1. Hcv infection and management in advanced liver disease
Kimberly Brown, M.D.
Chief, Division of Gastroenterology and Hepatology
Henry Ford Hospital

2. Disclosures
Grants/Research Support: Merck, Vertex, Ikaria, Hyperion, Exelenz, Gilead, BMS, ABBVIE, Janssen
Consultant: Merck, BMS, Gilead, Janssen, ABBVIE
Speakers’ Bureau: Gilead, ABBVIE, Simply Speaking, HCV Viewpoints
Stock Shareholder: none
Boards: CLDF, CLD Journal
Other Financial or Material Support: none

3. Learning Objectives
Review epidemiologic trends of liver-related morbidity and mortality in chronic HCV infection
Discuss HCV-related management approaches for patients with advanced fibrosis and cirrhosis
Discuss HCV-related management approaches for patients who are candidates for liver transplantation

4. Advanced Liver Disease: Basic Principles
Hepatic fibrosis
Not reliably diagnosed by ultrasound or other imaging modalities
Liver fibrosis rates
Not predictable or linear
Progression from compensated cirrhosis to decompensated liver disease
Occurs in 5% of patients per year
Hepatocellular carcinoma
Develops in 1% to 2% of patients with hepatitis-related cirrhosis each year
Slide: Advanced Liver Disease: Basic Principles
Hepatic fibrosis is not reliably diagnosed by ultrasound or other imaging modalities.1
Liver fibrosis rates are not predictable or linear.1
Progression from compensated cirrhosis to decompensated liver disease occurs in 5% of patients per year.1
Hepatocellular carcinoma develops in 1% to 2% of patients with hepatitis-related cirrhosis each year.1
Reference
Sherman KE. Advanced liver disease: what every hepatitis C virus treater should know. Top Antivir Med. 2011;19:
Sherman KE. Top HIV Med. 2011;19:

5. Chronic HCV Infection: Natural History
Exposure
(Acute phase)
15%-45%
55%-85%
5%-30%
Over Years
Chronic
Cirrhosis
Resolved
Slide: Chronic HCV Infection: Natural History
This slide illustrates the natural history of HCV infection.
A small percentage of individuals will go on to spontaneous resolution—about 15%—whereas 85% develop chronic disease. Of this 85% who develop chronic disease, about 80%, (68% of all infected individuals), will have stable chronic hepatitis without significant progression over the next 20 years. By contrast, 20% of those who develop chronic disease (17% of all infected individuals) will develop cirrhosis over the next years. Of these cirrhotic patients, many will continue to progress slowly, and about 25% will rapidly develop hepatocellular carcinoma (HCC) or liver failure. Thus, liver cancer and liver failure occur in approximately 4% of patients who are exposed to HCV over a 20- to 25-year period.
Reference
Poynard T, Bedossa P, Opoion P, et al. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet. 1997;349:
Co-morbidities
Liver Decompensation (5%/year)
HCC (2%-8%/year)
Poynard T, et al. Lancet. 1997;349:

6. Progression of Fibrosis in Viral Hepatitis on Biopsy (Metavir)
No Fibrosis
Stage 1
Stage 2
Fibrous expansion of
some portal areas
Fibrous expansion of most portal areas with occasional portal to portal bridging
Stage 3
Stage 4
Slide: Progression of Fibrosis in Viral Hepatitis on Biopsy (Metavir)
This slide contains examples of the progression of fibrosis according to the Metavir system.1
Reference
Faria SC, Ganesan K, Mwangi I, et al. MR imaging of liver fibrosis: current state of the art. Radiographics. 2009;29:
Fibrous expansion of portal areas
with marked bridging (portal-to-portal and portal-to-central)
Cirrhosis
Cirrhotic
Liver
Faria SC, et al. Radiographics. 2009;29: Adapted from Everson GT.

7. FibroScan FibroScan (kPa) 8.8 9.6 14.6 F0-F1 F2 F3 F4 Liver Fibrosis
The probe induces an elastic wave through the liver
The velocity of the wave is evaluated in a region located from
2.5 to 6.5 cm below the skin surface
Diagnostic accuracy:
Significant fibrosis: 0.79
Advanced fibrosis: 0.91
Cirrhosis: 0.97
FibroScan (kPa)
Slide: FibroScan
The FibroScan is a noninvasive method based on transient elastography that is designed to measure liver stiffness. Ziol and colleagues evaluated the use of liver stiffness measurement (LSM) in HCV patients with liver fibrosis (n=327). Patients underwent liver biopsy and LB and LSM.1
LSM was well correlated with fibrosis stage (Kendall correlation coefficient: 0.55; P<0.0001).1
>F2: 0.79 ( ).
>F3: 0.91 ( ).
>F4: 0.97 ( ).
The optimal LSM cutoff values of 8.7 and 14.6 kPa showed >F2 and F4, respectively.1
Reference
Ziol M, Handra-Luca A, Kettaneh A, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patients with chronic hepatitis C. Hepatology. 2005;41:48-54.
8.8
9.6
14.6
F0-F1 F2 F3 F4
Liver Fibrosis
(METAVIR)
Ziol M, et al. Hepatology. 2005;41:48-54.

8. Projected Burden of Advanced Fibrosis Over the Next Decade
1990  77.6% F0/1; cirrhosis =5%
2010  41.8% F0/1; cirrhosis =25%
2020  cirrhosis = 37.2%
Davis GL, Gastroenterology. 2010;138:

9. Progressive Increase in Incidence of HCV-Related Cirrhosis and HCC in US
Annual Prevalence Rates Between 1996 and 2006 Among HCV-Infected Veterans
El-Serag HB. Gastroenterology 2012;142:1264–1273.

10. Natural History of HCV Cirrhosis
100 80 60 40 20
Compensated
Survival
probability
(%)
After 1st complication
Deaths
Liver-related (70%)
Other cause (30%) 1 2 3 4 5 6 7 8 9 10
Years after diagnosis
Adapted from Fattovich G et al. Gastroenterology. 1997;112:

11. By 2007, Deaths From HCV Surpassed Those From HIV
Change in Mortality Rates From 1999 to 2007 7 6 5 4 3 2 1
HIV
15,106
12,734
Hepatitis C
Rate per 100,000 People
Hepatitis B
1,815
1999
2000
2001
2002
2003
2004
2005
2006
2007
Year
Ly KN, et al. Ann Intern Med. 2012;156(4):

12. Risk Factors for Progressive Fibrosis and Cirrhosis
Persistently elevated ALT levels
Longer duration of infection
Alcohol excess (>50 g/day)
Age >40 years at time of infection
HIV or HBV coinfection
High BMI
Male gender
Presence of steatosis on biopsy
Slide: Risk Factors for Progressive Fibrosis and Cirrhosis
Risk factors associated with progressive fibrosis and cirrhosis include:1,2
Persistently elevated ALT levels.
Longer duration of infection.
Alcohol excess (>50 g/day)
>3 standard drinks defined as 12 fluid ounces of regular beer, 5 fluid ounces of wine, or 1.5 fluid ounces of distilled spirits (80 proof) and contains approximately 0.5 ounces (14 grams) of pure alcohol.
Age >40 years at time of infection.
HIV or HBV coinfection.
High BMI.
Male gender.
References
Poynard T, Bedossa P, Opoion P, et al. Natural history of liver fibrosis progression in patients with chronic hepatitis C. Lancet. 1997;349:
Kim WR, Poterucha JJ, Benson JT, et al. The impact of competing risks on the observed rate of chronic hepatitis C progression. Gastroenterology. 2004;127:
Poynard T, et al. Lancet. 1997;349:
Kim WR, et al. Gastroenterology. 2004;127:

13. Incremental All-Cause Costs
HCV Incremental All-Cause Health Care Costs by Liver Disease Severity (USD 2009)
27,845
(965)
No liver disease (n=26,977)
Compensated cirrhosis (n=1521)
Decompensated cirrhosis (n=4249)
15,464
(710)
Incremental All-Cause Costs
(per-patient-per-year)
Slide: HCV Incremental All Cause Health Care Costs by Liver Disease Severity (USD 2009)
Costs for these HCV cohorts were significantly higher than those of the matched comparison cohorts with a mean difference of $5,870, $5,330, and $27,845 PPPY for HCV without liver disease and HCV, compensated cirrhosis, and decompensated cirrhosis, respectively.
Reference
McAdam-Marx C, McGarry LJ, Hane CA, et al. : all-cause and incremental per patient per year cost associated with chronic hepatitis C Virus and associated liver complications in the United States: A managed care perspective. J Manag Care Pharm. 2012;17:
5879
(157)
5818
(292)
5330
(491)
4526
(213)
3102
(157)
2659
(41)
1721
(123)
1893
(123)
810
(49)
974
(194)
1081
(275)
641
(37) 93
(130)
Total Health
Care Costs
Inpatient
Outpatient
Physician
Services
Pharmacy
Costs
Place of Service
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:

14. HCV Can Now Be Cured in Most Patients
Unlike HIV and HBV infection, HCV infection is a curable disease
What does cure mean?
Sustained Viral Response
Undetectable HCV RNA 12 weeks after completion of antiviral therapy for chronic HCV infection
Long term morbidity and mortality benefits
Ghany MG, et al. Hepatology. 2009;49(4):

