Post Conference HCV Update 65 th Annual Meeting of the American Association for the Study of Liver Diseases Simply Speaking ® Hepatitis “Post Conference

Post Conference HCV Update

65th Annual Meeting of theAmerican Association for the Study of Liver Diseases

Simply Speaking® Hepatitis “Post Conference HCV Update: 65th Annual Meeting of the American Association for the Study of Liver Diseases” isCopyrighted 2014 by Practice Point Communications, unless otherwise noted. All rights reserved.

Supported by an independent educational grant from Gilead Sciences Medical Affairs

This activity is jointly provided by the University of Nebraska Medical Centerand Practice Point Communications®

2

Educator

• Disclosures

– Grants/Research Support: list here

– Consultant: list here

– Speakers’ Bureau: list here

– Stock Shareholder: list here

– Other Financial or Material Support: list here

Educator Title, DegreeAffiliationCity, State

EDUCATOR TO COMPLETE

3

Sign-In Process

• Please clearly print all information on the sign-in sheet

• You must indicate your NAME, DEGREE, MAILING ADDRESS, EMAIL, and SIGNATURE in order to attend this lecture

• You must indicate a unique identification number to attend this lecture:

– MD/DO/PA = NPI Number

– NP/RN = State License Number

– PharmD/RPh = NAPB & Date of Birth

– Other = NPI or State License Number (if available)

• Completion is required for all healthcare providers

• Failure to provide complete information may disqualify you from participating in future lectures

4

Accreditation andDisclosure Information

• Please see the pastel-colored paper in your program handouts to review the following:

– Accreditation statements

– Disclosure policy

– Disclosures of content faculty, reviewers, and planners

5

Evaluation and Outcomes Measurement Process

• You will receive an electronic initial evaluation to the email address provided within 1 business day

• Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed

• Incomplete evaluations may preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area

• In addition, you will receive a long-term evaluation via email 8 to 12 weeks after completing this course to measure competence, performance, and/or patient outcomes achieved as a result of your participation in this CME/CNE/CPE sponsored educational activity

(Please note: If you attended multiple Simply Speaking® lectures throughout the year, a separate initial and long-term evaluation will be sent to you for each lecture.)

6

Learning Objectives(CME/CNE/CPE)

• Upon completion of this educational activity, participants should be able to:

– Screen for hepatitis C virus (HCV) infection according to the recommendations from the American Association for the Study of Liver Diseases (AASLD) and the Centers for Disease Control and Prevention (CDC)

– Appropriately select antiviral HCV treatment strategies according to the recommendations from the AASLD/IDSA guidelines

– Manage safety and tolerability problems with antiviral HCV agents, including side effect, drug-drug interactions, and resistance

– Evaluate new agents being investigated for HCV therapy to optimize information-based decision making about therapy

77

Program Overview

• Epidemiology and public health considerations

• Interferon-free regimens for HCV

– Sofosbuvir + simeprevir

– Ledipasvir/sofosbuvir

– ABT-450/r/ombitasvir + dasabuvir + RBV

– Daclatasvir + sofosbuvir

– Sofosbuvir + GS-5816

– Grazoprevir/elbasvir + sofosbuvir

• Difficult-to-cure and liver transplant patients

• HCV/HIV coinfection

88

CDC: Effectiveness of HCV Testing for Persons Born During 1945-1965

• 3 large primary care health systems (2012-2014)

– Systematic 1-time HCV test versus usual care (likely risk-based or medical indication-based testing)

– 3 independent HCV testing trials (results available for 2)

• Trial 1: stratified multi-clinic, individually randomized (9 clinics)

• Trial 2: cluster randomized (10 clusters)

– No prior HCV test or infection

• Birth-cohort HCV testing

– 4 times more effective in identifying persons with HCV infection compared with usual care

Smith BD, et al. Hepatology. 2014;60(suppl 1):295A. Abstract 194.

HCV Identified(per 1000 eligible)

Trial 1 Birth cohort testing (n=2996) Usual care (n=5996)

2.70.3

Trial 2 Birth cohort testing (n=2996) Usual care (n=5996)

3.01.1

Relative Probability of Identifying HCV-Positive Patients Using Birth Cohort Versus Usual Care

Risk Ratio: 4.0 (1.9-8.7)

HCV Testing Results

99

Chronic Hepatitis Cohort Study (CHeCS): Mortality and Progression to Decompensated Cirrhosis in HCV

• Population-based cohort (2001-2012)

– 4 large health systems

– Eligible patients who underwent liver biopsy (n=2839)

• Median observation time: 5.5 years

• Clinical endpoints

– All-cause death

– HCC

– Liver transplant

– Decompensated cirrhosis

• Substantial liver disease progression among patients meeting high or highest recommendation for treatment by the AASLD/IDSA guidelines

Moorman AC, et al. Hepatology. 2014;60(suppl 1):285A. Abstract 174.

Geisinger Health System (Danville, PA), Henry Ford Health System (Detroit), Kaiser Permanente (Honolulu and Portland).

F2(n=810)

F3(n=461)

F4(n=364)

Ever treated after biopsy (%) 46 72 62

Achieved SVR (%) 75 55 47

HCC (%) 1.0 4.6 11.3

Decompensated cirrhosis (%) 3.8 11.9 28.6

Liver transplant (%) 1.1 1.7 5.2

Death (%) 6.0 10.8 23.1

Clinical Outcomes byBaseline Biopsy Stage

P<0.001 for all outcomes across baseline biopsy stage.

1010

Program Overview











1111

Real-World Use of Sofosbuvir- and Simeprevir-Based Regimens: Trio Health Network

• Disease management program for HCV patients (n=1211)

– 31 academic and 119 community practices in the US

– Data collection via electronic prescription records

– 12-week HCV regimens (n=955)

• Interim SVR12 (ITT; n=822)

– All genotypes: 79%

Dieterich D, et al. Hepatology. 2014;60(suppl 1):220A. Abstract 46.

Sofosbuvir Plus

PR(n=384)

RBV(n=227)

Simeprevir + RBV(n=320)

Mean age (years) 55 58 59

Male (%) 61 56 60

Black (%) 20 7 17

Genotype 1a/1b (%) 63/22 4/1 63/28

Cirrhosis (%) 22 25 45

Platelets <100K/µL (%) 9(n=321)

13 (n=193)

25(n=301)

Treatment experienced (%) Null responder Partial responder/relapse Prior PR Prior PI + PR Unknown prior regimen

423660302842

292074452

53

523859492131

HCV RNA <2 million IU/mL (%) 53 49 54

Baseline Characteristics

PR: pegIFN + RBV.

12

Trio Health Network: SVR12 Rates in HCV Genotype 1 Patients


Sofosbuvir plus

PR Simeprevir + RBV

0

20

40

60

80

100

SV

R12

(%

)

81% 83%

Treatment-Naïve

Overall(n=169/132)

HCV Subtype

PR: pegIFN + RBV.SVR12 rates (sofosbuvir + PR and sofosbuvir + simprevir + RBV): Prior PR failure (73% and 82%; prior PI failure (67% and 87%).

