Medical Director of Liver Transplantation Intermountain · PDF fileSlide 6 of 93 Foster G,...

Up to the Minute Management of HCV Infection:

Pearls, Pitfalls and Predictions

FORMATTED: 05-15-2015

Chicago, IL: May 19, 2015

Michael R. Charlton, MBBS, FRCPHepatology Director

Medical Director of Liver Transplantation

Intermountain Medical Center

Salt Lake City, Utah

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GT 1

http://www.hcvguidelines.org

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Foster G, EASL, 2014, O66

SVR Rates of SOF-Based Regimens Across Genotypes and Among Patients with Multiple Negative Predictive Factors

Retrospective analysis of data from Phase 2 and 3 SOF studies to identify variables associated with relapse

Effect of Negative Predictors on SVR Rates Across SOF Studies

SV

R1

2 (

%)

Number of Negative Predictors

SVR12 Rates by Number of Negative Predictors and Genotype

4/4

5/5

26/26

22/22

22/22

69/69

69/70

43/43

114/122

78/81

55/59

89/104

65/69

57/66

11/18

26/33

23/37

4/6

8/15

Negative predictors: Male gender, body weight ≥ 75kg, IL28B nonCC, baseline HCV RNA ≥ 800,000 IU/mL, prior treatment failure, cirrhosis

89% of patients in the Phase 3 program had ≤4 negative predictors

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Chicago, IL: May 19, 2015 1

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All oral therapy for HCV Genotype 1 infection

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Case 1.

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Slide 9 of 93

Case 1.

48 yr old man

New diagnosis of HCV infection identified during blood donation. Used intranasal cocaine as a teen.

HCV genotype 1 (not able to subtype), HCV RNA 6.48 million IU/ml

ALT 183, AST 211, normal total bilirubin

– 1:120 ASMA

– Has elevated Cr 1.74 mg/dl, GFR 45

PMH notable for gastro esophageal reflux disease and mild hypertension

Meds: amlodipine and “antacid”

Exam unremarkable

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Case 1.

Biopsy inflammation grade 3, fibrosis stage 3

HCV GT1, fibrosis stage 3

Treatment inexperienced

Moderate renal insufficiency

Should we treat HCV infection?

If so, with what?

Are there any special considerations?

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Trial Pt typeTreatment

durationSVR12 Virologic failure

SAPPHIRE-I GT1, TN 12 wks

96%

GT1a – 95%

GT1b – 98%

VBT 0.2%

Relapse 1.5%

SAPPHIRE-II GT1, TE 12 wks

96%

GT1a – 96%

GT1b – 97%

VBT 0%

Relapse 2.4%

PEARL-IV GT1a, TN 12 wks

92% overall

90% no RBV

97% + RBV

No RBV – 8%

+ RBV – 2%

PEARL-III GT1b, TN 12 wks 99% overall

99% +/- RBV

No RBV– none

+ RBV:

VBT 0.5%;

relapse 0%

PEARL-II GT1b, TE 12 wks

98% overall

100% no RBV

97% + RBV

None

TURQUOISE-II

GT1 with

compensated

cirrhosis,

TN, TE

12 or 24

wks

94% overall

92% 12 wks

96% 24 wks

12 wk :

VBT 0.5%;

relapse 5.9%

24 wk :

VBT 1.7%;

relapse 0.6%

Target Profile

FDC paritaprevir/RTV/ombitasvir dosed QD (2 pills)

dasabuvir dosed BID

12 week treatment duration for non-cirrhotic patients

GT1a TN, GT1 TE, and cirrhotic patients require RBV in regimen

Generic Drug Names

ABT-333 = Dasabuvir (NNI)

ABT-267 = Ombitasvir (NS5A)

ABT-450 = Paritaprevir (PI)

AbbVie HCV Clinical Development ProgramABT-450/RTV/ABT-267+ABT-333±RBV in GT 1 Patients

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96%

GT1a – 95%

GT1b – 98%

VBT 0.2%

Relapse 1.5%


96%

GT1a – 96%

GT1b – 97%

VBT 0%

Relapse 2.4%


92% overall

90% no RBV

97% + RBV

No RBV – 8%

+ RBV – 2%


99% +/- RBV

No RBV– none

+ RBV:

VBT 0.5%;

relapse 0%


98% overall

100% no RBV

97% + RBV

None

TURQUOISE-II

GT1 with

compensated

cirrhosis,

TN, TE

12 or 24

wks

94% overall

92% 12 wks

96% 24 wks

12 wk :

VBT 0.5%;

relapse 5.9%

24 wk :

VBT 1.7%;

relapse 0.6%

Target Profile


dasabuvir dosed BID



Generic Drug Names




AM PM

450/r/267 450/r/267 333

333

RBVRBVRBV

RBV

RBVRBV

RBV

RBV


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96%

GT1a – 95%

GT1b – 98%

VBT 0.2%

Relapse 1.5%


96%

GT1a – 96%

GT1b – 97%

VBT 0%

Relapse 2.4%


92% overall

90% no RBV

97% + RBV

No RBV – 8%

+ RBV – 2%


99% +/- RBV

No RBV– none

+ RBV:

VBT 0.5%;

relapse 0%


98% overall

100% no RBV

97% + RBV

None

TURQUOISE-II

GT1 with

compensated

cirrhosis,

TN, TE

12 or 24

wks

94% overall

92% 12 wks

96% 24 wks

12 wk :

VBT 0.5%;

relapse 5.9%

24 wk :

