 FU-96
Pa
tie
nts
Wit
h N
S5
A R
AV
s (
%)
Registry Study
N=63 N=58 N=43 N=45 N=55 N=58
(Dvory-Sobol et al., EASL 2015)
Persistence of RAVs in Patients
who Relapsed after 3D 67/2510 patients with genotype 1a
and virologic failure after 3D
(Krishnan et al., EASL 2015)
NS5A RAVs
(ombitasvir)
NS5B RAVs
(dasabuvir)
NS3 RAVs
(paritaprevir)
24 wks post-treatment
48 wks post-treatment
Pre
vale
nce o
f R
AV
s (
%)
0
10
20
30
40
50
60
70
80
90
100
N=70 N=44 N=35 N=51 N=67 N=57
46%
9%
97% 96%
75%
57%
Retreatment of Patients with Persistent
RAVs after IFN-free regimen failure
Retreatment of Patients who Failed 8 or 12
Weeks of LDV/SOF with LDV/SOF 24 Weeks
(Lawitz et al., EASL 2015)
Cirrhosis
SV
R12 r
ate
(%
)
0
10
20
30
40
50
60
70
80
90
100
68%
74% 80%
46%
100%
60%
No Yes
Prior Rx duration
8 wks 12 wks
Baseline NS5A RAVs
No Yes
N=22 N=19 N=30 N=11 N=11 N=30
Retreatment of Patients who
Failed an IFN-Free Regimen
• Recommendations are based on indirect evidence and
subject to change when more data become available
• The retreatment regimen should contain
• Sofosbuvir because of the high barrier to resistance
• 1 or 2 other DAA(s), if possible with no cross-resistance
with the DAA(s) already administered
• Ribavirin
• Treatment duration should be 12 or 24 weeks (24
weeks recommended in F3-F4)
(EASL Recommendations on Treatment of Hepatitis C 2015)
Retreatment Options
• Sofosbuvir + Daclatasvir + Simeprevir
• Sofosbuvir + 3D
• Sofosbuvir + Grazoprevir + Elbasvir
(AASLD 2015)
Utility of HCV Resistance Testing
Utility of HCV Resistance Testing
• Lack of standardization of the assays
• Best timing for testing • Prior to therapy
• At the time of relapse
• At the time of retreatment
• Guidelines for interpretation and
retreatment decisions
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