highlights fromhighlights from easl 2013
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Highlights FromHighlights FromEASL 2013Seng Gee Lim, MDNational University Hospitaly pSingapore
1
Sponsored by:
Highlights of EASL 2013
HCV Highlights– HCV Highlights
– Non-HCV Highlightsg g
2
H Fontaine1* C Hezode2 C Dorival3 D Larrey4 F Zoulim5 V De Ledinghen6 V Canva7 L Alric8 MH. Fontaine , C. Hezode , C. Dorival , D. Larrey , F. Zoulim , V. De Ledinghen , V. Canva , L. Alric , M. Bourlière9, S. Pol10, T. Poynard11, G. Riachi12, P.-H. Bernard13, J.-J. Raabe14, J. Gournay15, S. Métivier16, J.-M.
Pawlotsky17, D. Samuel18, Y. Barthe3, F. Carrat3, J.-P. Bronowicki19, ANRS CO 20 CUPIC Study Group
1Hepatology Unit, Cochin Hospital AP-HP, Paris, 2Hepatology Unit, Henri Mondor Hospital, Créteil, 3UMR-S 707, INSERM, Paris, 4Hepatology Unit, Saint-Eloi Hospital, Montpellier, 5U871, INSERM, Lyon, 6Hepatology
Unit, Haut Leveque Hospital, Bordeaux, 7Hepatology Unit, Claude Huriez Hospital, Lille, 8Medecine Unit, Purpan Hospital, Toulouse, 9Hepatology Unit, Saint Joseph Hospital, Marseille, 10Hepatology Unit, Cochin Hospital, 11Hepatology Unit, Pitié-Salpétrière Hospital, Paris, 12Hepatology Unit, Charles Nicolle Hospital, p p gy p p p gy p
Rouen, 13Hepatology Unit, Saint-André Hospital, Bordeaux, 14Hepatology Unit, Bon Secours Hospital, Metz, 15Hepatology Unit, Nantes Hospital, Nantes, 16Hepatology Unit, Purpan Hospital, Toulouse, 17Virology Unit,
Henri Mondor Hospital, Créteil, 18Hepatology Unit, Paul Brousse Hospital, Villejuif, 19Hepatology Unit, BraboisHospital, Nancy, France.
3
p , y,
CUPIC: French early access programCUPIC: French early access program– EASL 2012 report: increased SAEs and deaths
Design: cohort study– Design: cohort study• Selection of boceprevir or telaprevir made by the clinician
– PatientsPatients• Genotype 1• Patients with compensated cirrhosis
– Approximately 1/3 would not have qualified for phase 3 trials
• Prior relapse and partial response
Regimens– Regimens• Standard protocols for boceprevir (lead-in) and telaprevir• 48 weeks for all patients
4
p
H. Fontaine et al, Abstract 60. EASL, April 2013
CUPIC SVR12 Results100
CUPIC SVR12 Results
80
%)
Boceprevir
41
51
4040
53
3240
60
SVR
12 (%
Telaprevir
11
32 29
20
S
32 43 8
0All patients Prior relapse Prior partial Prior null
4385
3280
19
79190
61116
43135
828
118295
5
H. Fontaine et al, Abstract 60. EASL, April 2013
CUPIC: French early access programCUPIC: French early access program
– Predictors of response
• Prior relapse > prior partial/null response
G t 1b 1• Genotype 1b > 1a
6
H. Fontaine et al, Abstract 60. EASL, April 2013
CUPIC: French early access programCUPIC: French early access programPatients, n (% patients with at least one event) Telaprevir n=295 Boceprevir n=190
Serious adverse events (SAEs) 535 in 160 patients (54.2%)
321 in 97 patients(51.0%)
Premature discontinuation / Due to SAEs 139 (47.1%) / 63 (21.3%) 80 (42.1%) / 27 (14.2%)
Death 7 (2 4%) 3 (1 6%)Death 7 (2.4%) 3 (1.6%)
Infection (Grade 3/4) 27 (9.1%) 8 (4.2%)
Hepatic decompensation (Grade 3/4 ) 15 (5.1%) 9 (4.7%)
Anemia (Grade 3/4 : Hb < 8 g/dL) 38 (12.9%) 19 (10%)( g ) ( %) ( %)
Rash (Grade 3/SCAR) 16 (5.4%) / 2 (0.6%) 2 (1.0%) / 0
EPO use / Blood transfusion 168 (57%) / 53 (18%) 119 (62.6%) / 26 (13.7%)
GCSF use 8 (2.7%) 13 (6.8%)
