Resistance to DAA’s before and after treatment

Douglas T. Dieterich, M.D

Professor of Medicine Division of Liver Diseases,

Icahn School of Medicine at Mount Sinai

Disclosure

• Dr Dieterich has served as a consultant or scientific advisor for AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Idenix Pharmaceuticals, Inc, Merck & Co, Inc, and Janssen Therapeutics. He has received grants or research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Inc, Merck & Co, Inc, and Janssen Therapeutics (Updated 02/17/14)

Do you think DAA resistance is important to know about now?

• I have a pt w harvoni failure.

• Q80k positive (although seems SIM resistance is not predicted) and q30h y93h also positive.

• Can only think to give peg riba sovaldi or sovaldi riba unless you have any clinical trials w daa. I could ask for sim sof but the argument may be muted since recent guidelines suggest that patients with both NS5,3 ravs be referred to clinical trials.

• She is child A. Really appreciate any help she can get.

Virologic Barriers to Resistance

Genetic barrier Number and type of nucleotide changes required for a virus to

acquire resistance to an antiviral regimen[1]

Viral fitness Relative capacity of a viral

variant to replicate in a given environment

1. Rong L, et al. Sci Transl Med. 2010;2:30ra32. 2. Le Pogam S et al. J Virol.

2006;80:6146-6154. 3. Le Pogam S, et al. J Infect Dis. 2010;202:1510-1519

Fitness of Polymerase Inhibitor Mutants[2,3]

1

.75

.5

.25

0

% F

itn

ess

Resistant Variants Are Present Before and

Can Be Selected During Treatment • HCV is a mixture of related but distinct populations of virions in each

pt[1]

• Most resistant variants are unfit and may be undetectable prior to therapy[2,3]

1. Pawlotsky JM. Clin Liver Dis. 2003;7:45-66. 2. Kuntzen T, et al. Hepatology. 2008;48:1769-1778.

3. Bartels DJ, et al. J Infect Dis. 2008;198:800-807. Image reproduced and adapted with permission

from Forum for Collaborative HIV Research. www.hivforum.org

Antiviral therapy eliminates

sensitive variants Resistant variants expand

Sensitive

virus

Resistant

virus

Antiviral

therapy

HCV NS3/4A Protease Resistance

Lenz O, et al. Antimicrob Agents Chemother. 2010;54:1878-1887. Reproduced with permission from

American Society for Microbiology. doi:10.1128/AAC.01452-09 Copyright © 2010, American Society

for Microbiology. All Rights Reserved.

Q80

R155

D168

A156

F43

Naive Exp’d 1a + Q80K

1a no Q80K

All pts

97

Impact of Treatment Exp, Q80K Depends on

Cirrhosis (12 Wks’ SMV + SOF in GT1)

1. Kwo P, et al. EASL 2015. Abstract LP14. 2. Lawitz E, et al. EASL 2015. Abstract LP04.

SV

R1

2 (

%)

100

80

60

40

20

0

97 95 96

112/

115

38/

40

44/

46

68/

70 n/N =

Naive Exp’d

Treatment History

HCV GT

1a + Q80K

1a no Q80K

97

150/

155

All pts

88

79 74

92

44/

50

42/

53

25/

34

35/

38

Treatment History

HCV GT

83

86/

103

No Cirrhosis (OPTIMIST-1[1]) Cirrhosis (OPTIMIST-2[2])

100

80

60

40

20

0

n/N =

OPTIMIST-2: Resistance Analysis in GT1

Cirrhotics in Whom SMV + SOF Failed

• Treatment-emergent NS3 mutations detected in 79% (11/14) of evaluable pts who did not achieve SVR12

– Observed at position 168, R155K, or combinations

• NS5B polymorphism S282T not detected at baseline or at time of treatment failure

• No NS3 baseline polymorphisms observed aside from Q80K

Lawitz E, et al. EASL 2015. Abstract LP04.

AASLD/IDSA Guidance for Resistance

Testing When Considering SMV + SOF

In pts with both genotype 1a HCV infection and compensated cirrhosis, if considering SMV + SOF, test for Q80K polymorphism – If Q80K variant is present, consider a regimen other

than SMV + SOF

Applies to treatment-naive and treatment-experienced pts

Q80K testing not required for: – Pts with genotype 1b HCV infection – Pts without cirrhosis – Pts in whom you are considering other DAAs

AASLD/IDSA/IAS-USA. HCV Guidance.

