HCV Management in Decompensated Cirrhosis: …s3.gi.org/meetings/mn2016/16ACG_Hep_School_Midwest_0009.pdf1/1 1/1 2/2 CP Score 24-wk DCV + SOF All patients24-wk DCV + SOF + RBV Phase

Paul Y. Kwo, MD, FACG

Treatment of Patients with Decompensated Cirrhosis and Liver

Transplant Recipients

Paul Y. Kwo, MD, FACGProfessor of Medicine

Medical Director, Liver TransplantationGastroenterology/Hepatology DivisionIndiana University School of Medicine

975 W. Walnut, IB 327Indianapolis, IN 46202-5121

phone 317-274-3090fax 317-274-3106email [email protected]

HCV Management in Decompensated Cirrhosis:

Current Therapies

ACG 2016 Midwest Hepatitis School Copyright 2016 American College of Gastroenterology

Page 1 of 15


Dose Adjustments in Cirrhosis

Childs Class PEG IFN alfa 2a, μg/wkPEG IFN alfa 2b,

μg/kg/wkRibavirin Daily

A 180 1.5 1000-1200 mg/day

B No No 600 mg

C No No 600 mg

Childs Class Sofosbuvir SimeprevirLedipasvir/sofosbuvir

PTV/OMB/DSB Daclatasvir

A 400 mg 150 mg 90mg/400mg75/50/12.5 mg + 250

mg60 mg

B 400 mg No* 90mg/400mg No*60 mg

C 400 mg No 90mg/400mg No60 mg

LDV/SOF + RBV: Genotype 1 and 4 with Advanced Liver Disease

Week 0 Week 12 Week 36Week 24

LDV/SOF + RBV

LDV/SOF + RBV

SVR12

SVR12

SOLAR-1

• Treatment naïve or experienced

• CPT Class B

• CPT Class C

• Post liver transplantation

SOLAR-2: (greater G4 population)

• Treatment naïve or experienced

• CPT Class B

• CPT Class C

• Post liver transplantation

•Charlton M, et al. Gastroenterology, 2015 [epub ahead of print]•Reddy RT, et al. Presented at: AASLD; November 7-11, 2014; Boston, MA. Abstract 8.•Manns M, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract G02.

SOLAR-1 and SOLAR-2


Page 2 of 15


LDV/SOF + RBV: SVR12 in Genotype 1 or 4 with Decompensated Cirrhosis

•1. Charlton M, et al. Gastroenterology, 2015 [epub ahead of print]•2. Flamm SL, et al. Presented at: AASLD; November 7-11, 2014; Boston, MA. Abstract 239. 3. Manns M, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract G02.

LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks

SOLAR-1: GT 1 and 4[1.2]

100

80

60

40

20

0

SV

R12

(%

)

CTP B CTP C

87 89 86 90

26/ 30

24/ 27

19/ 22

18/ 20n/N =

100

80

60

40

20

0S

VR

12 (

%)

CTP B CTP C

8796

20/23

22/23

85

72

13/18

17/20n/N =

SOLAR-2: GT 1[3]

AE, adverse event; CTP, Child-Turcotte-Pugh; LDV, ledipasvir; RBV, ribavirin; SAE, serious adverse event; SOF, sofosbuvir.

Comparable efficacy between SOLAR-1 and SOLAR-2 studies

LDV/SOF + RBV: Safety in Advanced Liver Disease Pre OLT

Treatment-related serious adverse events (SAEs) mostly related to RBV

No deaths or D/C attributed to treatment with study drug (LDV/SOF)

•Samuel D, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Poster P0774.

SOLAR-1 and SOLAR-2

Safety Outcome, n (%) Pretransplant CPT B + C (n = 215)

Grade 3/4 AE 51 (24)

SAE 61 (28)

Serious treatment-related AE 5 (2)

AE leading to discontinuation of LDV/SOF >2 patients

HCCSepsis

9 (4)

2 (<1)2 (<1)

Death 10 (5)

Liver Transplantation 11 (5)


Page 3 of 15


LDV/SOF + RBV: Change in MELD Score from Baseline to Follow-up Week 4 in CPT B or C Disease

•Manns M, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract G02.

*Missing FU-4: n = 24.

