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,

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

3. I
IFN--Ribavirine
TreatmentFailure

4. Treatment
Schedule
Host
Factors
Treatment
Failure
Disease
Characteristics
Viral Factors

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

8. Geographic Distribution
(Thomas et al, Nature, 2009;461:798-801)

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)

14. HCV Kinetics by Genotype
EC-sponsored DITTO-Trial
7
HCV RNA (log IU/ml)
*=
6
significant difference, 4 and
5
4
*
*
Genotype 4
3 Quantitative assay cutoff
2 Qualitative assay
Genotype 1
*
*
cutoff
*
*
1
*
0
-28
-7
01
4
(Pawlotsky et al., manuscript in preparation)
7 8
15
22
29
Genotype 3

15. HCV Kinetics by Genotype
EC-sponsored DITTO-Trial
7
HCV RNA (log IU/ml)
*=
6
significant difference, 4 and
5
4
*
*
Genotype 4
3 Quantitative assay cutoff
2 Qualitative assay
Genotype 1
*
*
cutoff
*
*
1
*
0
-28
-7
01
4
(Pawlotsky et al., manuscript in preparation)
7 8
15
22
29
Genotype 3

16. HCV Kinetics by Genotype
EC-sponsored DITTO-Trial
7
HCV RNA (log IU/ml)
*=
6
significant difference, 4 and
5
4
*
*
Genotype 4
3 Quantitative assay cutoff
2 Qualitative assay
Genotype 1
*
*
cutoff
*
*
1
*
0
-28
-7
01
4
(Pawlotsky et al., manuscript in preparation)
7 8
15
22
29
Genotype 3

17. HCV Kinetics by Genotype
EC-sponsored DITTO-Trial
7
HCV RNA (log IU/ml)
*=
6
significant difference, 4 and
5
4
*
*
Genotype 4
3 Quantitative assay cutoff
2 Qualitative assay
Genotype 1
*
*
cutoff
*
*
1
*
0
-28
-7
01
4
(Pawlotsky et al., manuscript in preparation)
7 8
15
22
29
Genotype 3

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

19. II
HCV resistance to DAAs

20. HCV Quasispecies
Major viral population
Intermediate viral
populations
Minor viral populations

21. Mechanisms of resistance

22. Mechanisms of Resistance
sensitive
resistant

23. Mechanisms of Resistance
Drug
sensitive
resistant

24. Mechanisms of Resistance
Drug
sensitive
sensitive
resistant
resistant

25. Mechanisms of Resistance
Drug
Stop drug
sensitive
sensitive
resistant
resistant

26. Mechanisms of Resistance
Drug
Stop drug
sensitive
sensitive
resistant
sensitive
resistant
resistant

27. Mechanisms of Resistance
Drug
Stop drug
sensitive
sensitive
sensitive
resistant
resistant
resistant + fit

28. Mechanisms of Resistance
Drug
Stop drug
sensitive
sensitive
resistant
resistant + very fit
sensitive
resistant

29. Chronic HCV
infection is curable
by therapy

30. Mechanisms of Resistance
sensitive
resistant

31. Mechanisms of Resistance
Drug
sensitive
resistant
resistant

32. Mechanisms of Resistance
Drug
Stop drug
sensitive
resistant
resistant
resistant

33. HCV resistance to DAAs

34. HCV Life Cycle
(Popescu & Dubuisson, Biol Cell 2009;102:63-74)

35. Barrier to Resistance
Low-barrier drug
High-barrier drug

36. 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

37. NS3/4A Protease Inhibitors
(Raney et al., J Biol Chem 2010:285:22725-31)

38. NS3/4A Protease Inhibitors
Phase
Dose
Duration
Median/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
Simeprevir (Janssen)
III
200 mg qd
7 days
-4.1
Faldaprevir (BI)
III
240 mg qd
14 days
-4.0
Asunaprevir (BMS)
III
300 mg bid
3 days
-3.3
ABT-450/r (AbbVie)
III
200 mg qd
3 days
-4.1
Danoprevir/r (Roche)
II
200 mg q8h
14 days
-3.8
Sovaprevir (Achillion)
II
600 mg qd
5 days
-3.8
GS-9451 (Gilead)
II
400 mg qd
3 days
-3.5
IDX320 (Idenix)
II
400 mg qd
3 days
-3.3
Japan
700 mg bid
8 days
-4.7
MK-5172 (2nd-gen, Merck)
II
400 mg qd
7 days
-5.4
ACH-2684 (2nd-gen, Achillion)
Ib
400 mg qd
3 days
-4.0
Drug
Vaniprevir (Merck)

