ANATOMICAL FAETURES OF BONES FOR NURSING STUDENTS .pptx
Shaping the Future.Clinicians and Faculty Define: Strategies for the Next Era of HCV Therapy.2014
1. Shaping the Future: Clinicians and
Faculty Define Strategies for the
Next Era of HCV Therapy
This program is supported by educational grants from
2. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Program Director
Mark S. Sulkowski, MD
Professor of Medicine
Medical Director, Viral Hepatitis Center
Divisions of Infectious Diseases and Gastroenterology/Hepatology
Johns Hopkins University School of Medicine
Baltimore, Maryland
3. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Faculty
Jordan J. Feld, MD, MPH
Assistant Professor of Medicine
University of Toronto
Hepatologist
Toronto Western Hospital Liver Centre
McLaughlin-Rotman Centre for Global
Health
Toronto, Ontario, Canada
Graham R. Foster, FRCP, PhD
Professor of Hepatology
The Liver Unit
Consultant Hepatologist
Queen Marys University of London
London, United Kingdom
Michael W. Fried, MD
Professor of Medicine
Director, UNC Liver Center
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
Alessandra Mangia, MD
Liver Unit Hospital ‘Casa Sollievo della
Sofferenza’
Istituto di Ricovero e Cura a Carattere
Scientifico
San Giovanni Rotondo, Italy
Fred Poordad, MD
Vice President, Academic and Clinical
Affairs
The Texas Liver Institute
Professor of Medicine
University of Texas Health Science Center
San Antonio, Texas
Stefan Zeuzem, MD
Professor of Medicine
Chief, Department of Medicine I
JW Goethe University Hospital
Frankfurt, Germany
4. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
New Standard of Care for HCV in
2013/2014
Standard
Interferon
Interferon +
Ribavirin
Peginterferon/
Ribavirin
1991 1998 2001
2005
Boceprevir or
Telaprevir +
P/R
GT1
GT2/3
2011 2013
2013
Simeprevir or
Sofosbuvir +
P/R
Sofosbuvir +
Ribavirin
5. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Key Questions That Define the Future of
Hepatitis C Virus Therapy
How do we determine the best regimen for genotype 1 going forward?
Jordan J. Feld, MD, MPH
Why does genotype 3 do poorly and how can we do better?
Stefan Zeuzem, MD
Is one-size-fits-all treatment a possibility and how would that change
management?
Alessandra Mangia, MD
How will we manage patients who fail direct-acting antiviral therapies?
Graham R. Foster, FRCP, PhD
Why do cirrhotics do poorly and how can we do better?
Fred Poordad, MD
How will high-risk patients be managed going forward?
Michael W. Fried, MD
6. Jordan J. Feld, MD, MPH
Assistant Professor of Medicine
University of Toronto
Hepatologist
Toronto Western Hospital
Liver Centre
McLaughlin-Rotman Centre for Global
Health
Toronto, Ontario, Canada
How Do We Determine the Best
Regimen for Genotype 1 Going
Forward?
7. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Summary of New Agents for GT1 in 2013
Sofosbuvir + P/R
– Sofosbuvir is oral, once daily
– 12 wks with P/R
– SVR rate 89% in naives
– Low impact of baseline factors
Simeprevir + P/R
– Simeprevir is oral, once daily
– 12 wks with P/R + 12-36 wks with P/R
– SVR rate 80% in naives
– Q80K testing will be needed in GT 1a
Baseline Factor SVR12, % (n/N)
Black
Non-Black
86 (43/50)
90 (218/242)
Genotype 1a
Genotype 1b
92 (206/225)
82 (54/66)
Cirrhosis*
No cirrhosis*
80 (43/54)
92 (252/273)
*Represents GT 1/4/5/6.
Sofosbuvir FDA hearing. October 25, 2013. Simeprevir FDA hearing. October 24, 2013.
Baseline Factor SVR12, % (n/N)
Black
Non-Black
67 (29/43)
81 (378/464)
GT1a with Q80K
GT 1a, no Q80K
GT 1b
58 (49/84)
84 (138/165)
85 (228/267)
F3-F4*
F0-F2*
68 (89/130)
84 (317/378)
8. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Priorities
SVR trumps all
But SVR is a necessity—assuming SVR > 90%, what is next?
