Treatment of HCV · 2014-08-19 · HCV RNA Treatment Duration Nuc High barrier to resistance RBV NS5A NNI Low barrier to resistance (esp to G1a) Modest barrier to resistance (esp

Treatment of HCV

Genotypes 1, 4, 5 and 6

Jordan J. Feld MD MPH Toronto Centre for Liver Disease

Sandra Rotman Centre for Global Health

University of Toronto

Disclosures

• Consulting/Advisory Board: AbbVie, Achillion,

Boehringer Ingelheim, Bristol-Myers Squibb,

Idenix, Janssen, Merck, Roche, Vertex

• Research Grants to Institution: AbbVie,

Boehringer Ingelheim, Gilead, Janssen, Merck,

Roche, Vertex

Rapid Improvement

Modified from J Hoofnagle

0%

20%

40%

60%

80%

100%

IFN IFN IFN/R IFN/R PegIFN PegIFN/R

Su

sta

ine

d V

iro

log

ica

l R

es

po

nse

16%

55%

6%

34% 42% 39%

6 mo 12 mo 6 mo 12 mo 12 mo

1991

1995

1998

2002

2001

Ribavirin

Peginterferon

Standard

Interferon

6-12 mo

75%

2011 PR + PI

PR/PI 12 mo 3 mo

90% 2013

PR + NI

PR/SOF

The HCV Toolbox

IFN

Genotype Subtype Cirrhosis

Challenges

Prior Trt/

IL28B BMI Ethnicity

HCV

RNA

Treatment Duration

Nuc High barrier

to resistance RBV NS5A NNI

Low barrier

to resistance

(esp to G1a)

Modest barrier

to resistance

(esp to G1a)

PI

The HCV Toolbox

IFN

Genotype Subtype Cirrhosis

Challenges

Prior Trt/

IL28B BMI Ethnicity

HCV

RNA

Treatment Duration

Nuc High barrier

to resistance RBV NS5A NNI

Low barrier

to resistance

(esp to G1a)

Modest barrier

to resistance

(esp to G1a)

PI

The HCV Toolbox: Mix & Match

Genotype Subtype Cirrhosis

Challenges Treatment Duration

Nuc

RBV NS5A NNI

PI

RBV

PI

NS5A

Nuc

The HCV Toolbox: Options Today

IFN

Genotype Subtype Cirrhosis

Challenges

Prior Trt/

IL28B BMI Ethnicity

HCV

RNA

Treatment Duration

Nuc

RBV

PI

100

80

60

40

20

0

SV

R12 (

%)

80

50

211/

264

65/

130

84

208/

257

50

67/

134

QUEST 1 QUEST 2

100

80

60

40

20

0

SV

R12 (

%)

79

36

206/

260 48/

133

PROMISE

Treatment Naïve Prior Relapsers

PR

PR + SMV

Peg/RBV + Simeprevir x 12 wks + Peg/RBV x 12 wks

Simeprevir/PR In G1 Naïve/Relapsers (QUEST 1 & 2 + PROMISE)

Jacobson I, et al. EASL 2013. Abst. 1425;

Manns M, et al. EASL 2013. Abst. 1413.

Jacobson AASLD 2013

Q80K – A Major Issue with Simeprevir

Combined QUEST 1/2 - Naive

• Q80K present in 33% of G1a, 0.1% of G1b

• No benefit of SMV if Q80K +ve

100

80

60

40

20

0

SV

R12 (

%)

85

58

228/

267

49/

84

84

138/

165

G1b G1a no Q80K G1a + Q80K

53

70/

133

43 55

36/

83

24/

44

Peg/RBV

Peg/RBV + SMV

Manns M, et al. EASL 2013. Abst. 1413.

