hcv resistance associated variants: impact on chronic...

HCV Resistance Associated variants: impact on chronic hepatitis C treatment

Dr. Stéphane Chevaliez Associate Professor of Medicine at the University of Paris-Est.

History of Resistance in HCV

• Concern Only Emerged With the Introduction of DAAs1-5

• IFN: Multiple antiviral targets preclude specific mutations in the HCV genome conferring resistance to it2,3

• RBV: Molecular mechanism of action unknown, major role in the prevention of relapse

• Treatment failure is due to host factors, disease characteristics, and viral factors

IFN/RBV-containing regimens

IFN alfa IFN alfa +

RBV pegIFN alfa +

RBV DAAs + pegIFN alfa + RBV or

DAAs only

1986 1998 2001 2011

• Target specific sites on the HCV molecule

• Selection of viral variants alters drug interactions with the target to confer resistance to the DAA2

First DAAs

DAA = direct-acting antiviral; IFN = interferon; PegIFN = pegylated interferon; RBV = ribavirin.

1. Sarrazin and Zeuzem. Gastroenterology. 2010;138:447; 2. Pawlotsky. Therap Adv Gastroenterol. 2009;2:205; 3. Chung et al. Hepatology. 2008;47:306; 4. Lau et al. Hepatology. 2002;35:1002.

NS5A Inhibitors5-8,14-16 • Daclatasvir

• Ledipasvir

• Ombitasvir

• ACH-3102

• GSK-805

• Elbasvir (MK-8742)

NS3/4 Protease Inhibitors1-13 • Boceprevir

• Telaprevir

• Simeprevir

• Asunaprevir

• Vaniprevir

• Paritaprevir

• Grazoprevir (MK-5172)

NS5B Polymerase Inhibitors17-24 • Sofosbuvir (nucleoside)

• MK-382 (nucleoside)

• Beclabuvir (NNI-1, thumb 1)

• Deleobuvir (NNI-1, thumb 1)

• VX222 (NNI-2, thumb 2)

• Setrobuvir (NNI-3, palm 1)

• Dasabuvir (NNI-1, palm 1)

Position V36

T54

V55

Q80

S122

R155

A156

V158

D168

M175

M28

Q30

L31

H58

Y93

S282

M414

L419

R422

M423

A421

P495

P496

V499

G554

D559

Drug-Resistant Variants Observed With All DAAs: Common RAVs in Non-SVR Patients in Clinical Trials

DAA = direct-acting antiviral; RAV = resistance-associated variant; SVR = sustained virologic response. 1. Boceprevir Prescribing Information; 2. Telaprevir Prescribing Information; 3. Lenz O, et al. Hepatology 2011 54 SUPPL. 1 (985A); 4. Lenz O, et al. Antiviral Therapy 2012 17 SUPPL. 1 (A28); 5. McPhee F, et al. Hepatology. 2013;58:902-911; 6. Lok AS, et al. N Engl J Med. 2012;366:216-224; 7. Chayama K, et al. Hepatology. 2012;55:742-748; 8. Karino Y, et al. J Hepatol. 2013;58:646-654; 8. Pasquinelli C, et al. Antimicrob Agents Chemother. 2012;56:1838-1844; 9. Barnard RJ, et al. Virology. 2013;443:278-284; 10. Lawitz E, et al. Antiviral Res. 2013;99:214-220; 11. Barnard R, et al. Journal of Hepatology 2013 58 SUPPL. 1 (S487); 12. Rodriguez-Torres M, et al. Journal of Hepatology 2013 58 SUPPL. 1 (S47); 13. Berger KL, et al. Antimicrob Agents Chemother. 2013;57:4928-4936; 14. Lawitz EJ, et al. Journal of Hepatology 2012 57:1 (24-31); 15.Wong K, et al. Hepatology International 2012 6:1 (200-201); 16. Yang G, et al. Journal of Hepatology 2013 58 SUPPL. 1 (S487-S488); 17. Dvory-Sobol H, et al. Journal of Hepatology 2013 58 SUPPL. 1 (S485); 18. Svarovskaia ES, et al. Hepatology 2012 56 SUPPL. 1 (551A); 19. Pockros PJ, et al. Hepatology. 2013;58:514-523; 20. Le Pogam S, et al. Antimicrob Agents Chemother. 2012 Nov;56(11):5494-502; 21. McPhee F, et al. Journal of Hepatology 2012 56 SUPPL. 2 (S473); 22. Larrey D, et al. Antimicrobial Agents and Chemotherapy 2013 57:10 (4727-4735); 23. Cote-Martin A, et al. Hepatology 2012 56 SUPPL. 1 (576A); 24. Lagace L, et al. Hepatology 2010 52 SUPPL. 1 (1205A-1206A).

