Clinical Management:

Treatment of HCV Mono-infection

Curtis Cooper, MD, FRCPC

Associate Professor-University of Ottawa

The Ottawa Hospital- Infections Diseases

Viral Hepatitis Program- Director

Disclosures Industry

Investigator: Merck, Vertex, Roche, BI, Janssen, GS, BMS, Abbvie, Idenix

Consultant /Advisor: Merck, Vertex, Roche, BI, GS, Abbvie

Speaker: Merck, Roche, BI, BMS

Government

OHTN

CIHR

Health Canada

Ontario MOH

CADTH

Overview

Current & Emerging Therapies

Best Practices & Clinical

Practice Guidelines

Therapies for Hepatitis C Virus

PEG-IFN α / RBV +/-

Protease Inhibitor

Duration of Tx / RGT

Definition of Therapeutic

Success

Plasma HCV RNA undetectable

6 months post therapy

(Sustained Virologic

Response=Cure)

clinicaloptions.com/hepatitis

Highlights From AASLD 2010

SPRINT-2: Response Rates According to

Race

0

20

40

60

80

100

Pati

en

ts (

%)

SVR Relapse

4-wk PR + 44 weeks BOC + PR 4-wk PR + response-guided BOC + PR 48-wk PR

67

68

40

8

23

9

0

20

40

60

80

100

Pati

en

ts (

%)

SVR Relapse

42

53

23

17 14

12

Nonblack Patients Black Patients

P < .0001 P = .044

P = .004

Poordad F, et al. AASLD 2010. Abstract LB-4.

n = 211 213 125 21 18 37 22 29 12 3 6 2

clinicaloptions.com/hepatitis

Highlights From AASLD 2010

PROVE 3: SVR Rates According to Prior

Response

0

20

40

60

80

100

SV

R (

%)

McHutchison JG, et al. N Engl J Med. 2010;362:1292-1303.

24-wk TVR + P (n = 111)

24-wk TVR + PR + 24-wk PR (n = 113)

12-wk TVR + PR + 12-wk PR (n = 115)

48-wk PR (n = 114)

Prior Nonresponders

39

Prior Relapsers

Prior Breakthrough

38

9 11

69

76

20

42

57

36

62

40

Overall

51*

14

24†

53*

*P < .001 vs control. †P = .02 vs control.

Advances Soon to Come

hypervariable region

capsid envelope protein

Protease / Helicase

RNA-dependent RNA Polymerase

c22

5’

core

E1 E2 NS2

NS3

33c

NS4

c-100

NS5a / NS5b

3’

Direct Acting Antivirals

Direct Acting Antiviral Drug (DAA) Combinations

•10

•‡

HCV-specific nucleotide polymerase

inhibitor (chain terminator)

Potent pan-genotypic antiviral

activity against HCV GT1–6

High barrier to resistance

Once-daily, oral, 400-mg tablet

Favorable clinical pharmacology profile

No food effect

No significant drug interactions

Generally safe and well-tolerated in clinical

studies to date (> 2,000 patients)

No safety signal in preclinical/clinical

studies

•Sofosbuvir (SOF, GS-7977)

•11

•‡

• Open label, single arm study of PegIFN-Ribavirin-SOF x 12/52

• Error bars represent 95% confidence intervals

• Lawitz E, et al. EASL 2013. Amsterdam, The Netherlands. Oral #1411

•Phase 3: NEUTRINO GT 1, 4, 5, 6 Treatment-Naïve SVR12 by HCV Genotype

•Pati

en

ts w

ith

HC

V R

NA

<L

LO

Q

(%)

•Overall •GT 1 •GT 4 •GT 5,6

•295/327 •261/292 •27/28 •7/7

•12

•‡

• Error bars represent 95% confidence intervals

• Gane E, et al. EASL 2013. Amsterdam, The Netherlands. Oral #5

•Phase 3: FISSION GT 2, 3 Treatment-Naïve Primary Endpoint and Virologic Response

•Post-treatment

•Week 12

•On treatment

•231/251 •76/241 •249/250 •158/236 •242/244 •207/224

•Week 2 •Week 4 •Week 24 •Pa

tie

nts

wit

h H

CV

RN

A <

LL

OQ

(%

)

•188/190 •NA

•Week 12

•170/253 •162/243

Study met primary endpoint of non-inferiority (P<0.001)

Relapse accounted for nearly all virologic failures

There was 1 instance of virologic breakthrough from a patient who had suspected non-adherence based on undetectable drug plasma levels

No S282T mutations observed by population or deep sequencing (1% cutoff)

•SMV 150mg od x 12/52

•91% meet RGT criteria for 24/52

Advances soon to come….

Sofosbuvir

Simeprevir

Faldaprevir

Still dealing with complex patients, complex

IFN-based regimens and toxicities

Interferon-Sparing Regimens

COSMOS- AASLD 2013

clinicaloptions.com/hepatitis

Highlights of AASLD 2012

ELECTRON: SOF-Ledipasvir-RBV

-Noncirrhotic, GT1

Interim analysis of nonrandomized phase II study with sofosbuvir ± GS-5885 (NS5A inhibitor)

SOF + RBV

Wk 12

Treatment naive (n = 25)

SOF + RBV

SOF + GS-5885 + RBV

SOF + GS-5885 + RBV

Null responders (n = 10)

Treatment naive (n = 25)

Null responders (n = 9)

Patients, %

EOT SVR4 SVR12

100 88 84

100 10 10

100 100

100 100*

Gane EJ, et al. AASLD 2012. Abstract 229.

*Data reported for 3 pts only. Data collection ongoing.

clinicaloptions.com/hepatitis

Highlights of AASLD 2012

AVIATOR: SVR12

ABT-450/r-ABT-267-ABT-333-RBV

8 wks 12 wks 12 wks

82 86

0

20

40

60

80

100

SV

R1

2 (

%)

96 100 100 100 100 100

84 96

56 24

79

100

29 12

85

100

52 27

83

96

52 25

96 100

54 25

81

100

26 18

89

100

28 17

Observed data

(above bar)

ITT (within bar)

n =

81

98

88 88

100 89

1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b ABT-450

ABT-267

ABT-333

RBV

ABT-450

ABT-333

RBV

ABT-450

ABT-267

RBV

ABT-450

ABT-267

ABT-333

ABT-450

ABT-267

ABT-333

RBV

ABT-450

ABT-267

RBV

ABT-450

ABT-267

ABT-333

RBV

Treatment-Naive Patients Null Responders

Kowdley KV, et al. AASLD 2012. Abstract LB-1.

clinicaloptions.com/hepatitis

Highlights of AASLD 2012

Daclatasvir-Asunaprevir-BMS-791325 (mITT Analysis)

Everson GT, et al. AASLD 2012. Abstract LB-3.

HC

V R

NA

< L

LO

QT

D o

r T

ND (

%)

24-Wk Treatment

(n = 16)

100

80

60

40

20

0 Wk 4 Wk 12 EOT SVR4

100 94 94

94

Missing data HCV RNA < LLOQTD or TND

12-Wk Treatment

(n = 16)

100

80

60

40

20

0

Wk 4 Wk 12 EOT SVR4 SVR12

100 88 100 94 94

HC

V R

NA

< L

LO

QT

D o

r T

ND (

%)

IFN-Sparing, All Oral Regimens

High SVR rates

Shorter Duration

Excellent Tolerance

Funding Issues

HCV Guidelines

Discussion