clinical case laurent castera 5th phc, paris, january 31 2012 service d’hépatologie hôpital...
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Clinical caseClinical case
Laurent CASTERA
5th PHC, Paris, January 31 2012
Service d’Hépatologie
Hôpital Beaujon, Université Paris-7,
Clichy, France
Patient Case: 43-year-old malePatient Case: 43-year-old male
Previous intravenous drug user
Alcohol intake > 50 g/day
HCV RNA 6 log10 copies/ml
Genotype 1
HBV and HIV negative
Weight 90 Kg; height 170 cm
Patient Case: past historyPatient Case: past history
In 1997: liver biopsy indicates chronic “active”
hepatitis (i.e. METAVIR A2F2)
Treatment with IFN 3M IU thrice a week
Treatment stopped after 3 months because of poor
tolerance and depression
Normalisation of ALT but no information on HCV RNA
Lost to follow-up until 2002
HB (g/dl)
WBC (/mm3)
Platelet count (/mm3)
AST (IU/L)
ALT (IU/L)
GGT (IU/L)
AP (IU/L)
Total bilirubin (µmol/L)
PT
2002: Laboratory & morphologic results
Liver US: steatosis, heterogenous parenchyma
14
6000
100 000
120
70
500
150
15
80%
Patient Case: liver biopsyPatient Case: liver biopsy
Metavir F3 with steatosis and NASH
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
AL
T (
UI/L
)
50
100
200
250108
0
150
Pegylated interferon alfa-2b 135 µg/w
Ribavirin 1200mg/day
ULN
Time (Weeks)
Patient Case: 1st retreatment Patient Case: 1st retreatment
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
AL
T (
UI/L
)
50
100
200
250108
0
4
150
Pegylated interferon alfa-2b 135 µg/w
Ribavirin 1200mg/day
RBV 600 mg
ULN
Time (Weeks)
Patient Case: 1st retreatment Patient Case: 1st retreatment
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
AL
T (
UI/L
)
50
100
200
250108
0
4
150
Pegylated interferon alfa-2b 135 µg/w
Ribavirin 1200mg/day
RBV 600 mg
103
PEG-IFN 100 µg
12
ULN
Time (Weeks)
Patient Case: 1st retreatment Patient Case: 1st retreatment
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
AL
T (
UI/L
)
50
100
200
250108
0
4 12 24
150
Pegylated interferon alfa-2b 135 µg/w
Ribavirin 1200mg/day
RBV 600 mg
103
PEG-IFN 100 µg
103
Patient Case: 1st retreatment Patient Case: 1st retreatment
ULN
Time (Weeks)
Factors associated with Factors associated with treatment failuretreatment failure
Failure
TREATMENT• IFN dosage• RBV dosage• Ttt duration
HOST• Ethnicity• Insulin-resistance• Poor adherence• Alcohol
VIRUS• Genotype 1• High viral load• Viral kinetics• Quasispecies
DISEASE• Cirrhosis• HIV coinfection• HBV coinfection
Factors associated with Factors associated with treatment failuretreatment failure
Failure
HOST• Insulin-resistance• Poor adherence• Alcohol
TREATMENT• IFN dosage• RBV dosage• Ttt duration
VIRUS• Genotype 1• High viral load• Viral kinetics• Quasispecies
DISEASE• Cirrhosis• HIV coinfection• HBV coinfection
Can be modified
HOST• Ethnicity
Cannot be modified
DietEducation
Withdrawal
EPO
Patient CasePatient Case
Lost to follow-up until 2007.
New evaluation
Patient Case: ultrasoundPatient Case: ultrasound
Splenomegaly, heterogenous parenchyma
Patient Case: FibroScanPatient Case: FibroScan
20.0
Patient Case: upper GI endoscopyPatient Case: upper GI endoscopy
Patient CasePatient Case
Not keen to start new antiviral treatment because of side effects.
What would you do ?
OptionsOptions
Retreatment with PegIFN+ RBV with optimization
Follow-up without treatment
Maintenance therapy with PegIFN monotherapy
Patient CasePatient Case
Alcohol withdrawal for 6 months
Strict Diet with weight loss: 90 -> 75 kg
Psychiatric care
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1400mg/day
Patient Case: 2nd retreatmentPatient Case: 2nd retreatment
EPO 30 000 IU/w
AL
T (
UI/L
)
50
100
200
250
0
150
Paroxetine 20 mg/d
ULN
Time (Weeks)
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1400mg/day
105
EPO 30 000 IU/w
AL
T (
UI/L
)
50
100
200
250
0
150
Paroxetine 20 mg/d
ULN
Time (Weeks)
Patient Case: 2nd retreatmentPatient Case: 2nd retreatment
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1400mg/day
105
EPO 30 000 IU/w
AL
T (
UI/L
)
50
100
200
250
0
150
Paroxetine 20 mg/d
ULN
Time (Weeks)12
103
Patient Case: 2nd retreatmentPatient Case: 2nd retreatment
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1400mg/day
105
EPO 30 000 IU/w
AL
T (
UI/L
)
50
100
200
250
0
150
Paroxetine 20 mg/d
ULN
Time (Weeks)12
103
24
Patient Case: 2nd retreatmentPatient Case: 2nd retreatment
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1400mg/day
105
EPO 30 000 IU/w
AL
T (
UI/L
)
50
100
200
250
0
150
Paroxetine 20 mg/d
ULN
Time (Weeks)12
103
24 48
Patient Case: 2nd retreatmentPatient Case: 2nd retreatment
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1400mg/day
105
EPO 30 000 IU/w
AL
T (
UI/L
)
50
100
200
250
0
150
Paroxetine 20 mg/d
ULN
Time (Weeks)12
103
24 48 72
Patient Case: 2nd retreatmentPatient Case: 2nd retreatment
Patient CasePatient Case
What would you do ?