15. Treatment Goals HCV Infection Viral Eradication Delay Disease
Progression
Delay Time to
Decompensation
Prevent HCC?

16. SVR Was Associated With Reduced Long-Term Risk of All-Cause Mortality in an International, Multicenter Study
All-Cause Mortality
Percent
Time (years)
International, multicenter, long-term follow-up study from 5 large tertiary care hospitals in Europe and Canada. Patients with chronic HCV infection started an interferon-based treatment regimen between 1990 and 2003 (n=530).
van der Meer AJ, et al. JAMA. 2012;308:

17. SVR Reduced Risk of All-Cause Mortality in a Retrospective VA Study
Genotype 1
(n=12,166)
Genotype 2
(n=2904)
Genotype 3
(n=1794)
SVR rate: 35%
SVR rate: 72%
SVR rate: 62%
Cumulative Mortality (%)
Years
Years
Years
Retrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility ( ).
SVR=sustained virological response.
Backus LI, et al. Clin Gastroenterol Hepatol. 2011;9:

18. SVR Was Associated With Improved Long-Term Liver-Related Outcomes in the HALT-C Trial Database
Cumulative Incidence of Any Liver-Related Outcome Among Patients With Bridging Fibrosis or Cirrhosis
Percent
Analysis of liver outcomes (decompensation, HCC, or death) in the HALT-C trial database. All comparisons P<.0001.
*Detectable HCV RNA at treatment week 20 (combination therapy was discontinued at week 24). HALT-C=Hepatitis C Antiviral Long-Term Treatment against Cirrhosis. Morgan TR, et al. Hepatology. 2010;52:

19. Hepatocellular Carcinoma in HCV
Untreated
Interferon
0.6
0.5
Cumulative incidence
0.4
0.3
0.2
0.1 1 2 3 4 5 6 7 8 9 10
Years
Yoshida H et al. Ann Intern Med. 1999;131:178.

20. AASLD/IDSA Recommendations: HCV-Related Cirrhosis
Treatment-naive patients with compensated cirrhosis, including those with HCC
Should receive the same treatment as recommended for patients without cirrhosis
AASLD and IDSA. Available at: Version January 29, 2014.

21. CDC & USPSTF recommend 1-time testing of baby boomers (born 1945-1965)
HCV-Infected Persons in the US: Estimated Rates of Detection, Referral to Care and Cure
CDC & USPSTF recommend 1-time testing of baby boomers (born )
50%
X1000 persons
32-38%
20-23%
7-11%
5-6%
Infected Diagnosed Referred HCV RNA Treated ‘Cure’
to care test
Holmberg S, N Engl J Med 2013; 368: 1859

22. Barriers to Cure for Hepatitis C: Data From a Large Integrated Health System
Evaluate linkages between HCV screening and treatment
Calculate the “missed opportunity” at each transition of care
Analyze patient characteristics which may influence the “missed opportunity” at each transition of care
Brown et al, AASLD 2013

23. Brown et al, AASLD 2013 HCV Ab+ N=566 Death < 365 Days Testing N=39
Left System <
6 mo Testing
N=69
RNA
Screen?
N=458
No RNA Screen
N=87 (19%)
RNA Screen
N=371 (81%)
Negative RNA
N=63 (17%)
Positive RNA
N=308 (83%)
Brown KA. et al., AASLD 2013
Brown et al, AASLD 2013

24. with positive HCV-RNA were seen by Gastroenterology
HCV Ab+
(586 patients)
Death <
365 days testing
(39 patients)
Excluded
458
Left system <
6 mo testing
(69 patients)
RNA
Screen
No RNA
87 (19%)
RNA Screen
371 (81%)
Referral?
N=308
No Referral
N=125 (41%)
Self Referral
N=3 (1%)
Referred
N=180 (58%)
Gastro Visit?
N=183
Only 38% (117/308) of patients
with positive HCV-RNA were seen by Gastroenterology
No Visit
N=66 (36%)
Visit
N=117 (64%)
Brown KA. et al., AASLD 2013
Brown et al, AASLD 2013
RNA negative (3)
Substance Abuse (14)
No follow up (11)
Transplant evaluation (15)
Co-morbidities (23)
External follow up VA (3)
Waiting for new treatment (6)
Patient declined (12)
Previous treatment (9)
Treat-ment No
Treatment
96 (82%)
Treatment
21 (18%)
NoSVR
13 (62%)
SVR 8
(38%)

25. with positive HCV-RNA were treated
HCV Ab+
(586 patients)
Death <
365 days testing
(39 patients)
Excluded
458
Left system <
6 mo testing
(69 patients)
RNA
Screen
No RNA
87 (19%)
RNA Screen
371 (81%)
Negative RNA
63 (17%)
Positive RNA
308 (83%)
Referral
No Referral
125 (41%)
Self Referral
3 (1%)
Referred
180 (58%)
Treatment Decision
N=117
Only 6.8% (21/308) of patients
with positive HCV-RNA were treated
Only 2.6% (8/308) SVR No
Treatment*
N=96 (82%)
Treatment
N=21 (18%)
No SVR
N=13 (62%)
SVR
N=8
(38%)
*Reasons for No Treatment: RNA negative (3); substance abuse (14); no follow up (11); transplant evaluation (15); co-morbidities (23); external follow up VA (3); waiting for new treatment (6); patient declined (12); previous treatment (9)
Brown KA. et al., AASLD 2013
Brown et al, AASLD 2013

26. HCV treatment considerations in advanced fibrosis and cirrhosis

27. 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
SVR12
Telaprevir: 40% (range: 29%-53%)
Boceprevir: 41% (range: 11%-51%)
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%
Factors Associated With
Death and Severe Complications (n=62)
Adjusted
Odds Ratio
Platelet <100,000/mm3
3.1 (P=0.0105)
Serum albumin <35 g/dL
6.33 (P=0.0001)
Slide: French National Early Access Program: Interim Analysis of the CUPIC Cohort (Genotype 1)
The French National Early Access Program is a prospective cohort of HCV genotype 1 patients with compensated cirrhosis who had a prior relapse or prior partial responders to PR. The overall SVR rates with telaprevir- and boceprevir-based triple therapy were 40% (range: 29% to 53%) and 41% (range: 11%-51%), respectively.1-3
SVR12 predictors included those who had a prior partial response to PR (versus relapse) and genotype 1b (versus 1a).
This cohort found a high incidence of serious adverse events (40%), discontinuations (47%) and early treatment discontinuation (21.3%). There was also a high incidence of death (2.0%), anemia (<9.0 g/dL) (29.4%), and hepatic decompensation (2.4%).1-3
Death or severe complications were related to platelets count <100,000/mm3 (Odds ratio: 3.11; P=0.0105) and albumin <35 g/dL (Odds ratio: 6.33; P=0.0001), with a risk of 44.1% in patients with both.3
References
Fontaine H, Hezode C, Dorival C, et al. SVR12 rates and safety of triple therapy including telaprevir or boceprevir in 455 cirrhotic non responders treated in the French early access program (ANRS CO2O-CUPRIC). J. Hepatol. 2013;58(suppl 1): S27. Abstract 60.
Hezode C, Dorival C, Zoulim F, et al. Safety and efficacy of telaprevir or boceprevir in combination with peginterferon alfa/ribavirin, in 455 cirrhotic non responders. Week 16 analysis of the French early access program (ANRS CO2O-CUPRIC) in real-life setting. Hepatology. 2012;56(suppl 4):217A-218A. Abstract 51.
Hézode C, Fontaine H, Dorival C, et al. Triple therapy in treatment-experienced patients with HCV-cirrhosis in a multicentre cohort of the French Early Access Programme (ANRS CO20-CUPIC) - NCT J Hepatol. 2013;59:
Risk of Death or Severe Complications (%)
Platelets (/mm3)
>100,000
<100,000
Albumin (g/dL)
>35 (n=298/69)
3.4
4.3
<35 (n=28/34)
7.1
44.1
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:

28. Sofosbuvir + RBV + PegIFN: SVR12 by Fibrosis Stage (Genotypes 1-6)
Retrospective analysis of 4 phase 3 clinical trials
Baseline fibrosis stage by FibroTest/FibroSure
F0-F2 (55%), F3 (17%), F4 (28%)
General decline in SVR with advancing fibrosis
SVR12 rates among patients with thrombocytopenia (platelets <125/mm3) were similar to rates in cirrhotic patients across all HCV genotypes
Slide: Sofosbuvir + RBV + PegIFN: SVR12 by Fibrosis Stage (Genotypes 1-6)
Patel and colleagues conducted a retrospective analysis of SVR12 rates and safety data across four phase 3 clinical trials (FISSION, POSITRON, FUSION, and NEUTRINO) by degree of liver fibrosis (F0-F4) and extent of thrombocytopenia.1
The SVR12 rates among patients with thrombocytopenia (platelets <125/mm3) were similar to rates in cirrhotic patients across all HCV genotypes. Data by fibrosis will be shown in the next slides.1
Reference
Patel K, Gordon SC, Sheikh AM, et al. Efficacy and safety of sofosbuvir in patients according to fibrosis stage: an analysis of phase 3 data. Hepatology. 2013;58(suppl 1):738A-739A. Abstract 1093.
Patel K, et al. Hepatology. 2013;58(suppl 1):738A-739A. Abstract 1093.

