Thomas Berg Sektion Hepatologie

Klinik und Poliklinik für Gastroenterologie und Rheumatologie

Universitätsklinikum Leipzig

Leber- und Studienzentrum am Checkpoint, Berlin

Treatment Challenges in special patient populations

Decompensated Cirrhosis

DAA in the management of patients with HCV-induced decompensated cirrhosis

Topics to discuss…

• Virologic response – Outcome predictors

• Clinical response – Point of no return?

• Safety of DAA

• The patient on the „waiting list“ – Debate: should we start treatment before or after

liver transplantation?

•

Current regimens used for patients with decompensated disease and

virologic response rates

Selection of studies evaluating all oral interferon-free regimes in patients with HCV-induced decompensted disease

ALLY-11

OPTIMIST-22

SATURN4

SOLAR-23

CORAL5

Controlled trials ‚REAL World‘-cohorts and Early Access Programme:

HCV-TARGET6

French ATU7

UK EAP8

EU CUP9

1. Poordad et al. EASL 2015, abstract L08. 2. Lawitz et al. EASL 2015, abstract LP04. 3. Manns et al. EASL 2015, oral G02. 4. Forns et al. EASL 2015. Abstract 0004. 5. Kwo PY, et al. N Engl J Med. 2014;371:2375-82. 6. Reddy et al. EASL 2015, abstract O007. 7. De Ledinghen et al. EASL 2015, abstract PO795. 8. Foster et al. EASL 2015, abstract O002. 9. Welzel et al. EASL 2015, Poster PO772.

DCV + SOF before and after LTx

SMV + SOF before LTx, Cirrhosis

LDV + SOF before

and after LTx

SMV + DCV after LTx

PTV/r + OMV +

DSV +/- RBV

SOF + SMV

+/- RBV

DCV + SOF +/- RBV

SOF-containing regimen

SOF + DCV or LDV

+/- RBV

Register studies in UK, France, and Germany

Selection of studies evaluating all oral interferon-free regimes in patients with HCV-induced decompensted disease

ALLY-11

OPTIMIST-22

SATURN4

SOLAR-23

CORAL5

Controlled trials ‚REAL World‘-cohorts and Early Access Programme:

HCV-TARGET6

French ATU7

UK EAP8

EU CUP9

1. Poordad et al. EASL 2015, abstract L08. 2. Lawitz et al. EASL 2015, abstract LP04. 3. Manns et al. EASL 2015, oral G02. 4. Forns et al. EASL 2015. Abstract 0004. 5. Kwo PY, et al. N Engl J Med. 2014;371:2375-82. 6. Reddy et al. EASL 2015, abstract O007. 7. De Ledinghen et al. EASL 2015, abstract PO795. 8. Foster et al. EASL 2015, abstract O002. 9. Welzel et al. EASL 2015, Poster PO772.

DCV + SOF before and after LTx

SMV + SOF before LTx, Cirrhosis

LDV + SOF before

and after LTx

SMV + DCV after LTx

PTV/r + OMV +

DSV +/- RBV

SOF + SMV

+/- RBV

DCV + SOF +/- RBV

SOF-containing regimen

SOF + DCV or LDV

+/- RBV

Register studies in UK, France, and Germany

Number of patients with Child Pugh Stage C limited

Percentage of patients with MELD > 15 appr. 10% (0-22%)

Treatment duration 12 or 24 weeks ± ribavirin

Summary of SVR rates in studies evaluating all oral DAA in decompensated HCV cirrhosis

Regimen SVR % Author

SOF/SMV ± RBV 73-78% Saxena et al. 2015 Aqel et al. 2015

SOF/LDV ± RBV Solar 1 and 2 TARGET UK NHS E

86-89% Manns MP 2015 Charlton M 2015

Terrault 2015 Foster GR 2015

SOF/DCV ± RBV ALLY-1 UK NHS E CUP

82-83% (98% CUP)

