shaping the future.clinicians and faculty define: strategies for the next era of hcv therapy.2014
TRANSCRIPT
Shaping the Future: Clinicians and Faculty Define Strategies for the Next Era of HCV Therapy
This program is supported by educational grants from
clinicaloptions.com/hepatitisClinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Program Director
Mark S. Sulkowski, MD Professor of MedicineMedical Director, Viral Hepatitis CenterDivisions of Infectious Diseases and Gastroenterology/HepatologyJohns Hopkins University School of MedicineBaltimore, Maryland
clinicaloptions.com/hepatitisClinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Faculty
Jordan J. Feld, MD, MPHAssistant Professor of MedicineUniversity of TorontoHepatologistToronto Western Hospital Liver CentreMcLaughlin-Rotman Centre for Global HealthToronto, Ontario, Canada
Graham R. Foster, FRCP, PhDProfessor of HepatologyThe Liver UnitConsultant HepatologistQueen Marys University of LondonLondon, United Kingdom
Michael W. Fried, MDProfessor of MedicineDirector, UNC Liver CenterUniversity of North Carolina at Chapel HillChapel Hill, North Carolina
Alessandra Mangia, MDLiver Unit Hospital ‘Casa Sollievo della Sofferenza’Istituto di Ricovero e Cura a Carattere ScientificoSan Giovanni Rotondo, Italy
Fred Poordad, MDVice President, Academic and Clinical AffairsThe Texas Liver InstituteProfessor of MedicineUniversity of Texas Health Science CenterSan Antonio, Texas
Stefan Zeuzem, MD Professor of Medicine Chief, Department of Medicine I JW Goethe University Hospital Frankfurt, Germany
clinicaloptions.com/hepatitisClinicians 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
clinicaloptions.com/hepatitisClinicians 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
Jordan J. Feld, MD, MPHAssistant Professor of MedicineUniversity of TorontoHepatologistToronto Western HospitalLiver CentreMcLaughlin-Rotman Centre for Global HealthToronto, Ontario, Canada
How Do We Determine the Best Regimen for Genotype 1 Going Forward?
clinicaloptions.com/hepatitisClinicians 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)
BlackNon-Black
86 (43/50)90 (218/242)
Genotype 1aGenotype 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)
BlackNon-Black
67 (29/43)81 (378/464)
GT1a with Q80KGT 1a, no Q80KGT 1b
58 (49/84)84 (138/165)85 (228/267)
F3-F4*F0-F2*
68 (89/130)84 (317/378)
clinicaloptions.com/hepatitisClinicians 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
clinicaloptions.com/hepatitisClinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Over-treatmentof some
Tailoredregimen for each
population
Priorities
Cost
Fewestdrugs
Shortestduration
SimplicityOne size
fits all
clinicaloptions.com/hepatitisClinicians 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
Un
det
ecta
ble
HC
V
RN
A (
IU/m
L)
100
80
60
40
20
0
58
100
17
95
7/12 20/20 19/20
Genotype 1a, IL28B CCGenotype 1b
clinicaloptions.com/hepatitisClinicians 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
SV
R12
(%
)
100 100 100 100 100
79
100
29 12
85
100
52 27
8396
52 25
96 100
54 25
81
100
26 18
89100
28 17
Observed data (above bar)
ITT (within bar)
n =
81
988888
10089
1a 1b 1a 1b 1a 1b 1a 1b 1a 1b 1a 1b
ABT-450
ABT-333RBV
ABT-450ABT-267
RBV
ABT-450ABT-267ABT-333
ABT-450ABT-267ABT-333
RBV
ABT-450ABT-267
RBV
ABT-450ABT-267ABT-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?
clinicaloptions.com/hepatitisClinicians 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
clinicaloptions.com/hepatitisClinicians 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?
SV
R12
(%
)
0
20
40
60
80
100
19/20
SOFLDV
SOFLDVRBV
SOFLDV
95100
21/21
95
18/19
95
SOFLDV
100
18/19
21/21
8 Wks 12 Wks 12 Wks
SOFLDVRBV
NaivePI failure
n/N =
Lawitz E, et al. AASLD 2013. Abstract 215.
clinicaloptions.com/hepatitisClinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Are We Moving to Primary Care?