Simeprevir is Well Tolerated

• Mild unconjugated hyperbilirubinemia transporter

• No anemia signal beyond P/R

• Rash up to 25% (mild)

Bilirubin Hemoglobin

Mean

valu

es (

µm

ol/L

)

Mean

valu

es (

µm

ol/L

)

Weeks

SMV/PR

Placebo/PR

SMV/PR

Placebo/PR

Weeks

100

80

60

40

20

0

SV

R24 (

%)

85

37

45/

53 10/

27

70

32/

46

9

2/23

Relapsers Partials

Treatment Experienced

SMV + PR x 12 + PR x 36

• Longer therapy for prior non-responders

45

15/

33

19

3/16

Nulls

Extending Beyond Phase 3

FDA Analysis

Summary of Simeprevir

Pros

•Once daily PI

•Well tolerated with less rash and no anemia

•>85% shorten to 6 mo and most achieve SVR → No need for

RGT…just follow the stopping rules

Cons

•Q80K major issue with SMV – pre-treatment testing required in all G1a

•DDIs still an issue – less than TVR/BOC

•Resistance profile similar to telaprevir/boceprevir

•Unreliable PK in advanced cirrhosis

The HCV Toolbox: Options Today

IFN

Genotype Subtype Cirrhosis

Challenges

Prior Trt/

IL28B BMI Ethnicity

HCV

RNA

Treatment Duration

Nuc

RBV

100

80

60

40

20

0

SV

R1

2 (

%)

90

295/

327

All

92

206/

225

82

54/

66

96

27/

28

100

1/1

100

6/6

G1a G1b G4 G5* G6*

SOF 400 mg OD + Peg/RBV x 12 wks

AEs similar to Peg/RBV no control arm

Sofosbuvir + PR G1, 4-6 Naïve (NEUTRINO)

*not in label

Lawitz E, et al. NEJM 2013

Post-treatment On treatment

HC

V R

NA

<L

LO

Q (

%)

50/54 52/54 53/53

Week 2 Week 4 Week 12 Week 12

43/54 249/273 269/271 267/267 252/273

Lawitz E, et al. NEJM 2013

A Major Advance for Patients With Cirrhosis

What About Sofosbuvir for Prior Treatment Failures?

FDA Analysis

100

80

60

40

20

0

SV

R24 (

%)

71

37/

52

G1, Non-CC

F3/4, High VL

100

80

60

40

20

0

SV

R12 (

%)

Sofosbuvir + PR x 12 weeks

78

Modeled Numbers

SOF/P/R an unknown quantity in prior treatment failures

100

80

60

40

20

0

SV

R12 (

%)

Observed Data

Summary on Sofosbuvir

Pros

•Once daily Nuc Polymerase Inhibitor

•Very well tolerated

•Given for only 12 weeks in ALL patients (no RGT)

•High SVR even in cirrhosis (80%)

•Some data in non-G1

•High barrier to resistance - no breakthrough → only relapse

Cons

•Would have been nice to have a control group!

•No data in treatment experienced – naïve only

The HCV Toolbox: The Near Future

Treatment Duration

Nuc

RBV NS5A NNI

PI

PI NS5A NNI RBV Nuc NS5A

PI Nuc RBV

Can We Get Rid of IFN?

PI NS5A

100

80

60

40

20

0

36

Daclatasvir (NS5A) + asunaprevir (PI) x 24 wks (IFN-Free)

SV

R2

4 (

%)

US [1]

90 Japan [2]

9/10 4/11

• Great for G1b…not adequate for G1a

US Study

9/11 G1a

Japanese Study

10/10 G1b

PI + NS5A in Prior Null Responders

1. Lok et al NEJM 2012;366:216-24

2. Chayama et al, AASLD 2011, oral (LB-4)

1. Chayama AASLD 2011, Manns EASL 2014 Abst 0166

PI + NS5A for G1b

• Simple, cheap good for areas with 1b Asia

• Major caveat: 12% NS5A resistance SVR 40%

• Reasonable option….but 24 wks…probably not ‘good enough’

100

80

60

40

20

0

Daclatasvir (NS5A) + asunaprevir (PI) x 24 wks (IFN-Free) in G1b

SV

R1

2 (

%)

90

9/10

90

182/

203

82

168/

205

82

192/

235

Naive Null/

Partial

IFN

Ineligible

50/

68

73

Cirrhosis

Can We Get Rid of IFN?

PI NS5A What about a better PI and NS5A?

