Patients with Cirrhosis: Managing the
HCV Peri-Transplant Patient Fred Poordad, MD Professor of Medicine
University of Texas Health Science Center
VP, Academic and Clinical Affairs
The Texas Liver Institute
San Antonio, TX
Disclosures
• Grant/Research support: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix Pharmaceuticals, Idera Pharmaceuticals, Intercept Pharmaceuticals, Janssen, Medarex, Medtronic, Merck, Novartis, Santaris Pharmaceuticals, Scynexis Pharmaceuticals, Vertex Pharmaceuticals, ZymoGenetics
• Speaker: Gilead, Kadmon, Janssen, Merck, Onyx/Bayer, Genentech, Salix and Vertex
• Consultant/Advisor: AbbVie, Achillion Pharmaceuticals, Anadys Pharmaceuticals, Biolex Therapeutics, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, GlobeImmune, Idenix, Merck, Novartis, Tibotec/Janssen, Theravance and Vertex.
Hepatitis C is the Leading Cause for Liver Transplant in the US
Berg et al. Am J Transplant. 2009;9(part 2):907.
160,000
140,000
120,000
100,000
80,000
60,000
40,000
20,000
0
1950 1960 1970 1980 1990 2000 2010 2020 2030
Year
Hepatocellular cancer
Decompensated cirrhosis
Nu
mb
er
of
Ca
se
s
Curves indicate gender and age at time of initial HCV infection. Data are for the United States.
Davis et al. Gastroenterology. 2010;138:513.
Numbers of HCV Patients With Decompensated Cirrhosis
and HCC Are Expected to Peak in 2020 in the US
• Increasing prevalence of decompensated cirrhosis and HCC could increase number
of patients on liver transplant waiting list
Ba
se
20
10
co
st
($/p
ati
en
t/ye
ar)
Summary of Studies Reporting Incremental Cost by Sequela (In 2010 US $)a
Costs of Liver Transplant Much Higher Than Costs
of Less Advanced Sequelae for Hepatitis C
aStudies use a patient cohort model to estimate total cost using cost and transition probability for each sequela.
El Khoury et al. J Viral Hepat. 2012;19:153.
UK
$97,040 ($52,490-$164,390)
United States $201,110 ($173,760- $223,460)
Brazil
$64,170
Japan
$163,140 ($74,920-$299,690)
Australia
$132,040 ($127,920-$136,170)
Taiwan
$23,150 ($15,430-$30,860)
Canada
$113,280 ($61,490-$165,070)
New Zealand
$82,530
Spain
$253,460 ($132,260-$443,700)
The lowest transplantation costs have been reported in Taiwan and the highest in Western Europe
El Khoury et al. J Med Econ. 2012;15:887.
Costs of Liver Transplants Vary Around the World
Potential Transplant Need
Nu
mb
er
of
Pers
on
s
20,000
0 5 10 15 20 25 30
40,000
60,000
80,000
100,000
120,000
140,000
160,000
180,000
0
Year in Model
18,193 25,573 27,175 26,207 24,258 21,994
49,013
91,310
126,296
150,617
162,559 162,747
No treatment 25% 50% 75% treated All treated
Desai et al. The Liver Meeting 2013. Abstract 1427.
Widespread Use of Effective Therapy Could Significantly Reduce Need for Transplants
HCC
ESLD
Incidence rate ratioa for HCC: 1.118 (95% CI, 1.107–1.130); P<0.001
10
12
8
6
4
2
0 2003
Ad
juste
da I
R p
er
10
0,0
00
2004 2005 2006 2007 2008 2009 2010
aAdjusted for age and sex.
Fleming et al. The Liver Meeting 2013. Abstract 12.
