Transcript Management of HBV Infection in Challenging Patient Populations

HCV INFECTION AND
MANAGEMENT IN ADVANCED
LIVER DISEASE
Kimberly Brown, M.D.
Chief, Division of Gastroenterology and Hepatology
Henry Ford Hospital
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
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
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
Sherman KE. Top HIV Med. 2011;19:121-125.
Chronic HCV Infection:
Natural History
Exposure
(Acute phase)
15%-45%
Resolved
55%-85%
Chronic
5%-30%
Over 20-30 Years
Cirrhosis
Co-morbidities
Liver Decompensation (5%/year)
HCC (2%-8%/year)
Poynard T, et al. Lancet. 1997;349:825-832.
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
Fibrous expansion of portal areas
with marked bridging (portal-to-portal
and portal-to-central)
Cirrhosis
Faria SC, et al. Radiographics. 2009;29:1615-1635. Adapted from Everson GT.
Cirrhotic
Liver
FibroScan
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)
8.8
F0-F1
Ziol M, et al. Hepatology. 2005;41:48-54.
9.6
F2
F3
Liver Fibrosis
(METAVIR)
14.6
F4
Projected Burden of Advanced Fibrosis
Over the Next Decade
• 1990  77.6% F0/1;
cirrhosis =5%
Davis GL, Gastroenterology. 2010;138:513-521.
• 2010  41.8% F0/1;
cirrhosis =25%
• 2020  cirrhosis = 37.2%
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.
Natural History of HCV Cirrhosis
100
Compensated
80
Survival
probability
(%)
60
After 1st
complication
40
Deaths
Liver-related (70%)
Other cause (30%)
20
0
0
1
2
3
4
5
6
7
Years after diagnosis
Adapted from Fattovich G et al. Gastroenterology. 1997;112:466-467.
8
9
10
By 2007, Deaths From HCV Surpassed
Those From HIV
Change in Mortality Rates From 1999 to 2007
7
HIV
Rate per 100,000 People
6
5
4
15,106
12,734
Hepatitis C
3
2
1
Hepatitis B
1,815
0
1999
2000
2001
Ly KN, et al. Ann Intern Med. 2012;156(4):271-278.
2002
2003
Year
2004
2005
2006
2007
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
-
Long term morbidity and mortality benefits
Undetectable HCV RNA 12 weeks after completion of
antiviral therapy for chronic HCV infection
Ghany MG, et al. Hepatology. 2009;49(4):1335-1374.
Treatment Goals
HCV Infection
Viral Eradication
Delay Disease
Progression
Delay Time to
Decompensation
Prevent HCC?
SVR Was Associated With Reduced Long-Term Risk
of All-Cause Mortality in an International, Multicenter
Study
Percent
All-Cause Mortality
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;308:2584-2593.
SVR Reduced Risk of All-Cause Mortality
in a Retrospective VA Study
Genotype 1
Genotype 2
Genotype 3
(n=12,166)
(n=2904)
(n=1794)
SVR rate: 72%
SVR rate: 62%
Years
Years
Years
Cumulative Mortality (%)
SVR rate: 35%
Retrospective analysis of veterans who received pegylated interferon plus ribavirin at any VA medical facility (2001-2008).
SVR=sustained virological response.
Backus17
LI, et al. Clin Gastroenterol Hepatol. 2011;9:509-516.
SVR Was Associated With Improved Long-Term
Liver-Related Outcomes in the HALT-C Trial
Database
Percent
Cumulative Incidence of Any Liver-Related Outcome Among Patients With Bridging Fibrosis or Cirrhosis
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;52:833-844.
Hepatocellular Carcinoma in HCV
Untreated
Interferon
0.6
0.5
Cumulative 0.4
incidence 0.3
0.2
0.1
0
0
1
2
3
4
5
Years
Yoshida H et al. Ann Intern Med. 1999;131:178.
6
7
8
9
10
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: http://www.hcvguidelines.org/full-report-view. Version January 29, 2014.
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 1945-1965)
3500
X1000 persons
3000
2500
50%
2000
1500
32-38%
20-23%
1000
500
7-11%
5-6%
Treated
‘Cure’
0
Infected Diagnosed Referred HCV RNA
to care
test
Holmberg S, N Engl J Med 2013; 368: 1859
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
Death <
365 Days Testing
N=39
HCV Ab+
N=566
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%)
Brown KA. et al., AASLD 2013
Brown et al, AASLD 2013
Positive RNA
N=308 (83%)
Referral?
