Treatment Challenges inTransplant Patients

Gregory T Everson, MDProfessor of MedicineDirector of Hepatology

University of Colorado Denver

DisclosuresAdvisory Boards: Roche/Genentech, Vertex, GlobeImmune,

BMS, Abbvie, Eisai, HGS/Novartis, Pfizer, Gilead, Janssen/Tibotec, Abbvie/Abbott

Consulting:                  Roche‐Genentech, HGS/Novartis, BMS,Three Rivers/Kadmon, Vertex, Abbvie, BioTest, Boehringer‐Ingelheim

DSMB: Merck, Centocor, Galectin

Stock/Ownership: Source, HepQuant LLCManagement:  HepQuant LLC

Research Grants: Roche/Genentech, Schering/Merck, Vertex,GlobeImmune, Gilead, HGS/Novartis, BMS,Pfizer, Source, Eisai, GSK, Pharmassett,Ortho Biotech, Janssen/Tibotec, Abbvie

Key Questions

1. Should we treat HCV pre‐ or post‐transplant?

2. What are the current antiviral choices?

3. What are the potential future choices?

Pre‐Transplant

1. SVR: Avoid LTx

2. SVR: Prevent Recurrence of HCV

3. On Rx at LTx: Suppress HCV toPrevent Recurrence (pTVR)

Treatment Goals

Pan‐GT: PEG/RBVSOF/PEG/RBVSOF/RBV**LDV/SOF ± RBV

GT 1 only: TT (SMV, TPV, or BOC)SMV/SOF ± RBV3D+r ± RBV

Possible Options

** Only FDA‐recommended Pre‐transplant treatment option.Otherwise, treatment of clinically decompensated cirrhosis is considered “off‐label”.

PEG/RBV

Everson GT, et al.  A Randomized Controlled Trial of Pretransplant Antiviral Therapy to PreventRecurrence of Hepatitis C After Liver Transplantation.  Hepatology 2013;57:1752‐1762.

LADR A2ALL:  pTVR related to Rx Duration

PEG/RBV + BOC or TPV(no data with SIM or SOF)

AlbuminPlatelet Count µL-1

> 100,000 ≤ 100,000

≥ 3.5 g/dLN 306 74

% SVR 55% 37%

% SAE/Death 6% 12%

< 3.5 g/dLN 31 37

% SVR 29% 27%

% SAE/Death 16% 51%

Impact of Disease SeverityCUPIC French open‐access Study

Hezode C, et al.  Effectiveness of Telaprevir or Boceprevir in Treatment‐experienced Patients with HCV Genotype 1 Infection and Cirrhosis. Gastroenterology 2014.  doi: 10.1053/j.gastro.2014.03.051. 

Albumin: < 3.5 g/dL

Platelet Count: < 100,000 µL

CUPIC Caveat

These laboratory features indicate high‐risk for treatment‐related SAEs with PEG/RBV plus BOC or TPV.

PEG/RBV/TPV:  pTVR

50

7180

67

0

20

40

60

80

100

Week 4 of TT Week 8 of TT Week 12 of TT pTVR

% HCV RNA negative

Verna EC, et al.  Columbia and Georgetown.  Hepatology 2012;56:218A.  Submitted.High Rates of SAEs, ANEMIA – EPO + Transfusions of pRBCs.  One pt underwent LTx at Week 3 of Rx, RNA negative post‐LTx.

Pan‐GT: PEG/RBVSOF/PEG/RBVSOF/RBVLDV/SOF ± RBV#

GT 1 only: TT (SMV, TPV, or BOC)SMV/SOF ± RBV3D+r ± RBV

Acceptable Options

# Daclatasvir (DAC) may substitute for ledipasvir (LDV) for GT 2 and 3.

SOF/RBV

Afdahl N, Everson GT, et al.  Sofosbuvir and Ribavirin for the Treatment of Chronic HCV with Cirrhosis and Portal Hypertension with and without Decompensation:  Early Virologic Response and Safety.  EASL 2014.

56

100 100 100 100

44

75

94 94 93

0

20

40

60

80

100

Week 2 Week 4 Week 8 Week 12 Week 24

CTP A CTP B

% with undetectable HCV RNA

SOF/RBV in Cirrhosis with Portal Hypertension(N=50, 1:1 Rx:No Rx Cntrl for 24 Wks, 48 Wks Rx, HVPG 16 (7-29), CTP<10)

Rx extended to 48 weeks. SVR in most. HVPG improved in a subset. EASL 2015.

pTVR

25

67 65

0

20

40

60

80

100

PEG/RBV TT‐TPV SOF/RBV

% Achieving pTVR

Center Multi Single Multi                       N 11/44 8/12 24/37%HCC 62% 39% 100%MELD 12 8 8*  No SAE was attributed to SOF.  Rate of SAEs was similar to rate of SAEs in Controls in LADR‐A2ALL.

