Case 1. Cirrhosis - IAS- · PDF file · 2017-07-19Medical Director of Liver...

6/2/2015

1

Formatted: 05-14-2015

Chicago, IL: May 19, 2015

Interactive Case-Based Presentations

and Audience Discussion

Michael R. Charlton, MBBS, FRCPHepatology Director

Medical Director of Liver Transplantation

Intermountain Medical Center

Salt Lake City, Utah

Slide 2 of 72

Case 1. Cirrhosis

Slide 3 of 72

Case 1.

62 yr old man

Long history of HCV infection (diagnosed 1992).

– “I did it all in the 60s.”

HCV genotype 1a, HCV RNA 112,000 IU/ml

ALT 53, AST 61, total bilirubin 3.7, albumin 2.9

– Cr 1.12mg/dl, INR 1.2

Exam notable for spider angiomata, mild emaciation, small amount of ascites.

Meds: carvedilol, spironolactone and furosemide

U/S – ascites, nodular liver, splenomegalyAuthor’s Last Name, Conference Name, Year, Presentation #

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2

Slide 4 of 72

Case 1.

Virological nonresponse to PEG/RBV in 2001

Should we treat HCV infection?

If so, with what?

Are there any special considerations?

Author’s Last Name, Conference Name, Year, Presentation #

Slide 5 of 72

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

Slide 6 of 72

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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Slide 7 of 72

All oral therapy for HCV Genotype 1 infection in Cirrhosis

Slide 8 of 72

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)

AM PM

450/r/267 450/r/267 333

333

RBVRBVRBV

RBV

RBVRBV

RBV

RBV

AbbVie HCV Clinical Development Program

ABT-450/RTV/ABT-267+ABT-333±RBV in GT 1 Patients ‡

Slide 9 of 72ABBV 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 10 of 72

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=172 SVR12

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

‡

Slide 11 of 72

Demographics

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

12 weeksN=208

24 weeksN=172

Mean age, y 57.1 56.5

Male, % 70.2 70.3

White race, % 95.7 93.6

Hispanic or Latino ethnicity, % 12.0 11.6

Mean BMI, kg/m2 27.9 27.9

IL28B non-CC, % 83.2 80.2

GT 1a, % 67.3 70.3

Treatment-naïve, % 41.3 43.0

Treatment experienced, % 58.7 57.0

PegIFN+RBV Relapse 13.9 13.4

PegIFN+RBV Partial responder 8.7 7.6

PegIFN+RBV Null responder 36.1 36.0

Serum albumin, < 3/5 g/L, % 12.0 10.5

Platelet count < 100 x109/L, % 21.6 19.2

Child-Pugh score > 5, % 18.3 18.6

Poordad F, EASL, 2014, LB O163. Poordad F, et al. N Engl J Med 2014; 2014 Apr 12 [Epub ahead of print]

‡

Slide 12 of 72


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


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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Slide 13 of 72

SVR in HCV Subtype 1a and Prior Treatment Response

88.6 92.2 93.3100

80

94.292.9

100 10092.9

0

20

40

60

80

100

GT 1a Naïve Prior Relapse Prior PartialResponse

Prior NullResponse

SV

R12

12 weeks 24 weeks

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

124/140 114/121 59/64 52/56 14/15 13/13 11/11 10/10 40/50 39/42



‡

Slide 14 of 72

The most common AEs in the 12 week and 24 week arm were

Fatigue: 32.7% and 46.5%, respectively, P<0.05

Headache: 27.9% and 30.8%, respectively, P=NS

Nausea: 17.8% and 20.3%, respectively, P=NS

Dyspnea: 5.8% and 12.2%, respectively, P<0.05

12 weeks

N=208

24 weeks

N=172

Any AE, % 91.8 90.7

Serious AEs, % 6.3 4.7

Treatment D/C due to AEs, % 1.9 2.3

Adverse Events




‡

Slide 15 of 72

Ledipasvir + Sofosbuvir

Author’s Last Name, Conference Name, Year, Presentation #

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Slide 16 of 72

Background

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

FDC, fixed-dose combination.

