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HCV Resistance and
DAA Treatment Failures
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
I
HCV Genetic Variability and
Mechanisms of Resistance
HCV RNA-Dependent
RNA Polymerase
• Errors during replication:
• frequent
• spontaneous
• at random positions
• Lack of “proofreading” activity
=> Accumulation of genomic mutations
=> Selection
Properties of HCV RdRp
Mutant Selection
• At the level of populations of infected
individuals:
• Genotypes and subtypes
• At the level of an infected individual:
• Viral quasispecies
Quasispecies Distribution
of Viruses
sensitive
resistant
Mechanisms of Resistance
sensitive
resistant
Drug
Mechanisms of Resistance
sensitive
resistant
Drug
resistant
Mechanisms of Resistance
sensitive
sensitive
resistant
Drug Stop drug
resistant
Mechanisms of Resistance
sensitive
sensitive
resistant
sensitive
resistant
Drug Stop drug
resistant
Mechanisms of Resistance
sensitive
sensitive
resistant
Drug Stop drug
resistant
Mechanisms of Resistance
sensitive
resistant + very fit
sensitive
II
HCV DAAs and Resistance
HCV Lifecycle
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
Available HCV DAA Classes
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
NS3/4A protease
inhibitors
Available HCV DAA Classes
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
NS3/4A protease
inhibitors
Nucleotide
analogues
Available HCV DAA Classes
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
NS3/4A protease
inhibitors
Nucleotide
analogues
Non-nucleoside
inhibitors
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
Summary
Low-barrier drug High-barrier drug
NS3 protease inhibitors
NS5A inhibitors
Non-nucleoside RdRp inhibitors
Nucleotide analogues
Nucleotide analogue
inhibitors of HCV RdRp
Catalytic
Site
Nucleotide Analogue
Inhibitors of HCV RdRp
Nucleotide analogues
Sofosbuvir (Gilead)
MK-3682 (Merck)
AL-335 (Janssen)
Pangenotypic
High barrier to resistance
Nucleotide Analogue
Inhibitors of HCV RdRp
Nucleotide Analogue Resistance
(Lontok et al., Hepatology 2015;62:1623-32)
NS5A inhibitors
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
1st-wave
Daclatasvir (BMS)
Ledipasvir (Gilead)
Ombitasvir (Abbvie)
2nd-wave
Elbasvir (Merck)
Velpatasvir (Gilead)
Odalasvir (Janssen)
Ravidasvir (Presidio)
Pangenotypic
(except ledipasvir)
Low barrier to resistance
Pangenotypic
Slightly higher barrier
to resistance?
NS5A Inhibitors
2nd-generation?
ABT-530 (Abbvie)
MK-8408 (Merck)
Pangenotypic
Higher barrier
to resistance?
1st-generation
NS5A Inhibitor Resistance
(Adapted from Tellinghuisen et al., Nature 2005;435:374-9)
H1
Conserved
surface
H1
58
Chain B
Amino Acids at RAV positions
24
30
28
58
9231
32 38
92
93 30
31
24
28
38
32
93
Chain A
NB: Residues 32 and 38 behind molecule
NS5A Inhibitor Resistance
(Lontok et al., Hepatology 2015;62:1623-32)
NS3/4A protease inhibitors
NS3 Protease Inhibitors
(Raney et al., J Biol Chem 2010:285:22725-31)
1st-wave
Telaprevir (Janssen)
Boceprevir (Merck)
2nd-wave
Simeprevir (Janssen)
Paritaprevir/r (Abbvie)
Asunaprevir (BMS, Asia)
Vaniprevir (Merck, Asia)
2nd-generation
Grazoprevir (Merck)
ABT-493 (Abbvie)
GS-9857 (Gilead)
Only genotype 1
Low barrier to resistance
All genotypes except 3
Low barrier to resistance
Pangenotypic (~)
Higher barrier to
resistance
NS3/4A Protease Inhibitors
*Not approved yet in US and EU
1st-generation
Protease Inhibitor Resistance
(Lontok et al., Hepatology 2015;62:1623-32)
Non-nucleoside
inhibitors of HCV RdRp
Non-Nucleoside Inhibitors (NNI)
Thumb I
Thumb II
Palm I
Palm II
A
B
C
D
Palm-1 inhibitors
Dasabuvir (Abbvie)
Non-Nucleoside Inhibitors (NNI)
Genotype 1 only
Low barrier to resistance
NNI Resistance
(Lontok et al., Hepatology 2015;62:1623-32)
III
HCV Resistance in
IFN-Free Regimens