TPO use 6 (2%) 3 (1.6%)
SCAR: severe cutaneous adverse reaction
7
H. Fontaine et al, Abstract 60. EASL, April 2013
CUPIC: French early access programCUPIC: French early access program
– Large “real life” cohort of patients with cirrhosisg p
– SVR12 rate comparable to subgroup of patients with severe fibrosis or cirrhosis of phase III studies
Increased risk of serious adverse events particularly– Increased risk of serious adverse events, particularly severe infections and anemia
8
H. Fontaine et al, Abstract 60. EASL, April 2013
I. Jacobson1*, G.J. Dore2, G.R. Foster3, M.W. Fried4, M. Radu5, V.V. Rafalskiy6, L. Moroz7, A. Craxì8, M. Peeters9, O. Lenz9, S. Ouwerkerk-Mahadevan10, R. Kalmeijer11, M. Beumont-Mauviel9
1Weill Cornell Medical College, New York, NY, USA, 2Kirby Institute, University of New South Wales, Sydney, NSW, Australia, 3Queen Mary University of London, Barts Health, London, UK, 4University of
North Carolina at Chapel Hill Chapel Hill NC USA 5Institutul de Boli infectioase BucharestNorth Carolina at Chapel Hill, Chapel Hill, NC, USA, Institutul de Boli infectioase, Bucharest, Romania, 6Smolensk Regional Clinical Hospital, Smolensk Oblast, Russia, 7Vinnytsia National
Medical University, Vinnytsia, Ukraine, 8Azienda Ospedaliera Universitaria Policlinico Paolo Giaccone, Palermo, Italy, 9Janssen Infectious Diseases BVBA, 10Janssen Research & Development,
B B l i 11J Gl b l S i LLC Tit ill NJ USABeerse, Belgium, 11Janssen Global Services, LLC, Titusville, NJ, USA.
9
I. Jacobson et al, Abstract 1425. EASL, April 2013
QUEST-1QUEST-1– Simeprevir: potent, once-daily, oral HCV NS3/4A protease inhibitor– Phase III, randomized, double-blind, placebo-controlled trial , , , p– Patients
• Treatment naïve genotype 1 infectionR i– Regimen• PEG + RBV + simeprevir 150 mg qd• PEG + RBV + placebo
– Algorithm• Simeprevir for first 12 weeks• Response guided therapyResponse guided therapy
– RVR: PEG/RBV x 24 weeks – No RVR: PEG/RBV x 48 weeks
10
I. Jacobson et al, Abstract 1425. EASL, April 2013
QUEST 1: SVR12 rates100
QUEST-1: SVR12 ratesP<0.0001
8080
)
50
40
60
SVR
12 (%
20
S
210 65
0PEG+RBV+SIMEPREVIR PEG+RBV+PLACEBO
210264
65130
11
I. Jacobson et al, Abstract 1425. EASL, April 2013
QUEST 1: SVR12 rates in subgroups
120
QUEST-1: SVR12 rates in subgroupsSIM + PR PR
8390 94
767880
100
70 7176
6560
49 5242
60
80
28 2420
40
152/ 54/ 54/ 11/ 105/ 36/ 105/ 29/ 72/ 29/ 114/ 32/ 24/ 4/
0F0-F2 F3-F4 1a 1b/other CC CT TT
Fibrosis Genotype IL28B genotype
152/183
54/90
54/77
11/40
105/147
36/74
105/117
29/56
72/77
29/37
114/150
32/76
24/37
4/17
12
I. Jacobson et al, Abstract 1425. EASL, April 2013
Fibrosis Genotype IL28B genotype
E. Lawitz1*, D. Wyles2, M. Davis3, M. Rodriguez-Torres4, K.R. Reddy5, K.V. Kowdley6,E. Svarovskaia7, D. Jiang7, J. McNally7, D.M. Brainard7, W.T. Symonds7, J.G. McHutchison7,
L. Nyberg8, Z. Younossi9
1Alamo Medical Research, San Antonio, TX, 2University of California, San Diego, San Diego, CA, 3DigestiveCARE-South Florida Center of Gastroenterology, Wellington, FL, USA, 4Fundación de
Investigación, San Juan, Puerto Rico, 5University of Pennsylvania School of Medicine, Philadelphia, PA, 6Digestive Diseases Unit, Virginia Mason Medical Center, Seattle, WA, 7Gilead Sciences, Inc., Foster City, 8Kaiser Permanente, San Diego, CA, 9Inova Fairfax Hospital, Falls Church, VA, USA.