1a(n=125/85)

1b(n=33/36)

No(n=138/7)

Yes(n=31/55)

Cirrhosis

81% 80% 82%

92%

81%

88%

81%

75%

Sofosbuvir plus

PR Simeprevir + RBV

0

20

40

60

80

100

SV

R12

(%

)

72%

81%

Treatment-Experienced

Overall(n=125/144)

HCV Subtype

1a(n=73/86)

1b(n=37/40)

No(n=39/74)

Yes(n=80/70)

Cirrhosis

71%

81%

70%

80%76%

87%

62%

76%

13

Trio Health Network: SVR12 Rates With Sofosbuvir + RBV in HCV Genotype 2 Patients


0

20

40

60

80

100

SV

R12

(%

)

85%

Treatment-Naïve

Overall(n=132)

No(n=109)

Yes(n=23)

Cirrhosis

89%

65%


0

20

40

60

80

100

SV

R12

(%

)

83%

Overall(n=47)

No(n=27)

Yes(n=20)

Cirrhosis

89%

75%

1414

Trio Health Network:Predictors of Response and Safety

• Predictors of achieving SVR12

– Cirrhosis was the most important predictor across all 12-week regimens for genotype 1 and 2 patients

• Most common adverse events were general intolerance and rash


Sofosbuvir Plus

PR(n=384)

RBV(n=227)

Simeprevir + RBV(n=320)

Reasons for treatmentdiscontinuations:

Adverse events (%) Genotype 1 Genotype 2

2.0--

--0

1.4--

Non-adherence (%) Genotype 1 Genotype 2

4.1--

--2.2

1.8--

Safety

PR: pegIFN + RBV.

1515

Real-World Use of Sofosbuvir-Containing Regimens: HCV TARGET

• Ongoing longitudinal, observational study of DAA-based therapy in HCV (n=2330)

– 38 academic and 15 community medical centers in the US, Germany, and Canada

– HCV treatment is administered according local standard of care

• Regimen selection made by health care provider

• Interim results for sequentially enrolled patients who started therapy with sofosbuvir-containing regimens on or before 4/15/14

– Sofosbuvir + PR (n=384)

– Sofosbuvir + RBV (n=667)

– Sofosbuvir + simeprevir + RBV (n=1012)

Jensen DM, et al. Hepatology. 2014;60(suppl 1):219A-220A. Abstract 45.

Patients(n=2063)

Male (%) 63.7Mean age (years) >65 years (%)

57.619.2

Black (%) 11.5Treatment experienced (%) Naïve Experienced PI failure

47.652.217.9

Cirrhosis (%) History of decompensation (%) MELD >10 (%)

48.443.133.8

Liver cancer (%) 10.2Liver transplant (%) 11.0

HIV coinfection (%) 2.3


PR: pegIFN + RBV.

16

HCV TARGET Study (Interim Results):SVR4 Rates With Sofosbuvir-Containing Regimens


PR: pegIFN + RBV.

0

20

40

60

80

100

SV

R12

(%

)

85%

Sofosbuvir + PR(n=164/127/37)

SVR4

Overall No cirrhosis Cirrhosis

90%

Sofosbuvir + Simeprevir + RBV

Prior PI Failures(n=54/20/34)

Genotype 1

Overall(n=303/123/180)

Genotype 2

Sofosbuvir + RBV(n=187/128/59)

70%

89%92%

87%81%

85%79%

90% 91% 88%

17

PR: pegIFN + RBV.Adjusted for cirrhosis status, genotype, treatment naïve/experienced, prior decompensation, and prior triple therapy failure.

HCV TARGET Study (Interim Results): Adjusted SVR4 Rates With Sofosbuvir + Simeprevir + RBV in HCV Genotype 1

Jensen DM, et al. Hepatology. 2014;60(suppl 1):219A-220A. Abstract 45.Sulkowski MS, et al. Hepatology. 2014(suppl 1):660A-661A. Abstract 955.

Sofosbuvir + Simeprevir

No RBV With RBV

0

20

40

60

80

100

SV

R12

(%

)

86%87%

Overall

Overall

Cirrhosis

Yes No Naïve Experienced

Prior Treatment

85% 83%

89% 90% 89% 87% 85% 86%

0

20

40

60

80

100

SV

R12

(%

)

84%82%

By HCV Subtype

Overall Yes No

Cirrhosis

82% 80%

88%87%92%

87% 88%


No RBV With RBV

Genotype 1a

Overall Yes No

Cirrhosis

Genotype 1b

93% 93% 94%

1818

HCV TARGET Study (Interim Results):Virologic Failure and Safety

• Virologic failure (breakthrough/relapse)

– Genotype 1: <1%/11%

• Highest relapse rates among prior PI failures (19%)

– Genotype 2: <1%/8%

• Very low discontinuation rates (1.6%-2.5%)

• Regimens without PR had lower incidences of key adverse events

– Lowest incidences were with simeprevir + sofosbuvir


PR: pegIFN + RBV.

1919

Program Overview











20

Ledipasvir/Sofosbuvir in HCV Genotype 1, Cirrhotic Patients Who Failed Previous PI-Based Therapy

Bourlierre P, et al. Hepatology. 2014;60(suppl 1). Abstract LB-6.

Ledipasvir/Sofosbuvir qd + RBV (n=77)

Ledipasvir/sofosbuvir qd (n=78)

Phase 2 (France)Double-blindGenotype 1Treatment experiencedCompensated cirrhosisDid not achieved SVR12 with sequential PR and PI + PR

Week 0 12 24

PR: pegIFN + RBV.Ledipasvir/sofosbuvir 90/400 mg qd + weight-based RBV(1000-1200 mg).Primary endpoint: SVR12.Baseline demographics: Male: 74%. Mean age: 56 years. White: 97%. Genotype 1a: 63%. HCV RNA (log10 IU/mL): 6.6. IL28B non-CC: 94%. BMI: 27.1 kg/m2. Mean MELD: 7. Varices: 26%. Platelets: 147 x 109/L. Albumin: 3.9 g/dL. Mean INR: 1.1. Mean bilirubin: 0.8 mg/dL.

Placebo(n=77)

2121

Treatment Outcomes: Ledipasvir/Sofosbuvir in Cirrhotic Patients Who Failed Previous PI-Based Therapy

• SVR12 rates were similar regardless of treatment duration or use of RBV

– Relapse: 3%

• SVR12 rates in patients with and without NS3/4A RAVs at baseline (96% and 97%, respectively)

• Both treatment arms produced significant improvements in albumin, ALT, and bilirubin (P<0.001)

• Safe and well tolerated

– Treatment discontinuations due to adverse events: 1%

– Most adverse events were mild or moderate in severity

• Lower incidence of adverse events were seen in the 12-week arm

– Headache and fatigue more common in the ledipasvir/sofosbuvir arms versus placebo

Bourlierre P, et al. Hepatology. 2014;60(suppl 1). Abstract LB-6.

0

20

40

60

80

100

Pat

ien

ts (

%)

SVR12 Rates

96%

Ledipasvir/SofosbuvirRBV

12 Weeks(n=77)

97%

Ledipasvir/Sofosbuvir--

24 Weeks(n=77)

22

Ledipasvir/Sofosbuvir + RBV for Retreatment of Previous Sofosbuvir-Based Failures (HCV Genotype 1)

Wyles DL, et al. Hepatology. 2014;60(suppl 1):317A-318A. Abstract 235.