Poordad F 2015 Foster GR 2015 Welzel T 2015

3D (Turqouise) + RBV

100% (only Child B) Mantry 2015

SOF/Valpatasvir ± RBV 83%-94% Curry MP 2015

Response predictors

Stage of decompensation Treatment duration

Role of ribavirin

ALLY-1 (SOF/DCV + RBV, 12 weeks) – SVR by Child Pugh Class

92 94

56

0

20

40

60

80

100

A B C

Child-Pugh class

91 96

78 76

91 84

89 97

75 75

56

100

73

No Yes No Yes >3.5 2.8 to 3.5

87 89 86 87 87

96

85

72

0

10

20

30

40

50

60

70

80

90

100

LDV/SOF + RBV12 weeks

LDV/SOF + RBV24 weeks

LDV/SOF + RBV12 weeks

LDV/SOF + RBV24 weeks

SVR1

2 (%

pat

ient

s)

Overall efficacy pre-transplant in GT-1 and GT-4

17 20

CTP B CTP C

Comparable efficacy in SOLAR-11 and SOLAR-22 studies

1. Charlton et al. 2015; Gastroenterology 149:649-59. 2. Manns et al. EASL 2015, abstract G02.

20 23

22 23

13 18

26 30

24 27

19 22

20 23

n = N

Pre-transplant

Solar 1 and 2 clinical trials: SOF/LDV with RBV in decompensated patients

Daclatasvir Plus Sofosbuvir With or Without Ribavirin in Patients With HCV Genotype 3 Infection:

Interim Analysis of a French Multicenter Compassionate Use Program

Christophe Hézode,1 Victor De Ledinghen,2 Helene Fontaine,3 Fabien Zoulim,4 Pascal Lebray,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 Raoudha Akremi,18

Yacia Bennai,18 Jean-Pierre Bronowicki,19 on behalf of Bristol-Myers Squibb

1Hépato-gastro-entérologie, CHU Henri-Mondor, Créteil; 2Centre d’Investigation de la Fibrose hépatique, Hôpital Haut-Lévêque, Centre Hospitalo-Universitaire de Bordeaux, Pessac; 3Hôpital Cochin, AP-HP, Université Paris-René Descartes, Paris; 4Hôpital de la Croix-Rousse,

Hospices Civils de Lyon, Lyon; 5Service d’Hépatogastroentérologie, Hôpital Pitié Salpêtrière, Paris; 6AP-HP, Hôpital Beaujon, Service d’Hépatologie, Clichy; 7Hépato-gastroentérologie, CHU de Montpellier, Hôpital Saint-Éloi, Montpellier; 8Service d’hépato-gastroentérologie et d’assistance nutritive,

laboratoire inflammation tissus epithéliaux et cytokines EA 4331, CHU Poitiers, Poitiers; 9Hôpital de la Conception, Marseille; 10CHU de Grenoble, Clinique universitaire d’hépato-gastroentérologie, Grenoble; 11Hôpital Saint-Joseph, Marseille; 12CHU Trousseau, Tours;

13Service d’Hépato-Gastroentérologie, CHU Angers, Angers; 14Service des Maladies du Foie, CHU Rennes, Rennes; 15Centre Hospitalier Intercommunal, Créteil; 16Service d’Hépato-gastroentérologie, CHU Amiens Nord, Amiens;

17Service d’Hépatologie et de soins intensifs digestifs, CHRU Jean Minjoz, Besançon; 18Bristol-Myers Squibb Research and Development, Rueil-Malmaison; 19Centre Hospitalier Universitaire de Nancy and Université de Lorraine, Vandoeuvre-lès-Nancy, France

The Liver Meeting® 2015: The 66th Annual Meeting of the American Association for the Study of Liver Diseases

San Francisco, CA, November 13–17, 2015

Oral 206 Corresponding author:

Christophe Hézode (christophe.hezode@aphp.fr)

SVR12 by Baseline Child–Pugh Score

11 a 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.

80,0 90,0

84,8

33,3

70,6 70,0

0102030405060708090

100

HCV

RNA

< LL

OQ

TD/T

ND (

%)

Child–Pugh A Child–Pugh B or C

24 30

2 6

90 100

12 17

28 33

7 10

1 1

12 Weeks DCV + SOF ± RBVa

24 Weeks DCV + SOF

24 Weeks DCV + SOF + RBV

■ Overall SVR12: – Child–Pugh A: 87% (142/163) – Child–Pugh B: 67% (18/27) – Child–Pugh C: 50% (3/6)

Chance for recompensation in decompensated disease after

achieving SVR

„point of no return“?