Wk 12

Treatment-naive,

noncirrhotic patients

with GT1 HCV

>85% G1a

MK-5172 100 mg + MK-8742 50 mg

+ RBV (n = 30)

MK-5172 100 mg + MK-8742 50 mg + RBV (n = 85)

MK-5172 100 mg + MK-8742 50 mg (n = 44)

Wk 8 SVR24

83%

94%

98%

Relatively Pan-genotypic PI and NS5A

Will be Combined as Single Pill

• Only 1 breakthrough despite >85% G1a

• Well tolerated – no hepatotoxicity

MK5172 (PI) + MK-8742 (NS5A)

Hezode et al EASL 2014 Abst 10

Tougher to Cure Population

*Excludes patients who have not yet reached SVR4

Lawitz et al EASL 2014 Abst 61

MK5172 (PI) + MK-8742 (NS5A) x 12-18 wks +/- RBV

28/

31

28/

29

30/

31*

29/

30*

30/

32

30/

33

32/

32*

29/

30*

SV

R4-8

(%

) 100

80

60

40

20

0 Treatment-Naive Pts

With Cirrhosis Null Responders

+/- Cirrhosis

+ RBV

No RBV

90

97 97 91 94

100 97 97

12 wks 18 wks 12 wks 18 wks

• Promising non-nuc FDC option

If 2 are Good, Would 3 be Better?

PI NS5A NNI

PI + NS5A in Prior Null Responders

1. Lok et al NEJM 2012;366:216-24;

2. Chayama AASLD 2011 LB-4 3. Everson AASLD 2013 LB-1

100

80

60

40

20

0

36

Daclatasvir (NS5A) + asunaprevir (PI) x 24 wks (IFN-Free)

SV

R24

(%

)

US [1]

90

Japan [2]

9/10 4/11

• 3rd drug Shorten to 12 wks, increase SVR • 1b still better than 1a • Would RBV help?

US Study

9/11 G1a

Japanese Study

10/10 G1b

Daclatasvir (NS5A) + asunaprevir (PI) + BMS 791325 (NNI) x 12 wks

121/

133

91

27/

28

96

G1a G1b

The HCV Toolbox: The Near Future

PI NS5A NNI RBV

SAPPHIRE I (naïve) & II (PR failure)

3D + RBV: Co-formulated ABT-450(PI)/r/ombitasvir(NS5A) 150 mg/100 mg/25 mg QD;

dasabuvir (NNI), 250 mg BID = 2 pill OD, 1 pill BID

N=473 (I)

N=297 (II)

N=158 (1)

N=97 (II)

Primary

Analysis: SVR12

Double-blind

Treatment Period

Open-label

Treatment Period

48 weeks post-treatment follow-up

48 weeks post-treatment follow-up

3D+RBV

Placebo 3D+RBV

Week 0 Week 12 Week 24 Week 60 Week 72

• No cirrhotics

• Placebo controlled real assessment of safety

PI + NS5A + NNI + RBV (SAPPHIRE 1&2)

Feld J EASL 2014 Abst 060, NEJM 2014 Zeuzem S EASL 2014 Abst 01, NEJM 2014

3D + RBV: ABT-450/r + ABT-267 (ombitasvir) + ABT-333 (dasabuvir) + RBV x 12 wks

100

80

60

40

20

0

SV

R1

2 (

%)

95

307/

322

G1a

98

148/

151

96

455/

473

All G1b

Naive

100

80

60

40

20

0

SV

R12

(%

)

96

166/

173

G1a

97

119/

123

96

286/

297

All G1b

Treatment Failures (49% nulls)

• 5 drugs (3 pills)

BUT 12 wks, 1

size fits all

• Very well tolerated

(vs. placebo), few

virologic failures

Treatment Failures

Feld J EASL 2014 Abst 060, NEJM 2014

• 1 breakthrough, 7 relapses

• 1 or more RAV – likely multidrug resistant

Patient GT Type of Virologic Failure NS3 NS5A NS5B

1 1a On-treatment failure at Week 12 R155K, D168V Q30R S556G, 559N

2 1a Relapse at PT Week 2 D168V M28T S556G

3 1a Relapse at PT Week 2 V36A, D168V M28T none

4 1a Relapse at PT Week 8 none M28V, H58P none

5 1a Relapse at PT Week 8 D168V Q30R Y561H

6 1a Relapse at PT Week 8 D168V Q30R none

7 1a Relapse at PT Week 12 D168V Y93N S556G

8 1b Relapse at PT Week 2 Y56H, D168V L31M, Y93H S556G

Can We Predict Failure?