Phase 2Open-labelPrior relapsers of sofosbuvir combination with PR or RBV in phase 3 studies Genotype 1Compensated cirrhosis allowed


Week 0 12 24

PR: pegIFN + RBV.Ledipasvir/sofosbuvir 90/400 mg qd + weight-based RBV (1000-1200 mg).Primary endpoint: SVR12.Baseline demographics: Male: 61%. Mean age: 54 years. Black: 16%. Genotype 1a: 59%. HCV RNA (log10 IU/mL): 6.2. IL28B non-CC: 92%. BMI: 30.4 kg/m2. Cirrhosis: 29%. Prior sofosbuvir treatment: Monotherapy (placebo): 10%. + RBV: 41%. + PR: 49%.

2323

Treatment Outcomes: Ledipasvir/Sofosbuvir + RBV Retreatment of Sofosbuvir-Based Failures (HCV Genotype 1)

• All genotype 1 patients achieved SVR

– Relapse in 1 patient (later found to be genotype 3a at baseline and at relapse, began treatment before viral sequencing results)

• SVR12 rates in patients with and without NS5A RAVs at baseline (100% and 98%)


– Treatment discontinuations due to adverse events: 2%


– Most common adverse events

• Fatigue, headache, diarrhea, rash, insomnia, nausea


0

20

40

60

80

100

Pat

ien

ts (

%)

SVR Rates:Ledipasvir/Sofosbuvir + RBV

98%

SVR4(n=51)

98%

SVR12(n=51)

SVR24(n=51)

98%

2424

Program Overview











2525

ABT-450/r/Ombitasvir + Dasabuvir + RBV in HCV Genotype 1a: Integrated Efficacy Analysis From Phase 3 Studies

• Pooled data from

– SAPPHIRE-I and SAPPHIRE-II

– PEARL-IV

– TURQUOISE-II

• HCV RNA >10K IU/mL

• No HBV or HIV coinfection

Everson GT, et al. Hepatology. 2014;60(suppl 1):239A-240A. Abstract 83.

Treatment-Naïve

(n=744)


(n=314)

No cirrhosis (%) 3D + RBV 3D

5727

550

Cirrhosis (%) 3D + RBV 16 45

Distribution of Genotype 1a Patients

3D: ABT-450/ritonavir/ombitasvir 150/100/25 mg qd; dasabuvir 250 mg bid. RBV (1000-1200 mg).

2626

SVR12 Rates With ABT-450/r/Ombitasvir + Dasabuvir + RBV in HCV Genotype 1a: Integrated Efficacy Analysis


PR: pegIFN + RBV.

ABT-450/r/Ombitasvir + Dasabuvir

No RBV With RBV

0

20

40

60

80

100

SV

R12

(%

)

90%96%

No Cirrhosis

Treatment-Naïve

(n=202/420)

Relapse(n=50)

Partial(n=36)

Null(n=87)

Prior PR Response

94%100%

95%

With CirrhosisABT-450/r/Ombitasvir + Dasabuvir + RBV

12 weeks 24 weeks

P=0.006

0

20

40

60

80

100

SV

R12

(%

)

92%95%

Treatment-Naïve

(n=66/56)

Relapse(n=15/13)

Partial(n=11/10)

Null(n=50/42)

Prior PR Response

100% 100%

93%93%

100%

80%

2727

Predictors of Response With ABT-450/r/Ombitasvir + Dasabuvir + RBV in HCV Genotype 1a: Integrated Efficacy Analysis

• RBV dose reduction had no impact on achieving SVR12

– SVR12 was >98% among patients requiring RBV dose reduction

• Predictors for not achieving SVR

– No cirrhosis

• Baseline BMI (P=0.005)

• No RBV in regimen (P=0.007)

– With cirrhosis

• IL28B TT genotype (P=0.008)

• Prior null response to PR (P=0.009)

• Region (North America versus EU) (P=0.045)

• History of IDU (P=0.047)


2828

Program Overview











29

ALLY-3 Study:Daclatasvir + Sofosbuvir in HCV Genotype 3

Nelson DR, et al. Hepatology. 2014;60(suppl 1). Abstract LB-3.

Daclatasvir 60 mg + Sofosbuvir 400 mg qd(n=101)

Daclatasvir 60 mg + Sofosbuvir 400 mg qd(n=101)

Phase 3Open-labelGenotype 3Treatment-naïve and experiencedCirrhosis allowed

Week 0 12

Previous sofosbuvir or alisporivir failures were included.Primary endpoint: SVR12.Baseline demographics: Male: 57%-63%. Mean age: 53-58 years. White: 88%-91%. HCV RNA >800K IU/mL: 69%-75%. IL28B non-CC: 60%-61%. Cirrhosis: 19%-25%. Prior treatment failure: Relapse: 61%. Null response: 14%. Partial response: 4%. IFN intolerant/virologic breakthrough: 22%.

Treatment-Naïve


3030

ALLY-3 Study: Treatment Outcomes With Daclatasvir + Sofosbuvir in HCV Genotype 3

• No virologic breakthroughs

• Virologic relapse (n=16)

– Cirrhosis (n=11)

– Y93H at relapse (n=9)

• Generally safe and well tolerated

– No discontinuations due adverse events

• Further options for optimizing SVR rates with daclatasvir + sofosbuvir in genotype 3 patients with cirrhosis are being evaluated

Nelson DR, et al. Hepatology. 2014;60(suppl 1). Abstract LB-3.

SVR12

0

20

40

60

80

100

SV

R12

(%

)

90%

Overall(n=101/51)

97% 94%

58%

No(n=75/34)

Cirrhosis

Yes(n=19/13)

Treatment-naïve Treatment-experienced

69%

86%

3131

Program Overview











32

Sofosbuvir + GS-5816 + RBV in Treatment-Naïve, Non-Cirrhotic, HCV Patients (Genotypes 1-6)

Everson GT, et al. J Hepatology. 2014;60(suppl 1):S46. Abstract O111.Tran TT, et al. Hepatology. 2014;60(suppl 1):237A. Abstract 80.

Phase 2(Part A: 12 Weeks)

Open-labelTreatment-naïveNon-cirrhoticBMI >18 kg/m2

HCV RNA: >10K IU/mL

Week 0 8 12 24Sofosbuvir 400 mg qd.Primary endpoint: SVR12.Baseline demographics: Male: 64%. Age: 50 years. Black: 8%. Genotype 1a: 29%. IL28B non-CC: 62%. HCV RNA (log10 IU/mL): 6.4.

Sofosbuvir + GS-5816 25 mg qd(n=27)




Sofosbuvir + GS-5816 25 mg qd(n=11/7/1/4)

Sofosbuvir + GS-5816 100 mg qd(n=10/7/0/5)

Genotype 1

Genotype 3

Genotypes 2, 4-6

SVR12 (%)Relapse(number)

91

100

93

93

1

0

1

1

2:4/5/6:

91100

00

2:4/6:

10086/100

00

33

Sofosbuvir + GS-5816 + RBV in Treatment-Naïve, Non-Cirrhotic, HCV Patients (Genotypes 1 and 2)

Tran TT, et al. Hepatology. 2014;60(suppl 1):237A. Abstract 80.