N=308
No Referral
N=125 (41%)
Self Referral
N=3 (1%)
Gastro
Visit?
N=183
Only 38% (117/308) of patients
with positive HCV-RNA were seen by
Gastroenterology
No Visit
N=66 (36%)
Brown KA. et al., AASLD 2013
Brown et al, AASLD 2013
Referred
N=180 (58%)
Visit
N=117 (64%)
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%)
*Reasons for No Treatment: RNA negative (3); substance
abuse (14); no follow up (11); transplant evaluation (15); comorbidities (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
Treatment
N=21 (18%)
No
SVR
N=13
(62%)
SVR
N=8
(38%)
HCV TREATMENT
CONSIDERATIONS IN
ADVANCED FIBROSIS AND
CIRRHOSIS
French National Early Access Program: Interim
Analysis of the CUPIC Cohort (Genotype 1)
●
Prospective cohort, HCV genotype 1,
compensated cirrhosis
Factors Associated With
Death and Severe Complications (n=62)
- Relapse or prior partial responders to PR
●
Adjusted
Odds Ratio
SVR12
- Telaprevir: 40% (range: 29%-53%)
- Boceprevir: 41% (range: 11%-51%)
●
Discontinuations: 47%
●
Serious adverse events: 40%
-
Early treatment discontinuation: 21.3%
Platelet <100,000/mm3
3.1 (P=0.0105)
Serum albumin <35 g/dL
6.33 (P=0.0001)
Risk of Death or Severe Complications (%)
Platelets (/mm3)
Death: 2.0%
>100,000
<100,000
Albumin (g/dL)
>35 (n=298/69)
3.4
4.3
<35 (n=28/34)
7.1
44.1
Anemia (<9.0 g/dL): 29.4%
Hepatic decompensation: 2.4%
Fontaine H, et al. J Hepatol. 2013;58(suppl 1):S27. Abstract 60.
Hezode C, et al. Hepatology. 2012;56(suppl 4):217A-218A. Abstract 51.
Hezode C, et al. J Hepatology. 2013;59:434-441.
Sofosbuvir + RBV + PegIFN (Multiple Genotypes):
SVR12 by Baseline Fibrosis Stage (FibroTest)
Sofosbuvir + RBV (FUSION)
Sofosbuvir + PR (NEUTRINO)
(16 weeks, treatment-experienced)
(12 weeks, treatment-naïve)
Genotype 2
100%
Genotype 3
Genotypes 1, 4-6
100%
97%
96%
89%
80%
85%
80%
63%
40%
Patients (%)
Patients (%)
67%
79%
F0
F1-F2
F3
F4
F0
F1-F2
F3
F4
(n=4/5)
(n=14/21)
(n=5/10)
(n=9/27)
(n=78)
(n=105)
(n=54)
(n=86)
PR: pegIFN + RBV.
Patel K, et al. Hepatology. 2013;58(suppl 1):738A-739A. Abstract 1093.
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)
Week 0
12
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor); simeprevir 150 mg (NS3/4A Inhibitor).
Weight-based ribavirin dosing (1000-1200 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.
24
COSMOS Subgroup Analysis:
SVR12 in HCV Genotype 1, METAVIR F3-F4
SVR12
SVR12 by HCV Subtype
Simeprevir + sofosbuvir
No RBV
With RBV
Simeprevir + sofosbuvir + RBV
100%
100%
93%
93%
96%
94%
1a
1a +
Q80K
CC
98%
95%
SVR12 (%)
SVR12 (%)
93%
95%
12 Weeks
24 Weeks
(n=14/27)
(n=16/30)
1b
Genotype
(n=18/40/26)
Lawitz E, et al. J Hepatol. 2014;60(suppl 1):S524. Abstract O165.