29. Sofosbuvir + RBV + PegIFN (Multiple Genotypes): SVR12 by Baseline Fibrosis Stage (FibroTest)
Sofosbuvir + RBV (FUSION)
(16 weeks, treatment-experienced)
Sofosbuvir + PR (NEUTRINO)
(12 weeks, treatment-naïve)
Genotype Genotype 3
Genotypes 1, 4-6
100%
100%
97%
96%
89%
85%
80%
80%
79%
67%
63%
Slide: Sofosbuvir + RBV + PegIFN (Multiple Genotypes): SVR12 by Baseline Fibrosis Stage (FibroTest)
A similar trend was observed among HCV patients receiving sofosbuvir + RBV for 16 weeks or sofosbuvir + PR for 12 weeks. SVR12 rates tended to be lower among those with cirrhosis at baseline, especially in patients who were HCV genotype 3.1
Reference
Patel K, Gordon SC, Sheikh AM, et al. Efficacy and safety of sofosbuvir in patients according to fibrosis stage: an analysis of phase 3 data. Hepatology. 2013;58(suppl 1):738A-739A. Abstract 1093.
Patients (%)
Patients (%)
40% F0
(n=4/5)
F1-F2
(n=14/21) F3
(n=5/10) F4
(n=9/27) F0
(n=78)
F1-F2
(n=105) F3
(n=54) F4
(n=86)
PR: pegIFN + RBV.
Patel K, et al. Hepatology. 2013;58(suppl 1):738A-739A. Abstract 1093.

30. COSMOS Subgroup Analysis: HCV Genotype 1, METAVIR F3-F4
Phase 2a
Open-label
Genotype 1
Prior PR null responder
or treatment-naïve
METAVIR F3-F4
No BMI limit
<70 years of age
Simeprevir + Sofosbuvir qd (n=14)
Simeprevir + Sofosbuvir qd
+ RBV (n=27)
Simeprevir + Sofosbuvir qd (n=16)
Simeprevir + Sofosbuvir qd + RBV (n=30)
Slide: COSMOS Subgroup Analysis: HCV Genotype 1, METAVIR F3-F4
COSMOS was an open-label, phase 2a study of 12- or 24-weeks of simeprevir (150 mg qd) and sofosbuvir (400 mg qd) in prior PR null responders with genotype 1. The analysis by Lawitz and colleagues focused on patients who had cirrhosis (F3-F4) at baseline.1
Reference
Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype 1 prior null-responder/treatment-naïve patients (COSMOS study): primary endpoint (SVR12) results in patients with metavir F3–4 (cohort 2). J Hepatol. 2014;60(suppl 1):S524. Abstract O165.
Week
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor); simeprevir 150 mg (NS3/4A Inhibitor).
Weight-based ribavirin dosing ( mg).
Baseline demographics and disease characteristics:
Male: 67%; age: 58 years; black: 9%.
Genotype 1a: 78%.
Genotype 1a with Q80K: 40%.
IL28B non-CC: 79%.
Cirrhosis: 47%.
HCV RNA (log10 IU/mL): 6.6.
Prior PR null responders: 54%.
Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.

31. COSMOS Subgroup Analysis: SVR12 in HCV Genotype 1, METAVIR F3-F4
SVR12 by HCV Subtype
Simeprevir + sofosbuvir
No RBV With RBV
Simeprevir + sofosbuvir + RBV
100%
100%
98%
95%
96%
95%
93%
93%
93%
94%
SVR12 (%)
1.1% Discontinuation
SVR12 (%)
Slide: COSMOS Subgroup Analysis: SVR12 in HCV Genotype 1, METAVIR F3-F4
SVR12 rates were high (93%-96%) among the 12- and 24-week arms regardless of RBV use. The presence of Q80K and IL28B TT genotype did not appear to negatively impact SVR12 rates.1
Reference
Lawitz E, Ghalib R, Rodriguez-Torres M, et al. Simeprevir plus sofosbuvir with/without ribavirin in HCV genotype 1 prior null-responder/treatment-naïve patients (COSMOS study): primary endpoint (SVR12) results in patients with metavir F3–4 (cohort 2). J Hepatol. 2014;60(suppl 1):S524. Abstract O165.
12 Weeks
(n=14/27)
24 Weeks
(n=16/30) 1b 1a
1a +
Q80K CC CT TT
IL28B Genotype
(n=17/48/19)
Genotype
(n=18/40/26)
Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.

32. LDV/SOF Phase 2 and 3 Program
An Integrated Safety and Efficacy Analysis of >500 Patients with compensated
Cirrhosis Treated with Ledipasvir/Sofosbuvir with or without Ribavirin
Wk 0
Wk 12
Wk 36
Wk 24
SVR12
LDV/SOF
LDV/SOF + RBV
n=118
n=204
n=133
n=58
The next study we would like to highlight is also being presented by Dr. Bourliere, on Sunday.
this is a retrospective, pooled analysis of 513 patients with compeansted cirrhosis.
513 patients with HCV GT 1, compensated cirrhosis
Pooled data from Phase 2 and 3 LDV/SOF ± RBV studies
LONESTAR, ELECTRON, ELECTRON-2, (Japan), ION-1, ION- 2, SIRIUS
Primary efficacy endpoint: SVR12
Bourliere et al, AASLD 2014

33. SVR12 Overall and by Treatment Duration
LDV/SOF Phase 2 and 3 Program: Cirrhotic Subjects
SVR12 (%)
493/513
305/322
188/191
Overall
12 Weeks
24 Weeks
Out of 513 patients, 20 failed to achieve SVR12
18 Relapsed
1 LTFU, 1 Death (presumed infection)
Bourliere et al, AASLD 2014
Error bars represent 95% confidence intervals.

34. Treatment Experienced
SVR12 by Regimen and Duration LDV/SOF Phase 2 and 3 Program: Cirrhotic Subjects
Total
Treatment Naïve
Treatment Experienced
Overall SVR12
Duration
12 wk
24 wk
Regimen
LDV/SOF
LDV/SOF + RBV
Duration/± RBV
LDV/SOF 12 wk
LDV/SOF + RBV 12 wk
LDV/SOF 24 wk
LDV/SOF + RBV 24 wk
96%
98%
95%
95%
97%
94%
98%
99%
98%
95%
96%
95%
97%
99%
96%
-The SVR among TE cirrhotic patients treated for 12 weeks was 90%
-But when RBV was added or treatment duration extended to 24 weeks, SVR rates of % were observed.
92%
96%
90%
96%
98%
96%
98%
97%
98%
100%
100%
100%
SVR12, %
Bourliere et al, AASLD 2014

35. ‡
Relapse Among Cirrhotic Subjects LDV/SOF Phase 2 and 3 Program: Cirrhotic Subjects
513
failed
SVR12
493
(96.1%) 20
(3.9%)
LTFU;Death
relapse 2 18
Plts ≥ 75
Plts < 75 13 5
Of the 513 patients evaluated, only 20 failed to achieve a SVR
Of these 20, 1 patient died on treatment, and 1 patient was lost to follow up after a single visit
This leaves 18 patients out of 513 who were true relapsers.
Of these, 5, had a platelet count of less than 75, and 4 of these were treated with LDV/SOF for 12 weeks –
In this group, the Relapse rate was 27% -- which contrasts with the 2-5% relapse rate observed in all other groups.
FDC 12
Other
FDC 12
Other 4
102 9
373 4 15 1 22 4%
(1.1%-9.7%) 2%
(1.1%-4.5%)
27%
(7.8%-55.1%) 5%
(0.1%-22.8%)
FDC 12 = LDV/SOF for 12 weeks
Other = LDV/SOF + RBV for 12 weeks or LDV/SOF for 24 weeks
LTFU = Lost to Follow Up (n=1)
Bourliere et al, AASLD 2014

36. SIRIUS Study Double-blinded
0 wk
12 wk
24 wk
36 wk
LDV/SOF + RBV
Placebo
SVR12
LDV/SOF + Placebo RBV
SVR12
The Goal of the SIRIUS study, which is the brainchild of Dr. Bourliere,
was to take “CUPIC-like failures”, cirrhotic patients who had failed PEG-RBV, and then a PI+PEG+RBV, and treat them with one of two regimens:
LDV SOF + RBV for 12 weeks, or LDV/SOF for 24 weeks.
Double-blinded
Treatment-experienced patients with compensated cirrhosis who did not achieve SVR following sequential PEG + RBV and PI + PEG + RBV regimens
Bourliere et al, AASLD 2014

37. Demographics SIRIUS (GS-US-337-0121)
Placebo 12 Weeks → LDV/SOF+RBV 12 Weeks n=77
LDV/SOF + Placebo RBV 24 Weeks n=78
Total N=155
Mean age, y (range)
56 (39–74)
57 (23–77)
56 (23–77)
Male, n (%)
58 (75)
56 (72)
114 (74)
White, n (%)
76 (99)
75 (96)
151 (97)
Mean BMI, kg/m2 (range)
28 (20–47)
26 (19–40)
27 (19–47)
IL28B non-CC, n (%)
73 (95)
72 (92)
145 (94)
Varices, n (%)
16 (21)
25 (32)
41 (26)
Mean platelets (range)
153 (54–316)
141 (59–278)
147 (54–316)
Platelets <100 x 103 /µL
14 (18)
13 (17)
27 (17)
Mean albumin g/dL
3.9 (3.2–4.6)
3.9 (3.0–4.9)
Albumin <3.5 g/dL, n (%)
6 (8)
14 (17)
20 (13)
155 TE patients with compensated cirrhosis were enrolled in this study – consistent with their compensated status, the mean platelet count was around 150, and the mean albumin was around 4.
Bourliere et al, AASLD 2014