Phase 2(Part B: 8 Weeks)

Open-labelTreatment-naïveNon-cirrhoticBMI >18 kg/m2

HCV RNA: >10K IU/mL

Week 0 8 12

Sofosbuvir 400 mg qd.Primary endpoint: SVR12.Baseline demographics: Male: 46%-64%. Age: 51-54 years. BMI: 26.4-29.5 kg/m2. White: 86%-91%. Genotype 1a: 44%-45%. IL28B non-CC: 58%-72%. HCV RNA (log10 IU/mL): 6.4-6.7.


Sofosbuvir + GS-5816 25 mg qd+ RBV (n=30)

Genotype 1

Genotype 2







34

SVR12 Rates: Sofosbuvir + GS-5816 + RBV in Treatment-Naïve, Non-Cirrhotic HCV Patients


0

20

40

60

80

100

SV

R12

(%

)

87%

Genotype 1

No RBV(n=30)

Sofosbuvir + GS-5816 25 mg

83%90%

Genotype 2

RBV(n=30)

81%

No RBV(n=29)


RBV(n=31)

0

20

40

60

80

100

SV

R12

(%

)

77%

No RBV(n=26)


88% 88%

RBV(n=25)

88%

No RBV(n=26)


RBV(n=26)

3535

Relapse Rates and Safety: Sofosbuvir + GS-5816 + RBV in Treatment-Naïve, Non-Cirrhotic, HCV Genotypes 1 and 2

• Relapse rates (genotype 1/2)

– GS-5816 25 mg arm: 13%/16%

– GS-5816 100 mg arm: 13%/12%

• Overall, 34% of virologic failures had detectable NS5A RAVS at time of failure

– Genotype 1 patients had similar SVR12 rates regardless of presence or absence of baseline NS5A RAVs (88% versus 86%)

– Genotype 2 patients with baseline NS5A RAVS had lower SVR12 rates versus those without baseline RAVS (94% versus 81%)

• Overall, SVR12 rates were lower and relapse rates higher in patients treated for 8 versus 12 weeks (genotype 1 and 2)


– Treatment discontinuations due to adverse events: <1%

• Most adverse events were mild or moderate in severity

– Fatigue, headache, nausea, diarrhea, insomnia

• Phase 3 studies evaluating the fixed-dose combination sofosbuvir/GS-5816 400/100 mg qd


36

Sofosbuvir + GS-5816 + RBV in Treatment-Experienced HCV Patients (Genotypes 1 and 3)

Pianko S, et al. Hepatology. 2014;60(suppl 1):297A-298A. Abstract 197.

Phase 2Open-labelGenotype 1 or 3Treatment-experienceCirrhosis allowedBMI >18 kg/m2

HCV RNA: >10K IU/mL

Sofosbuvir 400 mg qd.Primary endpoint: SVR12.Baseline demographics: Male: 66%-72%. Age: 55-56 years. BMI: 27.4-28.9 kg/m2. White: 86%-93%. Genotype 1a: 24%-28%. IL28B non-CC: 66%-80%. HCV RNA (log10 IU/mL): 6.5-6.6. Cirrhosis: 41%-45%. Prior relapse/breakthrough: 61%-80%.

Sofosbuvir + GS-5816 25 mg qd

Sofosbuvir + GS-5816 25 mg qd + RBV

Genotype 3Failed Prior PR

(no cirrhosis; n=107)



Week 0 12



Genotype 3Failed Prior PR

(cirrhosis; n=103)





Genotype 1Failed prior PI +PR(+ cirrhosis; n=111)



37

SVR12 Rates: Sofosbuvir + GS-5816 + RBV in Treatment-Experienced HCV Patients (Genotype 3)


0

20

40

60

80

100

SV

R12

(%

)

85%

No Cirrhosis

No RBV(n=26)


96%100%

With Cirrhosis

RBV(n=28)

100%

No RBV(n=27)


RBV(n=26)

0

20

40

60

80

100

SV

R12

(%

)

58%

No RBV(n=26)


84%88%

RBV(n=25)

96%

No RBV(n=26)


RBV(n=26)

Relapse(n=4)

Relapse(n=1)

NoRelapse

NoRelapse

Relapse(n=11)

Relapse(n=3)

Relapse(n=3)

Relapse(n=1)

3838

Additional Treatment Outcomes: Sofosbuvir + GS-5816 + RBV in Treatment-Experienced HCV Patients

• Baseline NS5A RAVs (deep sequencing): 20%

– Genotype 1 (16%): Q30H/R, L31M/V, Y93C/F/H

– Genotype 3 (21%): M28T, A30K/L/T/V, L31M, Y93H

• All virologic failures had NS5A RAVs at failure

– No S282T, L159F, or V321A


– RBV increased the incidence of adverse events and laboratory abnormalities


• Headache, fatigue, nausea, insomnia


SVR12 (Genotype 1)

0

20

40

60

80

100

SV

R12

(%

)

100%

No RBV(n=27)


97% 100%

RBV(n=29)

96%

No RBV(n=27)


RBV(n=28)

NoRelapse

Relapse(n=1)

NoRelapse

Relapse(n=1)

3939

Program Overview











40

Grazoprevir/elbasvir 100/50 mg qd + sofosbuvir 400 mg qd.Primary endpoint: SVR12.SVR4/8: SVR8 results are available for 98/102 patients, SVR4 results used for the remainder.Baseline demographics: Male: 62%-65%. Age: 51-57 years. White: 93%-100%. Genotype 1a: 76%-87%. IL28B non-CC: 67%-75%. HCV RNA (log10 IU/mL): 1.66-3.63.

Grazoprevir/Elbasvir + Sofosbuvir (4, 6, 8 Weeks): Treatment-Naïve, HCV Genotype 1 Patients

Lawitz E, et al. Hepatology. 2014;60(suppl 1). Abstract LB-33.

Phase 2(Interim Results)

Open-labelTreatment-naïveAny fibrosis stage allowedHemoglobin >9.5 g/dLHCV RNA: >10K IU/mL

Week 0 4 6 8

Grazoprevir/Elbasvir +Sofosbuvir (n=31)




No Cirrhosis

Cirrhosis

SVR4/8 (%)Relapse(number)

39

87

80

95

19

4

4

1

4141

Grazoprevir/Elbasvir + Sofosbuvir (4, 6, 8 Weeks): Treatment-Naïve, HCV Genotype 1 Patients

• Virologic relapse: 27% (28/102)

– Genotype 1a (n=25)/1b (n=3)

– Virologic sequencing at virologic failure (n=23, 12 had detectable RAVs)

• Most common RAVs at failure: NS5A (M28T, Q30R/K/H/L, L31M, Y93H/N)

• Baseline RAVs

– NS5A (n=8): 5 relapsed

– NS3 (n=1): achieved SVR 4/8

• Factors that may have impacted the likelihood of achieving SVR4/8

– HCV subtype, HCV RNA level at baseline, IL28B status, pharmacokinetics of the regimen components

• Overall the regimen was well tolerated

Lawitz E, et al. Hepatology. 2014;60(suppl 1). Abstract LB-33.

4242

Program Overview











43

Ledipasvir/Sofosbuvir + RBV in HCV Genotype 1 or 4 with Decompensated Cirrhosis

Flamm SL, et al. Hepatology. 2014;60(suppl 1):320A-321A. Abstract 239.