■ Emergent DCV RAVs observed at N-terminus of NS5A

■ Fold change in EC50 value is genotype (subtype)-dependent

■ Resistance barrier is genotype-specific

– 2 amino acid substitutions are required to substantially increase resistance in GT-1b

In Vitro Resistance Profile of Daclatasvir

0

2000

4000

6000

8000

Fold

Ch

ange

in E

C5

0 V

alu

e

GT-1a1 GT-4a4 GT-2a2 GT-1b1

360

1900

1100 610

6000

4000

28 24

7735

141 98 749

320

2752

1215

169 454

GT-3a3

7105

1. Fridell RA et al. Antimicrob Agents Chemother 2010; 54:3641–50; 2. Fridell RA et al. J Virol. 2011; 85(14):7312-20 3. Wang C et al, Antimicrob Agents and Chemother. 2013; 57(1):611-13; 4. Wang C et al, Antimicrob Agents Chemother. 2012; 56(3):1588–90.

■ GT-1a and GT-1b activity profiles of 1st generation NS5A inhibitors in advanced clinical development are generally comparable – Varied activity against GT-1a-NS5A-M28T and GT-1b-NS5A-Y93H

■ Profiles of NS5A inhibitors differ against GT-2 an GT-3 reference strains

Resistance Profile of NS5A Inhibitors in Advanced Development

Gao M. Curr. Opin. Virol. 2013; 3(5):514-20; DeGoey DA et al. J. Med. Chem. 2014; 57(5):2047-57.

0,001

0,01

0,1

1

10

100

1000

DCV

LDV

OBV

GT-1a (H77c)

GT-1b (con1)

GT-2a (JFH-1)

Rep

lico

n E

C5

0 (

nM

)

1 nM

Persistence of NS3/NS5A RAVs

■ Replacement of emergent NS5A resistance-asociated variants (RAV) is infrequent overtime ■ Complete NS5A replacement observed in 5% (3/59) of virological failures monitored ≥ 24

weeks post-treatment

■ Partial NS5A replacement observed in 27% (16/59) GT1b patients

■ NS3 RAVs are less fit than NS5A RAVs and complete replacement with wild-type sequences is more frequent ■ Complete replacement observed in 71% (29/41) GT1b patients

■ Partial replacement observed in 15% (6/41) GT1b patients

■ 3-year long-term follow-up study ongoing

Data on file - AI444-046 study interim analysis

■ Replacement of NS5A RAVs has been observed in patients

– Complete replacement of RAVs was observed by population sequencing in 10 of 73 (14%) GT 1a, 3 of 59 (5%) GT 1b, 1 of 4 (25%) GT 3a, and 0 of 2 GT 4 patients monitored during long-term follow-up

■ Complete replacement of NS3 RAVs with wild-type sequence is observed more frequently compared with NS5A RAVs

– Complete replacement was observed in 10 of 17 (59%) GT 1a and 29 of 41 (71%) GT 1b patients monitored during long-term follow-up

Reddy KR, et al. AASLD 2014. Poster 1965

Follow-up after post-treatment week 12 DCV + ASV

N = 383

Median days (weeks) 435 (62)

Days, min-max 85–1284

Persistence of NS3/NS5A RAVs

Lenz et al., J Hepatol 2015;62(5):1008-14.

Replacement of SMV-Resistant Viruses by Wild-Type Viruses

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)

McPhee et al., Hepatology 2013;58:902-911; Wang et al. Antimicrob Agents Chemother 2013;57:2054-65.

Persistence of NS5A Inhibitor-Resistant Viruses

?

