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1392GR16NP0155815/3/16
1392GR16NP0155815/3/16
1392GR16NP0155815/3/16
Chronic Hepatitis C:Local and Global
Treatment Guidelines
Nikolaos K. Gatselis
Department of Medicine& Research Laboratory of Internal
Medicine,Larissa Medical School,
Thessaly University
Nikolaos K. Gatselis
Department of Medicine& Research Laboratory of Internal
Medicine,Larissa Medical School,
Thessaly University
1392GR16NP0155815/3/16
Disclosure
• Research Support: Gilead, Janssen, Bayern, Roche,Abbvie, Regulus, MSD
• Speaker Bureau: BMS
• Travel expenses: Janssen, BMS, Novartis, Gilead, TEVA,Abbvie
• Research Support: Gilead, Janssen, Bayern, Roche,Abbvie, Regulus, MSD
• Speaker Bureau: BMS
• Travel expenses: Janssen, BMS, Novartis, Gilead, TEVA,Abbvie
5
Δεκέμβριος 2015
Indications for treatment: who shouldbe treated?
All treatment-naïve and -experienced patientswith compensated or decompensated chronicliver disease related to HCV, who are willing tobe treated and who have no contraindications
to treatment, should be considered for therapy.
Because not every HCV-infected patient canbe treated within the next year or so,
prioritisation is necessary.
All treatment-naïve and -experienced patientswith compensated or decompensated chronicliver disease related to HCV, who are willing tobe treated and who have no contraindications
to treatment, should be considered for therapy.
Because not every HCV-infected patient canbe treated within the next year or so,
prioritisation is necessary.
Criteria for prioritisation foradministration of DAAs
1.fibrosis stage
2.risk of progression towards more advanceddisease
3.presence of extrahepatic manifestations ofHCV infection
4.risk of HCV transmission
1.fibrosis stage
2.risk of progression towards more advanceddisease
3.presence of extrahepatic manifestations ofHCV infection
4.risk of HCV transmission
Prioritisation for administration of DAAs
• advanced liver disease (METAVIR: F3-F4)
• decompensated cirrhosis Child B or C
• HCV recurrence after liver transplantation
• HIV co-infection
• severe extrahepatic manifestations (symptomaticcryoglobulinemia, HCV immune complex nephropathy, non-Hodgkin Bcell lymphoma)
• chronic hemoglobinopathies
• advanced liver disease (METAVIR: F3-F4)
• decompensated cirrhosis Child B or C
• HCV recurrence after liver transplantation
• HIV co-infection
• severe extrahepatic manifestations (symptomaticcryoglobulinemia, HCV immune complex nephropathy, non-Hodgkin Bcell lymphoma)
• chronic hemoglobinopathies
KEELPNO 2015
Prioritisation for administration of DAAs
• Justified in F2 patients
• age >75 years old is NOT an exclusion criterion
• individuals at risk of transmitting HCV
(haemodialysis patients)
• Justified in F2 patients
• age >75 years old is NOT an exclusion criterion
• individuals at risk of transmitting HCV
(haemodialysis patients)
KEELPNO 2015
Goals & endpoints of HCV therapyPrevention of
• necroinflammation• fibrosis• cirrhosis• decompensation of cirrhosis• hepatocellurar carcinoma• severe extrahepatic manifestations• death
GOALSGOALS
Prevention of• necroinflammation• fibrosis• cirrhosis• decompensation of cirrhosis• hepatocellurar carcinoma• severe extrahepatic manifestations• death
GOALS
ENDPOINTENDPOINT
SVR12
undetectable HCV RNA 12 weeks after theend of therapy, as assessed by a sensitive
molecular method with LLD ≤15 IU/ml
Long term benefits of SVRFibrosis downstaging
Long term benefits of SVRDelisting from liver transplant list
Long term benefits of SVRRisk reduction for liver cancer
≥70% reduction in the risk of liver cancer
Morgan, Ann Intern Med 2013.
Geno1a
Geno1b
Geno2
Geno3
Geno4
Geno5/6
x24 w
naïveF1-F2
≤ 800000 IU/mlCC IL28B
RVR
x24 w
naïveF1-F2
(x12-16w,<800000 IU/ml,
RVR)
x24 w
naïveF1-F2
(x16w,<800000
IU/ml,RVR)
x24 w
naïveF1-F2
CC IL28BRVR
x24 w
naïveF1-F2
CC IL28BRVR
Peg-IFN + R combination is still here!
PR KEELPNO12/2015
x24 w
naïveF1-F2
≤ 800000 IU/mlCC IL28B
RVR
x24 w
naïveF1-F2
(x12-16w,<800000 IU/ml,
RVR)
x24 w
naïveF1-F2
(x16w,<800000
IU/ml,RVR)
x24 w
naïveF1-F2
CC IL28BRVR
x24 w
naïveF1-F2
CC IL28BRVR
RVR: the most important predictor of SVR when we treat we PR
Approved DAAs
EASL/AASLD/KEELPNO
Approved DAAs
Grazoprevir/ElbasvirNS3/4A protease
inhibitorNS5A inhibitor
• 100/50 mg/day
• geno 1, 4
• ↓ genetic barrier
• 100/50 mg/day
• geno 1, 4
• ↓ genetic barrier
Grazoprevir/ElbasvirNS3/4A protease
inhibitorNS5A inhibitor
• 100/50 mg/day
• geno 1, 4
• ↓ genetic barrier
• 100/50 mg/day
• geno 1, 4
• ↓ genetic barrier
ONLY AASLD 2016
IFN-Free Strategies
SIM DCVLDV
PRV/rGZR
SOF
OBV
DSV
EBR
Drug -drug interactions (I)HIV antiretrovirals Illicit recreational drugs
90mg
Lipid lowering drugs30mg
90mg
Drug-drug interactions (II)CNS drugs Cardiovascular drugs
Drug-drug interactions (III)
Immunosuppressants
Genotype 1 AASLD(02/2016)
EASL(03/2015)
GREECEKEELPNO(12/2015)
PR x24w or 48w
SOF+PR x12w x12w
SMV+PR / PR* x12w / 12w (naïve or RR) or 36w (PR or NR)&
(no in 1a-Q80K)
SOF+RBV* x24w
SOF+SIM*SOF+SIM+RBV
x12w (no Ci)x24w (Ci)
x12w (or 24w Ci)x12w (Ci)
x12w (no in 1a-Q80K)?
SOF+SIM*SOF+SIM+RBV
x12w (no Ci)x24w (Ci)
x12w (or 24w Ci)x12w (Ci)
x12w (no in 1a-Q80K)?
SOF+DCVSOF+DCV+RBV
x12w (no Ci)x24w (Ci)
x12w (or 24w Ci)x12w (Ci)
x12w (x24w in exp. Ci)x12w (exp. Ci)
SOF/LDVSOF/LDV+RBV
x12w (x24w Ci-exp.)x12w (Ci-exp.)
x12w (x8w naive-non Ci-<6.8log)x12-24w (Ci) or x24w (w/o RBV)
x12w (x8w naive-non Ci)x12w (exp. Ci)
PRV/r/OBV+DSV*PRV/r/OBV+DSV+RBV*
x12w (1b)x12w (1a-no Ci), x24w (1a-Ci)
x12w (non-Ci, 1b)x12w (Ci, 1b) or (non-Ci, 1a), x24w (Ci, 1a)
x12w for 1bx12w# for 1a
Elbasvir/GrazoprevirElbasvir/Grazoprevir+RBV
x12w (1a-no RAV) (1b)x16w (1a-with RAV)
*No in non-responders in BOC/TPV and no Q80K mutation detected for 1a,#x24w in exp. previous null responders; &stop if HCV RNA ≥25IU/ml at wk4,wk12, wk24; $Includes G1a polymorphisms at amino acid positions 28, 30,31, or 93. Amino acid substitutions that confer resistance.