CT
TT
IL28B Genotype
(n=17/48/19)
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 24
Wk 36
n=118
LDV/SOF
SVR12
n=204
LDV/SOF + RBV
SVR12
n=133
LDV/SOF
SVR12
n=58
LDV/SOF + RBV
SVR12
● 513 patients with HCV GT 1, compensated cirrhosis
● Pooled data from Phase 2 and 3 LDV/SOF ± RBV studies
–
LONESTAR, ELECTRON, ELECTRON-2, 337-0113 (Japan), ION-1, ION2, SIRIUS
● Primary efficacy endpoint: SVR12
Bourliere et al, AASLD 2014
SVR12 (%)
SVR12 Overall and by Treatment Duration
LDV/SOF Phase 2 and 3 Program: Cirrhotic
Subjects
493/513
Overall
305/322
12 Weeks
188/191
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.
SVR12 by Regimen and Duration
LDV/SOF Phase 2 and 3 Program: Cirrhotic
Subjects
Total
Treatment
Naïve
Treatment
Experienced
96%
98%
95%
12 wk
95%
97%
94%
24 wk
98%
99%
98%
LDV/SOF
95%
96%
95%
LDV/SOF + RBV
97%
99%
96%
LDV/SOF 12 wk
92%
96%
90%
LDV/SOF + RBV 12 wk
96%
98%
96%
LDV/SOF 24 wk
98%
97%
98%
LDV/SOF + RBV 24 wk
100%
100%
100%
Overall SVR12
Duration
Regimen
Duration/±
RBV
SVR12, %
Bourliere et al, AASLD 2014
SIRIUS Study
0 wk
12 wk
24 wk
36 wk
SVR12
Placebo
LDV/SOF + RBV
SVR12
LDV/SOF + Placebo RBV
● 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
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
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)
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)
3.9 (3.2–4.6)
3.9 (3.0–4.9)
3.9 (3.0–4.9)
6 (8)
14 (17)
20 (13)
Mean age, y (range)
Mean BMI, kg/m2 (range)
Mean albumin g/dL
Albumin <3.5 g/dL, n (%)
Bourliere et al, AASLD 2014
SVR12
SIRIUS (GS-US-337-0121)
74/77
LDV/SOF+RBV
12 Weeks
75/77
LDV/SOF
24 Weeks
Error bars represent 95% confidence intervals.
Bourliere et al, AASLD 2014
Adverse Events ≥15%
SIRIUS (GS-US-337-0121)
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)
7 (9)
17 (22)
11 (14)
13 (17)
Nausea
8 (10)
8 (11)
14 (18)
7 (9)
8 (10)
Fatigue
3 (4)
5 (7)
7(9)
13 (17)
15 (19)
Dry skin
6 (8)
5 (7)
12 (16)
4 (5)
4 (5)
Arthralgia
5 (6)
0
6 (8)
6 (8)
12 (15)
Bronchitis
1 (1)
4 (5)
4 (5)
4 (5)
13 (17)
Preferred
term, n (%)
Bourliere et al, AASLD
2014
●
Most AEs mild or moderate in severity
HCV INFECTION BEFORE
LIVER TRANSPLANTATION:
TREATMENT OF DECOMPENSATED
PATIENTS
STRATEGIES TO PREVENT RECURRENCE
OF HCV POST LIVER TRANSPLANT
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???
Agarwal K, et al. Dig Liver Dis. 2013;45(suppl 5):S349-S354.
Fried MW, et al. N Engl J Med. 2002;347:975-982.
Manns MP, et al. Lancet. 2001;358:958-965.
Hadziyannis SJ, et al. Ann Intern Med. 2004;140:346-355.
Bruno S, et al. Hepatology. 2010;51:388-397.
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)
Week 0
Sofosbuvir qd + RBV
24
Current Analysis
Sofosbuvir 400 mg (nucleotide NS5B polymerase inhibitor) + RBV (1000-1200 mg).
HVPG at day 0 and 48 in the sofosbuvir-treated patients.
Baseline demographics and disease characteristics:
Male: 72%-80%; age: 55-56 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: 3.0-3.3 g/dL; platelets: 75-99 x103.
ALT, AST: 87-105, 105-128 U/mL.
Ascites: 24%-36%.
Encephalopathy 8%-20%.
Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.