BaselinePrevalence of RAVs
S282T RAV in RdRp (NS5B)
• No S282T (0/8598) was detected in any pretreatment patient
samples (deep sequencing, cutoff = 1%)
Europe
n=1,767
Asia
n=954
Oceania
n=1,094
Africa
n=17
North America
n=4,766
(Gane et al., AASLD 2015)
Prevalence of NS5A RAVs (G1a)
Deep sequencing, 1% cutoff
(Zeuzem et al., AASLD 2015)
Europe
25% (130/517)
Asia Pacific
15% (4/27)
Oceania
27% (89/328)
North America
26% (686/2638)
USA
Canada
Puerto Rico
Belgium
Switzerland
Czech Republic
Germany
Spain
France
United Kingdom
Italy
Netherlands
Poland
China
India
Japan
Korea
Russia
Taiwan
Australia
New Zealand
Prevalence of NS5A RAVs (G1a)
Akin to population sequencing, 15% cutoff
(Zeuzem et al., AASLD 2015)
Europe
14%
Asia Pacific
7%
Oceania
16%
North America
13%
USA
Canada
Puerto Rico
Belgium
Switzerland
Czech Republic
Germany
Spain
France
United Kingdom
Italy
Netherlands
Poland
China
India
Japan
Korea
Russia
Taiwan
Australia
New Zealand
Prevalence of NS5A RAVs
by Region (G1a)
Prevalence(%)
4.9%
3.7%
2.1%
4.8%
4.1%
4.4%
1.2%
4.4%
7.6%
5.8%
2.4%
7.6%
0
5
10
15
20
Q30H/R L31M Y93H Multiple RAVs
North America Europe Oceania
N=2638 N=2638 N=2638 N=2638N=517 N=517 N=517 N=517N=328 N=328 N=328 N=328
Asia Pacific not included due to
low number of patients with GT1a
(n=27)
NB: Q30H/R, L31M and Y93H RAVs confer >100 fold shift to LDV.
(Zeuzem et al., AASLD 2015)
Prevalence of NS5A RAVs (G1b)
Deep sequencing, 1% cutoff
(Zeuzem et al., AASLD 2015)
Europe
25% (105/416)
Asia Pacific
26% (150/570)
Oceania
26% (26/99)
North America
23% (184/802)
USA
Canada
Puerto Rico
Belgium
Switzerland
Czech Republic
Germany
Spain
France
United Kingdom
Italy
Netherlands
Poland
China
India
Japan
Korea
Russia
Taiwan
Australia
New Zealand
Prevalence of NS5A RAVs (G1b)
Akin to population sequencing, 15% cutoff
(Zeuzem et al., AASLD 2015)
Europe
17%
Asia Pacific
20%
Oceania
19%
North America
16%
USA
Canada
Puerto Rico
Belgium
Switzerland
Czech Republic
Germany
Spain
France
United Kingdom
Italy
Netherlands
Poland
China
India
Japan
Korea
Russia
Taiwan
Australia
New Zealand
Prevalence of NS5A RAVs
by Region (G1b)
(Zeuzem et al., AASLD 2015)
8.5%
14.6%
1.1%
9.4%
16.1%
1.2%
13.1%
14.1%
1.0%
3.9%
18.2%
2.1%
0
2
4
6
8
10
12
14
16
18
20
L31M/I/V Y93H Multiple RAVs
North America Europe Oceania Asia Pacific
NB: L31M/I/V confer 3-43 fold shift to LDV; Y93H confers >100 fold shift to LDV
N=802 N=416 N=99 N=570 N=802 N=416 N=99 N=570 N=802 N=416 N=/99 N=570
Prevalence(%)
Influence of Baseline RAVs on
IFN-Free Treatment Outcomes
Sofosbuvir + Simeprevir ± RBV
COSMOS Cohort 2- Gen 1, Naive and NR, F3-F4
(Lawitz et al., Lancet 2014;384:1756-65)
93%
SVR12rate(%)
0
10
20
30
40
50
60
70
80
90
100
SOF+SIM+RBVAll patients SOF+SIM+RBVSOF+SIM
N=80 N=27 N=14 N=24
12 weeks 24 weeks
93%93%
SOF+SIM
N=15
100%
94%
Sofosbuvir + Simeprevir ± RBV
COSMOS Pooled cohorts 1 & 2- Subtype 1a, Q80K
88%
SVR12rate(%)
0
10
20
30
40
50
60
70
80
90
100
SOF+SIM+RBVAll patients SOF+SIM+RBVSOF+SIM
N=80 N=27 N=14 N=24
12 weeks 24 weeks
83%
89%
SOF+SIM
N=15
100%
88%
(Lawitz et al., Lancet 2014;384:1756-65)
92%
Any
RAV
N=318
97%
No
RAVs
N=1629
SVR According to Baseline NS5A RAVs
ION-1, -2, -3: Sofosbuvir + Ledipasvir ± RBV
SVR12rate(%)
0
10
20
30
40
50
60
70
80
90
100
(Sarrazin et al., manuscript submitted)
92%
Any
RAV
N=318
97%
No
RAVs
N=1629
SVR According to Baseline NS5A RAVs
ION-1, -2, -3: Sofosbuvir + Ledipasvir ± RBV
97%
SVR12rate(%)
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=89N=29 N=48
(Sarrazin et al., manuscript submitted)
SVR to Sofosbuvir/Ledipasvir According
to NS5A RAVs (513 cirrhotic patients)
(Sarrazin et al., EASL 2015)
SVR According to Baseline NS5A RAVs
(Zeuzem et al., AASLD 2015)
SVR12(%)
Without cirrhosis With cirrhosis
Rx-Naive Rx-Exp’dRx-Naive Rx-Exp’d
*HCV RNA < 6 million IU/mL.