Genotype 1 – SOF+PR
81 77 81
62
2030405060708090
100
0102030
12w
naive
non-CI
12w
exp
non-CI
12w
naive
CI
12w
exp
CI
• naïve, HCV RNA >800.000 IU/ml and/or F3-F4• naïve, HCV RNA ≤800.000 IU/ml and/or F1-F2 without RVR or experienced NR• naïve, HCV RNA >800.000 IU/ml and/or F3-F4• naïve, HCV RNA ≤800.000 IU/ml and/or F1-F2 without RVR or experienced NR
TRIO – real life studyTRIO – real life study
112/138 25/3130/39 53/85
Genotype 1 – SMV+PR
80 78-86 75
50
83-85
67-7858-6550
60708090
100
5058-65
01020304050
12w + 12W
naïve
12w + 12w
exp - Rel
12w + 36w
exp - partial
12w + 36w
exp - null
F0-F2 F3 F4
*stop treatment if HCV RNA >25 IU/ml at wk4 or detected at wk12 or wk24 – no in GT-1a Q80K
QUEST-1QUEST-2PROMISE
ASPIRE
97 9588
79 74
30405060708090
100
Genotype 1 – SOF/SIM
0102030
12w
1
naive
non-CI
12w
1
exp
non-CI
12w
1
naive
CI
12w
1
exp
CI
12w
1
1a-Q80K
CI
OPTIMIST1
OPTIMIST1
OPTIMIST1
OPTIMIST1
OPTIMIST2
OPTIMIST2
OPTIMIST2
OPTIMIST2
OPTIMIST2
OPTIMIST2
112/115 38/40 25/3444/50 42/53
94 95 97 96 97
30405060708090
100
Genotype 1 – SOF/LDV
0102030
8w
1
naive
non-CI
12w
1
exp
non-CI
12w
1
naive
CI
RBV
12w
1
exp
CI
24w
1
exp
CI
SIRIUSSIRIUS SIRIUSSIRIUSION-3ION-3 ION-1ION-1ION-2ION-2
HCV RNA<6 million
32/3383/87 74/77 75/77202/215
Genotype 1 – PrOD99 100 100 100 97 96 92 96 95
30405060708090
100
0102030
12w
1b
naive
non-CI
12w
1b
exp
non-CI
12w
1b
naive
CI
12w
1b
exp
CI
RBV
12w
1a
naive
non-CI
RBV
12w
1a
exp
non-CI
RBV
12w
1a
naive
CI
RBV
12w
1a
exp
CI
RBV
24w
1a
exp-null R
CI
PEARL-IVPEARL-IVPEARL-IIIPEARL-III SAPPHIRE-IISAPPHIRE-IIPEARL-IIPEARL-IITURQUOISE
-IITURQUOISE
-IITURQUOISE
-IITURQUOISE
-IITURQUOISE
-IITURQUOISE
-IITURQUOISE
-IIITURQUOISE
-III
genotype 1b genotype 1a
TURQUOISE-III
TURQUOISE-III
207/209 97/100 59/64 39/4391/91 25/26286/29733/3327/27
PRV/r/OBV
Genotype 1 – SOF/DCV97 100
8995
2030405060708090
100 AI444-237 – ANRS C022 HEPATHER(real life studies)
• 98-100%: 24w w/o RBV
• 95-100%: 24w with RBV
• 93.4%: 24w w/o RBV
• 100%: 12w with RBV01020
12w
1
naive
non-CI
12w
1
exp
non-CI
12w
1
naive
CI
±RBV
12-24w
1
exp
CI
ALLY-2ALLY-2 ALLY-2ALLY-2 ALLY-2ALLY-2
70/72 28/28 8/9
AI444-237 – ANRS C022 HEPATHER(real life studies)
• 98-100%: 24w w/o RBV
• 95-100%: 24w with RBV
• 93.4%: 24w w/o RBV
• 100%: 12w with RBV
Genotype 2 AASLD(02/2016)
EASL(03/2015)
GREECEKEELPNO(12/2015)
PR NO x12-16 or 24w
SOF+PR x12w (Ci-exp) x12w (Ci ± exp.)
SOF+RBV x12w (no Ci)x16-24w (Ci)
x12w(x16-20w in Ci - exp.) x12w
SOF+DCV x12w (no Ci-ineligible for RBV)x16-24w (Ci-ineligible for RBV)
x12w (Ci ± exp.)
Genotype 2 – SOF/RBV97 94
100
78
405060708090
100
010203040
12w
naive
non-CI
12w
exp
non-CI
12w
naive
CI
12w
exp
CI
VALENCEVALENCE VALENCEVALENCE VALENCEVALENCE VALENCEVALENCE
29/30 30/32 2/2 7/9
Genotype 2 – SOF/DCV100 100
92
405060708090
100
For patients who require
treatment but cannot tolerate
RBV, a regimen of daclatasvir
with sofosbuvir for 12wk is
recommended and consideration
of extending treatment up to 24
wks for patients with poor
baseline characteristics
(cirrhosis) is reasonable.
010203040
12w
naive
12w
exp
12w
naive
Wyles, NEJM 2015
11/11 2/2 24/26
Sulkowski, NEJM 2015
For patients who require
treatment but cannot tolerate
RBV, a regimen of daclatasvir
with sofosbuvir for 12wk is
recommended and consideration
of extending treatment up to 24
wks for patients with poor
baseline characteristics
(cirrhosis) is reasonable.
AASLD
Genotype 3 AASLD(02/2016)
EASL(03/2015)
GREECEKEELPNO(12/2015)
PR NA x16 or 24w
SOF+PR x12w x12w x12w
SOF+RBV* x24w (naïve(DCV and IFN ineligible) x24w (no in exp. Ci) x24w (no in exp. Ci)
SOF+DCVSOF+DVC+RBV
x12w (no Ci)x24w (Ci)
x12w (no Ci)x24w (in Ci)
x12w (no Ci)x12-24w (in Ci)
SOF/LDVSOF/LDV+RBV
x12w(not recommended due to
limited data)
Genotype 3 – SOF+RBV
9587
92
62
405060708090
100
010203040
24w
naive
non-CI
24w
exp
non-CI
24w
naive
CI
24w
exp
CI
VALENCEVALENCE VALENCEVALENCE VALENCEVALENCE VALENCEVALENCE
87/92 85/98 12/13 29/47
Genotype 3 – SOF+PR
9083 83
405060708090
100
010203040
12w
naive
non-CI
12w
exp
non-CI
12w
exp
CILONESTAR-2LONESTAR-2 LONESTAR-2LONESTAR-2Lancet Infect Dis 2013Lancet Infect Dis 2013
10/12 10/12
97 9488 86
405060708090
100
Genotype 3 – SOF+DCV
All (100%) stage 3 diseaseachieved SVR12
010203040
12w
naive
non-CI
12w
exp
non-CI
RBV
12w
exp
CI
RBV
16w
exp
CI
ALLY-3ALLY-3 ALLY-3ALLY-3 ALLY-3+ALLY-3+ ALLY-3+ALLY-3+
All (100%) stage 3 diseaseachieved SVR12
73/75 32/34 14/16 12/14
Genotype 4 AASLD(02/2016)
EASL(03/2015)
GREECEKEELPNO(12/2015)
PR NA x24 or 48w
SOF+PR x12w (naïve) (no Ci-exp.) x12w x12w
SMV+PR / PR* x12 / 12 (naive/RR) or 36w(in PR/NR)&
x12w / 12 (naive/RR) or36w (in PR/NR)&
SOF+RBV* x24w (exp.) x24w
SOF+SIM*SOF+SIM+RBV
x12w (no Ci), x24w (Ci)x12w (Ci) x12wSOF+SIM*
SOF+SIM+RBVx12w (no Ci), x24w (Ci)
x12w (Ci) x12w
SOF+DCVSOF+DVC+RBV
x12w (no Ci), x24w (Ci)x12w (Ci)
x12 or 24w
SOF/LDVSOF/LDV+RBV
x12w, x24w (Ci-exp.)x12w (Ci-exp.)