Considerations
– Several new P/R-based regimens completing phase III
– Faldaprevir + P/R
– Daclatasvir + P/R
– But with 89% SVR with 12-wk SOF + P/R, will there be a clinical role for
longer-duration P/R-based regimens?
– An all-oral future for GT1: multiple studies of 12- to 16-wk regimens
9. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Over-
treatment
of some
Tailored
regimen
for each
population
Priorities
Cost
Fewest
drugs
Shortest
duration
Simplicity
One size
fits all
10. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
2/12
One Size Fits All or Simpler Regimen for
Genotype 1b Only?
Genotype 1, naive
10% had cirrhosis
Dufour J-F, et al. AASLD 2013. Abstract 1102.
16-Wk Regimen: Faldaprevir (PI) 120 mg QD
+ Deleobuvir (NNI) 600 mg BID + RBV
(N = 32)
Simple regimen for genotype 1b only?
What if it were very cheap?
EOT SVR12
UndetectableHCV
RNA(IU/mL)
100
80
60
40
20
0
58
100
17
95
7/12 20/20 19/20
Genotype 1a,
IL28B CC
Genotype 1b
11. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
One Size Fits All or Simpler Regimen for
GT1b? Various Ways to Look at the Same Data
82
0
20
40
60
80
100
SVR12(%)
100 100 100 100 100
79
100
29 12
85
100
52 27
83
96
52 25
96 100
54 25
81
100
26 18
89
100
28 17
Observed data
(above bar)
ITT (within bar)
n =
81
98
8888
100
89
1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b
ABT-450
ABT-333
RBV
ABT-450
ABT-267
RBV
ABT-450
ABT-267
ABT-333
ABT-450
ABT-267
ABT-333
RBV
ABT-450
ABT-267
RBV
ABT-450
ABT-267
ABT-333
RBV
Treatment-Naive Patients Null Responders
Kowdley KV, et al. AASLD 2012. Abstract LB-1.
ABT-450/RTV (PI) ± ABT-333 (NNI) +
ABT-267 (NS5A) ± RBV x 12 Wks
One size fits all OR “simpler regimen” for GT1b?
12. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
What Is the Role of Ribavirin for
Genotype 1 Going Forward?
Still an enigma
Prevents/delays resistance
– Important for genotype 1a
– Important with NNI, PI, and NS5A
– Not relevant with NI-based combination
Reduces relapse
– May be relevant with shorter durations
– Limited data to date but does not look critical for most
NI-based combination regimens
13. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Same Duration for All or Shorter for Naive,
Longer for Previous Failures?
12 wks for all or 8 for naive and 12 for failures?
What about RBV? A third DAA for 6 wks?
SVR12(%)
0
20
40
60
80
100
19/
20
SOF
LDV
SOF
LDV
RBV
SOF
LDV
95
100
21/
21
95
18/
19
95
SOF
LDV
100
18/
19
21/
21
8 Wks 12 Wks 12 Wks
SOF
LDV
RBV
Naive
PI failure
n/N =
Lawitz E, et al. AASLD 2013. Abstract 215.
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Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Conclusions
Research continues for GT1 HCV
– More tailored approach in the near future
– Longer duration or additional agents for difficult-to-treat
populations?
One-size-fits-all approach ideal for inexperienced
providers
Rising demand for treatment anticipated
– Increased screening
– Availability of IFN-free regimens
16. Stefan Zeuzem, MD
Professor of Medicine
Chief, Department of Medicine
JW Goethe University Hospital
Frankfurt, Germany
Why Does Genotype 3 Do Poorly
and How Can We Do Better?
17. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Standard Treatment for GT2/3 HCV
Before treatment
(HCV RNA
quantification)
16 wks
therapy
HCV RNA
< 12-15
IU/mL
Pre-tx
< 8 x 105
IU/mL*
48 wks
therapy‡
HCV RNA
≥ 2 log
decline†
Wk 4
HCV RNA quantification
Wk 12
HCV RNA
quantification
24 wks
therapy
HCV RNA
< 12-15
IU/mL
*No treatment shortening in patients with advanced fibrosis, cirrhosis, metabolic syndrome, insulin resistance, HIV/HCV
coinfection, etc. No data for patients with persistently normal ALT levels. †
Detectable HCV RNA at Wk 24: discontinuation
of treatment.‡
Treatment duration of 36, 48, 72 wks in slow responders is currently investigated in prospective trials.