Curry MP, et al.  Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation.  Hepatology 2013;58:3134A.

SAE 46%Death 15%

SAE 31%Death 3%

SAE 18%*Death 0%

36

96

0

20

40

60

80

100

<30 Days >30 Days

% Achieving pTVR

Curry MP, et al.  Pretransplant Sofosbuvir and Ribavirin to Prevent Recurrence of HCV Infection after Liver Transplantation.  Hepatology 2013;58:3134A.

SOF/RBV: pTVR is related toDuration of undetectable HCV RNA

SMV/SOF

1. SMV: FDA‐approved 2013

2. SOF: FDA‐approved 2013

3. SMV/SOF: FDA‐approved 12/2014

AASLD/IDSA Guidelines:  “Daily sofosbuvir (400 mg) plus simeprevir (150 mg), with or without weight‐based RBV (1000 mg [<75kg] to 1200 mg [≥75 kg) for 12 weeks is recommended for IFN‐ineligible patients 

with HCV genotype 1infection, regardless of subtype.” “……..is recommended for retreatment of HCV genotype 1 infection,regardless of subtype or IFN eligibility.” The basis for these recommendations were an average SVR of 72% in 211 Rx‐Naïve GT1 patients treated with 24 Wks SOF/RBV.  SIM/SOF, 12 Wks, 

might be a more effective regimen in these patients. 

SMV/SOFCOSMOS Cohort 2:  F3/F4, 54% Null Responders

93 9393100

0

20

40

60

80

100

12 Weeks 24 Weeks

RBV No RBV

% SVR12

AASLD Guidelines January 30, 2014; Presented at EASL 2013, 2014 and AASLD 2013.

13/1424/27 27/30 16/16

HCV TARGET1012 Treated with SMV/SOF ± RBV (303 evaluable for SVR4)

9287

7585

79

0

20

40

60

80

100

No Cirrhosis Cirrhosis Decomp

All PI Failures% SVR4

Presented at AASLD 2014. RBV did not improve SVR overall or in any subpopulation.Lower SVR4: Low albumin, GT1a, Prior Decomp, TT failure. AEs: Anemia - RBV. SAEs 5 to 6%.

12 Deaths – 9 in patients with cirrhosis.

17/20113/123 27/34 61/81156/180

LDV/SOF

1. SOF: FDA‐approved 2013

2. LDV/SOF: FDA‐approved 12/2014

FDA approved without RBV. Addition of RBV may allow shortening 24 week course to 12 weeks.

LDV/SOF in >500 Patients with GT1 Cirrhosis

96 98 97 10090

96 98 100

0

20

40

60

80

100

12 Wk 12 Wk + RBV 24 Wk 24 Wk + RBV

Rx‐Naïve Rx‐Experienced% SVR 12

Bourliere M, et al.  AASLD 2014.

Results: SVR12GT 1 and 4, CTP 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

R12

(%)

26/30 19/22 18/20

Overall

24/2745/52 42/47

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

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

26

-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.

3D/r + RBV(Paritaprevir/r + Ombitasvir + Dasabuvir + RBV)

1. 3D/r ± RBV: FDA‐approved 12/2014

Integrated Efficacy Analysis of 4 Phase 3 Studies in HCV Genotype 1a‐Infected Patients Treated With ABT450/r/Ombitasvir and Dasabuvir With and Without Ribavirin|AASLD| November 711, 2014 28

126/142

61/66

14/15

11/11

40/50

115/121

53/56

13/13

10/10

39/42

High SVR12 Rates with 3D + RBV in GT1a Treatment‐Naïve and ‐Experienced Patients With Cirrhosis

12 weeks24 weeks

3D + RBV

p values from Fisher’s exact test

Normalization of liver –related laboratory parameters in HCV GT1‐infected patients with cirrhosis | ACG 2014 | 20 October 2014 29

Improvement from baseline in conjugated bilirubin at PTW12 

12‐week arm 24‐week arm

BL mean (mg/dL)

0.30 0.31

PTW12 mean(mg/dL)

0.19 0.17

Mean  from BL at PTW12(95% CI)

‐0.10(‐0.12, ‐0.09)

‐0.13(‐0.15, ‐0.11)