Numbers of HCV Patients on Liver Transplant:
HCC Numbers Have Nearly Doubled Since 2007
• The number of HCV patients wait-listed for HCC has risen by 12% per year on average (from 623
in 2003 to 1379 in 2010, or from 2.1 to 4.6 per 100,000)
• In contrast, wait-listing due to end-stage liver disease (ESLD) has remained relatively stable over
the study period (0.7% rise, from 1451 to 1674, or from 4.8 to 5.6 per 100,000)
pTVR12 SOF 400 mg + RBV 1000‒1200 mg (n=61)
• N=61 DDLT candidates with MELD exception for HCC
– Genotypes 1-4
– CPT ≤7 (43% CP=5)
– Median MELD =8 (8-14)
– CrCl ≥60 mL/min
– Rx-naïve (25%) or experienced (75%)
– Absence of HIV or HBV
Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation
SOF + RBV to Prevent HCV Recurrence Post-LT
• On-treatment HCV RNA suppression was rapid and similar to other patient populations on SOF
regimens
• Treatment with SOF + RBV was generally safe and well tolerated
Vir
al
Resp
on
se
Rate
(%
)
*3 subjects were >LLOQ at transplant †1 subject has not reached pTVR12, 1 subject lost to follow up at Week 8 post transplant
Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation
Virological Response
SOF + RBV to Prevent HCV Recurrence Post-Transplant
Analysis of Post-Transplant Recurrence in GT 1–4
Days HCV RNA Continuously TND Prior to Transplant
No Recurrence (n=29) Recurrence (n=10)
Median days TND
• No recurrence: 99
• Recurrence: 5.5
p <0.001*
No recurrence in 24/25 (96%) of
patients who maintained HCV RNA
TND >28 days
28
*Wilcoxon rank sum test.
Curry MP, et al. APASL 2014. Brisbane, Australia. Oral presentation
SOF + RBV
n=25
Observation
n=25
Male, n (%) 18 (72) 20 (80)
Median age, y (range) 56 (43‒69) 55 (44‒69)
BMI ≥30 kg/m2, n (%) 8 (32) 7 (28)
Mean HCV RNA, log10 IU/mL (range) 6.1 (4.4‒7.0) 6.1 (3.8‒6.9)
GT, n (%)
1a 10 (40) 9 (36)
1b 9 (36) 6 (24)
2 2 (8) 1 (4)
3 2 (8) 8 (32)
4 2 (8) 1 (4)
IL28B non-CC, n (%) 22 (88) 18 (72)
Prior HCV treatment, n (%) 17 (68) 23 (92)
Mean HVPG mmHg, n (range) 16.9 (9‒29) 16.2 (7‒27)
HVPG >12 mmHg, n (%) 19 (76) 20 (80)
SOF 400 mg + RBV
1000‒1200 mg
SVR12
Observation SOF 400 mg + RBV
1000‒1200 mg
SVR12
Arm 1
n=25
Arm 2
n=25
Wk 0 Wk 24 Wk 48 Wk 96 Wk 72
Preliminary results
Afdhal N, EASL, 2014, O68
SOF+RBV for Chronic HCV with Cirrhosis and Portal HTN
± Decompensation
• 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 (CTP 5–9)
HC
V R
NA
< L
LO
Q (
%)
Week *1 patient was a non-responder at Week 8.
Afdhal N, EASL, 2014, O68
Virologic Response
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
Platelets (103/µL) Albumin (g/dL)
SOF+RBV Observation 24 weeks
ALT (U/L)
CTP A CTP B
p=0.003
p=NS
p=0.001 p=0.001
Afdhal N, EASL, 2014, O68
Laboratory and Clinical Event Changes
SOF Compassionate Use Program SOF+RBV±PEG
n=104
Severe acute hepatitis/early recurrence (<12 months from liver transplant with typical
biochemical and histological findings) n=48
Post transplant compensated and decompensated cirrhosis [liver biopsy
(F4) or clinical decompensation] n=56
Completed 24-48 weeks treatment
N=72
Death N=13
Liver transplant n=12
Discon due to AE n=7
Forns, et al. EASL 2014
Sofosbuvir Compassionate Use Program: Patient Disposition
Demographics Overall
(n=104)
Male, n (%) 76 (73)
Median age, y (range) 55 (16-76)
Median HCV RNA, log10 IU/mL (range) 8.4 (1.3-8.9)
GT, n
1/1a/1b 8/29/51
2/3/4 1/7/8
Median bilirubin, mg/dL (range) 3.1 (0.4-45)
Median albumin, g/dL (range) 3.1 (1.3-12.2)
Median INR (range) 1.3 (0.8-4.5)
Median ALT, IU/L (range) 71 (8-1162)
Median platelets, x103/µL (range) 78 (19-340)
Median MELD (range) 15 (6-43)
Median months from LT to treatment (range) 17 (1-262) Forns, et al. EASL 2014
Results: Baseline Characteristics
Patients were excluded from this analysis if received a liver transplant (n=8 at EOT; n=12 at SVR12)
Forns, et al. EASL 2014
Results: Overall Virologic Response
81/93 53/85
0
20
40
60
80
100
EOT SVR12
Lost to follow-up
Death
HCV RNA>LLOQ
HCV RNA <LLOQ
53/85 81/93
Pati
en
ts (
%)
8/93
4/93
15/85
13/85
4/85
Results: Overall Virologic Response
Forns, et al. EASL 2014
• All patients who received ≥1 dose of SOF are included
21 21
100
80
60
40
20
0
Improved* Stable Worsened/Deceased
60/104 22/104 22/104
Pati
en
ts (
%)
*Significant decrease in hepatic encephalopathy, improvement or disappearance of ascites, or improvement in liver-
related laboratory values.