8 Wks* 12 Wks 12 Wks 12 Wks 12 Wks +
RBV
12 Wks +
RBV
24 Wks24 Wks
No RAVsWith RAVs
100
80
60
40
20
0
98 99 99 99
90
99 96 96
100 100
88
100
89
96
87
100
N=32 N=108 N=189 N=509 N=88 N=300 N=27 N=68 N=10 N=27 N=9 N=19 N=66 N=214 N=15 N=84
Grazoprevir + Elbasvir
C-EDGE TN– Phase III, Rx-naïve, Gt 1, w/o cirrhosis, 12 weeks
89%
SVR12rate(%)
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;163:1-13)
Grazoprevir + Elbasvir + RBV
Integrated analysis of patients with G1a from Phase II and III trials,
TN or TE, w/o cirrhosis, 12 or 16-18 weeks
(Thompson et al., AASLD 2015)
No NS5A RAVs (73%)
N=38
100%
NS5A RAVs (27%)
N=14
100%
SVR12rate(%)
0
10
20
30
40
50
60
70
80
90
100
No NS5A RAVs (66%)
N=289
98%
NS5A RAVs (34%)
N=150
91%
Rx-naïve and PR relapsers
12 weeks, no RBV
PR nonresponders
16-18 weeks, + RBV
Influence of Baseline NS5A RAVs
Grazoprevir-Elbasvir, 12 (no RBV) or 16-18 weeks (+RBV), prior NR
(Jacobson et al., AASLD 2015)
Pts with RAVs by population sequencingPts without RAVs
GT1a, Previous nonresponse GT1b, Previous nonresponse
100% 100%
N=51
EBR/GZR 12 wks EBR/GZR + RBV
16/18 wks
EBR/GZR 12 wks EBR/GZR + RBV
16/18 wks
SVR12(%)
100
80
60
40
20
0
EBR
RAVs
NS5A class
RAVs
EBR
RAVs
NS5A class
RAVs
EBR
RAVs
NS5A class
RAVs
EBR
RAVs
NS5A class
RAVs
97%
29%
N=61 N=7
96%
64%
N=54 N=14
100% 100%
N=44 N=8
100%
67%
N=28 N=6
100%
83%
N=22 N=12
100% 100%
N=26 N=12
100% 100%
N=22 N=16N=1
Summary
• The detection, by means of population
sequencing, of HCV RAVs at baseline has an
impact on the rate of SVR with IFN-free
regimens
• Parameters that matter include:
• The genotype/subtype
• The treatment regimen received (drugs, duration, RBV)
• The proportion of RAVs in the viral quasispecies at baseline
• The level of resistance conferred by the substitutions
Selection of RAVs in Patients
who Fail to Achieve an SVR
The Henri Mondor Experience
161 patients treated
in IFN-free regimens
in clinical trials
Protease inhibitors
received
Paritaprevir/r
Simeprevir
Faldaprevir
Asunaprevir
Danoprevir/r
NS5A inhibitors
received
Daclatasvir
Ombitasvir
Ledipasvir
Nucleotide analogue
received
Sofosbuvir
(Data on file; unpublished)
The Henri Mondor Experience
161 patients treated
in IFN-free regimens
in clinical trials
13 did not achieve
an SVR
8 relapses 3 breakthroughs 2 intolerant
(Data on file; unpublished)
The Henri Mondor Experience
Region Observed substitutions
NS3 protease
V36M, D103N, R155K
I71V
R155K
Q80K, R155K
A147V, D168V
A4M, V36M, R155K
P146S, Q80L
NS5A
Y93C
L31V, Y93H
NS5B RNA polymerase
L433F
Q65R, S189N/S
S47E
(Data on file; unpublished)
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)
Summary
• In most (if not all) patients who fail to achieve
an SVR on an IFN-free regimen, viruses that
are resistant to one or more of the DAAs
administered are present as the dominant
species at the time of relapse
Post-treatment RAV Persistence
in Patients who Fail to Achieve an SVR
Replacement of PI-Resistant
Viruses by Wild-Type Viruses
(Lenz et al., J Hepatol 2015;62:1008-14)
Persistence of RAVs in Patients
who Failed after LDV (no SOF)
98% 100% 98% 100%
95%
82%
0
20
40
60
80
100
VF
Parent
Study
Baseline FU-12 FU-24 FU-48 FU-96
PatientsWithNS5ARAVs(%)
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
PrevalenceofRAVs(%)
0
10
20
30
40
50
60
70
80
90
100
N=70 N=44 N=35N=51N=67 N=57
46%
9%
97% 96%
75%
57%