3D + RBV

Normalization of liver –related laboratory parameters in HCV GT1‐infected patients with cirrhosis | ACG 2014 | 20 October 2014 30

Improvement from baseline in albumin levels at PTW12 

12‐week arm 24‐week arm

BL mean (g/dL)

3.9 3.9

PTW12 mean (g/dL)

4.1 4.2

Mean  from BL at PTW12(95% CI)

0.2(0.17, 0.24)

0.3(0.21, 0.31)

3D + RBV

Others

Multi‐DAA in HCV GT1 Cirrhosis

96 92 93 94

0

20

40

60

80

100

LDV/SOF (Gilead) 3D r (Abbvie) 3D (BMS) 2D (Merck)

% SVR 12

RBV ± + ± ±Duration 12 vs 24 12 vs 24 12 12 vs 18Genotype 1a/1b 1a 1a/1b 1a/1bPhase 3 3 3 2

493/513 241/263 187/201 115/123

Genotypes 2 and 3

SOFOSBUVIR

RIBAVIRIN

Cirrhosis, Rx-Experienced12 Wks

Cirrhosis, Rx-Naive12 Wks

No Cirrhosis, Rx-Naive12 Wks

ExpectedSVR

TreatmentDuration

Genotype 2

95%1

94%1

60%2,*

Cirrhosis, Rx-Experienced16 Wks 78%2

1 Data from FISSION and POSITRON and 2 FUSION.*In VALENCE, an SVR of 78% (7/9) was achieved with 12 weeks SOF/RBV.  Given the

discordancy in results, optimal duration of SOF/RBV for Rx‐experienced cirrhosis is unknown.

No Cirrhosis, Rx-Experienced12 or 16 Wks 97%2

SOFOSBUVIR

RIBAVIRIN*

No Cirrhosis, Rx-Experienced24 Wks (85/98)

Cirrhosis, Rx-Naive24 Wks (12/13)

No Cirrhosis, Rx-Naive24 Wks (87/92)

ExpectedSVR

TreatmentDuration

95%

92%

87%Cirrhosis, Rx-Exp

24 Wks (29/47) 62%

Genotype 3 (based on VALENCE* study)

An alternative for IFN‐eligible patients could be SOF/PEG/RBV for 12 weeks.In PROTON and ELECTRON studies (Rx‐Naïve) 38/39 patients (97%) achieved SVR.

In LONESTAR‐2 (Rx‐Experienced), 83% (10/12) achieved SVR.* Zeuzem, et al.  NEJM 2014;370:1993‐2001.

Pan‐GT: SOF/RBVLDV/SOF ± RBV#

GT 1 only: SMV/SOF ± RBV3D+r ± RBV

Pre‐Transplant Options

# Daclatasvir (DAC) may substitute for ledipasvir (LDV) for GT 2 and 3.

Post‐Transplant

1. SVR

2. Improve Graft and Patient Survival

Treatment Goals

Pan‐GT: PEG/RBVSOF/PEG/RBVSOF/RBV**LDV/SOF ± RBV

GT 1 only: TT (SMV, TPV, or BOC)SMV/SOF ± RBV3D+r ± RBV

Possible Options

** None of these post‐transplant treatment options  are FDA‐approved.Treatment of post‐transplant patients is considered “off‐label”.

PEG/RBV

Gane EJ, Agarwal K.  Am J Transplant 2014;14:994‐1002.

PEG/RBV:  SVR

PEG/RBV + BOC or TPV(no data with SIM or SOF)

CRUSH C and French Multicenter Studies

Adverse Events• 20% Early discontinuation• 25‐59% Hospitalizations• 56% Blood transfusions• 14‐40% Renal insufficiency• 3‐17% Rejection• 7‐8% Liver‐related deathCRUSH-C French

%S

VR

12

100

80

60

40

20

59

53/90 36/79

Stravitz, et al. AASLD 2013. Abstract 416. Coilly A, et al. AASLD 2013. Abstract 216.

46

Pan‐GT: PEG/RBVSOF/PEG/RBVSOF/RBVLDV/SOF ± RBV#

GT 1 only: TT (SMV, TPV, or BOC)SMV/SOF ± RBV3D+r ± RBV

Acceptable Options

# Daclatasvir (DAC) may substitute for ledipasvir (LDV) for GT 2 and 3.

SOF/RBV ± PEG

SOF/RBVAll GTs, Rx‐N or –Exp, CTP ≤ 7, MELD ≤ 17, No Decomp, 63% F3/F4, N=40

100 100

7770 70

0

20

40

60

80

100

Week 4 EOT SVR 4 SVR 12 SVR 24

% with undetectable HCV RNA

Charlton M, et al. Presented at AASLD 2013; Samuel D, et al. Presented at EASL 2014.