48
72
Sofosbuvir + RBV: Cirrhosis and Portal
Hypertension + Decompensation
● High rates of virologic
suppression irrespective of
severity of liver disease
Outcomes at Week 24
● Decreased necroinflammation
with ALT normalization
HCV RNA <LLOQ (%)
CTP A (n=7)
CTP B (n=15)
● Improvements
Change
Platelets (103/µL)
CTP A
CTP B
Albumin (g/dL)
CTP A
CTP B
Bilirubin (mg/dL)
CTP A
CTP B
ALT (U/L)
CTP A
CTP B
-
Platelet count and albumin
Ascites and hepatic
encephalopathy
● Low rates of treatment
discontinuation due to adverse
events (4%)
Afdhal N, et al. J Hepatol. 2014;60(suppl 1):S28. Abstract O68.
Sofosbuvir
+ RBV
(n=25)
Observation
(n=25)
100
90
---
17
1
-9
-1
0.5
0.4
-0.1
0
0.5
-0.2
0.2
-0.1
-72
-75
13
0
SOLAR-1 (Decompensated Cirrhosis)
GT 1 and 4, CPT Class B and C
Wk 0
Wk 12
LDV/SOF + RBV
Wk 24
Wk 36
SVR12
LDV/SOF + RBV
SVR12
● 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
Flamm, et al, AASLD 2014
Baseline Disease Characteristics
GT 1 and 4, CPT Class B and C
CPT B
CPT C
12 Weeks
n=30
24 Weeks
n=29
12 Weeks
n=23
24 Weeks
n=26
<10
6 (20)
8 (28)
0
0
10‒15
21 (70)
16 (55)
16 (70)
13 (50)
16-20
3 (10)
5 (17)
7 (30)
12 (46)
21-25
0
0
0
1 (4)
Ascites, n (%)
17 (57)
17 (59)
22 (96)
25 (96)
Encephalopathy, n (%)
20 (67)
16 (55)
21 (91)
23 (88)
Median bilirubin, mg/dL (range)
2.0 (0.6-5.5)
1.4 (0.8-4.5)
2.9 (1.2-14.5)
3.8 (1.1-5.7)
Median albumin, g/dL (range)
2.9 (2.1-3.7)
3.0 (2.2-3.4)
2.6 (1.6-3.5)
2.6 (2.0-3.3)
Median INR, (range)
1.3 (1.0-1.5)
1.3 (1.0-2.6)
1.4 (1.2-1.9)
1.4 (1.1-2.2)
Median platelets, x 103/µL (range)
88 (36-212)
73 (30-154)
81 (39-177)
71 (32-179)
MELD score, n (%)
Flamm, et al, AASLD 2014
SVR12
GT 1 and 4, CPT Class B and C
SVR12 (%)
LDV/SOF + RBV 12 Weeks
3 relapses
1 death
45/52
42/47
Overall
Flamm, et al, AASLD 2014
26/30
LDV/SOF + RBV 24 Weeks
1 relapse
2 deaths
24/27
CPT B
1 relapse
2 death
1 LTFU
19/22
1 relapse
1 death
18/20
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.
.
Change in MELD Score Baseline Through
Follow-up Week 4
GT 1 and 4, CPT Class B and C
CPT C
CPT B
12 wk (n=30)*
12 wk (n=23)*
24 wk (n=29)*
24 wk (n=26)*
(+10)
n=5
Flamm, et al, AASLD 2014
n=2
n=5
n=3
*Missing FU-4: n=2 CPT B 12 wks; n=4 CPT(-8)
B 24 wks; n=2 CPT C 12 wk; n=7 CPT C 24 wk.
49
Safety Summary
GT 1 and 4, CPT Class B and C
CPT B
12 Weeks
n=30
24 Weeks
n=29
12 Weeks
n=23
24 Weeks
n=26
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)
11 (42)
Serious and related AEs
2 (7)
0
0
2 (8)
Treatment DC due to AE
0
1 (3)
0
2 (8)
1 (3)
2 (7)
2 (9)
1 (4)
Patients, n (%)
AE
Overall
Safety
CPT C
Death
 Related SAEs: Anemia (2), Hepatic Encephalopathy, Peritoneal Hemorrhage
Flamm, et al, AASLD 2014
Risk of HCC Remains After SVR in HCV
Patients With Advanced Hepatic Fibrosis
● Meta-analysis (n=1000)
-
Cumulative HCC by Age Group
10 cohorts, individual patient data
12.2%
Age Group
<45 years
45 to 60 years
>60 years
SVR with IFN-based therapy
Bridging fibrosis or cirrhosis
9.7%
● Patients with HCV-induced
cirrhosis who achieve SVR remain
at risk for HCC
Rate (%)
● 51 events of HCC over 5.1 years
of follow-up
P=0.006
● Risk increased with age, severity
of liver disease, and presence of
diabetes mellitus
2.6%
0
1
2
3
4
5
Years After SVR
van der Meer AJ, et al. Hepatology. 2013;58(suppl 1):280A. Abstract 143.