Slide 17 of 72

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

Slide 18 of 72



Overall Demographics


12 Weeks 24 Weeks

LDV/SOF

n=214

LDV/SOF+RBV

n=217

LDV/SOF

n=217

LDV/SOF+RBV

n=217

Mean age, y (range) 52 (18–75) 52 (18–78) 53 (22–80) 53 (24–77)

Male, n (%) 127 (59) 128 (59) 139 (64) 119 (55)

Black, n (%) 24 (11) 26 (12) 32 (15) 26 (12)

Hispanic, n (%) 26 (12) 20 (9) 29 (13) 26 (12)

Region Europe, n (%) 89 (42) 99 (46) 85 (39) 80 (37)

Mean BMI, kg/m2 (range) 27 (18–41) 27 (18–42) 27 (18–48) 26 (18–48)

Cirrhosis, n (%) 34 (16) 33 (15) 33 (15) 36 (17)

IL28B CC, n (%) 55 (26) 76 (35) 52 (24) 73 (34)

Interferon ineligible, n (%) 14 (7) 20 (9) 19 (9) 14 (7)

GT 1a, n (%) 144 (67) 148 (68) 146 (67) 143 (66)

Mean HCV RNA,

log10 IU/mL (range)6.4 (1.6–7.5) 6.4 (4.4–7.6) 6.3 (3.7–7.4) 6.3 (3.2–7.5)

HCV RNA ≥800,000 IU/mL 169 (79) 173 (80) 168 (77) 173 (80)

‡

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Slide 19 of 72

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




‡

Slide 20 of 72

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



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

‡

Slide 21 of 72

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 22 of 72

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

Slide 23 of 72

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 intervalsAfdhal N, EASL, 2014, O109



‡

Slide 24 of 72

Reasons for Not Achieving SVR



12 Weeks 24 Weeks

Patients, n (%)

LDV/SOF

n=109

LDV/SOF+RBV

n=111

LDV/SOF

n=109

LDV/SOF+RBV

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-Up 0 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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Slide 25 of 72

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

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

SVR12: Absence of Cirrhosis vs. Cirrhosis





‡

Slide 26 of 72

Pre-Liver Transplantation

Slide 27 of 72

Phase 2 Pre-Liver Transplant Pilot StudySOF + RBV to Prevent HCV Recurrence Post-Transplant

SOF + RBV (n=61)

Male, n (%) 49 (80)

Median age, y (range) 59 (46–73)

White, n (%) 55 (90)

BMI < 30 kg/m2, n (%) 43 (70)

HCV RNA > 6 log10 IU/mL, n (%) 41 (67)

Genotype, n (%)

1a

1b

2

3a

4

24 (39)

21 (34)

8 (13)

7 (12)

1 (2)

Non-CC allele, n (%) 47/60 (78)

CTP score, n (%)

5

67

8

26 (43)

18 (30)14 (23)

3 (5)

Median MELD score, (range) 8 (6–14)

Prior HCV treatment, n (%) 46 (75)

SOF 400 mg + RBV 1000–1200 mg

0 Liver transplant

(up to 48 weeks)

Time

Undergoing LT

for HCC 2° to

HCV, N=61

12 weeks

Post-transplant

virologicalresponse

(pTVR)

Pre-Liver Transplant Study (SOF+RBV)

LT, liver transplantation.Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation

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Slide 28 of 72

Results: Post-Transplant Virologic Response

93

70

0

20

40

60

80

100

Transplant pTVR12

43/46* 30/43*

*3 patients were >LLOQ at transplant.

Vira

l R

esp

on

se

Ra

te (

%)

ITT analysis: 30/61 (49%) pTVR

Slide 29 of 72

0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 480

Days with HCV RNA Continuously TND Prior to Liver Transplant

Days Continuously TND Prior to Transplant: No Recurrence vs Recurrence in GT 1–4

No Recurrence (n=30) Recurrence (n=10)

Median days TND

• No recurrence: 99

• Recurrence: 5.5

p <0.001*

>30 days TND

*Wilcoxon rank sum test.