VBT 1.7%;

relapse 0.6%

Target Profile


dasabuvir dosed BID



Generic Drug Names




AM PM

450/r/267 450/r/267 333

333

RBVRBVRBV

RBV

RBVRBV

RBV

RBV


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Feld JJ, EASL, 2014, O60

Feld JJ, et al. N Engl J Med 2014; 2014 Apr 11

HCV GT 1

Treatment-naïve,

non-cirrhotic

N=631

paritaprevir+RTV+ombitas

vir+dasabuvir+RBV, n=473SVR12

Placebo, n=158paritaprevir+RTV+ombitasvir

+dasabuvir+RBV

SVR12

Week 0 12 24

ABT-450+RTV+Ombitasvir+Dasabuvir+RBV for 12 Weeks in GT 1 Treatment-Naïve, Non-Cirrhotic Patients

Phase 3, randomized, double-blind, placebo-controlled study

SAPPHIRE I (paritaprevir/RTV+ombitasvir+dasabuvir+RBV): GT1

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Feld JJ, et al. N Engl J Med 2014; 2014 Apr 11]

96.2 95.3 98

0

20

40

60

80

100

All patients GT 1a GT 1b

SV

R12 (

ITT

), %

Patients missing data in SVR12 window count as failures

SVR and Virologic Failure Treatment Arm

455/473 307/322 148/151

On treatment virologic breakthrough: 1 (0.2%)

Relapse post-treatment: 7/463 (1.5%)

SAPPHIRE I (ABT-450+RTV+ombitasvir+dasabuvir+RBV): GT1

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ABBV DDI Exclusion Criteria – Phase 3 Medications Contraindicated for Use with the Study Drug Regimen1

Citeline.com (TrialTrove); accessed 2-19-20141- Drug regimen: ABT-450 (PI) + RTV; ABT-267 (NS5a); ABT-333 (non-nuc NS5b) +/- RBV, 6 pills, BID dosing

Not all medications contraindicated with ritonavir and ribavirin are listed below. Refer to the most current package inserts or product labeling of ritonavir and ribavirin for a complete list of contraindicated medications

Drug Class Drug

Antiarrhythmic Dronedarone, Amiodarone, Propafenone, Quinidine

Anti-asthmatic Montelukast, Salmeterol

Anticonvulsant Carbamazepine, Phenobarbital, Phenytoin

Antidepressant Nefazodone

Antidiabetic Pioglitazone, Rosiglitazone, Troglitazone

Antifungal Itraconazole, Ketoconazole, Voriconazole

Antihistamine Astemizole, Terfenadine

Antihyperlipidemic Lovastatin, Gemfibrozil, Simvastatin

Antihypertensive Bepridil, Eplerenone

Anti-infective Clarithromycin, Fusidic Acid, Telithromycin, Trimethoprim, Troleandomycin

Antimycobacterial Rifabutin, rifampin

Narcotic analgesic Methadone, Buprenorphine

Sedative/hypnotic Midazolam, Triazolam

Other

Alfuzosin (alpha adrenoreceptor antagonist)

Cisapride (GI motility agent)

Bosentan (endothelin receptor antagonist)

Conivaptan (cardiovascular agent)

Efavirenz (HIV)

Eleptriptan (selective serotonin receptor

agonist)

Ergot derivatives (neurologics) Everolimus

(anticancer)

Quercetin (anti-inflammatory) Mifepristone

(steroid)

Modafinil (stimulant)

Pimozide (antipsychotic)

St. John's Wort (herbal product)

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Slide 16 of 93

Discontinuations and Virologic Failures

Event, n/N (%)

450+RTV+267+333+

RBV

N=473

SVR12 455/473 (96.2)

Non-SVR12

Virologic failure

Breakthrough 1/473 (0.2)

Relapse 7/463 (1.5)

Prematurely discontinued study drug* 7/473 (1.5)

Lost to f/u after completion of treatment 3/473 (0.6)

Feld, EASL, 2014, O60

Feld et al. NEJM. April 11, 2014

* Patients (n=7) who prematurely discontinued without breakthrough; 2 due to AEs, 5 withdrew consent/lost to f/u

SAPPHIRE I (ABT-450+RTV+ombitasvir+dasabuvir+RBV): GT1

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Feld JJ, et al. N Engl J Med 2014; 2014 Apr 11 [Epub ahead of print]

455/473 307/322 148/151

Adverse Events

Paritaprevir/rtv+ombitasvir+

dasabuvir+RBV N=473

Placebo

N=158P-value

Any AE, n (%) 414 (87.5) 116 (73.4) <0.05

Fatigue, n (%) 164 (34.7) 45 (28.5) NS

Headache, n (%) 156 (33.0) 42 (26.6) NS

Nausea, n (%) 112 (23.7) 21 (13.3) <0.05

Pruritus, n (%) 80 (16.9) 6 (3.8) <0.05

Insomnia, n (%) 66 (14.0) 12 (7.6) <0.05

Diarrhea, n (%) 65 (13.7) 11 (7.0) <0.05

Asthenia, n (%) 57 (12.1) 6 (3.8) <0.05

Rash, n (%) 51 (10.8) 9 (5.7) NS

Dizziness (%) 8.0% 3.8% NS

Dyspnea (%) 8.0% 2.5% <0.05

Dry skin (%) 5.7% 0.6% <0.05

Anemia (%) 5.3% 0 <0.05

The AEs were more common with ABT-450+RTV+ombitasvir+dasabuvir+RBV than placebo.

