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Hépatite C: Résistance
aux Traitements
Prof. Jean-Michel Pawlotsky

CNR des Hépatites B, C et delta
Laboratoire de Virolog...
HCV Resistance
• IFN--ribavirin treatment failure
• HCV resistance to DAAs
• Treatment Failure with the combination
of Pe...
I
IFN--Ribavirine
TreatmentFailure
Treatment
Schedule

Host
Factors
Treatment
Failure

Disease
Characteristics

Viral Factors
Genome-Wide Association
Studies (GWAS)

A population with
distinct clinical
phenotypes

> 3 billion nucleotides
> 10 milli...
SNP and SVR in the IDEAL Trial
IL28B

(Ge et al, Nature, 2009;461:399-401)
Sustained virological response (%)

SVR in the IDEAL Trial According
to SNP rs12979860 (genotype 1)
100%

80%

60%

40%

2...
Geographic Distribution

(Thomas et al, Nature, 2009;461:798-801)
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 < 0.0...
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...
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
...
Summary
• In patients infected with HCV genotype
1, the rs12979860 genotype:
• Is strongly associated with the SVR

• Expl...
Incidence of Peg-IFN-Ribavirin
Treatment Failures
60

58%

54%

PEG-IFN-α2a+ribavirin (Fried et al)

48%

PEG-IFN-α2a+rib...
HCV Kinetics by Genotype
EC-sponsored DITTO-Trial
7

HCV RNA (log IU/ml)

*=

6

significant difference, 4 and

5

4

*
*
...
HCV Kinetics by Genotype
EC-sponsored DITTO-Trial
7

HCV RNA (log IU/ml)

*=

6

significant difference, 4 and

5

4

*
*
...
HCV Kinetics by Genotype
EC-sponsored DITTO-Trial
7

HCV RNA (log IU/ml)

*=

6

significant difference, 4 and

5

4

*
*
...
HCV Kinetics by Genotype
EC-sponsored DITTO-Trial
7

HCV RNA (log IU/ml)

*=

6

significant difference, 4 and

5

4

*
*
...
Summary
• HCV resistance to IFN- antiviral effect
exists
• Its molecular mechanisms are unknown
and probably complex
• It...
II
HCV resistance to DAAs
HCV Quasispecies
Major viral population

Intermediate viral
populations

Minor viral populations
Mechanisms of resistance
Mechanisms of Resistance

sensitive

resistant
Mechanisms of Resistance
Drug

sensitive

resistant
Mechanisms of Resistance
Drug

sensitive

sensitive

resistant

resistant
Mechanisms of Resistance
Drug

Stop drug

sensitive

sensitive

resistant

resistant
Mechanisms of Resistance
Drug

Stop drug

sensitive

sensitive

resistant

sensitive

resistant

resistant
Mechanisms of Resistance
Drug

Stop drug

sensitive
sensitive
sensitive

resistant

resistant

resistant + fit
Mechanisms of Resistance
Drug

Stop drug

sensitive

sensitive

resistant

resistant + very fit

sensitive

resistant
Chronic HCV
infection is curable
by therapy
Mechanisms of Resistance

sensitive

resistant
Mechanisms of Resistance
Drug

sensitive
resistant
resistant
Mechanisms of Resistance
Drug

Stop drug

sensitive
resistant
resistant

resistant
HCV resistance to DAAs
HCV Life Cycle

(Popescu & Dubuisson, Biol Cell 2009;102:63-74)
Barrier to Resistance
Low-barrier drug

High-barrier drug
DAAs in Development
• NS3/4A protease inhibitors
• Inhibitors of HCV replication
• Nucleoside/nucleotide analogue inhibito...
NS3/4A Protease Inhibitors

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

Dose

Duration

Median/mean
log HCV RNA
reduction

Telaprevir (Janssen)

Approved

750 m...
Amino Acid Substitutions
Associated with PI Resistance
Asp168

Arg155

Ala156

Thr54

Val36

(Pawlotsky J-M, Ther Adv Gast...
MK-5172 and Boceprevir
Resistance-Associated Variants

(Lahser et al., AASLD 2012)
MK-5172 Resistance Profile
10000.0

Replicon EC90 (nM)

1000.0

100.0

10.0

1.0
telaprevir
boceprevir
GS-9551
simeprevir
...
Nucleoside/Nucleotide Analogue
Inhibitors of HCV RdRp

Catalytic
Site
Nucleoside/Nucleotide Analogue
Inhibitors of HCV RdRp
Phase

Dose

Duration

Median/mean log
HCV RNA level
reduction

Sofo...
HCV Resistance to 2’-C-Methyl
Nucleoside Inhibitors
2’C-Me-ATP in the catalytic site