ALLY-1: DCV + SOF + RBV in decompensated HCV cirrhosis

Fontana RJ et al. AASLD 2015

ASTRAL-4: Sofosbuvir plus Velpatasvir ± RBV for 12 or 24 weeks in decompensated HCV cirrhosis

Curry MP et al. NEJM 2015

ASTRAL-4: Sofosbuvir plus Velpatasvir ± RBV for 12 or 24 weeks in decompensated HCV cirrhosis

Curry MP et al. NEJM 2015

HVPG Change Over Time

Afdhal, EASL, 2015, LB13

SOF+RBV for 48 weeks in Compensated and Decompensated Cirrhosis with Portal Hypertension

HVPG Change after treatment in the subset of patients with baseline HVPG ≥ 12 mmHg (n=33)

Afdhal, EASL, 2015, LP13

SOF+RBV for 48 weeks in Compensated and Decompensated Cirrhosis with Portal Hypertension

Chance for “delisting” when treating patients on a liver transplantation waiting list?

57%

13%

30%

HCC N=70

36%

28%

36%

Decompensated Cirrhosis N=53

* Total bilirubin < 35μmol/L + PT>50% + albumin>35g L + no ascites + no hepatic encephalopathy ** Child Class Change

21% Child B

25% Child C

72% Child A

Complete response* Partial response** No response

05

101520253035

1 2 3 4 5 6 7 8

8 patients with a MELD score of ≥ 20

MELD J0

MELD FUS12

LT LT

MEL

D sc

ore

Patients

Baseline FUW12

Coilly A et al. Hepatology 2015; 62(Suppl. S1): 257A.

Clinical and biological responses to antiviral therapy

Delisting

183 patients

Cirrhosis N=77

LT N=24 (31%)

Delisting N=14 (18%)

Improvement N=12 (16%) Other* N=2 (3%)

HCC N=106

LT N=57 (54%)

Drop out N=6 (6%)

*Two alcohol relapses.

Mean time of follow-up: 68 weeks [12-95]

Coilly A et al. Hepatology 2015; 62(Suppl. S1): 257A.

Australian experience in patients with MELD ≥ 15 (SOF/DCV 24 W; TOSCAR study)

McCaughan G et al. AASLD 2015 Hepatology 2015; 62(Suppl. S1): 257A.

pretx

EOT

+4wk

+12w

k0

10

20

3062% MELD

Safety

Lens S et al. Semin Liver Dis 2014; 34: 58

Pharmacokinetics of DAAs*: Effects of hepatic impairment on drug exposure

*Asunaprevir is not authorized in Switzerland.

3D + RBV in patients with decompensated cirrhosis Turquoise CPB

n=11 (HCV subtype 1a N=10), TN und TE ,Child Score 7-9 (MELD ≤ 18, PLT ≥ 25, Alb ≥ 2,8)

Mantry et al., AASLD 2015, #722

100 100 100 100

0

20

40

60

80

100

RVR EOT SVR4 SVR12

SVR1

2 (%

)

67/68

SAEs ■ Hyponatremia ■ SBP ■ GI bleeding ■ HE ■ Anemia (related) ■ Pancytopenia ■ Bilirubin increase grade 3 (7/11) ■ HCC ■ Renal insufficiency Pharmacokinetic OBV AUC - 30-40% PTV/DSV AUC + 100-200% FDA ■ Due to post-approval SAE reports

trial was stopped

Summary of safety outcomes when using DAA regimens in patients with HCV-induced

decompensated cirrhosis

• Serious adverse events: 15%

• Adverse events requiring hospitalisation 20%

• Hepatic decompensation events: 20%

• Treatment discontinuation rate: 10%

• Death rate: 0-4% (2%)

DAA-induced hepatoxicity in decompensated HCV cirrhosis – first reports

Case 1 Case 2

Dyson JK et al. J Hepatol 2015 epub

SOF/LDV + RBV SOF/DCV + RBV

Bilirubin

Bilirubin

MELD

MELD

Simeprevir plus Sofosbuvir in Child Pugh B/C Cirrhosis: Adverse Events (N=55)

Sayena V et al. Hepatology 2015; 62: 715

(MELD > 15 N=0)

The patient on the „waiting list“: should we start treatment before or

after liver transplantation?