Pre/Post-Transplantation (CPT B and C; n = 136)*

Ch

ang

e in

ME

LD

Sco

re

4

2

0

-2

-4

-6

-8

-10(-11)

(-17)

n = 18

(8)

**

*

SOLAR-2

Real-World Efficacy of SOF/SMV ± RBV & SOF/RBV Regimens in Cirrhosis Pts With MELD >10

HCV-Target Network: North America, Germany, Israel

GT1 Naive GT 1Exp’d

MELD 10-15 MELD 16-21 MELD > 21

100

80

60

40

20

0

SV

R12

(%

)

3/7

31/40

6/10

8/14

21/26

37/67

67/92

19/28

5573 6860

5768

7843

5/8

7/10

2/3

63 7067

0/1

6/6

1/1

100 100

n/N =

SOF + RBV (n = 102) SOF + SMV (n = 117) SOF + SMV + RBV (n = 34)

48/67

72

8/14

48/67

13/19

81GT 2 GT 3

39

10/26

HCV TARGET•Reddy RK, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract O007.


Page 4 of 15


HCV TARGET: SAEs, Death, Liver Transplantation

SOF/RBVN=88

SOF/SMVN=114

SOF/SMV/RBV N=32

Total N=234

Total patients with SAEs N (%) 27 (31) 8 (7) 9 (26) 44 (17)

Hepatic decompensation* 10 (11) 2 (2) 4 (12) 16 (6)

Infections 0 2 (2) 1 (3) 10 (4)

Death 0 2 (2) 1 (3) 3 (1)

Unspecified 0 0 1 (3) 1 (0.4)

Hepatic Failure 0 1 (1) 0 (0) 1 (0.4)

Shock 0 1 (1) 0 1 (0.4)

Underwent OLT on treatment 4 (5) 3 (3) 5 (16) 12 (5)

*Hepatic encephalopathy, variceal bleeding, hepatic failure, hepatic hydrothorax, bacterial peritonitis

Reddy RK, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract O007.

ALLY-1: SOF + DCV + RBV for 12 Weeks in Patients With Genotype 1 HCV and Cirrhosis

Child-Pugh score: A, B, or C

MELD scores 8-40

Hepatocellular carcinoma allowed•Poordad F, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract LO8.

SV

R12

, %

92 94

56

0

20

40

60

80

100

A B C

Child-Pugh class

All Genotypes

11/12 30/32 9/16

SV

R12

, %

ALLY-1

• Treatment naïve or treatment experienced adults with any HCV genotype

• DAA failures allowed, except NS5A

76100

80 83100

0

20

40

60

80

100

1a 1b 2 3 4Genotype


Page 5 of 15


•11

92.0 94.0

56.0

0

20

40

60

80

100

A B C

•Child-Pugh class

91.3 95.7

78 76

90.983.7

89.297

75 75

56

100

73

No Yes No Yes >3.5 2.8

to

3.5

<2.8

SVR12 by Baseline Disease SeverityS

VR

12, %

<1.7 1.7

to

2.3

>2.3 <2.0 2.0

to

3.0

>3.0

Ascites HE Albumin, g/dL INR T bili, mg/dL

•

SVR12 by Child-Pugh Class

Advanced cirrhosis cohort, all genotypes

•HE = hepatic encephalopathy

Treatment of Decompensated HCV Cirrhosis in Patients with Diverse Genotypes: 12 weeks Sofosbuvir and NS5A inhibitors

With/Without Ribavirin Non-randomized observational cohort study of National Health Service of England (N = 467)

Patients received 12 weeks SOF + LDV or DCV ± RBV at treating MD discretion (non-randomized)

•Foster GR, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract O002.

12-wk SOF + LDV + RBV 12-wk SOF + LDV 12-wk SOF + DCV + RBV 12-wk SOF + DCV

N =

100

80

60

40

20

0All GT1 GT3

SV

R12

, % (

ITT

)

P<.05

59

43

70 71

252 28 172 15 164 21 45 5 61 7 114 7

80 71 74 73

86 81 82

60

DCV, daclatasvir; GT, genotype; HCV, hepatitis C virus; ITT, intent to treat.

Other GT

100

3

8589

27 13


Page 6 of 15


European Compassionate Use Program (CUP): SOF + DCV ± RBV for 24 Weeks

Treatment naive or treatment experienced

– CP Category: 57% CP A; 36% CP B; 6% CP C

– MELD Scores: >50% had MELD Scores ≥ 9 and <15

DCV dose determined by country; inclusion of RBV based on physician discretion•Welzel TM, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract P0772.

n/N =

100

80

60

40

20

0A B C

SV

R12

, %

100 100 100

39/40

19/20

58/60

97 95 97 100 95 98

24/24

21/22

45/46

1/1 1/1 2/2

CP Score

24-wk DCV + SOF + RBV24-wk DCV + SOF All patients

Phase 2, nonrandomized, open-label study

30 patients with HCV G1 infection and CP-B cirrhosis

10 noncirrhotic patients with HCV G1 infection were enrolled for PK analyses

GZR and EBR administered as separate entities (FDC not used in C-SALT)

