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Singapore Viral Hepatitis Meeting

June 2014
HCV: management of the patient with
Cirrhosis: a focus on treatment
HCV and Cirrhosis
Robert G Gish MD

Professor Consultant
Stanford University

Vice Chair:
Executive Committee National Viral Hepatitis
Roundtable

Senior Medical Director
St Josephs Hospital and Medical Center
Phoenix Arizona
Disclosures
Dr Gish receives consulting fees from

BMS
Gilead
Merck
Idenix
AbbVie
Genentech

All income is then expensed or donated to research
and education
What is cirrhosis?
MELD over 6
CPT 7 and above
Liver biopsy
Elastography kPa value over 8-11
Spleen over 12 cm
Portal vein over 12 mm
Varices on EGD or abdominal imaging
Large left lobe with physical finding of portal
hypertension
Imaging with characteristic changes of liver
morphology and or portal hypertension
HCV Incremental All-Cause Health Care
Costs by Liver Disease Severity (USD 2009)
Difference between HCV and non-HCV matched controls.
Numbers in parentheses are +SD. Costs normalized to 2009 dollars using Consumer Price Index.
McAdam-Marx C, et al. J Manag Care Pharm. 2012;17:531-546.
I
n
c
r
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m
e
n
t
a
l

A
l
l
-
C
a
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e

C
o
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(
p
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r
-
p
a
t
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t
-
p
e
r
-
y
e
a
r
)

5879
(157)
5330
(491)
27,845
(965)
810
(49)
974
(194)
15,464
(710)
1721
(123)
1081
(275)
5818
(292)
641
(37)
93
(130)
4526
(213)
2659
(41)
3102
(157)
1893
(123)
No liver disease (n=26,977)
Compensated cirrhosis (n=1521)
Decompensated cirrhosis (n=4249)
Inpatient
Total Health
Care Costs
Outpatient
Physician
Services
Pharmacy
Costs
Place of Service
HCV Incremental All Cause Health Care
Costs by Liver Disease Severity (USD 2009)
Difference between HCV and non-HCV matched controls.
Numbers in parentheses are +SD. Costs normalized to 2009 dollars using Consumer Price Index.
McAdam-Marx C, et al. J Manag Care Pharm. 2012;17:531-546.
43,671
(2588)
93,609
(4482)
27,845
(965)
60,143
(3612)
17,197
(194)
15,464
(710)
5818
(292)
Decompensated cirrhosis (n=4249)
Hepatocellular carcinoma (n=959)
Liver transplantation (n=891)
12,307
(1069)
12,915
(829)
4526
(213)
9423
(1188)
11,697
(646)
1893
(123)
4632
(587)
8736
(363)
I
n
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A
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l
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C
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C
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)

Inpatient
Total Health
Care Costs
Outpatient
Physician
Services
Pharmacy
Costs
Place of Service
0
1000
2000
3000
4000
5000
6000
NCD CC ESLD NCD CC ESLD NCD CC ESLD
Treated
Untreated
1370
2389
1007
543
591
3634
885
4656
3186
1193
1224
1023
729
5137
3547
1802
1369
P<0.001 P<0.001 P<0.057 P<0.001 P<0.001 P<0.826
P
r
e
d
i
c
t
e
d
c
o
s
t
(
2
0
1
0
$
U
S
P
P
P
M
)
HCV-related costs Medical costs
Total costs
225
P<0.001
P<0.001
P<0.001
Mean follow-up per patient per month (PPPM)
by treatment history and liver disease severity
35%
lower
24%
lower
31%
lower
HCV Therapy Is Associated with Lower Healthcare Costs in
Non-Cirrhotic and ESLD Patients
PPPM=per-patient-per-month; NCD=non-cirrhotic disease; CC=compensated cirrhosis; ESLD=end-stage liver disease
Covariates adjusted for in the analysis included age, sex, geographical region, index year, baseline comorbidities, and
baseline treatment for HCV
Gordon S.C., et al. Aliment Pharmacol Ther. 2013; 38:784-793.
REALIZE: SVR by Baseline Fibrosis Stage and
Prior Response
Prior
relapsers
Prior partial
responders
Prior null
responders
No, minimal
or portal
fibrosis
Cirrhosis
Stage
Pooled T12/PR48
Pbo/PR48
P
a
t
i
e
n
t
s

w
i
t
h

S
V
R

(
%
)