x12w (no Ci), x24w (Ci)x12-24w (Ci)
x12w
PRV/r/OBV+RBV x12w x12w (no Ci), x24w (Ci) x12w
Elbasvir/Grazoprevirx12w (x16w +RBV in prior
on-treatment virologicfailure)
Genotype 4 – SOF+PR
96
30405060708090
100
• naïve, HCV RNA >800.000 IU/mland/or F3-F4
• naïve, HCV RNA ≤800.000 IU/mland/or F1-F2 without RVR orexperienced NR
• naïve, HCV RNA >800.000 IU/mland/or F3-F4
• naïve, HCV RNA ≤800.000 IU/mland/or F1-F2 without RVR orexperienced NR0
10203040
12w
naive
non-CI or Ci
• naïve, HCV RNA >800.000 IU/mland/or F3-F4
• naïve, HCV RNA ≤800.000 IU/mland/or F1-F2 without RVR orexperienced NR
• naïve, HCV RNA >800.000 IU/mland/or F3-F4
• naïve, HCV RNA ≤800.000 IU/mland/or F1-F2 without RVR orexperienced NR
NEUTRINONEUTRINO
27/28
83 86
6050
60
70
80
90
100
Genotype 4 – SMV+PR
40
0
10
20
30
40
50
12w + 12W
naïve
12w + 12w
exp - Rel
12w + 36w
exp - partial
12w + 36w
exp - null
*stop treatment if HCV RNA >25 IU/ml at wk4 or detected at wk12 or wk24 Moreno, J Hepatol 2015
29/35 19/22 6/10 16/40
Genotype 4 – SOF+RBV95
90
405060708090
100
010203040
24w
naive
non-CI / Ci
24w
exp
non-Ci / CiRuane, J Hepatol 2015
Doss, J Hepatol 2015Molina, Lancet 2015
Genotype 4 – SOF/LDV92
100
405060708090
100
• n=21 patients
• 60% naïve
• 43% F3-F4
• 33% F40
10203040
12w
naïve
non-CI / Ci
12w
exp.
non-CI / Ci
• n=21 patients
• 60% naïve
• 43% F3-F4
• 33% F4
SYNERGYSYNERGY
12/13 8/8
Genotype 4 – PrO + RBV100 100 97
405060708090
100
Safety issues regarding its
use in patients with
advanced liver disease
FDA, 22/10/20150
10203040
RBV
12w
naive
non-CI
RBV
12w
exp
non-CI
RBV
12w
naïve/exp.
CI
PEARL-IPEARL-I PEARL-IPEARL-I AGATE-IIAGATE-II
42/42 49/49 30/31
Safety issues regarding its
use in patients with
advanced liver disease
FDA, 22/10/2015
Genotype 4 – SOF+DCV
SOF+DCV x12w (no Ci), x24w (Ci)
SOF+DCV+RBV x12w (Ci)
EASL KEELPNO
SOF+SIM x12w (no Ci), x24w (Ci) x12w
SOF+SIM+RBV x12w (Ci)
Genotype 4 – SOF+SMV
KEELPNO, 2015EASL, 2015evidence for GT-1 studies
Genotype 5/6 AASLD(02/2016)
EASL(03/2015)
GREECEKEELPNO(12/2015)
PR NA x24 or 48w
SOF+PR x12w x12w x12wSOF+PR x12w x12w x12w
SOF+RBV* x24w
SOF+DCVSOF+DVC+RBV
x12w (no Ci), x24w (Ci)x24w (Ci)
SOF/LDVSOF/LDV+RBV
x12w x12w (no Ci)x12-24w (Ci)
Monitoring PatientsPre- & On-treatment
Prior to startingantiviraltreatment
• DDI• CBC, LFTs (INR, ALB, BILI, ALT, AST, ALP), GFR, TSH (if ifn used)• HCV genotype/subtype, HCV RNA• CHILD-PUCH score (paritaprevir, simeprevir, grazoprevir)• RAV
Monitoringduring antiviraltreatment
• clinic visits or telephone contact (adherence, AE, DDI)• wk2: LFTs and clinical signs of decompensation in cirrhotic under PRV/r• wk4: CBC, GFR, LFTs
- stop if ALT ↑ >10x, ALT ↑ <10x + symptoms or ↑ INR- monitor wk6 and wk8 if ALT ↑ <10x + asymptoma c
• TSH every 12 wks (if ifn used)• wk12: HCVRNA (EOT)• fup12: HCVRNA (SVR)• contraceptive measures
Contraceptivemeasures • during and 6 months after stopping
Conclusions• HCV is the only curable chronic viral infection
• A new toolbox of highly effective IFN-free strategies isavailable
• Major challenges remain in implementation
• Treatment recommendations will continue to evolve asmore data becomes available
• HCV is the only curable chronic viral infection
• A new toolbox of highly effective IFN-free strategies isavailable
• Major challenges remain in implementation
• Treatment recommendations will continue to evolve asmore data becomes available
Thank you for your attention!Thank you for your attention!
1392GR16NP0155815/3/16
CHRONIC HEPATITIS C: TREATMENT MANAGEMENTOF CIRRHOTIC PATIENTS
Konstantinos MimidisAssociate Professor in Internal MedicineDemocritus University of Thrace1392GR16NP01558
15/3/16
Disclosures
• Advisory / Lectures : Abbvie, Gilead, Novartis,
Bristol-Myers Squibb, MSD
• Research : Bristol Meyer Squibb, Gilead,
Novartis
• Advisory / Lectures : Abbvie, Gilead, Novartis,
Bristol-Myers Squibb, MSD
• Research : Bristol Meyer Squibb, Gilead,
Novartis
Change in the number of liver transplants, decompensatedChange in the number of liver transplants, decompensatedcirrhosis and HCC cases over timecirrhosis and HCC cases over time
Hatzakis A, et al. J Viral Hepat 2015;22:26-45
HCV-monoinfected or HCV/HIV Coinfected PatientsWith Chronic HCV With Compensated (CP-A) CirrhosisEASL Recommendations 2015
aTreatment-naïve patients and patients who failed a treatment based on Peg-IFNa + RBV. DOI: http://dx.doi.org/10.1016/j.jhep.2015.03.025; Accessed April 2015.
AASLD Clinical Practice Guidelines: HCV• Recommended regimens for treatment-naive patients with HCV genotype 3
infection.• Daily daclatasvir (60 mg*) and sofosbuvir (400 mg) for 12 weeks (no cirrhosis)
or 24 weeks with or without weight-based RBV (cirrhosis) is recommended fortreatment-naive patients with HCV genotype 3 infection.
• Rating: Class I, Level A (no cirrhosis); Class IIa, Level C (cirrhosis)
• Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN for 12weeks is recommended for IFN-eligible, treatment-naive patients with HCVgenotype 3 infection.
• Rating: Class I, Level A
• Alternative regimen for treatment-naive patients with HCV genotype 3infection.
• Daily sofosbuvir (400 mg) and weight-based RBV for 24 weeks is an alternativeregimen for treatment-naive patients with HCV genotype 3 infection who areIFN-ineligible.
• Rating: Class I, Level A
• Recommended regimens for treatment-naive patients with HCV genotype 3infection.
• Daily daclatasvir (60 mg*) and sofosbuvir (400 mg) for 12 weeks (no cirrhosis)or 24 weeks with or without weight-based RBV (cirrhosis) is recommended fortreatment-naive patients with HCV genotype 3 infection.
