Nezam Afdhal, MD Michael Fried, MD Ira Jacobson, MD · COBAS® ®AmpliPrep/COBAS Taqman® HCV Test. Roche Molecular Diagnostics. Accessed July 19, 2011. Harrington PR, et al. Hepatology.

Accredited by: Sponsored by:

Nezam Afdhal, MD Beth Israel Deaconess

Medical Center

Boston, MA

Kim Brown, MD Henry Ford Hospital

Detroit, MI

Jordan Feld, MD Toronto Western

Hospital Liver Center

Toronto, Canada

Michael Fried, MD University of North Carolina

Chapel Hill, NC

Ira Jacobson, MD Weill Cornell Medical College

New York, NY

Presented for attendees of the 63rd AASLD Annual Meeting (or The Liver Meeting®).

This event/function is sponsored by Chronic Liver Disease Foundation and supported by Vertex Pharmaceuticals.

This is not an official function/event of the American Association for the Study of Liver Diseases.

Supported by:

Welcome

• Tonight’s News Program

– Field Report – Breaking News on New CDC Recommendations

• Michael Fried, MD

– Case #1 – Treat Now or Wait for Future Therapies

• Kim Brown, MD; Jordan Feld, MD

– Field Report – Breaking News on Real-World Clinical Data

• Ira Jacobson, MD

– Case #2 – Optimizing Outcomes with Current Treatments

• Kim Brown, MD; Jordan Feld, MD

– Press Conference: Late Breaking Data, Q&A

Glenn: Patient Characteristics

• 55 year old male

• Shift worker

• History/risk factors

– BMI=34

– Hypertension and dyslipidemia

– Moderate drinker/cigarette smoker

• Concomitant medications

– Simvastatin 20 mg/day

– Lisinopril 10 mg/day

Glenn: Baseline Labs

• Hemoglobin 15.6 g/dL

• Neutrophils 1400 cells/mm3

• Platelets 210,000 cells/mm3

• AST/ALT 55/75 IU/L

• Albumin 4.1 g/dL

• Bilirubin 0.7 mg/dL

Glenn: Disease Characteristics

• Treatment naïve

• Genotype 1a

• IL28B CC

• METAVIR F3

• BL viral load 1,300,000 IU/mL

ARS #1

• How would you manage this patient?

1. Continue to monitor patient but do not start treatment

2. Start patient on first generation protease inhibitor/PEG-IFN/RBV

Modeling of Liver Fibrosis in Chronic Hepatitis C

n=1157 Patients

0

1

2

3

4

0 10 20 30 40 50

F M

eta

vir

Years

Rapid progressors Intermediate progressors

Slow progressors

Poynard et al, Hepatology 1999

D’Amico G et al. J Hepatol. 2006;44:217-231.

Pro

po

rtio

n o

f P

ati

en

ts 1.00

0.75

0.50

0.25

0.00

Pts at risk 806 513 402 302 243 217

months 0 24 48 72 96 120

Cumulative Proportion of Patients Transitioning from

Compensated to Decompensated Stage Over Time

0%

20%

40%

60%

80%

100%

Non-responders (n=1452)

Relapsers (n=464) Sustained responders (n=1094)

36% 43%

86%

43% 36%

12% 21% 21%

2%

% o

f p

ati

en

ts

Improved Stabilized Worsened

*Necrosis and Inflammation.

Poynard et al. Gastroenterology, 2002;122:1303-1313.