When should we treat?

DDI: drug–drug interaction

Pre-transplant Post-transplant

Compensated cirrhosis • Patients are treatable with high SVR rates • Damage to the liver is possibly reversible

Decompensated cirrhosis • Overall health of the patient has

deteriorated • Transplant is usually required • Damage to the liver is potentially

irreversible

Pre-emptive post-transplant treatment • Treat early to prevent HCV recurrence • Early treatment may reduce the risk of

disease progression • Response to treatment can vary

Reactive treatment • Treat HCV recurrence when it occurs • Wait until graft has stabilised • Which therapy? • Issues with DDIs with calcineurin

inhibitors

Pre-transplant Sofosbuvir plus Ribavirin prevent HCV recurrence after liver transplantation

Curry MP et al. Gastroenterology 2015; 148: 100

Efficacy of SOF/LDV + RBV for 12 or 24 weeks in patients with cholestatic hepatitis C recurrence (FCH) after liver

transplantation

Forns X et al. EASL 2015

Issues when treating patients with decompensated disease on the waiting list

• Time to transplant can be significant (unpredictable) – Potential need for long-term treatment, high costs

• Patients are at risk for acute intercurrent illnesess, diseases, hospitalisation, and decompensation (i.e. kidney failure,…) – Risk for drug toxicity, premature tx discontinuation – Risk for resistance development before transplant

• Limited experience in patients with high MELD score • Safety?

Antiviral treatment modalities in HCV-infected patients before and after liver transplantation

Achieving SVR – avoid transplantation

Achieving response – avoid reinfection

Treatment-associated morbidity (mortality?)

Intensified regimens – higher costs

Open questions: Reversal of cirrhosis

Reversal of portal hypertension Long-term HCC risk

Treat significant reinfection Prevent reinfection by immediate treatment

(potential of very short intervention)

Better outcome after transplantation

Transplantation

Transplantation

Transplantation

• High chance for cure with a 12 week regimen

• Compensated disease with HCC (Milan)

• Decompensated disease with MELD < 10, no HCC

• HCC and MELD > 10 and < 18 (?)

– DAA therapy part of the HCC treatment concept?

• High risk for relapse (need for extended tx duration)

− NS5A RAVs + other negative predictors

• Chance for avoiding OLT low + risk for tx-associated morbidity/ mortality high

– Decompensated disease with MELD > 18 (cut-off?)

• HCC and MELD > 15 – 18 (?)

Favours treatment before transplantation

Favours treatment after transplantation

Management of the transplant patient

SVR12 by Cohort

35

a HCV RNA < LLOQ (25 IU/mL); error bars reflect 95% confidence intervals.

82 95

0

20

40

60

80

100

SVR1

2, %

a

Post-transplant Advanced cirrhosis

83 94

0

20

40

60

80

100

𝟓𝟓𝟑𝟑𝟓𝟓𝟑𝟑

𝟓𝟓𝟑𝟑𝟏𝟏𝟑𝟑

Post-transplant Advanced cirrhosis

All Patients GT 1 (Primary Endpoint)

𝟑𝟑𝟗𝟗𝟒𝟒𝟏𝟏

𝟑𝟑𝟑𝟑𝟒𝟒𝟓𝟓

■ In a regression analysis, no difference by gender, age, IL28B, or HCV RNA in the advanced cirrhosis cohort with GT 1

Poordad et al. EASL 2015, abstract L08.

