Sponsored for CME credit by Rush University Medical Center

Post Conference Update

48th Annual Meeting of the EuropeanAssociation for the Study of the Liver

Sponsored for CME credit by Rush University Medical Center

Supported by an independent educational grant from Gilead Sciences Medical Affairs

2

Content Development & Training FacultyContent Development & Training Faculty

Robert S. Brown, Jr., MD, MPHFrank Cardile Professor of

Medicine and SurgeryChief, Center for Liver Disease

and TransplantationColumbia University College of

Physicians and SurgeonsNewYork-Presbyterian Hospital

New York, New York

● Disclosures- Grants/Research Support: Gilead Sciences, Jannsen, Merck Vertex

- Consultant: Gilead Sciences, Vertex

- Speakers’ Bureau: Genentech, Gilead Sciences, Merck, Vertex

- Stock Shareholder: None

- Other Financial or Material Support: None

3

Learning ObjectivesLearning Objectives(CME/CNE and CPE)(CME/CNE and CPE)

We Are Eliminating Hard Copy Evaluations!

● Upon completion of this activity, the participant intends to incorporate the following objectives into their practice of medicine:

- Screen and test for hepatitis B and C virus (HBV, HCV) infection in my patients 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 HBV and HCV treatment strategies for my patients with HBV and HCV infection

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

- Evaluate new agents being investigated for HBV and HCV therapy with patients in order to optimize information-based decision making about therapy

CME/CNECME/CNE● Upon completion of this activity, the

pharmacist should be able to:

- Review the screening and testing process for hepatitis B and C virus (HBV, HCV) infection in my patients according to the recommendations from the American Association for the Study of Liver Diseases (AASLD) and the Centers for Disease Control and Prevention (CDC)

- Discuss antiviral HBV and HCV treatment strategies in patients with HBV and HCV infection

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

- Evaluate new agents being investigated for HBV and HCV therapy with patients

CPECPE

4

Program Overview

● HCV and HBV: epidemiology and public health considerations

● Chronic HCV infection

- New and emerging HCV regimens

• Interferon-free regimens

• DAA + PR

- Clinical considerations with telaprevir-based regimens

- Liver transplantation and triple therapy

● Chronic HBV infection

5

ANRS CO12 CirVir: HCC in HCV- andHBV-Related Compensated Cirrhosis

● Prospective cohort (2006-2012)

- 35 French centers, consecutive enrollment

- Biopsy proven Child-Pugh A cirrhosis related to chronic HCV or HBV infection

- Absence of previous decompensation

- 6 month visits (HCC screening)

● Median follow-up: 33.9 months

● Receiving treatment

- HCV: 93.4%

- HBV: 92.4%

Trinchet JC, et al. J Hepatol. 2013;58(suppl 1):S50. Abstract 112.

HCV(n=1308)

HBV(n=315

)

Male (%) 63.4 82.3

Age (years) 55.4 53.0

Comorbidities (%) Alcohol Metabolic syndrome/NAFLD HIV

17.817.04.3

5.08.64.8

HCV characteristics (%) Genotype 1 Anti-HBc positive HCV RNA positive

56.029.371.3

------

HBV characteristics (%) Anti-HBe positive HDV positive HBV DNA positive

------

579.5

31.1

Baseline Characteristics

6

ANRS CO12 CirVir:Outcomes

● Comorbidities and the absence of viral control were more frequent in the HCV arm

● HCC incidence was higher in the HCV arm

● Only 48% of detected hepatic nodules were confirmed as primary liver cancer

● Complications and death were more frequent in the HCV arm

● Non-liver mortality accounts for half of deaths after 3 years

Trinchet JC, et al. J Hepatol. 2013;58(suppl 1):S50. Abstract 112.

HCV(n=1308)

HBV(n=315

)

Hepatic nodules detected at 4 years (%)

26.4 26.4

Primary liver cancer detected at 4 years (%)

11.6 7.0

Survival (%) 86.4* 97.2

Causes of death (%) HCC-related Non-HCC related Extra hepatic

18.028.448.0

HCC screening leads to Tumor within Milan criteria First-line curative treatment

7564

Outcomes

*P=0.0002 log-rank versus HBV arm.

7

HCV Treatment Rate in Select European Countries (2010)

● Approximately 6.7 million persons were HCV viremic in 22 European countries

- Russia (2.1 million) and Italy (1.5 million) comprised 55% of HCV prevalence

● Since 2008, there are signs of patients being warehoused in Western European countries

● Highest treatment rates were in Western Europe relative to Eastern Europe

- France has the highest treatment rate in Europe (and globally)

Razavi H, et al. J Hepatol. 2013;58(suppl 1):S22-S23. Abstract 51.

