Hépatite C: Résistanceaux Traitements

Prof. Jean-Michel Pawlotsky

CNR des Hépatites B, C et deltaLaboratoire de Virologie & INSERM U635

Hôpital Henri MondorUniversité Paris XII

Créteil

HCV Resistance

• IFN--ribavirin treatment failure

• HCV resistance to DAAs

• Treatment Failure with the combination of Peg-IFNa, ribavirin and a DAA

• HCV Resistance in All-oral, IFN-free regimens

I

IFN--Ribavirine TreatmentFailure

Viral FactorsDisease

Characteristics

HostFactors

TreatmentSchedule

TreatmentFailure

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 ofcommon genetic

variation

SNP associationBioinformatics to process data and

associate genotype with

phenotype

SNP and SVR in the IDEAL Trial

IL28B

(Ge et al, Nature, 2009;461:399-401)

SVR in the IDEAL Trial Accordingto SNP rs12979860 (genotype 1)

(Ge et al., Nature 2009;461:399-401)

0%

20%

40%

60%

80%

100%

TTN=186

CTN=559

CCN=392

Su

stai

ned

vir

olo

gic

al r

esp

on

se (

%)

Geographic Distribution

(Thomas et al, Nature, 2009;461:798-801)

Viral Kinetics According to to SNP rs12979860

-3.0

-2.0

-1.0

0

Weeks

Mea

n H

CV

RN

A D

ecre

ase

(Lo

g10 IU

/mL

)

-4.0

-5.0

2 4 120

-6.0

CTTT

CC

p < 0.001

(Thompson et al., Gastroenterology 2010:139;120-9)

VK on High-Dose Peg-IFNa According to IL28B Genotype

-6

-5

-4

-3

-2

-1

0

0 4 8 12 16 20 24

Weeks of therapyH

CV

RN

A r

edu

ctio

n (

Lo

g10

IU/m

L)

TT

CT

NS

P=0.045

P=0.021

P=0.004

P=0.0005

(Chevaliez S, et al., Gastroenterology 2011;141:119-127)

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)

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

Incidence of Peg-IFN-RibavirinTreatment Failures

2%

0

15

30

45

60 54%48%

58%

24%

16% 18%

Genotype 1 Genotypes 2/3

PEG-IFN-α2a+ribavirin (Fried et al)

PEG-IFN-α2a+ribavirin (Hadziyannis et al)

PEG-IFN-α2b+ribavirin (Manns et al)

(Manns et al, Lancet 2001 ; Fried et al, N Engl J Med 2002 ; Hadziyannis et al, Ann Intern Med 2004)

HCV Kinetics by GenotypeEC-sponsored DITTO-Trial

(Pawlotsky et al., manuscript in preparation)

0

1

2

3

4

5

6

7 HCV RNA (log IU/ml)

0 4 7 8 15 22 291-7-28

Genotype 4

Genotype 1

Genotype 3

* = significant difference, 4 and 1 vs 3

*

*

**

* **

Quantitative assay cutoff

Qualitative assay cutoff

HCV Kinetics by GenotypeEC-sponsored DITTO-Trial

0

1

2

3

4

5

6

7 HCV RNA (log IU/ml)

0 4 7 8 15 22 291-7-28

Genotype 4

Genotype 1

Genotype 3

* = significant difference, 4 and 1 vs 3

*

*

**

* **

Quantitative assay cutoff

Qualitative assay cutoff

(Pawlotsky et al., manuscript in preparation)

HCV Kinetics by GenotypeEC-sponsored DITTO-Trial

0

1

2

3

4

5

6

7 HCV RNA (log IU/ml)

0 4 7 8 15 22 291-7-28

Genotype 4

Genotype 1

Genotype 3

* = significant difference, 4 and 1 vs 3

*

*

**

* **

Quantitative assay cutoff

Qualitative assay cutoff

(Pawlotsky et al., manuscript in preparation)