Tx
discontinued
< 2 log decline
EASL Practice Guidelines.
18. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
FISSION: Poorer Response to SOF/RBV in
GT3 vs GT2 Naives, Especially Cirrhotics
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
SVR12(%)
All Patients Patients With Cirrhosis
n/N =
10/
11
13/
38
8/
13
11/
37
100
80
60
40
20
0
97
56
78
63
91
34
62
30
68/
70
52/
67
102/
183
110/
176
GT2 GT3
SOF/RBV 12 Wks
PegIFN/RBV 24 Wks
GT2 GT3
19. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
FUSION: Impact of Cirrhosis and Duration
on SVR Rates
Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
6/10 5/26
SVR12(%)
25/26 7/923/23 14/38 14/2325/40
No Cirrhosis
Sofosbuvir + RBV 12 wks Sofosbuvir + RBV 16 wks
No CirrhosisCirrhosis Cirrhosis
Genotype 2 Genotype 3
19
6163
37
n/N =
100
80
60
40
20
0
96
100
60
78
100
80
60
40
20
0
SVR12(%)
n/N =
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Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Wk 0 Wk 24 SVR4,
SVR12,
SVR24
Placebo*
(n = 85)
Sofosbuvir + Ribavirin
(n = 84)*
*Protocol amended to eliminate placebo arm. 12-wk arm predominantly GT2 patients
(N = 73); 11 GT3 patients completed 12 wks of SOF + RBV prior to amendment to extend
treatment duration.
Zeuzem S, et al. AASLD 2013. Abstract 1085.
VALENCE: Evaluating Impact of Duration
on SVR With SOF/RBV
Wk 12
Tx-naive or
-experienced
GT2 or GT3 pts
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Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Overall Treatment Naive Treatment Experienced
SVR4(%)
n/N =
2/
2
30/
33
12/
13
87/
100
100
80
60
40
20
0
93
97
85
94
100
9192
87
68/
73
212/
250
29/
30
86/
92
No Cirrhosis Cirrhosis
7/
8
27/
45
88
60
No Cirrhosis CirrhosisOverall
12 wks of SOF + RBV in GT2
24 wks of SOF + RBV in GT3
Zeuzem S, et al. AASLD 2013. Abstract 1085. Jacobson IM, et al. N Engl J Med. 2013;368:1867-1877.
Lawitz E, et al. N Engl J Med. 2013;368:1878-1887.
VALENCE Efficacy Summary: SVR12
Phase III GT3 SVR12 data summary:
– TN noncirrhotics, 12 wks: 61% (FISSION)
– TN cirrhotics, 12 wks: 34% (FISSION)
– TE noncirrhotics, 16 wks: 63% (FUSION)
– TE cirrhotics, 16 wks: 61% (FUSION)
22. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Conclusions
Most GT3 patients will be able to be treated with 24 wks of
SOF/RBV
GT3, treatment-experienced, cirrhotic patients most
challenging group to treat with all-oral regimens
– Experts recommend 12 wks of SOF + pegIFN/RBV in short
term
23. Alessandra Mangia, MD
Liver Unit Hospital 'Casa Sollievo della
Sofferenza'
Istituto di Ricovero e Cura a Carattere
Scientifico
San Giovanni Rotondo, Italy
Is One-Size-Fits-All Treatment a
Possibility and How Would That
Change Management?
24. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
How Far Are We?
One Size . . . . . . Fits All?
Same treatment regardless of
fibrosis level, previous treatment
experience, or HCV genotype?
25. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
AVIATOR: Less Impact of Traditional
Negative Predictors on SVR Rates
Comparable high SVR rates among 247 patients administered 12 or 24 wks of
treatment
All enrolled patients were noncirrhotic
Kowdley KV, et al. EASL 2013. Abstract 3.