AEs that occured more frequently with active therapy than placebo included nausea, pruritus, insomnia, diarrhea, and asthenia

SAPPHIRE I (paritaprevir/RTV+ombitasvir+dasabuvir+RBV): GT1

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Feld JJ, et al. N Engl J Med

455/473 307/322 148/151

Lab Abnormalities

Paritaprevir/RTV+ombitasvir

+dasabuvir+RBV N=469

Hemoglobin < 10–8.0 g/dL, n (%) 27 (5.8)

Hemoglobin < 8.0–6.5 g/dL, n (%) 0

Hemoglobin < 6.5 g/dL, n (%) 0

ALT > 5X ULN, n (%) 4 (0.9)

AST > 5X ULN, n (%) 3 (0.6)

Alkaline Phosphatase > 5X ULN, n (%) 0

Total bilirubin > 3X ULN 13 (2.8)

One patient received EPO; no patient was transfused

SAPPHIRE I: GT1

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What if my patient was treatment experienced?

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Zeuzem S, EASL, 2014, O1

Zeuzem S, et al. N Engl J Med 2014; 2014 Apr 11 [Epub ahead of print]

HCV GT 1

Treatment-

experienced,

non-cirrhotic

N=394

Paritaprevir/RTV+ombitasvir+

dasabuvir+RBV, n=297 SVR12

Placebo, n=97Paritaprevir/RTV+ombitasvir+

dasabuvir+RBV

SVR12

Week 0 12 24

Phase 3, randomized, double-blind, placebo-controlled study

SAPPHIRE II (ABT-450+RTV+ombitasvir+dasabuvir+RBV): GT1

Paritaprevir+RTV+Ombitasvir+Dasabuvir+RBV for 12 Weeks in GT 1 Treatment-Experienced, Non-Cirrhotic Patients

‡

Double-blind treatment period

Open-label treatment period

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Slide 21 of 93

Zeuzem S, EASL, 2014, O1

Zeuzem S, et al. N Engl J Med 2014; 2014 Apr 11 [Epub ahead of print] Patients missing data in SVR12 window count as failures

SVR12 Results in Treatment Arm

286/297 166/173 119/123 82/86 65/65 139/146

SAPPHIRE II (ABT-450+RTV+ombitasvir+dasabuvir+RBV): GT1

‡

96.3 96 96.7 95.3100

95.2

0

20

40

60

80

100

Overall GT 1a GT 1b Prior Relapse Prior PartialResponse

Prior NullResponse

SV

R12, %

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What if my patient had genotype 1b?Do I need ribavirin?

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Ferenci P, EASL, 2014, LB P1299

Clinical trials.gov: NCT01767116

HCV GT 1b

Treatment-naïve,

non-cirrhotic

N=419

SVR12

Week 0 12 24

Paritparevir+RTV+Ombitasvir+Dasabuvir±RBV for 12 weeks in GT 1b Treatment-Naïve, Non-Cirrhotic Patients

Phase 3, randomized, double-blind study

PEARL III

SVR12

paritaprevir+RTV+ombitasvir+

dasabuvir+RBV, n=210

paritaprevir+RTV+ombitasvir+

dasabuvir, n=209

‡

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Slide 24 of 93

SVR and Virologic Failure

Ferenci P, EASL, 2014, LB P1299

PEARL III (paritaprevir/RTV+ombitasvir+dasabuvir±RBV): GT1b

Reasons for lack

of SVR12

Paritpaprevir/RTV

+

ombitasvir+

dasabuvir+RBV

N=210

Paritaprevir/RTV+

ombitasvir+

dasabuvir

N=209

On treatment

failure1 0

Relapse 0 0

Lost to follow-up 0 2

3 of 419 Patients Did Not Achieve SVR12SVR12 Rates After 12 Weeks of Therapy

‡

99.5 99.0

0

20

40

60

80

100

SV

R12

% P

ati

en

ts

ABT-450+RTV+ombitasvir+

dasabuvir+RBV

ABT-450+RTV+ombitasvir+dasabuvir

207/209209/210

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Slide 25 of 93

What if my patient had cirrhosis?

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Poordad F, EASL, 2014, LB O163

Clinical trials.gov: NCT01704755

Poordad F, et al. N Engl J Med 2014; 2014 Apr 12]

HCV GT 1

Treatment-naïve and

exp., cirrhotic

N=380

SVR12

ABT-450+RTV+ombitasvir+dasabuvir+RBV, n=172SVR12

Week 0 12 24

Paritaprevir/RTV+Ombitasvir+Dasabuvir+RBV for 12 or 24 weeks in GT 1 Treatment-Naïve and -Experienced Cirrhotic Patients

Phase 3, randomized, open-label study

TURQUOISE II: GT1

ABT-450+RTV+ombitasvir+

dasabuvir+RBV, n=208

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Poordad F, EASL, 2014, LB O163

Poordad F, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]

91.8 95.9

0

20

40

60

80

100

12 Weeks 24 Weeks

SV

R12, %

Patients missing data in SVR12 window count as failures

On treatment virologic failure: 1 (0.5%) in 12 week group, 3 (1.7%) in 24 week group

Relapse: 12/203 (5.9%) in 12 week group, 1/164 (0.6%) in 24 week group

SVR and Virologic Failure

191/208 165/172

TURQUOISE II (paritaprevir/RTV+ombitasvir+dasabuvir+RBV): GT1

P=0.089

‡

Twelve in the 12 week group and 1 in the 24 week group relapsed. 7/12 relapsers were geno 1a null responders

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Ledipasvir + Sofosbuvir

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Background

FDC, fixed-dose combination.