*l i @ li*[email protected]
13
NEUTRINONEUTRINO– Sofosbuvir (GS-7977)
Patients– Patients• Genotypes 1, 4, 5, 6 treatment naive• 17% compensated cirrhosis• 17% black• 29% IL28B genotype CC
R i f ll ti t– Regimen for all patients• Sofosbuvir 400 mg qd• Ribavirin 1000/1200 mgRibavirin 1000/1200 mg • Peginterferon alfa-2a 180 mcg weekly
– Duration: 12 weeks
14
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013. DOI: 10.1056/NEJMoa1214853
NEUTRINO: SVR12 by genotype90 89
96100
100
NEUTRINO: SVR12 by genotype
60
80
%)
40
60
SVR
12 (%
n = 292 28 n = 7
20
295/327 261/292 27/28 7/7n = 292 n = 28 n = 70
All Patients 1 4 5, 6Genotype
15
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013. DOI: 10.1056/NEJMoa1214853
NEUTRINO: SVR12 rates by subgroup92
98
8787100
NEUTRINO: SVR12 rates by subgroup
8080
%)
40
60
SVR
12 (%
20
0n = 232n = 273 n = 54 n = 54
No cirrhosis Cirrhosis CC CT/TTIL28B genotype
Black
n = 95
16
g yp
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013. DOI: 10.1056/NEJMoa1214853
ConclusionsConclusions
– 12 weeks of treatment with SOF + PEG-IFN + RBV achieved 90% SVR12 in treatment naïve patients with HCV genotype 1, 4, 5, or 6C ge o ype , , 5, o 6
– 99% of patients had HCV RNA < LLOQ by treatment week 4 and relapse accounted for all virologic failures
This regimen was well tolerated– This regimen was well tolerated
17
E. Lawitz et al, Abstract 1411. EASL, April 2013; Lawitz et al., N Engl J Med 2013. DOI: 10.1056/NEJMoa1214853
M S Sulkowski1* D F Gardiner2 M Rodriguez Torres3 K R Reddy4 T Hassanein5 I Jacobson6 EM.S. Sulkowski1*, D.F. Gardiner2, M. Rodriguez-Torres3, K.R. Reddy4, T. Hassanein5, I. Jacobson6, E. Lawitz7, A.S. Lok8, F. Hinestrosa9, P.J. Thuluvath10, H. Schwartz11, D.R. Nelson12, G.T. Everson13, T. Eley2, M.