Treatment Naive Null Responders
100
80
60
40
20
0
M
aleFem
ale
1a
1b
≥
7log
F0-F1
<
7
log
F2-F3Non-CC
CC
SVR24(%)
SVR24(%)
n =
92 94 91
98
89
94 94 91
95
89
78 81 108 50 35 124 113 42 115 44
100
80
60
40
20
0
M
aleFem
ale
1a
1b
≥
7
log
F0-F1
<
7
log
F2-F3Non-CC
CC
n =
93
97 93 97
91
96 95 93 94
100
55 33 55 33 22 66 41 45 85 3
26. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
GT1 HCV Tx Naive: SVR Rates With
12 Wks of IFN-Free Tx in Phase II Studies
Few or no cirrhotic patients included in above studies
Corresponding rates for 24-wk regimens showed SVR12/24 of 52% (QUANTUM[1]
), 95%
to 100% (AI-444040[6]
), 93% (AVIATOR[5]
), 94% (A1443-014[8]
)
1. Lalezari LP, et al. EASL 2013. Abstract 845. 2. Gane E, et al. EASL 2013. Abstract 14. 3. Lawitz E, et al. AASLD 2013.
Abstract 215. 4. Sulkowski MS, et al. AASLD 2012. Abstract LB-2. 5. Kowdley K, et al. EASL 2013. Abstract 3. 6. Everson G,
et al. AASLD 2013. Abstract LB-1. 7. Lawitz E, et al. AASLD 2013. Abstract 76. 8. Sulkowski M, et al. EASL 2013. Abstract
1423.
Regimen N Study SVR 4/12, %
SOF (NS5B) + RBV 25 QUANTUM[1]
56
SOF (NS5B) + RBV 25 ELECTRON[2]
84
SOF (NS5B) + LDV (NS5A) 19 LONESTAR[3]
95
SOF (NS5B) + DCV (NS5A) ± RBV 82 AI-444040[4]
98-100
ABT-450 (PI) + ABT-267 (NS5A) + ABT-333
(NS5B) ± RBV
158 AVIATOR[5]
94
DCV (NS5A) + ASV (PI) + BMS-791325 (NS5B) 161 A1443-014[6]
92
MK-5172 (PI) + MK-8742 (NS5A) ± RBV 65 C-WORTHY[7]
96-100
27. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Phase III Studies of Sofosbuvir (Nuc) +
Ledipasvir (NS5A) ± RBV in GT1 HCV
ION-1*: GT1 Tx-Naive Pts
(16% Cirrhotic): SOF/LDV
FDC ± RBV for 12 Wks
Press release. These data are available in press release format only, have not been peer reviewed, may be incomplete,
and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.
*24-wk arms not yet reported.
ION-3: GT1 Tx-Naive Pts:
SOF/LDV FDC ± RBV
for 8 or 12 Wks
SOF/LDV FDC
SOF/LDV FDC +
RBV
n/N =
209/
214
211/
217
SVR12(%)
12 Wks
98 97100
90
60
40
20
0
8 Wks 12 Wks
202/
215
206/
216
201/
216
94 93 95
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Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
12-Wk Treatment in Previous Null
Responders?
ABT-450/RTV + ABT-267 +
ABT-333 + RBV
12 Wks
SVR12(%)
Naive
n/N =
42/
45
F0-F2 fibrosis
SVR4/12(%)
n/N =
SMV + SOF
+ RBV
12 Wks
SMV + SOF
12 Wks
*No F4
COSMOS[1,2]
Caveat: small numbers,
few patients with cirrhosis
1. Jacobson IM, et al. AASLD 2013. Abstract LB-3. 2. Lawitz E, et al. CROI 2013. Abstract 155LB.
3. Kowdley K, et al. EASL 2013. Abstract 3.
26/
27
13/
14
96 93
76/
79
14/
15
7/
7
93
100
F3/4 fibrosis
96 93
AVIATOR[3]
100
80
60
40
20
0
Null*
100
80
60
40
20
0
29. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
SAPPHIRE Phase III Studies: PI Backbone
+ 2 Other DAAs
SAPPHIRE-1: GT1 Tx-Naive
Noncirrhotic Pts:
ABT-450/RTV/ABT-267 FDC
+ ABT-333 + RBV for 12 Wks
Press release. These data are available in press release format only, have not been peer reviewed, may be incomplete,
and we await presentation or publication in a peer-reviewed format before conclusions should be made from these data.