Slide 30 of 72

Results: Adverse Events

*No SAEs were deemed related to SOF.

n (%)

SOF + RBV

(N=61)

SAEs* 11 (18)

Deaths

Pre transplant 2 (3)

Post transplant 3 (5)

AEs leading to DC of study treatment 2 (3)

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Slide 31 of 72

Liver Levels in Humans

Liver levels of triphosphate formed by sofosbuvir in excess of the inhibition constant for the HCV NS5B RNA-dependent RNA polymerase (Ki = 0.42 µM)

In vitro studies show that triphosphate is the predominant metabolite in hepatocytes for both sofosbuvir and ribavirin

Total U-metabolites0.01

0.1

1

10

100

1000

10000

Sofosbuvir

Liv

er

Co

nc

(µM

)

Total RBV-metabolites0.01

0.1

1

10

100

1000

10000

Ribavirin

Human liver explant total metabolite concentrations following between

3 and 32 weeks of sofosbuvir + ribavirin treatment

73 (0.2, 205)

Ki

356 (82, 1,800)

Indicated total concentrations are median (min, max)

of n = 25 subjects

Babusis D. et al. AASLD 2013. November 1-5, 2013. Washington DC, USA

HCV RNA < LLOQ 12 wk post-transplant

Reoccurrence post-transplantHCV RNA > LLOQ @ time of transplant

Slide 32 of 72

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

Slide 33 of 72

Study Design

GT 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 34 of 72

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

Slide 35 of 72Results: SVR12


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

Slide 36 of 72

Does cirrhosis get better?

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Slide 37 of 72

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

37

-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.

Slide 38 of 72

HC

V R

NA

(lo

g10

IU/m

L)

< L

LO

Q

Week

56

100 100 100 100

44

75

94 94 93

0

20

40

60

80

100

2 4 8 12 24

CPT A

CPT B

5/

9

9/

9

8/

8

8/

8

7/

7

7/

16

12/

16

15/

16

15/

16

14/

15

*


SOF+RBV for Treatment of Chronic HCV with Cirrhosis and Portal HTN ± Decompensation: Week 24 Interim Results

Randomized, open-label, safety and efficacy study of SOF+RBV for 48 weeks compared to observation for 6 months in patients with HCV cirrhosis and portal HTN (CPT 5–9)

SOF 400 mg + RBV

1000‒1200 mg

SVR1

2

ObservationSOF 400 mg + RBV

1000‒1200 mg

SVR

12

Wk 0 Wk

24

Wk

48

Wk

96

Wk

72

Arm 1

n=25

Arm 2

n=25

HVPG at Day 0 and Week 48

HVPG at Day 0, and Weeks 24 and 72

Preliminary results

*1 patient was a non-responder at Week 8

Slide 39 of 72

Laboratory and Clinical Event Changes

Ascites Hepatic Encephalopathy

Patients, n

SOF + RBV

n=25

Observation

n=25

SOF + RBV

n=25

Observation

n=25

Baseline 6 9 5 2

Week 12 5 8 3 3

Week 24 0 7 0 4

Cirrhosis and Portal Hypertension Study (SOF+RBV)

17

1

-9

-1

-15

-10

-5

0

5

10

15

20

CTP A CTP B

0.50.4

-0.1

0

-0.2-0.1

00.10.20.30.40.50.6

Platelets (103/µL) Albumin (g/dL)

SOF+RBV Observation 24 weeks

-72 -75

130

-80

-60

-40

-20

0

20

CTP A CTP B

ALT (U/L)

CTP A CTP B


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Slide 40 of 72

Conclusions


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

Slide 41 of 72

Post-Liver Transplantation

Slide 42 of 72

Case 2. Liver Transplantation

6/2/2015

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Slide 43 of 72

HCV RNA 19,000;

Total bili 5.6; AST

291; ALT 182; INR 1.7; Cr 0.73

(9/18/2013)

Biopsy = Cirrhosis

(donor liver Hep C +

and fibrosis)(9/24/2013)

Underwent Liver

Transplantation

(9/19/2013)

Case 2.