Ledipasvir

– Once-daily, oral, 90-mg NS5A inhibitor

Sofosbuvir

‒ Once-daily, oral, 400-mg

NS5B inhibitor

Ledipasvir/Sofosbuvir FDC

–Once-daily, oral, fixed-dose

(90/400 mg) combination tablet

–Single-tablet regimen for

hepatitis C

SOF nucleotide

polymerase

inhibitor

LDVNS5A

inhibitor

SOF nucleotide

polymerase

inhibitor

SOF nucleotide

polymerase

inhibitor

LDV

NS5A

inhibitor

SOF

nucleotide

polymerase

inhibitor

LDV

NS5A

inhibitor

SOF

nucleotide

polymerase

inhibitor

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Mangia A, EASL, 2014, O164

Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12

LDV/SOF Single Tablet Regimen in HCV Treatment-Naïve GT 1

Phase 3, randomized, open-label study of LDV/SOF ± RBV for 12 or 24 weeks in HCV GT 1 treatment-naive patients, including compensated cirrhotics

ION-1 (LDV/SOF±RBV)

‡

N = 865

TN GT 1

12 24Study Weeks 36

SVR 12

SVR 12

n=217

n=217

n=214

n=217

RBV 1000-1200 mg/d

HCV RNA analyzed by COBAS® TaqMan® HCV Test v2.0 HPS,

with LLOQ of 25 IU/mL

SVR 12

SVR 12

LDV/SOF 90/400 mg

LDV/SOF 90/400 mg + RBV

LDV/SOF 90/400 mg


0

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Slide 31 of 93

SVR12 – LDV/SOF Single Tablet Regimen in HCV Treatment-Naïve GT 1

99 97 98 99

0

20

40

60

80

100

211/217

12 Weeks 24 Weeks

LDV/SOF + RBV

211/214 212/217

SV

R1

2 (

%)

215/217

LDV/SOF + RBVLDV/SOF LDV/SOF

Error bars represent 95% confidence intervals




‡

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SVR12 by Presence of Cirrhosis - LDV/SOF Single Tablet Regimen in HCV Treatment Naïve GT 1

Error bars represent 95% confidence intervalsMangia A, EASL, 2014, O164

Afdhal N, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]


99 97 98 9994 100 94 100

0

20

40

60

80

100

Absence of Cirrhosis Cirrhosis

179/180 32/34 178/184 33/33 181/184 31/33 179/181 36/36

SV

R1

2 (

%)

12 Weeks 24 Weeks

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

‡

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LDV/SOF±RBV Safety Summary

12 Weeks 24 Weeks

Patients, n (%)

LDV/SOF

n=214

LDV/SOF

+ RBV

n=217

LDV/SOF

n=217

LDV/SOF

+ RBV

n=217

Overall

safety

AEs 169 (79) 185 (85) 178 (82) 200 (92)

Grade 3‒4 AEs 4 (2) 14 (6) 21 (10) 12 (6)

Serious AEs 1 (<1) 7 (3) 18 (8) 7 (3)

Treatment D/C due

to AEs0 0 4 (2) 6 (3)

Death 0 0 0 0

Grade 3‒4

laboratory

abnormality

10 (5) 21 (10) 22 (10) 27 (12)

Hb <10 g/dL 0 20 (9) 0 16 (7)

Hb <8.5 g/dL 0 1 (<1) 0 0




‡

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Slide 34 of 93

Would 8 weeks be enough?

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Kowdley K, EASL, 2014, O56

Kowdley K, et al. N Engl J Med 2014; 2014 Apr 11

LDV/SOF±RBV in Treatment-Naïve Non-Cirrhotic GT 1 HCV

Phase 3, randomized, open-label study of LDV/SOF ± RBV for 8 or 12 weeks in HCV GT 1 treatment-naïve patients without cirrhosis


‡

12 24Study Weeks 8

SVR 12 n=216

n=215

n=216

RBV 1000-1200 mg/d

HCV RNA analyzed by COBAS® TaqMan® HCV Test v2.0 HPS, with LLOQ of 25 IU/mL

SVR 12

SVR 12

LDV/SOF 90/400 mg

LDV/SOF 90/400 mg


N = 647

TN GT 1,

non-cirrhotic

0

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Slide 36 of 93

SVR12 - LDV/SOF±RBV in Treatment-Naïve Non-Cirrhotic GT 1 HCV

Error bars represent 95% confidence intervals.Kowdley K, EASL, 2014, O56


206/216

8 Weeks 12 Weeks

LDV/SOFLDV/SOF LDV/SOF + RBV

201/216202/215 206/216

SV

R1

2 (

%)

ION-3 (LDV/SOF±RBV) ‡

94 93 95

0

20

40

60

80

100

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Reasons for Not Achieving SVR

8 Weeks 12 Weeks

Patients, n (%)LDV/SOF

n=215

LDV/SOF +

RBV

n=216

LDV/SOF

n=216

SVR12 202 (94) 201 (93) 206 (95)

Breakthrough 0 0 0

Relapse 11 (5) 9 (4) 3 (1)

Lost to Follow-Up 1 (<1) 5 (2) 7 (3)

Kowdley K, EASL, 2014, O56



‡

All virologic failures were due to relapse

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What if my patient was treatment experienced?

