NS5A Resistance: What we Know

and What we Think we Know

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

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

NS5A RAVs

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 Inhibitor Resistance Low barrier to resistance

(Lontok et al., Hepatology 2015;62:1623-32)

Prevalence of Baseline NS5A RAVs

Prevalence of NS5A RAVs

(Zeuzem et al., AASLD 2015)

Deep sequencing, 1% cutoff

Influence of Baseline RAVs on

IFN-Free Treatment Outcomes

92%

Any

RAV

N=318

97%

No

RAVs

N=1629

SVR According to Baseline NS5A RAVs ION-1/2/3- Sofosbuvir/Ledipasvir ± RBV

(Dvory-Sobol et al., International Workshop on Antiviral Drug Resistance, June 2014)

SV

R12 r

ate

(%

)

0

10

20

30

40

50

60

70

80

90

100

92%

Any

RAV

N=318

97%

No

RAVs

N=1629

SVR According to Baseline NS5A RAVs ION-1/2/3- Sofosbuvir/Ledipasvir ± RBV

(Dvory-Sobol et al., International Workshop on Antiviral Drug Resistance, June 2014)

97%

SV

R12 r

ate

(%

)

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=89 N=29 N=48

SVR to Sofosbuvir/Ledipasvir According

to NS5A RAVs (513 cirrhotic patients)

(Sarrazin et al., EASL 2015)

Influence of NS5A RAVs Sofosbuvir-Ledipasvir

0

20

40

60

80

100

SV

R12

(%

)

LDV/SOF 8 wk

TN <6M

With RAVs

98

No RAVs

99 99 99 90

99

LDV/SOF 12 wk

TN

LDV/SOF 12 wk

TE

30

32 107

108

187

189 504

509

79

88

298

300

(Zeuzem et al., AASLD 2015)

0

20

40

60

80

100

SV

R12

(%

)

LDV/SOF + RBV

12 weeks

89 96

87

100

LDV/SOF

24 weeks

59

66

206

214

13

15 84

84

No cirrhosis Cirrhosis

Grazoprevir + Elbasvir C-EDGE TN– Phase III, Rx-naïve, Gt 1, w/o cirrhosis, 12 weeks

89%

SV

R12 r

ate

(%

)

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; epub ahead of print)

0

20

40

60

80

100

SV

R12 (

%)

No Baseline NS5A RAVs

99% 100%

12 weeks RBV, 16 weeks

1% (5XRAV)

20% (5XRAV)

20% (Position 30, 31, 58)

NGS Sensitivity Threshold

98% 100% 99% 100%

307

311

45

45

326

331

50

50

330

335

51

51 0

20

40

60

80

100

SV

R12 (

%)

With Baseline NS5A RAVs

64%

100%

1% (5XRAV)

20% (5XRAV)

20% (Position 30, 31, 58)

NGS Sensitivity Threshold

38%

100%

25%

100%

28

44

9

9

9

24

4

4

5

20

3

3

Influence of NS5A RAVs Grazoprevir-Elbasvir

(Jacobson et al., AASLD 2015)

Selection of RAVs in Patients

who Fail to Achieve an SVR

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)

Post-treatment RAV Persistence

in Patients who Fail to Achieve an SVR

(Lenz et al., EASL 2014)

Replacement of PI-Resistant

Viruses by Wild-Type Viruses

Persistence of RAVs in Patients

who Failed after LDV (no SOF)

98% 100% 98% 100% 95%

82%

0

20

40

60

80

100

VFParentStudy

Baseline FU-12 FU-24 FU-48 FU-96

Pa

tie

nts

Wit

h N

S5

A R

AV

s (

%)

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

Pre

vale

nce o

f R

AV

s (

%)

0

10

20

30

40

50

60

70

80

90

100

N=70 N=44 N=35 N=51 N=67 N=57

46%

9%

97% 96%

75%

57%

Retreatment of Patients with Persistent

RAVs after IFN-free regimen failure

Retreatment of Patients who Failed 8 or 12

Weeks of LDV/SOF with LDV/SOF 24 Weeks

(Lawitz et al., EASL 2015)

Cirrhosis

SV

R12 r

ate

(%

)

0

10

20

30

40

50

60

70

80

90

100

68%

74% 80%

46%

100%

60%

No Yes

Prior Rx duration

8 wks 12 wks

Baseline NS5A RAVs

No Yes

N=22 N=19 N=30 N=11 N=11 N=30

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)

(EASL Recommendations on Treatment of Hepatitis C 2015)

Retreatment Options

• Sofosbuvir + Daclatasvir + Simeprevir

• Sofosbuvir + 3D

• Sofosbuvir + Grazoprevir + Elbasvir

(AASLD 2015)

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

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@JMPawlotsky