Project ECHO
One size fits all may be critical
Project ECHO Web site.
clinicaloptions.com/hepatitisClinicians 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
Stefan Zeuzem, MDProfessor of MedicineChief, Department of MedicineJW Goethe University HospitalFrankfurt, Germany
Why Does Genotype 3 Do Poorly and How Can We Do Better?
clinicaloptions.com/hepatitisClinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Standard Treatment for GT2/3 HCVBefore treatment
(HCV RNA quantification)
16 wkstherapy
HCV RNA < 12-15 IU/mL
Pre-tx< 8 x 105 IU/mL*
48 wkstherapy‡
HCV RNA ≥ 2 log decline†
Wk 4HCV RNA quantification
Wk 12HCV RNA
quantification
24 wkstherapy
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.
clinicaloptions.com/hepatitisClinicians 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.
SV
R12
(%
)
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 WksPegIFN/RBV 24 Wks
GT2 GT3
clinicaloptions.com/hepatitisClinicians 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
SV
R12
(%
)
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
96100
60
78
100
80
60
40
20
0
SV
R12
(%
)
n/N =
clinicaloptions.com/hepatitisClinicians 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
clinicaloptions.com/hepatitisClinicians and Faculty Define Strategies for the Next Era of HCV Therapy
Overall Treatment Naive Treatment Experienced
SV
R4
(%)
n/N =2/2
30/33
12/13
87/100
100
80
60
40
20
0
9397
8594
1009192
87
68/73
212/250
29/30
86/92
No Cirrhosis Cirrhosis
7/8
27/45
88
60
No Cirrhosis CirrhosisOverall12 wks of SOF + RBV in GT224 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)
clinicaloptions.com/hepatitisClinicians 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
Alessandra Mangia, MDLiver 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?
clinicaloptions.com/hepatitisClinicians 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?
clinicaloptions.com/hepatitisClinicians 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 noncirrhoticKowdley KV, et al. EASL 2013. Abstract 3.
Treatment Naive Null Responders
100
80
60
40
20
0
Mal
eFe
mal
e 1a 1b≥
7 lo
g
F0-F
1
< 7
log
F2-F
3N
on-C
CC
C
SV
R24
(%
)
SV
R24
(%
)
n =
92 94 9198
8994 94 91 95
89
78 81 108 50 35 124 113 42 115 44
100
80
60
40
20
0
Mal
eFe
mal
e 1a 1b≥
7 lo
g
F0-F
1
< 7
log
F2-F
3N
on-C
CC
C
n =
9397 93 97
9196 95 93 94
100
55 33 55 33 22 66 41 45 85 3
clinicaloptions.com/hepatitisClinicians 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
clinicaloptions.com/hepatitisClinicians 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
SV
R12
(%
)
12 Wks
98 97100
90
60
40
20
08 Wks 12 Wks
202/215
206/216
201/216
94 93 95
clinicaloptions.com/hepatitisClinicians 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
SV
R12
(%
)
Naive
n/N =42/45
F0-F2 fibrosis
SV
R4/
12 (
%)
n/N =
SMV + SOF + RBV 12 Wks
SMV + SOF12 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
93100
F3/4 fibrosis
96 93
AVIATOR[3]
100
80
60
40
20
0
Null*
100
80
60
40
20
0
clinicaloptions.com/hepatitisClinicians 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
SV
R12
(%
)
96 95 98
Overall GT1a GT1b
n/N =286/297
166/173
119/123
100
80
60
40
20
0
SV
R12
(%
)
96 96 97
Overall GT1a GT1b
clinicaloptions.com/hepatitisClinicians 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
SV
R 4
/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 =
clinicaloptions.com/hepatitisClinicians 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 =
SV
R12
(%
)
100
90
60
40
20
012 Wks 24 Wks
102/109
107/111
108/109
110/111
94 96 99 99
clinicaloptions.com/hepatitisClinicians 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
clinicaloptions.com/hepatitisClinicians 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
Graham R. Foster, FRCP, PhDProfessor of HepatologyThe Liver UnitConsultant HepatologistQueen Marys University of LondonLondon, United Kingdom
How Will We Manage Patients Who Fail Direct-Acting Antiviral Therapies?
clinicaloptions.com/hepatitisClinicians 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?