– GZR 50 mg utilized in C-SALT, modelled upon the exposure of GZR in non-HCV-infected CP-B patients

EFFICACY AND SAFETY OF GRAZOPREVIR AND ELBASVIR IN HEPATITIS C GENOTYPE 1 INFECTED PATIENTS WITH CHILD-PUGH CLASS B CIRRHOSIS

•Follow-up:

•Primary endpoint:

•SVR12• HCV RNA <15 IU/mL

•(COBAS TaqMan v2.0 [LLoQ 15 IU/mL])

•GZR 50 mg / EBR 50 mg

•GZR 100 mg / EBR 50 mg

•D1 •TW4 •TW8 •TW12 •FUW4 •FUW8 •FUW12

•n=30

•Child-Pugh B

•n=10

•Noncirrhotic

•CP=Child-Pugh; EBR=elbasvir; GZR=grazoprevir; LoQ=limit of quantification; PK=pharmacokinetic; SVR=sustained virologic response

•Jacobson Presented at EASL ; April 22-26, 2015; Vienna, Austria


Page 7 of 15


SVR-12: C-SALT SAFETY RESULTS

Study DesignASTRAL-4 Childs B Cirrhosis

Open-label, randomized (1:1:1) US study

GT 1-6 treatment-naïve or -experienced patients with CPT B cirrhosis

Eligibility criteria: CrCL >50 mL/min, platelets >30,000 x 103/μL; no HCC or liver transplant

Weight-based RBV dosing (1000 or 1200 mg/day)

•Wk 0 •Wk 12 •Wk 24

SOF/VEL •SVR12

•Wk 36

SOF/VEL + RBV •SVR12

SOF/VEL •SVR12

n=75

n=75

n=75


Page 8 of 15


Results: SVR12 in GT 1 PatientsASTRAL-4

8896 92

0

20

40

60

80

100

•SOF/VEL+ RBV

•12 week

•SOF/VEL

•24 week

•65/68 •65/71

•SOF/VEL

•12 week

•60/68

•5 relapse

•2 death

•1 LTFU

•1 relapse

•2 deaths

•3 relapse

•3 LTFU

SVR-12

Results: SVR12 in GT 3 PatientsASTRAL-4

50

85

50

0

20

40

60

80

100

SOF/VEL+ RBV

12 week

SOF/VEL

24 week

•11/13 •6/12

SOF/VEL

12 week

•7/14

•6 relapses

•1 death

•1 breakthrough

•1 relapse

•1 breakthrough

•4 relapse

•1 death

SVR


Page 9 of 15


Post liver transplant treatment of HCV infection

Post transplant Drug interactions: DAAs as Culprits

•Dick TB, et al. Hepatology. 2015. [Epub ahead of print]

MedicationCyclosporine Tacrolimus Sirolimus Everolimus

Cmax AUC Cmax AUC Cmax AUC Cmax AUC

Ribavirin

Ledipasvir ND ND ND ND ND ND

Sofosbuvir 27% 9% ND ND ND ND

Simeprevir 16% 19% 24% 17% ND ND ND ND

Daclatasvir 4% 3% 5% ND ND ND ND

3D Regimen 1% 482% 299% 5613%Expected increase in both Cmax and

AUC.

Expected increase in both Cmax and

AUC.

•HCV infection inhibits cytochrome P450 through direct and indirect mechanisms. SVR leads to lower CNI levels

and risk of ACR.


Page 10 of 15


Post transplant Drug interactions: DAAs as Victims

•Dick TB, et al. Hepatology. 2015. [Epub ahead of print]

(CYA and TAC affect DAA metabolism or transport)

MedicationDaclatasvir Ledipasvir Sofosbuvir Simeprevir

Cmax AUC Cmax AUC Cmax AUC Cmax AUC

Cyclosporine 4% 40% ND ND 154% 353% 374% 481%

Tacrolimus 7% 5% ND ND 3% 13% 79% 85%

SOLAR-1: SVR12 Rates in OLT Patients Receiving LDV/SOF + RBV

In the 24-week arm, 8 patients with CPT B and 1 patient with CPT C have not reached the follow-up week 12 visit

MELD scores improved from baseline through follow-up Week 4 in 15/48 patients with CPT A and 8/41 patients with CPT B disease

Reddy RT, et al. Hepatology. 2014;60(suppl): Abstract 8.