ION-2: DAAs Effective Against NS3

RAVs After Boceprevir or Telaprevir

• Virologic failure: 1 breakthrough in 24-wk LDV/SOF + RBV due to nonadherence; 11 relapses (7 in

12-wk LDV/SOF, 4 in 12-wk LDV/SOF + RBV)

• 14% of pts had NS5A RAVs at baseline; 89% of these achieved SVR12; 71% of pts had NS3 RAVs

at baseline; 98% of these achieved SVR12

40/ 43

62/ 66

45/ 47

62/ 64

58/ 58

49/ 50

58/ 59

51/ 51

12 Wks 24 Wks

LDV/SOF + RBV LDV/SOF + RBV LDV/SOF LDV/SOF

SV

R12 (

%)

100

80

60

40

20

0

93 94 96 97 100 98 98 100

Failure of pegIFN/RBV

Failure of PI

Treatment History

Afdhal N, et al. N Engl J Med. 2014;370:1483-1493.

Fold-Change in EC50 Genotype 1a Genotype 1b

Position M28T Q30R L31M/V Y93H/N L31V Y93H/N

FDA approved

Daclatasvir[1,3] > 100 x > 1000 x > 100 x > 1000 x < 10 x < 100 x

Ledipasvir[1] 20 x > 100 x > 100 x > 1000 x > 1000 x/?

Ombitasvir[2] > 1000 x > 100 x < 3 x

> 10,000 x < 10 x < 100 x > 100 x

1. Cheng G, et al. EASL 2012. Abstract 1172. 2. Krishnan P, et al. Antimicrob Agents Chemother. 2015;59:979-987. 3. Yang G, et al. EASL 2013. Abstract 1199. 4. Ng T, et al. CROI 2014. Abstract 639.

Resistance Analysis of Select NS5A

Inhibitors in Genotype 1 HCV

> 100 x 3 to 100 x < 3 x

NS5A RAVS with < 100 x resistance

Sarrazin C. AASLD 2014. Abstract 1926.

Impact of Duration of LDV/SOF on SVR12 in

Pts With Baseline NS5A Resistance

100

80

60

40

20

0

100

80

60

40

20

0

100 83 95

100

65 95 100 100 99

100 92 96 100 96 97

12/

12

24/

29

184/

193

110/

116

11/

17

5/

5

27/

27

44/

46

362/

373

95/

96

6/

6

7/

7

8/

8

24/

25

174/

183

8 Wks 12 Wks 24 Wks

Treatment Naive

Treatment Experienced

12 Wks 24 Wks

SV

R1

2 (

%)

SV

R1

2 (

%)

n/N =

n/N =

NS5A RAVS with > 100 x resistance No NS5A RAVs

ALLY-1: Multicenter, Open-Label Phase 3 Study

18 a HCV RNA < lower limit of assay quantitation (LLOQ) at posttreatment Week 12 by Roche HCV COBAS TaqMan Test v2.0 (LLOQ 25 IU/mL).

Follow-up

DCV 60 mg QD + SOF 400 mg QD + RBV

Week 0 Week 24 SVR12a

Week 36

DCV 60 mg QD + SOF 400 mg QD + RBV

Week 12

Advanced cirrhosis N = 60

Post-liver transplant N = 53

• Primary endpoint: SVR12 in GT1 in each cohort

• 12 weeks of treatment: DCV 60 mg + SOF 400 mg + RBV – RBV initially 600 mg/day, adjusted to 1000 mg/day based on Hgb levels and CrCl

• Advanced cirrhosis patients with treatment interrupted by liver transplantation could receive an additional 12 weeks of treatment immediately post-transplant

SVR12 by Cohort

19 a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals.

82 95

0

20

40

60

80

100

SVR

12

, %a

Post-transplant Advanced cirrhosis

SVR12 by Cohort

83 94

0

20

40

60

80

100

Post-transplant Advanced cirrhosis

All Patients GT 1 (Primary Endpoint)

■ In a regression analysis, no difference by gender, age, IL28B, or HCV RNA

in the advanced cirrhosis cohort with GT 1

Baseline resistance polymorphisms

• NS5A-28, -30, -31, or -93 polymorphisms detected in 22 of 112 patients – 82% (18/22) achieved SVR12

• 10/14 in cirrhosis cohort; 8/8 in post-transplant cohort

– 90% (81/90) without NS5A polymorphisms achieved SVR12 • 39/45 in cirrhosis cohort; 42/45 in post-transplant cohort

• No NS5B-S282 variants detected at baseline or failure

NS5A resistance-associated variants in patients with virologic failure

20

Resistance Analyses

Advanced cirrhosis Post-transplant

Virologic failures, N 10 3

NS5A RAVs at baseline, n/Na 4/10 0/3

NS5A RAVs at failure, n/Na 10/10 3/3 a Assessed by population-based sequencing.