Bridging
fibrosis
No, minimal
or portal
fibrosis
Cirrhosis Bridging
fibrosis
No, minimal
or portal
fibrosis
Cirrhosis Bridging
fibrosis
2/
15
n/N= 53/
62
145/
167
12/
38
0/
5
10/
18
36/
47
3/
17
0/
9
16/
38
11/
32
1/
5
1/
15
48/
57
24/
59
1/
18
7/
50
1/
10
Presented at AASLD November 6th, 2011
Telaprevir

Category, n (%)
Cirrhotics (F4)
N=139
Non-cirrhotics (F03)
N=391
Patients without SVR 73 (53) 107 (27)
On-treatment virologic failure*
Prior relapsers
Prior partial and null responders
44 (32)
1 (1)
43 (31)
52 (13)
2 (1)
50 (13)
Relapse

Prior relapsers
Prior partial and null responders
17 (12)
3 (2)
14 (10)
20 (5)
5 (1)
15 (4)
Other

Prior relapsers
Prior partial and null responders
12 (9)
5 (4)
7 (5)
35 (9)
24 (6)
11 (3)
REALIZE: Reasons for not Achieving an SVR in
TVR-treated Patients
*Includes patients with viral breakthrough and/or patients who discontinued due to a virologic stopping rule

Relapse rate calculated relative to total number of patients

Includes patients with detectable HCV RNA at the end of treatment (for reasons other than virologic stopping rules) without viral
breakthrough, or who had undetectable HCV RNA at the end of treatment but were subsequently lost to follow up before Week 72
Presented at AASLD November 6th, 2011
REALIZE: AEs in 25% of TVR-treated Patients
during Any Treatment Phase*

AE, n (%)
Cirrhotics (F4)
N=139
Non-cirrhotics (F03)
N=391
Rash SSC 93 (67) 206 (53)
Pruritus SSC 82 (59) 205 (52)
Fatigue 62 (45) 214 (55)
Headache 54 (39) 167 (43)
Anemia SSC

59 (42) 134 (34)


Nausea 52 (37) 129 (33)
Influenza-like illness 55 (40) 124 (32)
Insomnia 39 (28) 113 (29)
Anorectal symptoms

33 (24) 101 (26)


Diarrhea 33 (24) 102 (26)
Pyrexia 34 (25) 97 (25)
*Grouped special search category (SSC);

Anemia reported by the investigator as an adverse event;



Grouped term including several different AEs in the anorectal area; AE = adverse event
CUPIC: French EAP: Baseline Demographics
and Characteristics
Characteristic
Telaprevir
N=295
Boceprevir
N=190
Child-Pugh score A/B, n (%)* 280 (95) / 6 (2) 177 (93) /1 (1)
MELD score, mean (range) 8.1 (6-22) 8.1 (6-28)
Prothrombin time ratio, mean % (range) 86 (27100) 87 (23100)
Serum albumin g/L, mean (range) 40.0 (20.753.2) 40.7 (27.050.3)
Total bilirubin mol/L, mean (range) 15.5 (4.073.0) 15.2 (4.078.0)
Hb level g/dL, mean (range) 14.5 (9.019.7) 14.8 (10.818.4)
Neutrophils, mean (range) (10
9
/mm
3
) 3.3 (0.8-8.5) 3.2 (0.5-8.5)
Platelet count, mean (range) (10
3
/mm
3
)
151
(18604)
144
(34346)
Esophageal varices, n (%) 51/145 (35.2) 37/97 (38.1)
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
* Missing data : 21
CUPIC: Virological response (ITT)
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
TELAPREVIR BOCEPREVIR
0
10
20
30
40
50
60
70
80
90
100
49%
P
a
t
i
e
n
t
s

w
i
t
h

u
n
d
e
t
e
c
t
a
b
l
e

H
C
V

R
N
A

(
P
e
r
c
e
n
t
a
g
e
)

79% 81%
56%
W4 W8 W12 W24 W48
W60
W16
77 %
68 %
146
295
234
295
239
295
227
295
200
295
165
295
118
295
0
10
20
30
40
50
60
70
80
90
100
16%
51%
62%
65%
67%
W4 W8 W12 W16 W24 W48
W60
31
190

97
190
118
190
124
190
128
190
108
190
57%
79
190
40% 41%
CUPIC: SVR12 According to
Prior Treatment Response
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
61/116 43/135 8/28
Relapsers