Forns, et al. EASL 2014
62
Results: Clinical Outcomes
12
10
8
6
4
2
0
Baseline EOT FU Wk12
0
0.5
1
1.5
2
Baseline EOT FU Wk12
5
4
3
2
1
0
Baseline EOT FU Wk12
Bil
iru
bin
(mg
/dL
)
Alb
um
in (
g/L
)
INR
25
20
15
10
5
0
Baseline EOT FU Wk12 M
EL
D
Forns, et al. EASL 2014
Results: Laboratory Tests (Median and Interquartile Ranges)
0 24 Study Week
SOF 400 mg + RBV 400–1200 mg SVR 12 TN & TE with
recurrent HCV N=40
Low, ascending-dose RBV regimen starting at 400 mg/day, escalated based on hemoglobin levels
Samuel D, EASL, 2014, P1232
SOF+RBV for Established Recurrent HCV Post-Liver Transplant
Study inclusion criteria
– Liver transplant ≥ 6 months and ≤ 150 months
– CTP ≤ 7 and MELD ≤ 17
Exclusion: Prednisone >5 mg/day
Key baseline characteristics
– 55% GT1a, 28% GT1b, 15% GT3, 3% GT4
– 88% treatment experienced (23% PI/PEG/RBV failures)
– 40% F4 cirrhotic
40/40 40/40 29/40 28/40 28/40
Samuel D, EASL, 2014, P1232
Virologic Response
• Relapse was not influenced by RBV dose or exposure
• No TAC or CsA toxicities or drug interactions were observed - 4 patients increased TAC dosing due to
improved liver function
Adverse Events, n (%)
SOF + RBV,
N=40
SAEs* 6 (15)
AEs that led to D/C of study treatment† 2 (5)
AEs in ≥ 15% of patients
Fatigue 12 (30)
Diarrhea 11 (28)
Headache 10 (25)
Arthralgia 9 (23)
Nausea 8 (20)
Anemia 8 (20)
Cough 7 (18)
Grade 3 and 4 Lab Abnormalities, n (%)
SOF + RBV,
N=40
Overall Grade 3 11 (28)
Overall Grade 4 11 (28)
Lymphocytes (5 G3; 9 G4) 13 (33)
Hemoglobin (G3) 8 (20)
Hyperglycemia (3 G3; 1 G4) 4 (10)
White blood cell count (G3) 3 (8)
Hyperbilirubinemia (G4) 1 (3)
Lipase (G4) 1 (3)
Neutrophils (G3) 1 (3)
AST (G3) 1 (3)
Adverse Events and Lab Abnormalities
*All SAEs assessed as unrelated to SOF: ascites, pyrexia (2 cases), jaundice, pneumonia, urinary tract infection, hemarthrosis,
osteoporotic fracture, confusion, hallucination; †Recurrence of hepatocellular carcinoma and pneumonia.
AST, aspartate aminotransferase; DC, discontinuation; G, grade; SAE, serious adverse event.