Ledipasvir/Sofosbuvir RBV qd (n=55)

Phase 2Open-labelGenotype 1 or 4CPT class B or CTreatment-naïve or experiencedNo organ transplantation or HCCTotal bilirubin <10 mg/dL Hemoglobin >10 g/dLCrCl: >40 mL/minPlatelets: >30K x 103/µL

Week 0 12 24

CPT: Child-Pugh-Turcotte.Ledipasvir/sofosbuvir 90/400 mg qd + weight-based RBV(1000-1200 mg).Primary endpoint: SVR12.Baseline demographics: Male: 61%-73%. Mean age: 58-60 years. White: 90%-97%. Genotype 1a: 63%-76%. HCV RNA (log10 IU/mL): 5.6-5.9. IL28B non-CC: 73%-87%. BMI >30 kg/m2: 33%-57%.

44

Ledipasvir/Sofosbuvir + RBV in HCV Genotype 1 or 4:Baseline Liver Status


CPT B CPT C

12 Weeks(n=30)

24 Weeks(n=29)

12 Weeks(n=23)

24 Weeks(n=26)

MELD score (%) <10 10-15 16-20 21-25

2070100

2855170

070300

050464

Ascites (%) 57 59 96 96

Encephalopathy (%) 67 55 91 88

Median bilirubin (mg/dL) 2.0 1.4 2.9 3.8

Median albumin (g/dL) 2.9 3.0 2.6 2.6

Median INR 1.3 1.3 1.4 1.4

Median platelets (x 103/µL) 88 73 81 71

Median hemoglobin (g/dL) 13.1 13 12.3 12.6

Median creatinine clearance (mL/min) 98 81 77 78

CPT: Child-Pugh-Turcotte.

4545

Ledipasvir/Sofosbuvir + RBV in HCV Genotype 1 or 4:Preliminary Results

• High SVR12 rates in HCV patients with advanced liver disease

• CPT B and C patients at post-treatment week 4

– Significant improvements in median total bilirubin and albumin

– Change in CPT scores

• Improved: 70%

• Stable: 21%

• Worsened: 9%

– Change in MELD score (CPT B/C)

• Improved: 64%/70%

• Stable: 19%/13%

• Worsened: 17%/18%


SVR12

0

20

40

60

80

100

SV

R12

(%

)

87%

Overall(n=52/47)

87% 89% 86%

CPT B(n=30/27)

CPT C(n=22/20)

Ledipasvir/Sofosbuvir + RBV 12 weeks 24 weeks

90%89%

Relapse(n=3)

Relapse(n=1)

Relapse(n=1)

Relapse(n=1)

46

Ledipasvir/Sofosbuvir + RBV in HCV Genotype 1 or 4:Preliminary Safety Summary


CPT B CPT C

12 Weeks(n=30)

24 Weeks(n=29)

12 Weeks(n=23)

24 Weeks(n=26)

Grade 3/4 adverse events (%) 7 28 26 42

Serious adverse events (%) 10 34 26 42

Treatment-related serious adverse event (%)

7 0 0 8

Treatment discontinuations due to adverse events (%)

0 3 0 8

Death (%) 3 7 9 4

CPT: Child-Pugh-Turcotte.Treatment-related serious adverse events: anemia (n=2), hepatic encephalopathy (n=1), peritoneal hemorrhage (n=1).Early discontinuations (n=1 for each): sepsis, hepatic encephalopathy, peritoneal hemorrhage.Deaths: septic shock (n=2), multi-organ failure and shock (n=2), oliguric renal failure (n=1), cardiac arrest (n=1).

4747

C-WORTHY Trial:Grazoprevir + Elbasvir + RBV in HCV Genotype 1

Lawitz E, et al. Hepatology. 2014;60(suppl 1):296A-297A. Abstract 196.Lawitz E, et al. Lancet. 2014;Nov 11. [Epub ahead of print].

Phase 2Open-labelGenotype 1Treatment-naïve or prior PR therapyCirrhosis allowedALT/AST: <350 IU/LAlbumin: >3.0 g/dLPlatelets: >70K/mm3

No HBV or HIV

Grazoprevir 100 mg qd + elbasvir 50 mg qd.Primary endpoint: SVR12.Baseline demographics: Male: 54%-67%. Age: 54-58 years. White: 90%-94%. Genotype 1a: 57%-70%. Cirrhosis: 35%-100%. IL28B non-CC: 65%-100%. HCV RNA >2M IU/mL: 65%-86%.

Grazoprevir + Elbasvir(n=31)

Grazoprevir + Elbasvir + RBV(n=290)

Treatment-NaïveCirrhotics

Prior PR Null Responders+ Cirrhosis







Week 0 12 18

4848

C-WORTHY Trial: SVR12 Rates With Grazoprevir + Elbasvir + RBV in HCV Genotype 1


Grazoprevir + Elbasvir

No RBV With RBV

0

20

40

60

80

100

SV

R12

(%

)

97%

Treatment-Naïve + Cirrhosis

12 Weeks(n=29/31)

18 Weeks(n=31/32)

Prior Null Responders + CirrhosisGrazoprevir + Elbasvir

No RBV With RBV

90%97%

94%

0

20

40

60

80

100

SV

R12

(%

)

91%

12 Weeks(n=33/32)

18 Weeks(n=32/33)

94%97% 100%

Relapse(n=1)

Relapse(n=2)

Relapse(n=2)

NoRelapse

Relapse(n=3)

NoRelapse

NoRelapse

NoRelapse

4949

C-WORTHY Trial: Resistance and Safety Results With

Grazoprevir + Elbasvir + RBV in HCV Genotype 1

• Virologic failure: 4% (10/253)

– Relapse (n=8 [7 genotype 1a])

– Breakthrough (n=2)

• SVR12 rates were not significantly impacted by the presence or absence of baseline NS5A or NS3 RAVs

– Most common RAVS at virologic failure

• NS3: Y56H, A156T/G/V, D168A/Y

• NS5A: M28T, Q30L/R, L31M, Y93H/N

• Discontinuations due to adverse events (1%)

• Serious adverse events (3%, not related to study drug)

• Most common adverse events: fatigue, headache, asthenia


5050

TURQUOISE-II: ABT-450/r/Ombitasvir + Dasabuvir + RBV in HCV Genotype 1, Compensated Cirrhotics

Fried MW, et al. Hepatology. 2014;60(suppl 1):238A. Abstract 81.Poordad F, et al. N Engl J Med. 2014;370:1973-1982.

ABT-450/r/Ombitasvir + Dasabuvir + RBV (n=208)

Phase 3Open-labelGenotype 1Treatment-naïve and PR experienced Child-Pugh APlatelets: >60K/mLSerum albumin: >2.8 g/dLTotal bilirubin: <3 g/dLINR: <2.3AFP: <100 ng/mL Week 0 12 24

ABT-450/ritonavir/ombitasvir 150/100/25 mg qd; dasabuvir 250 mg bid. RBV (1000-1200 mg). PR: pegIFN + RBV.Primary endpoint: SVR12 versus historical control SVR rate: 43% and 54% for non-inferiority and superiority, respectively (telaprevir + PR).Baseline demographics and disease characteristics: Male: 70%; age: 57 years; black: 4%-6%. Genotype 1a: 67%-70%. IL28B non-CC: 80%-83%. Treatment naïve: 41%-43%. Prior PR response: Relapse: 13%-14%. Partial response: 8%-9%. Null response: 36%. Child-Pugh score >5: 18%-19%.