Tre

atm

ent

Rat

e (

%)

Treatment Rates in Select Countries (2010)

6.7%

3.4%3.0%

0.8%

France Sweden Germany UK Austria Italy Russia

4.3% 4.3%

0.3%

8

Predictors of Mortality Among US Veterans With Chronic HCV Infection

● Retrospective cohort study of US Veterans using ERCHIVES

- HCV positive (n=195,585)

- HCV negative (n=202,739)

● All-cause mortality for HCV infected and non-infected

- 43.9 and 24.0 per 1000 person-years, respectively

● Strongest predictors of mortality among HCV infected

- Decompensated liver disease, anemia, cancer, chronic kidney disease, and COPD

● HCV treatment was associated with a lower risk of mortality (HR: 0.43)

Erqou S, et al. J Hepatol. 2013;58(suppl 1):S185. Abstract 453.

ERCHIVES: Electronically retrieved cohort of HCV Infected Veterans.

HCVPositive

(n=195,585)

HCVNegative

(n=202,739)

Decompensated liver disease

3.05(2.97, 3.14)

2.38(2.3, 2.47)

Anemia 2.03(1.98, 2.08)

2.19(2.12, 2.27)

Cancer 1.72(1.67, 1.77)

1.68(1.62, 1.74)

Chronic kidney disease

1.42(1.38, 1.46)

1.57(1.52, 1.63)

COPD 1.40(1.35, 1.44)

1.59(1.54, 1.66)

Predictors of Mortality(Adjusted Hazard Ratios)

9

Program Overview





• DAA + PR




10

FISSION Trial: Sofosbuvir + RBV in Treatment-Naïve, HCV Genotype 2 or 3

Gane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

Phase 3Open-labelTreatment-Naïve Genotype 2 or 3

Week 0 12 24 36

Sofosbuvir (nucleotide NS5B polymerase inhibitor).No upper limit to age or BMI.Opioid substitution permitted.Platelet >75,000/mm3 (cirrhotic: 20% maximum).Stratified by genotype, HCV RNA, and cirrhosis.Primary efficacy endpoint: SVR12 (non-inferiority margin: 15%).

Follow-UpSofosbuvir 400 mg qd + RBV 1000-1200 mg/day

(n=256)

PegIFN + RBV (800 mg/day)(n=243)

Follow-Up

11

FISSION Trial: SVR12 Ratesby Prespecified Subgroups


Pat

ien

ts (

%)

78%

67%

97%

56%

67%

Overall*(n=253/243)

63%66%

75%

62%

72%67%

74%

Sofosbuvir + RBVPR

47%

38%

2(n=70/67)

3(n=183/176)

<6(n=107/106)

>6(n=146/137)

No(n=204/193)

Yes(n=49/50)

Genotype BaselineHCV RNA (log)

Cirrhosis

Male(n=168/156)

Female(n=85/87)

Gender

79%76%

61% 62%

*Non-inferiority criteria met.

12

FISSION Trial: SVR12 Ratesby Genotype and Cirrhosis


Pat

ien

ts (

%)

Genotype 2

98%91%

82%

62%

No Cirrhosis(n=59/54)

Cirrhosis(n=11/13)

Pat

ien

ts (

%)

Genotype 3

61%

71%

34%30%


Cirrhosis(n=38/37)

Sofosbuvir + RBVPR

Sofosbuvir + RBVPR

13

FISSION Trial:Resistance and Safety

● No resistance detected in sofosbuvir + RBV virologic failures

- Relapse accounted for all but 1 virologic failure (nonadherence)

● Safety of sofosbuvir + RBV

- Well tolerated and few adverse events

- Most common adverse events

• Fatigue (36%), headache (25%), nausea (18%), insomnia (12%)

- Safety profile consistent with ribavirinGane E, et al. J Hepatol. 2013;58(suppl 1):S3. Abstract 5.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

14

FUSION Trial: Sofosbuvir + RBV for 12 Versus 16 Weeks in

HCV Genotype 2/3, Previously Failed PR Therapy

Nelson DR, et al. J Hepatol. 2013;58(suppl 1):S3-S4. Abstract 6.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

Phase 3Double-blindFailed Prior PegIFN-Based Therapy Genotype 2 or 3

Sofosbuvir (nucleotide NS5B polymerase inhibitor).No upper limit to age or BMI.Opioid substitution permitted.Platelet >50,000/mm3, no neutrophil minimum.Cirrhosis at baseline (34%). Prior relapsers (76%).Stratified by genotype and cirrhosis.Primary efficacy endpoint: SVR12.