6
7
8
HCV Treatment Before Liver Transplantation
in Patients With Decompensated Cirrhosis
Crippin 2002
G1
(%)
Child-Pugh
(%)
Treatment
73
11.9
IFN + RBV
(pilot study; n=15)
Thomas 2003
67
10.0
(randomized,
controlled; n=79)
NA
0
IFN
NA
20
30/82
13/50
26
30
NA
20
60
7.4
IFN + RBV
(LADR)
70
A (50%);
B (43%); C (7%)
IFN + RBV
80
A (45%);
B (43%); C (4%)
PR
20/100
NA
20
56
7.0
PR
(LADR)
41/53
NA
25
(case controlled; n=51)
Everson 2013
33
70
(single cohort; n=30)
Carrion 2009
HCV RNA Negative
Post Transplant (%)
(overall)
(single cohort; n=124)
Forns 2003
SVR
G1/non-G1 (%)
(overall)
(single cohort; n=20)
Everson 2005
EOTR
G1/non-G1 (%)
(overall)
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;8:350-355; Thomas RM, et al. Liver Transpl. 2003;9:905-915;
Everson GT, et al. Hepatology. 2005;42:255-262; Forns X, et al. J Hepatol. 2003;39:389-396;
Carrion JA, et al. J Hepatol. 2009;50:719-728; Everson GT, et al. Hepatology. 2013;57:1752-1762.
Pre-Liver Transplant Sofosbuvir + RBV:
Prevention of Recurrent HCV
●
Baseline Characteristics
Open-label, phase 2 study conducted at
16 sites (n=61)
Treatment
(n=61)
- Deceased donor liver transplantation
●
candidates with HCV
Male (%)
80
HCC meeting MILAN criteria
Age (years)
59
MELD exception for HCC
BMI <30 kg/m2 (%)
43
CPT <7
Exclusion: decompensated cirrhosis,
prior solid organ transplantation, HBV or
HIV coinfection, renal impairment
Up to 48 weeks of sofosbuvir 400 mg +
RBV (1000-1200 mg) pre-transplant
Genotype (%)
1a/1b
2/3
4
39/34
13/12
4
HCV RNA >6 log10 IU/mL (%)
41
IL28 B non-CC (%)
78
MELD
8
CPT score 5-7 (%)
Prior HCV treatment (%)
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
95%
75
Pre-Liver Transplant Sofosbuvir + RBV:
Virologic Response in HCV Genotypes 1-4
● HCV recurrence prevented in
64% of patients HCV RNA <LLOQ
at time of transplantation
HCV RNA Undetectable
93%
91%
● On treatment HCV RNA
suppression was rapid (1 week)
Patients (%)
64%
Overall
(n=44)
>12 Weeks
Treatment
(n=33)
At Transplant
TND: target not detected.
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
PostTransplant
Week 12
(n=39)
Pre-Liver Transplant Sofosbuvir + RBV:
Target Not Detected and Safety in Genotypes 1-4
● Median days TND
No HCV recurrence (n=28): 95
● Sofosbuvir + RBV was
generally well tolerated
-
HCV recurrence (n=10)
No HCV recurrence (n=28)
HCV recurrence (n=10): 5.5
(P<0.001)
Discontinuations due to
adverse events: 3% (none
related to sofosbuvir)
Individual Patient Data
-
Days Continuously TND Before Liver
Transplant and Preventing HCV Recurrence
>30 days
TND
HCV RNA Continuously TND (Days)
TND: target not detected.
Curry MP, et al. Hepatology. 2013;58(suppl 1):314A-315A. Abstract 213.
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)
Ghany MG, et al. Hepatology. 2009;49:1335-1374.