Wind-Rotolo14, S.-P. Huang14, M. Gao15, F. McPhee15, D. Hernandez15, D. Sherman2, R. Hindes16, W. Symonds17, C. Pasquinelli2, D.M. Grasela2, AI444040 Study Group
1Johns Hopkins University, Baltimore, MD, 2Bristol-Myers Squibb, Hopewell, NJ, USA, 3Fundación de Investigación, San Juan, Puerto Rico, 4University of Pennsylvania, Philadelphia, PA, 5Southern California
Liver Center, Coronado, CA, 6Weill Cornell Medical College, New York, NY, 7Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, 8University of Michigan, Ann Arbor, MI, 9Orlando ImmunologyTexas Health Science Center, San Antonio, TX, University of Michigan, Ann Arbor, MI, Orlando Immunology
Center, Orlando, FL, 10Mercy Medical Center, Baltimore, MD, 11Miami Research Associates, South Miami, 12University of Florida, Gainesville, FL, 13University of Colorado, Denver, CO, 14Bristol-Myers Squibb,
Princeton, NJ, 15Bristol-Myers Squibb, Wallingford, CT, 16Consultant, 17Gilead Sciences, Foster City, CA, USA.*msulkowski@jhmi edu
18
BackgroundBackground – Patients who experience virologic failure on telaprevir or boceprevir-
based regimens currently have no treatment options
– Daclatasvir (DCV): NS5A inhibitor
– Sofosbuvir (SOF): nucleotide NS5B polymerase inhibitor
– DCV plus SOF with or without RBV achieved SVR4 in 98% of 126 HCV GT 1-infected treatment-naive patients (Sulkowski et al AASLD 2012)(Sulkowski et al. AASLD 2012)
Aim: T l t th ffi d f t f DCV l SOF ith ith t– To evaluate the efficacy and safety of DCV plus SOF with or without RBV for 24 weeks in HCV GT 1-infected patients who failed prior treatment with TVR or BOC + pegIFN-alfa/RBV
19
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
Study Design
Prior TVR/BOCn = 21 DCV 60 mg QD + SOF 400 mg QD Follow-up
Study Design
Prior TVR/BOC failures, GT 1a/1b(N = 41) Follow-upn = 20 DCV 60 mg QD + SOF 400 mg QD + RBV
Week 24SVR4
SVR12– Patients• Genotype 1, non-cirrhotic• Prior nonresponse, relapse, or breakthrough during treatment
i h PEG/RBV TVR BOCwith PEG/RBV + TVR or BOC• Patients who discontinued TVR or BOC due to an adverse
event were excluded
20
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
event were excluded
Virologic response100
tient
s) DCV + SOF
Virologic response
60
80
OQ
(%
pat
DCV + SOF + RBV
Missing
20
40
RN
A <
LLO Missing
0
EOT
HC
V
Week 2 SVR4
N =
Week 4
21 20
SVR12
21 20 21 20 21 20 21 20
4 12
– 1 patient missing at post-treatment (PT) Week 12: HCV RNA was undetectable at PT Week 4 and at PT Week 2421/41 patients have reached PT Week 24; all have achieved SVR
21
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
– 21/41 patients have reached PT Week 24; all have achieved SVR24
ConclusionConclusion
– The all-oral, once-daily combination of DCV + SOF with , yor without RBV achieved SVR in all HCV GT 1-infected patients (n=41) who failed prior treatment with TVR or pa e s ( ) o a ed p o ea e oBOC + pegIFN-alfa/RBV
– DCV + SOF with or without RBV was well tolerated
• No grade 3 or 4 hepatic or hematologic abnormalities• No grade 3 or 4 hepatic or hematologic abnormalities
22
M.S. Sulkowski et al, Abstract 1417. EASL, April 2013
K V K dl 1* E L it 2 F P d d2 D E C h 3 D N l 4 S Z 5 G T E 6 PK.V. Kowdley1*, E. Lawitz2, F. Poordad2, D.E. Cohen3, D. Nelson4, S. Zeuzem5, G.T. Everson6, P. Kwo7, G.R. Foster8, M. Sulkowski9, W. Xie3, L. Larsen3, A. Khatri3, T. Podsadecki3, B. Bernstein31
Digestive Disease Institute, Virginia Mason Medical Center, Seattle, WA, 2University of Texas Health Science Center San Antonio TX 3Abbott Laboratories Abbott Park IL 4University of Florida CollegeScience Center, San Antonio, TX, 3Abbott Laboratories, Abbott Park, IL, University of Florida College
of Medicine, Gainesville, FL, USA, 5J.W. Goethe University, Frankfurt, Germany, 6University of Colorado Denver, Aurora, CO, 7Indiana University, Indianapolis, IN, USA, 8Queen Mary’s University of
London, Barts Health, London, UK, 9Johns Hopkins University, Baltimore, MD, USA.