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Afdhal N, EASL, 2014, O109


LDV/SOF Single Tablet Regimen in Treatment-Experienced GT 1 HCV

Phase 3, randomized, open-label study of LDV/SOF ± RBV for 12 or 24 weeks in HCV GT 1 treatment-experienced patients who previously failed PegIFN + RBV ± PI


‡

N = 440

TE GT 1

12 24Study Weeks 36

SVR 12

SVR 12

n=109

n=111

n=109

n=111

RBV 1000-1200 mg/d

HCV RNA analyzed by COBAS® TaqMan® HCV Test v2.0 HPS, with LLOQ of 25 IU/mL

SVR 12 LDV/SOF 90/400 mg + RBV

LDV/SOF 90/400 mg


SVR 12 LDV/SOF 90/400 mg

0

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Slide 40 of 93

SVR12 - LDV/SOF±RBV in Treatment-Experienced GT 1 HCV

94 96 99 99

0

20

40

60

80

100

107/111

12 Weeks 24 Weeks

LDV/SOF + RBV

102/109 108/109

SV

R1

2 (

%)

110/111

LDV/SOF + RBVLDV/SOF LDV/SOF

Error bars represent 95% confidence intervals




‡

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Reasons for Not Achieving SVR



12 Weeks 24 Weeks

Patients, n (%)

LDV/SOF

n=109

LDV/SOF+RB

V

n=111

LDV/SOF

n=109

LDV/SOF+RB

V

n=111

SVR12 102 (94) 107 (96) 108 (99) 110 (99)

Breakthrough 0 0 0 1 (<1)

Relapse 7 (7) 4 (4) 0 0

Lost to Follow-

Up0 0 1 (<1) 0

Single on-treatment breakthrough was due to non-compliance

– Patient had no detectable levels of LDV or SOF at multiple time points prior to and at the time of virologic failure


‡

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93 96 100 9894 97 98 100

0

20

40

60

80

100

Failed PegIFN+RBV Failed Protease Inhibitor

SV

R1

2 (

%)

40/43 62/66 45/47 62/64 58/58 49/50 58/59 51/51

12 Weeks 24 Weeks


SVR12 in PegIFN+RBV vs. PI+PegIFN+RBV Failures

Error bars represent 95% confidence intervalsAfdhal N, EASL, 2014, O109



‡

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95 100 99 9986 82100 100

0

20

40

60

80

100

Absence of Cirrhosis Cirrhosis

SV

R1

2 (

%)

83/87 19/22 89/89 18/22 86/87 22/22 88/89 22/22

12 Weeks 24 Weeks


SVR12: Absence of Cirrhosis vs. Cirrhosis

Error bars represent 95% confidence intervalsAfdhal N, EASL, 2014, O109



‡

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Conclusions

LDV/SOF RBV for 12 weeks resulted in SVR12 rates of

94–96% in treatment-experienced GT 1 patients–Adding RBV and/or extending LDV/SOF treatment duration to 24

weeks did not significantly increase SVR12 rates

24 weeks is needed in treatment experienced patients with

cirrhosis




‡

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Slide 45 of 93

Gane E, EASL, 2014, O6

LDV/SOF±RBV in Difficult-to-Treat HCV Populations

ELECTRON-2 (LDV/SOF±RBV)

Wk 0 Wk 12 Wk 24

SVR12

LDV/SOF, n=20GT 1

CPT class B

LDV/SOF + RBV, n=19GT 1

Prior SOF exposure

LDV/SOF + RBV, n=26

LDV/SOF, n=25GT 3

Treatment naïve

Ran

do

miz

ed

Prior treatment history of SOF relapsers included SOF + RBV ± DAA

Cirrhosis was present in all CPT class B and 16% of GT 3 patients

Phase 2, open-label study of LDV/SOF RBV for 12 weeks in HCV GT 1 prior SOF relapsers, GT 1 patients with decompensated cirrhosis, and treatment-naïve GT 3 patients

‡

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Slide 46 of 93

100

65 64

100

0

20

40

60

80

100

GT1 Retreatment GT1 CPT Class B GT3 Naïve GT3 Naïve

SV

R12 (

%)

19/19 13/20 16/25 26/26

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

SVR12 Results with LDV/SOF±RBV for 12 Weeks

13/20 16/25 26/2619/19

Gane E, EASL, 2014, O6

ELECTRON-2 (LDV/SOF±RBV)

‡

LDV/SOF+RBV for 12 weeks achieved 100% SVR12 (19/19) in HCV GT 1 patients who previously relapsed after SOF-based regimens, including short-

duration LDV/SOF

LDV/SOF without RBV for 12 weeks achieved 65% SVR12 (13/20) in HCV GT 1 patients with CPT B cirrhosis who currently have no treatment options

LDV/SOF + RBV for 12 weeks achieved 100% SVR12 (26/26) in HCV GT 3 naive patients

LDV/SOF without RBV for 12 weeks achieved 64% SVR12 (16/25) in HCV GT 3 naïve patients

The regimens were safe and well tolerated

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Are responses durable?

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Slide 48 of 93

Gordon S, EASL, 2014, P1171SOF 400 mg/d; PegIFN 180 μg/wk; RBV 1000-1200 mg/d for SOF+RBV arms and 800 mg/d for PegIFN+RBV arm

Integrated Safety Analysis of SOF-Based HCV Treatment Regimens from Phase 3 Studies

Safety data from patients enrolled in 5 Phase 3 studies (NEUTRINO, VALENCE, FISSION, POSITRON, and FUSION)

0 12 16 24Week 48

Historical Control: TVR or BOC + PegIFN + RBV

PegIFN-Unable: POSITRON

PBO, n=71

SOF + RBV, n=207 SVR12

Treatment-Naïve: FISSION

SOF + RBV, n=256 SVR12

No response-guided therapy

PegIFN + RBV, n=243 SVR12

Treatment-Naïve: NEUTRINO

GT 1,4,5,6

GT 2,3

GT 2,3

IFN-

LIMITING

Treatment-Experienced: FUSION

SOF + RBV, n=103 PBO SVR12

SOF + RBV, n=98 SVR12GT 2,3

ALL

ORAL

THERAPY

Treatment-Naïve and Treatment-Experienced: VALENCE

SVR12SOF + RBV, n=73

SVR12SOF + RBV, n=250GT 3

GT 2

SVR12

SOF + PegIFN + RBV, n=327 SVR12

36

Integrated Safety Analysis of SOF Phase 3 Studies

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Cheng W, EASL, 2014, P1112

• SVR24 was durable in 100% of 480 patients with available data from Phase 3 trials