HCV THERAPY AFTER LIVER
TRANSPLANTATION
Early Antiviral Therapy to Prevent HCV
Recurrence After Liver Transplantation
Mazzafero 2001
G1
(%)
Treatment Initiation
Post-Transplant
(weeks)
Treatment
83
3
IFN + RBV
(single cohort; n=36)
Sugawara 2004
83
4
IFN + RBV
74
3
0
0
25
26
31
12
39
PR
8
(G1/4: 5 G2/3: 14)
NR
2 to 6
(randomized,
controlled; n=54)
Bzowej 2011
33
(G1/4: 33 G2/3: 100)
(phase 3b study; n=54)
Shergill 2005
Rejection
(%)
(G1/4: 20 G2/3: 100)
(single cohort; n=21)
Chalasani 2005
SVR
(%)
Treatment
Discontinuation
(%)
79
10 to 26
(randomized,
controlled; n=115)
Untreated
0
32
21
pegIFN
4.5
41
22.7
PR
18.2
NR
NR
PR
22
28
5.6
Untreated
0
NR
NR
PR: pegIFN + RBV; G: genotype; NR: not reported.
Mazzafero V , et al. Transplant Proc. 2001;33:1355-1357; Sugawara Y, et al. Transplantation. 2004;78:13081311; Chalasani N, et al. Hepatology. 2005;41:289-298; Shergill AK, et al. Am J Transplant. 2005;5:118-124;
Bzowej N, et al. Liver Transplant. 2011;17:528-538.
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
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;26:531-548.
Roche B, et al. Liver Int. 2011;32(suppl 1):120-128.
Delayed Antiviral Therapy to Treat
HCV Recurrence After Liver Transplantation
Dumortier 2004
G1
(%)
Advanced
Fibrosis
(%)
Treatment Initiation
Post-Transplant
(months)
Treatment
SVR
(%)
Treatment
Discontinuation
(%)
80
NR
28
PR
45
20
91
33
63
PR
44
24
(single cohort; n=20)
Oton 2006
(2-center cohort; n=55)
Angelico 2007
(G1: 40)
83
NR
44
(randomized, controlled;
n=42)
Carrion 2007
90
33
15
(randomized, controlled;
n=81)
Picciotto 2007
PR
33
29
pegIFN
38
24
PR
48
40
Untreated
19
0
87
46
25
PR
28
15
79
19
15
PR
35
26
(single center; n=61)
Hanouneh 2008
(retrospective, medical
records; n=53)
PR: pegIFN + RBV; G: genotype; NR: not reported.
Dumortier J, et al. J Hepatol. 2004;40:669-674; Oton E, et al. Am J Transplant. 2006;6:2348-2355; Angelico M,
et al. J Hepatol. 2007;46:1009-1017; Carrion JA, et al. Gastroenterology. 2007;132:1746-756; Picciotto FP, et
al. J Hepatol. 2007;46:459-465; Hanouneh IA, et al. Liver Transplant. 2008;14:53-58.
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 lifethreatening 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
41
37
35
22
Grade 3/4 creatinine increase (%)
4
Renal failure
11
PR: pegIFN + RBV.
Brown K, et al. Hepatology. 2013;58(suppl 1):209A. Abstract 3.
CRUSH-C:
Virologic Response in HCV Genotype 1
-
Discontinuations: 20%
SVR12
eRVR
No eRVR
86%
Patients (%)
● eRVR is highly
predictive of SVR12
● Treatment duration <36
weeks negatively affects
SVR12 rates
● Adverse events led to
treatment
93%†
59%
50%
33%‡
Interruption: 7%
16%
5%
Overall
Yes
No
<36
>36
(n=90)
(n=56)
(n=32)
(n=5/10)
(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).
Stravitz R, et al. Hepatology. 2013;58(suppl 1):429A. Abstract 461.
Achieved
eRVR
Treatment
Duration (weeks)
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
Stravitz R, et al. Hepatology. 2013;58(suppl 1):429A. Abstract 461.
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)
3.1
INR
1.3
MELD score
15
Time from liver transplantation
(months)
17
PR: pegIFN + RBV.
Forns X, et al. J Hepatol. 2014;60(suppl 1):S26. Abstract O62.