23
AVIATORAVIATOR– Phase 2, randomized, open-label, multicenter study– PatientsPatients
• Genotype 1 (66% genotype 1a)• Treatment-naïve and prior null response• Non cirrhotic• Non-cirrhotic
– Medications• ABT-450/r (HCV protease inhibitor boosted with ritonavir 100 mg)• ABT-267 (NS5A inhibitor) • ABT-333 (non-nucleoside NS5B inhibitor)• Ribavirinba
– Duration• 8, 12 and 24 weeks
24
K.V. Kowdley et al, Abstract 3. EASL, April 2013
SVR12 SVR24 VBT/N SVR12 SVR24 VBT/SVR12 (%)
SVR24(%)
VBT/Relapse
89 88 0/10
85 83 1/4
N Regimen/duration SVR12 (%)
SVR24(%)
VBT/Relapse
80 ABT450 ABT267 ABT333 RBV 89 88 0/10
41 ABT450 ABT333 RBV 85 83 1/4
aive
91 89 1/8
90 87 1/5
99 96 0/1
79 ABT450 ABT267 RBV 91 89 1/8
79 ABT450 ABT267 ABT333 90 87 1/5
79 ABT450 ABT267 ABT333 RBV 99 96 0/1eatm
ent n
a
99 96 0/1
93 90 0/2
79 ABT450 ABT267 ABT333 RBV 99 96 0/1
80 ABT450 ABT267 ABT333 RBV 93 90 0/2
Week 8 12 24
Tre
SVR12 (%)
SVR24(%)
VBT/Relapse
89 89 0/5
93 93 3/0
N Regimen/duration SVR12 (%)
SVR24(%)
VBT/Relapse
45 ABT450 ABT267 RBV 89 89 0/5
45 ABT450 ABT267 ABT333 RBV 93 93 3/0resp
onse
93 93 3/0
98 95 1/0
45 ABT450 ABT267 ABT333 RBV 93 93 3/0
43 ABT450 ABT267 ABT333 RBV 98 95 1/0Nul
l r
25
K.V. Kowdley et al, Abstract 3. EASL, April 2013
AVIATOR ConclusionsAVIATOR Conclusions
– Comparable SVR12 and SVR24 seen with 12 and 24 weeks of treatment
• Selection of a 12-week duration of therapy in these populationsSelection of a 12-week duration of therapy in these populations
– SVR rates >90% were achieved in naïve and prior null responder patients with a 3-DAA+RBV regimen
• No clinically meaningful differences were observed by sex, y g y ,HCV subtype, IL28B genotype, baseline HCV-RNA or severity of fibrosis.
26
K.V. Kowdley et al, Abstract 3. EASL, April 2013
Highlights From EASL 2013
HCV Highlights– HCV Highlights
– Non-HCV Highlightsg g
27
G.A. Palumbo1,2*, L. Belloni1,2,3, S. Valente4, D. Rotili4, N. Pediconi1,2,A. Mai4, M. Levrero1,2,3A. Mai , M. Levrero
1Dip. di Medicina Interna (DMISM), 2EAL Inserm U 785, 3Life Nanosciences Laboratory, 4Dip. di Chimica e Tecnologie del Farmaco, Sapienza University, Rome, Italy.
* @ li it*[email protected]
28
BackgroundBackground
– The HBV cccDNA is organized into mini-chromosomes in the l f i f t d ll b hi t d hi t t inucleus of infected cells by histone and non-histone proteins.
By using a cccDNA-specific chromatin immunoprecipitation(ChIP)-based assay, we showed that HBV replication is regulated, both in a cell replication system and in the liver of HBV chronically infected patients, by the acetylation status of cccDNA-boundH3/H4 histones.
– We have also shown that interferon-α (IFNα) inhibits HBV transcription and replication in vitro and in vivo by favoring the long term recruitment to the nuclear cccDNA mini-chromosome of the class III HDAC hSirt1 and of the PRC2 repressive complex, including the transcriptional co-repressors HDAC1 and Ezh2.