Cr increase (1.79)

led to decrease

TAC dosing and levels

(10/5/2013)

Sept 2013

Started Compassionate

Use

SOF + RBV 200 mg/day

(anemia limiting dose)

(9/29/2013)

HCV RNA undetectable (Wk 8)

Total bili, AST and ALT normal(11/12/2013)

Nov 2013

Patient discharged

from hospital

(11/14/2013)

Biopsy- acute cellular

rejection, treated with

mycophenolate and increasing TAC dosing

(10/16/2013)

51 yo female with cirrhosis secondary to HCV GT 1b, complicated by hepatopulmonary syndrome

HCV RNA 456,000;

Total bili 19.1; AST

56; ALT 55; Cr 1.26(9/28/2013)

Oct 2013

Hypoxic on maximal

oxygen support. No

embolizable lesions on pulmonary

angiography.

Blood type O+

MELD score 29 by

exception

Cholestatic from

outset, ascites,

encephalopathy

Slide 44 of 72

Slide 45 of 72

45

6/2/2015

16

Slide 46 of 72

0

5

10

15

20

25

0

50

100

150

200

250

300

350

400

450

500

AST

ALT

Total Bilirubin

Tota

lBil

iru

bin

(mg/

dL)

AST &

ALT (IU

/L)

Sep-19 Oct Nov Nov-13

Compassionate use began

Case 2.

Slide 47 of 72

Charlton M, Gastroenterology, 2014.

0 24 36Study Week

SOF 400 mg + RBV 400–1200 mg SVR 12

TN & TE with

recurrent

HCV

SOF+RBV for Established Recurrent HCV Post-Liver Transplant

Post-Liver Transplant Study (SOF+RBV)

n=40

Low, ascending-dose RBV regimen starting at 400 mg/day, escalated based on hemoglobin levels

Slide 48 of 72

Samuel D, EASL, 2014, P1232

100 100

7370 70

0

20

40

60

80

100

Week 4 EOT SVR4 SVR12 SVR24

HC

V R

NA

< L

LO

Q (

%)

LLOQ, lower limit of quantification (25 IU/mL)

40/40 40/40 29/40 28/40 28/40

Virologic ResponsePost-Liver Transplant Study (SOF+RBV)

Twenty-four weeks of SOF+RBV resulted in high SVR rates in this difficult-to-treat post-transplant population, including many cirrhotics and treatment-experienced patients

Relapse was not influenced by RBV dose or exposure

SOF + RBV in patients with recurrent HCV after liver transplantation was safe and well tolerated

6/2/2015

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Slide 49 of 72

Kwo P, NEJM, 2014.

ABT-450+RTV+Ombitasvir+Dasabuvir+RBV in LT Recipients with Recurrent HCV GT 1

M12-999 (ABT-450+RTV+ombitasvir+dasabuvir+RBV)

Adjusted doses of TAC: 0.5mg/wk or 0.2mg every 3 days

Adjusted dose of CYA: 1/5th

daily dose

One patient D/C due to AEs (rash, memory impairment, and anxiety) after Week 18

Anemia Grade 3 (6.5–8 g/dl) in one patient, and 5 patients received EPO

Phase 2 single-arm trial assessing a NS3/4A/5A/5B inhibitor plus RBV for 24 weeks in 34 adult liver transplant recipients with recurrent HCV GT1 infection, fibrosis stage ≤ F2, excluding post-transplant treatment experience

* 4 patients experienced a TAC level > 15 ng/mL (15.7–34.0 ng/mL); All 4 patients had TAC dosing errors; 2 patients had associated creatinine increases (1.8 and 1.4 mg/dL), which normalized when dosing was corrected