Partial
responders
Null
responders
53%

32%

29%

P=0.004
P=0.001
P=0.03
TELAPREVIR TELAPREVIR
0
10
20
30
40
50
60
70
80
90
100
0
10
20
30
40
50
60
70
80
90
100
31
190

43/85 32/80 1/9
P=0.003
51%

40%

11%

BOCEPREVIR
Relapsers

Partial
responders
Null
responders
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
CUPIC: Virological Failure
Non
response
0
10
20
30
40
50
60
70
80
90
100
V
i
r
o
l
o
g
i
c
a
l

f
a
i
l
u
r
e



(
P
e
r
c
e
n
t
a
g
e
)

33/177 25/177*
47/177
Premature
discontinuation
Relapse Breakthrough
19%

14%

27%

72/177
41%

TELAPREVIR
0
10
20
30
40
50
60
70
80
90
100
V
i
r
o
l
o
g
i
c
a
l

f
a
i
l
u
r
e



(
P
e
r
c
e
n
t
a
g
e
)

40/111 12**/111 30/111
Premature
discontinuation
Relapse
Breakthrough
36%

11%

27%

29/111
26%

Non
response
BOCEPREVIR
*22 without failure

**10 without failure

CUPIC:
SVR 12 According to HCV Subtype
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
Genotype
1a

Genotype
1b
Undetermined
genotype 1
33/98 75/162 9/33
34%

46%

27%

P=0.004
0
10
20
30
40
50
60
70
80
90
100
S
V
R

1
2

(
I
T
T

)

(
P
e
r
c
e
n
t
a
g
e
)

TELAPREVIR
Genotype
1a

Genotype
1b
Undetermined
genotype 1
0
10
20
30
40
50
60
70
80
90
100
31
190

6/16
P=0.03
31%

51%

37%

49/96 24/77
BOCEPREVIR
S
V
R

1
2

(
I
T
T

)

(
P
e
r
c
e
n
t
a
g
e
)

CUPIC:
SVR12 According to Initial Viremia
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
< 800000 IU/mL 800000 IU/mL
48/108 68/182
45%

37%

TELAPREVIR
0
10
20
30
40
50
60
70
80
90
100
S
V
R

1
2

(
I
T
T

)

(
P
e
r
c
e
n
t
a
g
e
)

< 800000 IU/mL 800000 IU/mL
0
10
20
30
40
50
60
70
80
90
100
51/122
41%
42%

BOCEPREVIR
27/65
S
V
R

1
2

(
I
T
T

)

(
P
e
r
c
e
n
t
a
g
e
)

CUPIC: SVR12 Safety Findings
Patients, n
(% patients with at least one event) Telaprevir n=295 Boceprevir n=190
Serious adverse events (SAEs)*
535 in 160 patients
(54.2%)
321 in 97 patients
(51.0%)
Premature discontinuation /
due to SAEs
139 (47.1%) /
63 (21.3%)
80 (42.1%)/
27 (14.2%)
Death 7 (2.4 %) 3 (1.6%)
Infection (Grade 3/4) 27 (9.1 %) 8 (4.2%)
Hepatic decompensation
(Grade )
15 (5.1 %) 9 (4.7%)
Anemia (Grade : Hb < 8 g/dL) 38 (12.9 %) 19 (10%)
Rash (grade 3/SCAR) 16 (5.4 %)/ 2 (0.6 %) 2 (1.0%)/
EPO
use / blood transfusion
168 (57 %) /
53 (18 %)
119 (62.6%) /
26 (13.7%)
GCSF use 8 (2.7 %) 13 (6.8%)
TPO use 6 (2 %) 3 (1.6%)
Fontaine H, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 60
SAEs in patients
SCAR: severe cutaneous adverse reaction
CUPIC:
Predictors of Severe Anemia <8 g/dl
Predictors OR 95%CI p-value
Gender: Female 2.19 1.11-4.33 0.023
No lead-in phase 2.25 1.15-4.39 0.018
Age 65 years 3.04 1.54-6.02 0.0014
Hemoglobin level
12 g/dL for female
13 g/dL for male
5.30 2.49-11.25 <0.0001
Multivariate analysis:
baseline factors related to anaemia <8g/dl or blood transfusion
Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 51.
Factors
Platelets count
>100,000/mm
3