29
G.A. Palumbo et al, Abstract 56. EASL, April 2013
g p p
The HBV cccDNA as a “minichromosome”
L R li ti
The HBV cccDNA as a minichromosome
PCAF
300 PCAF
p300
High Replication Low Replication
Si t1
Sirt1HDAC1HDAC1
Ezh2
p300 PCAF Sirt1
spontaneouslyi t i
Histones Histones
iatrogenicImmunosuppression
30
AimAim– We sought to assess the feasibility to inhibit HBV
t i ti d li ti b t ti th i titranscription and replication by targeting the epigenetic control of nuclear cccDNA mini-chromosome with small
d ti diff t l f h ticompounds active on different classes of chromatinmodifying enzymes.
31
G.A. Palumbo et al, Abstract 56. EASL, April 2013
MethodsMethods– Capsid-associated HBV-DNA (TaqMan real-time PCR),
DNA (T M l ti PCR) d RNA l lcccDNA (TaqMan real-time PCR) and pgRNA levels (quantitative real-time PCR with specific primers), were
d i H G2 ll t f t d ith f ll l thassessed in HepG2 cells transfected with full length HBV genomes left untreated and/or treated with • Class I/II and class III histone deacetylase inhibitors (HDACi)• p300 and PCAF histone acetyltransferases (HAT) inhibitors
hSi t1 ti t• hSirt1 activators• JMJD3 histone demethylase inhibitors
32
G.A. Palumbo et al, Abstract 56. EASL, April 2013
ResultsResults
– The combined inhibition of p300 and PCAF HATs (compound 26 ) fEML-264) resulted in an evident reduction of HBV replication that
mirrored the decrease of pgRNA transcription. The hSirt1/2 activators MC2562 and MC2791, albeit with different efficiency, , y,both inhibited HBV replication and cccDNA transcription.
– Potentiation of Ezh2 activity through the inhibition of JMJD3Potentiation of Ezh2 activity through the inhibition of JMJD3 histone demethylase with compound MC3119 resulted in a >50% reduction of pgRNA transcription. Notably, inhibition of hSirt1/2 (MC2344) or Ezh2 (MC2887) strongly induced cell death, thus hampering the evaluation of their effects on viral replication.
33
G.A. Palumbo et al, Abstract 56. EASL, April 2013
ConclusionsConclusions
– Altogether these results represent a proof of concept that activation of hSirt1 and Ezh2 by small molecules can induce an “active epigenetic suppression” of HBV cccDNA minichromosome similar to that observed with IFNα.
34
G.A. Palumbo et al, Abstract 56. EASL, April 2013
W.R. Kim1*, T. Berg2, R. Loomba3, R. Aguilar Schall4, P. Dinh4, L.J. Yee4, E.B. Martins4, J.F. Flaherty4, S. Gurel5, M. Buti6, P. Marcellin7
1Mayo Clinic, Rochester, MN, USA, 2University Hospital Leipzig, Leipzig, Germany, 3Universityf C lif i S Di L J ll 4Gil d S i F Ci CA USA 5U i i f Ul dof California San Diego, La Jolla, 4Gilead Sciences, Foster City, CA, USA, 5University of Uludag,
Bursa, Turkey, 6Hospital General Universitari Vall d'Hebron, Barcelona, Spain, 7Hopital Beaujon, Clichy, France.
*kim woong@mayo [email protected]
35
BackgroundBackground
– Efficacy trials have shown that antiviral therapy improves short to intermediate term outcomes in patients with chronic hepatitis B, such as HBV DNA suppression, HBe seroconversion and regression of fibrosis and cirrhosis. g
– The effect of antiviral therapy on incidence of HCC has not been well establishedbeen well established.
Aim:
– To examine HCC incidence using a prediction model.
36
W.R. Kim et al, Abstract 43. EASL, April 2013
MethodsMethods
– The incidence of HCC in patients treated with TDF was obtained from the 6-year follow-up data of the registration trials forHBeAg-positive (GS-US-174-0103) and HBeAg-negative(GS US 174 0102) patients(GS-US-174-0102) patients.
– The predicted risk of HCC in individual patients was estimated using a model validated in cirrhotics and non-cirrhotics (the REACH-B model: Yang et al., Lancet Oncology, 2011).
– Standardized incidence ratios [SIR] were calculated between the observed and predicted numbers of HCC in the study cohort.