n/N =
455/
473
307/
322
148/
151
SAPPHIRE-2: GT1 Tx-Experienced
Noncirrhotic Pts (49% Null Responders):
ABT-450/RTV/ABT-267 FDC
+ ABT-333 + RBV for 12 Wks
100
80
60
40
20
0
SVR12(%)
96 95 98
Overall GT1a GT1b
n/N =
286/
297
166/
173
119/
123
100
80
60
40
20
0
SVR12(%)
96 96 97
Overall GT1a GT1b
30. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
SOF-Based IFN-Free DAA Treatment in
GT1 Treatment-Experienced Patients
SOF + LDV + RBV x 12 wks
(prior null, noncirrhotic)
100
80
60
40
20
0
SVR4/12(%)
100[1]
2 DAAs + RBV
SOF + LDV x 12 wks (prior
PI failures, 50% cirrhotic)
2 DAAs, No RBV
7/10
70[2]
9/9
100[2]
SOF + LDV + RBV x 12 wks
(TE with cirrhosis)
SOF + LDV x 12 wks
(TE with cirrhosis)
95[3]
1. Gane EJ, et al. CROI 2013. Abstract 41LB. 2. Gane EJ, et al. AASLD 2013. Abstract 73. 3. Lawitz E, et
al. AASLD 2013. Abstract 215.
18/199/9n/N =
31. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Phase III Studies of Sofosbuvir (Nuc) +
Ledipasvir (NS5A) ± RBV in GT1 HCV
Press release. These data are available in press release format only, have not been peer reviewed, may be incomplete, and we
await presentation or publication in a peer-reviewed format before conclusions should be made from these data.
SOF/LDV FDC SOF/LDV FDC + RBV
ION-2: GT1 Treatment-Experienced Pts (20% Cirrhotic):
SOF/LDV FDC ± RBV for 12 or 24 Wks
n/N =
SVR12(%)
100
90
60
40
20
0
12 Wks 24 Wks
102/
109
107/
111
108/
109
110/
111
94 96 99 99
32. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Challenging Patient Groups
Patients with cirrhosis
HCV genotype 3 infection
Patients nonresponsive to DAA regimens
HIV coinfection
33. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Conclusions
Future role for specialists in HCV
– Treating more complex cases
– Determining indication for starting treatment
– Surveillance of cirrhotic patients following successful therapy
34. Graham R. Foster, FRCP, PhD
Professor of Hepatology
The Liver Unit
Consultant Hepatologist
Queen Marys University of London
London, United Kingdom
How Will We Manage Patients Who
Fail Direct-Acting Antiviral
Therapies?
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Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
DAA Failures: The Principles
In other viral infections, “failure” can be resolved by
complementary drugs
– eg, in HBV, lamivudine failures respond to adefovir or
tenofovir
Will the same hold true for HCV?
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Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
High SVR Rates With 24 Wks of All-Oral
Therapy in GT1 Patients With PI Failure
Sulkowski MS, et al. EASL 2013. Abstract 1417.
*1 patient in daclatasvir/sofosbuvir/RBV arm had missing data at Wk 12 posttreatment; this patient had
undetectable HCV RNA at Wk 4 and Wk 24 posttreatment.
SVR4 SVR12
24 wks of daclatasvir
+ sofosbuvir
24 wks of daclatasvir
+ sofosbuvir + RBV
100 100 100
95*100
80
60
40
20
0
Patients(%)
n/N =
21/
21
20/
20
21/
21
19/
20
37. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
LONESTAR: High SVR Rates With 12 Wks
of Therapy in GT1 Patients With PI Failure
Lawitz E, et al. AASLD 2013. Abstract 215.
12 wks of SOF/LDV FDC
12 wks of SOF/LDV FDC + RBV
95
100
100
80
60
40
20
0
SVR12(%)
n/N =
18/
19
21/
21
38. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Complementary Regimens:
Drug Classes for the Future
Nucleotide polymerase inhibitors (eg, sofosbuvir)
NS5A inhibitors (eg, daclatasvir, ledipasvir)
Protease inhibitors (eg, simeprevir, faldaprevir)
Non-nucleotide polymerase inhibitors (3 different classes)
Host-targeting drugs (cyclophilins, microRNAs RIG-I
activators)
Which will work best together?
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Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Conclusions
Second-line therapy and beyond
– New challenges with increased treatment options
– Continued treatment failures anticipated with more difficult-
to-treat populations
Managing treatment failures
– Determine cause
– Risk factors – modifiable?