Samuel D, EASL, 2014, P1232
Day 0 Week 24
SVR12
To Week 72
3D + RBV (N=34)
Kwo, et al. EASL 2014
ABT-450/r/ABT-267 + ABT-333 + Ribavirin in Liver Transplant Recipients With Recurrent HCV
• 3D: co-formulated ABT-450/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
Kwo, et al. EASL 2014
Calcineurin Inhibitor (CNI) Dosing With 3D Regimen
• A phase 1 drug-drug interaction study demonstrated that dosing tacrolimus
(TAC) or cyclosporine (CYA) with the 3D regimen compared to either alone
resulted in a
– 7-fold increase in TAC half-life
– 3-fold increase in CYA half-life
• Based on these findings, recommended dosing during 3D treatment was
– TAC
• 0.5 mg once weekly or
• 0.2 mg every 3 days
– CYA
• 1/5 of the daily pre-3D treatment dose given once daily
Kwo, et al. EASL 2014
Eligibility Criteria
• 18 to 70 years of age, inclusive
• HCV GT1 infection
• Liver transplantation due to HCV infection >12 months before screening
• Treatment-naïve after transplantation
– PegIFN/RBV treatment prior to transplantation was permitted
• Screening liver biopsy-confirmed Metavir score <F2
• No history of steroid-resistant rejection
• Receiving a stable TAC- or CYA-based immunosuppressant regimen
– Prednisone use permitted at doses ≤5 mg/day
– Use of mTOR inhibitors not permitted
3D + RBV (N=34)
Mean time since transplantation, months 47.9
Male (%) 79.4
Black/white race (%) 11.8 / 85.3
Hispanic or Latino ethnicity (%) 17.6
Mean age (years) 59.6
Mean BMI (kg/m2) 29.7
Fibrosis stage (%)
F0-F1/F2 53 / 47
IL28B non-CC (%) 76.5
HCV subtype (%)
GT1a/GT1b 85.3 / 14.7
Mean HCV RNA (log10 IU/mL) 6.6
Immunosuppressive medication (%)
Tacrolimus/cyclosporine 85.3 / 14.7
Mean creatinine clearance (mL/min) 90.5
Mean creatinine (mg/dL) 1.1
Mean ALT/AST/GGT (U/L) 78.9 / 63.9 / 170.3
Baseline Patient Characteristics
Kwo, et al. EASL 2014
No patient had breakthrough; One patient had a relapse (post-treatment day 3)
Kwo, et al. EASL 2014
Preliminary Efficacy Results %
Pati
en
ts
34/34
97.0%
34/34
96.2%
32/33 25/26
SVR4 SVR12 RVR (Week 4)
EOTR (Week 24)
100% 100%
Adverse Events Occurring in >15% of Patients
Event, n (%)
3D + RBV (N=34)
Any AE 33 (97.1)
Headache 15 (44.1)
Fatigue 14 (41.2)
Cough 10 (29.4)
Insomnia 9 (26.5)
Asthenia 8 (23.5)
Diarrhea 8 (23.5)
Nausea 8 (23.5)
Rash 7 (20.6)
Anemia 6 (17.6)
Dizziness 6 (17.6)
Muscle spasms 6 (17.6)
Pyrexia 6 (17.6) Kwo, et al. EASL 2014
• No episodes of acute or chronic
rejection
• 1 patient discontinued study drug due to
AEs (moderate rash, memory
impairment, and anxiety) after week 18
– Patient achieved SVR12
• 2 patients had serious AEs
– Hypotension and tachycardia associated
with initiation of tamsulosin after elective
surgery
– Moderate peripheral edema and pain in
extremity in a diabetic patient with history of
peripheral edema
Event, n (%)
3D + RBV
(N=34)
<LLN-10.0 g/dL (Grade 1) 12 (35.3)
<10.0-8.0 g/dL (Grade 2) 8 (23.5)
<8.0-6.5 g/dL (Grade 3) 1 (2.9)
<6.5 g/dL (Grade 4) 0
• 5 patients received erythropoietin at investigator discretion
• No patient underwent transfusion
• No patient discontinued study drugs due to anemia
Kwo, et al. EASL 2014
Hemoglobin Effect
RBV total daily dose (mg), n (%)
Baseline
(N=34)
End of Treatment