HCV Kinetics by GenotypeEC-sponsored DITTO-Trial

0

1

2

3

4

5

6

7 HCV RNA (log IU/ml)

0 4 7 8 15 22 291-7-28

Genotype 4

Genotype 1

Genotype 3

* = significant difference, 4 and 1 vs 3

*

*

**

* **

Quantitative assay cutoff

Qualitative assay cutoff

(Pawlotsky et al., manuscript in preparation)

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

II

HCV resistance to DAAs

HCV Quasispecies

Major viral population

Intermediate viral populations

Minor viral populations

Mechanisms of resistance

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

sensitive

resistant + fit

Drug Stop drug

resistant

Mechanisms of Resistance

sensitive

sensitive

resistant

Drug Stop drug

resistant

Mechanisms of Resistance

sensitive

resistant + very fit

sensitive

Chronic HCV infection is curable

by therapy

sensitive

resistant

Mechanisms of Resistance

sensitive

resistant

Drug

resistant

Mechanisms of Resistance

sensitive

resistant

Drug Stop drug

resistant

Mechanisms of Resistance

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 inhibitors

of RdRp•Non-nucleoside inhibitors of RdRp (NNIs)•NS5A inhibitors•Cyclophylin inhibitors

NS3/4A Protease Inhibitors

(Raney et al., J Biol Chem 2010:285:22725-31)

NS3/4A Protease Inhibitors

Drug Phase Dose DurationMedian/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

Vaniprevir (Merck) 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

Asp168

Ala156

Arg155

Thr54

Val36

(Pawlotsky J-M, Ther Adv Gastroenterol 2009;2: 205-219)

Amino Acid Substitutions Associated with PI Resistance

MK-5172 and Boceprevir Resistance-Associated Variants

(Lahser et al., AASLD 2012)

MK-5172 Resistance Profile

1a W

T

1a_V

36M

1a_R

155K

1a_T

54S

1a_A

156S

1a D

168A

1a_V

36M

_R15

5K

1a_T

54S_R

155K

1a R

155K

/D16

8N

1b W

T

1b A

156S

1b A

156T

1b D

168Y

0.1

1.0

10.0

100.0

1000.0

10000.0

MK-5172BMS-032

simeprevirGS-9551

boceprevirtelaprevir

MK-5172 BMS-032 simeprevir GS-9551 boceprevir telaprevir

Re

plic

on

EC

90

(n

M)

(Lahser et al., AASLD 2012)

CatalyticSite

Nucleoside/Nucleotide Analogue Inhibitors of HCV RdRp

Drug Phase Dose DurationMedian/mean logHCV 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

Nucleoside/Nucleotide Analogue Inhibitors of HCV RdRp

2’C-Me-ATP in the catalytic site

(Migliaccio et al., J Biol Chem 2003;278:49164-70)

HCV Resistance to 2’-C-Methyl Nucleoside Inhibitors

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)

Non-Nucleoside Inhibitors (NNI)

Thumb I

Thumb II

Palm I

Palm II

A

BC

D

Non-Nucleoside Inhibitors of HCV RdRp (NNIs)

Drug Phase Dose DurationMedian/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

Non-Nucleoside Inhibitors (NNI)

Thumb IDeleobuvir (BI207127)

BMS-791325 TMC647055

Thumb IIFilibuvir

Lomibuvir (VX-222)GS-9669

Palm ISetrobuvirABT-333ABT-072

Palm IITegobuvir

A

BC

D

HCV NNI Resistance Mutations

(courtesy of Isabel Najera, Roche)

FingersThumb

Palm

A

B

C

D

NS5A Protein

Domain III

Domain II

Domain I

Required for HCV RNA replication

Required for HCV viral particle assembly

May be involved in the release of HCV particles

NS5A Dimer

ER membrane

Cytosol

ER lumen

NS5A Inhibitors

Drug Phase Dose DurationMedian/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

NS5A Inhibitor Resistance

Primary and secondary mutation sites

NS5A Dimer, Domain I

Mutation Fold Resistance Replication Level, %a

Wild-type 1 100

F28S 7735 125 49

L31M 141 83 37

C92R 98 10 8

Y93H 749 81 21

Effect of NS5A Domain I Mutations on Replication and Daclatasvir Potency

Means standard deviations from transient-transfection assays with luciferase reporter replicon.