92

100

91

0/1

200/

218

AVIATOR: No Impact of Baseline RAVs in

GT1a Pts Treated With OMV/PTV/RTV + DSV • Treatment naive pts or null responders to previous pegIFN/RBV

• All differences in SVR24 with vs without baseline RAVs were nonsignificant

Krishnan P, et al. Antimicrob Agents Chemother. 2015;59:5445-5454.

100

80

60

40

20

0

NS3 RAVs

Q80K D168

88 94

0

92 100

80

60

40

20

0

NS5A RAVs

M28V/T Q30R L31V

86 92

100

91 100

80

60

40

20

0

NS5B RAVs

S556G C316Y

100

50

93

With RAV

n/N = n/N = n/N = 12/

14

3/

3

1/

1

192/

209

201/

220

203/

222

7/

7

1/

2

220/

239

226/

244

Y93C/N/H

80

92

4/

5

200/

218

78/

89

122/

130

SV

R2

4 (

%)

SV

R2

4 (

%)

SV

R2

4 (

%)

Without RAV

Durability of Treatment-Emergent NS5A

RAVs After Virologic Failure

• Study of pts not achieving SVR after receiving LDV without SOF

• NS5A RAVs persisted in majority of pts for 96 wks

100

80

60

40

20

0 VF Baseline FU-12 FU-24 FU-48 FU-96

98 100 98 100 95

86

Pts

Wit

h N

S5A

RA

Vs

(%)

Registry Study

62/

63

58/

58

42/

43

45/

45

52/

55

50/

58 n/N =

Dvory-Sobol H, et al. EASL 2015. Abstract O059.

Pooled Analysis: RAV Persistence After

Failure of PTV/RTV-, OMV-, DSV-Based Tx

100

80

60

40

20

0

PTV-Containing Regimens

Any D168 R155K

46

9

38

77

29

4

100

80

60

40

20

0

OMV-Containing Regimens

Any M28V/T Q30E/K/R

97 96 97 100

93 89

100

80

60

40

20

0

DSV-Containing Regimens

Any S556G

75

90

57

77

Follow-up Wk 24 Follow-up Wk 48

n/N = n/N = n/N = 31/

67 5/57 21/

55 2/53

10/

13 2/7

68/

70 32/

33

38/

41

49/

51 21/

21

25/

28

33/

44 27/

30

20/

35 17/

22

RA

Vs

(%

)

RA

Vs

(%

)

RA

Vs

(%

)

NS3/4A Position NS5A Position NS5B Position

Krishnan P. EASL 2015. Abstract O057.

Wyles DL, et al. Hepatology. 2015;61:1793-1797.

GT1 HCV with

previous SOF

failure

(29% cirrhotic)*

(N = 51)

LDV/SOF + RBV

12 Wks

*25 pts (49%) were previously treated with SOF + pegIFN/RBV, 21 (41%) with SOF ± RBV, 5 (10%) with

SOF placebo plus pegIFN/RBV or GS-0938 monotherapy, 1 (2%) with SOF monotherapy. †1 pt who relapsed found to have GT3a HCV infection and enrolled in error.

SVR12, %

98†

LDV/SOF + RBV in GT 1 HCV Pts With

Previous Failure on Sofosbuvir

Regimens

• Phase II trial

• GT1 HCV–infected pts with and without cirrhosis previously treated with 8 or 12 wks of LDV/SOF ± RBV or LDV/SOF + GS-966

24 Wks of LDV/SOF Retreatment After

Failure of 8-12 Wks of LDV/SOF-Based Tx

Lawitz E, et al. EASL 2015. Abstract O005.

Previous Tx Duration

100

80

60

40

20

0

SV

R12 (

%)

All No Yes

71 68 74

15/ 22

14/ 19

No Yes 8 Wks 12 Wks

Cirrhosis BL NS5A RAVs

80

46

60

100

24/ 30

5/ 11

11/ 11

18/ 30 n/N =

29/ 41

24 Wks of LDV/SOF After Failure of LDV/

SOF-Based Tx: Effect of Baseline RAVs

NS5B variants emerged during retreatment in 33% of pts (4/12)

with virologic failure – S282T: n = 2; L159F: n = 1; S282T + L159F: n = 1

Lawitz E, et al. EASL 2015. Abstract O005.