39. Amino Acid Substitutions
Associated with PI Resistance
Asp168
Arg155
Ala156
Thr54
Val36
(Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219)

40. MK-5172 and Boceprevir
Resistance-Associated Variants
(Lahser et al., AASLD 2012)

41. MK-5172 Resistance Profile
10000.0
Replicon EC90 (nM)
1000.0
100.0
10.0
1.0
telaprevir
boceprevir
GS-9551
simeprevir
BMS-032
MK-5172
0.1
MK-5172
(Lahser et al., AASLD 2012)
BMS-032
simeprevir
GS-9551
boceprevir
telaprevir

42. Nucleoside/Nucleotide Analogue
Inhibitors of HCV RdRp
Catalytic
Site

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)

46. Non-Nucleoside Inhibitors (NNI)
Thumb I
Palm I
A
B
C
D
Thumb II
Palm II

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)

53. Replicon EC90 (nM)
MK-8742 Resistance Profile
100
10
1
0.1
0.01
0.001
GS-5885
Daclatasver
MK-8742
MK-8742
(Merck, unpublished data)
Daclatasver
GS-5885

54. nd-Generation
2
GS-5816, a
NS5A Inhibitor
(Gilead, data on file)

55. Cyclophilins
Cyclophilin A

56. Antiviral Efficacy of
Cyclophylin Inhibitors
Phase
Dose
Duration
Median/mean
log HCV RNA
reduction
Alisporivir (DEBIO-025)
III
1200 mg bid
14 days
-3.6
SCY-465
II
900 mg qd
15 days
-2.2
Drug

57. Alisporivir Resistance in vitro
HCV
EMCV
neo
5’UTR
IRES
NS3
A
A
IRES
36
213
NS5A
250
Domain I
A241P
NS4
B
342 356
Domain II
R262Q
3’UTR
NS5B
447
Domain III
R318W
D320E
A241P +
R262Q
Foldchange
vs wt
A241P +
R318W
R262Q +
R318W
R318W +
D320E
A241P +
R262Q +
R318W
1.02
1.58
1.37
3.67
1.72
(Coelmont et al., EASL 2009)
A241P +
R262Q +
R318W +
D320E
3.89

58. III
Treatment Failure with the
Triple Combination of PegIFN, Ribavirin and a DAA

59. Treatment failure on telaprevir
or boceprevir triple combo

60. Response
1a
1a
1b
1b
1a
1b
1a
1a
1a
1a
1a
1b
1b
1b
1b
1a
1a
1b
TVR
HCV
subtype
CT
CT
CT
TT
CT
CT
CT
CT
CC
CC
TT
CT
CT
TT
CT
CT
CT
CT
RBV
IL28B
genotype
Pt-1
Pt-2
Pt-3
Pt-4
Pt-5
Pt-6
Pt-7
Pt-8
Pt-9
Pt-10
Pt-11
Pt-12
Pt-13
Pt-14
Pt-15
Pt-16
Pt-17
Pt-18
pegIFN
Patient
Pre-existing HCV Resistant
Variants by UDPS
V36
A/M
T54
A/S
V55A
Q80
R/K
R155
K/T/Q
NR
NR
RR
RR
RR
RR
SVR
SVR
SVR
SVR
RR
SVR
SVR
NR
SVR
SVR
SVR
SVR
4.2%
-
90.0%
29.4%
11.1%
47.4%
20.0%
100.0%
1.3%
-
0.7%
0.1%
0.5%
-
0.1%
0.1%
0.5%
0.1%
0.1%
0.1%
0.6%
0.6%
6.0%
0.2%
0.1%
0.4%
7.8%
0.1%
0.1%
SVR: sustained virological response; RR: response-relapse; NR: non-response
(Chevaliez S., et al. EASL 2011)
A156
D168
S/T/V A/V/T/H
0.4%
1.1%
0.5%
1.3%
2.9%
0.1%
0.3%
0.5%
1.8%
3.2%
0.3%
0.2%
0.2%
0.2%
0.2%
0.4%
0.4%
0.1%
0.1%
0.1%
0.1%
0.1%
0.1%
0.1%
0.1%
0.1%
I170
A/T
0.5%
0.2%
0.2%
0.1%
0.1%
0.3%
0.1%
0.3%
0.1%
0.8%
0.1%
0.1%
0.1%
0.1%
0.1%
*SNP rs12979860