(Fridell et al., Hepatology 2011;54:1924; Aghemo & De Francesco Hepatology 2013;58:428)

MK-8742 Resistance Profile

(Merck, unpublished data)

1a WT

1a_M28V

1a_Q30R

1a_L31V

1a_L31F

1a_Y93H

1a_Y93N

1b WT

1b_Y93H

1b_L31V

0.001

0.01

0.1

1

10

100

1000

MK-8742

Daclatasver

GS-5885

MK-8742 Daclatasver GS-5885

Rep

lico

n E

C90

(n

M)

GS-5816, a 2nd-GenerationNS5A Inhibitor

(Gilead, data on file)

Cyclophilins

Cyclophilin A

Antiviral Efficacy of Cyclophylin Inhibitors

Drug Phase Dose DurationMedian/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

Alisporivir Resistance in vitro

3’UTRNS3 NS4

A BNS5A

ANS5B5’UTR neo

HCV

IRES

EMCV

IRES

Domain I Domain II Domain III

36 213 250 342 356 447

R262Q R318WA241P D320E

A241P + R262Q

A241P + R318W

R262Q + R318W

R318W + D320E

A241P + R262Q + R318W

A241P + R262Q + R318W +

D320E

Fold-changevs wt

1.02 1.58 1.37 3.67 1.72 3.89

(Coelmont et al., EASL 2009)

III

Treatment Failure with the Triple Combination of Peg-IFNa, Ribavirin and a DAA

Treatment failure on telaprevir or boceprevir triple combo

Pre-existing HCV Resistant Variants by UDPS

PatientIL28B

genotype

HCV subtype

pegIFN

RBV

TVR

Response

V36A/M

T54A/S V55A Q80

R/KR155K/T/Q

A156S/T/V

D168A/V/T/H

I170A/T

Pt-1 CT 1a NR - 90.0% - - 0.1% 0.4% 0.1% 0.5%Pt-2 CT 1a NR - - - - 0.1% 1.1% - 0.2%Pt-3 CT 1b RR - - - - 0.5% 0.5% - 0.2%Pt-4 TT 1b RR - 29.4% - - - 1.3% - 0.1%Pt-5 CT 1a RR - - - - 0.1% 2.9% 0.1% -Pt-6 CT 1b RR 4.2% - - - 0.1% 0.1% 0.1% 0.1%Pt-7 CT 1a SVR - 11.1% - 0.7% - 0.3% - 0.3%Pt-8 CT 1a SVR - - - - 0.1% 0.5% 0.1% -Pt-9 CC 1a SVR - - - - 0.6% 1.8% - -

Pt-10 CC 1a SVR - - - - 0.6% - - 0.1%Pt-11 TT 1a RR - - 100.0% 0.1% 6.0% 3.2% 0.1% 0.3%Pt-12 CT 1b SVR - - - - - 0.3% - 0.1%Pt-13 CT 1b SVR - - - - 0.2% 0.2% - 0.8%Pt-14 TT 1b NR - - - - 0.1% 0.2% - 0.1%Pt-15 CT 1b SVR - - - - 0.4% 0.2% 0.1% 0.1%Pt-16 CT 1a SVR - - 1.3% 0.5% 7.8% 0.2% 0.1% 0.1%Pt-17 CT 1a SVR - 47.4% - - 0.1% 0.4% 0.1% 0.1%Pt-18 CT 1b SVR - 20.0% - - 0.1% 0.4% 0.1% 0.1%

*SNP rs12979860

(Chevaliez S., et al. EASL 2011)

SVR: sustained virological response; RR: response-relapse; NR: non-response

Treatment Failures on Triple Combination with a DAA

• Due to an inadequate response to Peg-IFN and ribavirin

• Results in uncontrolled outgrowth of resistant HCV variants selected by the protease inhibitor