(n=103)

Week 0 12 16 24

Placebo

Sofosbuvir 400 mg qd +RBV 1000-1200 mg/day (n=98)

Follow-Up

15

FUSION Trial: SVR12 Ratesby Prespecified Subgroups


Pat

ien

ts (

%)

94%

50%

86%

30%

73%*

Overall(n=100/95)

62%*

77%

50% 50%

61%62%

76%

Sofosbuvir + RBV 12 weeks 16 weeks

31%

66%

2(n=36/32)

3(n=64/63)

<6(n=26/29)

>6(n=74/66)

No(n=64/63)

Yes(n=36/32)


Cirrhosis

Male(n=71/64)

Female(n=29/31)

Gender

69%

87%

42%

66%

*P<0.001 versus 12 weeks of active therapy.

16

FUSION Trial: SVR12 Ratesby Genotype and Cirrhosis


Pat

ien

ts (

%)

Genotype 2

96%

60%

100%

78%


Cirrhosis(n=10/9)

Pat

ien

ts (

%)

Genotype 3

37%

63%

19%

61%


Cirrhosis(n=26/23)



17

FUSION Trial:Resistance and Safety




• No discontinuations due to adverse events



- Safety profile consistent with ribavirin

• Hemoglobin <10 g/dL: 7.5%

• Hemoglobin <8.5 g/dL: 1%


18

POSITRON Trial: Sofosbuvir + RBV in HCV Genotype 2 or 3 With Limited Options

Jacobson IM, et al. J Hepatol. 2013;58(suppl 1):S28. Abstract 61.Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.

Phase 3Double-blind, placebo-controlledInterferon-Ineligible, Intolerant, or unwilling Genotype 2 or 3

Sofosbuvir (nucleotide NS5B polymerase inhibitor).No upper limit to age or BMI.Opioid substitution permitted.No lower limit to platelet or neutrophil count.Cirrhosis at baseline (16%). Prior relapsers (76%).Stratified by presence or absence of cirrhosis.Primary efficacy endpoint: SVR12.


(n=207)

Week 0 12 24

Placebo (n=71)Follow-Up

19

POSITRON Trial: SVR12 Rates With Sofosbuvir + RBV by Prespecified Subgroups

Pat

ien

ts (

%)

93%

78%

Overall(n=207)

61%

79%76%81%

61%

2(n=109)

3(n=98)

<6(n=67)

>6(n=140)

No(n=176)

Yes(n=31)


Cirrhosis

Male(n=117)

Female(n=90)

Gender

84%

73%

SVR12 rate was 0% in the placebo arm.


20

POSITRON Trial: SVR12 Rates WithSofosbuvir + RBV by Genotype and Cirrhosis

Pat

ien

ts (

%)

Genotype 2

92% 94%

No Cirrhosis(n=92)

Cirrhosis(n=17)

Pat

ien

ts (

%)

Genotype 3

68%

21%

No Cirrhosis(n=84)

Cirrhosis(n=14)

SVR12 rate was 0% in the placebo arm.


21

POSITRON Trial:Resistance and Safety




• Treatment discontinuations due to adverse events: 2%




• Hemoglobin <10 g/dL: 7%



22

Phase 2aPrior Nonresponse, Relapse, or Breakthrough with Telaprevir or Boceprevir With PRGenotype 1

Study 040: Sofosbuvir + Daclatasvir + RBV in Previous Telaprevir or Boceprevir Failures

Week 0 12 24 48

Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd (n=21)

Sofosbuvir 400 mg qd +Daclatasvir 60 mg qd + RBV (n=20)

Follow-Up

Follow-Up

Sulkowski MS, et al. J Hepatol. 2013;58(suppl 1):S570. Abstract 1417.

Sofosbuvir (nucleotide NS5B polymerase inhibitor).Daclatasvir (NS5A replication complex inhibitor).HCV RNA >105 IU/mL.No upper limit to age or BMI.METAVIR score: F0-F1 (12%), >F2 (88%).NS3 polymorphisms conferring resistance to boceprevir or telaprevir as baseline: 46%NS5A polymorphisms conferring resistance to daclatasvir: 7%Excluded: patients who discontinued telaprevir or boceprevir due to an adverse event.Primary efficacy endpoint: SVR12.

23

Study 040 (24-Week Treatment):SVR4 and SVR12 Rates

● No virologic failures

● Neither baseline NS3 PI resistance nor use of RBV influenced response

● Sofosbuvir + daclatasvir + RBV was well tolerated

- No discontinuations due to adverse events

● Most common adverse events (without RBV)

- Fatigue (29%), headache (33%), arthralgia (14%)

● No grade 3/4 elevations in ALT, AST, or total bilirubin

● Anemia (hemoglobin <9 g/dL): 0%

Sulkowski MS, et al. J Hepatol. 2013;58(suppl 1):S570. Abstract 1417.

