pawlotzky hcv resistances.pptx du16
TRANSCRIPT
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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 HospitalUniversity of Paris-Est
Créteil, France
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I
HCV Genetic Variability and Mechanisms of Resistance
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HCV RNA-DependentRNA Polymerase
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• Errors during replication:• frequent• spontaneous• at random positions
• Lack of “proofreading” activity
=> Accumulation of genomic mutations
=> Selection
Properties of HCV RdRp
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Mutant Selection
• At the level of populations of infected individuals:
• Genotypes and subtypes
• At the level of an infected individual:• Viral quasispecies
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Quasispecies Distributionof Viruses
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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
Drug Stop drug
resistant
Mechanisms of Resistance
sensitive
resistant + very fit
sensitive
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II
HCV DAAs and Resistance
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HCV Lifecycle
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
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Available HCV DAA Classes
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
NS3/4A protease inhibitors
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Available HCV DAA Classes
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
NS3/4A protease inhibitors
Nucleotide analogues
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Available HCV DAA Classes
(Pawlotsky JM, Antivir Ther 2012;17:1109-17)
NS3/4A protease inhibitors
Nucleotide analogues
Non-nucleoside inhibitors
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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
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SummaryLow-barrier drug High-barrier drug
NS3 protease inhibitorsNS5A inhibitors
Non-nucleoside RdRp inhibitors
Nucleotide analogues
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Nucleotide analogue inhibitors of HCV RdRp
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CatalyticSite
Nucleotide Analogue Inhibitors of HCV RdRp
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Nucleotide analogues
Sofosbuvir (Gilead)MK-3682 (Merck)AL-335 (Janssen)
PangenotypicHigh barrier to resistance
Nucleotide Analogue Inhibitors of HCV RdRp
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Nucleotide Analogue Resistance
(Lontok et al., Hepatology 2015;62:1623-32)
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NS5A inhibitors
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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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1st-wave
Daclatasvir (BMS) Ledipasvir (Gilead)Ombitasvir (Abbvie)
2nd-wave
Elbasvir (Merck)Velpatasvir (Gilead)Odalasvir (Janssen)Ravidasvir (Presidio)
Pangenotypic(except ledipasvir)
Low barrier to resistancePangenotypic
Slightly higher barrier to resistance?
NS5A Inhibitors2nd-generation?
ABT-530 (Abbvie)MK-8408 (Merck)
PangenotypicHigher barrier to resistance?
1st-generation
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NS5A Inhibitor Resistance
(Adapted from Tellinghuisen et al., Nature 2005;435:374-9)
H1Conservedsurface
H1
58Chain B
Amino Acids at RAV positions
2430
2858
923132 38
9293 30
3124
28
3832
93 Chain A
NB: Residues 32 and 38 behind molecule
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NS5A Inhibitor Resistance
(Lontok et al., Hepatology 2015;62:1623-32)
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NS3/4A protease inhibitors
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NS3 Protease Inhibitors
(Raney et al., J Biol Chem 2010:285:22725-31)
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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 1Low barrier to resistance
All genotypes except 3Low barrier to resistance
Pangenotypic (~)Higher barrier to
resistance
NS3/4A Protease Inhibitors
*Not approved yet in US and EU
1st-generation
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Protease Inhibitor Resistance
(Lontok et al., Hepatology 2015;62:1623-32)
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Non-nucleoside inhibitors of HCV RdRp
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Non-Nucleoside Inhibitors (NNI)
Thumb I
Thumb II
Palm I
Palm II
A
BC
D
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Palm-1 inhibitors
Dasabuvir (Abbvie)
Non-Nucleoside Inhibitors (NNI)
Genotype 1 onlyLow barrier to resistance
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NNI Resistance
(Lontok et al., Hepatology 2015;62:1623-32)
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III