clinicaloptions.com/hepatitisClinicians 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 + sofosbuvir24 wks of daclatasvir + sofosbuvir + RBV
100 100 10095*100
80
60
40
20
0
Pat
ien
ts (
%)
n/N =21/21
20/20
21/21
19/20
clinicaloptions.com/hepatitisClinicians 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 FDC12 wks of SOF/LDV FDC + RBV
95100
100
80
60
40
20
0
SV
R12
(%
)
n/N =18/19
21/21
clinicaloptions.com/hepatitisClinicians 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?
clinicaloptions.com/hepatitisClinicians 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
Fred Poordad, MDVice President Academic and Clinical AffairsThe Texas Liver InstituteProfessor of MedicineUniversity of Texas Health Science CenterSan Antonio, Texas
Why Do Cirrhotics Do Poorly and How Can We Do Better?
clinicaloptions.com/hepatitisClinicians 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
SV
R12
(%
)
Overall Relapsers PRs NRs
40 41
53 51
3240
29
11
Telaprevir + P/RBoceprevir + 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)
clinicaloptions.com/hepatitisClinicians 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/RP/R
100
80
60
40
20
0
SV
R12
(%
)
No Cirrhosis Cirrhosis
QUEST-1: Simeprevir + P/R
Treatment-Naive GT1
172/212
30/45
9/16
100
80
60
40
20
0
81
6756
< F3 ≥ F3 F4
STARTVerso1: Faldaprevir + P/R
Treatment-Naive GT1
Faldaprevir + P/R
clinicaloptions.com/hepatitisClinicians 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.
SV
R12
(%
)
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
0n/N =
9891
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
clinicaloptions.com/hepatitisClinicians 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/RBVFUSION: 16 wks of SOF/RBVVALENCE: 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.
SV
R12
(%
)
14/38
25/40
87/100
5/26
14/23
27/45
Genotype 3
100
80
60
40
20
0
96 93100
83 83 83
Genotype 2 Genotype 3
SV
R12
(%
)
Overall Cirrhotic Noncirrhotic
n/N =22/23
13/14
9/9
20/24
10/12
10/12
clinicaloptions.com/hepatitisClinicians 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
SV
R4/
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 + RBVSimeprevir + sofosbuvir
100
80
60
40
20
018/19 21/21
95100
Sofosbuvir/ledipasvir Sofosbuvir/ledipasvir + RBV
100
80
60
40
20
0
87
Daclatasvir + asunaprevir + BMS-791325
13/15n/N =
clinicaloptions.com/hepatitisClinicians 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
Michael W. Fried, MDProfessor of MedicineDirector, UNC Liver CenterUniversity of North Carolina at Chapel HillChapel Hill, North Carolina
How Will High-Risk Patients Be Managed Going Forward?
clinicaloptions.com/hepatitisClinicians 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
clinicaloptions.com/hepatitisClinicians 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
clinicaloptions.com/hepatitisClinicians 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
Tre
ated
LT
Pat
ien
ts (
%)
100
80
60
40
20
0Overall(n = 44)
GT1/4/6(n = 23)
GT2/3(n = 44)
59
25
52
22
67
29
HCV RNA negative at LTHCV RNA negative 12 wks of post-LT
clinicaloptions.com/hepatitisClinicians 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.
clinicaloptions.com/hepatitisClinicians 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 300Days 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: 95Recurrence: 5.5
clinicaloptions.com/hepatitisClinicians 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.
HC
V R
NA
< L
OD
(%
)
100
80
60
40
20
0EOTR 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 functionCr increase > 0.5 mg/dL, %Max ↑ in Cr, mg/dL (range)
340.4 (0-2.5)
Rejection, %† 4
Death, % 6
*Significantly differed between groups (P = .02). †Any treated rejection during or after TT.
clinicaloptions.com/hepatitisClinicians 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
Lo
g H
CV
RN
A (
IU/m
L)
Treatment Wk
400
350
300
250
200
150
100
50
0
AL
T (IU
/L)
Alk P
ho
s (IU/L
)
0 1 2 3 4 6 8 1012 14 1618 20 22 2425 2848 56 60
ALTAlk PhosHCV RNA
clinicaloptions.com/hepatitisClinicians 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
Res
po
nse
(%
)
100
80
60
40
20
0
100 100
77
40/40 39/39 27/35†
clinicaloptions.com/hepatitisClinicians 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.
clinicaloptions.com/hepatitisClinicians 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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