Pat

ien

ts (

%)

Genotype 1SVR4 SVR12

100% 100%95%*

Sofosbuvir +Daclatasvir

(n=21)

100%

Sofosbuvir +Daclatasvir + RBV (n=20)*1 patient missing at post-treatment 12 weeks,

HCV RNA undetectable at post-treatment week 24 (preliminary).

24

ELECTRON Study: Sofosbuvir + RBV + Either Ledipasvir (NS5A Inhibitor) or GS-9669 (NS5B Non-Nucleoside Inhibitor)

Week 0 4 8 12 24

Follow-Up

Treatment-Naïve(n=25)

Sofosbuvir (nucleotide NS5B polymerase Inhibitor).No cirrhosis. Weight-based ribavirin dosing (1000-1200 mg).

Sofosbuvir 400 mg qd + RBV

Sofosbuvir 400 mg qd + RBVNull Responders

(n=10)

Sofosbuvir 400 mg qd + Ledipasvir+ RBV

Follow-Up


Sofosbuvir 400 mg qd + Ledipasvir+ RBV

Follow-Up

Null Responders(n=9)

Gane EJ, et al. J Hepatol. 2013;58(suppl 1):S6-S7. Abstract 14.

Phase 2bGenotype 1 Follow-Up

Sofosbuvir 400 mg qd + GS-9669+ RBV

Follow-Up


Sofosbuvir 400 mg qd + GS-9669+ RBV

Follow-Up

Null Responders(n=9)

25

ELECTRON Study (Genotype 1 Cohort):Interim Analysis of SVR12 Rates


Pat

ien

ts (

%)

Treatment-Naive

84%92%

Sofosbuvir + RBV(n=25)

Null Responders100%

Sofosbuvir + Ledipasvir

+ RBV(n=25)

Sofosbuvir + GS-9669

+ RBV(n=25)

Pat

ien

ts (

%)

10%

100%

Sofosbuvir + RBV(n=10)

100%

Sofosbuvir + Ledipasvir

+ RBV(n=9)

Sofosbuvir + GS-9669

+ RBV(n=3)

26

ELECTRON Study(Genotype 1 Cohort): Safety

● Adding ledipasvir to sofosbuvir + RBV

- No additional safety or tolerability issues

● Adding GS-9669 to sofosbuvir + RBV

- No additional safety or tolerability issues

● Fix-dose combination of sofosbuvir/ledipasvir

- Undergoing phase 3 trial in patients with and without cirrhosis

- Additional studies exploring shorter duration of therapy


27

Phase 2Treatment-naïveGenotype 1

AVIATOR Study: ABT-450/r-Based Therapy (Treatment-Naïve Cohort)

Week 0 8 12 24

ABT-450/r 150/100 mg qd +ABT-267 + ABT-333 + RBV (n=80)

Follow-Up

ABT-450/r 150/100 mg qd +ABT-333 + RBV (n=41)

Follow-Up

ABT-450/r 100/100 or 200/100 mg qd +ABT-267 + RBV (n=79)

ABT-450 (NS3/4A protease inhibitor); ABT-267 (NS5A replication complex inhibitor); ABT-333 (non-nucleoside NS5B polymerase inhibitor).HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV.ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid.Primary outcome: SVR24.

Follow-Up

ABT-450/r 150/100 mg qd +ABT-267 + ABT-333 (n=79)

Follow-Up

ABT-450/r 100/100 or 150/100 mg qd +ABT-267 + ABT-333 + RBV (n=79)

Follow-Up

ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=80)

Kowdley KV, et al. J Hepatol. 2013;58(suppl 1):S2. Abstract 3.

28

AVIATOR Study (ITT): OverallSVR Rates (Treatment-Naïve Cohort)

Pat

ien

ts (

%)

83%89%

85%91%88%

ABT-450/rABT-267ABT-333

RBV(n=80)

8 Weeks 12 Weeks

ABT-450/r--

ABT-333RBV

(n=41)

ABT-450/rABT-267

--RBV

(n=79)


--(n=79)


RBV(n=79)


89%96%

90%

99%93%

87% 90%


RBV(n=80)

24 Weeks

SVR12SVR24

29

AVIATOR Study: SVR24 by Baseline Subgroups (Treatment-Naïve Cohort)

Pat

ien

ts (

%)

98%92% 91%

94%

Male(n=78)


89% 91%94% 94% 95%

89%

ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined)

Female(n=81)

1a(n=108)

1b(n=50)

>7(n=35)

<7(n=124)

F0-F1(n=113)

F2-F3(n=42)

Non-CC(n=115)

CC(n=44)

Genotype HCV RNA(log)

Fibrosis Stage

IL28B Genotype

30

Phase 2Null RespondersGenotype 1

AVIATOR Study: ABT-450/r-Based Therapy (Null Responders Cohort)

Week 0 8 12 24

Received at least 12 weeks of pegIFN + RBV and failed to achieve >2 log10 IU/mL HCV RNA decrease.HCV RNA >50K IU/mL, absence of cirrhosis, no HIV or HBV.IL28B CC genotype (~3%).ABT-267 25 mg qd; ABT-333 400 mg bid. Ribavirin 1000-1200 mg divided bid.Primary outcome: SVR24.