HCV Resistance in IFN-Free Regimens
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BaselinePrevalence of RAVs
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S282T RAV in RdRp (NS5B)• No S282T (0/8598) was detected in any pretreatment patient
samples (deep sequencing, cutoff = 1%)
Europe n=1,767
Asian=954
Oceanian=1,094
African=17
North America n=4,766
(Gane et al., AASLD 2015)
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Prevalence of NS5A RAVs (G1a)Deep sequencing, 1% cutoff
(Zeuzem et al., AASLD 2015)
Europe25% (130/517)
Asia Pacific15% (4/27)
Oceania27% (89/328)
North America26% (686/2638)USACanadaPuerto Rico
BelgiumSwitzerlandCzech RepublicGermanySpainFranceUnited KingdomItalyNetherlandsPoland
ChinaIndiaJapanKoreaRussiaTaiwan
AustraliaNew Zealand
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Prevalence of NS5A RAVs (G1a)Akin to population sequencing, 15% cutoff
(Zeuzem et al., AASLD 2015)
Europe14%
Asia Pacific7%
Oceania16%
North America13% USACanadaPuerto Rico
BelgiumSwitzerlandCzech RepublicGermanySpainFranceUnited KingdomItalyNetherlandsPoland
ChinaIndiaJapanKoreaRussiaTaiwan
AustraliaNew Zealand
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Prevalence of NS5A RAVs by Region (G1a)
Prev
alen
ce (%
)
Q30H/R L31M Y93H Multiple RAVs0
5
10
15
20
4.9%3.7%
2.1%
4.8%4.1% 4.4%
1.2%
4.4%
7.6%
5.8%
2.4%
7.6%
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)
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Prevalence of NS5A RAVs (G1b)Deep sequencing, 1% cutoff
(Zeuzem et al., AASLD 2015)
Europe25% (105/416)
Asia Pacific26% (150/570)
Oceania26% (26/99)
North America23% (184/802)USACanadaPuerto Rico
BelgiumSwitzerlandCzech RepublicGermanySpainFranceUnited KingdomItalyNetherlandsPoland
ChinaIndiaJapanKoreaRussiaTaiwan
AustraliaNew Zealand
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Prevalence of NS5A RAVs (G1b)Akin to population sequencing, 15% cutoff
(Zeuzem et al., AASLD 2015)
Europe17%
Asia Pacific20%
Oceania19%
North America16% USACanadaPuerto Rico
BelgiumSwitzerlandCzech RepublicGermanySpainFranceUnited KingdomItalyNetherlandsPoland
ChinaIndiaJapanKoreaRussiaTaiwan
AustraliaNew Zealand
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Prevalence of NS5A RAVs by Region (G1b)
(Zeuzem et al., AASLD 2015)
L31M/I/V Y93H Multiple RAVs0
2
4
6
8
10
12
14
16
18
20
8.5%
14.6%
1.1%
9.4%
16.1%
1.2%
13.1%14.1%
1.0%
3.9%
18.2%
2.1%
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
Prev
alen
ce (%
)
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Influence of Baseline RAVs on IFN-Free Treatment Outcomes
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Sofosbuvir + Simeprevir ± RBVCOSMOS Cohort 2- Gen 1, Naive and NR, F3-F4
(Lawitz et al., Lancet 2014;384:1756-65)
93%
SVR
12 ra
te (%
)
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%
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Sofosbuvir + Simeprevir ± RBVCOSMOS Pooled cohorts 1 & 2- Subtype 1a, Q80K
88%
SVR
12 ra
te (%
)
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)
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92%
AnyRAV
N=318
97%
No RAVs
N=1629
SVR According to Baseline NS5A RAVs ION-1, -2, -3: Sofosbuvir + Ledipasvir ± RBV
SVR
12 ra
te (%
)
0
10
20
30
40
50
60
70
80
90
100
(Sarrazin et al., manuscript submitted)
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92%
AnyRAV
N=318
97%
No RAVs
N=1629
SVR According to Baseline NS5A RAVs ION-1, -2, -3: Sofosbuvir + Ledipasvir ± RBV
97%
SVR
12 ra
te (%
)
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)
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SVR to Sofosbuvir/Ledipasvir According to NS5A RAVs (513 cirrhotic patients)
(Sarrazin et al., EASL 2015)
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SVR According to Baseline NS5A RAVs
(Zeuzem et al., AASLD 2015)
SVR
12 (%
)
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 9990
99 96 96 100 10088
10089
9687
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
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Grazoprevir + ElbasvirC-EDGE TN– Phase III, Rx-naïve, Gt 1, w/o cirrhosis, 12 weeks
89%
SVR
12 ra
te (%
)
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 BsNS3 RAVs
Bs NS3
RAVs
No BsNS3
RAVs
BsNS5ARAVs
No BsNS5ARAVs
BsNS5A RAVs
No BsNS5A RAVs
GT 1a GT 1b GT 1a GT 1b(Zeuzem et al., Ann Intern Med 2015;163:1-13)
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Grazoprevir + Elbasvir + RBVIntegrated 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%
SVR
12 ra
te (%
)
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 relapsers12 weeks, no RBV
PR nonresponders16-18 weeks, + RBV
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Influence of Baseline NS5A RAVsGrazoprevir-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
SVR
12 (%
)
100
80
60
40
20
0EBR 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