Impact According to Response of 10 Different Treatment Regimens

on Evolution of Activity* in 3010 Patients with Paired Biopsies

Jacobson et al. EASL 2011

*T12PR = T+PR12 weeks, then PR12 or 36 weeks depending on eRVR status

**T8PR = T+PR8 weeks, then PR16 or 40 weeks depending on eRVR status

In Patients Tested for IL28B (%)

In All

ADVANCE

Patients

CC CT TT Total

T12PR* 90 71 73 78 75

T8PR** 87 58 59 67 69

PR 64 25 23 38 44

ADVANCE: IL28B Genotype Effect on

Telaprevir Therapy

SVR Rates in F1/2 vs F3/4 Naïve Patients

0

10

20

30

40

50

60

70

80

90

100

Boceprevir Telaprevir

F1/2

F3/4 76%

67% 67%

48% SV

R

Poordad F et al, NEJM, 2011; 364: 1195-1206

Jacobson IM et al, NEJM, 2011; 364: 2405-2416

OPTIMIZE Trial: Telaprevir BID vs TID

• PR + TVR 1125 mg BID versus 750 mg TID

• Response-guided therapy

• 740 patients

• 29% bridging fibrosis or cirrhosis

• 57% G1a, IL28B CC 29%

Buti M et al, Abstract LB-8, AASLD 2012

OPTIMIZE Trial: Results

0

20

40

60

80

100

RVR SVR

TVR 1125 mg BID

TVR 750 mg TID

(%)

69% 67%

74% 73%

Buti M et al, Abstract LB-8, AASLD 2012

Should Glenn Be Treated Now?

• F3 disease – risk of progression with waiting

• IL28B CC

• Potential BID option is attractive

• I would treat

• Multiple issues with current therapy

– Compliance – pill burden

– Co-morbidities

– Adverse effects

The Case for Waiting

BOC = 18/d TVR = 12/d

Pill Burden Food Requirement

RBV 4-7/d RBV 4-7/d

Compliance

• Cardiac Risk Factors

– Hypertension, hyperlipidemia, smoker

• Pre Treatment

– DDI – Statin with TVR/BOC likely just stop it

• On Treatment

– Anemia management consider pre-treatment cardiac testing

Co-Morbidities

Drugs with the Potential to Interact with First Generation

Protease Inhibitors are Commonly Used by HCV Patients

Mayer et al, Abstract #136, AASLD 2012

Drug Name Percent Drug Name Percent

Zolpidem * 17.4 Diazepam 7.9

Codeine 16.0 Bupropion * 7.2

Prednisone 15.4 Trazodone 7.1

Tramadol * 14.3 Fluconazole 6.8

Citalopram 13.5 Sertraline 6.4

Fluticasone 13.1 Clarithromycin 6.1

Methylprednisolone 13 Sildenafil (Viagra) 5.4

Alprazolam * 11.8 Clonazepam 5.3

Amlodipine * 10.2 Simvastatin 5.2

Escitalopram * 8.1 Venlafaxine 5.0

* One of the 20 most frequently filled

• No clinically significant interactions

– Boceprevir

• Prednisone (abstract #1896)

• Omeprazole (abstract #1808)

• Ethinyl estrodiol/norethidrone (abstract #1901)

– Simeprevir (TMC-435)

• Cyclosporine/tacrolimus (abstract #80)

• Ethinyl estrodiol/norethidrone (abstract #773)

New Drug-Drug Interaction Data at AASLD

2012: HCV Protease Inhibitors

0

10

20

30

40

50

60

70

80

90

100

< 10 g/dL < 8.5 g/dL

BOC

PR

5/5 11/13 13/14

0

10

20

30

40

50

60

70

80

90

100

< 10 g/dL < 8.5 g/dL

TVR

PR

% o

f p

ati

en

ts

36%

17% 14%

5%

49%

28%

7% 3%

Anemia is a Known Side Effect with First

Generation Protease Inhibitor Based Therapies

% o

f p

ati

en

ts

Telaprevir (INCIVEK™) Prescribing Information. Vertex Pharmaceuticals Incorporated, Cambridge, MA. October, 2012.

Boceprevir (VICTRELIS™) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, November 2012.