Follow-Up

Follow-Up

ABT-450/r 100/100 or 150/100 mg qd + ABT-267 + ABT-333 + RBV (n=43)


ABT-450/r 100/100 or 200/100 mg qd +ABT-267 + RBV (n=45)

ABT-450/r 100/100 or 150/100 mg qd +ABT-267 + ABT-333 + RBV (n=45)

31

AVIATOR Study (ITT): OverallSVR Rates (Null Responders Cohort)

Pat

ien

ts (

%)

89% 89%

12 Weeks

ABT-450/rABT-267

--RBV

(n=45)


RBV(n=45)



RBV(n=43)

24 Weeks

SVR12SVR24

93% 93%98% 95%

32

AVIATOR Study: SVR24 by Baseline Subgroups (Null Responders Cohort)

Pat

ien

ts (

%)

97%93% 93%

97%

Male(n=55)


91% 93%96% 95% 94%

100%

ABT-450r + ABT-267 + ABT-333 + RBV (12- and 24-Week Arms Combined)

Female(n=53)

1a(n=55)

1b(n=33)

>7(n=22)

<7(n=66)

F0-F1(n=41)

F2-F3(n=45)

Non-CC(n=85)

CC(n=3)

Genotype HCV RNA(log)

Fibrosis Stage

IL28B Genotype

33

AVIATOR Study:Virologic Relapse and Safety

● Virologic relapse in prior null responders

- 8-, 12-, and 24-week arms: 12.5%, 6.3%, 2.5%

● Discontinuations due to adverse events in the 12- and 24-week arms: 2.4%

- Considered related to treatment (n=4/6): hepatitis cholestatic, feeling jittery, homicidal ideation, decreased creatinine clearance

● Most common adverse events

- Headache (31%), fatigue (30%), nausea (23%), insomnia (20%), diarrhea (15%)

- Bilirubin increase: 2.4%

- Anemia (hemoglobin 6.5 to <8 g/dL): 2.4%


34

Program Overview





• DAA + PR




35

NEUTRINO Study: Sofosbuvir + PR in Treatment-Naïve, HCV Genotype 1, 4, 5, and 6

Lawitz E, et al. J Hepatol. 2013;58(suppl 1):S567. Abstract 1411.Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.

Phase 3Open-labelTreatment-Naïve Genotype 1, 4, 5, and 6

Week 0 12 24 36

Sofosbuvir (nucleotide NS5B polymerase Inhibitor).No upper limit to age or BMI.Opioid substitution permitted.Platelets >90,000/mm3, neutrophils >1500/mm3 or 1000/mm3 (blacks).Cirrhosis permitted (17% enrolled).Primary efficacy endpoint: SVR12.Prespecified comparison to historical SVR control rate of 60%.

Follow-UpSofosbuvir 400 mg qd + PR (n=327)

36

NEUTRINO Study: SVR12 Ratesby Prespecified Subgroups


Pat

ien

ts (

%)

82%

90%*96%

92%

Overall(n=327)

100%96%

89% 92%

80%

98%

1a(n=225)

1b(n=66)

<6(n=71)

>6(n=256)

No(n=273)

Yes(n=54)


Cirrhosis

CC(n=98)

Non-CC(n=232)

IL28B

87%

4(n=28)

5/6(n=7)

*P<0.001 versus historical SVR rate of 60%.

Sofosbuvir 400 mg qd + PR (12 weeks)

37

NEUTRINO Study:Resistance and Safety

● No resistance detected in sofosbuvir + PR virologic failures and 1 relapse patient who discontinued therapy (HCV RNA >1000 IU/mL)

● Safety of sofosbuvir + PR

- Well tolerated and no additive effects of the addition of sofosbuvir to PR

• Discontinuations due to adverse events: 2%


• Fatigue (59%), headache (36%), nausea (34%), insomnia (25%), anemia (21%), rash (18%)


• Hemoglobin <10 g/dL: 23%



38

QUEST-2 Trial: Simeprevir + PR in Treatment-Naïve, HCV Genotype 1

Manns M, et al. J Hepatol. 2013;58(suppl 1):S568. Abstract 1413.