38. Disposition SIRIUS (GS-US-337-0121)
Randomized N=155
Placebo 12 wk n=78
D/C treatment
due to AE (n=1)
LDV/SOF + RBV 12 Wk n=77
LDV/SOF 24 Wk n=77*
Of note, 1 subject discontinued therapy due to septic arthritis, while on placebo, and has been excluded from the efficacy analysis.
Completed study treatment
n=77
Completed study treatment
n=77
Completed follow-up wk 12 n=77
Completed follow-up wk 12 n=77
*1 patient was randomized to receive placebo 12 weeks then LDV/SOF+RBV for 12 weeks but received LDV/SOF for 24 weeks. Efficacy is assessed as ITT; for demographics and safety, they are analyzed according to treatment received.
Bourliere et al, AASLD 2014

39. SVR12 SIRIUS (GS-US-337-0121) LDV/SOF+RBV 12 Weeks LDV/SOF 24 Weeks
The SVR12 results are shown here; with 96 and 97% of patients achieving a sustained virologic response in the two arms. in total,
74/77
75/77
LDV/SOF+RBV 12 Weeks
LDV/SOF 24 Weeks
Error bars represent 95% confidence intervals.
Bourliere et al, AASLD 2014

40. Adverse Events ≥15% SIRIUS (GS-US-337-0121)
Preferred term, n (%)
Placebo 12 Wk → LDV/SOF + RBV 12 Wk
LDV/SOF 24 Wk
Placebo 12 Wk
n=77
LDV/SOF +RBV 12 Wk
n=76
Overall Period n=77
First 12 Wk
n=78
Overall Period n=78
Asthenia
24 (31)
29 (38)
45 (58)
28 (36)
35 (45)
Headache
16 (21)
13 (17)
21 (27)
27 (35)
31 (40)
Pruritus
14 (18)
11 (14)
22 (29)
4 (5)
7 (9)
Insomnia
9 (12)
17 (22)
Nausea
8 (10)
8 (11)
Fatigue
3 (4)
5 (7)
7(9)
15 (19)
Dry skin
6 (8)
12 (16)
Arthralgia
5 (6)
12 (15)
Bronchitis
1 (1)
Two adverse events occurred more frequently with LDV/SOF than Placebo – Headache and Fatigue
Most AEs mild or moderate in severity
Bourliere et al, AASLD 2014

41. HCV infection before liver transplantation: Treatment of decompensated patients strategies to prevent recurrence of hcv post liver transplant

42. 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)
Preferred Regimen
Any Genotype
Sofosbuvir + RBV for up to 48 weeks
(consider creatinine clearance and hemoglobin)
Slide: AASLD and IDSA Recommendations: HCV-Related Cirrhosis
This slide lists the AASLD/IDSA HCV regimens for patients with HCV-related cirrhosis.1
Reference
AASLD and IDSA. Recommendations for testing, managing, and treating hepatitis C. Available at: Version January 29, 2014.
Regimens Not Recommended
Any Genotype
Any IFN-based therapy
Monotherapy with pegIFN, RBV, or a DAA
Telaprevir-, boceprevir-, or simeprevir-based regimens
AASLD and IDSA. Available at: Version January 29, 2014.

43. Antiviral Therapy Before Liver Transplantation
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
Expectations???
Slide: Antiviral Therapy Before Liver Transplantation for HCV-Infected Recipients With Advanced Fibrosis and Cirrhosis
The use of anti-viral HCV therapy in patients with advanced liver disease is problematic, with poor tolerance, increased side effects including risk hepatic decompensation and less sensitivity to interferon resulting in suboptimal SVR rates.1-5
Treatment for these groups of patients requires significant oversight and input and should only be undertaken in experienced transplant centers.1-5
References
Agarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis. 2013;45(suppl 5):S349-S354.
Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. New Engl J Med. 2002;347:
Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:
Hadziyannis SJ, Sette Jr H, Morgan TR, et al. Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose. Ann Intern Med. 2004;140:
Bruno S, Shiffman ML, Roberts SK, et al. Efficacy and safety of peginterferon alfa-2a (40 KD) plus ribavirin in hepatitis C patients with advanced fibrosis and cirrhosis. Hepatology. 2010;51:
Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.
Fried MW, et al. N Engl J Med. 2002;347:
Manns MP, et al. Lancet. 2001;358:
Hadziyannis SJ, et al. Ann Intern Med. 2004;140:
Bruno S, et al. Hepatology. 2010;51:

44. Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation
Open-Label
Genotypes 1-4
Treatment-naïve and
experienced
Compensated cirrhosis
(Child-Pugh 5-6, A)
Decompensated cirrhosis
(Child-Pugh 7-9, B)
Esophageal or gastric varices
Hepatic venous gradient
(HVPG): >6 mm Hg)
Sofosbuvir qd + RBV
(n=25)
Observation
(n=25)
Sofosbuvir qd + RBV
Week
Current Analysis
Slide: Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation
Afdhal and colleagues conducted an open-label study to evaluate the safety and efficacy of 48 weeks of sofosbuvir and RBV in patients with HCV cirrhosis and portal hypertension (CTP 5–10).1
Outcomes included on-treatment virologic response, safety, and change in CTP, MELD, and HVPG. Rapid virologic response at treatment weeks 4 (RVR4) and 8 (RVR8) were defined by HCV RNA <25 IU/mL.1
Reference
Afdhal N, Everson G, Calleja JL, 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. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + RBV ( mg).
HVPG at day 0 and 48 in the sofosbuvir-treated patients.
Baseline demographics and disease characteristics:
Male: 72%-80%; age: years; white: 84%-96%, treatment-naive: 68%-92% .
Genotype 1a, 1b, 2, 3, 4: 36%-40%, 24%-36%, 4%-8%, 8%-32%, 4%-8%.
IL28B non-CC: 72%-88%.
HVPG >12 mm Hg: 76%-80%.
CTP score 5-6, 7-9: 36%-44%, 56%-60%.
MELD <10, 10-15: 32%, 56%-60%.
Albumin: g/dL; platelets: x103.
ALT, AST: , U/mL.
Ascites: 24%-36%.
Encephalopathy 8%-20%.
Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.

45. Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation
High rates of virologic suppression irrespective of severity of liver disease
Decreased necroinflammation with ALT normalization
Improvements
Platelet count and albumin
Ascites and hepatic encephalopathy
Low rates of treatment discontinuation due to adverse events (4%)
Outcomes at Week 24
Sofosbuvir
+ RBV
(n=25)
Observation
HCV RNA <LLOQ (%)
CTP A (n=7)
CTP B (n=15)
100 90 --
Change
Platelets (103/µL)
CTP A
CTP B
Albumin (g/dL)
Bilirubin (mg/dL)
ALT (U/L) 17 1
0.5
0.4
-0.2
-72
-75 -9 -1
-0.1
0.2 13
Slide: Sofosbuvir + RBV: Cirrhosis and Portal Hypertension + Decompensation
High rates of virologic suppression were achieved with 48 weeks of sofosbuvir + RBV irrespective of severity of liver disease (90%-100%). There was also a decrease in necroinflammation markers and ALT normalization. Other improvements were seen with platelet count, serum albumin, ascites, and hepatic encephalopathy.1
Overall, there was a low rate of treatment discontinuation due to adverse events (4%).1
Reference
Afdhal N, Everson G, Calleja JL, 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. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.
Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.

46. SOLAR-1 (Decompensated Cirrhosis) GT 1 and 4, CPT Class B and C
LDV/SOF + RBV
Wk 0
Wk 12
Wk 24
SVR12
Wk 36
108 patients randomized 1:1 to 12 or 24 Weeks of Treatment
Broad inclusion criteria
Total bilirubin ≤10 mg/dL, Hemoglobin ≥ 10 g/dL
CLcr ≥ 40 mL/min, platelets > 30,000 x 103/µL,
CPT ≤ 12
Stratified by CPT score B or C
With this picture in mind, We’d like to turn to patients with decompensated cirrhosis.
These patients are being evaluated in the first cohort of SOLAR-1.
And will be discussed by Dr. Flamm on Tuesday.
All patients received LDV/SOF+RBV – for either 12 or 24 weeks.
Both CPT B and C patients were included
However CPT C patients with a score of were excluded due to their high near term mortality.
Flamm, et al, AASLD 2014

47. Baseline Disease Characteristics GT 1 and 4, CPT Class B and C
CPT B
CPT C
12 Weeks
n=30
24 Weeks
n=29
n=23
n=26
MELD score, n (%)
<10
6 (20)
8 (28)
10‒15
21 (70)
16 (55)
16 (70)
13 (50)
16-20
3 (10)
5 (17)
7 (30)
12 (46)
21-25
1 (4)
Ascites, n (%)
17 (57)
17 (59)
22 (96)
25 (96)
Encephalopathy, n (%)
20 (67)
21 (91)
23 (88)
Median bilirubin, mg/dL (range)
2.0 ( )
1.4 ( )
2.9 ( )
3.8 ( )
Median albumin, g/dL (range)
2.9 ( )
3.0 ( )
2.6 ( )
2.6 ( )
Median INR, (range)
1.3 ( )
1.3 ( )
1.4 ( )
1.4 ( )
Median platelets, x 103/µL (range)
88 (36-212)
73 (30-154)
81 (39-177)
71 (32-179)
Consistent with a cohort of subjects with decompensated cirrhoris:
The prevalence of ascites or encephalopathy at baseline was high in CPT B patients, and nearly universal for CPT C patients.
Flamm, et al, AASLD 2014