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

63. REALIZE
Patients With Undetectable HCV
RNA (%)
Rx-experienced, Gen 1, Telaprevir
100
94%
<1 log decrease
82%
≥1 log decrease
80
62%
60
40
56%
59%
54%
33%
20
15%
0
Overall
(Foster et al., EASL 2011)
Prior
relapse
Prior partial
response
Prior
null-response

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

65. Post-Failure Follow-up
(Boceprevir)
Genotype 1a
Genotype 1b
100%
90%
% Variant viral résistant détecté
% resistant viral variants detected
100%
80%
70%
60%
50%
40%
All
T54S
R155K
V36M
30%
20%
10%
0%
90%
All
T54S
T54A
80%
70%
60%
50%
40%
30%
20%
10%
0%
0
0.5
1
1.5
Time after treatment failure (years)
(Barnard et al., CROI 2011)
2
0
0.5
1
1.5
Time after treatment failure (years)
2

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)

68. Treatment failure on
simeprevir triple combo

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)

72. Treatment failure on
sofosbuvir triple combo

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

75. IV
HCV Resistance in All-oral,
IFN-free regimens

76. Principles

77. Barrier to Resistance
Low-barrier drug
High-barrier drug

78. Barrier to Resistance
• Low barrier to resistance
• First-generation protease inhibitors
• Non-nucleoside inhibitors of RdRp
• NS5A inhibitors (subtype 1a)
• High barrier to resistance
•
•
•
•
Nucleoside/nucleotide analogues
Cyclophylin inhibitors
NS5A inhibitors (subtypes other than 1a)
2nd-generation protease and NS5A inhibitors

79. GS-9256 (PI) + Tegobuvir (NNI)
HCV RNA IU/mL (Log)
8
GS-9256 + tegobuvir
7
6
5
4
3
2
(<25 IU/mL)
1
0
0
7
(Zeuzem et al., Hepatology 2012;55:749-58)
14
Days
21
28

80. Danoprevir (PI) + Mericitabine (NI)
INFORM-1 Trial
Increasing doses of danoprevir and RG7128
Days
(Gane et al., Lancet 2010;376:1467-757)
Danoprevir, 900 mg bid + RG7128
Danoprevir, 900 mg bid + pegIFNand ribavirin
Days
Days

81. Daclatasvir (NS5A)/Asunaprevir (PI)
HCV Genotype 1b
(Suzuki et al., EASL 2012)

82. IFN-free treatment failures

83. IFN-Free Combination Options
NI
PI
NS5A
NNI
RBV
Ledipasvir
GS-9669
±
Nucleos(t)ide analogue-based strategies
Gilead
Vertex/others
Roche
Sofosbuvir
VX-135
Simeprevir
Mericitabine
Daclatasvir
Danoprevir/r
±
Setrobuvir
±
Nucleoside-free triple combo strategies
Abbvie
ABT-350/r
ABT-267
ABT-333
±
BMS
Asunaprevir
Daclatasvir
BMS791325
±
BI/Presidio
Faldaprevir
PPI-668
Deleobuvir
±
Janssen/GSK
Simeprevir
GSK2336805
TMC647055
±
Nucleoside-free, second-generation double combo strategies
Merck
MK-5172
MK-8742
±
Achillion
ACH-2684
ACH-3102
±

84. Sofosbuvir + RBV in Gen 2
Phase III, 12 weeks, cirrhosis vs no cirrhosis
100
97%
83%
90
90%
92%
78%
SVR12 rate (%)
80
70
60%
60
50
40
30
20
10
N=61
0
N=12
12 wk
12 wk
No cirrhosis Cirrhosis
FISSION (Rx-naïve)
(FDA hearings, October 25, 2013)
N=29
N=26
N=10
N=9
12 wk
16 wk
12 wk
16 wk
No cirrhosis
Cirrhosis
FUSION (Rx-experienced)