• Rating: Class I, Level A (no cirrhosis); Class IIa, Level C (cirrhosis)
• Daily sofosbuvir (400 mg) and weight-based RBV plus weekly PEG-IFN for 12weeks is recommended for IFN-eligible, treatment-naive patients with HCVgenotype 3 infection.
• Rating: Class I, Level A
• Alternative regimen for treatment-naive patients with HCV genotype 3infection.
• Daily sofosbuvir (400 mg) and weight-based RBV for 24 weeks is an alternativeregimen for treatment-naive patients with HCV genotype 3 infection who areIFN-ineligible.
• Rating: Class I, Level A
ΚΕΕΛΠΝΟ ΚΑΤΕΥΘΥΝΤΗΡΙΕΣ ΟΔΗΓΙΕΣ ΓΙΑ ΤΗΧΡΟΝΙΑ ΗΠΑΤΙΤΙΔΑ C
ION-1:16%
TURQUOISE-II
Cohort 2: F3-F4: 93%
BMS ALLY Phase 3 Program
• Patients with cirrhosis or post-livertransplant
• GT 1 to 6• DCV + SOF + RBV, 12 weeks
ALLY-1N = 113
All-Oral DCV + SOF
• Patients with cirrhosis or post-livertransplant
• GT 1 to 6• DCV + SOF + RBV, 12 weeks
• Patients with HIV coinfection• GT 1 to 6• DCV + SOF, 8 or 12 weeks
ALLY-2N = 203
• Patients with GT 3 infection• Treatment-naive or treatment-experienced• DCV + SOF, 12 weeks
ALLY-3N = 152
ALLY-1: Πολυκεντρική μελέτη, φάση 3
Follow-upDCV 60 mg QD +SOF 400 mg QD + RBV
Week 0 Week 24SVR12a
Week 36
DCV 60 mg QD +SOF 400 mg QD + RBV
Week 12
Advanced cirrhosisN = 60
Post-liver transplantN = 53
73
Week 0 Week 24SVR12a
Week 36Week 12
• Τελικό σημείο: SVR12 στο GT1 σε κάθε σκέλος
• 12 εβδομάδες θεραπείας: DCV 60 mg + SOF 400 mg + RBV– RBV αρχικά 600 mg/day, προσαρμογή στα 1000 mg/day ανάλογα επίπεδα Hgb
και CrCl
• Advanced cirrhosis patients with treatment interrupted by liver transplantation could receive an additional 12 weeks oftreatment immediately post-transplant
SVR12 by CohortSV
R12,
%a
SVR12 by Cohort
All Patients GT 1 (Primary Endpoint)
74a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals.
SVR1
2, %
a
Post-transplantAdvancedcirrhosis
Post-transplantAdvancedcirrhosis
■ In a regression analysis, no difference by gender, age, IL28B, or HCV RNAin the advanced cirrhosis cohort with GT 1
Post-transplant
BMS ALLY Phase 3 Program
• Patients with cirrhosis or post-livertransplant
• GT 1 to 6• DCV + SOF + RBV, 12 weeks
ALLY-1N = 113
All-Oral DCV + SOF
• Patients with cirrhosis or post-livertransplant
• GT 1 to 6• DCV + SOF + RBV, 12 weeks
• Patients with HIV coinfection• GT 1 to 6• DCV + SOF, 8 or 12 weeks
ALLY-2N = 203
• Patients with GT 3 infection• Treatment-naive or treatment-experienced• DCV + SOF, 12 weeks
ALLY-3N = 152
ALLY-1
HCV GT3
Acceleratedfibrosis
SteatosisHighermortality
Burden ofdisease
Increasedrisk for HCC
Lower ratesof SVR
Higher riskfor future
event
Highermortality
HCV genotype 3 is associated withHCV genotype 3 is associated withaccelerated fibrosis progressionaccelerated fibrosis progressionMarkov modelling in HCV-infected patients in Switzerland (N=1189)
Bochud PY, et al. J Hepatol 2009;51:655-66
HCV γον3 – κίρρωση - ΗΚΚ
Kanwal F, et al. Hepatology 2014;60:98-105
BMS ALLY Phase 3 Program
• Patients with cirrhosis or post-livertransplant
• GT 1 to 6• DCV + SOF + RBV, 12 weeks
ALLY-1N = 113
All-Oral DCV + SOF
• Patients with cirrhosis or post-livertransplant
• GT 1 to 6• DCV + SOF + RBV, 12 weeks
• Patients with HIV coinfection• GT 1 to 6• DCV + SOF, 8 or 12 weeks
ALLY-2N = 203
• Patients with GT 3 infection• Treatment-naive or treatment-experienced• DCV + SOF, 12 weeks
ALLY-3N = 152
All-Oral Treatment With Daclatasvir PlusSofosbuvir Plus Ribavirin for 12 or 16
Weeks inHCV Genotype 3-Infected Patients With
Advanced Fibrosis or Cirrhosis:The ALLY-3+ Phase 3 Study
Leroy V,1 Angus P,2 Bronowicki JP,3 Dore G,4 Hézode C,5 Pianko S,6 Pol S,7Stuart K,8 Tse E,9 McPhee F,10 Bhore R,11 Jimenez-Exposito MJ,11
Thompson A4
1CHU de Grenoble, La Tronche, France; 2Austin Hospital, Heidelberg, Australia; 3CHU Nancy & LorraineUniversity, Nancy, France; 4St. Vincent’s Hospital and Kirby Institute, Sydney, Australia; 5CHU Henri Mondor,
Créteil, France; 6Monash Medical Centre, Clayton, Australia; 7Hôpital Cochin, Paris, France; 8Gallipoli MedicalResearch Foundation, Greenslopes, Australia; 9Royal Adelaide Hospital, Adelaide, Australia; 10Bristol-Myers
Squibb Research & Development, Wallingford, CT; 11Bristol-Myers Squibb Research & Development, Princeton,NJ.
The Liver Meeting 2015®San Francisco, CA, 13–17 November 2015
Oral LB-31392GR15NP08054-0120/11/2017
SVR12: Patients with cirrhosisALLY-3+
ΑΝΑΛΥΣΗ ITTΑΝΑΛΥΣΗ ΠΑΡΑΤΗΡΗΜΕΝΩΝ ΤΙΜΩΝ
89 88 89
HC
V R
NA
< LL
OQ
TD/T
ND
(%)
86 83 89
HC
V R
NA
< LL
OQ
TD/T
ND
(%)
87
VBT 0 0 0Υποτροπή 4 2 2Θάνατος 1 1 0
VBT 0 0 0Υποτροπή 4 2 2
1618
Συνολικά 12 Εβδ. 16 Εβδ.H
CV
RN
A <
LLO
QTD
/TN
D(%
)
3135
1517
1518
1618
Συνολικά 12 Εβδ. 16 Εβδ.
HC
V R
NA
< LL
OQ
TD/T
ND
(%)
3136
Hepatology. 2016 Jan 28. doi: 10.1002/hep.28473. [Epub ahead of print]
ConclusionsALLY-3+
■ Συνολικά, επιτεύχθηκε SVR12 σε ποσοστό 90% σε ασθενείς με λοίμωξη από HCVγονότυπου 3 και προχωρημένη ίνωση ή αντιρροπούμενη κίρρωση οι οποίοι έλαβανθεραπεία με DCV + SOF + RBV– Η SVR12 ήταν συγκρίσιμη για την ομάδα της θεραπείας 12 εβδομάδων (88%)
και την ομάδα της θεραπείας 16 εβδομάδων (92%)– Καμία ιολογική αποτυχία στη διάρκεια της θεραπείας, δύο υποτροπές σε κάθε
ομάδα θεραπείας
■ SVR12 σε ποσοστό 100% στους ασθενείς με προχωρημένη ίνωση
■ SVR12 σε ποσοστό 86% στους ασθενείς με κίρρωση (οι περισσότεροι είχανπροηγούμενη λήψη θεραπείας)
■ Η θεραπεία ήταν ασφαλής και καλά ανεκτή – κανένας ασθενής δεν διέκοψε τηθεραπεία λόγω ΑΕ
■ Η αγωγή DCV + SOF + RBV επί 12 ή 16 εβδομάδες είναι μια εξαιρετικάαποτελεσματική θεραπεία για ασθενείς με γονότυπο 3 οι οποίοι έχουνπροχωρημένη ίνωση ή αντιρροπούμενη κίρρωση.