SVR12 by Baseline NS5A RAVs, n/N (%) LDV/SOF for 24 Wks

Number of RAVs

0 11/11 (100)

1 11/16 (69)

≥ 2 7/14 (50)

Single NS5A RAV

Q30R or M28T 5/5 (100)

L31M 4/5 (80)

Y93H/N 2/6 (33)

GT1 Pts With NS5A Failure: Who Needs

Resistance Testing?

If previous failure of any NS5A inhibitors (including DCV + SOF, LDV/SOF, OMV/PTV/RTV + DSV) and minimal liver disease, deferral preferred pending further data

– If cirrhosis or other need for urgent treatment, test for NS3 and NS5A RAVs

Applies to genotype 1a and 1b HCV infection

NS3 and NS5A testing not required for:

– Previous failure of NS3/4A PIs (including simeprevir, boceprevir, telaprevir)

– Previous failure of NS5B inhibitors (sofosbuvir)

– Tx-naive pts (unless considering SMV + SOF in cirrhotic GT1a)

AASLD/IDSA/IAS-USA. HCV Guidance.

Selecting Treatment Based on

Resistance Testing Results

• If genotype 1a or 1b HCV infection and previous

failure with any NS5A inhibitors and cirrhotic or other

need for urgent treatment:

AASLD/IDSA/IAS-USA. HCV Guidance.

RAV Testing Result Retreatment Regimen Duration

No NS5A RAVs Ledipasvir/sofosbuvir + ribavirin 24 wks

NS5A but no NS3 RAVs Simeprevir + sofosbuvir + ribavirin 24 wks

NS5A and NS3 RAVs Retreatment in a clinical trial setting

Is Ribavirin Required for Pts With

Cirrhosis?

• Integrated analysis of > 500 pts with cirrhosis treated with LDV/SOF ±

RBV

• Treatment-experienced pts had previously received HCV PI

• Although NS5A resistance not measured, RBV overcomes shorter

treatment duration in patients with HCV cirrhosis and prior treatment

failure

SVR12, % Total

(N = 513)

Treatment Naive

(n = 161)

Treatment Experienced

(n = 352)

Overall 96 98 95

12 wks ± RBV 95 97 94

24 wks ± RBV 98 99 98

Without RBV 95 96 95

With RBV 97 99 96

12 wks without RBV 92 96 90

12 wks with RBV 96 98 96

24 wks without RBV 98 97 98

24 wks with RBV 100 100 100

Reddy KR, et al. Hepatology. 2015;62:79-86.

Is Ribavirin Required for Pts With

Cirrhosis and NS5A RAVs?

• Integrated analysis of > 500 pts with

cirrhosis treated with LDV/SOF ± RBV

• Treatment experienced patients had

previously received HCV PI SVR12, % (n/N)18 With NS5A RAVs Without NS5A RAVs

Overall 91 (86/94) 98 (407/417)

12 wks without RBV 88 (23/26) 95 (86/91)

12 wks with RBV 94 (32/34) 97 (164/169)

24 wks without RBV 85 (17/20) 100 (113/113)

24 wks with RBV 100 (14/14) 100 (44/44)

Reddy KR, et al. Hepatology. 2015;62:79-86.

Personal Recommendations for Resistance

in GT3 and GT4 HCV Infection

• Genotype 3

– Treatment failures on daclatasvir should be tested for NS5A RAVs

– BOSON: Adding pegIFN to SOF/RBV appears to help overcome virologic failure due to resistance in GT3[1]

• Improved SVR12 vs SOF/RBV alone in both treatment-naive and treatment-experienced pts, with or without cirrhosis

• Genotype 4

– Resistance testing should be performed if considering retreatment after LDV/SOF failure

– Use SMV/SOF/RBV for NS5A RAVs

1. Foster GR, et al. EASL 2015. Abstract LO5.

CONCLUSIONS • Approved treatments work extremely well (96%)

• There are some patients who fail however

• Resistance to NS5A inhibitors, both baseline and acquired is becoming more important

• Resistance testing is recommended after failure of any NS5A containing regimen

• In addition, repeat Genotyping should be done to make sure that you treated the correct genotype or that there are not multiple or recombinant genotypes.