Platelets count
100,000/mm
3

Albumin 35 g/L
3.4 %
(10/298)
4.3 %
(3/69)
Albumin <35 g/L
7.1 %
(2/28)
44.1 %
(15/34)
8%
CUPIC: Risk of Occurrence of Death
or Severe Complications
Hezode, C, et al. 63rd AASLD; Boston, MA; November 9-13, 2012. Abst. 51.
French National Early Access Program: Interim
Analysis of the CUPIC Cohort (Genotype 1)
Prospective cohort, HCV genotype 1,
compensated cirrhosis
Relapse or prior partial responders to PR
No HBV or HIV
SVR12
Telaprevir: 40% (range: 29%-53%)
Boceprevir: 41% (range: 11%-51%)
SVR12 predictors: partial responders, 1b
Discontinuations: 47%
Serious adverse events: 40%
Early treatment discontinuation: 21.3%
Death: 2.0%
Anemia (<9.0 g/dL): 29.4%
Hepatic decompensation: 2.4%
Fontaine H, et al. J Hepatol. 2013;58(suppl 1):S27. Abstract 60.
Hezode C, et al. Hepatology. 2012;56(suppl 4):217A-218A. Abstract 51.
Hezode C, et al. J Hepatology. 2013;59:434-441.
Adjusted
Odds Ratio
Platelet <100,000/mm
3
3.1 (P=0.0105)
Serum albumin <35 g/dL 6.33 (P=0.0001)
Factors Associated With
Death and Severe Complications (n=62)
Platelets (/mm
3
)
>100,000 <100,000
Albumin (g/dL)
>35 (n=298/69)


3.4

4.3
<35 (n=28/34) 7.1 44.1
Risk of Death or Severe Complications (%)
Triple Therapy for HCV in Patients with Compensated
Liver Cirrhosis: Real-World Experience
n=48 cirrhotic pts, 31% nave, platelets 144
50% anemia <10 g/dl, 27<8.5 g/dl, dose reduction in 50%
TVR 33 (69%), BOC 15 (31%)

Group A
Platelets <110/nl
and
Child-Pugh Score >5
n=7
Group B
Platelets <110/nl
or
Child-Pugh Score >5
n=16
Group C
Platelets 110/nl
and
Child-Pugh Score 5
n=20
#

Treatment Failure 100% (n=7/7) 69% (n=11/16) 30% (n=6/14)
SAE 57% (n=4/7) 63% (n=10/16) 25% (n=5/20)
Either SAE or
Treatment
Failure
100% 94% 50%
Almost every patient (96%; n=22/23) with a Child-Pugh Score >5 and/or baseline platelets
<110/nl (Group A/B) experienced either a treatment failure and or at least one SAE until EOT
Massoumy B, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 857.
Triple Therapy for HCV GT1 Difficult to Treat
Patients: Real Word Experience
High rates of serious adverse events:
64% (BOC) and 53% (TVR)
Severe anemia (<9g/dl) occurred in 65%, blood tx 38%
All pts >60 yrs and all cirrhotic patients received blood tx
Discontinuation rate 33% (BOC) and 31% (TVR)
Baseline characteristics

n = 143
Median age
55yrs
30% > 60a
male 67%
Caucasian 90%
Genotype 1a / 1b 39% / 60%
Advanced fibrosis >F3 48%
F4 and platelets < 120/nl 23%
Tx nave / pretreated 26% / 74%
Non responder 50%
Tx BOC / TVR 69 / 74
Patients at risk for
development of SAE
and treatment failure