Future Options for Waiting? (Short-Term)

Simeprevir 150 mg OD x 12 wks + PR x 24-48

81

0

20

40

60

80

100

%

n/

N =

62/

77

50/

77

65

P=0.013

SVR

PILLAR (G1 Naïve)1

PR x 48

Faldaprevir 240 mg OD x 24 wks + PR x 24-48

83

%

n/

N =

118/

142

40/

71

56

P=0.001

SVR

SILEN C1 (G1 Naïve)2

PR x 48

93

57/

61

79

61/

77

SVR Met RGT

93

53/

57

87

124/

142

SVR Met RGT

2. Sulkowski et al. EASL 2011

0

20

40

60

80

100

1. Fried et al. AASLD 2011

Anemia with

Simeprevir + P/R1

Anemia with

Faldaprevir + P/R2

2. Sulkowski et al, EASL 2011

No Incremental Decline in Hemoglobin or

Neutrophils with Simeprevir or Faldaprevir

1. Jacobson et al, IDSA, 2012

Should Glenn Delay Treatment?

• IL28B CC ~80% chance of shortened therapy

- 80-90% chance of SVR

• F3 disease – risk of progression with waiting

• No clear issues with IFN

• Seems anxious and willing to be treated now

• I would suggest treatment

Glenn: On Treatment Response

• Glenn was started on TVR/PEG/RBV

• TW4 and TW12

– HCV RNA undetectable

ARS #2

• Which regimen should Glenn receive?

1. 12 weeks TVR/PEG/RBV

2. 12 weeks TVR/PEG/RBV + 12 weeks PEG/RBV



5. 24 weeks TVR/PEG/RBV

Recommended Treatment Duration

Treatment-Naïve and Prior Relapse Patients

HCV-RNA Triple Therapy

TVR/Peg-IFN/RBV

Dual Therapy

Peg-IFN/RBV

Total

Treatment

Duration

Undetectable at TW4 and

TW12

First 12 weeks Additional 12 weeks 24 weeks

Detectable (<1000 IU/mL)

at TW4 and/or TW12

First 12 weeks Additional 36 weeks 48 weeks


HCV-RNA Levels and Lab Assays

4/6 13/14

Assay Name LLOQ

Roche COBAS®

AmpliPrep/COBAS®

Taqman® HCV Test

43 IU/mL

Roche COBAS®

Taqman® HCV Test,

v2.0

25 IU/mL†

Abbott RealTime HCV

Assay 12 IU/mL

LLOQ Values for Various Assays*

*Package Inserts state the “the assay should have a lower limit of HCV-RNA

quantification ≤ 25 IU/mL and a limit of HCV-RNA detection of approximately

10-15 IU/mL. † Usually considered 25 IU/mL, but 23 IU/mL per FDA-approved label.

• “Undetectable” (or “target not

detected”) result is required for

assessing RGT eligibility

• Below LLOQ but still “detectable”

is not sufficient to shorten

therapy—ie, patient should

continue for full 48 wks

COBAS® AmpliPrep/COBAS® Taqman® HCV Test. Roche Molecular Diagnostics. Accessed July 19, 2011. Harrington PR, et al. Hepatology.

2012;55: 1046-1057. United States Food and Drug and Drug Administration (FDA), FDA Division of Antiviral Products; June 30, 2011.

• 45 year old African American female

• History/risk factors

– BMI=32

• CHC diagnosed in 2002

• Treated with Peg-IFN/RBV in 2007

– Tolerability issues: fatigue, anemia, neutropenia, alopecia,

anxiety, depression after 6 months (treated with paroxetine)

Jackie: Patient Characteristics

Jackie: Disease Characteristics

• Prior relapser (early virologic response)

• Genotype 1a

• IL28B CT

• METAVIR F1 in 2007

• BL viral load 18,000,000 IU/mL

Jackie: Baseline Labs

• Hemoglobin 12.1 g/dL

• Neutrophils 1300 cells/mm3

• Platelets 200,000 cells/mm3

• Serum creatinine 0.9 mg/dL

• AST/ALT 73/56 IU/L

• Albumin 4.1 g/dL

• Bilirubin 0.8 mg/dL

• INR 0.9

ARS #3

• Would you reassess stage of fibrosis before retreatment

and, if so, how?