37
W.R. Kim et al, Abstract 43. EASL, April 2013
ResultsResults
– In the two studies, 641 patients received TDF for6 years.
During this time 13 cases of HCC were reported– During this time, 13 cases of HCC were reported.
• 9 were HBeAg- at baseline; among them 3 were cirrhotic.
• 4 were HBeAg+ at baseline; among them 3 were cirrhotic.
• 4 were genotype (gt) C 5 gt D 1 gt B 1 gt E 1 gt F and 1• 4 were genotype (gt) C, 5 gt-D, 1 gt-B, 1 gt-E, 1 gt-F and 1 unable to genotype.
38
W.R. Kim et al, Abstract 43. EASL, April 2013
25 • The arrow indicates the 10th
HCC case which occurred at 3 3 years at which time theC
cas
es
25
20Predicted
3.3 years, at which time the REACH-B model predicted 11.2 cases.
ber o
f HC
C
15
Observed
• The SIR was 0.94 (95% confidence interval [CI]=0.47-at
ive
num
b
10
1.88) at 2.4 years, 0.89 (95% CI=0.48-1.66) at 3.3 years and 0 55 (95% CI=0 32-0 94)
Cum
ula
5
0 and 0.55 (95% CI=0.32-0.94) at the latest follow-up (median 5.52 years).
0
0 1 2 3 4 5 6
Years
39
W.R. Kim et al, Abstract 43. EASL, April 2013
W. Sieghart1*, F. Hucke1, M. Pinter1, I. Graziadei2, W. Vogel2, C. Müller1, H. Heinzl1, M. Trauner1,
M. Peck-Radosavljevic1
1Medical University of Vienna, Vienna, 2Medical University of Innsbruck, Innsbruck, Austria.
*wolfgang sieghart@meduniwien ac [email protected]
40
BackgroundBackground
– We aimed to establish an objective point score to guide the decision for retreatment with transarterialchemoembolization (TACE) in patients with hepatocellular carcinoma (HCC).
41
W. Sieghart et al, Abstract 102. EASL, April 2013
MethodsMethods– 222 patients diagnosed with HCC and treated with multiple TACE
cycles between 1/1999 and 12/2009 at the Departments ofcycles between 1/1999 and 12/2009 at the Departments of Gastroenterology/Hepatology of the Medical Universities of Vienna (training cohort) and Innsbruck (validation cohort) were included.
– We investigated the effect of the first TACE on parameters of liver function and tumor response and their impact on overall survival (OS, log rank test) and developed a point score (ART-score: Assessment for Retreatment with TACE) in the training cohort (n=107 Vienna) by using a stepwise Cox regression model(n 107, Vienna) by using a stepwise Cox regression model.
– The ART-score was externally validated in an independent validation cohort (n=115, Innsbruck).
42
W. Sieghart et al, Abstract 102. EASL, April 2013
validation cohort (n 115, Innsbruck).
ResultsResults– The increase of AST by >25% (Hazard Ratio (HR) 8.4; p< 0.001),
the increase of Child-Pugh score of one (HR 2 0) or ≥2 pointsthe increase of Child-Pugh score of one (HR 2.0) or ≥2 points(HR 4.4) (p< 0.001) from baseline and absence of radiologic tumor response (HR 1.7; p=0.026) remained independent negative prognostic factors for OS and were used to create the ART scoreprognostic factors for OS and were used to create the ART-score.
– The ART-score differentiated 2 groups (0-1.5 points; ≥2.5 points) with distinct prognosis (median OS: 23 7 vs 6 6 months; p< 0 001)with distinct prognosis (median OS: 23.7 vs. 6.6 months; p< 0.001) and a higher ART-score was associated with major adverse events after the second TACE (p=0.011).
– These results were confirmed in the external validation cohort and remained significant irrespective of Child-Pugh stage and the presence of ascites prior the second TACE.
43
W. Sieghart et al, Abstract 102. EASL, April 2013
p p
ConclusionConclusion
– An ART-score of ≥2.5 prior the second TACE identifies patients with dismal prognosis who may not profit from further TACE sessions.
44
W. Sieghart et al, Abstract 102. EASL, April 2013