0

2

4

6

8

10

12

14

16

Ta

cro

lim

us

Co

nc

en

tra

tio

n (

ng

/mL

) *

Pre-Rx on-Rx

SVR12 of 96%

Slide 50 of 72

Study Design

GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C

223 patients randomized 1:1 to 12 or 24 weeks of treatment

GT 1 or 4 treatment-naïve or -experienced post-transplant patients

Broad inclusion criteria

– ≥ 3 months from liver transplant

– No hepatocellular carcinoma (HCC)

– Total bilirubin ≤10 mg/dL

– CLcr ≥ 40 mL/min

– Platelets >30,000 x 103/µL

– Hemoglobin ≥10 g/dL

Stratified at screening: F0–F3, CPT A, B, C

RBV dosing

– F0–F3/CPT A cirrhosis: weight-based

– CPT B and C cirrhosis: dose escalation, 600–1200 mg/d

LDV/SOF + RBV

LDV/SOF + RBV

Wk 0 Wk 12 Wk 24

SVR12

SVR12

Wk 36

Slide 51 of 72

Results: Baseline Characteristics – 12 and 24 Weeks


F0-F3

n=111

CPT A

n=51

CPT B

n=52

CPT C

n=9

MELD (n, %)

<10 N/A 28 (55) 13 (25) 1 (11)

10-15 N/A 20 (39) 33 (63) 5 (56)

16-20 N/A 3 (6) 4 (8) 2 (22)

21-25 N/A 0 2 (4) 1 (11)

Ascites, n (%) 2 (2) 2 (4) 40 (77) 9 (100)

Encephalopathy, n (%) 1 (1) 3 (6) 23 (44) 7 (78)

Median bilirubin,

mg/dL (range)0.7 (0.3-3.6) 0.8 (0.2-2.9) 1.2 (0.5-3.7) 2.1 (0.7-9.9)

Median albumin,

g/L (range)3.8 (2.4-4.6) 3.7 (2.6-4.5) 3.2 (2.3-4.2) 2.4 (1.6-2.9)

Median INR (range) 1.0 (0.9-1.3) 1.1 (0.9-2.4) 1.2 (0.9-3.4) 1.3 (1.0-1.5)

Median platelets,

x 103/µL (range)146 (71-429) 108 (41-358) 93 (32-225) 79 (54-189)

Median hemoglobin,

g/dL (range)14.0 (10.1-18.3) 13.6 (11.2-17.9) 12.9 (9.6-17.0) 11.5 (9.6-14.2)

Median CLCr,

mL/min (range)

65.0

(20.4-116.8)

62.1

(26.8-110.9)

58.9

(29.0-118.9)

66.6

(39.5-72.1)

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Slide 52 of 72

Results: Mean HCV RNA Change During TreatmentGT 1 or 4: Post-Transplant F0–F3, CPT A, B, C

0

1

2

3

4

5

6

7F0-F3 (n=111)

CPT A (n=51)

CPT B (n=52)

CPT C (n=9)

Mean H

CV

RN

A (

log

10

IU/m

L)

Week

Baseline 1 2 4 6

LLOQ

Slide 53 of 72

96 96

85

60

98 96

83

67

0

20

40

60

80

100

F0–F3

SV

R1

2 (

%)

53/55 22/26 15/18

CPT B

55/56 25/26 24/25 2/3

CPT A

Results: SVR12


Error bars represent 2-sided 90% exact confidence intervals.8 CPT B 24 Week and 1 CPT C 24 Week subjects still to reach Week 12 posttreatment.


3/5

CPT C

Slide 54 of 72

96 96

85

60

98 96

83

67

0

20

40

60

80

100

F0–F3

SV

R1

2 (

%)

53/55 22/26 15/18

CPT B

55/56 25/26 24/25 2/3

CPT A

Results: SVR12GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C

Error bars represent 2-sided 90% exact confidence intervals.8 CPT B 24 Week and 1 CPT C 24 Week subjects still to reach Week 12 posttreatment.