Week 0 12 24 48 72

Simeprevir (NS3/4A protease inhibitor).HCV RNA >10,000 IU/mL.PR: pegIFN (alpha 2a or 2b) + RBV (weight-based dosing: 1000-1200 mg).Patients stratified by HCV subtype and IL28B genotype.Response-guided therapy criteria: HCV RNA <25 IU/mL at week 4 and undetectable at week 12.METAVIR score: F0-F1 (50%); >F2 (50%).Primary efficacy endpoint: SVR12.

Simeprevir150 mg qd + PR

(n=257)

Follow-Up

Follow-Up

Phase 3Treatment-naïveGenotype 1

PRPR

PR (n=134)Follow-Up

39

QUEST-2 Trial: SVR12 Ratesby Prespecified Subgroups


Pat

ien

ts (

%)

46%

81%* 80%* 82%*

50%

Overall(n=257/134)

53%

41%

96%*

80%*

58%*

81%

19%

Simeprevir + PRPR

85%*

51%

1a(n=107/57)

1b(n=150/77)

CC(n=75/42)

CT(n=142/71)

TT(n=40/21)

F0-F2(n=195/102)

Genotype IL28B Genotype METAVIR Score

F3(n=37/17)

F4(n=17/15)

65%*

40%

67%*

53%

*P<0.01 versus PR.

40

QUEST-2 Trial:Resistance and Safety

● NS3 PI mutations were detected in the time of failure 98% of simeprevir-treated patients not achieving an SVR

- Genotype 1: mainly R155 alone

- Genotype 1b: mainly D168V or Q80R + D168E

● Simeprevir + PR was well tolerated

- Simeprevir treatment discontinuations due to adverse events: 1.6%

● Adverse event profile of simeprevir + PR was similar to the PR arm

- Headache, pyrexia, fatigue, influenza-like illness, rash, anemia, pruritus


41

STARTVerso1 Trial: Faldaprevir + PRin Treatment-Naïve, Genotype 1

Ferenci P, et al. J Hepatol. 2013;58(suppl 1):S569-S570. Abstract 1416.

Week 0 12 24 48 72

ETS, Follow-Up

Follow-Up

Faldaprevir120 mg qd + PR

(n=261)

PR

Faldaprevir240 mg qd + PR

(n=262)PR

ETS, Follow-Up

PRFollow-Up

Faldaprevir (NS3/4A protease inhibitor).Platelets >90,000 cells/mm3.No HBV or HIV coinfection. Fibrosis stage >F3: 17%ETS: early treatment success (HCV RNA <25 IU/mL at week 4 and undetectable at week 8.Primary efficacy endpoint: SVR12

Phase 3Treatment-NaïveGenotype 1

PRFollow-Up

PRFaldaprevir + PR

No ETS

No ETS

42

STARTVerso1 Trial: SVR12 Ratesby Prespecified Subgroups


Pat

ien

ts (

%)

36%

69%

84%83%76%

Overall(n=259/261/132)

60%

70%

90%

63%69%

95%

51%

Faldaprevir 120 mg qd + PRFaldaprevir 240 mg qd + PRPR

76%

1a(n=87/90/45)

1b(171/171/86)

CC(n=75/42)

CT(n=142/71)

TT(n=40/21)

Genotype IL28B Genotype

ETS Patients

(n=225/232)

86%89%

79%

28%

*P<0.0001 versus PR.

79%*80%*

52%

43

STARTVerso1 Trial:Resistance and Safety

● No significant effect of Q80K on SVR12 in genotype 1a patients

● Faldaprevir + PR was well tolerated

- Discontinuations due to adverse events: 4%

● Adverse event profile of faldaprevir + PR was similar to the PR arm

- Most common adverse events of at least moderate severity

• Rash (8%), anemia (12%)

● Total bilirubin elevations >2.6 x ULN with faldaprevir + PR were benign and transient

- 120 mg qd: 12%

- 240 mg qd: 53%


The Q80K mutation is associated with a decreased susceptibility to some NS3/4A protease inhibitors.

44

Program Overview





• DAA + PR




45

HEP3002 Study: Impact of Anemia inSevere Fibrosis and Compensated Cirrhosis

● International telaprevir early access program

- Open-label, genotype 1

- No HIV or HBV coinfection

- No history of decompensated liver disease

● Telaprevir + PR

- Severe fibrosis (F3)

- Compensated cirrhosis (F4)

● Interim analysis of the first 609 patients with data to week 16

Colombo M, et al. J Hepatol. 2013;58(suppl 1):S329-S330. Abstract 806.

