PowerPoint Presentation - Livemedia.gr...Genotype 4 – SMV+PR 40 0 10 20 30 40 12w + 12W naïve 12w + 12w exp - Rel 12w + 36w exp - partial 12w + 36w exp - null *stop treatment if

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


Grazoprevir/ElbasvirNS3/4A protease

inhibitorNS5A inhibitor

• 100/50 mg/day

• geno 1, 4


• 100/50 mg/day

• geno 1, 4


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 in 1a-Q80K)?

SOF+DCVSOF+DCV+RBV



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


EASL(03/2015)


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


EASL(03/2015)


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 (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


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


EASL(03/2015)


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)


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 F1-F2 without RVR orexperienced NR0

10203040

12w

naive

non-CI or Ci





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)


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.


• 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.


• 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.


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 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




ALLY-1N = 113

All-Oral DCV + SOF




ALLY-2N = 203


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




ALLY-1N = 113

All-Oral DCV + SOF




ALLY-2N = 203


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


• 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)


• Patients with genotype 2,3

– Sofosbuvir + Daclatasvir + RBV (600mg) :12w


• 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

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