Summary
• After IFN-free treatment failure, HCV variants
resistant to protease inhibitors progressively
disappear by population sequencing,
replaced by wild-type virus
• In contrast, viruses resistant to NS5A
inhibitors and to NNIs persist for years,
maybe for ever, as dominant species
IV
Retreatment Options
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)
(European Association for the Study of the Liver. J Hepatol 2015;63:199-236)
SVR12rate(%)
0
10
20
30
40
50
60
70
80
90
100
87%
Total
80%
Genotype 1a
100%
Genotype 1b
Retreatment of NS5A Inhibitor Failures
with Sofosbuvir + Simeprevir 12 wks
100%
Genotype 4
(Hézode et al., AASLD 2015)
N=15 N=10 N=3 N=2
SVR12rate(%)
0
10
20
30
40
50
60
70
80
90
100
92%
1a, no cirrhosis
12 wks + RBV
100%
1a, cirrhosis
24 wks + RBV
100%
1b
12 wks, no RBV
Retreatment of DAA Failures with
Sofosbuvir + 3D 12 wk (QUARTZ-I)
(Poordad et al., AASLD 2015)
N=15 N=6 N=2
100%
Overall
N=23
Retreatment with Sofosbuvir + Grazoprevir/Elbasvir + RBV
C-SWIFT Retreatment- G1, short (4-6-8 wk) SOF-GZR-EBR treatment failures
(Lawitz et al., AASLD 2015)
100%
SVR12rate(%)
0
10
20
30
40
50
60
70
80
90
100
No
100%
Yes
100%
4 wk
100%
6-8 wk
100%
No
100%
Yes
N=18 N=8 N=5 N=18N=5 N=15
Cirrhosis Prior Rx
duration
Baseline
NS5A RAVs
V
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
VI
Avoiding Treatment Failures
European Association for the Study of the Liver. J Hepatol 2015;63:199-236
Characteristics that Inform
Treatment Option Selection
Treatment
selection
Prior
treatment
experience
HCV
genotype/
subtype
Severity of
liver
disease
Patient co-
morbidities
PK profile
of
treatment
Drug-drug
interactions
(European Association for the Study of the Liver. J Hepatol 2015;63:199-236)
SVR12rate(%)
0
10
20
30
40
50
60
70
80
90
100
90%
12 wk
No RBV
96%
12 wk
+RBV
98%
24 wk
No RBV
Sofosbuvir/Ledipasvir ± RBV
Rx-experienced patients with compensated cirrhosis
100%
24 wk
+RBV
(Reddy et al., Hepatology 2015;62:79-86)
SVR to Sofosbuvir/Ledipasvir According
to NS5A RAVs (513 cirrhotic patients)
88% 94% 85% 100%95% 97% 100% 100%
0
20
40
60
80
100
LDV/SOF LDV/SOF+RBV LDV/SOF LDV/SOF+RBV
SVR12(%)
N=26 N=91 N=34 N=169 N=20 N=113 N=14 N=44
12 Weeks 12 Weeks 24 Weeks 24 Weeks
Pre-existing NS5A RAVs No pre-existing NS5A RAVs
(Sarrazin et al., EASL 2015)
Ombitasvir/Paritaprevir/r + Dasabuvir ± RBV
TURQUOISE II-Phase III, Genotype 1, Rx-naïve and -experienced,
Compensated cirrhosis (CPA), 12-24 weeks
(Poordad et al., N Engl J Med 2014;370:1973-82)
92%
93% 100%
80%
93% 100% 100% 93%
0
20
40
60
80
100
Naive Prior
relapse
Prior partial
response
Prior null
response
N=64 N=15N=56 N=13 N=11 N=50N=10 N=42
SVR12(%)
12 weeks
24 weeks
Genotype 1a
Conclusions
• Optimizing first-line treatment is required
to avoid DAA-based treatment failures
associated with HCV resistance
• Retreatment options exist, based on the
combination of sofosbuvir plus 2 or 3
other DAAs, eventually with ribavirin
Follow me on Twitter
@JMPawlotsky

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Pawlotzky hcv resistances.pptx du16

  • 1. HCV Resistance and DAA Treatment Failures 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
  • 2. I HCV Genetic Variability and Mechanisms of Resistance
  • 4. • Errors during replication: • frequent • spontaneous • at random positions • Lack of “proofreading” activity => Accumulation of genomic mutations => Selection Properties of HCV RdRp
