Nezam H. Afdhal, MD, FRCPI Professor of Medicine Harvard Medical School Beth Israel Deaconess Medical Center Boston, Massachusetts HCV Alert: New Data

Nezam H. Afdhal, MD, FRCPIProfessor of MedicineHarvard Medical SchoolBeth Israel Deaconess Medical CenterBoston, Massachusetts

HCV Alert: New Data on Resistance to DAAs and Implications for Therapy

Jointly provided by the Annenberg Center for Health Sciences at Eisenhower and Clinical Care Options, LLC

This activity is supported by an independent educational grant from Janssen Therapeutics.

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clinicaloptions.com/hepatitisHCV Alert: New Data on Resistance to DAAs and Implications for Therapy

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 viralvariant 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]

Wild

Typ

e

L419

M

M42

3T

I482

LL4

19M

/M42

3T

S28

2T

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 virusResistant 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

R12

(%

)

100

80

60

40

20

0

97 95 96

112/115

38/40

44/46

68/70n/N =

Naive Exp’d

Treatment History

HCV GT

1a + Q80K

1a no Q80K

97

150/155

All pts

88

7974

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

0n/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 DAAsAASLD/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 + RBVLDV/SOF LDV/SOF

SV

R12

(%

)

100

80

60

40

20

0

93 94 96 97 1009898100

Failure of pegIFN/RBV

Failure of PI

Treatment History

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


ION-2: NS3 RAVs After Boceprevir or Telaprevir Respond to DAAs

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 + RBVLDV/SOF LDV/SOF

SV

R12

(%

)

100

80

60

40

20

0

93 94 96 97 1009898100

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

10083 95

10065

95 100 100 99

100 92 96100 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

R12

(%

)S

VR

12 (

%)

n/N =

n/N =

NS5A RAVS with > 100 x resistance No NS5A RAVs


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

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

98 100 98 10095

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 10093

89100

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.


92

100

91

0/1200/218

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

8894

0

92100

80

60

40

20

0

NS5A RAVs

M28V/T Q30R L31V

86 92

100

91100

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

R24

(%

)

SV

R24

(%

)

SV

R24

(%

)

Without RAV


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 6874

15/22

14/19

No Yes8 Wks 12 Wks

Cirrhosis BL NS5A RAVs

80

46

60

100

24/30

5/11

11/11

18/30n/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.


Summary

Baseline RAVs (especially NS5A) are present in treatment-naive pts

Treatment-emergent RAVs (including multidrug-resistant RAVs) seen in treatment failure and in all DAA classes and rarely with SOF

NS3 RAVs have low replication efficacy and disappear over 9-18 mos

– If considering SMV + SOF: In treatment-naive and treatment-experienced pts with both genotype 1a HCV infection and compensated cirrhosis, ensure no Q80K

NS5A treatment-emergent RAVs persistent and a clinical challenge

– If failure with any NS5A inhibitors (including DCV + SOF, LDV/SOF, OMV/PTV/RTV + DSV), and treatment is urgent, test for NS3 and NS5A RAVs

– Use SMV + SOF + RBV if NS5A but no NS3 RAVs

– Use LDV/SOF + RBV if no NS5A RAVs

– Treat in clinical trial if both NS5A and NS3 RAVs present

Resistance testing may be of benefit in treatment failures

Documents

Nezam H. Afdhal, MD, FRCPI Professor of Medicine Harvard Medical School Beth Israel Deaconess Medical Center Boston, Massachusetts HCV Alert: New Data