ABT-450/r/Ombitasvir+ Dasabuvir + RBV(n=172)

5151

TURQUOISE-II: SVR12 Rates With ABT-450/r/Ombitasvir + Dasabuvir + RBV in HCV Genotype 1, Compensated Cirrhotics

Fried MW, et al. Hepatology. 2014;60(suppl 1):238A. Abstract 81.

0

20

40

60

80

100

SV

R12

(%

)

Relapser(n=29/23)

Partial(n=18/13)

Overall(n=208/172)

Treatment Naïve(n=86/84)

Prior Response to PR

92% 94%100% 100%

87%

95%97%97% 96%94%

Null(n=75/62)

ABT-450/r/Ombitasvir + Dasabuvir + RBV

12 weeks 24 weeks

PR: pegIFN + RBV.

5252

TURQUOISE-II: SVR12 Rates With ABT-450/r/Ombitasvir + Dasabuvir + RBV in HCV Genotype 1, Compensated Cirrhotics


ABT-450/r/Ombitasvir + Dasabuvir + RBV

12 weeks 24 weeks

0

20

40

60

80

100

1a(n=140/121)

1b(n=68/51)

CC(n=35/34)

CT(n=132/105)

IL28B Genotype HCV Subtype

<800K(n=32/19)

>800K(n=174/153)

HCV RNA (IU/mL)

TT(n=41/33)

94%99%

95%100%

94%91%

81%

92%89%

97% 97%95%90%

97%

SV

R12

(%

)

5353

TURQUOISE-II: HCV Genotype 1, Compensated Cirrhotics Not Achieving SVR12 With ABT-450/r/Ombitasvir + Dasabuvir + RBV

• Demographic factors not associated with lower SVR12 rates

– Age, gender, race, BMI, diabetes, baseline HCV RNA level, albumin, platelets

• Factors significantly associated with lower rates of SVR12

– IL28B TT genotype (P=0.021)

– Prior null response (P=0.038)

– HCV genotype 1a (P=0.046)

• Non-statistically significant trends were observed for AFP, treatment duration, and IDU


Number12 Weeks(n=208)

24 Weeks(n=172)

Did not achieve SVR12 17 6

Premature discontinuation On-treatment breakthrough Relapse

41

12

231

Genotype 1a HCV RNA >800K IU/mL AFP >20 ng/mL Prior null responder IL28B TT Platelet <90 x 109/L BMI >30 kg/m2

Albumin <3.5 g/dL

1111975543

10000011

Not Achieving SVR12With ABT-450/r/Ombitasvir + Dasabuvir + RBV

5454

Real-World Use of Sofosbuvir-Based Regimens in Recurrent HCV Post-Liver Transplantation: HCV TARGET Study

• Ongoing longitudinal, observational study of DAA-based therapy in recurrent HCV post-liver transplant (n=245)

– 38 academic and 15 community medical centers in the US, Germany, and Canada

– HCV treatment is administered according local standard of care

• Regimen selection made by health care provider

• Interim results for sequentially enrolled patients who started therapy with sofosbuvir-containing regimens

– Genotype 1 (n=179): sofosbuvir + simeprevir + RBV (79.7%), sofosbuvir + PR (13.4%), sofosbuvir + RBV (7.3%)

– Genotype 2 (n=20): sofosbuvir + RBV (100%)

– Genotype 3 (n=19): sofosbuvir + RBV (94.7%), sofosbuvir + PR (5.3%)

Brown RS, et al. Hepatology. 2014;60(suppl 1). Abstract LB-4.

Patients(n=227)

Male (%) 73.6Mean age (years) >65 years (%)

60.019.8

Black (%) 8.4Treatment experienced (%) Naïve Experienced PI failure

42.757.311.5

Cirrhosis (%) MELD >10 (%)

56.431.3

Immunosuppression (%) TAC CSA Everolimus/sirolimus MMF/MPA

76.712.315.942.3


PR: pegIFN + RBV.

5555

HCV TARGET Study (Interim Results): Crude SVR4 Rates WithSofosbuvir + Simeprevir + RBV in Recurrent HCV Post-Liver Transplantation


0

20

40

60

80

100

SV

R4

Rat

e (%

)

SOFSIMRBV(n=11)

Yes(n=37)

No(n=31)

Yes(n=37)

Cirrhosis

No(n=31)

Treatment Experienced

SOFSIM

--(n=57)

<10(n=12)

>10(n=13)

1a(n=36)

MELD

1b(n=19)

Genotype

82%

91%86%

94%89% 90% 92%

77%83%

95%


No RBV With RBV

HCV Genotype 1

5656

HCV TARGET Study (Interim Results): Treatment Outcomes WithSofosbuvir + Simeprevir + RBV in Recurrent HCV Post-Liver Transplantation

• Additional SVR4 rates

– Sofosbuvir + PR: 83% (10/12 genotype 1); 100% (1/1 genotype 3)

– Sofosbuvir + RBV: 90% (9/10 genotype 2), 60% (3/5 genotype 3)

• Predictors of SVR4 (adjusted for cirrhosis status, previous treatment, prior decompensation)

– For: baseline hemoglobin, age

– Against: baseline total bilirubin

• Safety

– >1 adverse event (82%, most deemed mild in severity)

– Discontinuations due to adverse events (2.2%)

– Serious adverse events (8.5%)

– No episodes of acute cellular rejection

– Renal failure (n=3; sofosbuvir + simeprevir [2], sofosbuvir + simeprevir + RBV [1])


PR: pegIFN + RBV.

5757

Ledipasvir/Sofosbuvir + RBV for Post-Transplantation HCV Recurrence (Genotype 1 or 4)

Reddy KR, et al. Hepatology. 2014;60(suppl 1):200A-201A. Abstract 8.



Phase 2Open-labelGenotype 1 or 4CPT class A, B, or CTreatment-naïve or experiencedNo HCCTotal bilirubin <10 mg/dL Hemoglobin >10 g/dLCrCl: >40 mL/minPlatelets: >30K x 103/µL

Week 0 12 24

CPT: Child-Pugh-Turcotte.Ledipasvir/sofosbuvir 90/400 mg qd.RBV (F0-F3 and CPT A cirrhosis: weight based; CBT B and C: continuous dose escalation 600-1200 mg).Primary endpoint: SVR12.Baseline demographics: Male: 80%-100%. Mean age: 59-61 years. White: 80%-89%. Genotype 1a: 67%-78%. HCV RNA (log10 IU/mL): 6.3-6.6. IL28B non-CC: 67%-85%. Median time from orthotopic liver transplantation: 2.9-8.1 years. Prior HCV treatment: 78%-90%.