  • 5. Mutant Selection • At the level of populations of infected individuals: • Genotypes and subtypes • At the level of an infected individual: • Viral quasispecies
  • 12. sensitive resistant Drug Stop drug resistant Mechanisms of Resistance sensitive resistant + very fit sensitive
  • 13. II HCV DAAs and Resistance
  • 14. HCV Lifecycle (Pawlotsky JM, Antivir Ther 2012;17:1109-17)
  • 15. Available HCV DAA Classes (Pawlotsky JM, Antivir Ther 2012;17:1109-17) NS3/4A protease inhibitors
  • 16. Available HCV DAA Classes (Pawlotsky JM, Antivir Ther 2012;17:1109-17) NS3/4A protease inhibitors Nucleotide analogues
  • 17. Available HCV DAA Classes (Pawlotsky JM, Antivir Ther 2012;17:1109-17) NS3/4A protease inhibitors Nucleotide analogues Non-nucleoside inhibitors
  • 18. 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
  • 19. Summary Low-barrier drug High-barrier drug NS3 protease inhibitors NS5A inhibitors Non-nucleoside RdRp inhibitors Nucleotide analogues
  • 22. Nucleotide analogues Sofosbuvir (Gilead) MK-3682 (Merck) AL-335 (Janssen) Pangenotypic High barrier to resistance Nucleotide Analogue Inhibitors of HCV RdRp
  • 23. Nucleotide Analogue Resistance (Lontok et al., Hepatology 2015;62:1623-32)
  • 25. 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
  • 26. 1st-wave Daclatasvir (BMS) Ledipasvir (Gilead) Ombitasvir (Abbvie) 2nd-wave Elbasvir (Merck) Velpatasvir (Gilead) Odalasvir (Janssen) Ravidasvir (Presidio) Pangenotypic (except ledipasvir) Low barrier to resistance Pangenotypic Slightly higher barrier to resistance? NS5A Inhibitors 2nd-generation? ABT-530 (Abbvie) MK-8408 (Merck) Pangenotypic Higher barrier to resistance? 1st-generation
  • 27. NS5A Inhibitor Resistance (Adapted from Tellinghuisen et al., Nature 2005;435:374-9) H1 Conserved surface H1 58 Chain B Amino Acids at RAV positions 24 30 28 58 9231 32 38 92 93 30 31 24 28 38 32 93 Chain A NB: Residues 32 and 38 behind molecule
  • 28. NS5A Inhibitor Resistance (Lontok et al., Hepatology 2015;62:1623-32)
  • 30. NS3 Protease Inhibitors (Raney et al., J Biol Chem 2010:285:22725-31)
  • 31. 1st-wave Telaprevir (Janssen) Boceprevir (Merck) 2nd-wave Simeprevir (Janssen) Paritaprevir/r (Abbvie) Asunaprevir (BMS, Asia) Vaniprevir (Merck, Asia) 2nd-generation Grazoprevir (Merck) ABT-493 (Abbvie) GS-9857 (Gilead) Only genotype 1 Low barrier to resistance All genotypes except 3 Low barrier to resistance Pangenotypic (~) Higher barrier to resistance NS3/4A Protease Inhibitors *Not approved yet in US and EU 1st-generation
  • 32. Protease Inhibitor Resistance (Lontok et al., Hepatology 2015;62:1623-32)
  • 34. Non-Nucleoside Inhibitors (NNI) Thumb I Thumb II Palm I Palm II A B C D
  • 35. Palm-1 inhibitors Dasabuvir (Abbvie) Non-Nucleoside Inhibitors (NNI) Genotype 1 only Low barrier to resistance
  • 36. NNI Resistance (Lontok et al., Hepatology 2015;62:1623-32)
  • 39. S282T RAV in RdRp (NS5B) • No S282T (0/8598) was detected in any pretreatment patient samples (deep sequencing, cutoff = 1%) Europe n=1,767 Asia n=954 Oceania n=1,094 Africa n=17 North America n=4,766 (Gane et al., AASLD 2015)
  • 40. Prevalence of NS5A RAVs (G1a) Deep sequencing, 1% cutoff (Zeuzem et al., AASLD 2015) Europe 25% (130/517) Asia Pacific 15% (4/27) Oceania 27% (89/328) North America 26% (686/2638) USA Canada Puerto Rico Belgium Switzerland Czech Republic Germany Spain France United Kingdom Italy Netherlands Poland China India Japan Korea Russia Taiwan Australia New Zealand
