1. HCV treatment focusing on transplant setting in the era of DAA
Yonsei University College of Medicine
Gangnam Severance Hospital
Jung Il Lee

2. HCV Prevalence
Country
Prevalence (%)
Vietnam
6.1
Pakistan
5.3
Taiwan
4.4
Mainland China
3.2
Cambodia
2.3
Thailand
2.2
Indonesia
2.1
South Korea
1.3
Laos
1.1
Myanmar
0.9
India
Japan
0.5
Philippines
Singapore
0.4
Hong Kong
0.1
Nguyen LH, Nguyen MH. Aliment Pharmacol Ther 2013;37:921–36.

3. Annual proportion of liver transplantation
Proportion of liver transplantation for HCV was gradually increased in Korea
A total of 5,663 adult liver transplantations (LTs) were performed between 2000 and HCV-related liver disease was responsible for 277 LTs (4.9%).
The annual proportion of LT for HCV fluctuated during the study period, but largely
showed a gradually increasing pattern
Although <20% of patients transplanted for HCV may have no significant lesions 5 years after LT, most recipients display progressive chronic hepatitis, which is clearly more aggressive than in immunocompetent subjects, and leads to cirrhosis in 10∼50% of recipients at 5 years post-LT.
Annual proportion of liver transplantation
for hepatitis C virus (HCV)
Proportion (%)
Year 8
2000
1.3 7 6 5 4 3 2 1
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2.9
5.6
3.0
2.2
5.2
3.7
6.3
7.4
5.3
Lee HW, et al. J Korean Soc Transplant. 2012;26:

4. HCV and Liver Transplantation
Recurrence of HCV infection post-transplant occurs in nearly all transplanted patients
Post–liver transplantation outcomes are worse for those who undergo transplantation for HCV than other etiologies
Progression to graft cirrhosis and subsequent complications can be rapid and compromises patient and graft survival
Fibrosing cholestatic hepatitis: 2 ~ 8%
Peg-IFN + RBV-based therapy is poorly tolerated in patients with advanced liver disease on transplant waiting lists and also in post- transplant patients with deteriorating liver function

5. Post-transplant survival rate is lower in HCV+ recipient vs HCV- recipients
365
730
1095
1460
1825
2190
2555
2920
3285
3650 25
Days Since Transplant
Patient Survival, % 50 75
100
HCV–
HCV+
Factors Leading to Worse Outcome2
Donor/Recipient
Donor age >60 y
Female gender and non-white race
HLA matching
IL-28b genotype
Pre-transplant Factors
Higher recipient age
High viral load
Post-transplant Factors
Prolonged ischemic time
Shorter time to recurrence
Treatment of acute rejection
Higher immunosuppressive intensity
Based on 2009 OPTN/SRTR Annual Report and deceased donor transplants
Significant difference in unadjusted 3-year and 5-year patient survival between HCV-positive (82%, 75%) and HCV-negative (86%, 81%, P<0.0001) recipients with living donor liver transplants
1. Thuluvath et al. Am J Transplant ;10(4 Pt 2):1003; 2. Wertheim et al. Am J Transplant. 2011;11:1773.

6. Problems concerning treatment
In Pre- and Post-transplant setting has been…
Pre-transplantation
Poor tolerance of Peg-IFN regimens
Impaired hepatic metabolism
Renal insufficiency
Post-transplantation
Impact of immunosuppression
Drug–drug interactions
Rejection
Outcome of recurrence: accelerated fibrosis in post-transplant patients with recurrence
Overall SVR rates with Peg-IFN plus RBV are low, ranging between 10 and 40%

7. Progress in HCV Treatment
The great days are coming !!
≒ 90~100
Boceprevir or Telaprevir + P/R
Simeprevir or Sofosbuvir + P/R
67~75
Interferon + Ribavirin
SVR (%)
2011
54~56
2013
2015
GT1
IFN-free DAA
combinations (GT1)
1991
1998
2001
38~43
GT2/3
Peginterferon/ Ribavirin
25~30
Standard Interferon
2013
15~20
8~12
Sofosbuvir Ribavirin
IFN 6m
IFN
12~18m
IFN/RBV
6~12m
PegIFN
6~12m
PegIFN/RBV
6~12m
PI +
PegIFN/RBV
6~12m
DAAs