SOF/RBV ± PEGPost‐LT Compassionate Use for Severe HCV Recurrence, N=104

87

62 62

21 21

0

20

40

60

80

100

EOT SVR12 Improved Stabilized Worse/Died

% of Patients

Forns X, et al. Presented at AASLD 2013 and EASL 2014. Wide range of disease severity,some very sick. Improved Bili, INR, Alb, and MELD.

SMV/SOF

HCV TARGET143 Treated with SMV/SOF ± RBV (68 evaluable for SVR4)

9486

0

20

40

60

80

100

No Cirrhosis Cirrhosis

All% SVR4

Presented at AASLD 2014. Anemia from RBV was a common AE.8.5% had an SAE.

29/3127/34

32/37156/180

3D/r + RBV(Paritaprevir/r + Ombitasvir + Dasabuvir + RBV)

ABT450/r/Ombitasvir/Dasabuvir/RBVGT1, Rx‐N, <F3, No Decomp, N=34

100 100 97 96

0

20

40

60

80

100

Week 4 EOT SVR 4 SVR 12

% with undetectable HCV RNA

Kwo P, et al. Presented at EASL 2014.

LDV/SOF

96 96

85

60

98 96

83

67

0

20

40

60

80

100

F0–F3

SV

R12

(%)

53

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 have not reached the Week 12 post treatment visit.

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

3/5

CPT C

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

54

CPT A Patients (n=48)

-8

-6

-4

-2

0

2

4

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)

Pan‐GT: SOF/RBVLDV/SOF ± RBV#

GT 1 only: SMV/SOF ± RBV3D+r ± RBV

Post‐transplant Options

# Daclatasvir (DAC) may substitute for ledipasvir (LDV) for GT 2 and 3.

Longer duration of 24 weeks and addition of RBV may be required,particularly for liver recipients with cirrhosis.

1. From IFN‐based Treatment• Low efficacy (both pre‐ and post‐LT)• High Toxicity (especially in cirrhosis)• Limited Applicability

2. To IFN‐free Treatments• Improved efficacy (both pre‐ and post‐LT)• Limited Toxicity (both pre‐ and post‐LT)• Treat either pre‐ or post‐LT

Paradigm Shift

“Anybody can jump a motorcycle. The trouble begins when you try to land it.”      Evel Kneivel

Drug‐Drug Interactions

Clinical Pharmacist

Resources for DDIs• Outstanding – University of Liverpool (David Back,  Editorial Board, EASL reps); sponsored by Janssen, MSD, Roche, Vertex:– http://www.hep‐druginteractions.org

• FDA:– http://www.fda.gov/Drugs/DrugSafety/

• Other Online Resources –– http://www.drugs.com/drug‐interactions/html– http://www.merckmedicus.com/pp/us/hep– Epocrates– Micromedex, Lexicomp and Others

Can Hepatitis C Virus be Cured?

Yes

But, someone has to pay for it!

Panic:  5 x 106 cases @ 105 $/case

= $500,000,000,000

• Study of economic burden of chronic hepatitis C in the US, stratified by disease severity, based upon a large health insurance claims database.

• Based on data from 53,796 patients with chronic hepatitis C – 78% without cirrhosis, 7% with compensated cirrhosis, 15% with ESLD

• Overall Annual Healthcare Costs per Patient: $24,176

• Annual Costs per Patient Without Cirrhosis: $17,277

• Annual Costs per Patient With Compensated Cirrhosis: $22,752

• Annual Costs per Patient With ESLD: $59,995

• Estimated US Average Charges per LTx in 2011: $577,100

The Price of NOT Treating Chronic Hepatitis C

Reau N, Jensen D.  Review/Editorial HEPATOLOGY 2014;59:1246‐1249.Gordon SC, et al.  Disease Burden in Patients with chronic hepatitis C in US …….2003 to 2010.   Presented at AASLD 2011.

http://digestive.niddk.nih.gov/ddiseases/pubs/livertransplant/http://digestive.niddk.nih.gov/before‐the‐transplant/financing‐a‐transplant/the‐costs/

1. MELD “Purgatory”?• MELD decreases with SVR• Portal hypertension and clinical 

complications persist

2. HCV+ Donor?• HCV+ recipient – wait to treat?• HCV‐ recipient – accept liver?• Renal transplantation – wait to treat?• Renal candidate HCV+ or ‐ ‐ accept kidney?

Intriguing Questions