SVR12 by HCV Genotype

36

76

97 100 90

80 83 91

100 100

0

20

40

60

80

100

SVR1

2, %

1a 1b 2 3 4 6

𝟏𝟏𝟏𝟏𝟑𝟑𝟒𝟒

𝟑𝟑𝟑𝟑𝟑𝟑𝟏𝟏

𝟏𝟏𝟏𝟏𝟏𝟏𝟏𝟏

𝟗𝟗𝟏𝟏𝟑𝟑

𝟒𝟒𝟓𝟓

𝟑𝟑𝟑𝟑

𝟓𝟓𝟏𝟏

𝟏𝟏𝟑𝟑𝟏𝟏𝟏𝟏

𝟒𝟒𝟒𝟒

𝟑𝟑𝟑𝟑

𝟑𝟑𝟑𝟑

𝟏𝟏𝟏𝟏

Genotype

1a 1b 2 3 4 6

Advanced cirrhosis cohort N = 60

Post-transplant cohort N = 53

Poordad et al. EASL 2015, abstract L08.

SVR12 by Child-Pugh Class Advanced cirrhosis cohort, all genotypes

37

92 94

56

0

20

40

60

80

100

A B C

Child-Pugh class

91 96

78 76

91 84

89 97

75 75

56

100

73

No Yes No Yes >3.5 2.8 to 3.5

LDV/SOF+RBV for 12 or 24 Weeks in 329 Decompensated and Post-Liver Transplant HCV GT 1 and GT 4 Patients

38

CTP C (10–12) Pre-Transplant

Post-Transplant

Fibrosis (F0–F3)

CTP B (7–9)

FCH

CTP A (5–6)

Week 0 12 24 36

CTP B (7–9)

CTP C (10–12)

SVR12

SVR12 LDV/SOF + RBV

LDV/SOF + RBV

Broad inclusion criteria: – No hepatocellular carcinoma (HCC) – Total bilirubin ≤ 10 mg/dL, Haemoglobin ≥ 10 g/dL – CrCl ≥ 40 mL/min, Platelets > 30,000/mL

RBV dosing – F0–F3 and CTP A cirrhosis: weight-based (< 75 kg = 1000 mg; ≥ 75 kg = 1200 mg) – CTP B and C cirrhosis: dose escalation, 600–1200 mg/d

SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients

Manns et al. EASL 2015, abstract G02.

Clinical trials: SOF/LDV with RBV is effective in decompensated and post-liver transplantation patients

87 89 86 87 87

96

85

72

0

10

20

30

40

50

60

70

80

90

100

LDV/SOF + RBV12 weeks

LDV/SOF + RBV24 weeks

LDV/SOF + RBV12 weeks

LDV/SOF + RBV24 weeks

SVR1

2 (%

pat

ient

s)

Overall efficacy pre-transplant in GT-1 and GT-4

17 20

85 88

60

75

95 100

50

75

0

20

40

60

80

100

12 weeks 24 weeks 12 weeks 24 weeks

SVR1

2 (%

pat

ient

s)

Overall efficacy post-transplant in GT-1 and GT-4

SOLAR-1 SOLAR-2CTP B CTP C CTP B CTP C

Comparable efficacy in SOLAR-11 and SOLAR-22 studies

1. Charlton et al. 2015; Gastroenterology 149:649-59. 2. Manns et al. EASL 2015, abstract G02.

20 23

22 23

13 18

19 20

16 16

1 2

3 4

26 30

24 27

19 22

20 23

22 26

23 26

3 5

3 4

n = N

n = N

Pre-transplant Post-transplant

Liver Function Change from Baseline to Follow-Up Week 4

40

MELD Score Change Change in CTP Class

*Missing FU-4: n=24

Pre/Post-Transplant (CTP B and C, n=136*) Baseline CTP

A (5–6) n=73

B (7–9) n=100

C (10–12) n=54

Follow-up Week 4 CTP

A (5–6) 67 (96) 31 (35) 2 (5)

B (7–9) 3 (4) 57 (65) 20 (48)

C (10–12) 0 0 20 (48)

-10

-8

-6

-4

-2

0

2

4

n=95

(-17)

Chan

ge in

MEL

D Sc

ore

(-11)

(+8)

no assessment: CTP A, n=3; CTP B, n=12; CTP C, n=12

n=22

n=18

SOLAR-2: LDV/SOF + RBV in Decompensated and Post-Liver Transplant Patients

Manns et al. EASL 2015, abstract G02.