5858

Ledipasvir/Sofosbuvir + RBV for Post-Transplantation HCV Recurrence (Genotype 1 or 4): Baseline Liver Status


CPT

F0-F3(n=111)

A(n=51)

B(n=52)

C(n=9)

MELD score (%) <10 10-15 16-20 21-25

--------

553960

256384

11562211

Ascites (%) 2 4 77 100

Encephalopathy (%) 1 6 44 78

Median bilirubin (mg/dL) 0.7 0.8 1.2 2.1

Median albumin (g/dL) 3.8 3.7 3.2 2.4

Median INR 1.0 1.1 1.2 1.3

Median platelets (x 103/µL) 146 108 93 79

Median hemoglobin (g/dL) 14.0 13.6 12.9 11.5

Median creatinine clearance (mL/min) 65 62 59 67


5959

Preliminary Outcomes: Ledipasvir/Sofosbuvir + RBV for Recurrent HCV Post-Transplantation (HCV Genotype 1 or 4)

• High SVR12 rates in HCV patients with advanced liver disease

• CPT A and B patients at post-treatment week 4

– Significant improvements in median total bilirubin and albumin

– Change in MELD score (CPT A/B)

• Improved: 42%/68%

• Stable: 27%/12%

• Worsened: 32%/20%



SVR12

0

20

40

60

80

100

SV

R12

(%

)

96%

F0-F3(n=55/56)

96%

85%

60%

CPT A(n=26/25)

CPT C(n=5/3)

Ledipasvir/Sofosbuvir + RBV 12 weeks 24 weeks

67%

98%

Relapse(n=2)

NoRelapse

CPT B(n=26/18)

96%

83%

NoRelapse

NoRelapse

Relapse(n=1)

NoRelapse

Relapse(n=2)

Relapse(n=1)

6060

Ledipasvir/Sofosbuvir + RBV for Post-Transplantation HCV Recurrence (Genotype 1 or 4): Preliminary Safety Summary


F0-F3 CPT A CPT B CPT C

12Weeks(n=30)

24 Weeks(n=29)

12Weeks(n=30)

24 Weeks(n=29)

12 Weeks(n=30)

24 Weeks(n=29)

12 Weeks(n=23)

24 Weeks(n=26)

Grade 3/4 adverse events (%)

27 25 15 28 23 35 20 25

Serious adverse events (%) 11 21 12 16 19 42 20 100

Treatment-related serious adverse event (%)

4 2 8 8 0 4 0 0

Treatment discontinuations due to adverse events (%)

0 4 4 0 0 12 0 0

Death (%) 0 0 4 0 4 8 0 0

CPT: Child-Pugh-Turcotte.Adverse events leading to discontinuation (n-1 for each): shortness of breath, hemoperitoneum, thoracis aorta aneurysm, seizure, elevated ALT/AST, dyspnea.Treatment-related serious adverse events: anemia (n=4), hemolytic anemia (n=2), portal vein thrombosis (n=1), sicks sinus syndrome (n=1), sinus arrhythmia (n=1).Treatment emergent deaths (n=1 for each): progressive multifocal leukoencephalitis, thoracic aorta aneurysm, internal bleeding, complications of cirrhosis.

6161

Multicenter Experience Using Sofosbuvir + Simeprevir + RBV for HCV Genotype 1 After Liver Transplantation

• Mayo Clinic (3 centers)

– Histologic evidence of HCV recurrence following liver transplantation (n=109)

– Sofosbuvir + simeprevir + RBV

• Median follow-up: 23 weeks

• Maintenance immunosuppression (minimal dose adjustment required)

– Tacrolimus (n=99)

– Cyclosporine (n=9)

– Sirolimus (n=1)

• No immunosuppression-related adverse events nor biopsy proven acute rejection

• RBV used in 24 patients, no difference in viral kinetics during treatment

Pungpapong S, et al. Hepatology. 2014;60(suppl 1):201A. Abstract 9.

Patients(n=109)

Male (%) 76Mean age (years) 61Non-Caucasian (%) 25Median time since liver transplantation

(months)29

Genotype 1a (%) 62IL28B non-CC (%) 71Previous HCV treatment failure (%) PR PI + PR Sofosbuvir + PR

69121

METAVIR F3-F4 (%) 29Cholestatic recurrence (%) 11HCV RNA >800K IU/mL (%) 90eGFR <30 mL/min 5


PR: pegIFN + RBV.

6262

SVR12 Rates: Sofosbuvir + Simeprevir + RBV for HCV Genotype 1 After Liver Transplantation


SV

R12

(%

)

0

20

40

60

80

100

PI/SOF(n=10)

PR(n=56)

Overall(n=66)

No RBV(n=47)

Genotype 1a

Overall(n=43)

F0-F2(n=32)

Prior HCVTreatment Failure

RBV(n=19)

91%97%

91%

64%

80%

94%93%91% 89%

96%94%

F3-F4(n=11)

Genotype 1b

Overall(n=23)

F0-F2(n=17)

F3-F4(n=6)

PR: pegIFN + RBV.

6363

Safety: Sofosbuvir + Simeprevir + RBV for HCV Genotype 1 After Liver Transplantation

• Sofosbuvir + simeprevir + RBV was well tolerated

– Fatigue (9%), hyperbilirubinemia (5%), nausea (4%), headache (4%), pruritus (3%), anemia in non-RBV versus RBV patients (2% verus 42%)

– RBV dose reduction (100%), erythropoietin (50%)

• Serious adverse events

– Acute pancreatitis (n=1)

• Resolved following treatment discontinuation for 2 weeks

• Treatment resumed and completed, achieved SVR12

– Drug-induced liver injury (n=1)

• Progressed to multi-organ failure and death


6464

CORAL-I Study: ABT-450/r/Ombitasvir + Dasabuvir + RBV for HCV Genotype 1 After Liver Transplantation

• Ongoing phase 2 study of 24 weeks of ABT-450/r/ombitasvir + dasabuvir + RBV

– HCV genotype 1 (n=34)

– Liver transplantation due to HCV infection

• PR permitted prior to transplantation

• Treatment-naïve post transplantation

– METAVIR <F2

• On stable immunosuppression

– Tacrolimus (85%)

– Cyclosporine (15%)

• Primary outcome: SVR12

Mantry PS, et al. Hepatology. 2014;60(suppl 1):298A-299A. Abstract 198.

Patients(n=34)

Male (%) 79

Mean age (years) 59.6

Fibrosis stage (%) F0/F1/F2 18/38/44

Median time since liver transplantation (months)

39.5

Genotype 1a (%) 85

IL28B non-CC (%) 77

HCV RNA (log10 IU/mL) 6.6

Creatinine clearance (mL/min) 90.5

ALT/AST (U/L) 78.9/63.9


ABT-450/ritonavir/ombitasvir 150/100/25 mg qd; dasabuvir 250 mg bid. RBV (1000-1200 mg).Tacrolimus: 0.5 mg once weekly or 0.2 mg every 3 days.Cyclosporine: 1/5 of daily dose given once daily prior to HCV therapy.

6565

CORAL-I Study: Treatment Outcomes With ABT-450/r/ Ombitasvir + Dasabuvir + RBV After Liver Transplantation

• SVR12 and SVR24 in HCV genotype 1: 97%

– No virologic breakthroughs

– Relapse (n=1)

• Emergent RAVs at time of relapse: R155K, M28T+Q30R, G554S

• No deaths, graft losses, or episodes of acute or chronic rejection

• Discontinuations due to adverse events (n=1)

• Serious adverse events (n=2)

– Hypotension and tachycardia associated with tamsulosin

– Moderate peripheral edema and pain in extremities in a diabetic patient

• All patients who required RBV dose reduction achieved SVR12

Mantry PS, et al. Hepatology. 2014;60(suppl 1):298A-299A. Abstract 198.