48. SVR12 GT 1 and 4, CPT Class B and C
LDV/SOF + RBV 12 Weeks
LDV/SOF + RBV 24 Weeks
SVR12 (%)
Overall, almost 90% of subjects with decompensated disease achieved a SVR
Being treated for 12 versus 24 weeks did not appear to impact SVR12 rates
Similar SVR12 rates were observed between CPT B and CPT C subjects.
3 relapses
1 death
1 relapse
2 deaths
2 death
1 LTFU
1 relapse
1 death
45/52
42/47
26/30
24/27
19/22
18/20
Overall
CPT B
CPT 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. .
Flamm, et al, AASLD 2014

49. Change in MELD Score Baseline Through Follow-up Week 4 GT 1 and 4, CPT Class B and C
CPT B
CPT C
12 wk (n=30)*
24 wk (n=29)*
12 wk (n=23)*
24 wk (n=26)*
(+10)
n=5
n=5
n=2
n=3
Virologic Supression was also associated with an improvement in MELD score.
Seen here is a waterfall plot, where each bar represents a difference patient and their change in MELD score.
Patients with increased MELD scores were not enriched with relapsers
Patient who increased by 10 was due to an AE of increased INR – up to 3.2
Flamm, et al, AASLD 2014
*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.
(-8)

50. Safety Summary GT 1 and 4, CPT Class B and C
CPT B
CPT C
Patients, n (%)
12 Weeks
n=30
24 Weeks
n=29
n=23
n=26
Overall Safety AE
29 (97)
27 (93)
23 (100)
26 (100)
Grade 3‒4 AE
2 (7)
8 (28)
6 (26)
11 (42)
Serious AE
3 (10)
10 (34)
6 (26)
Serious and related AEs
2 (8)
Treatment DC due to AE
1 (3)
Death
2 (9)
1 (4)
With respect to Safety,
There were few treatment realted SAEs,
Related SAEs: Anemia (2), Hepatic Encephalopathy, Peritoneal Hemorrhage
Flamm, et al, AASLD 2014

51. Cumulative HCC by Age Group
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
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
Cumulative HCC by Age Group
Age Group
<45 years
45 to 60 years
>60 years
12.2%
9.7%
P=0.006
Rate (%)
Slide: Risk of HCC Remains After SVR in HCV Patients With Advanced Hepatic Fibrosis
Van der Meer and colleagues conducted a meta-analysis of 10 cohorts using individual patient data (n=1000) to assess SVR rates with IFN-based therapy. Patients had bridging fibrosis or cirrhosis without HIV or HBV coinfection.1
There were a total of 51 events of HCC over 5.1 years of follow-up post achievement of an SVR with IFN-based therapy. These data illustrated the concern that patients with HCV-induced cirrhosis who achieve SVR remain at risk for HCC. This risk increased with age, severity of liver disease, and presence of diabetes mellitus.1
Reference
Van der Meer AJ, Feld JJ, Hafer H, et al. The risk for hepatocellular carcinoma among patients with chronic HCV infection and advanced hepatic fibrosis following sustained virological response. Hepatology. 2013;58(suppl 1):280A. Abstract 143.
2.6%
Years After SVR
van der Meer AJ, et al. Hepatology. 2013;58(suppl 1):280A. Abstract 143.

52. 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
Randomized to either pegIFN + RBV (LADR) or control (untreated)
Primary endpoint
Post-transplant HCV RNA undetectable at week 12
Baseline Characteristics
Treatment
(n=63)
Control
(n=16)
Male (%) 73 81
Age (years) 56
Genotype (%)
1/4 or 6
2/3
47/4
24/25
88/12
0/0
HCV RNA (log10 IU/mL)
5.7
HCC upgrade (%) 54 94
MELD
12.0
CPT score
7.0
6.3
Hemoglobin (g/dL)
13.1
13.5
ANC (/µL)
794
531
Platelets (x103/µL) 92 93
Previous IFN treatment (%)
Slide: Adult-to-Adult Living Donor Liver Transplant Cohort Study (A2ALL)
The Adult-to-Adult Living Donor Liver Transplantation Cohort Study is the most recent trial evaluating standard-duration interferon-based therapy pre-transplantation.1
This study included patients who had been listed for either living donation or HCC with MELD exception, underwent treatment with a standard duration PR and were compared to untreated controls.
Exclusion criteria included prior null responders, creatinine (>2.2 mg/dL); hemoglobin (<10 g/dL); ANC (<750/µL); and platelets (<35K/µL).
The primary endpoint was post-transplant HCV RNA undetectable at week 12.
Reference
Everson GT, Terrault NA, Lok AS, et al. Adult-to-Adult Living Donor Liver Transplantation Cohort Study. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis c after liver transplantation. Hepatology. 2013;57:
PR: pegIFN + RBV; LADR: low accelerating dose regimen.
Everson GT, et al. Hepatology. 2013;57:

53. A2ALL Study: Virologic Response With PR
by Genotype
Virologic Response
by Treatment Duration
HCV RNA Undetectable
At liver transplantation
Week 12 post-transplant
HCV RNA Undetectable
At liver transplantation
Week 12 post-transplant
67%
68%
64%
59%
52%
50%
Treated Patients (%)
Treated Patients (%)
Slide: Adult-to-Adult Living Donor Liver Transplant Cohort Study (A2ALL)
A total of 57 patients underwent transplantation (44 treated and 13 controls).
59% and 25% of treated patients had undetectable HCV RNA at the time of transplant and at post-transplant week 12, respectively.
Treatment response increased with increasing duration of therapy pre-transplant.
Reference
Everson GT, Terrault NA, Lok AS, et al. Adult-to-Adult Living Donor Liver Transplantation Cohort Study. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis c after liver transplantation. Hepatology. 2013;57:
29%
25%
25%
22%
18% 0%
Overall
(n=44)
1, 4, 6
(n=23)
2, 3
(n=21)
<8
(n=8)
8 to 16
(n=22)
>16
(n=14)
HCV Genotype
PegIFN + RBV Duration (Weeks)
Per protocol analysis. PR: pegIFN + RBV.
Everson GT, et al. Hepatology. 2013;57:

54. HCV Treatment Before Liver Transplantation in Patients With Decompensated CirrhosisG1
(%)
Child-Pugh
Treatment
EOTR
G1/non-G1 (%)
SVR
HCV RNA Negative
Post Transplant (%)
Crippin 2002
(pilot study; n=15) 73
11.9
IFN + RBV 33
(overall) NA
Thomas 2003
(single cohort; n=20) 67
10.0
IFN 60 20
Everson 2005
(single cohort; n=124) 70
7.4
(LADR)
30/82
13/50 26
Forns 2003
(single cohort; n=30)
A (50%);
B (43%); C (7%) 30
Carrion 2009
(case controlled; n=51) 80
A (45%);
B (43%); C (4%) PR
20/100
Everson 2013
(randomized,
controlled; n=79) 56
7.0
41/53 25
Slide: HCV Treatment Before Liver Transplantation in Patients With Decompensated Cirrhosis
This slide summarizes the key studies in the use of standard-duration interferon-based therapy administered pre-transplantation to prevent HCV recurrence post-transplantation.1-6
References
Crippin JS, McCashland T, Terrault N, et al. A pilot study of the tolerability and efficacy of antiviral therapy in hepatitis C virus-infected patients awaiting liver transplantation. Liver Transpl. 2002;8:
Thomas RM, Brems JJ, Guzman-Hartman G, et al. Infection with chronic hepatitis C virus and liver transplantation: a role for interferon therapy before transplantation. Liver Transpl. 2003;9:
Everson GT, Trotter J, Forman L, et al. Treatment of advanced hepatitis C with a low accelerating dosage regimen of antiviral therapy. Hepatology. 2005;42:
Forns X, Garcia-Retortillo M, Serrano T, et al. Antiviral therapy of patients with decompensated cirrhosis to prevent recurrence of hepatitis C after liver transplantation. J Hepatol. 2003;39:
Carrion JA, Martinez-Bauer E, Crespo G, et al. Antiviral therapy increases the risk of bacterial infections in HCV-infected cirrhotic patients awaiting liver transplantation: a retrospective study. J Hepatol. 2009;50:
Everson GT, Terrault NA, Lok AS, et al. Adult-to-Adult Living Donor Liver Transplantation Cohort Study. A randomized controlled trial of pretransplant antiviral therapy to prevent recurrence of hepatitis c after liver transplantation. Hepatology. 2013;57:
G: genotype; EOTR: end-of-treatment response (HCV RVA undetectable); PR: peg IFN + RBV; LADR: low accelerating dose regimen.
Crippin JS, et al. Liver Transpl. 2002;8: ; Thomas RM, et al. Liver Transpl. 2003;9: ;
Everson GT, et al. Hepatology. 2005;42: ; Forns X, et al. J Hepatol. 2003;39: ;
Carrion JA, et al. J Hepatol. 2009;50: ; Everson GT, et al. Hepatology. 2013;57:

55. 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 ( mg) pre-transplant
Baseline Characteristics
Treatment
(n=61)
Male (%) 80
Age (years) 59
BMI <30 kg/m2 (%) 43
Genotype (%)
1a/1b
2/3 4
39/34
13/12
HCV RNA >6 log10 IU/mL (%) 41
IL28 B non-CC (%) 78
MELD 8
CPT score 5-7 (%)
95%
Prior HCV treatment (%) 75
Slide: Pre-Liver Transplant Sofosbuvir + RBV: Prevention of Recurrent HCV
Curry and colleagues conducted an open-label, phase 2 study to assess the efficacy and safety of up to 48 weeks of sofosbuvir 400 mg qd + RBV in patients with chronic HCV infection of any genotype listed for liver transplantation due to hepatocellular carcinoma (Milan criteria and well compensated cirrhosis [Child-Pugh-Turcotte score of <7).1
The primary endpoint was HCV RNA <25 IU/mL 12 weeks after liver transplantation.
The post-liver transplantation immunosuppressive regimen was tacrolimus plus prednisone with or without mycophenolate mofetil.
Reference
Curry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.