Majority of patients showed improvements in MELD and CTP scores

OPTIMIST-2: SVR12 by platelets, albumin and Fibroscan score (ITT)

Lawitz E. et al. EASL 2015, LB-Poster 04

SVR12 in GT 1 Patients with History of Decompensated Cirrhosis

NHS England EAP: SOF + NS5A ± RBV for 12 Weeks

81 86

60

82

0

20

40

60

80

100

SVR

12, %

42

LDV/SOF LDV/SOF +RBV

SOF+DCV SOF+DCV +RBV

17/21 141/164 3/5 37/45

Majority of patients received RBV

Foster et al. EASL 2015, abstract O002

LDV/SOF±RBV for 12 weeks resulted in high SVR rates in GT 1 decompensated cirrhotics

SVR12 in GT 3 Patients with History of Decompensated Cirrhosis

NHS England EAP: SOF + NS5A ± RBV for 12 Weeks

43

43

59 71 70

0

20

40

60

80

100

SVR

12, %

3/7 36/61 5/7 80/114

LDV/SOF LDV/SOF +RBV

SOF+DCV SOF+DCV +RBV

Majority of patients received RBV

SVR rates were comparable to those seen in other studies of SOF+NS5A±RBV for 12 weeks in decompensated cirrhotics

Foster et al. EASL 2015, abstract O002

MELD Improvement in GT 1 and 3 Patients with History of Decompensated Cirrhosis

NHS England EAP: SOF + NS5A ± RBV for 12 Weeks

44

Non-transplanted Transplanted on treatment

Chan

ges i

n M

ELD

Scor

e

Comparative MELD scores available for 217 patients

-20

-15

-10

-5

0

5

10

15

n = 33

Number of Patients

n = 53

n = 131

Foster et al. EASL 2015, abstract O002

Improvement of > 2 MELD scores was observed in 41% by FU Week 4 and 48% had no significant changes

HCV TARGET: SMV + SOF +/- RBV

Crude SVR4+ rates. Groups include patients with decompensated liver disease unless otherwise indicated G: genotype; w/o: without

PI experienced excluded

92 87

75

96 86

95

0

20

40

60

80

100

Non-cirrhotic Cirrhotic Priordecomp.

Cirrhotic w/oprior decomp.

G1a G1b

SVR

4+ (%

)

113/123 156/180 61/81 154/180 88/93 95/99

Adapted from Jensen D, et al. AASLD 2014. Oral presentation 45

CUP: DCV+SOF +/-RBV

a HCV RNA < LLOQ (TD or TND). b Observed values. c 9 patients on DCV + SOF and 2 patients on DCV + SOF + RBV had indeterminate cirrhosis status; all 11 achieved SVR12. d 10 patients on DCV + SOF had indeterminate cirrhosis status; all 10 achieved SVR12; 1 patient on DCV + SOF + RBV with indeterminate cirrhosis status did not achieve SVR12. e 1 relapse. f 1 relapse, 1 HCV RNA > LLOQ but discontinuation before week 12.

DCV + SOF DCV + SOF + RBV Overall

100 100 100 100 100 95 100 100 100 97 100

0

20

40

60

80

100

Cirrhosis

5 5

4 4

No cirrhosis Cirrhosis No cirrhosis

9 9

10 10

8 8

18 18

59e 60

95 98

2 2

1 1

3 3

Post-Liver Transplantc No Liver Transplantd

SVR1

2 (%

) a,b

98

36f 38

Welzel TM, et al. EASL 2015, Poster PO772.

CUP: DCV+SOF +/-RBV

47 47

a HCV RNA < LLOQ (TD or TND). b Observed cases. d 1 relapse. e 1 HCV RNA > LLOQ but discontinuation before week 12. h 2 relapse. Descriptive analysis only, results cannot be directly compared across subgroups or by treatment group.

DCV + SOF DCV + SOF + RBV Overall

97 100 100 95 95 100 97 98 100

0

20

40

60

80

100

SVR1

2 (%

) a,b

A

B

C

39 40

19 20

58 60

24 24

21 22

45 46

1 1

1 1

2 2

d h d e e

Child-Pugh Class

Welzel TM, et al. EASL 2015, Poster PO772.