88
■ Συνολικά, επιτεύχθηκε SVR12 σε ποσοστό 90% σε ασθενείς με λοίμωξη από HCVγονότυπου 3 και προχωρημένη ίνωση ή αντιρροπούμενη κίρρωση οι οποίοι έλαβανθεραπεία με DCV + SOF + RBV– Η SVR12 ήταν συγκρίσιμη για την ομάδα της θεραπείας 12 εβδομάδων (88%)
και την ομάδα της θεραπείας 16 εβδομάδων (92%)– Καμία ιολογική αποτυχία στη διάρκεια της θεραπείας, δύο υποτροπές σε κάθε
ομάδα θεραπείας
■ SVR12 σε ποσοστό 100% στους ασθενείς με προχωρημένη ίνωση
■ SVR12 σε ποσοστό 86% στους ασθενείς με κίρρωση (οι περισσότεροι είχανπροηγούμενη λήψη θεραπείας)
■ Η θεραπεία ήταν ασφαλής και καλά ανεκτή – κανένας ασθενής δεν διέκοψε τηθεραπεία λόγω ΑΕ
■ Η αγωγή DCV + SOF + RBV επί 12 ή 16 εβδομάδες είναι μια εξαιρετικάαποτελεσματική θεραπεία για ασθενείς με γονότυπο 3 οι οποίοι έχουνπροχωρημένη ίνωση ή αντιρροπούμενη κίρρωση.
Ombitasvir plus paritaprevir plus ritonavir with or withoutribavirin in treatment-naive and treatment-experienced
patients with genotype 4 chronic hepatitis C virus infection(PEARL-I): a randomised, open-label trial
PEARL-I: Non-cirrhotics
Asselah T, et al. Efficacy and Safety of Ombitasvir/Paritaprevir/Ritonavir Co-Administered with Ribavirin inAdults with Genotype 4 Chronic Hepatitis C Infection and Cirrhosis (AGATE-I) [Abstract 714].
66th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD). November 13-17, 2015a; San Francisco, CA.
• The AGATE-I trial,
• randomized 120 treatment-naïve and -experienced patients with genotype 4 HCV andcompensated cirrhosis to receive 12 weeks or 16 weeks ofparitaprevir/ritonavir/ombitasvir (PrO) plus weight-based ribavirin.
• The SVR12 rates in the 12-week and 16-week arms were 96% and 100%,respectively. The regimens were well tolerated
• Additionally, AGATE-II randomized 60 treatment-naïve and -experienced genotype 4-infected patients with compensated cirrhosis to receive either 12 or 24 weeks of PrOplus weight-based RBV.
• The SVR12 rate from the 12-week arm, reported recently, was 97%. These datacontinue to support the use of PrO plus RBV for 12 weeks in treatment-experiencedgenotype 4 patients, including those with cirrhosis.
• The AGATE-I trial,
• randomized 120 treatment-naïve and -experienced patients with genotype 4 HCV andcompensated cirrhosis to receive 12 weeks or 16 weeks ofparitaprevir/ritonavir/ombitasvir (PrO) plus weight-based ribavirin.
• The SVR12 rates in the 12-week and 16-week arms were 96% and 100%,respectively. The regimens were well tolerated
• Additionally, AGATE-II randomized 60 treatment-naïve and -experienced genotype 4-infected patients with compensated cirrhosis to receive either 12 or 24 weeks of PrOplus weight-based RBV.
• The SVR12 rate from the 12-week arm, reported recently, was 97%. These datacontinue to support the use of PrO plus RBV for 12 weeks in treatment-experiencedgenotype 4 patients, including those with cirrhosis.
Genotype 4, IFN-free: cirrhosis(No data, results from gen1 studies)
• Option 3– Sofosbuvir + Simeprevir + RBV: 12w– Sofosbuvir + Simeprevir: 24w
• Option 4– Sofosbuvir + Daclatasvir + RBV: 12w (+ALLY 1)
– Sofosbuvir + Daclatasvir: 24w
• Option 3– Sofosbuvir + Simeprevir + RBV: 12w– Sofosbuvir + Simeprevir: 24w
• Option 4– Sofosbuvir + Daclatasvir + RBV: 12w (+ALLY 1)
– Sofosbuvir + Daclatasvir: 24w
Genotype 5 or 6, IFN-free: cirrhosis(No data, results from gen1 studies)
• Option 1• PegIFN-α + RBV + Sofosbuvir: 12w (NEUTRINO TRIAL)
• Option 2– Sofosbuvir + Ledipasvir + RBV: 12w– Sofosbuvir + Ledipasvir : 24w
• Option 3– Sofosbuvir + Daclatasvir + RBV: 12w– Sofosbuvir + Daclatasvir: 24w
• Option 1• PegIFN-α + RBV + Sofosbuvir: 12w (NEUTRINO TRIAL)
• Option 2– Sofosbuvir + Ledipasvir + RBV: 12w– Sofosbuvir + Ledipasvir : 24w
• Option 3– Sofosbuvir + Daclatasvir + RBV: 12w– Sofosbuvir + Daclatasvir: 24w
Recommendations for decompensatedcirrhosis (CP B or C)
• Special expertise
• Patients with genotype 1,4– Sofosbuvir + Ledipasvir + RBV (600mg) :12w– Sofosbuvir + Daclatasvir + RBV (600mg) :12w– Sofosbuvir + Ledipasvir: 24w– Sofosbuvir + Daclatasvir: 24w
– Sofosbuvir + Ledipasvir: + RBV (600): 24w
• Special expertise
• Patients with genotype 1,4– Sofosbuvir + Ledipasvir + RBV (600mg) :12w– Sofosbuvir + Daclatasvir + RBV (600mg) :12w– Sofosbuvir + Ledipasvir: 24w– Sofosbuvir + Daclatasvir: 24w
– Sofosbuvir + Ledipasvir: + RBV (600): 24w
Recommendations for decompensatedcirrhosis (CP B or C)
• Special expertise
• Patients with genotype 2,3
– Sofosbuvir + Daclatasvir + RBV (600mg) :12w
• Special expertise
• Patients with genotype 2,3
– Sofosbuvir + Daclatasvir + RBV (600mg) :12w
1392GR16NP0155815/3/16
DACLATASVIR:REAL WORLD CLINICAL EXPERIENCE SO FAR
Themistoklis G. VasileiadisAssociate Professor of Internal Medicine – Hepatology
3rd Department of Internal Medicine
Aristotle University of Thessaloniki
“G.Papageorgiou Hospital”
1392GR16NP0155815/3/16
Disclosures
• I have received consulting fees and funds for research support fromAbbVie, Bristol-Myers Squibb, and Merck.