1. No, I don’t believe it is necessary

2. Yes, I would re-biopsy the patient

3. Yes, I would use non-invasive test

ARS #4

• Which of the following statements is most accurate?

1. Jackie has a low likelihood of success because she is African

American and IL28B CT.

2. Jackie has a very high likelihood of success because she is a

prior relapser.

3. If restaging shows cirrhosis, Jackie has a very low chance of

success.

4. Treatment is contraindicated for Jackie since she developed

depression while on PEG/RBV.

86%

59%

32%22%

15%5%

0

20

40

60

80

100

REALIZE: SVR by Response to Previous

Peg-IFN/RBV Therapy

All Patients

%S

VR

All T12/PR48

Placebo/PR48

Relapsers Partial Responders Null Responders


72%

46%

31%

7%

0

20

40

60

80

100

%S

VR

BOC*

PR

Prior Relapsers Partial Responders

*Response Guided Therapy and 48 Week Arms Combined

150/208 16/51 53/115 2/29

RESPOND 2: SVR by Response to Previous

Peg-IFN/RBV Therapy

Boceprevir (VICTRELIS™) Prescribing Information. Merck Sharp & Dohme Corp., Whitehouse Station, NJ, November 2012.

Prior Response Trumps Other Pretreatment

Baseline Factors

• Ethnicity

• IL28B Genotype

• Baseline Viral Load

• Fibrosis Score

• G1 Subtype

Jackie: On Treatment Labs

Hemoglobin

(g/dL)

Neutrophil Count

(cells/mm3)

HCV RNA

(IU/mL)

Baseline 12.1 1300 18,000,000

TW2 11.0 1100 3,300

TW4 9.5 900 Undetectable

ARS #5

• How would you manage Jackie’s anemia?

1. No change to treatment

2. Add EPO

3. Reduce RBV from 1200 mg to 1000 mg

4. Reduce RBV from 1200 mg to 600 mg

5. Add EPO and reduce RBV (1200 to 600 mg)

82

72

10

82

71

10

0

10

20

30

40

50

60

70

80

90

100

EOT Response SVR Relapse

% o

f P

ati

en

ts

RBV DR Arm EPO Arm

203/

249 19/

196

178/

249

178/

251 205/

251 19/

197

Patients Randomized When

Hb <10 g/dL

Boceprevir: No Difference in SVR Rate in Anemic

Patients Undergoing RBV DR vs EPO Use

Adapted from Poordad F et al. Abstract 1419. Poster presented at the 47th Annual Meeting of the European Association for the Study of the

Liver. April 2012, Barcelona, Spain.

70

64

79

82 71

71 68

70

88

71

0

10

20

30

40

50

60

70

80

90

100

≤4 Wks >4-8 Wks >8-12 Wks >12-16Wks >16 Wks

SV

R (

%;

95

% C

I)

Timing of the Start of Anemia Management

RBV DR EPO Use

38/

54

39/

55

58/

90

60/

88

49/

62

47/

67

18/

22

15/

17

15/

21

17/

24

SVR Rates Did Not Vary with the

Start Time of Anemia Management

Poordad F et al, Abstract 154, AASLD 2012

Adapted from Sulkowski MS et al. Abstract 1162. Poster presented at the 47th Annual Meeting of the European Association for the

Study of the Liver. April 21, 2012, Barcelona, Spain.

0

10

20

30

40

50

60

70

80

90

Any Dose reduction Received ≤600 mg/day Received 800-1000 mg/day

Never reduced

T12PR

PR

74% 74% 75% 79%

47% 42%

54%

46%

SV

R, n

/N(%

)

RBV Dose Reductions

329/

446

291/

395

38/

51

346/

439

29/

62

16/

38

13/

24

134/

292

SVR Rates in Treatment Naïve Patients

by RBV Dose/Day

Jackie: On Treatment Labs

Hemoglobin

(g/dL)

Neutrophil Count

(cells/mm3)

HCV RNA

(IU/mL) Action

Baseline 12.1 1300 18,000,000

TW2 11.0 1100 3,300

TW4 9.5 900 Undetectable Decreased RBV

(1200 to 600 mg/day)



TW12 10.9 900 Undetectable Increased RBV

(600 to 800 mg/day)

TW16 11.5 1050 Undetectable Increased RBV

(800 to 1000 mg/day)

Jackie: Non-hematologic Adverse Events

How do you manage?

