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,

*[email protected]

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


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


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


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


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.

*[email protected]

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


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


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


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


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


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


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

[email protected]

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


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


– 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


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.

*[email protected]

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


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


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


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


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


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


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


– 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


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


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. 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


– 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


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


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


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Highlights FromHighlights From EASL 2013

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