Gender Race IL28B

Genotype

Baseline

HCV RNA

RBV

Modification

0

25

50

75

100

SV

R12, %

Pati

en

ts

95.2 97.5 96.4 96.2 96.5 96.0 93.5 96.4

271 202 28 445 144 329 31 442 N

98.1 95.7

104 369

BMI

(kg/m2)

402 71

97.0 91.5

Feld J EASL 2014 Abst 060, NEJM 2014

100

80

60

40

20

0

SV

R12 (

%)

100

65/

65

Partial

95

139/

146

95

82/

86

Relapsers Nulls

SAPPHIRE II: PI + NS5A + NNI + RBV x 12 wks

• Very similar to treatment naïve pop’n

• No effect of prior response Zeuzem S EASL 2014 Abst 01, NEJM 2014

What About Prior Response?

*p<0.05

Feld J EASL 2014 Abst 060, NEJM 2014; Zeuzem S EASL 2014 Abst 01, NEJM 2014

Adverse Events

AE, (%) 3D + RBV

(N=473)

Placebo

(N=158) Difference

Any AE 87.5* 73.4 14.1

Fatigue 34.7 28.5 6.2

Headache 33.0 26.6 6.4

Nausea 23.7* 13.3 10.4

Pruritus 16.9* 3.8 13.1

Insomnia 14.0* 7.6 6.4

Diarrhea 13.7* 7.0 6.7

Asthenia 12.1* 3.8 8.3

Rash 10.8 5.7 5.1

Even better in SAPPHIRE II – only pruritus> placebo

Adverse Events (AEs)

SAPPHIRE I SAPPHIRE II

3 DAA + RBV (n = 473)

Placebo (n = 158)

3 DAA + RBV (n = 297)

Placebo (n = 97)

Any AE, n (%) 414 (87.5) 116 (73.4) 271 (91.2) 80 (82.5)

AE leading to D/C, n (%) 3 (0.6) 1 (0.6) 3 (1.0) 0

Any serious AE, n (%) 10 (2.1) 0 6 (2.0) 1 (1.0)

Grade 3/4 lab events, n/N (%)

ALT>5x ULN 4/469 (0.9) 7/158 (4.4) 5/296 (1.7) 3/96 (3.1)

Creatinine -- -- 2/297 (0.7) 0

Total bilirubin 13/469 (2.8) 0 7/296 (2.4) 0

Hemoglobin 8-10 g/dL* 27 (5.8) 0 14/296 (4.7) 0

• ALT improved with continued dosing

• Bilirubin – total, related to transporter inhibition

• None met Hy’s law not hepatotoxicity

• Anemia – RBV dose reduction 5.5-6.4%, no effect on SVR

Safety/Tolerability

Feld J EASL 2014 Abst 060, NEJM 2014; Zeuzem S EASL 2014 Abst 01, NEJM 2014

Is RBV Necessary?

PEARL – G1b

Ferenci CROI 2014

100

80

60

40

20

0

SV

R12

(%

) 99

207/

209

3 DAA

99

209/

210

3 DAA + RBV

Naïve non-cirrhotic

ABT-450/r + ABT-267 (ombitasvir) + ABT-333 (dasabuvir)

+/- RBV x 12 wks

100

80

60

40

20

0

SV

R12

(%

)

100

81/

81

3 DAA

97

85/

88

3 DAA + RBV

Experienced non-cirrhotic

• Problem solved: G1b no need for RBV • Do we really need 12 weeks?

• Largest trial of cirrhotics in HCV – n=380!