• Constitutional symptoms (fatigue, arthralgia)

• Mouth sores

• Rash

• Anorectal burning

• Depression

*12-week groups (G and H) were enrolled after 24-week groups (A, C, and E)

RBV: 1000-1200 mg/d, weight-based (GT1)

n = 41

n = 15

n = 14

SVR12 Week 24 SVR24

Follow-up

n = 41

n = 15

Follow-up

Follow-up

Follow-Up

SVR4 Week 12

Follow-Up

Group C: DCV 60 mg QD + SOF 400 mg QD

Group E: DCV 60 mg QD + SOF 400 mg QD + RBV

Group A: SOF 400 mg QD x 7d, then DCV 60 mg QD + SOF 400 mg QD

Group G: DCV 60 mg QD + SOF 400 mg QD

Group H: DCV 60 mg QD + SOF 400 mg QD + RBV

SVR4 SVR48

SVR48

Sulkowski MS et al, Abstract LB-2, AASLD 2012

LB-2: Daclatasvir (NS5A) +

Sofosbuvir (GS-7977, nuc) in GT1a/1b

20

SVR4

0

20

40

60

80

100

Week 4 SVR12

n = EOT

15 14 15

SVR24

C: DCV + SOF

A: SOF LI + DCV

E: DCV + SOF

+ RBV

87 93 73 % of patients

with HCV RNA

<LLOQ-TND

100 100 100 100 100 100 100 100 100 100 100

• Group A: 1 patient with detectable HCV RNA at PT Week 24: HCV RNA cleared 4 weeks later, sequence not

consistent with relapse

100

15 14 15 15 14 15 15 14 15 15 14 15

93

100 100 100 100 100 100 100 100 100 100 100 100 100

93

HC

V R

NA

< L

LO

Q (%

pa

tie

nts

)

Virologic Response is Maintained at PT Week 24

(GT1a/1b; 24-Week Treatment Groups)


0

20

40

60

80

100

SVR4

HC

V R

NA

< L

LO

Q

(% p

ati

en

ts)

Week 4

n =

EOT

G: DCV + SOF (12-wk)

H: DCV + SOF + RBV (12-wk)

% of patients

with HCV RNA

<LLOQ-TND

• Group G: 1 patient with missing HCV RNA at PT Week 4—patient achieved SVR12

• Group H: 1 patient with missing HCV RNA at PT Week 4—patient achieved SVR12; 1 patient with HCV RNA < LLOQ-TND at PT week 2 and HCV RNA = 54 IU/mL at PT week 4 (not confirmed)—patient achieved SVR12

100 95 100 100 98 95

78 76 100 100 98 95

41 41 41 41 41 41

Virologic Response During and After Treatment

12 Week Treatment Groups


LB-3: Daclatasvir (NS5A), Asunaprevir (PI), and

BMS-791325 (non-nuc)

• 32 treatment naïve, G1 patients w/o cirrhosis

• ASV 200 mg BID, DCV 60 mg QD, BMS-791325 75 mg

BID (part 2 with 150 mg BID)

• Patients randomized to 24 vs 12 weeks

• Majority of patients G1a and non-CC

• Most common AEs: headache, diarrhea, asthenia Everson G et al, Abstract LB-3, AASLD 2012

94%**

SV

R(%

)

* One d/c’ed early with HCV RNA<LLOQ

**One lost to follow up

Daclatasvir, Asunaprevir, and

BMS-791325 (non-nuc)