• 435 (91%) and 90 (19%) had available Week 24 and 48 data, respectively

Durability of SVR24Long-Term Follow-Up of SOF Phase 3 Studies

100 100 100 100100 100 100

0

20

40

60

80

100

FISSION (n=85) POSITRON (n=94) FUSION (n=91) NEUTRINO (n=210)

SVR48 SVR72

Du

rab

le S

VR

, %

78/78 52/52 88/88 37/37 1/1185/185NA84/84

NA, no available data.

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–SVR 24 is durable

ConclusionsLong-Term Follow-Up of SOF Phase 3 Studies

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Slide 51 of 93


–Patient starts SOF/LDV for 12 weeks.

–HCV RNA negative at 4-12 weeks.

–Arthralgias and rash 6 weeks after end of treatment

–HCV RNA 4.5 million IU/ml

–What happened??

Case 1.

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Genotype 4

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Wk 0 Wk 24Wk 12

SOF+RBV

(n=31)*

SOF+RBV (n=29)*

SVR12

Wk 36 Wk 48

SVR24SVR4

SVR24

*SOF 400 mg/d; RBV 1000–1200 mg/d

SOF+RBV for GT 4 HCV

Randomized, open-label, single-center study conducted in the US of the safety and efficacy of all-oral SOF + RBV in patients of Egyptian ancestry with HCV GT 4

79

100

59

87

0

20

40

60

80

100

13/15

Treatment Naïve Treatment Experienced

12 Weeks

SOF+RBV

24 Weeks

SOF+RBV

SV

R1

2 (

%)

11/14 10/17

12 Weeks

SOF+RBV

24 Weeks

SOF+RBV

14/14

‡

Ruane P, EASL, 2014, P1243 *1 patient had RBV D/C after Day 35 due to AE of dyspnea, and completed SOF 24 wk

SOF/LDV

(n=22)*

SVR12 SVR24SVR4

12 Weeks

SOF/LDV

38% SOF/LDV patients Rx experienced43% bridging fibrosis/cirrhosis

95

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Slide 54 of 93

An Alternative View of Cirrhosis in Genotypes 1 and 4

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Ledipasvir/Sofosbuvir With Ribavirin for the Treatment of HCV in Patients With Decompensated

Cirrhosis: Preliminary Results of a Prospective, Multicenter Study

Michael R. Charlton3, Steven L. Flamm1, Gregory T. Everson2, Jill M. Denning4, Sarah Arterburn4, Theo Brandt-Sarif4, Phillip S. Pang4, John

G. McHutchison4, K. Rajender Reddy5, Nezam H. Afdhal6

1Northwestern Feinberg School of Medicine, Chicago, IL; 2University of Colorado Denver, Aurora, CO; 3Intermountain Medical Center, Murray, UT; 4Gilead Sciences, Inc., Foster City,

CA; 5University of Pennsylvania School of Medicine, Philadelphia, PA; 6Beth Israel Deaconess Medical Center, Boston, MA

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Study DesignGT 1 and 4, CPT Class B and C

108 patients randomized 1:1 to 12 or 24 Weeks of Treatment

GT 1 or 4 treatment-naïve or -experienced patients with decompensated cirrhosis (CPT class B [7-9] or C [score 10–12])

Broad inclusion criteria

– No history of major organ transplant, including liver

– No hepatocellular carcinoma (HCC)

– Total bilirubin ≤10 mg/dL, Hemoglobin ≥ 10 g/dL

– CLcr ≥ 40 mL/min, platelets > 30,000 x 103/µL,

Stratified by CPT score B or C

LDV/SOF + RBV

LDV/SOF + RBV

Wk 0 Wk 12 Wk 24

SVR12

SVR12

Wk 36

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Slide 57 of 93

CPT B CPT C

12 Weeks

n=30

24 Weeks

n=29

12 Weeks

n=23

24 Weeks

n=26

MELD score, n (%)

<10 6 (20) 8 (28) 0 0

10‒15 21 (70) 16 (55) 16 (70) 13 (50)

16-20 3 (10) 5 (17) 7 (30) 12 (46)

21-25 0 0 0 1 (4)

Ascites, n (%) 17 (57) 17 (59) 22 (96) 25 (96)

Encephalopathy, n (%) 20 (67) 16 (55) 21 (91) 23 (88)

Median bilirubin, mg/dL (range) 2.0 (0.6-5.5) 1.4 (0.8-4.5) 2.9 (1.2-14.5) 3.8 (1.1-5.7)

Median albumin, g/L (range) 2.9 (2.1-3.7) 3.0 (2.2-3.4) 2.6 (1.6-3.5) 2.6 (2.0-3.3)

Median INR, (range) 1.3 (1.0-1.5) 1.3 (1.0-2.6) 1.4 (1.2-1.9) 1.4 (1.1-2.2)

Median platelets, x 103µL (range) 88 (36-212) 73 (30-154) 81 (39-177) 71 (32-179)

Results: Baseline CharacteristicsGT 1 and 4, CPT Class B and C

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Slide 58 of 93

Results: SVR12GT 1 and 4, CPT Class B and C

6 subjects (2 CPT B/24 Wk, 1 CPT C/12 Wk and 3 CPT C/24 Wk) excluded (transplant on study); 3 subjects CPT C/24 Wk have not reached SVR12.Error bars represent 90% confidence intervals.