100

80

60

40

20

0F0-F3 CPT A CPT B CPT C

12 wks LDV/SOF + RBV24 wks LDV/SOF + RBV

96 98 96 9683 60

6785

SV

R12

(%

)

53/55

55/56

25/26

24/25

22/26

15/18

3/5

2/3n/N =


Page 11 of 15


Solar-2: LDV/SOF + RBV: SVR12* in Genotype 1 or 4

. Manns M, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract G02.

LDV/SOF + RBV 12 weeks LDV/SOF + RBV 24 weeks

SOLAR-2: GT 1

100

80

60

40

20

0

SV

R12

(%

)

F0-F3, CPT A CTP B&C

96 98 88 89

72/75

57/ 58

57/ 65

54/ 61n/N =

100

80

60

40

20

0S

VR

12 (

%)

CTP B&C

91100

10/11

7/7

57

86

6/74/7n/N =

SOLAR-2: GT 4

Comparable efficacy between 12 and 24 week durations

F0-F3, CPT A

-8

-6

-4

-2

0

2

4

Change in MELD ScoreSOLAR-1: LDV/SOF + RBV in Post Transplant

Missing FU-4: n=3 CTP A 12 wk; n=5 CTP B 12 wk; n=5 CTP B 24 wk

•Change from Baseline to Follow-Up Week 4

•CTP A Patients (n=48) •CTP 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)

Reddy, AASLD, 2014, Oral #8


Page 12 of 15


Ally-1: SOF +DCV+RBV 600 Post OLT

SVR12 by HCV Genotype

94.0 9790 91

100

0

20

40

60

80

100

10/11 1/1

SV

R12

, %

Overall 1a 1b

Genotype

3 6

N = 53

50/53 30/31 •9/10

•Poordad F, et al. Presented at: EASL; April 22-26, 2015; Vienna, Austria. Abstract LO8.

SOF +DCV+RBV 600 Post OLTInterim SVR12 Results

Post-transplant CohortDCV + SOF DCV + SOF + RBV All patients

89

100

89

100 10091 91

0

20

40

60

80

100

GT 1 GT 3 All GT

•SV

R 1

2, %

•11

•2528

•66

•3033

•11

•3134

•2427

•Relapse, n=1Deaths, n=2

■ NS5A sequencing (population-based) in relapse patient identified Y93S RAV

•HCV genotype


Page 13 of 15


CORAL-1: GT1 Patients After Liver Transplantation (F0-F2)

PTV/OMB/DSB: co-formulated paritaprevir/r/ombitasvir, 150 mg/100 mg/25 mg QD; dasabuvir, 250 mg BID

RBV: dosing was managed at the discretion of the investigator and closely monitored per protocol

Tacrolimus 0.5 mg q 1-2 weeks, Cyclosporin reduced to 20% of daily dose

Day 0 Week 24

SVR12

To Week 72

PTV/OMB/DSB + RBV

(n=34)

Kwo PY, et al. N Engl J Med. 2014;371(25):2375-2382.

CORAL-1: SVR Rates in GT1 Liver Transplant Patients

No patient had breakthrough

One patient had a relapse (post-treatment day 3)

– At the time of relapse, this patient had R155K in NS3 protease, M28T+Q30R in NS5A, and G554S+G557R in NS5B, none of which were present at baseline

Study now including F3-F4, 12 week duration

100% 97% 97% 97%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

EOTR SVR4 SVR12 SVR24


Page 14 of 15


CirrhoticGenotype

1a 1b

MELD

<10 ≥ 10

Overall Tx

Experienced

Yes No

0

100

80

60

40

20

94/104

90%

52/60 42/44

87%95%

51/58

88%

27/28

96%

59/67 35/37

Yes

88%

No

19/21 8/10

HCV-TARGET – Post TransplantHCV RNA Outcomes for SOF+SMV±RBV:

Genotype 1 interim analysis

95% 90%80%

SV

R %

Summary

Patients with decompensated cirrhosis may be treated successfully across all genotypes

– SVR rates are good, lower than compensated cirrhosis

– SOF/RBV, SOF/LDV ± RBV 12-24 weeks, SOF/DCV ± RBV 12-24 weeks

– Carefully consider who to treat in transplant setting to avoid MELD purgatory

Post Liver Transplant

– No graft should fail due to recurrent HCV across all genotypes

– 12 weeks of SOF/LDV/RBV or SOF/DCV/RBV

– 24 weeks of SOF/LDV or SOF/DCV

– 24 weeks of PTV/OMB/DSV/RBV


Page 15 of 15

Documents

HCV Management in Decompensated Cirrhosis: …s3.gi.org/meetings/mn2016/16ACG_Hep_School_Midwest_0009.pdf1/1 1/1 2/2 CP Score 24-wk DCV + SOF All patients24-wk DCV + SOF + RBV Phase