F3(n=271)

F4(n=335

)

Male (%) 64 69

Age (years) 52.4 54.5

Genotype (%) 1a 1b

2968

2868

BMI (kg/m2) 26.4 27.2

HCV RNA (%) <800K IU/mL >800K IU/mL

2869

3363

Prior response (%) Treatment-naïve + relapsers Prior non-responders + viral breakthrough

5149

4753


46

HEP3002 Study: Impact of Anemia inSevere Fibrosis and Compensated Cirrhosis

● Incidence of grade 3 or 4 amenia: 31%

- More common in patients with F4 stage disease at baseline

- Discontinuations due to anemia: 3%

● Anemia management

- Dose-reduced RBV: 34%

- Erythropoietin: 24%

- Transfusion: 11%

- Iron-based therapy: 1%

Colombo M, et al. J Hepatol. 2013;58(suppl 1):S329-S330. Abstract 806.

F3(n=271)

F4(n=335)

Rash 5.5 4.5

Anemia 1.1 4.8

Asthenia 1.1 1.2

Abdominal pain 0.4 1.5

Nausea 1.1 0.9

Pruritus 0.4 1.5

Vomiting 1.5 0.6

Discontinuations due to Adverse Events (%)

47

C219 Rollover Study: Telaprevir + PR in PR Failures From the REALIZE Study

● Phase 3b, single-arm, open-label study

- Patients not achieving SVR with PR in REALIZE study (n=81)

● Telaprevir + PR for 12 weeks followed by an addition 36 weeks of PR

● Baseline sequencing revealed V36L in one patient

Mathurin P, et al. J Hepatol. 2013;58(suppl 1):S356-S357. Abstract 868.

PriorRelapsers

(n=27)

PriorNon-

Responders(n=22)

Prior Null Responders

(n=32)

Male (%) 70 68 72

Age (years) 55 51 52

Genotype (%) 1a 1b

4456

6238

4753

BMI (kg/m2) 25.7 28.1 26.2

HCV RNA (log10 IU/mL)

6.5 6.7 6.6

Cirrhosis (%) 22 14 34


48

C219 Rollover Study: Telaprevir + PR in PR Failures From the REALIZE Study

● Overall SVR rate: 60%

- Higher rates in prior relapsers and prior partial responders

● NS3 variants among those not achieving SVR

- Consistent with previously described mutations that confer decreased susceptibility to telaprevir

● Safety profile was similar to previous studies

Mathurin P, et al. J Hepatol. 2013;58(suppl 1):S356-S357. Abstract 868.

SVR24 Rates

Pat

ien

ts (

%)

PriorRelapsers

(n=27)

Overall(n=81)

PriorPartial

Responders(n=22)

PriorNull

Responders(n=32)

81%

60%

73%

34%

49

Program Overview





• DAA + PR




50

CRUSH-C: Triple Therapy inHCV-Infected Transplant Recipients

• Multicenter, retrospective, cohort study of consecutive HCV-infected, genotype 1 liver transplant recipients (n=112)

– 6 US transplantation centers

• Protease inhibitor

– Telaprevir: 90%

– Boceprevir: 10%

• Median time from liver transplant to triple therapy: 3.7 years

• Median days of LI and total treatment

– LI <90 arm (n=97): 30 and 282 days

– LI >90 arm (n=15): 182 and 370 days

Verna EC, et al. J Hepatol. 2013;58(suppl 1):S10-S11. Abstract 23.

Patients(n=112)

Male (%) 76

Age (years) 58

Race (%) Black Hispanic White

102362

Genotype 1a/1b (%) 55/38

Fibrosis F2-F4 (%) 84

Fibrosing cholestatic hepatitis (%) 11

Prior treatment status (%) Null responder Partial responders Prior relapser

482725


LI: lead-in period with only PR therapy.

51

CRUSH-C:Virologic Response (LI <90 Days Arm)

● Median HCV RNA (log10 IU/L)

- Start of LI: 6.6

- Prior to PI: 5.1 (1.5 log decline)

- Week 2: 1.3 (3.8 log decline)

● HCV RNA >1 log decline in those achieving an early response

- eRVR (n=97): 64%

● Early discontinuations

- Virologic breakthrough: 10%

- Due to adverse events: 11%

• Advanced disease: 27%


SVR4

Pat

ien

ts (

%)

No(n=13)

Overall(n=43)

Yes(n=27)

Yes(n=9)

No(n=34)

AchievedeRVR

Advanced Disease

19%

65%

93%*

44%

71%

*P<0.001 versus not achieving an eRVR.Advanced disease: F4 or Fibrosing cholestatic hepatitis.