87 87 8689 89 90

0

20

40

60

80

100

CPT B CPT C

SV

R1

2 (

%)

26/30 19/22 18/20

Overall

24/2745/52 42/47

LDV/SOF + RBV 12 Weeks LDV/SOF + RBV 24 Weeks

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Laboratory Results: Change in MELD Score From Baseline Through Follow-up Week 4

59

-6

-4

-2

0

2

4

-6

-4

-2

0

2

4

n=5 n=5 n=2 n=3

(-8)

(+10)

CPT B CPT C

12 wk (n=30)* 24 wk (n=29)* 12 wk (n=23)* 24 wk (n=26)*

*Missing FU-4: n=2 CPT B 12 wks; n=4 CPT B 24 wks; n=2 CPT C 12 wk; n=7 CPT C 24 wk.

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ConclusionsGT 1 and 4, CPT Class B and C

LDV/SOF + RBV for 12 weeks resulted in a high SVR12 rate in HCV patients with GT 1 and 4 and advanced liver disease

– Extending treatment duration to 24 weeks did not increase the response rate

Virologic response was associated with improvements in bilirubin, albumin, MELD and CPT scores in both CPT class B and C patients

LDV/SOF + RBV for 12-24 weeks was generally safe and well tolerated in CPT class B and C patients

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Slide 61 of 93

Summary

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Preferred Regimens for Genotype 1a or Genotype 1 not subtyped

www.HCVguidelines.org

No-cirrhosis Compensated Cirrhosis

Naïve SOF/LDV x 12 weeks SOF/LDV x 12 weeks

3D + RBV x 12 weeks 3D + RBV x 24 weeks

SIM/SOF x 12 weeks SIM/SOF x 24 weeks

Experienced SOF/LDV x 12 weeks SOF/LDV x 24 weeks

SOF/LDV + RBV x 12 weeks

3D + RBV x 12 weeks* 3D + RBV x 24 weeks*

SIM/SOF x 12 weeks SIM/SOF x 12-24 weeks

* Do not use 3D regimens in prior protease inhibitor failures

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Slide 63 of 93

Preferred Regimens for Genotype 1b




3D x 12 weeks 3D + RBV x 12 weeks

SIM/SOF x 12 weeks SIM/SOF x 24 weeks


SOF/LDV + RBV x 12 weeks

3D x 12 weeks* 3D + RBV x 12 weeks*

SIM/SOF x 12 weeks SIM/SOF x 12-24 weeks


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Slide 64 of 93

Preferred Regimens for Genotype 4




SOF + RBV x 24 weeks SOF + RBV x 24 weeks




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SOF + RBV x 24 weeks SOF + RBV x 24 weeks




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Slide 66 of 93




Naïve SOF + RBV x 12 weeks SOF + RBV x 16 weeks

Experienced SOF + RBV x 12 weeks SOF + RBV x 16 weeks

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Slide 67 of 93




Naïve SOF + RBV x 24 weeks SOF + RBV x 24 weeks

SOF/LDV + RBV x 12

weeks

Experienced SOF + RBV x 24 weeks SOF + RBV x 24 weeks

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Sofosbuvir/DAA Treatment Failures, Liver Transplant and Decompensated Cirrhosis patients


Refer to hepatology program

Basic principles for SOF/DAA failures

–If mild disease - wait

–If cirrhosis / must treat SOF / LDV +/- RBV x 24 weeks

Decompensated cirrhosis and Liver Transplant

–SOF/LDV + RBV x 12 weeks

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Slide 69 of 93

DAA Combination Therapy

NS5A-I

Ribavirin

Protease-Inh.

NI and NNI

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Slide 70 of 93

NS5A-I

Protease-Inh.

NI and NNI

DAA Combination Therapy

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Prioritization Criteria

Sustained virologic response rate

Side effects

Drug-drug interaction

Class of therapy

Number of direct-acting antiviral drugsD

ecr

eas

ing

imp

ort

ance

in n

ear

-te

rm

Most important

Secondary attributes determining treatment with non-inferior SVR

Differentiating Attributes of Future Therapy Beyond Cure

Abbreviation: SVR, sustained virologic response.Source: Leerink physician interviews. Leerink Swann Consulting.

Cost

Dosing/Treatment duration

Pan-genotypic

Least important

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Slide 72 of 93

Prioritization Criteria

Sustained virologic response rate

Side effects

Drug-drug interaction

Class of therapy

Number of direct-acting antiviral drugsD

ecr

eas

ing

imp

ort

ance

in n

ear

-te

rm

Most important

Secondary attributes determining treatment with non-inferior SVR

Differentiating Attributes of Future Therapy Beyond Cure

Abbreviation: SVR, sustained virologic response.Source: Leerink physician interviews. Leerink Swann Consulting.

