HCV Resistance and

Remaining Challenges

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 12

Créteil, France

HCV Resistance

• Selection of preexisting HCV variants that are resistant to the specific drug, due to the presence of amino acid substitutions generally located within or in close vicinity to the target region, which grow according to their in vivo fitness and fill in the replication space

I

HCV Resistance to DAAs

Asp168

Ala156

Arg155

Thr54

Val36

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

Amino Acid Substitutions

Associated with PI Resistance

Resistance and Fitness

In vivo

fitness

Resistance

(Kieffer T, et al. Hepatology 2007;46:631-9)

(Reesink HW, et al. Gastroenterology 2006;131:997-1002)

Telaprevir Resistance

-5

-4

-3

-2

-1

0

1

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14

Study Time (Days)

Med

ian

HC

V R

NA

Ch

an

ge

fro

m B

aselin

e (

Lo

g10

IU/m

L)

Placebo VX-950 450 mg q8h VX-950 1250 mg q12h

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

RdRp Resistance Mutations

(courtesy of Isabel Najera, Roche)

499

495

496

316

365

201

482

423

419

95

176

451

414

411448

142 96

282

499

495

496

316

365

201

482

423

419

95

176

451

414

411448

142 96

282

499

495

496

316

365

201

482

423

419

95

176

451

414

411448

142 96

282

FingersThumb

Palm

A

B

C

D

pol

Filibuvir (Pfizer) Resistance in IFN Null-Responders

(Mori et al., EASL 2010)

Thumb 2 domain

M423

Filibuvir

BMS-790052 Resistance in vitro

Subtype Sustitution EC50 Fold-changeReplication

level (% wt)

1b replicon

wt 2.6±0.3 1 100

L31V 61±15 24 144±47

Y93H 49±13 19 20±7

wt 5.9±3.7 1 100

1a replicon

M28T 4,100±360 360 31±23

Q30H 8,700±1,900 1,900 75±31

Q30R 7,300±1,100 1,100 41±16

L31M 2,100±610 610 55±15

L31V 20,000±6,000 6,000 117±29

Y93C 11,000±4,000 4,000 11±7

(Gao et al., Nature 2010;465:96-100)

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-

change

vs wt

1.02 1.58 1.37 3.67 1.72 3.89

(Coelmont et al., EASL 2009)

II

Failure of the Triple Combination of PegIFN, Ribavirin and a PI to

Eradicate HCV

Treatment Failures on Triple Combination with a DAA

• Treatment-Naïve: 20-30%

• Treatment-experienced: 40-50%

Expected Higher Failure Ratesin Difficult-to-Treat Patients

• Advanced liver disease

• Liver transplant

• HIV coinfected

• Hemodialysis

• Immunosuppressed patients

• African Americans

• etc…

Treatment Failures on Triple Combination with a DAA

• Insufficient response to Peg-IFN and ribavirin

• Uncontrolled outgrowth of DAA-resistant HCV variants

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

29%

39%

82%

% o

f p

ati

en

ts

wit

h S

VR

0

10

20

30

40

50

60

70

80

90

100

BOC/RGT BOC/PR48

(Poordad et al., AASLD 2010)

82%

<1 log HCV RNA

decrease

≥1 log HCV RNA

decrease

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

33% 34%

79%

% o

f p

ati

en

ts

wit

h S

VR

0

10

20

30

40

50

60

70

80

90

100

BOC/RGT BOC/PR48

(Bacon et al., AASLD 2010)

73%

<1 log HCV RNA

decrease

≥1 log HCV RNA

decrease

Telaprevir Rollover Study 107

0

20

40

60

80

100

37%

55%

75%

97%

59%

Pati

en

ts W

ith

Un

dete

cta

ble

HC

V R

NA

(%

)

TOTAL

N=117

Prior

null-response

N=51

Prior partial

response

N=29

Prior

breakthrough

N=8

Prior

relapse

N=29

(Berg et al., EASL 2010)

REALIZE Trial-Telaprevir Arms

0

20

40

60

80

100

31%

57%

86%

65%

Pati

en

ts W

ith

Un

dete

cta

ble

HC

V R

NA

(%

)

TOTAL Prior

null-response

Prior partial

response

Prior

relapse

(Vertex press release, Sept 7, 2010)

Incidence of HCV resistance

(Hézode et al., N Engl J Med 2009;360:1839-50)

Arm Event N VL <LOD Wild-typeLow-level

resistance

High-level

resistance

T12PR24Breakthrough 4 - - - 4

Relapse 8 - 1 4 3

T12PR12Breakthrough 1 - 1 - -

Relapse 19 3 1 13 2

T12P12Breakthrough 19 2 - 9 8

Relapse 22 4 - 16 2

Long-Term Follow-Up After Treatment Failure (EXTEND)

100 100

Overall 36 155 156 36+15554

NS3 variant positions

9288 8589

0

20

40

60

80

100

% o

f sam

ple

s w

ith

no

dete

cta

ble

vari

an

t at

en

d o

f fo

llo

w-u

p

Median follow-up 22 months (range 5-35)

(Zeuzem et al., AASLD 2010)

Conclusions

• The administration of DAAs is always associated with the selection of resistant HCV variants

• In combination regimens, the antiviral effect of pegylated IFN and ribavirin prevents the growth of DAA-resistant variants and leads to viral eradication

• Treatment failure with the triple combination of pegylated IFN, ribavirin and a DAA is due to an insufficient antiviral response to IFN and ribavirin

• Treatment failure is characterized by the outgrowth of DAA-resistant HCV variants, as a result of virtual monotherapy with the DAA

• Prevention of treatment failure in patients with an insufficient response to pegylated IFN and ribavirin is based on:

• An accurate assessment of IFN responsiveness (lead-in phase, baseline parameters)

• Alternative options for true IFN null responders that must be assessed in prospective clinical trials

Conclusions