(N=34)
400 3 (8.8) 4 (11.8)
600 to 800 19 (55.9) 25 (73.5)
1000 to 1200 12 (35.3) 5 (14.7)
• 600 to 800 mg daily was the most frequent RBV dosage
both at baseline and end of treatment
3D + RBV
Kwo, et al. EASL 2014
Ribavirin Dose Modifications
• Ctrough levels were comparable pre-
treatment and on-treatment
• TAC dose was 0.5 to 1.0 mg at 1-2
week intervals for most patients
• 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
Pre-Treatment On-Treatment
(Treatment Weeks 1-4)
Ta
cro
lim
us
Co
nc
en
tra
tio
n (
ng
/mL
)
16
14
12
10
8
6
4
2
0
Kwo, et al. EASL 2014
Pre-Treatment and On-Treatment Tacrolimus Ctrough Concentrations
• CYA levels were
maintained within the
desired range with the
recommended dosing
regimen (N=5 patients)
• On-treatment CYA dose
was 1/5 of the pre-
treatment dose in these
patients
Pre-Treatment On-Treatment
Cyc
los
po
rin
e
Co
nc
en
tra
tio
n (
ng
/mL
)
200
150
100
50
Kwo, et al. EASL 2014
Pre-Treatment and On-Treatment Cyclosporine Ctrough Concentrations
HC
V R
NA
<L
LO
Q
Pa
tie
nts
, %
Patients Achieving SVR12
14
16
15
15 12
14
14
14 41
41
39
41
15
15 14
14
21
21
19
20
GT2/3 GT1a/1b
Treatment-naive;
24 wk of treatment Treatment-naive;
12 wk of treatment
Prior PI failures;
24 wk of treatment
Sulkowski et al. N Engl J Med. 2014;370:211.
DCV+SOF: A1 444-040 Study Shows High SVR Rates in Multiple Genotypes
• Safety Highlights
– DCV + SOF has an acceptable tolerability profile
• Only 2/211 (<1%) patients receiving SOF + DCV with and without RBV discontinued therapy due to adverse events
• The most common adverse events were fatigue (29%-50%), headache (16%-38%), and nausea (10%-32%), which were mild-to- moderate
LI SOF
+DCV
DCV
+SOF
DCV
+SOF
+RBV
LI SOF
+DCV
DCV
+SOF
DCV
+SOF
+RBV
DCV
+SOF
DCV
+SOF
+RBV
DCV +SOF DCV +SOF
+RBV
Pre-transplant (n=60)
Post-transplant (n=50)
DCV 60 mg QD + SOF
400 mg QD
24-wk follow-up DCV 60 mg QD +
SOF 400 mg QD
Therapy up to 12 wk
Study Week 24 0 12 36
3 mo – 12 y
SVR12
24-wk follow-up
OR Transplant 24-wk follow-up
AI444-215.
www.ClinicalTrials.gov/ct2/show/NCT02032875.
DCV + SOF: ALLY 1 Cirrhosis and Post-Transplant Study Design
• Objective: Assess the efficacy and safety of DCV 60 mg QD + SOF 400 mg
QD in treatment-naive or -experienced GT1–6 patients with advanced liver
disease awaiting liver transplantation, or with recurrent HCV post-transplant
• Primary end point: SVR12
• Objective: Assess the effect of DCV + SMV on the pharmacokinetics of cyclosporine
and tacrolimus and the efficacy and safety of DCV + SMV + RBV in post–orthotopic
liver transplantation participants with recurrent HCV genotype 1b infection
• Primary end point: SVR12
• Inclusion criteria – Liver transplant between 6 months and 10 years prior to screening visit
– Screening HCV RNA level >10,000 IU/mL
– No post–orthotopic liver transplant anti-HCV treatment
– Receiving stable immunosuppressant therapy with cyclosporine or tacrolimus for >3 months prior to the screening visit
Week 24 SVR12
Part 1: DCV + SMV + RBV Follow-up
Part 2: DCV + SMV + RBV Follow-up
Recurrent HCV
GT 1b (n=40)
Metavir Score
F1-F2
F1-F4
SMV = simeprevir.
NCT01938625; http://clinicaltrials.gov/ct2/show/study/NCT01938625.
Study Design of DCV + SMV + RBV