– Adherence with all-oral regimens
– Patient education and adherence management key
40. Fred Poordad, MD
Vice President
Academic and Clinical Affairs
The Texas Liver Institute
Professor of Medicine
University of Texas Health Science Center
San Antonio, Texas
Why Do Cirrhotics Do Poorly and
How Can We Do Better?
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Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
CUPIC: Telaprevir or Boceprevir + P/R
in GT1 Treatment-Experienced Cirrhotics
Fontaine H, et al. EASL 2013. Abstract 60. Hezode C, et al. J Hepatol. 2013;59:434-441.
n/N =
118/
295
79/
190
61/
116
43/
85
43/
135
32/
80
8/
28 1/9
100
80
60
40
20
0
SVR12(%)
Overall Relapsers PRs NRs
40 41
53 51
32
40
29
11
Telaprevir + P/R
Boceprevir + P/R
Risk of Death or Severe
Complications, % (n/N)
Platelet Count
> 100,000 cells/mm3
Platelet Count
≤ 100,000 cells/mm3
Albumin ≥ 35 g/L 3.4 (10/298) 4.3 (3/69)
Albumin < 35 g/L 7.1 (2/28) 44.1 (15/34)
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Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Impact of Cirrhosis on SVR12 With
Next-Generation PI + P/R
Jacobson I, et al. EASL 2013. Abstract 1425. Ferenci P, et al. EASL 2013. Abstract 1416.
18/
31n/N =
5/
17
188/
229
60/
113
82
53
58
29
Simeprevir + P/R
P/R
100
80
60
40
20
0
SVR12(%)
No Cirrhosis Cirrhosis
QUEST-1:
Simeprevir + P/R
Treatment-Naive GT1
172/
212
30/
45
9/
16
100
80
60
40
20
0
81
67
56
< F3 ≥ F3 F4
STARTVerso1:
Faldaprevir + P/R
Treatment-Naive GT1
Faldaprevir + P/R
43. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Impact of Cirrhosis on SVR12 With
Sofosbuvir-Based Therapy in Tx-Naive Pts
Lawitz E, et al. EASL 2013. Abstract 1411. Zeuzem S, et al. AASLD 2013. Abstract 1085.
SVR12(%)
92
80
252/
273 43/54
NEUTRINO:
12 Wks of SOF +
P/R
GT1/4/5/6
Genotype 2 Genotype 3
58/59 10/11 89/145 13/38
100
80
60
40
20
0
n/N =
98
91
61
34
FISSION:
12 Wks of SOF + RBV
GT2/3
CirrhoticNoncirrhotic
94
86/92 12/13
92
VALENCE:
24 Wks of SOF +
RBV
GT3
Genotype 1/4/5/6 Genotype 3
100
80
60
40
20
0
100
80
60
40
20
0
44. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
100
80
60
40
20
0
37
63
87
19
61 60
No Cirrhosis Cirrhosis
Impact of Duration, Addition of PegIFN on
Efficacy of SOF in Tx-Experienced GT2/3
FUSION: 12 wks of SOF/RBV
FUSION: 16 wks of SOF/RBV
VALENCE: 24 wks of SOF/RBV
LONESTAR-2:
12 Wks of SOF + PegIFN/RBV
Sofosbuvir FDA hearing. October 25, 2013. Lawitz E, et al. AASLD 2013.
SVR12(%)
14/
38
25/
40
87/
100
5/
26
14/
23
27/
45
Genotype 3
100
80
60
40
20
0
96 93
100
83 83 83
Genotype 2 Genotype 3
SVR12(%)
Overall Cirrhotic Noncirrhotic
n/N =
22/
23
13/
14
9/
9
20/
24
10/
12
10/
12
45. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Efficacy of IFN-Free DAA Combinations in
Tx-Naive and Tx-Experienced Cirrhotics
COSMOS:
12-Wk Regimens in GT1 HCV Cirrhotic
Tx-Naive or Previous Null Responders
SVR4/12(%)
Jacobson IM, et al. AASLD 2013. Abstract LB-3. Lawitz E, et al. AASLD 2013. Abstract 215. Everson GT,
et al. AASLD 2013. Abstract LB-1.