Everson G et al, Abstract LB-3, AASLD 2012

0

20

40

60

80

100

Week 12 (24 week group) SVR4 (12 wk group)

94%*

15/16 15/16

Abstract LB-1: ABT-450/r, ABT-267, ABT-333 +/- RBV in HCV

Genotype 1 Treatment Naïve Patients

• Randomized to treatment for 8, 12, or 24 weeks with:

– ABT-450/r (Protease inhibitor + ritonavir boost) combined with ABT-

267(NS5A inhibitor) +/- ABT-333 (Non-nuc polymerase inhibitor) +/-

Ribavirin

• Patient characteristics:

– Non-cirrhotic

– Genotype 1a = 66%

– IL28B non-CC= >90%

– N=438 naïve

– N=133 prior null responders

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

0

20

40

60

80

100

Overall G1a G1b

+RBV

-RBV

% S

VR

Treatment Naive

% S

VR

Null Responders +RBV

0

10

20

30

40

50

60

70

80

90

100

Overall G1a G1b

+RBV

77/

79

52/

54

43/

52

25/

25

24/

25

69/

79 42/

45

25/

28

17/

17

97.5%

87.3%

96%

83%

100% 96% 93.3%

89%

100%

Abbott Press Release, Nov. 10, 2012, Kowdley KV et al, Abstract LB-1, AASLD 2012

LB-1: SVR12 Results

Zeuzem S et al, Abstract 232, AASLD 2012; Soriano V et al, Abstract 84, AASLD 2012

• Five arm study that evaluated different doses and durations in regimens

with faldaprevir (PI) and BI207127 (non-nuc) with or without RBV

– Durations: 16, 28 or 40 weeks

– BID vs TID

• Randomization was stratified by genotype (1a vs 1b) and IL28B

– 9% of patients had cirrhosis

• SVR12 ranged between 52% to 69% in RBV-containing arms and 39%

without RBV

– SVR in cirrhotics is 54%

• IL28B CC, genotype 1b and female gender were favorably associated with

SVR12

Abstract 232: Final Results of SOUND-C2 and

Predictors of Response

Sofosbuvir +RBV

Sofosbuvir + RBV

Sofosbuvir +RBV

Sofosbuvir +

RBV

Sofosbuvir +

RBV (800mg/d)

0 12 Weeks 8

Prior Null

GT 1

Naive

GT 1

Experienced

GT 2/3

Naive

GT 2/3

Naive

GT 2/3

SVR12

1/10 (10%)

21/25 (84%)

17/25 (68%)

16/25 (64%)

6/10 (60%)

SVR8

Gilead Press Release, Nov. 10, 2012

• Evaluate sofosbuvir

+RBV as single

agent treatment for

HCV

• Small phase IIb

exploratory study

• Non-cirrhotic

patients

• Well-tolerated

regimen

Abstract 229: Once Daily Sofosbuvir (GS-7977) Plus RBV in

Patients with HCV G1, 2, and 3: The ELECTRON Trial

Press Conference

Q&A

Conclusions

• More patients will be screened, diagnosed and referred

into HCV specialty practices as a result of new

recommendations

• Many of these patients are good candidates for

treatment today

• Treatment outcomes with current treatments can be

optimized with appropriate management/interventions

• The HCV pipeline is promising with potential new

treatment modalities in the near future

We thank… Vertex Pharmaceuticals

for the educational grant to support this activity

Accredited by: Sponsored by:

Presented for attendees of the 63rd AASLD Annual Meeting (or The Liver Meeting®).

This event/function is sponsored by Chronic Liver Disease Foundation and supported by Vertex

Pharmaceuticals.

This is not an official function/event of the American Association for the Study of Liver Diseases.

Supported by:

Nezam Afdhal, MD Michael Fried, MD Ira Jacobson, MD · COBAS® ®AmpliPrep/COBAS Taqman® HCV Test. Roche Molecular Diagnostics. Accessed July 19, 2011. Harrington PR, et al. Hepatology.

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