56. 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)
HCV RNA Undetectable
93%
91%
64%
Patients (%)
Slide: 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) included days continuously TND prior to transplantation: 1.04 (1.01, 1.08; P=0.0007).1
Reference
Curry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
Overall
(n=44)
>12 Weeks
Treatment
(n=33)
Post-
Transplant
Week 12
(n=39)
At Transplant
TND: target not detected.
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.

57. Individual Patient Data HCV RNA Continuously TND (Days)
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)
Days Continuously TND Before Liver Transplant and Preventing HCV Recurrence
HCV recurrence (n=10)
No HCV recurrence (n=28)
>30 days TND
Individual Patient Data
Slide: Pre-Liver Transplant Sofosbuvir + RBV: Target Not Detected and Safety in Genotypes 1-4
The days of continuously target not detect prior to transplant was predictive of HCV recurrence. No HCV recurrence occurred in patients who had a median of 95 continuous days of TND prior to transplant.1
Overall, sofosbuvir + RBV was generally well tolerated, with only discontinuations due to adverse events in 3% (none related to sofosbuvir). Selected incidence of adverse events included fatigue (38%), anemia (23%), headache (23%), nausea (16%), and rash (15%).1
Reference
Curry MP, Forns X, Chung RT, et al. Pretransplant sofosbuvir and ribavirin to prevent recurrence of HCV infection after liver transplantation. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
HCV RNA Continuously TND (Days)
TND: target not detected.
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.

58. HCV Treatment Considerations for Transplant Recipients
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
Child’s C cirrhotics
Risks usually outweigh benefits
Transplantation evaluation
Complete before initiating HCV treatment begins (in case patient should decompensate)
Slide: HCV Treatment Considerations for Transplant Recipients
The use of low-accelerating dose regimen can yield sustained virologic responses in select HCV patients with cirrhosis and who had a decompensating event. Achievement of a sustained virologic response in such patients can prevent posttransplantation HCV recurrence. However, the associated risks of this approach needs to considered (ie, risk of sepsis, liver failure, and death) in relation to the potential benefits.1
The risks of this approach usually outweigh the benefits in advanced cirrhotics, particularly those with Child-Turcotte-Pugh’s C grade cirrhosis.1
To this end, patients should undergo a transplantation evaluation prior to considering a low-accelerating dose regimen.1
Reference
Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:
Ghany MG, et al. Hepatology. 2009;49:

59. Hcv therapy after liver transplantation

60. Early Antiviral Therapy to Prevent HCV Recurrence After Liver TransplantationG1
(%)
Treatment Initiation Post-Transplant (weeks)
Treatment
SVR
Treatment Discontinuation (%)
Rejection (%)
Mazzafero 2001
(single cohort; n=36) 83 3
IFN + RBV 33
(G1/4: 20 G2/3: 100)
Sugawara 2004
(single cohort; n=21) 4 39
(G1/4: 33 G2/3: 100) 25 26
Chalasani 2005
(phase 3b study; n=54) 74 PR
Untreated 8
(G1/4: 5 G2/3: 14) 31 32 12 21
Shergill 2005
(randomized,
controlled; n=54) NR
2 to 6
pegIFN
4.5
18.2 41
22.7
Bzowej 2011
controlled; n=115) 79
10 to 26 22 28
5.6
Slide: Early Antiviral Therapy to Prevent HCV Recurrence After Liver Transplantation
The use of early IFN-based therapy to prevent HCV recurrence yields an SVR rate that ranges from 8% to 39% (median 16%), in 5% to 33% of genotype 1 patients and 14% to 100% of genotype 2/3 patients, respectively. The main drawbacks are that treatment can only be administered to a low proportion of patients, and that drug dose reduction and discontinuation are necessary in approximately 70% and 30% of patients respectively.1-5
References
Mazzaferro V, Tagger A, Schiavo M, et al. Prevention of recurrent hepatitis C after liver transplantation with early interferon and ribavirin treatment. Transplant Proc 2001;33:
Sugawara Y, Makuuchi M, Matsui Y, et al. Preemptive therapy for hepatitis C virus after living-donor liver transplantation. Transplantation. 2004;78:
Chalasani N, Manzarbeitia C, Ferenci P, et al. Peginterferon alfa-2a for hepatitis C after liver transplantation: two randomized, controlled trials. Hepatology. 2005;41:
Shergill AK, Khalili M, Straley S, et al. Applicability, tolerability and efficacy of preemptive antiviral therapy in hepatitis C-infected patients undergoing liver transplantation. Am J Transplant. 2005;5:
Bzowej N, Nelson DR, Terrault NA, et al. PHOENIX: a randomized controlled trial of peginterferon alfa-2a plus ribavirin as a prophylactic treatment after liver transplantation for hepatitis C virus. Liver Transpl. 2011;17:
PR: pegIFN + RBV; G: genotype; NR: not reported.
Mazzafero V , et al. Transplant Proc. 2001;33: ; Sugawara Y, et al. Transplantation. 2004;78: ; Chalasani N, et al. Hepatology. 2005;41: ; Shergill AK, et al. Am J Transplant. 2005;5: ;
Bzowej N, et al. Liver Transplant. 2011;17:

61. Delayed Antiviral Therapy to Treat HCV Recurrence After Liver Transplantation
Advantages of delaying treatment until established HCV recurrence
Reduced risk of acute cellular rejection
Better graft function
Lower doses of immunosuppression
Numerous studies with PR
SVR rates: 8% to 45%
Challenges
High discontinuation rates
Poor tolerability (fatigue, asthenia, pyrexia, cytopenias), especially in severe hepatitis post-transplant
Slide: Delayed Antiviral Therapy to Treat HCV Recurrence After Liver Transplantation
The advantages of delaying treatment until established HCV recurrence occurs is that there is a reduced risk of acute cellular rejection, higher chances for better graft function, and the need for lower doses of immunosuppression.1-3
There are numerous studies with PR in this treatment setting, with SVR rates ranging from 8% to 45%.1-3
However, challenges do exist, such as high discontinuation rates and poor tolerability (fatigue, asthenia, pyrexia, cytopenias), especially in severe hepatitis post-transplant.1-3
There are a limited studies with direct-acting antiviral therapy in this setting, however early results are promising and establish the feasibility of this approach.1-3
References
Agarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis. 2013;45(suppl 5):S349-S354.
Terrault N. Liver transplantation in the setting of chronic HCV. Best Pract Res Clin Gastroenterol. 2012;26:
Roche B, Samuel D. Hepatitis C virus treatment pre- and post-liver transplantation. Liver Int. 2011;32(suppl 1):
PR: pegIFN + RBV.
Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.
Terrault N. Best Best Pract Res Clin Gastroenterol. 2012;26:
Roche B, et al. Liver Int. 2011;32(suppl 1):

62. Delayed Antiviral Therapy to Treat HCV Recurrence After Liver TransplantationG1
(%)
Advanced
Fibrosis (%)
Treatment Initiation Post-Transplant (months)
Treatment
SVR
Treatment Discontinuation (%)
Dumortier 2004
(single cohort; n=20) 80 NR 28 PR 45 20
Oton 2006
(2-center cohort; n=55) 91 33 63 44
(G1: 40) 24
Angelico 2007
(randomized, controlled;
n=42) 83
pegIFN 38 29
Carrion 2007
n=81) 90 15
Untreated 48 19 40
Picciotto 2007
(single center; n=61) 87 46 25
Hanouneh 2008
(retrospective, medical
records; n=53) 79 35 26
Slide: Delayed Antiviral Therapy to Treat HCV Recurrence After Liver Transplantation
Earlier studies that evaluated this strategy reported low SVR rates between 12% and 24% with peginterferon monotherapy.1-6
Studies utilizing PR show SVR rates for all genotypes ranging between 8% and 45%, with SVR rates in genotype 1 patients being considerably lower (range: 13% and 33%).1-6
These study cohorts were heterogeneous with wide variation in the time from liver transplantation to the start of treatment and the percentage of patients with advanced fibrosis. Despite this, high discontinuation rates and poor tolerability were consistently high in these studies.1-6
References
Dumortier J, Scoazec JY, Chevallier P, et al. Treatment of recurrent hepatitis C after liver transplantation: a pilot study of peginterferon alfa-2b and ribavirin combination. J Hepatol. 2004;40:
Oton E, Barcena R, Moreno-Planas JM, et al. Hepatitis C recurrence after liver transplantation: viral and histologic response to full-dose PEG-interferon and ribavirin. Am J Transplant. 2006;6:
Angelico M, Petrolati A, Lionetti R, et al. A randomized study on Peg-interferon alfa-2a with or without ribavirin in liver transplant recipients with recurrent hepatitis C. J Hepatol. 2007;46:
Carrion JA, Navasa M, Garcia-Retortillo M, et al. Efficacy of antiviral therapy on hepatitis C recurrence after liver transplantation: a randomized controlled study. Gastroenterology. 2007;132:
Picciotto FP, Tritto G, Lanza AG, et al. Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation. J Hepatol. 2007;46:
Hanouneh IA, Miller C, Aucejo F, et al. Recurrent hepatitis C after liver transplantation: on-treatment prediction of response to peginterferon/ribavirin therapy. Liver Transplant. 2008;14:53-58.
PR: pegIFN + RBV; G: genotype; NR: not reported.
Dumortier J, et al. J Hepatol. 2004;40: ; Oton E, et al. Am J Transplant. 2006;6: ; Angelico M, et al. J Hepatol. 2007;46: ; Carrion JA, et al. Gastroenterology. 2007;132: ; Picciotto FP, et al. J Hepatol. 2007;46: ; Hanouneh IA, et al. Liver Transplant. 2008;14:53-58.