(Pawlotsky JM. Hepatology 2011;53:1742-51)

SVR According to Lead-in (SPRINT-2, non-black)

29%

39%

82%

% o

f p

atie

nts

wit

h S

VR

0

10

20

30

40

50

60

70

80

90

100

BOC/RGT BOC/PR48

82%

<1 log HCV RNA decrease

≥1 log HCV RNAdecrease

(Poordad et al., N Engl J Med 2011;364:1185-206)

0

20

40

60

80

100

Pat

ien

ts W

ith

Un

det

ecta

ble

HC

V

RN

A (

%)

Priornull-response

Prior partialresponse

Priorrelapse

(Foster et al., EASL 2011)

REALIZERx-experienced, Gen 1, Telaprevir

62%

94%

56%59%

15%

54%

<1 log decrease

≥1 log decrease

Overall

33%

82%

Median time to wild-type by population sequencing =7 months (95% CI: 5-8)

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Pro

bab

ility

0 2 4 6 8 10 12 14 16 18

Time after treatment failure (months)

median

Probability of Telaprevir-Resistant Variant Detection

(Sullivan et al., EASL 2011)

Genotype 1b

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Time after treatment failure (years)

0   0.5   1   1.5   2

T54AT54SAll

Genotype 1a

% r

esis

tan

t vi

ral v

aria

nts

det

ecte

d

2

Time after treatment failure (years)

0.5 1 1.5       0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

V36M

T54SR155K

All

0

(Barnard et al., CROI 2011)

% V

aria

nt

vir

al r

ésis

tan

t d

étec

té

Post-Failure Follow-up (Boceprevir)

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

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)

Treatment failure on simeprevir triple combo

(Jacobson et al., EASL 2013; Manns et al., EASL 2013)

80%

50%

SV

R24

rat

e (%

)

0

10

20

30

40

50

60

70

80

90

100

QUEST-1 QUEST-2

N=264 N=130

81%

50%

N=257 N=134

Placebo + PRSimeprevir + PR(RGT 12+12)

P + R + Simeprevir-QUEST-1/2Phase III, Treatment-naive, Gen 1

(Jacobson et al., AASLD 2013; Choe et al., AASLD 2013; FDA AVDAC, Oct 24, 2013)

P + R + Simeprevir-QUEST-1/2Role 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%

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)

Treatment failure on sofosbuvir triple combo

89%

SV

R12

rat

e (%

)

0

10

20

30

40

50

60

70

80

90

100

Genotype 1(89%)

96%

100%

TOTAL

90%

P + R + Sofosbuvir-NEUTRINOPhase III, 12 weeks, Gen 1-4-5-6,

Treatment-naive

Genotype 5, 6(2%)

Genotype 4 (9%)

N=327 N=28N=292

(Lawitz et al., N Engl J Med 2013;368:1878-87)

N=7

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

IV

HCV Resistance in All-oral, IFN-free regimens

Principles

Barrier to Resistance

Low-barrier drug High-barrier drug

• 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

Barrier to Resistance

GS-9256 (PI) + Tegobuvir (NNI)

0 7 14 21 280

1

2

3

4

5

6

7

8

(<25 IU/mL)HC

V R

NA

IU

/mL

(L

og

)

Days

GS-9256 + tegobuvir

(Zeuzem et al., Hepatology 2012;55:749-58)

Danoprevir (PI) + Mericitabine (NI)INFORM-1 Trial

Days DaysDays

Danoprevir, 900 mg bid + RG7128Danoprevir, 900 mg bid + pegIFNand ribavirin Increasing doses of danoprevir and RG7128

(Gane et al., Lancet 2010;376:1467-757)

(Suzuki et al., EASL 2012)

