Xavier Forns, MDLiver Unit , Hospital ClínicIDIBAPS and CIBREHD

Barcelona, Octubre 2013

Tratamiento de poblaciones especialesTratamiento de poblaciones especiales

Curso de Residentes AEEHCurso de Residentes AEEH

Patient survival in HCV-positive and HCV-negative individuals. ONT/ RETH (1991-2011)

Patient survival in HCV-positive and HCV-negative individuals. ONT/ RETH (1991-2011)

Hepatitis C recurrence after liver transplantation

• 65-year old patient with HCV-related liver cirrhosis

• An US examination reveals 2 HCC (3,5+1 cm diameter)

• After extensive evaluation the patient is included in the waiting list for liver transplantation.

Treatment of hepatitis C in the waiting list of liver transplantation

• Genotype 1b IL28 CT; Viral load 830.000 IU/mL

• Previous therapy with PegIFN and RBV in 2008: partial responder (> 2 log decrease in VL at week 12).

• Should we treat this patient in the waiting list?

• Bilirubin 1 mg/dL, albumin 39 g/dL, platelets 119.000

No ascites, transient elastography 19 kPa.

• What treatment would you propose?

a) PegIFN + RBV

b) PegIFN+RBV+PI (telaprevir/boceprevir)

Treatment of hepatitis C in the waiting list of liver transplantation

Triple therapy in patients with cirrhosis (CUPIC): efficacy

Increased on treatment virological response with PR + BOC/TPV

Hezode et al EASL 2013

0

20

40

60

80

% p

atie

ntn

s w

ith

HC

V-R

NA

< L

OD

49%

51%

62%

81%

77%

58%

BOC (n=190)TVR (n=295)

100

79%

16%

Cirrhotic patients (CUPIC) relapsers/partial responders

Cirrhotic patients (CUPIC) relapsers/partial responders

Week 4 Week 8 Week 12 Week 16

Pro

bab

ility

of

bac

teri

al in

fect

ion

s

0 60 120 180 240 3000,0

0,2

0,4

0,6

0,8

1,0P < 0.01

Control (n = 51)

Peg-IFN + RBV (n = 51)

Time (days)P

rob

abili

ty o

f b

acte

rial

infe

ctio

ns

0 60 120 180 240 3000,0

0,2

0,4

0,6

0,8

1,0P < 0.01

Child B–C(n = 57)

Child A (n = 45)

Time (days)

Risk of life-threatening side effects: bacterial infections (SBP, SB)

Carrion JA ,et al. J Hepatol. 2009

Safety of antiviral therapy in patients awaiting liver transplantation

Patients, n (% patients with at least one event) Telaprevir n=295

Serious adverse events (SAEs)* 160 (54.2%)

Premature discontinuationDue to SAEs

139 (47.1%)63 (21.3%)

DeathSepticemia, Septic shock, GI Bleeding, Encephalopathy, others

7 (2.1%)

Infection (Grade 3/4) 27 (9.1%)

Hepatic decompensation (Grade 3/4) 15 (5.1%)

Boceprevir n=190

97 (51%)

80 (42.1%)27 (14.2%)

3(1.6%)

8 (4.2%)

9 (4.7%)

CUPIC French Cohort: safety analysis

Hezode et al EASL 2013

Factor OR IC 95% p

Platelets < 100.000/mm3 3,11 1,3-7,7 0,009

Albumin < 3,5 g/dl 6,33 2,6-15 < 0,0001

Triple therapy in patients in the waiting list for liver transplantation

Treatment: PegIFN alfa2a 180 + RBV 1.000 mg/d + Telaprevir 1125/12 h

-24 -20 -16 -12 -8 -4 0 4 8 12 16 20 24

LT

Vir

al l

oad

(IU

/mL

)

Time (weeks)

101

102

103

104

105

106

Ramirez et al, Am J Transpl 2009

Risk of relapse post-LTRisk of relapse post-LTClinical and virological outcomeClinical and virological outcome

0 4 8 12 16

Vir

al l

oad

(IU

/mL

) -

101

102

103

104

105

106

Hem

og

lob

in l

evel

(g

/dL

) -

20

8

10

12

14

16

RBV to 600 mg/d

TVPTVPPRPR

LTLT

Treatment in patients awaiting LT: risk of resistance

Years after end of therapy

0 0.5 1.0 1.5 2.0

91%

71%

62%59%

100

80

60

40

20

0

V36MT54S

R155KAny mutation

Cum

ula

tive

rat

e of

re

vers

ion

to w

ild-t

ype

(%

)

Weeks after end of therapy

Vierling et al EASL 2010

Selection of PIs resistance strains may compromise treatment after LT in case of severe hepatitis C recurrence

Wk 0 +12

Sofosbuvir 400 mg QD + RBVSofosbuvir 400 mg QD + RBV SVR12

CONTAINMENT: Sofosbuvir + RBV Prior to Liver Transplant

40-60 HCV Patients on LT list due to HCC– Expected transplant within 3-12 months

Primary efficacy endpoint : SVR12 post-LT

LTTreat up to time of LT or maximum of 24 weeks

ClinicalTrials.gov. NCT01559844 ClinicalTrials.gov. NCT01559844

DAA and prevention of hepatitis C recurrence

• 66-year old patient with hepatitis C recurrence after LT

• Transient elastography (12 months after LT) 10 kPa.