7

11 12

4

15

18

5

10

12

2

10

13

1

6 6

5

7

12

0

2

4

6

8

10

12

14

16

18

20

L28M R30Q L28M or R30Q(no L31 or Y93H)

L31F/I/M/V Y93H L31 or Y93H

Japan (N=374)

Korea or Taiwan (N=125)

Non-Asian countries (N = 489)

Prevalence of NS5A Preexisting RAVs in GT-1b

■ Baseline RAVs in NS5A were generally more common among Asian patients than non-Asians

■ Japanese patients had a higher prevalence of L31 and/or Y93 RAVs than patients from other Asian or non-Asian countries

Pro

po

rtio

n o

f p

atie

nts

wit

h R

AV

at

bas

elin

e (%

)

Data from HALLMAK Nippon (026) and HALLMAK DUAL (028) trials

69 374

16 125

57 489

30 489

35 489

24 489

30 489

15 125

45 374

56 374

13 125

16 374

3 125

43 374

12 125

27 374

6 125 7/48

McPhee et al. 2015 APASL Conference Poster.

74 79

87

42 37 39

87 87 86 88 92 94

0

10

20

30

40

50

60

70

80

90

100

L28M R30Q L28M or R30Q(no L31 or Y93H)

L31F/I/M/V Y93H L31 or Y93H

With RAP Without RAP

DUAL SVRs by Baseline RAV Status

■ Among all GT-1b patients, only baseline L31 or Y93 RAVs were associated with reduced SVR12 following DCV+ASV

– No influence of L28M or R30Q substitutions in the absence of L31 or Y93H

GT-1b patients with baseline sequence data and excluding non-virologic failures (N = 979)

SVR

12 (

%)

29 39

813 940

66 84

776 895

18 43

824 936

38 103

804 876

77 89

765 890

55 141

787 838

McPhee et al. 2015 APASL Conference Poster

With RAV Without RAV

39

54

29

39

93 97

92 91

0

10

20

30

40

50

60

70

80

90

100

All patients Treatment-naïve Priornon-responders

IFNineligible/intolerant

DUAL SVRs by Baseline RAV Status

Non-Asian countries (N = 485)

22 57

400 428

7 13

128 132

6 21

134 145

9 23

138 151

SVR

12 (

%)

McPhee et al. 2015 APASL Conference Poster.

With RAV Without RAV

DCV+ASV: RESISTANCE ASSOCIATED POLYMORPHISM (RAP)

• Baseline NS5A polymorphisms L31 and/or Y93 were present in ~18% of Japanese and ~12% of non-asian patients

• Baseline NS5A polymorphisms at amino acid positions 31 and 93 affect virologic response to DUAL

• Baseline resistance testing to select those without key NS5A polymorphisms increases chance of achieving SVR

• Across all patient groups of prior treatment experience, age and cirrhosis, very high SVR12 rates were observed in patients without baseline L31 and Y93H polymorphisms

DACLATASVIR+ASUNAPREVIR: RE-TREATMENT OPTIONS

■ When GT-1b patients fail DCV/ASV, NS5A-L31M-Y93H and NS3-D168V are most frequently detected together

■ NS5A and NS3 RAPs can persist – NS5A resistance variants persist > 1 year post-treatment

– Although NS3 resistance variants frequently replaced by 1 year post-treatment, persistence has been observed

• HCV replicon harboring NS5A-L31M-Y93H and NS3-D168V used to study potential retreatment options

Re-Treatment of GT-1b Patients who do not Achieve SVR with DCV/ASV

In-Vitro Analysis: Retreatment Options for Patients not Achieving SVR with DCV/ASV

Friborg J, et al. Infect Dis Ther 2014

BMS-791325 = NS5B Thumb 1 inhibitor; alfa = interferon-alfa



■ No elimination of HCV replicons harboring NS5A-L31M-Y93H and NS3-D168V after treatment with DCV/ASV

■ DCV-Trio eliminates DCV/ASV-resistant replicons at 30x EC50 when compared with DCV/ASV

■ Best potential treatment options against DCV/ASV-resistant replicons include:

– DCV/SOF and SOF/LDV

– DCV-Trio + SOF and SOF/IFNα/RBV

– SOF/next-gen NS3 PI and SOF/next-gen NS5A offer future options

■ Retreatment clinical studies required to confirm in vitro findings



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