Daclatasvir Plus Sofosbuvir With or Without Ribavirin in Patients WithHCV Genotype 3 Infection:Interim Analysis of a French Multicenter Compassionate Use Program
108
■ Christophe Hézode,1 Victor De Ledinghen,2 Helene Fontaine,3 Fabien Zoulim,4 PascalLebray,5 Nathalie Boyer,6 Dominique Larrey,7 Christine Silvain,8 Danielle Botta-Fridlund,9
Vincent Leroy,10
■ Marc Bourliere,11 Louis d’Alteroche,12 Isabelle Hubert-Fouchard,13 Dominique Guyader,14
■ Isabelle Rosa,15 Eric Nguyen-Khac,16 Vincent Di Martino,17 Larysa Fedchuk,18 RaoudhaAkremi,18
■ Yacia Bennai,18 Jean-Pierre Bronowicki,19 on behalf of Bristol-Myers Squibb
The Liver Meeting® 2015: The 66th Annual Meeting of the American Association for the Study of Liver DiseasesSan Francisco, CA, November 13–17, 2015
Oral 206
■ Adult patients with:– METAVIR fibrosis F3 or abovea
or– Irrespective of fibrosis score: severe extrahepatic manifestations;
post-liver transplant HCV recurrence, or indication for liver or kidney transplant
■ Recommended regimen and treatment duration‒ DCV 60 mg QD + SOF 400 mg QD for 24 weeks‒ RBV use and/or shorter treatment duration (12 weeks) at physician’s discretion
■ Endpoints
‒ Efficacy: SVR12b at post-treatment Week 12 (PT12)‒ Safety: based on serious adverse events (SAEs), AEs, and
treatment discontinuation
Patients and Endpoints
■ Adult patients with:– METAVIR fibrosis F3 or abovea
or– Irrespective of fibrosis score: severe extrahepatic manifestations;
post-liver transplant HCV recurrence, or indication for liver or kidney transplant
■ Recommended regimen and treatment duration‒ DCV 60 mg QD + SOF 400 mg QD for 24 weeks‒ RBV use and/or shorter treatment duration (12 weeks) at physician’s discretion
■ Endpoints
‒ Efficacy: SVR12b at post-treatment Week 12 (PT12)‒ Safety: based on serious adverse events (SAEs), AEs, and
treatment discontinuation
a Biopsy, FibroScan ( 9.6 kPa), or FibroTest ( 0.59);b HCV RNA < lower limit of quantification (LLOQ), target detected (TD), or target not detected (TND). 109
20.6%1.8%
(n = 5)
DCV + SOF12 Weeks
Treatment Regimens and Proportions
18.8%(n = 53)
DCV + SOF + RBV24 Weeks
Total: N = 282a
1.8%(n = 5)
DCV + SOF + RBV12 Weeks
110a Excludes 2 patients with unknown treatment duration. Total efficacy population: 284.
58.9%(n = 166)
18.8%(n = 53)
DCV + SOF24 Weeks
Baseline Characteristics
ParameterDCV + SOF ± RBVa
12 weeksn = 63
DCV + SOF24 weeksn = 166
DCV + SOF + RBV24 weeks
n = 53
Overall(N = 284)b
Age, median (range) years 53.4 (39–78) 55.0 (27–79) 53.2 (40–72) 54.1 (27–79)
Male, n (%) 43 (68.3) 123 (75.0) 40 (80.0) 208 (74.6)
HCV RNA, median (range) log10 IU/mL 5.99 (2.40–7.83) 6.00 (3.03–7.40) 5.60 (1.60–7.25) 5.94 (1.60–7.83)
Advanced fibrosis (F3),c n (%) 19 (30.2) 21 (12.7) 2 (3.8) 42 (14.8)
Cirrhosis,d n (%) 37 (58.7) 135 (82.3) 48 (90.6) 222 (78.7)
30 (83.3) /3 (8.3) / 3 (8.3)
98 (85.2) /15 (13.0) / 2 (1.7)
33 (76.7) /9 (20.9) / 1 (2.3)
162 (82.7) /28 (14.3) / 6 (3.1)
111
a DCV + SOF + RBV, n = 5; b Overall totals include data for 2 patients with missing regimen details (not shown);c Advanced fibrosis defined by biopsy, FibroScan ( 9.6 kPa), or FibroTest ( 0.59);d Cirrhosis defined by biopsy, FibroScan ( 14.6 kPa), or FibroTest ( 0.75).All percentages are of patients with available data in indicated category. Missing data due to unknown: sex (n = 5); HCV RNA (n = 1);previous HCV treatment status (n = 2); cirrhosis status (n = 2); Child–Pugh category (n = 26); fibrosis stage (n = 2); platelet count (n = 20);albumin count (n = 26). 111
Child–Pugh A / B / C, n (%) 30 (83.3) /3 (8.3) / 3 (8.3)
98 (85.2) /15 (13.0) / 2 (1.7)
33 (76.7) /9 (20.9) / 1 (2.3)
162 (82.7) /28 (14.3) / 6 (3.1)
Platelets < 100 ×109 cells/L, n (%) 18 (32.1) 55 (35.0) 27 (55.1) 102 (38.6)
Albumin ˂ 35 g/L, n(%) 19 (31.7) 39 (26.5) 14 (28.6) 74 (28.7)
Liver transplant recipient, n (%) 3 (4.8) 16 (9.6) 5 (9.4) 24 (8.5)
Pre-liver or renal transplant stage, n(%) 4 (6.3) 16 (9.6) 5 (9.4) 25 (8.8)
Treatment-experienced, n (%) 38 (60.3) 125 (76.2) 40 (75.5) 205 (72.7)
Coinfection with HIV / HBV, n (%) 7 (11.3) / 0 31 (18.7) / 5 (3.0) 3 (5.7) / 2 (3.7) 41 (14.4) / 7 (2.5)
SVR12 in Patients Without Cirrhosis(70% With Advanced Fibrosis [F3])
96,0 10010080,0
60708090
100HC
V RN
A <
LLO
QTD
/TN
D(%
)DCV + SOF DCV + SOF + RBV NO CIRRHOSIS or F3
12 W D+S
112
0102030405060
12 Weeks 24 WeeksHCV
RNA
< LL
OQ
TD/T
ND
(%)
2425
45
2929
11
■ Overall SVR12 97% (58/60)– By regimen: 98% (53/54) for DCV + SOF; 83% (5/6) for DCV + SOF + RBV– By treatment duration: 96% (25/26) for 12 weeks; 97% (33/34) for 24 weeks
Data missing for 2 patients due to unknown treatment duration or cirrhosis status.
SVR12 in Patients With Cirrhosis
69,785,9
10081,3
60708090
100HC
V RN
A <
LLO
QTD
/TN
D(%
)
DCV + SOF DCV + SOF + RBV D+S24W
113
0102030405060
12 Weeks 24 Weeks
HCV
RNA
< LL
OQ
TD/T
ND
(%)
116135
2333
3948
44
■ Overall SVR12 82% (182/222)– By regimen: 83% (139/168) for DCV + SOF; 83% (43/52) for DCV + SOF + RBV– By treatment duration: 73% (27/37) for 12 weeks; 85% (155/183) for 24 weeks
Data missing for 2 patients due to unknown treatment duration or cirrhosis status.
SVR12 by Baseline Child–Pugh Score
80,090,0 84,8
33,3
70,6 70,0
405060708090
100HC
V RN
A <
LLO
QTD
/TN
D(%
)
Child–Pugh A Child–Pugh B or C CTP A: 12W D+S+Ror 24W D+SCTP B or C24 W D+S
114a 4 patients received RBV for 12 weeks, all were Child–Pugh A, and all achieved SVR12.Missing data for 26 patients of unknown Child–Pugh score, and 2 patients of unknown treatment duration.