6666

Program Overview











6767

ERADICATE Trial: Ledipasvir/Sofosbuvir in HCV Genotype 1 Patients With HIV Coinfection

Townsend KS, et al. Hepatology. 2014;60(suppl 1):240A-241A. Abstract 84.

Ledipasvir/Sofosbuvir qd(n=13)

Lediapsvir/Sofosbuvir qd(n=37)

NIAID SponsoredOpen-labelGenotype 1HCV treatment-naïveNo cirrhosisART-naïve (stable HIV disease)ART-treated (HIV RNA <50 copies/mL)

Week 0 12

ART Untreated

ART Treated

Lediapsvir/sofosbuvir 90/400 mg qd.Primary endpoint: SVR12.ART was FTC/TDF plus either efavirenz (41%), raltegravir (27%), rilpivirine (21%).Baseline characteristics (HIV untreated/received ART): Male: 54%/81%. Genotype 1a: 75%/81%. Black: 77%/86%. IL28B non-CC: 85%/84%. HCV RNA: 6.06/5.97 log10 IU/mL. HAI stage 3 fibrosis: 38%/22%. CD4: 687/576 cells/µL. On ART: 97%.

6868

ERADICATE Trial: Ledipasvir/Sofosbuvir in HCV Genotype 1 Patients With HIV Coinfection

• Relapse (n=1 at SVR2)

• HCV RNA detectable at SVR36 (n=1)

• HIV status

– HIV RNA breakthrough (n=1) due to ART non-adherence, re-suppressed on same ART regimen

– No change in CD4 counts

• Well tolerated

– No discontinuations due to adverse events


• Fatigue, insomnia, headache, nausea

– No renal toxicity observed

Townsend KS, et al. Hepatology. 2014;60(suppl 1):240A-241A. Abstract 84.

SVR12

0

20

40

60

80

100

SV

R12

(%

)

100%

Not on ART (n=13)

On ART(n=37)

NoRelapse

Relapse(n=1)

97%

6969

C-WORTHY Trial: Grazoprevir + Elbasvir + RBV in HCV Genotype 1 With and Without HIV Infection

Sulkowski MS, et al. Hepatology. 2014;60(suppl 1):318A-319A. Abstract 236.Sulkowski MS, et al. Lancet. 2014;Nov 11. [Epub ahead of print].

Phase 2Open-labelGenotype 1No cirrhosisStable raltegravir + 2 NRTIsCD4 >300 cells/mm3

HIV RNA undetectableHad not failed more than 1 ART regimen

Grazoprevir 100 mg qd + elbasvir 50 mg qd.Primary endpoint: SVR12.Baseline characteristics (HCV/HCV-HIV): Male: 51%/80%. Age: 49/45 years. White: 91%/81%. Genotype 1a: 70%/78%. METAVIR F3: 8%/8%. IL28B non-CC: 77%/78%. HCV RNA: 6.3/6.35 log10 IU/mL. CD4: --/626 cells/mm3.


HCV Mono-Infected



Week 0 8 12

Genotype 1a

Genotype 1a + 1b

Genotype 1a + 1b

HCV/HIV Co-InfectedGrazoprevir + Elbasvir + RBV

(n=29)


Genotype 1a + 1b

Genotype 1a + 1b

7070

C-WORTHY Trial: Treatment Outcomes With Grazoprevir + Elbasvir + RBV in HCV Genotype 1 With and Without HIV Infection

• Virologic failure: 4%

– 12 weeks: 4%

– 8 weeks: 16%

• SVR12 rates were not impacted by presence of baseline NS5A or NS3 RAVs

• Most common RAVS at virologic failure

– NS3: Y56H, A156T/G/V, D168A/Y

– NS5A: M28T, Q30L/R, L31M, Y93H/N

• No discontinuations due to adverse events

• Serious adverse events (1%-3%)

• Most common adverse events: fatigue, headache, nausea, diarrhea

• No HIV breakthroughs

Sulkowski MS, et al. Hepatology. 2014;60(suppl 1):318A-319A. Abstract 236.

0

20

40

60

80

100

SV

R12

(%

)

HCV Monoinfected

8 Weeks(n=30)

12 Weeks(n=85/44)

2430

HIV/HCVCoinfected

12 Weeks(n=29/30)

SVR12

80%

93%98% 97%

87%

Grazoprevir + Elbasvir

With RBV No RBV

Relapse(n=5)

Relapse(n=2)

Relapse(n=1)

Relapse(n=1)

NoRelapse

7171

TURQUOISE-I: ABT-450/r/Ombitasvir + Dasabuvir + RBV in HCV Genotype 1 With HIV Co-Infection


Phase 3Open-label HCV genotype 1HCV RNA >10,000 IU/mLHCV treatment-naïve or PR experiencedChild-Pugh A cirrhosisStable HIV diseaseART restricted to regimens based on: Atazanavir (44%) Raltegravir (56%)



ABT-450/r/ombitasvir 150/100/25 mg qd; dasabuvir 250 mg bid. RBV (1000-1200 mg).PR: pegIFN + RBV.Primary endpoint: SVR12.Baseline demographics and disease characteristics: Male: 92%; age: 51 years; black: 24%. Genotype 1a: 89%. IL28B non-CC: 81%. Treatment naïve: 67%. Prior PR response: Relapse: 6%. Partial response: 11%. Null response: 16%.Cirrhosis: 19%.

Week 0 12 24

7272

TURQUOISE-I: ABT-450/r/Ombitasvir + Dasabuvir + RBV in HCV Genotype 1 With HIV Co-Infection

• Virologic failure (n=2)

– Both were genotype 1a, prior PR null responders, and cirrhotic at baseline

– Relapse (12-week regimen) and breakthrough (24-week regimen)

• Emergent RAVs in >2 targets at time of virologic failure

• HIV RNA breakthroughs (n=5/63)

• Safety

– No treatment-emergent serious adverse events or discontinuations due to adverse events

– RBV dose reduction (n=6, all achieved SVR)


• Fatigue, insomnia, nausea, headache

• Indirect hyperbilirubinemia most common laboratory abnormality (17/63 overall; 15 of 17 were receiving atazanavir-based ART)


0

20

40

60

80

100

SVR4(n=31/32)

SVR12(n=31/32)

Pat

ien

ts (

%)

94% 94% 94%

SVR RatesABT-450/r/Ombitasvir + Dasabuvir + RBV

12 weeks 24 weeks

91%

73

Evaluation and Outcomes Measurement Process

• You will receive an electronic initial evaluation to the email address provided within 1 business day

• Reminder email communications will be sent up to 5 days post lecture until the evaluation is completed

• Incomplete evaluations may preclude attendees from receiving their CME/CNE/CPE certificate & future communications about lectures in your area

• In addition, you will receive a long-term evaluation via email 8 to 12 weeks after completing this course to measure competence, performance, and/or patient outcomes achieved as a result of your participation in this CME/CNE/CPE sponsored educational activity

(Please note: If you attended multiple Simply Speaking® lectures throughout the year, a separate initial and long-term evaluation will be sent to you for each lecture.)

Documents

Post Conference HCV Update 65 th Annual Meeting of the American Association for the Study of Liver Diseases Simply Speaking ® Hepatitis “Post Conference