52

CRUSH-C:Safety (All Patients)

• High rates of hospitalizations (22%) and >0.5 mg/dL increase in creatinine (34%)

- May be more common in patients with advanced disease

• Hospitalizations: 38%

• >0.5 mg/dL increase in creatinine: 47%

• Anemia is a significant problem

– RBV dose reduction/erythropoietin/blood transfusions: 80%/79%/46%

• Significant drug interaction

– Cyclosporine and tacrolimus doses reduced by 75% and 88%, respectively

• Focus of future studies

– Identifying predictors of non-response to avoid unnecessary treatment and toxicities


53

Program Overview





• DAA + PR




54

REVEAL-HBV Study: HBeAg, HBV DNA,and HBsAg Seroclearance and HCC Risk

● Prospective, observational cohort study

- 2946 HBsAg+, anti-HCV seronegative, no cirrhosis from 7 Taiwanese townships

• Recruited 1991-1992

• HBeAg and HBsAg serostatus and HBV DNA followed until 2004

• HCC assessed 2008

● HBsAg seroclearance: 8%

● HBV DNA decreased to undetectable: 20%

● HBeAg seroclearance: 43%

● HCC: 5.2%

Liu J, et al. J Hepatol. 2013;58(suppl 1):S17. Abstract 40.

55

REVEAL-HBV Study: HCC Risk According to Biomarker Seroclearance

● Most HCC cases (78.4%) occurred before HBV DNA and HBsAg seroclearance

● HBV DNA seroclearance was able to significantly reduce HCC risk

● HBeAg seroclearance

- Effect seen with HBeAg seroclearance is determined by HBV DNA levels

- Even at HBeAg seroclearance, HBV DNA was 5.18 log10 copies/mL: still at high risk for HCC

● HBsAg seroclearance

- Not enough follow-up time to see more incident HCC cases

- More follow-up time of people who reached HBV DNA seroclearance is needed

Liu J, et al. J Hepatol. 2013;58(suppl 1):S17. Abstract 40.

*Adjusted for age, gender, smoking, alcohol consumption, ALT level, HBeAg serostatus, and HBV DNA levels.

All(n=2946)

HBV DNADetectable(n=2191)

HBeAg Seropositive

(n=444)

HBsAg seroclearance (yes verus no)

0.63(0.29-1.38)

HBV DNA decreased to undetectable (yes versus no)

0.37(0.16-0.86)(P=0.02)

HBeAg seroclearance (yes verus no)

0.97(0.56-1.69)

Multivariate Hazard Ratios of HCC*(95% CI)

56

Long-Term Tenofovir DF Therapy for Chronic HBV Infection and HCC Risk

Kim WR, et al. J Hepatol. 2013;58(suppl 1):S19. Abstract 43.

Double-BlindStudy 103*

HBeAg-Positive Treatment-Naïve

Study 102* HBeAg-Negative

Lamivudine naïve or experienced

Tenofovir DF 300 mg

Adefovir 10 mg

Year 0 1 2 3 4 5 6 7 8 240 384

Randomization2:1

7 YearsOpen-Label

Tenofovir DF 300 mg

Tenofovir DF 300 mg

CurrentAnalysis

• Compare observed HCC incidence with the predicted HCC incidence based on the REACH-B risk calculator

− Primary analysis: noncirrhotic patients (n=482)− Sensitivity analysis: cirrhotic patients (n=152)

*Pretreatment liver biopsy. Other eligibility criteria: age 18-69 years, compensated liver disease, HBV DNA >10 6 copies/mL, ALT >2 x ULN and <10 x ULN, Knodell necroinflammatory score >3, seronegative for HIV, HDV, and HCV. †If HBV DNA >400 copies/mL, option to add emtricitabine to tenofovir DF in a fixed-dose tablet.

57

Observed Versus Predicted HCC Cases During Long-Term Tenofovir DF Therapy


Cu

mu

lati

ve N

um

ber

of

HC

C C

ases

Non-Cirrhotic at Baseline

0 48 96 144 192 240 288 336

Week

Observed

Predicted

SIR: standard incidence ratios.P<0.05 versus predicted HCC cases.

SIR: 0.45*(0.227-0.909)

Cu

mu

lati

ve N

um

ber

of

HC

C C

ases

Cirrhotic at Baseline

0 48 96 144 192 240 288 336

Week

Observed

Predicted

58

Long-Term Tenofovir DF Therapyand HCC Risk: Summary

● Incidence of HCC in Studies 102 and 103

- Lower than predicted by the REACH-B model

- Non-cirrhotics

• Effect of tenofovir DF become noticeable at approximately 2 years, significant at 6 years

- Cirrhotics

• Effect of tenofovir DF less pronounced

● Limitations

- No placebo arms

- Patients with active liver disease

- Relatively small number of cirrhotics

- REACH-B is designed for non-cirrhotics and may underestimate risk in cirrhotics


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