8. Direct Acting Agents (DAAs)p7
NS2
NS3
NS4A
NS4B
NS5A
NS5B
NS3
NS5A
NS5B
The NS3/4A serine protease is essential for post-translational processing of HCV polyproteins
Multifunctional membrane-associated pho sphoprotein essential component of the H CV RNA replication complex
NS5B is an HCV-specific RNA-dependent RNA polymerase
Boceprevir
Telaprevir
Asunaprevir
Simeprevir
ABT-450/r
Faldaprevir
Danoprevir/r
GS-9451
GS-9256
MK-5172
Vaniprevir
SovaprevirACH-806/GS-9132
Daclatasvir
Ledipasvir
MK-8742
ABT-267
ACH-2928
ACH-3102
Samatasvir
PPI-561
PPI-668
AZ-689
GSK
Nucleos(t)ide analogues
Sofosbuvir
Mericitabine
PSI-6130
VX-135
Non-nucleoside analogues
ABT-333
BMS
TMC
VX-759, 222
Tegobuvir
Setrobuvir
Filibuvir

9. Sofosbuvir + Ribavirin to Prevent Post-Transplant HCV recurrence
Curry MP, et al. Gastroenterology. 2015;148:100-7.

10. Sofosbuvir + Ribavirin to Prevent Post-Transplant HCV recurrence
Virologic Response at Transplant and Post-Transplant
Conclusions: “Administration of sofosbuvir and ribavirin before liver transplantation can prevent post-transplant HCV recurrence.”
43/46
31/43
31/43
30/43
Data for the 43 patients with HCV RNA <25 IU/mL at time of transplant
Curry MP, et al. Gastroenterology. 2015;148:100-7.

11. Days With HCV RNA Continuously TND Prior to Liver Transplant
Duration of undetectable HCV RNA before transplant predicted lack of recurrence
Median days undetectable(P < 0.001)
No recurrence: 95
Recurrence: 5.5
64% of pts HCV RNA negative 12 wks post-LT (93% at LT)
Continuous days TND pre-LT only factor predicting HCV recurrence in multivariate analysis
Only 1/24 pts with > 30 days TND experienced recurrence
330 30 60 90
120
150
180
210
240
270
300
Days With HCV RNA Continuously TND Prior to Liver Transplant
> 30 days TND (target not detected)
No recurrence (n = 28) Recurrence (n = 10)
Curry MP, et al. Gastroenterology. 2015;148:100-7.

12. Sofosbuvir-Ledipasvir + Ribavirin in Decompensated and Post liver transplant HCV GT 1,4
SOLAR-1 and SOLAR-2 study
Week 0 12 24 36
Pre-Transplant
CTP B (7–9)
CTP C (10–12)
LDV/SOF + RBV
SVR12
Post-Transplant
Fibrosis (F0–F3)
CTP A (5–6)
LDV/SOF + RBV
CTP B (7–9)
SVR12
CTP C (10–12)
FCH
Broad inclusion criteria:
No hepatocellular carcinoma (HCC)
Total bilirubin ≤ 10 mg/dL, Hemoglobin ≥ 10 g/dL
CrCl ≥ 40 mL/min, Platelets > 30,000/mL
RBV dosing
F0–F3 and CTP A cirrhosis: weight-based (< 75 kg = 1000 mg; ≥ 75 kg = 1200 mg)
CTP B and C cirrhosis: dose escalation, 600–1200 mg/d
Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