n = 83
Platelets <100.000 /ul
and albumin <40g/l
n=17
100%
treatment
failure and
100% SAE
Petersen J, et al. 48th EASL; Amsterdam, Netherlands; April 24-28, 2013. Abst. 891.
Patients, n (% patients with at least one event) Telaprevir n = 295
Serious adverse events (SAEs)* 535 in 160 patients (54.2%)
Premature discontinuation / due to SAEs 139 (47.1%) / 63 (21.3%)
Death 7 (2.4 %)
Infection (Grade 3/4) (3 septicemia, 1 variceal hemmoragia, 1 enkephalopthy,
1 pulmonary neoplasia, 1 pulmonary infection)
27 (9.1 %)
Hepatic decompensation (Grade 3/4) 15 (5.1 %)
Rash (grade 3/SCAR) 16 (5.4 %) / 2 (0.6 %)
Anemia (Grade 3/4 : Hb < 8 g/dL) 38 (12.9 %)
EPO use / blood transfusion 168 (57 %) / 53 (18 %)
GCSF use 8 (2.7 %)
TPO use 6 (2 %)
* SAEs in patients; SCAR: severe cutaneous adverse reaction
Telaprevir : SVR12 safety findings
Patients, n (% patients with at least one event) Boceprevir n = 190
Serious adverse events (SAEs)* 321 in 97 patients (51.0%)
Premature discontinuation / due to SAEs 80 (42.1%) / 27 (14.2%)
Death (1 pulmonary infection, 1 anevrysmal beeding, 1 septicemia) 3 (1.6 %)
Infection (Grade 3/4) 8 (4.2 %)
Hepatic decompensation (Grade 3/4) 9 (4.7 %)
Rash (grade 3/SCAR) 2 (1.0 %)
Anemia (Grade 3/4: Hb < 8 g/dL) 19 (10.0 %)
EPO use / blood transfusion 119 (62.6 %) / 26 (13.7 %)
GCSF use 13 (6.8 %)
TPO use 3 (1.6 %)
* SAEs in patients; SCAR: severe cutaneous adverse reaction
Boceprevir : SVR12 safety findings
Evaluation of the true direct cost of treatment with PI+PR in unselected sequential
population of patients (n=200) treated at a tertiary care center (BIDMC, Boston) for HCV
GT1

Real World Cost per SVR of HCV Triple Therapy with PIs
The mean cost per SVR was $172,889
SVR rate of 49%
Yes
n=82
No
n=118
TN
n=57
R
n=61
P/NR
n=82
Yes
n=109
No
n=91
Yes
n=33
No
n=167
Yes
n=39
No
n=161
Prior Response Cirrhosis Anemia Thrombocytopenia Hospitalization
Sethi N, et al. AASLD 2013. Washington, DC. #1847
TN: Treatment-nave; R: Relapsers; P/NR: Partial or null responders

PR + telaprevir or boceprevir or simeprevir
Monotherapy with pegIFN, RBV, or a DAA
Do not treat decompensated cirrhosis with pegIFN or simeprevir
AASLD and IDSA HCV Regimens: Failed
Previous PR + Telaprevir or Boceprevir
Sofosbuvir 12 weeks + PR 24 weeks
PR: pegIFN + RBV.
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.
Genotype 1a
Sofosbuvir 12 weeks + PR 12-48 weeks Genotype 1b
Preferred Regimens
Sofosbuvir + RBV 24 weeks
Genotype 1a
Sofosbuvir + RBV 24 weeks Genotype 1b
Alternative Regimens
Genotypes 1a or 1b
Regimens Not Recommended
HCV Treatment Considerations
for Transplant Candidates
Achieving sustained virologic response
Possible in some well-selected patients with HCV and decompensated
cirrhosis
Post-transplantation recurrence of HCV may be prevented if SVR is
achieved pretransplant
Potential benefits of HCV therapy need to be balanced against the
risk of sepsis, hepatic failure, and death
Childs C cirrhotics
Risks usually outweigh benefits
Transplantation evaluation
Complete before initiating HCV treatment begins (in case patient should
decompensate)
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
Antiviral Therapy Before Liver Transplantation for HCV-
Infected Recipients With Advanced Fibrosis and Cirrhosis
Lower SVR rates in cirrhotics
Child-Pugh class A versus C: 40% to 50% versus 7% to 26%
Suboptimal SVR rates by genotype 1/4 versus 2/3
Advanced fibrosis: 51% versus 61%
Cirrhosis: 33% versus 57%
Marked step-wise reduction in SVR by fibrosis stage in genotype 1
No fibrosis verus cirrhosis: 70% verus 10% (P<0.0001)
RVR is the strongest on-treatment predictor of SVR, regardless of
genotype

Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.
Fried MW, et al. N Engl J Med. 2002;347:975-982.
Manns MP, et al. Lancet. 2001;358:958-965.
Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.
Bruno S, et al. Hepatology. 2010;51:388-397.
Antiviral Therapy Before Liver Transplantation for HCV-
Infected Recipients With Advanced Fibrosis and Cirrhosis
Challenges
Poor tolerance
Increased adverse events
Risk of hepatic decompensation
Suboptimal SVR rates
HCV treatment in this patient population requires
significant oversight and input in an experienced practice
Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.
Fried MW, et al. N Engl J Med. 2002;347:975-982.
Manns MP, et al. Lancet. 2001;358:958-965.
Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.
Bruno S, et al. Hepatology. 2010;51:388-397.
Pre-Transplant Antiviral Treatment Strategies
for HCV-Infected Liver Transplant Recipients
Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354; Terrault N. Best Pract Res Clin
Gastroenterol. 2012;26:531-548; Roche B, et al. Liver Int. 2011;32(suppl 1):120-128.
Standard Duration
Antiviral Treatment
(24 to 48 weeks)
Post-Transplant Follow-Up
Transplantation
Follow-Up
HCV Goal:
SVR
Candidates:
Compensated cirrhosis
Mild decompensated cirrhosis
(MELD <18)
Projected HCV outcome:
Prevents HCV recurrence in 100%
if SVR achieved pre-transplant
Short Duration
Antiviral Treatment
(12 to 16 weeks)
Post-Transplant Follow-Up
Transplantation
HCV Goal:
Undetectable
HCV RNA
On-Treatment
Candidates:
Compensated cirrhosis
Mild decompensated cirrhosis
(MELD <18)
Projected HCV outcome:
Prevents HCV recurrence in 30% if HCV RNA
negative at time of transplantation; 50% if
HCV RNA negative >16 weeks pre-transplant
HCV Treatment Before Liver Transplantation
in Patients With Decompensated Cirrhosis
G1
(%)
Child-Pugh
(%)

Treatment
EOTR
G1/non-G1 (%)
SVR
G1/non-G1 (%)
HCV RNA Negative
Post Transplant (%)
Crippin 2002
(pilot study; n=15)
73 11.9 IFN + RBV 33
(overall)
NA 0
Thomas 2003
(single cohort; n=20)
67 10.0 IFN 60
(overall)
NA 20
Everson 2005
(single cohort; n=124)
70 7.4 IFN + RBV
(LADR)
30/82 13/50 26
Forns 2003
(single cohort; n=30)
70 A (50%);
B (43%); C (7%)
IFN + RBV 30
(overall)
NA 20
Carrion 2009
(case controlled; n=51)
80 A (45%);
B (43%); C (4%)
PR 20/100 NA 20
Everson 2013
(randomized,
controlled; n=79)
56 7.0 PR
(LADR)
41/53 NA 25
Crippin JS, et al. Liver Transpl. 2002;8:350-355; Thomas RM, et al. Liver Transpl. 2003;9:905-915;
Everson GT, et al. Hepatology. 2005;42:255-262; Forns X, et al. J Hepatol. 2003;39:389-396;
Carrion JA, et al. J Hepatol. 2009;50:719-728; Everson GT, et al. Hepatology. 2013;57:1752-1762.
G: genotype; EOTR: end-of-treatment response (HCV RVA undetectable); PR: peg IFN + RBV; LADR: low accelerating dose regimen.
Adult-to-Adult Living Donor
Liver Transplant Cohort Study (A2ALL)
First, randomized, controlled trial of pre-
transplant PR (LADR) to prevent
recurrent HCV post-transplant
HCC, MELD waiting list upgrade, stable
clinical status, MELD <20
>12 weeks to transplantation
Exclusion criteria
Prior null responders
Creatinine (>2.2 mg/dL); Hb (<10 g/dL); ANC
(<750/L); platelets (<35K/L)
Randomized to either pegIFN + RBV
(LADR) or control (untreated)
Primary endpoint
Post-transplant HCV RNA undetectable at
week 12
Everson GT, et al. Hepatology. 2013;57:1752-1762.
PR: pegIFN + RBV; LADR: low accelerating dose regimen.
Treatment
(n=63)
Control
(n=16)
Male (%) 73 81
Age (years) 56 56
Genotype (%)
1/4 or 6
2/3

47/4
24/25

88/12
0/0
HCV RNA (log
10
IU/mL) 5.7 5.7
HCC upgrade (%) 54 94
MELD 12.0 12.0
CPT score 7.0 6.3
Hemoglobin (g/dL) 13.1 13.5
ANC (/L) 794 531
Platelets (x10
3
/L) 92 93
Previous IFN treatment (%) 92 93
Baseline Characteristics
A2ALL Study:
Virologic Response With PR
T
r
e
a
t
e
d

P
a
t
i
e
n
t
s

(
%
)