  • 41. Prevalence of NS5A RAVs (G1a) Akin to population sequencing, 15% cutoff (Zeuzem et al., AASLD 2015) Europe 14% Asia Pacific 7% Oceania 16% North America 13% USA Canada Puerto Rico Belgium Switzerland Czech Republic Germany Spain France United Kingdom Italy Netherlands Poland China India Japan Korea Russia Taiwan Australia New Zealand
  • 42. Prevalence of NS5A RAVs by Region (G1a) Prevalence(%) 4.9% 3.7% 2.1% 4.8% 4.1% 4.4% 1.2% 4.4% 7.6% 5.8% 2.4% 7.6% 0 5 10 15 20 Q30H/R L31M Y93H Multiple RAVs North America Europe Oceania N=2638 N=2638 N=2638 N=2638N=517 N=517 N=517 N=517N=328 N=328 N=328 N=328 Asia Pacific not included due to low number of patients with GT1a (n=27) NB: Q30H/R, L31M and Y93H RAVs confer >100 fold shift to LDV. (Zeuzem et al., AASLD 2015)
  • 43. Prevalence of NS5A RAVs (G1b) Deep sequencing, 1% cutoff (Zeuzem et al., AASLD 2015) Europe 25% (105/416) Asia Pacific 26% (150/570) Oceania 26% (26/99) North America 23% (184/802) USA Canada Puerto Rico Belgium Switzerland Czech Republic Germany Spain France United Kingdom Italy Netherlands Poland China India Japan Korea Russia Taiwan Australia New Zealand
  • 44. Prevalence of NS5A RAVs (G1b) Akin to population sequencing, 15% cutoff (Zeuzem et al., AASLD 2015) Europe 17% Asia Pacific 20% Oceania 19% North America 16% USA Canada Puerto Rico Belgium Switzerland Czech Republic Germany Spain France United Kingdom Italy Netherlands Poland China India Japan Korea Russia Taiwan Australia New Zealand
  • 45. Prevalence of NS5A RAVs by Region (G1b) (Zeuzem et al., AASLD 2015) 8.5% 14.6% 1.1% 9.4% 16.1% 1.2% 13.1% 14.1% 1.0% 3.9% 18.2% 2.1% 0 2 4 6 8 10 12 14 16 18 20 L31M/I/V Y93H Multiple RAVs North America Europe Oceania Asia Pacific NB: L31M/I/V confer 3-43 fold shift to LDV; Y93H confers >100 fold shift to LDV N=802 N=416 N=99 N=570 N=802 N=416 N=99 N=570 N=802 N=416 N=/99 N=570 Prevalence(%)
  • 46. Influence of Baseline RAVs on IFN-Free Treatment Outcomes
  • 47. Sofosbuvir + Simeprevir ± RBV COSMOS Cohort 2- Gen 1, Naive and NR, F3-F4 (Lawitz et al., Lancet 2014;384:1756-65) 93% SVR12rate(%) 0 10 20 30 40 50 60 70 80 90 100 SOF+SIM+RBVAll patients SOF+SIM+RBVSOF+SIM N=80 N=27 N=14 N=24 12 weeks 24 weeks 93%93% SOF+SIM N=15 100% 94%
  • 48. Sofosbuvir + Simeprevir ± RBV COSMOS Pooled cohorts 1 & 2- Subtype 1a, Q80K 88% SVR12rate(%) 0 10 20 30 40 50 60 70 80 90 100 SOF+SIM+RBVAll patients SOF+SIM+RBVSOF+SIM N=80 N=27 N=14 N=24 12 weeks 24 weeks 83% 89% SOF+SIM N=15 100% 88% (Lawitz et al., Lancet 2014;384:1756-65)
  • 49. 92% Any RAV N=318 97% No RAVs N=1629 SVR According to Baseline NS5A RAVs ION-1, -2, -3: Sofosbuvir + Ledipasvir ± RBV SVR12rate(%) 0 10 20 30 40 50 60 70 80 90 100 (Sarrazin et al., manuscript submitted)
  • 50. 92% Any RAV N=318 97% No RAVs N=1629 SVR According to Baseline NS5A RAVs ION-1, -2, -3: Sofosbuvir + Ledipasvir ± RBV 97% SVR12rate(%) 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=89N=29 N=48 (Sarrazin et al., manuscript submitted)
  • 51. SVR to Sofosbuvir/Ledipasvir According to NS5A RAVs (513 cirrhotic patients) (Sarrazin et al., EASL 2015)