CostDosing/Treatment duration

Pan-genotypic

Least important

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Slide 73 of 93

Relationship Efficacy & Treatment Duration

Slope and Optimal Treatment Duration

0

10

20

30

40

50

60

70

80

90

100

0 2 4 6 8 10 12 14 16

SV

R (

%)

Treatment duration (weeks)

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TreatmentParadigm

SVR for GT1

Triple Therapy• Naive 70%1,2

• Exp 40%1,2

Triple Therapy:

Next Generation

• Naive 89%3

• Naive 80%4

• Naive 89%5

IFN and RBV-

Free Therapy

Expected

• Naive = >90%

• Exp = >90%

Expected

• Naive = >90%

• Exp = >80%

IFN-free

Therapy

Wave 1

Evolution of Therapies for GT1

2011

2013 -

2014

2016 +

2015

TimingTreatmentRegimens

• Telaprevir + PEG-IFN + RBV

• Boceprevir + PEG-IFN + RBV

• Sofosbuvir + PEG-IFN + RBV

• Simeprevir + PEG-IFN + RBV

• Faldeprevir + PEG-IFN + RBV

• Multiple combinations in development

• Pangenotypic

• Multiple combinations in development

Abbreviations: GT1, HCV genotype 1; IFN, interferon; PEG-IFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response.1. Telaprevir [US package insert]. October 2012; 2. Boceprevir [US package insert]. July 2012; 3. Lawitz E, et al. EASL 2013. Abstract 1411; 4. Jacobson I, et al. EASL 2013. Abstract 1425; 5. Ferenci P, et al. EASL 2013. Abstract 1416.

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Slide 75 of 93

CirrhosisNormal

Nodules

Irregular surface

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Slide 76 of 93

Advanced Fibrosis / Cirrhosis -

Diagnosis

Cirrhosis is a histological diagnosis

However, in patients with chronic liver disease, various clinical, laboratory, and radiological features can suggest cirrhosis

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FibroTest

ELF Panel

Fibromètre

biopredictive.com Biols.fr

Fibrometer

SERUM MARKERS TRANSIENT ELASTOMETRY

Non-invasive Fibrosis Staging

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Slide 78 of 93

Staging fibrosis with NFS, FIB-4, and others …

High (>92%) NPV for advanced fibrosis

Useful in clinical practice for excludingadvanced fibrosis

ELF performed only marginally betterthan NFS

Modest PPV – liver biopsy stillnecessary

McPherson, Gut 2010

Guha, Hepatology 2008

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Slide 79 of 93

Transient Elastography

Measures elasticity using sound waves

Stiffness determined by multiple factors

–Degree of Fibrosis

–Degree of Inflammation- not good for acute hepatitis

Degree of Steatosis

–Not effective in morbidly obese patients >3.5cm

Approved in U.S. 4-2013

– now have XL probes

J Gastrointestin Liver Dis. 2008 Jun;17(2):155-163

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Prediction of advanced fibrosis by Fibroscan

Wong, Hepatology 2010

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Slide 81 of 93

Crespo, J Hepatol 2012

Fibroscan + ELF Algorithm

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Slide 82 of 93

MR Elastography of the Liver

Plastic Tube

Passive Driver

-90

0

+90

Am

pli

tud

e (m

m)

-70

0

+70

Am

pli

tud

e (m

m)

Active Driver

Gra

die

nt-

Ech

o M

RE

Phase

Difference

θ

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Liver Stiffness Correlates With Fibrosis Stage

0 1 2 3 4

Normal Chronic Liver Disease

< 0.0001*

< 0.0001*

< 0.0001*

Kruskal Wallis

Dunnett’s Test

α = 0.05

0

2

4

6

8

10

12

14

Liv

er

Stiffn

ess (

kP

a)

(Fibrosis Stage)Yin et al. CGH 2007;5:1207-13

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2006

24 exams

2006

25 exams

2007

85 exams

2007

88 exams

2008

141 exams

2010

88 exams

Slide 84 of 93

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2006

24 exams

2006

25 exams

2007

85 exams

2007

88 exams

2008

141 exams

2010

88 exams

Slide 84b of 93

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Short-term variability of elastometry measurements

531 paired liver stiffness measurements in 432 patients

> 1 day and <1 year apart

Nascimbeni F, Clin Gastro Hepatol in press

6.5-7 kPa

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Slide 86 of 93Transient

Elastography

0

Shear Stiffness (kPa)

105

MRE

Shear Stiffness (kPA)

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Slide 87 of 93

Date of download: 4/18/2014Copyright © 2014 American Medical

Association. All rights reserved.

From: Coffee, Cirrhosis, and Transaminase Enzymes

Arch Intern Med. 2006;166(11):1190-1195. doi:10.1001/archinte.166.11.1190

N=125,580

F/U 22 yrs

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Copyright © 2014 American Medical

Association. All rights reserved.

From: Coffee, Cirrhosis, and Transaminase Enzymes

Arch Intern Med. 2006;166(11):1190-1195.

N=125,580

F/U 22 yrs

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Associations between the Consumption of 4 or More Cups of Coffee per Day and Mortality

Freedman ND et al. N Engl J Med 2012;366:1891-1904

N=617,000 follow up 5,148,000 person years

Slide 89a of 93

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Associations between the Consumption of 4 or More Cups of Coffee per Day and Mortality

Freedman ND et al. N Engl J Med 2012;366:1891-1904

N=617,000 follow up 5,148,000 person years

Overall Hazards ratio = 0.88 (95% CI, 0.84 to 0.93)

P<0.001

Slide 89b of 93

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Slide 91 of 93

Evolving Concepts in Allocation:Mortality Rates by MELD – “Transplant Benefit”

HR=3.64

P<0.001

HR=2.35

P<0.001

HR=1.21

P=0.41

HR=0.62

P<0.01

HR=0.38

P<0.001

HR=0.22

P<0.001

HR=0.18

P<0.001

HR=0.07

P<0.001

HR=0.04

P<0.001

1

10

100

1000

10000Waitlist

Transplant

Mortality

rate per

1000

patients

6-11 12-14 15-17 17-20 21-23

MELD

24-26 27-29 30-39 40+

HR=hazard ratio

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Slide 92 of 93

GT 1

http://www.hcvguidelines.org

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