33,3
010203040
HCV
RNA
< LL
OQ
TD/T
ND
(%)
2430
26
90100
1217
2833
710
11
12 WeeksDCV + SOF ± RBVa
24 WeeksDCV + SOF
24 WeeksDCV + SOF + RBV
■ Overall SVR12:– Child–Pugh A: 87% (142/163)– Child–Pugh B: 67% (18/27)– Child–Pugh C: 50% (3/6)
EAP UKLDV/SOF ± RBV orDCV + SOF ± RBVEarly Access Program UK cohort
The NHS England EAP provided 12 weeks of therapy to a cohort of 467 patients• 94% had present or history of decompensated cirrhosis• 189 (40.5%) patients had GT-3 infection
Inclusion criteria:• Decompensated cirrhosis with
ascites/variceal bleed/encephalopathy CTPscore ≥7
• Non-hepatic manifestation likely to lead toirreversible damage in 12 months andintolerant to or failed PegIFN/RBV
• Exceptional circumstances by panel review
GT-3, n (%) Total, n (%)
SOF + LDV + RBV 61 (13.1) 252 (54.0)
Physician treatment selectionInclusion criteria:• Decompensated cirrhosis with
ascites/variceal bleed/encephalopathy CTPscore ≥7
• Non-hepatic manifestation likely to lead toirreversible damage in 12 months andintolerant to or failed PegIFN/RBV
• Exceptional circumstances by panel review
SOF + LDV + RBV 61 (13.1) 252 (54.0)
SOF + DCV + RBV 114 (24.4) 172 (36.8)
Without RBV 14 (3.0) 43 (9.2)
Total 189 (41.5) 467 (100)
Foster et al. EASL 2015. Presentation O002.
EAP UKLDV/SOF ± RBV orDCV + SOF ± RBVEAP UK cohort: efficacy and safety
80
5971
43
74 7073 71
0
20
40
60
80
100
SVR1
2 ra
te, %
(ITT
)
SOF + LDV +RBVSOF + LDV
17 15 114
Patients that received RBV:• Total on RBV: n = 426 (91.2% of total
population)• RBV discontinued: n = 30 (6.4% of total
population)• RBV dose reduction: n = 91 (19.5% of total
population)• Hb ≤100 g/L: n = 142 (30.4% of total
population)• Hb ≤ 80 g/L: n = 24 (5.1% of total
population)
252 28
61 7 70
All GT-3SVR1
2 ra
te, %
(ITT
)
252
Patients that received RBV:• Total on RBV: n = 426 (91.2% of total
population)• RBV discontinued: n = 30 (6.4% of total
population)• RBV dose reduction: n = 91 (19.5% of total
population)• Hb ≤100 g/L: n = 142 (30.4% of total
population)• Hb ≤ 80 g/L: n = 24 (5.1% of total
population)
Number of events(% of total SAEs)
Number of patients(% of total population)
Total SAEs 175 119 (25.5%)
Likely related to liver disease and/or HCV therapy 138 (78.9%) 100 (21.4%)
Likely unrelated to liver disease and/or HCVtherapy 37 (21.1%) 37 (7.9%)
Summary of safety results
Foster et al. EASL 2015. Presentation O002.
28
DCV + SOF ±RBV
summary:Story flow
• Overall DCV+SOF (± RBV) is currently the optimal all-oral, approved DAA
regimen for urgent-to-treat, GT-3 patients including cirrhotics
– DCV + SOF for 12 weeks without RBV achieved a high cure rate of 96% in
non-cirrhotic GT-3 patients in ALLY-31
– Addition of RBV to a 12-week duration helps to improve the SVR in GT-3
patients with advanced fibrosis or compensated cirrhosis
• With addition of RBV, overall cure rate was comparable with 12-week
(88%) and 16-week (92%) duration of therapy2
– Real world (EAP) data show that 24 weeks of therapy may be an option for
patients3,4:
• RBV intolerant
• GT-3 treatment-experienced
• GT-3 with decompensation
GT-3 Overall
• Overall DCV+SOF (± RBV) is currently the optimal all-oral, approved DAA
regimen for urgent-to-treat, GT-3 patients including cirrhotics
– DCV + SOF for 12 weeks without RBV achieved a high cure rate of 96% in
non-cirrhotic GT-3 patients in ALLY-31
– Addition of RBV to a 12-week duration helps to improve the SVR in GT-3
patients with advanced fibrosis or compensated cirrhosis
• With addition of RBV, overall cure rate was comparable with 12-week
(88%) and 16-week (92%) duration of therapy2
– Real world (EAP) data show that 24 weeks of therapy may be an option for
patients3,4:
• RBV intolerant
• GT-3 treatment-experienced
• GT-3 with decompensation
DAA, direct-acting antiviral; DCV, daclatasvir; EAP, early access program; GT, genotype; RBV, ribavirin; SOF, sofosbuvir.1. Nelson et al. Hepatol 2015;61(4):1127-1135. 2. Leroy et al. AASLD 2015, oral LB-3. 3. Hézode et al. AASLD 2015, oral206. 4. Welzel et al. AASLD 2015. Oral 37.
Daclatasvir in Combination With SofosbuvirWith Or Without Ribavirin Is Safe and Efficacious inLiver Transplant Recipients With HCV Recurrence:
Interim Results of a European MulticenterCompassionate Use Program
Herzer K,1 Welzel TM,2 Ferenci P,3 Petersen J,4 Gschwantler M,5 Cornberg M,6
Berg T,7 Spengler U,8 Weiland O,9 Van der Valk M,10 Klinker H,11 Rockstroh J,8
Schott E,12 Peck-Radosavljevic M,3 Zhou Y,13 Jimenez-Exposito MJ,13 Zeuzem S2
Herzer K,1 Welzel TM,2 Ferenci P,3 Petersen J,4 Gschwantler M,5 Cornberg M,6
Berg T,7 Spengler U,8 Weiland O,9 Van der Valk M,10 Klinker H,11 Rockstroh J,8
Schott E,12 Peck-Radosavljevic M,3 Zhou Y,13 Jimenez-Exposito MJ,13 Zeuzem S2
1Universitätsklinikum Essen (AöR), Essen, Germany; 2Universitätsklinikum der Johann Wolfgang GoetheUniversität, Frankfurt, Germany; 3Medizinische Universität Wien, Vienna, Austria; 4IFI Institut für Interdisziplinäre
Medizin, Hamburg, Germany; 5Wilhelminenspital, Vienna, Austria; 6Medizinische Hochschule Hannover,Hannover, Germany; 7Universitätsklinikum Leipzig, Leipzig, Germany; 8Universitätsklinikum Bonn, Bonn,
Germany; 9Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden; 10Academic Medical Center,University of Amsterdam, Amsterdam, Netherlands; 11Universitätsklinikum Würzburg, Würzburg, Germany;
12Charité Universitätmedizin Berlin; Berlin, Germany; 13Bristol-Myers Squibb, Princeton, NJ, USA.
The Liver Meeting 2015®San Francisco, CA, 13–17 November 2015
European DCV Compassionate Use Program
Primary objective: To provide access to DCV to patients with life-threateningchronic HCV infection who have no other treatment options
Week 24# Week 36Day 1
DCV (60 mg)* +SOF (400 mg) ± RBV† Follow-Up
SVR12‡
Primary endpoint
Additional Optional Follow-Up
Week 48 Week 72
SVR24
Inclusion criteria■ Age ≥ 18 years with no treatment options■ High risk of hepatic decompensation or
death within 12 months if left untreated– Or urgent need of viral clearance
(extrahepatic manifestations/comorbidities)
Exclusion criteria■ Creatinine clearance ≤ 30 mL/min■ Pregnancy or not using
contraception
3
SVR12‡
Primary endpointSVR24
#Addition of RBV and shorter duration oftreatment at the discretion of the physician
*Dose adjusted for concomitant ARVs‡HCV RNA < LLOQ, TD or TND at post treatment Week 12(next value carried backward approach)
All Treated Liver TransplantPatients with HCV recurrence
N = 87
Efficacy PopulationN = 80
Excluded from this interim analysis, N = 7a
■ Did not reach post-treatment Week 12, n = 3;■ Informed consent withdrawal, n = 1■ Missing data (not caused by death or
treatment discontinuation due to AE), n = 3
Safety PopulationN = 87
Populations and Statistical Analysis
All TreatedPatientsN = 485
120
Efficacy PopulationN = 80
Excluded from this interim analysis, N = 7a
■ Did not reach post-treatment Week 12, n = 3;■ Informed consent withdrawal, n = 1■ Missing data (not caused by death or
treatment discontinuation due to AE), n = 3
■ Primary Efficacy Analysis (mITT):– HCV RNA < LLOQ, TD or TND at post-treatment Week 12 (next value carried backward)
– Patients with missing data who died, discontinued treatment due to AEs, or had virologicbreakthrough / relapse before post-treatment Week 12 were classified as failures
■ Safety Analysis:– Clinical (AE, serious AE, AE leading to discontinuation and death) and laboratory
abnormalitiesaAll excluded patients had HCV RNA < LLOQ TD or TND at EOT (Week 24) or at the last available assessment (On-treatment Week 12).