3/5

CPT C

2 relapses

1 relapse 1 death 1 death

1 relapse

2 deaths

1 consentwithdrawn

3 deaths 2 relapses 1 relapse

6/2/2015

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Slide 55 of 72

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

CPT A Patients (n=48) CPT B Patients (n=41)

n=4 n=1

-8

-6

-4

-2

0

2

4

n=9 n=4

(-11)

12 Wk (n=23) 24 Wk (n=25) 12 Wk (n=21) 24 Wk (n=20)

-8

-6

-4

-2

0

2

4

Slide 56 of 72Results: Overall Safety Summary


F0-F3 CPT A CPT B CPT C

Patients, n (%)12 Wk

n=55

24 Wk

n=56

12 Wk

n=26

24 Wk

n=25

12 Wk

n=26

24 Wk

n=26

12 Wk

n=5

24 Wk

n=4

Serious and

related AEs2 (4) 1 (2) 2 (8) 2 (8) 0 1 (4) 0 0

Treatment DC due

to AE0 2 (4) 1 (4) 0 0 3 (12) 0 0

Treatment

emergent Death0 0 1 (4) 0 1 (4) 2 (8) 0 0

AE’s leading to DC: shortness of breath, hemoperitoneum, thoracic

aorta aneurysm dissection, seizure, elevated ALT/AST, dyspnoea,

Deaths: internal bleeding*, intestinal perforation/multi-organ failure,

unknown, sepsis, thoracic aorta aneurysm dissection*, complications

of cirrhosis*, progressive multifocal leukoencephalitis*

Slide 57 of 72Conclusions


In patients with recurrent HCV post

transplantation, treatment with

LDV/SOF+RBV for 12 or 24 weeks resulted

in:

–High rates of SVR12 irrespective of disease

severity or duration of therapy (i.e. 12 = 24 weeks)

–Decreases in MELD scores

No on-treatment virologic failure occurred

Generally safe and well tolerated

6/2/2015

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Slide 58 of 72

Prior Treatment Failures

Slide 59 of 72

Retreatment with SOF Regimens for HCV GT 2 or 3 Who Failed Prior SOF+RBV Therapy

Retreatment of GT 2/3 Study (SOF+PegIFN±RBV)

Open-label study offered to n=107 GT 2 or 3 treatment failures from FISSION, POSITRON and FUSION who received SOF+RBV

SVR 12

SOF + PegIFN + RBVSVR 12

n=34

SOF + RBVn=73

Wk 0 Wk 12 Wk 24 Wk 36GT 2 or 3

treatment

failures

from

FISSION,

POSITRON

and

FUSION

4/4 1/2 20/22 24/38

13/14 7/8 17/23 7/15

SOF + PegIFN + RBV

n=34

SOF + RBV

n=73

Mean age, y (range) 53 (31–70) 53 (38-63)

Male, n (%) 26 (77) 63 (86)

Black, n (%) 1 (1%) 0

Mean BMI, kg/m2 (range) 29 (22–39) 28 (20-41)

Cirrhosis* n (%) 14 (41) 25 (34)

Genotype 2, n (%) 6 (18) 5 (7)

Genotype 3, n (%) 28 (82) 68 (93)

Mean baseline HCV RNA, log10 IU/mL (range) 6.3 (4.8-7.8) 6.6 (4.4–7.6)

‡

*Cirrhosis status determined in parent protocol

Esteban R, EASL, 2014, O8

Slide 60 of 72

Retreatment with SOF Regimens for HCV GT 2 or 3 Who Failed Prior SOF+RBV Therapy

Retreatment of GT 2/3 Study (SOF+PegIFN±RBV)

13/14 7/8 17/23 7/15

10091

50

63

0

20

40

60

80

100

Genotype 2 Genotype 3

SV

R1

2 (%

)

12 weeks SOF+PegIFN+RBV 24 weeks SOF+RBV

4/4 1/2 20/22 24/38

93

74

88

47

0

20

40

60

80

100

12 weeks SOF +PegIFN+RBV

24 weeks SOF+RBV

SV

R1

2 (

%)