Overall
(n=44)
59%
25%
22%
2, 3
(n=21)
Virologic Response
by Genotype
52%
HCV RNA Undetectable
At liver transplantation
Week 12 post-transplant
Everson GT, et al. Hepatology. 2013;57:1752-1762.
29%
67%
1, 4, 6
(n=23)
HCV Genotype
Per protocol analysis. PR: pegIFN + RBV.
T
r
e
a
t
e
d

P
a
t
i
e
n
t
s

(
%
)

<8
(n=8)
25%
0%
18%
>16
(n=14)
Virologic Response
by Treatment Duration
68%
HCV RNA Undetectable
At liver transplantation
Week 12 post-transplant
50%
64%
8 to 16
(n=22)
PegIFN + RBV Duration (Weeks)
A2ALL Study:
Predictors of Response and Safety
Predictors of undetectable HCV RNA 12 weeks post-transplant
Increased duration of treatment (P<0.01)
Nonsignificant trend
Genotype 2 or 3, lower baseline HCV RNA, growth factors during treatment, achieved target
doses of antiviral therapy
Serious adverse events
Similar incidence between treated and controls (68% versus 55%)
Higher number per patient in treated versus controls (2.7 versus 1.3; P=0.003)
No association with MELD score
Death
Pretransplant HCV treatment not associated with increased risk of death versus
controls (15% versus 10%)
Transplant recipients versus no transplant (7.0% versus 31.8%)
Everson GT, et al. Hepatology. 2013;57:1752-1762.
AASLD and IDSA Recommendations:
HCV-Related Cirrhosis
Patients with decompensated cirrhosis (moderate or severe hepatic
impairment; CTP class B or C)
Should be referred to a medical practitioner with expertise in that
condition (ideally in a liver transplant center)
AASLD and IDSA. Available at: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.
Preferred Regimen
Sofosbuvir + RBV for up to 48 weeks
(consider creatinine clearance and hemoglobin)
Any Genotype
Any IFN-based therapy
Monotherapy with pegIFN, RBV, or a DAA
Telaprevir-, boceprevir-, or simeprevir-based regimens
Any Genotype
Regimens Not Recommended
Mangia A, et al. AASLD 2013. Washington, DC. #1115.
No Cirrhosis vs Cirrhosis: SVR12 Rates
No cirrhosis Cirrhosis
98
92
96
100
91
94
60
78
FISSION POSITRON FUSION 12 FUSION 16
58/59 85/92 25/26 23/23
10/11 16/17 6/10 7/9
61
68
37
63
34
21
19
61
FISSION POSITRON FUSION 12 FUSION 16
13/38 3/14 5/26 14/23
89/145 57/84 14/38 25/40 252/273
43/54
GT 2 GT 3 GT 1, 4, 5, 6
92
80
NEUTRINO
0
20
40
60
80
100
S
V
R
1
2


(
%
)
Virologic Response: Cirrhosis
SOF Phase 3 Analysis in Patients with Traditional
Negative Factors
40/40 40/40 29/40 28/40 28/40
Virologic Response
Post-Liver Transplant Study (SOF+RBV)
Samuel D, EASL, 2014, P1232
LLOQ, lower limit of quantification (25 IU/mL)
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
No TAC or CsA toxicities or drug interactions were observed - 4 patients increased TAC
dosing due to improved liver function


Pre-Liver Transplant Sofosbuvir + RBV:
Prevention of Recurrent HCV
Open-label, phase 2 study conducted at
16 sites (n=61)
Deceased donor liver transplantation
candidates with HCV
HCC meeting MILAN criteria
MELD exception for HCC
CPT <7
Exclusion: decompensated cirrhosis, prior
solid organ transplantation, HBV or HIV
coinfection, renal impairment
Up to 48 weeks of sofosbuvir 400 mg +
RBV (1000-1200 mg) pre-transplant
Post-transplant, immunosuppressive
regimen: tacrolimus + prednisone +
mycophenolate mofetil.
Primary endpoint: SVR12 post-liver
transplant
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
Baseline Characteristics
Treatment
(n=61)
Male (%) 80
Age (years) 59
BMI <30 kg/m
2
(%) 43
Genotype (%)
1a/1b
2/3
4