63. Direct-Acting Antiviral Agents to Treat HCV Recurrence After Liver Transplantation
Telaprevir or boceprevir + PR
Promising preliminary SVR rates in genotype 1
Significant dose reductions required for cyclosporine and tacrolimus
Increased adverse event profile
Anemia occurs in most patients
RBV dose reduction and hematologic growth support factors/blood transfusions
No data on viral resistance and impact on post-transplant period
IFN-free regimens
Simplified dosing
Promising preliminary SVR rates in multiple genotypes
No drug interactions with common immunosuppressant agents (?SMV)
Lower incidence of adverse events, including anemia
Slide: Direct-Acting Antiviral Agents to Treat HCV Recurrence After Liver Transplantation
The use of DAAs in the post-transplant setting has been limited. Early pharmacokinetic data tempered expectations of the use of these agents in the liver transplant setting. Data on the use of telaprevir in healthy volunteers resulted in a significant increase in cyclosporin (5-fold) and tacrolimus levels (70-fold) due to the inhibition of the P4503A cytochrome. At present the data are based on mono-centric experiences and specific recommendations are difficult to make, aside from demonstrating that PI based triple therapy is feasible in this challenging population, albeit with a significant cumulative burden of side effects and drug–drug interactions.1-4
The development of side-effects, in particular anemia, is universal, requiring the combination of ribavirin dose reduction, the use of hematological growth support factors and/or blood transfusion. Also no data are currently available regarding the development of viral resistance and its impact in the post-transplant period.
The use of IFN-free regimens with simplified dosing has shown promising preliminary SVR rates in multiple genotypes. These regimens appear to have no or limited drug interactions with common immunosuppressant agents and are associated with a lower incidence of adverse events, including anemia.1-4
References
Lucey MR, Terrault N, Ojo L, et al. Long‐term management of the successful adult liver transplant: 2012 practice guideline by the American Association for the Study of Liver Diseases and the American Society of Transplantation. Liver Transpl. 2013;19:3-26.
Agarwal K, Barnabas A. Treatment of chronic hepatitis C virus infection after liver transplantation. Dig Liver Dis. 2013;45(suppl 5):S349-S354.
Terrault N. Liver transplantation in the setting of chronic HCV. Best Pract Res Clin Gastroenterol. 2012;26:
Roche B, Samuel D. Hepatitis C virus treatment pre- and post-liver transplantation. Liver Int. 2011;32(suppl 1):
PR: pegIFN + RBV.
Lucey MR, et al. Liver Transplant. 2013;19:3-26; Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354; Terrault N. Best Best Pract Res Clin Gastroenterol. 2012;26: ; Roche B, et al. Liver Int. 2011;32(suppl 1):

64. REFRESH Study: Telaprevir + PR in HCV Genotype 1 Liver Transplant Recipients
Interim results with telaprevir + PR show promising efficacy
Anemia
Mild or moderate: 41%
Severe: 6.5%
RBV dose reduction: 43%
Erythropoietin/blood transfusions: 30%/6.5%
No reports of
Rejections, autoimmune hepatitis, or deaths
Severe or potentially life-threatening cases of rash or pruritus
Interim Results
Patients
(n=46)
HCV RNA <25 IU/mL (%)
Week 4
Week 12 53 60
Serious adverse events (%) 15
Adverse events (%)
Fatigue
Anemia
Headache
Nausea
Anorectal
Diarrhea
Rash
Pruritus 59 48 46 41 37 35 22
Grade 3/4 creatinine increase (%) 4
Renal failure 11
Slide: REFRESH Study: Telaprevir + PR in HCV Genotype 1 Liver Transplant Recipients
Interim results with telaprevir + pegIFN + RBV in this challenging patient population show promising efficacy. Undetectable HCV RNA levels were achieved in 53% and 60% of patients at week 4 and 12, respectively.1
Mild or moderate anemia was reported in 41% of patients and severe anemia in 6.5% of patients. RBV dose reduction was required in 43% of patients and erythropoietin use or blood transfusions was needed for 30% and 6.5%, respectively.1
There were no reports of rejections, autoimmune hepatitis, or deaths or of severe or potentially life-threatening cases of rash or pruritus.1
Reference
Brown K, Fontana RJ, Russo MW, et al. Twice-daily telaprevir in combination with peginterferon alfa-2a/ribavirin in genotype 1 HCV liver transplant recipients: interim week 16 safety and efficacy results of the prospective, multicenter REFRESH study. Hepatology. 2013;58(suppl 1):209A. Abstract 3.
PR: pegIFN + RBV.
Brown K, et al. Hepatology. 2013;58(suppl 1):209A. Abstract 3.

65. CRUSH-C: Virologic Response in HCV Genotype 1
eRVR is highly predictive of SVR12
Treatment duration <36 weeks negatively affects SVR12 rates
Adverse events led to treatment
Discontinuations: 20%
Interruption: 7%
SVR12
eRVR
No eRVR
93%†
86%
59%
50%
Patients (%)
Slide: CRUSH-C: Virologic Response in HCV Genotype 1
The overall SVR12 rate was 59%, with the highest SVR12 rates being seen among patients who achieved an eRVR and had received >36 weeks of therapy and achieved an eRVR.1
Adverse events led to treatment discontinuation and interruption in 20% and 7% of patients, respectively.1
Reference
Stravitz R, Levitsky J, Dodge JL, et al. Higher sustained virologic response (SVR-12) achievable in liver transplant (LT) recipients with hepatitis C (HCV) treated with protease inhibitor (PI) triple therapy (TT). Hepatology. 2013;58(suppl 1):429A. Abstract 461.
33%‡
16% 5%
Overall
(n=90)
Yes
(n=56) No
(n=32)
<36
(n=5/10)
>36
(n=46/11)
*P<0.001 versus not achieving an eRVR.
†P=0.04 versus <36 weeks (eRVR).
‡P=0.003 versus <36 weeks (no eRVR).
Achieved
eRVR
Treatment Duration (weeks)
Stravitz R, et al. Hepatology. 2013;58(suppl 1):429A. Abstract 461.

66. CRUSH-C (All Patients): Safety in HCV Genotype 1
High rates of hospitalizations (27%) and >0.5 mg/dL increase in creatinine (41%)
Anemia is a significant problem
PegIFN + RBV dose reduction: 38%/86%
Erythropoietin/blood transfusions: 84%/56%
Death (7%)
Mainly due to liver-related causes, usually in patients with advanced disease
Slide: CRUSH-C (All Patients): Safety in HCV Genotype 1
There were high rates of hospitalizations (27%) and cases of >0.5 mg/dL increase in creatinine (41%).1
Anemia was a significant problem during the study, with pegIFN and RBV dose reduction being required by 38% and 86%, respectively and erythropoietin use and need for blood transfusions by 84% and 56% of patients, respectively.1
Death occurred in 7% of patients and was mainly due to lever-related causes, usually in patients with advanced disease.1
Reference
Stravitz R, Levitsky J, Dodge JL, et al. Higher sustained virologic response (SVR-12) achievable in liver transplant (LT) recipients with hepatitis C (HCV) treated with protease inhibitor (PI) triple therapy (TT). Hepatology. 2013;58(suppl 1):429A. Abstract 461.
Stravitz R, et al. Hepatology. 2013;58(suppl 1):429A. Abstract 461.

67. Baseline Characteristics
Sofosbuvir Compassionate Use Program: Recurrent HCV Following Liver Transplantation
Patients with severe recurrent HCV infection following liver transplantation
Likely to have <1 year life expectancy
Sofosbuvir 400 mg qd + RBV + pegIFN for up to 48 weeks
Baseline Characteristics
Patients
(n=104)
Male (%) 73
Age (years) 55
Genotype (%)
1a/1b
2/3/4
28/49
1/7/8/
ALT (IU/L) 71
Bilirubin (mg/dL)
3.1
Albumin (g/dL)
INR
1.3
MELD score 15
Time from liver transplantation (months) 17
Slide: Sofosbuvir Compassionate Use Program: Recurrent HCV Following Liver Transplantation
Forns and colleagues reported on the compassionate use of sofosbuvir 400 mg qd with RBV and with or without pegIFN for 48 weeks n in patients with severe recurrent HCV infection following liver transplantation. Patients in this study were likely to have less than a 1 year life expectancy.1
The recommended time of clinical assessments were:1
On treatment: weeks 4, 12, 24, 36, and 48.
Follow-up: weeks 4, 12, and 24.
Reference
Forns X, Prieto M, Charlton M, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C including fibrosing cholestatic hepatitis following liver transplantation. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.
PR: pegIFN + RBV.
Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.