85. Sofosbuvir + RBV in Gen 3
Phase III, Treatment-experienced
FUSION (12 wk)
100
FUSION (16 wk)
VALENCE (24 wk)
85
63
61
SVR12, %
80
60
60
37
19
40
20
0
N=38
N=40
N=100
N=26
N=23
N=45
12 wks 16 wks 24 wks
12 wks 16 wks 24 wks
No cirrhosis
Cirrhosis
(Jacobson et al., N Engl J Med 2013;368:1867-77; Zeuzem et al., AASLD 2013; FDA hearings, October 25, 2013)

86. Sofosbuvir/Ledipasvir FDC ± RBV
ION-2-Phase III, Gen 1, Rx-experienced, 20% cirrhosis
99.1%
99.1%
93.6%
96.4%
N=109
N=111
N=109
N=111
SOF/LDV
100
SOF/LDV+RBV
SOF/LDV
SOF/LDV+RBV
90
SVR12 rate (%)
80
70
60
50
40
30
20
10
0
12 weeks
(Gilead press release, December 18, 2013)
24 weeks

87. Sofosbuvir/Ledipasvir FDC ± RBV
Relapse Pt with multidrug resistance
NS5B: No RAVs
NS5A: L31M (25.5%)
HCV RNA (log10 IU/mL)
7
6
5
NS5B: S282T (91.2%)
NS5A: Q30L (4.5%)
L31M (>99%)
Y93H (96.7%)
NS5B: S282T (8.0%)
NS5A: Q30L (3.5%)
L31M (94.4%)
L31V (4.7%)
Y93H (98.2%)
4
3
2
LLOQ-TD
LLOQ-TND
SVR12
0
SOF/LDV
8 Weeks
(Lawitz et al., AASLD 2013)
PostTreatment
Re-treatment:
SOF/LDV + RBV
24 Weeks
PostTreatment

88. IFN-Free Combination Options
NI
PI
NS5A
NNI
RBV
Ledipasvir
GS-9669
±
Nucleos(t)ide analogue-based strategies
Gilead
Vertex/others
Roche
Sofosbuvir
VX-135
Simeprevir
Mericitabine
Daclatasvir
Danoprevir/r
±
Setrobuvir
±
Nucleoside-free triple combo strategies
Abbvie
ABT-350/r
ABT-267
ABT-333
±
BMS
Asunaprevir
Daclatasvir
BMS791325
±
BI/Presidio
Faldaprevir
PPI-668
Deleobuvir
±
Janssen/GSK
Simeprevir
GSK2336805
TMC647055
±
Nucleoside-free, second-generation double combo strategies
Merck
MK-5172
MK-8742
±
Achillion
ACH-2684
ACH-3102
±

89. ABT-450/r (PI) ± ABT-267 (NS5A) ± ABT-333
(NNI)SAPPHIRE I-Phase III, Genotype 1, Rx-naïve, N=631
96%
95%
All genotypes 1
100
Subtype 1a
98%
90
SVR12 rate (%)
80
70
60
50
40
30
20
10
0
(Abbvie press release, November 18, 2013)
Subtype 1b

90. IFN-Free Combination Options
NI
PI
NS5A
NNI
RBV
Ledipasvir
GS-9669
±
Nucleos(t)ide analogue-based strategies
Gilead
Vertex/others
Roche
Sofosbuvir
VX-135
Simeprevir
Mericitabine
Daclatasvir
Danoprevir/r
±
Setrobuvir
±
Nucleoside-free triple combo strategies
Abbvie
ABT-350/r
ABT-267
ABT-333
±
BMS
Asunaprevir
Daclatasvir
BMS791325
±
BI/Presidio
Faldaprevir
PPI-668
Deleobuvir
±
Janssen/GSK
Simeprevir
GSK2336805
TMC647055
±
Nucleoside-free, second-generation double combo strategies
Merck
MK-5172
MK-8742
±
Achillion
ACH-2684
ACH-3102
±

91. MK-5172 (2nd-gen PI) + MK-8742 (2nd-gen NS5A)
C-WORTHY, Gen 1, Rx-naive, noncirrhotic, 12 wks
100
96%
90
100%
89%
SVR12 rate (%)
80
70
60
50
40
30
20
10
N=24
N=27
N=12
5172
+ 8742 20 mg
+ RBV
5172
+ 8742 50 mg
+ RBV
5172
+ 8742 50 mg
No RBV
0
(Lawitz et al., EASL 2013)

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