Management of patients with RAVs after DAA failure?

49

Parent Study

Persistence of NS5A RAVs Proportion of Patients With Any NS5A RAVs at More Than 1%

98 100 98 100 9586

0

20

40

60

80

100

VF Baseline FU-12 FU-24 FU-48 FU-96

Patie

nts W

ith N

S5A

RAVs

(%)

Registry Study

62/63 58/58 42/43 45/45 52/55 50/58

♦ NS5A RAVs persisted in majority of patients for 96 weeks

Wyles D et al. EASL 2015

Diagramm1

VF

Baseline

FU-12

FU-24

FU-48

FU-96

Series 1

98

100

98

100

95

86

Sheet1

Series 1Column1Column2

VF98

Baseline100

FU-1298

FU-24100

FU-4895

FU-9686

Slide Number 1DAA in the management of patients with HCV-induced decompensated cirrhosis�Topics to discuss…Current regimens used for patients with decompensated disease and virologic response ratesSelection of studies evaluating all oral interferon-free regimes in patients with HCV-induced decompensted diseaseSelection of studies evaluating all oral interferon-free regimes in patients with HCV-induced decompensted diseaseSlide Number 6Response predictors���Stage of decompensation�Treatment duration �Role of ribavirinSlide Number 8Solar 1 and 2 clinical trials: SOF/LDV with RBV in decompensated patientsDaclatasvir Plus Sofosbuvir With or Without Ribavirin in Patients With HCV Genotype 3 Infection: �Interim Analysis of a French Multicenter Compassionate Use ProgramSVR12 by Baseline Child–Pugh ScoreChance for recompensation in decompensated disease after achieving SVRALLY-1: DCV + SOF + RBV in �decompensated HCV cirrhosisASTRAL-4: Sofosbuvir plus Velpatasvir ± RBV for 12 or 24 weeks in decompensated HCV cirrhosisASTRAL-4: Sofosbuvir plus Velpatasvir ± RBV for 12 or 24 weeks in decompensated HCV cirrhosisHVPG Change Over TimeHVPG Change after treatment in the subset of patients with baseline HVPG ≥ 12 mmHg (n=33)Chance for “delisting” when treating patients on a liver transplantation waiting list?Clinical and biological responses to antiviral therapyDelistingAustralian experience in patients with MELD ≥ 15 (SOF/DCV 24 W; TOSCAR study)SafetySlide Number 233D + RBV in patients with decompensated cirrhosis Turquoise CPBSummary of safety outcomes when using DAA regimens in patients with HCV-induced decompensated cirrhosisDAA-induced hepatoxicity in decompensated HCV cirrhosis – first reportsSimeprevir plus Sofosbuvir in Child Pugh B/C Cirrhosis: Adverse Events (N=55)The patient on the „waiting list“: should we start treatment before or after liver transplantation?When should we treat?Pre-transplant Sofosbuvir plus Ribavirin prevent HCV recurrence after liver transplantationSlide Number 31Issues when treating patients with decompensated disease on the waiting listAntiviral treatment modalities in HCV-infected patients before and after liver transplantationManagement of the transplant patientSVR12 by CohortSVR12 by HCV GenotypeSVR12 by Child-Pugh Class�Advanced cirrhosis cohort, all genotypesLDV/SOF+RBV for 12 or 24 Weeks in 329 Decompensated and Post-Liver Transplant HCV GT 1 and GT 4 Patients Clinical trials: SOF/LDV with RBV is effective in decompensated and post-liver transplantation patientsLiver Function Change from Baseline to Follow-Up Week 4�OPTIMIST-2: SVR12 by platelets, albumin and �Fibroscan score (ITT)SVR12 in GT 1 Patients with History of �Decompensated CirrhosisSVR12 in GT 3 Patients with History of �Decompensated CirrhosisMELD Improvement in GT 1 and 3 Patients with History of Decompensated CirrhosisHCV TARGET: SMV + SOF +/- RBVCUP: DCV+SOF +/-RBVCUP: DCV+SOF +/-RBVManagement of patients with RAVs after DAA failure?Persistence of NS5A RAVs �Proportion of Patients With Any NS5A RAVs at More Than 1%