  • 52. SVR According to Baseline NS5A RAVs (Zeuzem et al., AASLD 2015) SVR12(%) Without cirrhosis With cirrhosis Rx-Naive Rx-Exp’dRx-Naive Rx-Exp’d *HCV RNA < 6 million IU/mL. 8 Wks* 12 Wks 12 Wks 12 Wks 12 Wks + RBV 12 Wks + RBV 24 Wks24 Wks No RAVsWith RAVs 100 80 60 40 20 0 98 99 99 99 90 99 96 96 100 100 88 100 89 96 87 100 N=32 N=108 N=189 N=509 N=88 N=300 N=27 N=68 N=10 N=27 N=9 N=19 N=66 N=214 N=15 N=84
  • 53. Grazoprevir + Elbasvir C-EDGE TN– Phase III, Rx-naïve, Gt 1, w/o cirrhosis, 12 weeks 89% SVR12rate(%) 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;163:1-13)
  • 54. Grazoprevir + Elbasvir + RBV Integrated analysis of patients with G1a from Phase II and III trials, TN or TE, w/o cirrhosis, 12 or 16-18 weeks (Thompson et al., AASLD 2015) No NS5A RAVs (73%) N=38 100% NS5A RAVs (27%) N=14 100% SVR12rate(%) 0 10 20 30 40 50 60 70 80 90 100 No NS5A RAVs (66%) N=289 98% NS5A RAVs (34%) N=150 91% Rx-naïve and PR relapsers 12 weeks, no RBV PR nonresponders 16-18 weeks, + RBV
  • 55. Influence of Baseline NS5A RAVs Grazoprevir-Elbasvir, 12 (no RBV) or 16-18 weeks (+RBV), prior NR (Jacobson et al., AASLD 2015) Pts with RAVs by population sequencingPts without RAVs GT1a, Previous nonresponse GT1b, Previous nonresponse 100% 100% N=51 EBR/GZR 12 wks EBR/GZR + RBV 16/18 wks EBR/GZR 12 wks EBR/GZR + RBV 16/18 wks SVR12(%) 100 80 60 40 20 0 EBR RAVs NS5A class RAVs EBR RAVs NS5A class RAVs EBR RAVs NS5A class RAVs EBR RAVs NS5A class RAVs 97% 29% N=61 N=7 96% 64% N=54 N=14 100% 100% N=44 N=8 100% 67% N=28 N=6 100% 83% N=22 N=12 100% 100% N=26 N=12 100% 100% N=22 N=16N=1
  • 56. Summary • The detection, by means of population sequencing, of HCV RAVs at baseline has an impact on the rate of SVR with IFN-free regimens • Parameters that matter include: • The genotype/subtype • The treatment regimen received (drugs, duration, RBV) • The proportion of RAVs in the viral quasispecies at baseline • The level of resistance conferred by the substitutions
  • 57. Selection of RAVs in Patients who Fail to Achieve an SVR
  • 58. The Henri Mondor Experience 161 patients treated in IFN-free regimens in clinical trials Protease inhibitors received Paritaprevir/r Simeprevir Faldaprevir Asunaprevir Danoprevir/r NS5A inhibitors received Daclatasvir Ombitasvir Ledipasvir Nucleotide analogue received Sofosbuvir (Data on file; unpublished)
  • 59. The Henri Mondor Experience 161 patients treated in IFN-free regimens in clinical trials 13 did not achieve an SVR 8 relapses 3 breakthroughs 2 intolerant (Data on file; unpublished)
  • 60. The Henri Mondor Experience Region Observed substitutions NS3 protease V36M, D103N, R155K I71V R155K Q80K, R155K A147V, D168V A4M, V36M, R155K P146S, Q80L NS5A Y93C L31V, Y93H NS5B RNA polymerase L433F Q65R, S189N/S S47E (Data on file; unpublished)
  • 61. 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)
  • 62. 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)
  • 63. Summary • In most (if not all) patients who fail to achieve an SVR on an IFN-free regimen, viruses that are resistant to one or more of the DAAs administered are present as the dominant species at the time of relapse
  • 64. Post-treatment RAV Persistence in Patients who Fail to Achieve an SVR
  • 65. Replacement of PI-Resistant Viruses by Wild-Type Viruses (Lenz et al., J Hepatol 2015;62:1008-14)