• Mixed naïve and treatment failures Poordad EASL 2014, LB, NEJM 2014

TURQUOISE

Day 0 Week 24 Week 12

SVR12

SVR12

3D + RBV

(N=208)

3D + RBV

(N=172) All patients to be followed through 48 weeks post-treatment

100

80

60

40

20

0

SV

R1

2 (

%)

94

114/

121

89

120/

140

G1a

51/

51

67/

68

100 99

G1b

24 wks

12 wks

• 12 weeks clearly adequate for G1b

• What about G1a?? Poordad EASL 2014, LB, NEJM 2014

3D + RBV in Cirrhosis by G1 Subtype

G1a Null Cirrhotics Need 24 Weeks…

100

80

60

40

20

0

SV

R12 (

%)

93

52/

56

93

59/

64

Naive

100

13/

13

93

14/

15

Relapsers

100

10/

10

100

11/

11

Partials

93

39/

42

80

40/

50

Nulls

• Suggests that 24 wks optimal for G1a null cirrhotics

• 12 wks adequate for all others

Poordad EASL 2014, LB, NEJM 2014

24 wks

12 wks

Summary 3D + RBV

• Highly effective 12 week regimen

– SVR 96% naïve/experienced

– Similar G1a (95%) and G1b (98%)

• Large cirrhotic trial

– Similar efficacy & safety

– 12 weeks adequate for all but G1a nulls → 24 wks

• Safety

– Placebo controlled – minimal toxicity

– Mostly to do with RBV – not needed for G1b

• Resistance

– Very few breakthroughs – 5 in all 3 trials!

– Relapsers 2 or 3D resistance

The HCV Toolbox: The Near Future

Treatment Duration

Nuc

RBV NS5A NNI

PI

PI NS5A NNI RBV Nuc NS5A

PI Nuc RBV

The HCV Toolbox: The Near Future

Nuc NS5A

80

100

60

40

20

0

SV

R12

(%

) How About a Single Pill?

Mangia EASL 2014, Afdhal EASL 2014, Kowdley EASL 2014

Naïve

Prior Trt

(incl PI)

Failures

ION 1, 2 & 3: SOF (nuc) + LDV (NS5A) FDC +/- RBV

• 8 wks adequate for non-cirrhotic naïve

• RBV no benefit

• No resistance

99

211/

214

97

211/

217

S/L S/L/R

12 wks

94

102/

109

S/L

107/

111

96

S/L/R

12 wks

108/

109

99

S/L

24 wks

110/

111

99

S/L/R

94

202/

215

93

201/

216

95

8 wks 12 wks

S/L S/L/R S/L

206/

216

98

212/

217

99

215/

217

S/L S/L/R

24 wks

SOF/LDV +/- RBV in Cirrhosis

No cirrhosis

Cirrhosis

83/

87

19/

22

89/

89

18/

22

86/

87

22/

22

88/

89

22/

22

12 Weeks 24 Weeks

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

SV

R12 (

%)

100

80

60

40

20

0

95 86 100 82

100 99 100 99

• Cirrhotics need 24 wks of therapy

• RBV still not helpful Afdhal EASL Abst O109

Very Effective for Prior PI Failures

40/

43

62/

66

45/

47

62/

64

58/

58

49/

50

58/

59

51/

51

12 Weeks 24 Weeks

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

SV

R1

2 (

%)

100

80

60

40

20

0

93 94 96 97 100 98 98 100

• No cross resistance with PI and either SOF/LDV

Afdhal EASL Abst O109

P/R Failure

PI Failure

Summary SOF/LDV FDC

• Very effective single pill regimen

• RBV clearly not necessary

• No difference G1a vs G1b

• 8 wks adequate for naive, non-cirrhotics

• May consider extension beyond 12 wks for cirrhotic – probably need less than 24 wks

• Very well tolerated

• No issue with resistance

The HCV Toolbox: The Near Future

Treatment Duration

Nuc

RBV NS5A NNI

PI

PI NS5A NNI RBV Nuc NS5A

PI Nuc RBV

The HCV Toolbox: The Near Future

PI Nuc RBV

If only we could all just get along…

SMV SOF

FDA

80

100

60

40

20

0

SV

R12

(%

) COSMOS: Nuc (Sofosbuvir) +

PI (Simeprevir) +/- RBV

• No breakthrough on therapy – 6 relapses • 12 similar to 24, RBV no effect • Caveats: small n, no Phase 3 trial not approved