13. Sofosbuvir-Ledipasvir + Ribavirin in Decompensated and Post liver transplant HCV GT 1,4
Pre-Transplant
Post-Transplant
Total n=659
Patients, n (%)
CTP B + C n=215
F0–3 + CTP A n=330
CTP B + C n=114
HCV GT, n (%) 1a
124 (58)
197 (60)
71 (62)
392 (59) 1b
78 (36)
111 (34)
36 (32)
225 (34) 4
13 (6)
22 (7)
7 (6)
42 (6)
IL28B non-CC, n (%)
167 (77)
272 (83)
92 (81)
431 (81)
Prior HCV treatment, n (%)
150 (70)
270 (82)
96 (84)
516 (78)
Cirrhosis, n (%)
215 (100)
118 (36)
114 (100)
447 (68)
Median eGFR, mL/min/1.73 m2 (range)
84 (34–224)
63 (20–132)
64 (29–124)
69 (20–224)
MELD, n (%)
<10
24 (11)
64 (54)
26 (23)
114 (26)
10-15
132 (61)
51 (43)
69 (61)
252 (56)
16–20
54 (25)
3 (3)
16 (14)
73 (16)
21–25
5 (2)
8 (2)
Median albumin, g/dL (range)
2.8 (1.6–4.0)
3.9 (2.4–4.8)
3.0 (1.6–4.2) NR
Median platelets, x 103/µL (range)
76 (27–212)
136 (35–434)
90 (32–237)
Ascites, n (%)
163 (76)
9 (3)
83 (73)
Encephalopathy, n (%)
140 (65)
4 (1)
53 (46)
Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

14. Sofosbuvir-Ledipasvir + Ribavirin in Pre-transplant HCV GT 1,4
SOLAR-1
SOLAR-2
SVR12 (%)
26/30
22/26
24/27
24/25
19/22
17/21
20/23
14/20
LDV/SOF + RBV
12 wks
LDV/SOF + RBV
24 wks
LDV/SOF + RBV
12 wks
LDV/SOF + RBV
24 wks
CTP B
CTP C
Comparable efficacy between SOLAR-1 and SOLAR-2 studies
The SVR12 analysis included all subjects except those who had undergone transplantation prior to SVR12 at last visit prior to transplantation.
Error bars represent 90% confidence intervals.
Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

15. Sofosbuvir-Ledipasvir + Ribavirin in Post-transplant HCV GT 1,4
SOLAR-1
SOLAR-2
SVR12 (%)
78/81
82/86
79/81
64/65
22/26
21/22
23/26
19/19
3/5
1/3
3/4
3/4
LDV/SOF + RBV
12 wks
LDV/SOF + RBV
24 wks
LDV/SOF + RBV
12 wks
LDV/SOF + RBV
24 wks
LDV/SOF + RBV
12 wks
LDV/SOF + RBV
24 wks
F0-F3 & CTP A
CTP B
CTP C
Comparable efficacy between SOLAR-1 and SOLAR-2 studies
The SVR12 analysis included all subjects except those who had undergone transplantation prior to SVR12 at last visit prior to transplantation.
Error bars represent 90% confidence intervals.
Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

16. Sofosbuvir-Ledipasvir + Ribavirin in Decompensated and Post liver transplant HCV GT 1,4
Pre-Transplant
Post-Transplant
Total n=659
Patients, n (%)
CTP B + C n=215
F0–3 + CTP A n=330
CTP B + C n=114
Any AE
208 (97)
316 (96)
109 (96)
633 (96)
Grade 3–4 AE
51 (24)
76 (23)
33 (29)
160 (24)
Serious AE
61 (28)
49 (15)
34 (30)
144 (22)
Serious treatment-related AE
5 (2)
10 (3)
4 (4)
19 (3)
AE leading to D/C of LDV/SOF
9 (4)
5 (4)
Death
10 (5)
4 (1)
6 (5)
20 (3)
Rejection episode 1
Graft loss 2
Liver transplantation 11
Treatment-related SAEs were mostly related to RBV treatment
Deaths and AEs that led to D/C of LDV/SOF were not attributed to study treatment
LDV/SOF+RBV was safe and well tolerated in decompensated cirrhosis and post-transplantation
Charlton M, et al. Gastroenterology2015;149:649-59; Reddy, AASLD, 2014, Oral #8; Manns, EASL, 2015,

17. Liver Function Change from Baseline to Follow-Up Week 4‡
SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients
Liver Function Change from Baseline to Follow-Up Week 4
MELD Score Change
Change in CTP Class
Pre/Post-Transplant (CTP B and C, n=136*)
Baseline CTP
A (5–6) n=73
B (7–9) n=100
C (10–12) n=54
Follow- up Week 4 CTP
A (5–6)
67 (96)
31 (35)
2 (5)
B (7–9)
3 (4)
57 (65)
20 (48)
C (10–12)
n=95
(-17)
Change in MELD Score
(-11)
(+8)
n=18
n=22
no assessment: CTP A, n=3; CTP B, n=12; CTP C, n=12
*Missing FU-4: n=24
Majority of patients showed improvements in MELD and CTP scores
Manns, EASL, 2015, GO2

18. DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1
Design: Multicenter, prospective, open-label, phase 3 study of daclatasvir plus sofosbuvir plus ribavirin in treatment-naïve and treatment-experienced patients with advanced cirrhosis or post-liver transplant HCV recurrence.
Setting: Five centers in United States
Entry Criteria - Treatment-naïve or treatment-experienced - Chronic HCV genotypes HCV RNA >10,000 IU/ml - Cirrhosis (compensated and decompensated) allowed - Post-liver transplant: received transplant ≥3 months prior to screening
Outcome Measure: Primary = SVR12
Poordad F, et al. Hepatology January 11. [Epub ahead of print]

19. ALLY-1: SVR12 Results for Advanced Cirrhosis Cohort by Genotype
DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1
ALLY-1: SVR12 Results for Advanced Cirrhosis Cohort by Genotype
50/60
26/34
11/11
4/5
5/6
4/4
0/0
Poordad F, et al. Hepatology January 11. [Epub ahead of print]

20. ALLY-1: SVR12 Results for Advanced Cirrhosis Cohort by CTP
DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1
ALLY-1: SVR12 Results for Advanced Cirrhosis Cohort by CTP
50/60
11/12
30/32
9/16
Poordad F, et al. Hepatology January 11. [Epub ahead of print]

21. ALLY-1: SVR12 Results for Post-Transplant Cohort by Genotype
DCV + SOF + RBV in Advanced cirrhosis and Post-Liver Transplant : ALLY-1
ALLY-1: SVR12 Results for Post-Transplant Cohort by Genotype
Conclusion: “The pan-genotypic combination of daclatasvir, sofosbuvir, and ribavirin was safe and well tolerated. High SVR rates across multiple HCV genotypes were achieved by patients with post-liver transplant recurrence or advanced cirrhosis.”
50/53
30/31
9/10
0/0
10/11
0/0
1/1
Poordad F, et al. Hepatology January 11. [Epub ahead of print]

22. Guidance for Decompensated Cirrhosis
KASL HCV Guidelines

23. Guidance for Recurrent HCV Post Liver Transplant
The is the summary of KASL guidelines for recurrent HCV after liver transplantation. Please pay attention to the changes that would come in the very near future.
KASL HCV Guidelines

24. Drug-Drug interactions between HCV DAAs and immunosuppresants
Drug Class
Drug
DDI With CNIs
Yes No
Protease inhibitors
Boceprevir ✔
Telaprevir
Simeprevir
CsA ✔
Tac ✔
ABT-450/RTV
Nucleoside
Sofosbuvir
Nonnucleoside
Dasabuvir
NS5A
Ledipasvir
Daclatasvir
Ombitasvir
✔ (in combo)
Finally I would like to emphasize the drug-drug interactions especially between the immune suppressant and DAA that you might be using. You can always look up the information from the websites.
(University of Liverpool)
Tischer S et al. J Hepatol 2014;60:

25. Drug-Drug interactions between HCV DAAs and lipid lowering drugs
EASL HCV Guidelines

26. Drug-Drug interactions between HCV DAAs and cardiovascular drugs
EASL HCV Guidelines

27. Summary and Key Messages
HCV eradication in advanced liver disease
Reduces decompensation
Does not prevent HCC
Prevents HCV recurrence post-transplant
IFN-based therapy is suboptimal in decompensated cirrhosis and post- transplantation
Lower SVR rate
Higher toxicity
Data with new DAAs evolving
Promise for IFN-free therapy pre- and post-transplant
High efficacy and significantly improved tolerability
As choices increase, the factors that are likely to influence treatment choices are
Drug-Drug interactions
Availability/Cost
Previous treatment experience (resistance)

28. Cure
Assessment
Testing
Treatment
Counseling
Screening
Thank you !