Boceprevir
Relapsers
Partial responders
Telaprevir
Relapsers
Partial responders
Null responders
+ 60%
+ 40%
+ 25%
+ 50%
+ 45%
Triple therapy in genotype 1 non SVR
363600 24241212 4848
TLR in treatment-experienced patientsTLR in treatment-experienced patientsREALIZE study: designREALIZE study: design
6060 7272
TVR 750 mg q8h
+ Peg-IFN2a + RBV
Follow-upFollow-upPeg-IFN2a + RBV
Peg-IFN2
a + RBV
Peg-IFN2a + RBV
Follow-upFollow-up
282844
Peg-IFN2a + RBV
Follow-upFollow-up
TVR 750 mg q8h
+ Peg-IFN2a + RBV
N = 260
N = 260
N = 130
*eRVR = HCV RAN undetectable at W4 et W12Weeks
Zeuzem et al. NEJM 2011
16
Proportion of patients with cirrhosisProportion of patients with cirrhosisREALIZEREALIZE
Zeuzem et al. NEJM 2011
169 cirrhotic patients
N=663 patients
SVR SVR REALIZE study REALIZE study
SV
R (
%)
Relapsers Partial Responders
Pbo/PR48
T12/PR48
LI T12/PR48
Pbo/PR48
T12/PR48
LI T12/PR48
Pbo/PR48
T12/PR48
LI T12/PR48
Null responders
Zeuzem et al. NEJM 2011 N=663 patients
16
SVR according to FibrosisSVR according to Fibrosis
Pol et al. AASLD 2011
Boceprevir in previously treated patients Boceprevir in previously treated patients RESPOND-2 RESPOND-2
Bacon et al. NEJM 2011 N=403 patients
Bacon et al. NEJM 2011 N=403 patients
49 cirrhotic patients
Proportion of patients with cirrhosisProportion of patients with cirrhosisRESPOND-2RESPOND-2
RV
S (
%)
0153045607590
Relapsers Partial responders
29
PR48
69
BOC TGR
75
BOC/PR48
7
PR48
40
BOC TGR
52
BOC/PR48
SVR with BOC in non respondersSVR with BOC in non respondersRESPOND-2 study RESPOND-2 study
Bacon et al. NEJM 2011 N=403 patients
SVR according to response at W4 SVR according to response at W4
of Lead in phaseof Lead in phase
Decrease <1 log Decrease ≥ 1 log
SV
R (
%)
0
20
40
60
80
100
SV
R (
%)
0
20
40
60
80
100
PR48
25
17/67
BOC TGR
73
80/110
BOC/PR48
79
90/1140
0/12
PR48
33
15/46
BOC TGR
34
15/44
BOC/PR48
ToleranceTolerance
Telaprevir Boceprevir
Rash (37%) Anemia x 2 (50%)
(Severe 7%)
Anemia Dysgueusia
Discontinuation AE: 13-20% Discontinuation AE: 9-19%
Patient CasePatient Case
What would you do ?