68. Sofosbuvir Compassionate Use Program: Initial Treatment Evaluations
Overall, liver function tests significantly improved over time
Most patients improved clinically or remained stable
All serious adverse events (48%)
Leading to treatment discontinuation (13%)
Deaths (13%) were mostly a result of disease progression in this very sick population
On treatment (n=8)
Post treatment follow-up (n=5)
Treatment Outcomes
62%
62%
Patients (%)
Slide: Sofosbuvir Compassionate Use Program: Initial Treatment Evaluations
The overall SVR12 rate was 62%, with a higher SVR12 rate being achieved among patients receiving sofosbuvir + RBV versus pegIFN + RBV.1
Overall, liver function tests significantly improved over time. Most patients improved clinically or remained stable (62% and 21%, respectively), with 21% having declining clinical condition or died.1
There was a low incidence of treatment-related adverse events leading to discontinuation (3%). Deaths (13%) were mostly a result of disease progression in this very sick population.1
Reference
Forns X, Prieto M, Charlton M, et al. Sofosbuvir compassionate use program for patients with severe recurrent hepatitis C including fibrosing cholestatic hepatitis following liver transplantation. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.
21%
21%
SVR12
(n=85)
Improved*
Stable
Worse
Clinical Outcomes
(n=104)
*Improved: improvement in decompensation events
(ie, significant decrease in hepatitic encephalopathy
episodes, improvement or disappearance of ascites, and improvement in liver-related laboratory values.
Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.

69. Sofosbuvir + RBV: Treatment of Recurrent HCV After Liver Transplantation
Key Results
Open-label study
Genotype 1(83%), 3 (15%), 4 (3%)
CTP <7 and MELD <17
Time liver transplantation: 4.3 years
METAVIR F3/F4: 23%/40%
Sofosbuvir 400 mg qd + RBV (starting at 400 mg) for up to 24 weeks
Safety
No deaths, graft losses, or rejection
Discontinuations due adverse events: 5%
Patients
(n=40)
HCV RNA <25 IU/mL (%)
Week 4
SVR4
SVR12
SVR24
100 73 70
Concomitant immunosuppression (%)
Tacrolimus
Mycophenolate mofetil
Prednisone
Cyclosporin
Azathioprine 35 28 25 5
Adverse events (%)
Fatigue
Headache
Arthralgia 23
Grade 3/4 laboratory abnormalities (%)
25/28
Slide: Sofosbuvir + RBV: Treatment of Recurrent HCV After Liver Transplantation
Samuel and colleagues reported interim results of an ongoing single-arm, open-label interferon-free pilot study of HCV naïve and treatment-experienced patients with recurrent HCV infection (any HCV genotype) after liver transplantation. Patients received up to 24 weeks of sofosbuvir 400 mg qd + RBV.1
Genotype 1(83%), 3 (15%), 4 (3%).
Prior HCV treatment (88%).
CPT <7 and MELD <17.
Time liver transplantation: 4.3 years.
METAVIR F3/F4: 23%/40%
The interim SVR12 rate was 70% with no reports of deaths, graft losses, or rejection. Discontinuations due adverse events were low for this patient population (5%) and RBV dose escalation was manageable. No drug-drug interactions were noted with the variety of common immunosuppressant agents used.1
Reference
Samuel D, Charlton M, Gane E, et al. Sofosbuvir and ribavirin for the treatment of recurrent hepatitis C infection after liver transplantation: results of a prospective, multicenter study. J Hepatol. 2014;60(suppl 1):S499. Abstract P1232.
Samuel D, et al. J Hepatol. 2014;60(suppl 1):S499. Abstract P1232.

70. SOLAR: GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
Wk 0
Wk 12
Wk 24
Wk 36
LDV/SOF + RBV
SVR12
LDV/SOF + RBV
SVR12
223 patients randomized 1:1 to 12 or 24 weeks of treatment
GT 1 or 4 treatment-naïve or -experienced post-transplant patients
≥ 3 months from liver transplant
RBV dosing
F0–F3/CPT A cirrhosis: weight-based
CPT B and C cirrhosis: dose escalation, 600–1200 mg/d
With respect to post-transplantation patients,
These patients are being evaluated in the second cohort of SOLAR-1.
And will be discussed by Dr. reddy on Sunday.
Five groups of patients are beign evaluated, spanning the post-transplant spectrum”:
F0-F3, Compensated Cirrhosis, CPT B and CPT C Decompensated cirrhosis, and FCH
- FCH patients will be presented at EASL and not discussed here.
Reddy et al, AASLD 2014

71. Baseline Disease Characteristics – 12 and 24 Weeks GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
CPT B
n=52
CPT C
n=9
MELD (n, %)
<10
N/A
28 (55)
13 (25)
1 (11)
10-15
20 (39)
33 (63)
5 (56)
16-20
3 (6)
4 (8)
2 (22)
21-25
2 (4)
Ascites, n (%)
2 (2)
40 (77)
9 (100)
Encephalopathy, n (%)
1 (1)
23 (44)
7 (78)
Median bilirubin, mg/dL (range)
0.7 ( )
0.8 ( )
1.2 ( )
2.1 ( )
Median albumin, g/L (range)
3.8 ( )
3.7 ( )
3.2 ( )
2.4 ( )
Median INR (range)
1.0 ( )
1.1 ( )
1.2 ( )
1.3 ( )
Median platelets, x 103/µL (range)
146 (71-429)
108 (41-358)
93 (32-225)
79 (54-189)
Median hemoglobin, g/dL (range)
14.0 ( )
13.6 ( )
12.9 ( )
11.5 ( )
Median CLCr, mL/min (range)
65.0
( )
62.1
( )
58.9
( )
66.6
( )
Baseline disease characteristics are shown here.
As expected, as the patients’ clinical status worsens, their bilirubin increase, and their albumin drops.
Reddy et al, AASLD 2014

72. SVR12 GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
LDV/SOF + RBV 12 Weeks
LDV/SOF + RBV 24 Weeks
SVR12 (%)
Here are the SVR rates
whether patients were treated for 12 or 24 weeks did not appear to impact SVR rates.
Also, the differences obsereved between CPT B and C patients are likely due to the small number of CPT C patients that were studied – only 8 in total.
53/55
55/56
25/26
24/25
22/26
15/18
3/5
2/3
F0–F3
CPT A
CPT B
CPT C
*Subject completed 8 days of treatment and withdrew consent
8 CPT B 24 Week and 1 CPT C 24 Week subjects have not reached the Week 12 post treatment visit. .
Reddy et al, AASLD 2014

73. Deaths GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
Cause of Death
Treatment Duration
(Weeks)
Treatment Related
CPT A
Progressive multifocal leukoencephalitis 12 No
Unknown† 24
CPT B
Thoracic aorta aneurysm dissection
Sepsis
Multi-organ failure/intestinal perforation
Internal bleeding – esophageal varices
Complications of cirrhosis (sepsis, thrombosis)
In total, there were 7 deaths – but there was no pattern to these deaths.
Observation Period: Day 1 through Post-treatment Week 12
†per family request
Reddy et al, AASLD 2014

74. CORAL-I Study: ABT-450/r/Ombitasvir + Dasabuvir + RBV for HCV Genotype 1 After Liver Transplantation
Ongoing phase 2 study of 24 weeks of ABT-450/r/ombitasvir + dasabuvir + RBV
HCV genotype 1 (n=34)
Liver transplantation due to HCV infection
Median time from txp mo
METAVIR <F2, no prior PI
SVR 97%
Relapse 1
No deaths, graft losses, rejection
RBV dose reduction: No impact on overall SVR
Slide: CORAL-I Study: ABT-450/r/Ombitasvir + Dasabuvir + RBV for HCV Genotype 1 After Liver Transplantation
Mantry and colleagues reported on an ongoing phase 2 study on 24 weeks of ABT-450/r/ombitasvir + dasabuvir + RBV for HCV genotype 1 recurrence after liver transplantation due to HCV infection (n=34).1
Therapy with PR was permitted prior to transplantation.
Treatment-naïve post transplantation.
METAVIR <F2
On stable immunosuppression: tacrolimus (85%), cyclosporine (15%).
The primary outcome was SVR12.1
Reference
Mantry PS, Kwo PY, Coakley E, et al. High sustained virologic response rates in liver transplant recipients with recurrent HCV genotype 1 infection receiving ABT-450/r/ombitasvir+dasabuvir plus ribavirin. Hepatology. 2014;60(suppl 1):298A-299A. Abstract 198.
ABT-450/ritonavir/ombitasvir 150/100/25 mg qd; dasabuvir 250 mg bid. RBV ( mg).
Tacrolimus: 0.5 mg once weekly or 0.2 mg every 3 days.
Cyclosporine: 1/5 of daily dose given once daily prior to HCV therapy.
Mantry PS, et al. Hepatology. 2014;60(suppl 1):298A-299A. Abstract 198.

75. Summary 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
Lower SVR rate
Higher toxicity
Data with new DAAs evolving
Promise for IFN-free therapy pre- and post-transplant in the future
Slide: Summary
HCV eradication in advanced liver disease reduces decompensation, does not prevent HCC, and prevents HCV recurrence post transplant.
IFN-based therapy is suboptimal in decompensated cirrhosis as it associated with lower SVR rates and higher toxicity burden.
Data with new DAAs is evolving, with future promise for IFN-free therapies administered both pre- and post-transplant .