  • 66. Persistence of RAVs in Patients who Failed after LDV (no SOF) 98% 100% 98% 100% 95% 82% 0 20 40 60 80 100 VF Parent Study Baseline FU-12 FU-24 FU-48 FU-96 PatientsWithNS5ARAVs(%) Registry Study N=63 N=58 N=43 N=45 N=55 N=58 (Dvory-Sobol et al., EASL 2015)
  • 67. 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 PrevalenceofRAVs(%) 0 10 20 30 40 50 60 70 80 90 100 N=70 N=44 N=35N=51N=67 N=57 46% 9% 97% 96% 75% 57%
  • 68. Summary • After IFN-free treatment failure, HCV variants resistant to protease inhibitors progressively disappear by population sequencing, replaced by wild-type virus • In contrast, viruses resistant to NS5A inhibitors and to NNIs persist for years, maybe for ever, as dominant species
  • 70. 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) (European Association for the Study of the Liver. J Hepatol 2015;63:199-236)
  • 71. SVR12rate(%) 0 10 20 30 40 50 60 70 80 90 100 87% Total 80% Genotype 1a 100% Genotype 1b Retreatment of NS5A Inhibitor Failures with Sofosbuvir + Simeprevir 12 wks 100% Genotype 4 (Hézode et al., AASLD 2015) N=15 N=10 N=3 N=2
  • 72. SVR12rate(%) 0 10 20 30 40 50 60 70 80 90 100 92% 1a, no cirrhosis 12 wks + RBV 100% 1a, cirrhosis 24 wks + RBV 100% 1b 12 wks, no RBV Retreatment of DAA Failures with Sofosbuvir + 3D 12 wk (QUARTZ-I) (Poordad et al., AASLD 2015) N=15 N=6 N=2
  • 73. 100% Overall N=23 Retreatment with Sofosbuvir + Grazoprevir/Elbasvir + RBV C-SWIFT Retreatment- G1, short (4-6-8 wk) SOF-GZR-EBR treatment failures (Lawitz et al., AASLD 2015) 100% SVR12rate(%) 0 10 20 30 40 50 60 70 80 90 100 No 100% Yes 100% 4 wk 100% 6-8 wk 100% No 100% Yes N=18 N=8 N=5 N=18N=5 N=15 Cirrhosis Prior Rx duration Baseline NS5A RAVs
  • 75. 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
  • 77. European Association for the Study of the Liver. J Hepatol 2015;63:199-236
  • 78. Characteristics that Inform Treatment Option Selection Treatment selection Prior treatment experience HCV genotype/ subtype Severity of liver disease Patient co- morbidities PK profile of treatment Drug-drug interactions (European Association for the Study of the Liver. J Hepatol 2015;63:199-236)
  • 79. SVR12rate(%) 0 10 20 30 40 50 60 70 80 90 100 90% 12 wk No RBV 96% 12 wk +RBV 98% 24 wk No RBV Sofosbuvir/Ledipasvir ± RBV Rx-experienced patients with compensated cirrhosis 100% 24 wk +RBV (Reddy et al., Hepatology 2015;62:79-86)
  • 80. SVR to Sofosbuvir/Ledipasvir According to NS5A RAVs (513 cirrhotic patients) 88% 94% 85% 100%95% 97% 100% 100% 0 20 40 60 80 100 LDV/SOF LDV/SOF+RBV LDV/SOF LDV/SOF+RBV SVR12(%) N=26 N=91 N=34 N=169 N=20 N=113 N=14 N=44 12 Weeks 12 Weeks 24 Weeks 24 Weeks Pre-existing NS5A RAVs No pre-existing NS5A RAVs (Sarrazin et al., EASL 2015)
  • 81. Ombitasvir/Paritaprevir/r + Dasabuvir ± RBV TURQUOISE II-Phase III, Genotype 1, Rx-naïve and -experienced, Compensated cirrhosis (CPA), 12-24 weeks (Poordad et al., N Engl J Med 2014;370:1973-82) 92% 93% 100% 80% 93% 100% 100% 93% 0 20 40 60 80 100 Naive Prior relapse Prior partial response Prior null response N=64 N=15N=56 N=13 N=11 N=50N=10 N=42 SVR12(%) 12 weeks 24 weeks Genotype 1a
  • 82. Conclusions • Optimizing first-line treatment is required to avoid DAA-based treatment failures associated with HCV resistance • Retreatment options exist, based on the combination of sofosbuvir plus 2 or 3 other DAAs, eventually with ribavirin
  • 83. Follow me on Twitter @JMPawlotsky