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
AL
T (
UI/L
)
50
100
200
250
0
150
ULN
Time (Weeks)12 24 48
Patient Case: 3rd retreatmentPatient Case: 3rd retreatment
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1200 mg/day
TVR 2250 mg/d
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
AL
T (
UI/L
)
50
100
200
250
0
150
ULN
Time (Weeks)12 24 48
Patient Case: 3rd retreatmentPatient Case: 3rd retreatment
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1200 mg/day
TVR 2250 mg/d
REALIZE: Laboratory Abnormalities
Cirrhotics (F4) N=139
Non-cirrhotics (F0–3) N=391
Hemoglobin
≤10g/dL
≤8.5g/dL
46 %
14 %
40 %
13 %
Neutrophils
Grade 3 (500 to <750/mm3)
Grade 4 (<500/mm3)
Grade 3/4
25 %
7 %
32 %
17 %
2 %
19 %
Platelets
Grade 3 (25,000 to <50,000/mm3)
Grade 4 (<25,000/mm3)
Grade 3/4
12 %
1 %
13 %
3 %
<1 %
3 %
Pol et al, AASLD 2011Pol et al, AASLD 2011
Peg-IFN α-2a + RBVTVR + Peg-IFN α-2a
+ RBV Follow-up
Weeks
BOC + Peg-IFN α-2b + RBV Follow-upPeg-IFN + RBV
484 160 128 7236
BOC : 800 mg/8h; peg-IFNα-2b : 1,5 µg/kg/week; RBV : 800 -1400 mg/d
TVR : 750 mg/8h; peg-IFNα-2a : 180 µg/week; RBV : 1000 à 1200 mg/d
Interim analysis
Tolerance in F3-F4 non respondersTolerance in F3-F4 non respondersthe French CUPIC observatory the French CUPIC observatory
CUPIC: preliminary safety findingsTelaprevir
Patients, n (%) Telaprevir (n=176)
Serious AEs 90 (51)*
Discontinuation due to serious AE
21 (12)
Death 3 (1.7)
Rash Grade 3 SCAR
12 (6.8)0
Infection (Grade 3/4) 6 (3.4)
Other AEs (Grade 3/4) 92 (52)
Hézode C, et al, Hepdart 2011
CUPIC: preliminary safety findingsTelaprevir
Telaprevir (n=176)
Anemia Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8.0 g/dL) EPO use Transfusion
58 (33) 23 (13)96 (55)32 (18)
Neutropenia Grade 3 (500 – <1000/mm3) Grade 4 (<500/mm3) G-CSF use
20 (11)2 (1)5 (3)
Thrombopenia Grade 3 (25,000 – <50,000) Grade 4 (<25,000)
26 (15)12 (7)
Hézode C, et al, Hepdart 2011
Patients, n (%) Boceprevir (n=134)
Serious AEs 39 (29)*
Discontinuation due to serious AE
8 (6)
Death 1(1)
Rash Grade 3 SCAR
00
Infection (Grade 3/4) 0
Other AEs (Grade 3/4) 43 (32)
Hézode C, et al, Hepdart 2011
CUPIC: preliminary safety findingsBoceprevir
Patients, n (%) Boceprevir (n=134)
Anemia Grade 2 (8.0 – <10.0 g/dL) Grade 3/4 (<8.0 g/dL) EPO use Transfusion
41 (31)8 (6)
70 (52)8 (6)
Neutropenia Grade 3 (500 – <1000/mm3) Grade 4 (<500/mm3) G-CSF use
10 (7)5 (4)7 (5)
Thrombopenia Grade 3 (25,000 – <50,000) Grade 4 (<25,000)
8 (6)3 (2)
Hézode C, et al, Hepdart 2011
CUPIC: preliminary safety findingsBoceprevir
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
AL
T (
UI/L
)
50
100
200
250
0
150
ULN
Time (Weeks)12 24 48
Patient Case: 3rd retreatmentPatient Case: 3rd retreatment
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1200 mg/day
TVR 2250 mg/d
Patient Case: rashPatient Case: rash
> 90% mild or moderate
Inci
denc
e of
ras
h (%
)
Inci
denc
e of
ras
h (%
)
55
33
0
20
40
60
80
100
TLR control
Cutaneous reaction with Telaprevir phase II & III studies
Mild Moderate severe
(n=1346) (n=764)(n=764)
Cacoub P et al, J Hepatol 2012;56:455-63Cacoub P et al, J Hepatol 2012;56:455-63
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
AL
T (
UI/L
)
50
100
200
250
0
150
ULN
Time (Weeks)12 24 48
Patient Case: 2nd retreatmentPatient Case: 2nd retreatment
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1200 mg/day
TVR 2250 mg/d
% of patients with rectal burning
T12/PR(750 mg
q8h)N=1346
Placebo/PR48
N=764
AE 26.2 5
AE of at least Grade 3 0.7 0
AE leading to permanent discontinuation of telaprevir/placebo 0.5 0
1. http://www.fda.gov/downloads/AdvisoryCommittees/Committees/MeetingMaterials/Drugs/AntiviralDrugsAdvisoryCommittee/UCM252562.pdf
2. Telaprevir EU SmPC
In clinical trials, the majority of these events (e.g., haemorrhoids, anorectal discomfort, anal pruritus, and rectal burning) were mild to moderate, very few led to treatment discontinuation and resolved after completion of telaprevir dosing2
Rectal burning with Telaprevir phase II & III studies
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
AL
T (
UI/L
)
50
100
200
250
0
150
ULN
Time (Weeks)12 24 48
Patient Case: 2nd retreatmentPatient Case: 2nd retreatment
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1200 mg/day
TVR 2250 mg/d
0
102
104
106
HC
V-R
NA
(lo
g10
) IU
/mL
108
4
AL
T (
UI/L
)
50
100
200
250
0
150
ULN
Time (Weeks)12 24 48
Patient Case: 2nd retreatmentPatient Case: 2nd retreatment
72
SVR !!
Pegylated interferon alfa-2a 180 µg/w
Ribavirin 1200 mg/day
TVR 2250 mg/d