Sofosbuvir Compassionate Use Program:
Initial Treatment Evaluations
Treatment Outcomes
● Overall, liver function tests
significantly improved over time
● Most patients improved clinically
or remained stable
-
Leading to treatment
discontinuation (13%)
● Deaths (13%) were mostly a result
of disease progression in this very
sick population
-
Patients (%)
● All serious adverse events (48%)
62%
62%
21%
21%
On treatment (n=8)
Post treatment follow-up (n=5)
SVR12
(n=85)
Improved* Stable
Worse
Clinical Outcomes
*Improved: improvement in decompensation events
(n=104)
(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.
Sofosbuvir + RBV: Treatment of
Recurrent HCV After Liver Transplantation
●
●
●
Key Results
Open-label study
Patients
(n=40)
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%
HCV RNA <25 IU/mL (%)
Week 4
SVR4
SVR12
SVR24
100
73
70
70
Concomitant immunosuppression (%)
Tacrolimus
Mycophenolate mofetil
Prednisone
Cyclosporin
Azathioprine
70
35
28
25
5
Adverse events (%)
Fatigue
Headache
Arthralgia
28
25
23
Grade 3/4 laboratory abnormalities (%)
Samuel D, et al. J Hepatol. 2014;60(suppl 1):S499. Abstract P1232.
25/28
SOLAR:
GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
Wk 0
Wk 12
LDV/SOF + RBV
Wk 24
Wk 36
SVR12
LDV/SOF + RBV
●
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
Reddy et al, AASLD
2014
SVR12
Baseline Disease Characteristics – 12 and 24 Weeks
GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
F0-F3
n=111
CPT A
n=51
CPT B
n=52
CPT C
n=9
<10
N/A
28 (55)
13 (25)
1 (11)
10-15
N/A
20 (39)
33 (63)
5 (56)
16-20
N/A
3 (6)
4 (8)
2 (22)
21-25
N/A
0
2 (4)
1 (11)
Ascites, n (%)
2 (2)
2 (4)
40 (77)
9 (100)
Encephalopathy, n (%)
1 (1)
3 (6)
23 (44)
7 (78)
Median bilirubin,
mg/dL (range)
0.7 (0.3-3.6)
0.8 (0.2-2.9)
1.2 (0.5-3.7)
2.1 (0.7-9.9)
Median albumin,
g/L (range)
3.8 (2.4-4.6)
3.7 (2.6-4.5)
3.2 (2.3-4.2)
2.4 (1.6-2.9)
Median INR (range)
1.0 (0.9-1.3)
1.1 (0.9-2.4)
1.2 (0.9-3.4)
1.3 (1.0-1.5)
Median platelets,
x 103/µL (range)
146 (71-429)
108 (41-358)
93 (32-225)
79 (54-189)
14.0 (10.1-18.3)
13.6 (11.2-17.9)
12.9 (9.6-17.0)
11.5 (9.6-14.2)
65.0
(20.4-116.8)
62.1
(26.8-110.9)
58.9
(29.0-118.9)
66.6
(39.5-72.1)
MELD (n, %)
Median hemoglobin,
g/dL (range)
Median CLCr,
mL/min (range)
Reddy et al, AASLD 2014
SVR12
GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
LDV/SOF + RBV 24 Weeks
SVR12 (%)
LDV/SOF + RBV 12 Weeks
53/55
55/56
F0–F3
25/26
24/25
CPT A
22/26
15/18
CPT B
3/5
2/3
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
Deaths
GT 1 or 4: Post-Transplant F0–F3, CPT A, B, C
Treatment
Duration
(Weeks)
Treatment
Related
Progressive multifocal leukoencephalitis
12
No
Unknown†
24
No
Thoracic aorta aneurysm dissection
12
No
Sepsis
12
No
Multi-organ failure/intestinal perforation
24
No
Internal bleeding – esophageal varices
24
No
Complications of cirrhosis (sepsis, thrombosis)
24
No
Cause of Death
CPT A
CPT B
Observation Period: Day 1 through Post-treatment Week 12
†per family request
Reddy et al, AASLD 2014
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
● SVR 97%
● Relapse 1
● No deaths, graft losses,
rejection
● RBV dose reduction: No
impact on overall SVR
- Median time from txp 39.5
mo
- METAVIR <F2, no prior PI
ABT-450/ritonavir/ombitasvir 150/100/25 mg qd; dasabuvir 250 mg bid. RBV (1000-1200 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.
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