• Liver biopsy: F3

Treatment of hepatitis C in the liver transplant setting

Should we treat the patient? How?

1) PegIFN-RBV

2) PegIFN-RBV + PI

Carrion JA, et al. Gastroenterology 2007;

Effect of SVR on disease progression

4

8

12

16

20

HV

PG

(m

mH

g)

0

12.0

6.7

5.0 3.5

p = 0.047

p = 0.004

p = 0.003

NO (n = 26) YES (n = 11)

Sustained virological response

Berenguer M, et al. Am J Transpl. 2008

Patient survival in SVR (n = 33) vs NR (n = 56)

P= 0.032

Follow-up since LT (days)

Outcomes and response to antiviral therapy after LT

• Immunosuppression: tacrolimus 2 mg/d (levels 7 ng/mL)

Treatment of hepatitis C in the liver transplant setting

• Bilirubin 1 mg/dL, AST 243 IU/L, GGT 323 IU/L, Br 1,6 mg/dL, Hb 12,6 g/L, platelets 121.000, neutrophils 2300

• If we use a PI, use telaprevir or boceprevir?

Absorption

Metabolism

P-glycoprotein: absorption excretion of substrates

CYP3A4: CsA and tacrolimus

Protease inhibitors (PI): substrates and inhibitors

CsA reduce to ~ 1/4 (200 mg/d to 50 mg/d)

TAC reduce to ~ 1/30 (2 mg/d to 0.5 mg/week)

Telaprevir: first day IS dosing

CsA reduce to ~ 1/2 (200 mg/d to 100 mg/d)

TAC reduce to ~ 1/8 (4 mg/d to 0.5 mg/d)

Boceprevir: first day IS dosing

• Check every other day during first week of triple therapy (or until steady state)• Back to baseline dose after IP interruption (check weekly for at least 1 month)

Coilly et al, Liver Int 2013

Safety and efficacy of triple therapy in the LT setting

0 8 12 24 48

Vir

al l

oad

(IU

/mL

)

101

102

103

104

105

106

Hem

og

lob

in l

evel

(g

/dL

)

12

8

10

12

14

16

RBV 600 mg/d

Transfusion and EPO

4

Fs 10 kPaFs 10 kPa Fs 6,3 kPaFs 6,3 kPa

Treatment of hepatitis C in the liver transplant setting

RBV 400 mg/d

Tarcolimus 2 mg/d a 0,4 mg/d Tarcolimus 0,4 mg/d a 2,5 mg/d

PRPR PR+ BOCPR+ BOC

Coilly et al EASL 2013; Verna et al EASL 2013

Safety and efficacy of triple therapy in the LT setting

Baseline characteristics French cohort n=98

Median age (years) 50

F2-F4 (%)FCH (%)

6910

Time to LT (months) 37

Naïve /Non response/relapse (%) 48/37/15

CsA vs TAC (%) 41/53

Genotype 1a vs 1b 30/70

Telaprevir vs Boceprevir 58/42

USA cohort n=112

58

7510

42

47/40/13

41/57

55/38

88/12

Coilly et al EASL 2013

French cohort

Efficacy of triple therapy in the LT setting

Week 12 EVR

0

20

40

60

80

% p

atie

ntn

s w

ith

HC

V-R

NA

< L

OD

61%

82%

BOC TVR

100

38%

88%

Week 48 EOT

n=41n=41 n=57n=57 n=17n=17 n=16n=16

USA cohort

Week 4 RVR

0

20

40

60

80

% p

atie

ntn

s w

ith

HC

V-R

NA

< L

OD

63%

100

67%

Week 48 EOT

n=43n=43 n=43n=43

Verna et al EASL 2013

65%

Week 52 SVR4

n=43n=43

Coilly et al EASL 2013; Verna et al EASL 2013

Safety and efficacy of triple therapy in the LT setting

Frequency and type of side effect French cohort n=98

Serious adverse events leading discontunuation 21%

Anemia requiring EPOAnemia requiring Transfusion

95%43%

Rejection 8%

Renal failure 16%

Death 6,3%

USA cohort n=102

11%

79%46%

4%

34%

6%

Patients awaiting LT (HCV)

Child-Pugh < 8 (MELD < 18)

Genotype 2,3 o 4

Peg-IFN + RBV a

Genotype 1

Peg-IFN + RBV+/- TVP/BOCa,b

Child-Pugh ≥ 8 (MELD ≥ 18)

No treatmentConsider clinical trial IFN-free (DAA)

a Naive, relapsers and partials (in nulls lead-in phase)b Do not add PI if portal hypertension and albumin < 35g/L

HCV recurrence

Follow-up, individualize therapy (or wait for DAA)

Mild progression of recurrence

Liver Stiffness < 8.7 kPa

F ≥ 2 and HVPG ≥ 6 mmHg

Liver Stiffness > 8.7 kPa

G2 or G3Peg-RBV

G1Peg-RBV+/- IP

Crespo et al Gastroenterology, 2012

HCV-infected patient with fibrosing cholestatic hepatitis 6 months post-LT

Daclatasvir 60 mg/d + Sofosbuvir 400 mg/d (24 weeks)

Fontana et al AASLD 2012

IFN-free regimen in HCV-infected LT recipients

Viral Hepatitis UnitViral Hepatitis Unit

Liver Transplantation UnitLiver Transplantation Unit