LONESTAR:
12-Wk Regimens in GT1 HCV
PI Failures (55% Cirrhotic)
AI443-014:
12-Wk Regimen in GT1
Tx-Naive Cirrhotics
100
80
60
40
20
0
91
100
10/11 7/7
Simeprevir + sofosbuvir + RBV
Simeprevir + sofosbuvir
100
80
60
40
20
0
18/19 21/21
95
100
Sofosbuvir/ledipasvir
Sofosbuvir/ledipasvir + RBV
100
80
60
40
20
0
87
Daclatasvir + asunaprevir
+ BMS-791325
13/15n/N =
46. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Conclusions
Eradication of HCV optimal before progression to cirrhosis
Poorer response of cirrhotic patients likely multifactorial
– Poor prior IFN response and GT3 most challenging
Treatment approaches
– GT3 experienced, cirrhotic: 12 wks of SOF + pegIFN/RBV
– GT3 naive, cirrhotic: 24 wks of SOF + RBV
Further improvements anticipated with DAA combinations
47. Michael W. Fried, MD
Professor of Medicine
Director, UNC Liver Center
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina
How Will High-Risk Patients Be
Managed Going Forward?
48. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Goals of Antiviral Therapy
Decompensated cirrhosis
– Eradicate HCV to prevent further deterioration
– Eradicate HCV to prevent reinfection of graft
– Improve hepatic functional status
– Delay or obviate the need for transplantation
Posttransplantation
– Treat acute complications of HCV reinfection
– Prevent/arrest progression to cirrhosis
– Improve morbidity and mortality
– Liver related
– Extrahepatic effects on cardiovascular disease
49. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
HCV Management Issues Unique to
Pre- and Posttransplantation Patients
Pretransplantation
– Intolerance to peginterferon regimens
– Impaired hepatic metabolism
– Renal insufficiency
Posttransplantation
– High HCV RNA/impact of immunosuppression
– Fibrosing cholestatic hepatitis
– Drug–drug interactions
– Renal insufficiency
– Other medical comorbidities
50. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
PegIFN/RBV Before Transplantation to
Minimize HCV Recurrence Post-LT
Everson GT, et al. Hepatology. 2013;57:1752-1762.
P = .6011
TreatedLTPatients(%)
100
80
60
40
20
0
Overall
(n = 44)
GT1/4/6
(n = 23)
GT2/3
(n = 44)
59
25
52
22
67
29
HCV RNA negative at LT
HCV RNA negative 12 wks of post-LT
51. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Characteristic SOF + RBV
(N = 61)
Median age, yrs (range) 59 (46-73)
HCV genotype, %
1a 39
1b 34
2 13
3a 12
4 2
Non-CC IL28B genotype, % 78
CTP score, %
5-7 96
8 5
Previous HCV treatment, % 75
Pretransplant Sofosbuvir + RBV to
Prevent Posttransplant HCV Recurrence
Study 025: single-arm, open-label,
phase II study from 16 LT sites
– Listed for LT due to HCC meeting
Milan criteria
– MELD exception for HCC
– CTP score ≤ 7
Excluded decompensated cirrhosis,
renal impairment, living donor LT
Pre-LT therapy: SOF 400 mg/day +
RBV 1000-1200 mg/day for 48 wks
or until time of LT
– Post-LT immunosuppression:
≥ 12 wks of tacrolimus +
prednisone + MMF
Curry MP, et al. AASLD 2013. Abstract 213.
52. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Duration of Undetectable HCV RNA Before
Transplant Predicted Lack of Recurrence
64% of pts HCV RNA negative 12 wks
post-LT (93% at LT)
Continuous days TND pre-LT only
factor predicting HCV recurrence in
multivariate analysis
– Only 1/24 pts with > 30 days TND
experienced recurrence
Curry MP, et al. AASLD 2013. Abstract 213.
3300 30 60 90 120 150 180 210 240 270 300
Days With HCV RNA Continuously TND Prior to LT
> 30 days TND
No recurrence (n = 28)
Recurrence (n = 10)
Median days TND (P < .001)
No recurrence: 95
Recurrence: 5.5
53. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
CRUSH C: PI + PegIFN/RBV in Liver
Transplantation Recipients
112 patients: 30 were F4 or FCH
Treatment: TVR 88% or BOC 12%
– P/R lead-in 96%
Verna EC, et al. EASL 2013. Abstract 23.