Daclatasvir (NS5A)/Asunaprevir (PI)HCV Genotype 1b

IFN-free treatment failures

IFN-Free Combination OptionsNI PI NS5A NNI RBV

Nucleos(t)ide analogue-based strategies

Gilead Sofosbuvir Ledipasvir GS-9669 ±

Vertex/others VX-135 Simeprevir Daclatasvir ±

Roche Mericitabine 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 ±

12 wkCirrhosis

83%

N=12

SV

R12

rat

e (%

)

0

10

20

30

40

50

60

70

80

90

100

12 wkNo cirrhosis

97%

Sofosbuvir + RBV in Gen 2Phase III, 12 weeks, cirrhosis vs no cirrhosis

FISSION (Rx-naïve)

(FDA hearings, October 25, 2013)

N=61

92%

16 wk12 wk

90%

FUSION (Rx-experienced)

N=29 N=26

78%

16 wk12 wk

60%

N=10 N=9

No cirrhosis Cirrhosis

Sofosbuvir + RBV in Gen 3Phase III, Treatment-experienced

(Jacobson et al., N Engl J Med 2013;368:1867-77; Zeuzem et al., AASLD 2013; FDA hearings, October 25, 2013)

Series10

20

40

60

80

100

37

6385

19

6160

12 wks 16 wks 24 wks 12 wks 16 wks 24 wks

SV

R1

2, %

No cirrhosis Cirrhosis

FUSION (12 wk) FUSION (16 wk) VALENCE (24 wk)

N=38 N=40 N=100 N=26 N=23 N=45

96.4%

SV

R12

rat

e (%

)

0

10

20

30

40

50

60

70

80

90

100

SOF/LDV+RBV

99.1%

99.1%

SOF/LDV

93.6%

SOF/LDV+RBVSOF/LDV

12 weeks 24 weeks(Gilead press release, December 18, 2013)

N=109 N=111 N=109 N=111

Sofosbuvir/Ledipasvir FDC ± RBVION-2-Phase III, Gen 1, Rx-experienced, 20% cirrhosis

Sofosbuvir/Ledipasvir FDC ± RBVRelapse Pt with multidrug resistance

(Lawitz et al., AASLD 2013)

0

2

3

4

5

6

7

NS5B: No RAVsNS5A: L31M (25.5%)

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%)

LLOQ-TDLLOQ-TNDH

CV

RN

A (

log

10 IU

/mL

)

SOF/LDV 8 Weeks

Re-treatment:SOF/LDV + RBV

24 Weeks

Post-Treatment

Post-Treatment

SVR12

IFN-Free Combination OptionsNI PI NS5A NNI RBV

Nucleos(t)ide analogue-based strategies

Gilead Sofosbuvir Ledipasvir GS-9669 ±

Vertex/others VX-135 Simeprevir Daclatasvir ±

Roche Mericitabine 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 ±

96%

SV

R12

rat

e (%

)

0

10

20

30

40

50

60

70

80

90

100

All genotypes 1

95%

Subtype 1a

98%

Subtype 1b

ABT-450/r (PI) ± ABT-267 (NS5A) ± ABT-333 (NNI)SAPPHIRE I-Phase III, Genotype 1, Rx-naïve, N=631

(Abbvie press release, November 18, 2013)

IFN-Free Combination OptionsNI PI NS5A NNI RBV

Nucleos(t)ide analogue-based strategies

Gilead Sofosbuvir Ledipasvir GS-9669 ±

Vertex/others VX-135 Simeprevir Daclatasvir ±

Roche Mericitabine 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 ±

(Lawitz et al., EASL 2013)

MK-5172 (2nd-gen PI) + MK-8742 (2nd-gen NS5A)C-WORTHY, Gen 1, Rx-naive, noncirrhotic, 12 wks

5172+ 8742 20 mg

+ RBV

96%

SV

R12

rat

e (%

)

0

10

20

30

40

50

60

70

80

90

100

N=24

89%

N=27

100%

N=12

5172+ 8742 50 mg

+ RBV

5172+ 8742 50 mg

No RBV

Conclusions

• In the real life, 5-15% of patients receiving all-oral, 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