(Migliaccio et al., J Biol Chem 2003...
Sofosbuvir Resistance
• Sofosbuvir binds to the highly conserved catalytic
site of the HCV RdRp
• S282T
• Is the only know...
Non-Nucleoside Inhibitors (NNI)

Thumb I

Palm I

A

B
C
D
Thumb II

Palm II
Non-Nucleoside Inhibitors
of HCV RdRp (NNIs)
Phase

Dose

Duration

Median/mean log
HCV RNA reduction

Tegobuvir (Gilead)
...
Non-Nucleoside Inhibitors (NNI)
Thumb I
Deleobuvir (BI207127)
BMS-791325
TMC647055

Palm I
Setrobuvir
ABT-333
ABT-072

A

...
HCV NNI Resistance Mutations
95
142

Thumb

A

C

495

499
496

423
419

411

96

451
448

316
365
201

Palm
D

(courtesy ...
NS5A Protein
 Required for HCV RNA
replication

NS5A Dimer
Domain III
Domain II
Domain I
Cytosol

 Required for HCV vira...
NS5A Inhibitors
Phase

Dose

Duration

Median/mean log
HCV RNA reduction

Daclatasvir (BMS)

III

10 mg qd

1 day

-3.2

L...
NS5A Inhibitor Resistance
Effect of NS5A Domain I Mutations on
Replication and Daclatasvir Potency
Mutation

Fold Resistan...
Replicon EC90 (nM)

MK-8742 Resistance Profile
100
10
1
0.1
0.01
0.001
GS-5885
Daclatasver
MK-8742

MK-8742
(Merck, unpubl...
nd-Generation
2

GS-5816, a
NS5A Inhibitor

(Gilead, data on file)
Cyclophilins

Cyclophilin A
Antiviral Efficacy of
Cyclophylin Inhibitors
Phase

Dose

Duration

Median/mean
log HCV RNA
reduction

Alisporivir (DEBIO-...
Alisporivir Resistance in vitro
HCV

EMCV

neo

5’UTR
IRES

NS3
A
A

IRES

36

213

NS5A

250

Domain I

A241P

NS4
B

342...
III
Treatment Failure with the
Triple Combination of PegIFN, Ribavirin and a DAA
Treatment failure on telaprevir
or boceprevir triple combo
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
...
Treatment Failures on Triple
Combination with a DAA
• Due to an inadequate response to PegIFN and ribavirin
• Results in ...
SVR According to Lead-in
(SPRINT-2, non-black)
100

% of patients with SVR

90

82%

82%

80
70

60

<1 log HCV RNA
decrea...
REALIZE
Patients With Undetectable HCV
RNA (%)

Rx-experienced, Gen 1, Telaprevir
100

94%

<1 log decrease

82%

≥1 log d...
Probability of TelaprevirResistant Variant Detection
1.0

0.9

Median time to wild-type by population
sequencing =7 months...
Post-Failure Follow-up
(Boceprevir)
Genotype 1a

Genotype 1b
100%

90%

% Variant viral résistant détecté

% resistant vir...
Practical Recommendations

• Prior to therapy:
• All patients should be considered as harboring minor viral
populations th...
Practical Recommendations
• In case of treatment failure:
• Protease inhibitor-resistant viral populations have been
enric...
Treatment failure on
simeprevir triple combo
P + R + Simeprevir-QUEST-1/2
Phase III, Treatment-naive, Gen 1
Simeprevir + PR
(RGT 12+12)

100
90

SVR24 rate (%)

80

Pl...
P + R + Simeprevir-QUEST-1/2
Role of HCV subtype and Q80K substitution

*Q80K prevalence in 1500 clinical specimens sent t...
Summary of Simeprevir
Resistance Data
• Baseline Q80K polymorphism
• Present in 41% of patients with genotype 1a infection...
Treatment failure on
sofosbuvir triple combo
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...
Sofosbuvir Resistance in
Phase III Trials
• S282T identified as primary mutation in
all replicon genotypes (1–6)
• No geno...
IV
HCV Resistance in All-oral,
IFN-free regimens
Principles
Barrier to Resistance
Low-barrier drug

High-barrier drug
Barrier to Resistance
• Low barrier to resistance
• First-generation protease inhibitors
• Non-nucleoside inhibitors of Rd...
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...
Danoprevir (PI) + Mericitabine (NI)
INFORM-1 Trial
Increasing doses of danoprevir and RG7128

Days

(Gane et al., Lancet 2...
Daclatasvir (NS5A)/Asunaprevir (PI)
HCV Genotype 1b

(Suzuki et al., EASL 2012)
IFN-free treatment failures
IFN-Free Combination Options
NI

PI

NS5A

NNI

RBV

Ledipasvir

GS-9669

±

Nucleos(t)ide analogue-based strategies
Gilea...
Sofosbuvir + RBV in Gen 2
Phase III, 12 weeks, cirrhosis vs no cirrhosis
100