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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
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Selection of RAVs in Patients who Fail to Achieve an SVR
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The Henri Mondor Experience161 patients treated in IFN-free regimens
in clinical trials
Protease inhibitors received
Paritaprevir/rSimeprevirFaldaprevirAsunaprevirDanoprevir/r
NS5A inhibitors received
DaclatasvirOmbitasvirLedipasvir
Nucleotide analoguereceived
Sofosbuvir
(Data on file; unpublished)
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The Henri Mondor Experience161 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)
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The Henri Mondor ExperienceRegion Observed substitutions
NS3 protease
V36M, D103N, R155KI71VR155KQ80K, R155KA147V, D168VA4M, V36M, R155KP146S, Q80L
NS5A Y93CL31V, Y93H
NS5B RNA polymeraseL433FQ65R, S189N/SS47E
(Data on file; unpublished)
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Selection of RAVs in Patients who Failed after LDV (no SOF)
16%(12/76)
84%(64/76)
BeforeLDV Treatment
99%(72/73)
1%
At Virologic Failure With LDV Treatment
Patients without NS5A RAVsPatients with NS5A RAVs
Patients who failed after a ledipasvir-containing treatment
(without sofosbuvir)
(Dvory-Sobol et al., EASL 2015)
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Treatment Failures in SAPPHIRE-2Genotype 1, Rx-experienced, 3D ± Ribavirin
Virologic failure in 7/297 patients (2.4%)
(Zeuzem et al., N Engl J Med 2014;370:1604-1614)
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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
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Post-treatment RAV Persistence in Patients who Fail to Achieve an SVR
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Replacement of PI-Resistant Viruses by Wild-Type Viruses
(Lenz et al., J Hepatol 2015;62:1008-14)
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Persistence of RAVs in Patients who Failed after LDV (no SOF)
0
20
40
60
80
100 98% 100% 98% 100%95%
82%Pa
tient
s W
ith N
S5A
RA
Vs (%
)
Registry Study
N=63 N=58 N=43 N=45 N=55 N=58
(Dvory-Sobol et al., EASL 2015)
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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
Prev
alen
ce o
f RAV
s (%
)
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%
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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
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IV
Retreatment Options
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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)
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SVR
12 ra
te (%
)
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
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SVR
12 ra
te (%
)
0
10
20
30
40
50
60
70
80
90
100 92%
1a, no cirrhosis12 wks + RBV
100%
1a, cirrhosis24 wks + RBV
100%
1b12 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
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100%
Overall
N=23
Retreatment with Sofosbuvir + Grazoprevir/Elbasvir + RBVC-SWIFT Retreatment- G1, short (4-6-8 wk) SOF-GZR-EBR treatment failures
(Lawitz et al., AASLD 2015)
100%
SVR
12 ra
te (%
)
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
BaselineNS5A RAVs
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V
Utility of HCV Resistance Testing
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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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VI
Avoiding Treatment Failures
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European Association for the Study of the Liver. J Hepatol 2015;63:199-236
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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)
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SVR
12 ra
te (%
)
0
10
20
30
40
50
60
70
80
90
100 90%
12 wkNo RBV
96%
12 wk+RBV
98%
24 wkNo RBV
Sofosbuvir/Ledipasvir ± RBVRx-experienced patients with compensated cirrhosis
100%
24 wk+RBV
(Reddy et al., Hepatology 2015;62:79-86)
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SVR to Sofosbuvir/Ledipasvir According to NS5A RAVs (513 cirrhotic patients)
LDV/SOF LDV/SOF+RBV LDV/SOF LDV/SOF+RBV0
20
40
60
80
100 88% 94% 85% 100%95% 97% 100% 100%
SVR1
2 (%
)
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)
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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)
0
20
40
60
80
100 92%93% 100%
80%93% 100% 100% 93%
N=64 N=15N=56 N=13 N=11 N=50N=10 N=42
SVR
12 (%
)
12 weeks24 weeks
Genotype 1a
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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
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