39/34
13/12
4
HCV RNA >6 log
10
IU/mL (%) 41
IL28 B non-CC (%) 78
MELD 8
CPT score 5-7 (%) 95%
Prior HCV treatment (%) 75
Pre-Liver Transplant Sofosbuvir + RBV:
Virologic Response in HCV Genotypes 1-4
HCV recurrence prevented in 64%
of patients HCV RNA <LLOQ at
time of transplantation
On treatment HCV RNA
suppression was rapid (1 week)
Factors associated with HCV
recurrence (multivariate exact
odds ratio)
Days continuously TND prior to
transplantation: 1.04 (1.01, 1.08;
P=0.0007)
TND: target not detected.
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
P
a
t
i
e
n
t
s

(
%
)

Overall
(n=44)
93%
Post-
Transplant
Week 12
(n=39)
HCV RNA Undetectable
91%
64%
>12 Weeks
Treatment
(n=33)
At Transplant
Pre-Liver Transplant Sofosbuvir + RBV:
Target Not Detected and Safety in Genotypes 1-4
Median days TND
No HCV recurrence (n=28): 95
HCV recurrence (n=10): 5.5
(P<0.001)
Sofosbuvir + RBV was generally
well tolerated
Discontinuations due to adverse
events: 3% (none related to
sofosbuvir)
Selected adverse events
Fatigue: 38%
Anemia: 23%
Headache: 23%
Nausea: 16%
Rash: 15%
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
TND: target not detected.
I
n
d
i
v
i
d
u
a
l

P
a
t
i
e
n
t

D
a
t
a

Days Continuously TND Before Liver
Transplant and Preventing HCV Recurrence
HCV RNA Continuously TND (Days)
>30 days
TND
HCV recurrence (n=10)
No HCV recurrence (n=28)
Cost Per Cure of Sofosbuvir vs PIs:
Treatment-Nave With and Without Cirrhosis Genotype 1
-$10,708
(-10%)
-$18,039
(-16%)
-$17,153
(-13%)
-$31,472
(-24%)
T
o
t
a
l

C
o
s
t

p
e
r

S
u
c
c
e
s
s
f
u
l
l
y

T
r
e
a
t
e
d

P
a
t
i
e
n
t

BOC + PR TVR + PR SOF + PR BOC + PR TVR + PR SOF + PR

AMCP Dossier Data on file, Gilead Sciences December 2013
Cost Per SVR of Sofosbuvir vs Simeprevir: Treatment
Nave With and Without Cirrhosis Genotype 1
T
o
t
a
l

C
o
s
t

p
e
r

S
u
c
c
e
s
s
f
u
l
l
y

T
r
e
a
t
e
d

P
a
t
i
e
n
t

-$6,730 (-6%)
Without Cirrhosis (F0-F3) With Cirrhosis (F4)
-$33,573 (-20%)

Gordon SC, et al. Hepatology. 2012;56(5):1651-60.
Lawitz E, et al. N Engl J Med. 2013 May;368(20):1878-87.
Lenz O, et al. AASLD 2011. San Francisco, CA, USA. Poster #1329
Jacobson I, et al. EASL 2013. Amsterdam, the Netherlands. Poster #1525
Manns M, et al. EASL 2013. Amsterdam, the Netherlands. Poster #1525
McAdam-Marx C, et al. J Manag Care Pharm. 2011;17(7):531-46.
Zein NN, et al. Clin Microbiol Rev. 2000 Apr;13(2):223-35.
Risk of HCC Remains After SVR in HCV
Patients With Advanced Hepatic Fibrosis
Meta-analysis (n=1000)
10 cohorts, individual patient data
SVR with IFN-based therapy
Bridging fibrosis or cirrhosis
No HIV or HBV coinfection
51 events of HCC over 5.1 years of
follow-up
Patients with HCV-induced
cirrhosis who achieve SVR remain
at risk for HCC
Risk increased with age, severity of
liver disease, and presence of
diabetes mellitus

van der Meer AJ, et al. Hepatology. 2013;58(suppl 1):280A. Abstract 143.
R
a
t
e

(
%
)

Cumulative HCC by Age Group
0 1 2 3 4 5 6 7 8
Years After SVR
P=0.006
12.2%
2.6%
9.7%
Age Group
<45 years
45 to 60 years
>60 years
Conclusion
Patients with HCV cirrhosis globally remain an
enigma as to timing of treatment
Cirrhosis: when present, are those patients most in
need of treatment today
Treat with INF based therapy down to albumin of 3.5
and platelets of 100,000

With the advent of new therapies, all oral regimens
Cirrhosis treatment will evolve to be simple and
expedient
Prices will need to be aligned with GDP and health
care allocations per country