97%
83%

90

90%

92%
78%

SVR12 rate (%)

8...
Sofosbuvir + RBV in Gen 3
Phase III, Treatment-experienced
FUSION (12 wk)

100

FUSION (16 wk)

VALENCE (24 wk)

85

63

6...
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...
Sofosbuvir/Ledipasvir FDC ± RBV
Relapse Pt with multidrug resistance
NS5B: No RAVs
NS5A: L31M (25.5%)

HCV RNA (log10 IU/m...
IFN-Free Combination Options
NI

PI

NS5A

NNI

RBV

Ledipasvir

GS-9669

±

Nucleos(t)ide analogue-based strategies
Gilea...
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...
IFN-Free Combination Options
NI

PI

NS5A

NNI

RBV

Ledipasvir

GS-9669

±

Nucleos(t)ide analogue-based strategies
Gilea...
MK-5172 (2nd-gen PI) + MK-8742 (2nd-gen NS5A)
C-WORTHY, Gen 1, Rx-naive, noncirrhotic, 12 wks
100

96%

90

100%
89%

SVR1...
Conclusions
• In the real life, 5-15% of patients receiving alloral, IFN-free regimens may fail to eradicate
HCV
• In most...
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Transcript of "Pawlotsky jm résist tt hcv 2014"

  1. 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. 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. 3. I IFN--Ribavirine TreatmentFailure
  4. 4. Treatment Schedule Host Factors Treatment Failure Disease Characteristics Viral Factors
  5. 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. 6. SNP and SVR in the IDEAL Trial IL28B (Ge et al, Nature, 2009;461:399-401)
  7. 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. 8. Geographic Distribution (Thomas et al, Nature, 2009;461:798-801)
  9. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 19. II HCV resistance to DAAs
  20. 20. HCV Quasispecies Major viral population Intermediate viral populations Minor viral populations
  21. 21. Mechanisms of resistance
  22. 22. Mechanisms of Resistance sensitive resistant
  23. 23. Mechanisms of Resistance Drug sensitive resistant
  24. 24. Mechanisms of Resistance Drug sensitive sensitive resistant resistant
  25. 25. Mechanisms of Resistance Drug Stop drug sensitive sensitive resistant resistant
  26. 26. Mechanisms of Resistance Drug Stop drug sensitive sensitive resistant sensitive resistant resistant
  27. 27. Mechanisms of Resistance Drug Stop drug sensitive sensitive sensitive resistant resistant resistant + fit
  28. 28. Mechanisms of Resistance Drug Stop drug sensitive sensitive resistant resistant + very fit sensitive resistant
  29. 29. Chronic HCV infection is curable by therapy
  30. 30. Mechanisms of Resistance sensitive resistant
  31. 31. Mechanisms of Resistance Drug sensitive resistant resistant
  32. 32. Mechanisms of Resistance Drug Stop drug sensitive resistant resistant resistant
  33. 33. HCV resistance to DAAs
  34. 34. HCV Life Cycle (Popescu & Dubuisson, Biol Cell 2009;102:63-74)
  35. 35. Barrier to Resistance Low-barrier drug High-barrier drug
  36. 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. 37. NS3/4A Protease Inhibitors (Raney et al., J Biol Chem 2010:285:22725-31)
  38. 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. 39. Amino Acid Substitutions Associated with PI Resistance Asp168 Arg155 Ala156 Thr54 Val36 (Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219)
  40. 40. MK-5172 and Boceprevir Resistance-Associated Variants (Lahser et al., AASLD 2012)
  41. 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. 42. Nucleoside/Nucleotide Analogue Inhibitors of HCV RdRp Catalytic Site
  43. 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. 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. 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. 46. Non-Nucleoside Inhibitors (NNI) Thumb I Palm I A B C D Thumb II Palm II
  47. 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. 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. 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. 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. 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. 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. 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. 54. nd-Generation 2 GS-5816, a NS5A Inhibitor (Gilead, data on file)
  55. 55. Cyclophilins Cyclophilin A
  56. 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. 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. 58. III Treatment Failure with the Triple Combination of PegIFN, Ribavirin and a DAA
  59. 59. Treatment failure on telaprevir or boceprevir triple combo
  60. 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. 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. 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. 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. 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. 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. 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. 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. 68. Treatment failure on simeprevir triple combo
  69. 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. 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. 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. 72. Treatment failure on sofosbuvir triple combo
  73. 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. 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. 75. IV HCV Resistance in All-oral, IFN-free regimens
  76. 76. Principles
  77. 77. Barrier to Resistance Low-barrier drug High-barrier drug
  78. 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. 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. 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. 81. Daclatasvir (NS5A)/Asunaprevir (PI) HCV Genotype 1b (Suzuki et al., EASL 2012)
  82. 82. IFN-free treatment failures
  83. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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
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