HCVRNA<LOD(%)
100
80
60
40
20
0
EOTR SVR4
67 65
n = 43
Adverse Effect All Patients
(N = 112)
AE requiring treatment d/c, % 11
Dose reduction, %
PegIFN/RBV 34/80
Transfusion, % 46
Erythropoietin, % 79
G-CSF 41
Hospitalization, %* 21
Renal function
Cr increase > 0.5 mg/dL, %
Max ↑ in Cr, mg/dL (range)
34
0.4 (0-2.5)
Rejection, %†
4
Death, % 6
*Significantly differed between groups (P = .02).
†
Any treated rejection during or after TT.
54. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Daclatasvir 60 mg/day +
Sofosbuvir 400 mg/day
Case Report: Sofosbuvir + Daclatasvir in
Post-LT Fibrosing Cholestatic Hepatitis
Fontana RJ, et al. Am J Transplant. 2013;13:1601-1605.
8
7
6
5
4
3
2
1
0
LogHCVRNA(IU/mL)
Treatment Wk
400
350
300
250
200
150
100
50
0
ALT(IU/L)
AlkPhos(IU/L)
0 1 2 3 4 6 8 1012 14 1618 20 222425 2848 56 60
ALT
Alk Phos
HCV RNA
55. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Sofosbuvir + RBV for Treatment of
Post-LT HCV Recurrence
Ongoing prospective,
multicenter, single-arm,
open-label pilot study
– Median time since LT: 4.3 yrs
(range: 1.02-10.6)
– CTP ≤ 7 and MELD ≤ 17
– 83% GT1, 33% IL28B CC, 40%
with comp’d cirrhosis
SOF 400 mg/day + RBV
400-1200 mg/day for ≤ 24 wks
– RBV started at 400 mg/day and
increased based on hemoglobin
levels
Charlton MR, et al. AASLD 2013. Abstract LB-2. Reproduced with permission.
Virologic Response Rates
*1 patient still on treatment.
†
4 patients had not reached SVR4 visit.
Wk 4 EOT* SVR4
Response(%)
100
80
60
40
20
0
100 100
77
40/40 39/39 27/35†
56. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Other Studies Recruiting
Sofosbuvir/ledipasvir FDC + RBV for 12 or 24 wks in
patients with advanced liver disease or posttransplantation
recurrence[1]
Simeprevir + daclatasvir + RBV for 24 wks in genotype 1b
patients with posttransplantation recurrence[2]
ABT-450/RTV/ABT-267 FDC + ABT-333 + RBV for 24 wks
in liver transplantation recipients[3]
1. ClinicalTrials.gov. NCT01938430. 2. ClinicalTrials.gov. NCT01938625. 3. ClinicalTrials.gov.
NCT01782495.
57. clinicaloptions.com/hepatitis
Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Conclusions
Pre- and post-LT patients greatest challenge to eradication
of HCV
– Recent data encouraging
– Significant challenges remain
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Hinweis der Redaktion
GT, genotype; HCV, hepatitis C virus; P/R, peginterferon/ribavirin.
DAA, direct-acting antiviral; HCV, hepatitis C virus.
HCV, hepatitis C virus.
DAA, direct-acting antiviral; HBV, hepatitis B virus; HCV, hepatitis C virus.
GT, genotype; HCV, hepatitis C virus; PI, protease inhibitor; RBV, ribavirin; SVR4, sustained virologic response rate at 4 weeks posttreatment; SVR12, sustained virologic response rate at 12 weeks posttreatment.
For more information on this study, review the CCO Capsule Summary at: http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/Amsterdam%202013/Viral%20Hepatitis/Capsules/1417.aspx.
CTP, Child-Turcotte-Pugh; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; LT, liver transplantation; MELD, Model for End-Stage Liver Disease; MMF, mycophenolate mofetil; RBV, ribavirin; SOF, sofosbuvir.
For more information about this study, please see the CCO Capsule Summary at:
http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202013/Other%20Highlights/Capsules/213.aspx
HCV, hepatitis C virus; LT, liver transplantation; TND, target not detected.
For more information about this study, please see the CCO Capsule Summary at:
http://www.clinicaloptions.com/Hepatitis/Conference%20Coverage/AASLD%202013/Other%20Highlights/Capsules/213.aspx