ParameterDCV + SOF
N = 62DCV + SOF + RBV
N = 25All Patients
N = 87Age, median (range) yr 58 (40–75) 58 (39–74) 58 (39–75)Male, n (%) 46 (74) 15 (60) 61 (70)White, n (%)a 59 (95) 22 (88) 81 (93)HCV genotype, n (%)
1a 21 (34) 7 (28) 28 (32)1b 32 (52) 9 (36) 41 (47)1 subtype unknown 5 (8) 2 (8) 7 (8)
Demographic and Baseline Disease Characteristics
1 subtype unknown 5 (8) 2 (8) 7 (8)3 4 (6) 4 (16) 8 (9)4 0 2 (8) 2 (2)Unknown 0 1 (4) 1 (1)
HCV RNA, median (range) log10 IU/mLa 6.3 (0–7.5) 6.2 (0–7.2) 6.2 (0–7.5)HCV RNA ≥ 2,000,000 IU/mL, n (%)a 30 (48) 10 (40) 40 (46)
ALT, median (range) IU/La 55 (9–347) 49 (14–235) 53 (9–347)Albumin, median (range) g/La 41 (20–49) 41 (24–47) 41 (20–49)Prior HCV therapy, n (%) 41 (66) 19 (76) 60 (69)HBV coinfection, n (%) 3 (5) 2 (8) 5 (6)a Excludes patients with missing data.
121
Baseline Disease Characteristics
ParameterDCV + SOF
N = 62DCV + SOF + RBV
N = 25All Patients
N = 87Time since LT, median (range) years 3.9 (0.3–21.5) 2.2 (0.3–9.1) 3.4 (0.3–21.5)Cirrhosis, n (%)a 24 (39) 13 (52) 37 (43)
Child-Pugh class, n (%)b
A 12 (50) 9 (69) 21 (57)B 8 (33) 4 (31) 12 (32)
C 4 (17) 0 4 (11)MELD score, median (range) 10 (6–25) 10 (6–18) 10 (6–25)
122
MELD score, median (range) 10 (6–25) 10 (6–18) 10 (6–25)MELD score > 15, n (%)b 7 (29) 1 (8) 8 (22)
Fibrosing cholestatic hepatitis, n (%) 8 (13) 2 (8) 10 (11)Immunosuppressive therapy, n (%)c
Tacrolimus 44 (71) 20 (80) 64 (74)Cyclosporine 15 (24) 3 (12) 18 (21)Everolimus 6 (10) 4 (16) 10 (11)Sirolimus 2 (3) 0 2 (2)
Mycophenolate 30 (48) 14 (56) 44 (51)Prednisone/prednisolone 11 (18) 3 (12) 14 (16)
a Diagnosed by liver biopsy (Metavir >F3, Ishak >4, or the equivalent), n=2; FibroScan (>14.6 kPa), n=19; orFIB-4 score (>3.25), n=16; b Percentages based on cirrhotic patients; c Excludes patients with missing data.
Primary Efficacy Analysis – SVR12 (mITT)
93 91 93
20
40
60
80
100
DCV + SOFDCV + SOF + RBVOverall
HCV
RNA
< LL
OQ
, TD
or T
ND
%±
95%
CI
24W D+S
7
0
20 5458
2022
7480HC
V RN
A <
LLO
Q, T
D or
TN
D%
±95
% C
I
■ 75 of 80 patients treated for 24 weeks; 72 of these 75 (96%) achieved SVR12
Not Achieving SVR12 4 2 6Breakthrough or relapse 0 0 0Discontinuation (AE) 0 1 1Deathsa 4 1 5
a 3 deaths occurred during post-treatment follow-up.
SVR12 (mITT) by HCV Genotype
93 95 94100
94100 100 100 100
60
80
100
DCV + SOF DCV + SOF + RBV
HCV
RNA
< LL
OQ
, TD
or T
ND,
%
8
0
20
40
All GT 1ᵃ 1a 1b 3 4
1920
77
3032
88
33
44
00
11
HCV genotype b
HCV
RNA
< LL
OQ
, TD
or T
ND,
%
5155
1516
aGT 1 subtype unknown in 4 patients: DCV + SOF (n = 3); DCV + SOF + RBV (n = 1); 2 patients achieved SVR12;1 patient in each arm died.b Excludes 1 patient (DCV + SOF + RBV) with unknown GT; patient discontinued Day 58 due to AE (treatmentfailure).
Changes in Liver Disease Parameters FromBaseline to Post-Treatment Week 12
ALT
Baseline Follow-up0
255075
100125
300400
IU/m
LALT
N = 73N = 86
IU/L
Total Bilirubin
Baseline Follow-up0
25
50
200
300
IU/m
L
Total Bilirubin
N = 69N = 77
mg/
dLm
g/dL
μmol
/L
11Data indicate median, IQR, range.
ALT
Baseline Follow-up0
255075
100125
300400
IU/m
L
Albumin
Baseline Follow-up0
102030405060
mg/
L
Platelets
Baseline Follow-up0
100
200
300
400
500
plat
elet
s/L
(×10
9 )
Albumin Platelets
N = 73N = 86
N = 71N = 87N = 57N = 75
g/L
plat
elet
s×10
9 /L
Total Bilirubin
Baseline Follow-up0
25
50
200
300
IU/m
L
N = 69N = 77
Summary and Conclusion
■ In a real-world setting, DCV + SOF ± RBV achieved a high SVR12 rate (93%)in 80 liver transplant recipients with recurrent HCV infection– High SVR12 rate regardless of HCV genotype, cirrhosis status or RBV use
– No virologic breakthrough or relapse
■ Median ALT, bilirubin, and albumin levels improved between baseline andpost-treatment Week 12
■ DCV + SOF ± RBV was generally safe and well tolerated– Few discontinuations due to adverse events, treatment-related serious AE, or
grade 3 or 4 laboratory abnormalities
■ These results suggest that the pangenotypic, all-oral combination ofDCV + SOF + RBV represents an effective and well-tolerated treatment forliver transplant recipients with recurrent HCV, including patients withadvanced disease
In Summary
■ In a real-world setting, DCV + SOF ± RBV achieved a high SVR12 rate (93%)in 80 liver transplant recipients with recurrent HCV infection– High SVR12 rate regardless of HCV genotype, cirrhosis status or RBV use
– No virologic breakthrough or relapse
■ Median ALT, bilirubin, and albumin levels improved between baseline andpost-treatment Week 12
■ DCV + SOF ± RBV was generally safe and well tolerated– Few discontinuations due to adverse events, treatment-related serious AE, or
grade 3 or 4 laboratory abnormalities
■ These results suggest that the pangenotypic, all-oral combination ofDCV + SOF + RBV represents an effective and well-tolerated treatment forliver transplant recipients with recurrent HCV, including patients withadvanced disease
11
127
Thank you for your attention
1392GR16NP0155815/3/16
1392GR16NP0155815/3/16