No Cirrhosis Cirrhosis

13/14 7/8 17/23 7/15

Retreatment with a SOF-based regimen was successful in GT2 or GT3 patients who previously failed SOF-containing regimens

12-weeks of SOF+PegIFN+RBV had higher overall SVR rates, including patients with cirrhosis

The 24-week IFN-free regimen was safe and well tolerated and offers a retreatment option for those ineligible to receive IFN

HCV GT 3 by Cirrhosis Status

‡

Esteban R, EASL, 2014, O8

6/2/2015

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Slide 61 of 72

Sofosbuvir/Ledipasvir FDC with or without RBV for patients with genotype 1 including patients with cirrhosis and prior protease inhibitor failure: LONESTAR

Treatment naïve, n=60– SOF/LDV +/- RBV for 8 or

12 weeks

PI virologic failure, n=40– Cirrhosis, n=22

– SOF/LDV +/- RBV for 12 weeks

Non-SVR, n=3– Lost to follow-up, n=1

– Viral relapse, n=2 Naïve, 8 wks, no RBV

TE cirrhosis, 12 wks, no RBV

TN relapse patient was retreated

No treatment discontinuation due to AE

Lawitz E et al. Lancet 383: 9916, p515-523, 2014.

Slide 62 of 72

0

2

3

4

5

6

7

NS5A: L31M 25.5%

NS5B: No RAVs

NS5A: Q30L (4.50%)

L31M (>99%)

Y93H (96.74%)

NS5B: S282T (91.24%)

NS5A: Q30L (3.47%)

L31M (94.38%)

L31V (4.67%)

Y93H (98.19%)

NS5B: S282T (8.00%)

Retreatment of a single patient who relapsed with multi-DAA resistant virus following 8 weeks of SOF/LDV: Lonestar

LLOQ-TD

LLOQ-TND

HC

V R

NA

(lo

g10 I

U/m

L)

SOF/LDV

8 Weeks

Re-treatment:

SOF/LDV + RBV24 Weeks

Post-

Treatment

Post-

Treatment

SVR12

Lawitz E et al. Lancet 383: 9916, p515-523, 2014.

Slide 63 of 72

Genotype 4

6/2/2015

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Slide 64 of 72

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

Slide 65 of 72

Summary

Slide 66 of 72

Preferred Regimens for Genotype 1 or 4

www.HCVguidelines.org

Compensated Cirrhosis Decompensated or LTx

Naïve SOF/LDV x 12 weeks SOF/LDV + RBV x 12 weeks

3D + RBV x 24 weeks

SIM/SOF x 24 weeks

Experienced

(IFN or PI)

SOF/LDV x 24 weeks SOF/LDV x 24 weeks

SOF/LDV + RBV x 12 weeks SOF/LDV + RBV x 12 weeks

(IFN) 3D + RBV x 24 weeks* SOF + RBV x 24 weeks

(SOF) SOF/LDV + RBV x 24 weeks SOF/LDV + RBV x 24 weeks

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

http://www.hcvguidelines.org/

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Slide 67 of 72

Preferred Regimens for Genotype 2 or 3

www.HCVguidelines.org

Compensated Cirrhosis Decompensated or LTx

Naïve SOF + PEG x 12 weeks SOF + RBV x 24 weeks

SOF + RBV x 12-16 weeks

(24 weeks for geno 3)

Experienced SOF + PEG x 12 weeks SOF + RBV x 24 weeks

SOF + RBV x 12-16 weeks

(24 weeks for geno 3)

Formatted: 05-14-2015

Chicago, IL: May 19, 2015

Interactive Case-Based Presentations

and Audience Discussion

Michael R. Charlton, MBBS, FRCPHepatology Director

Medical Director of Liver Transplantation

Intermountain Medical Center

Salt Lake City, Utah

http://www.hcvguidelines.org/

Case 1. Cirrhosis - IAS- · PDF file · 2017-07-19Medical Director of Liver...

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