Cohort 2: F3-4 NULL/NAIVE

SVR12 Relapse Non-virologic failure

19/24

S/S/R

24 wks

S/S

93

14/15

7

79

17 4

Cohort 1: F0-2 NULL

96 93

S/S/R S/S

F0-2

26/27 13/14

12 wks

7 4

93 93

S/S S/S/R

F3-4

25/27 13/14

12 wks

7 7

24 wks

93

28/30

7 100

16/16

S/S S/S/R

Jacobson AASLD 2013 LB-3; Lawitz EASL 2014 Abst 165

Questions About COSMOS Regimen

1. What about Q80K with SOF/SMV?

– 93% (50/54) SVR12 in Q80K +ve in COSMOS

– But…4 of 6 relapsers were G1a, Q80K +ve

– Would RBV help? Maybe…but not obviously, 4 of 6 relapsers

received RBV

2. What about PI (Telaprevir/Boceprevir) failures?

– No data

– Cross resistance with most PI-resistant variants

– May be best to wait for alternatives

$$$$$$$$$$$

Who’s going to pay for it?

The Most Important Question

100

80

60

40

20

0

SV

R1

2 (

%)

96

27/

28

12 wks

SOF + PR

• Other options: SOF + SMV – no data but should work • 3D +/- RBV – under study

100

80

60

40

20

0

79

11/

14

12 wks

100

14/

14

24 wks

SOF + RBV

12 wks

+ 24-48 wks PR

100

80

60

40

20

0

65

70/

107

SMV + PR

Lawitz NEJM 2013, Ruane EASL 2014, Moreno EASL 2014

Options for G4

14- 02- 10 6:34 PMRecommendations for Testing, Managing, and Treating Hepatit is C

Page 1 of 3http:/ / www.hcvguidelines.org/

Recommendations for

Testing, Managing, and

Treating Hepatitis C

Background of the Hepatitis C

Guidance

New direct-acting oral agents capable of curing hepatitis C

virus (HCV) infection have been approved for use in the

United States. The initial direct-acting agents were

approved in 2011, and many more oral drugs are expected

to be approved in the next few years. As new information is

presented at scientific conferences and published in peer-

reviewed journals, health care practitioners have expressed

a need for a credible source of unbiased guidance on how

best to treat their patients with HCV infection. To provide

healthcare professionals with timely guidance, the American

Association for the Study of Liver Diseases (AASLD) and

the Infectious Diseases Society of America (IDSA) in

collaboration with the International Antiviral Society-USA

(IAS-USA) have developed a web-based process for the

rapid formulation and dissemination of evidence-based,

expert-developed recommendations for hepatitis C

management.

New sections will be added, and the recommendations will

be updated on a regular basis as new information becomes

available. An ongoing summary of "recent changes" will

also be available for readers who want to be directed to

What’s New and

Updates/Changes

HCV Guidance

Wednesday, January 29,

2014

The Recommendations for

Testing, Managing, and

Treating Hepatitis C are now

available.

Read more >>

Official PressRelease

Wednesday, January 29,

2014

View Official Press Release:

Online...

Read more >>

Home Full Report Panel Organizations Process Contact Us

Search website

www.hcvguidelines.org

A Useful Resource

Summary

• Treatment evolving rapidly

• Options for G1 now

– Peg/RBV + SOF x 12w

– Peg/RBV + SMV x 12w + PR x 12w – remember Q80K

– SOF-SMV x 12w

• Approved IFN-free options very soon

– 3D (PI + NS5A + NNI) +/- RBV x 12w

– SOF/LDV (FDC) x 8-12w

• G4 will follow G1 – good options

• G5/6 – need more patients to get approvals!

A Bit Confusing Now

H. pylori

But interferon is about to be

replaced by a DAA – Pak…