how to manage g1 relapsers and non-responders george v. papatheodoridis, md associate professor in...
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How to manage G1 relapsers and non-responders
George V. Papatheodoridis, MD
Associate Professor in Medicine & Gastroenterology
2nd Department of Internal Medicine,
Athens University Medical School,
Hippokration General Hospital,
Athens, Greece
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Case 1 - AM
01/2008
• Male, 42 y.o., H: 1.75 m, W 77 Kg, BMI 25.1 Kg/m2, no other disease
G1a, HCV RNA 1,200,000 IU/mL, Fibroscan 6.3 (0.9) kPa
• Peg-IFNa-2a (180 μg/wk) + RBV (1.2 g/d) x48 wks
• HCV RNA (-) at 12 & 48 wks, (+) at 72 wks
2009-2011
• No therapy - Transient, mild ALT elevations
12/2011
• HCV RNA 2,200,000 IU/mL, Fibroscan 6.0 (1.0) kPa
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Case 1 – AM – Question 1
Would you retreat this patient today?
(BOC/TPV available)
1. No
2. Yes
a. Peg-IFN + RBV
b. Peg-IFN + RBV + BOC/TPV
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SV
R (
%)
4-wk PR + 44-wk BOC+PR
All relapsers
48-wk PR 4-wk PR + 32-wk BOC+PR ± 12-wk PR
RESPOND-2: SVR after ΒΟC based therapyin G1 relapsers
Bacon BR et al. ΝΕJM 2011; 364: 1207-17
29
6975
0
20
40
60
80
100
Ν= 51 105 103
33
0
74
43
76
86
FO/F1/F2/F3 Relapsers F4
N= 42 87 81 6 14 14
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PROVE 3 / REALIZE: SVR under TPV based therapy in G1 relapsers
0
20
40
60
80
100
SV
R (
%)
McHutchison JG et al. NEJM 2010;362:1292-303. Zeuzem S et al. NEJM 2011;364:2417-28.
12-wk TPV+PR 24-wk TPV+PR 48-wk PR + 12-wk PR + 24-wk PR
6976
20
PROVE 3 trial
8388
24
P < .0001
12-wk TPV+PR 4-wk PR + 48-wk PR + 36-wk PR 12-wk TPV+PR + 32-wk PR
REALIZE trial
P < .0001
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REALIZE: SVR in G1 prior relapsers by baseline fibrosis stage
Stage No, minimal or portal Bridging fibrosis Cirrhosis fibrosis
Pa
tie
nts
wit
h S
VR
, %
87 85 84
32
137
0
20
40
60
80
100Pooled T12/PR48 Pbo/PR48
n/N 145/167 12/38 53/62 2/15 48/57 1/15
Pol S et al. Hepatology 2011;54(Suppl. S1): 374A-375A.
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Case 1 – AM – Question 2
If you retreat this patient with a triple
combination, do you think that the virological
response during a 4-week lead-in period with
only Peg-IFN+RBV might offer useful information
even in case of TPV based triple therapy?
1. No
2. Yes
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REALIZE (telaprevir): SVR by Week 4 on-treatment response according to prior response category
SV
R (
%)
<1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase
≥1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase
n/N =
Foster GR et al. J Hepatol 2011; 54 (Suppl.): S3.
Prior relapsers
8/13
Prior partial responders
10/18
Prior null responders
6/41
Prior relapsers
106/113
Prior partial responders
16/27
Prior null responders
15/28
6256
15
0
20
40
60
80
100 94
5954
P=0.001P=0.001
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SVR by Week 4 on-treatment response in the LI T12/PR48 arm in prior relapsers
6760
9289
95
0
20
40
60
80
100
SV
R (
%)
Zeuzem S et al. Hepatology 2011; 54 (Suppl. S1): 986A-987A.
Reduction in HCV RNA at Week 4, log10 IU/mL
0-0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.00-0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.0
n/N= 2/3 6/10 11/12 16/18 79/83
Proportions of patients in each group 2% 8% 10% 14% 66%
Proportions of patients in each group 2% 8% 10% 14% 66%
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Case 1 – AM – Question 4
Would you retreat this patient with?
1. BOC based triple therapy
2. TPV based triple therapy
3. Any of the above combinations
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BOC or TPV in G1 prior relapsers without cirrhosis
Boceprevir, Telaprevir EU SmPC
240 4812 364Weeks
TPV + PR PR
PRif RNA detectable at Week 4 or 12
HCV RNA
Stop treatment at Week 24 if RNA undetectable at Week 4 and 12
If >1000 IU/mL at Week 4 or 12:discontinue all drugs
If detectable at Week 24 or 36:discontinue PR
PRlead-in
BOC + PR PR
0 484 24 3612
If ≥100 IU/mL: If detectable:
Discontinue all drugs
HCV RNA
Weeks
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Case 2 - GS 02/2009
• Female, 58 years, H 1.60 m, W 70 Kg, BMI 27.3 Kg/m2, Diabetes
G1b, HCV RNA 2,000,000 IU/mL, Fibroscan 14.3 (1.9)
kPa
• Peg-IFNa-2b (100 μg/wk) +RBV (1.0 g/d)
• HCV RNA 1,200,000 IU/mL at 12 wks – stop treatment
05/2009-12/2011
• Moderate ALT elevations, increased γ-globulin
12/2011
• HCV RNA 1,000,000 IU/mL, Fibroscan 17.5 (2.5) kPa
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Would you retreat this patient today?
(BOC/TPV available)
1. No
2. Yes
a. Peg-IFN + RBV
b. Peg-IFN + RBV + BOC/TPV
Case 2 – GS – Question 1
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REALIZE: SVR under TPV based therapy in G1 null responders
Zeuzem S et al. NEJM 2011;364:2417-28.
2933
5
0
20
40
60
80
100P
ati
en
ts w
ith
SV
R, %
12-wk TPV+PR 4-wk PR + 48-wk PR + 36-wk PR 12-wk TPV+PR + 32-wk PR
12-wk TPV+PR 4-wk PR + 48-wk PR + 36-wk PR 12-wk TPV+PR + 32-wk PR
P<0.001P<0.001
n/N 21/72 25/37 2/37n/N 21/72 25/37 2/37
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REALIZE: SVR in G1 prior null responders by baseline fibrosis stage
Stage No, minimal or portal Bridging fibrosis Cirrhosis fibrosis
Pa
tie
nts
wit
h S
VR
, %
41 42
14
60
10
0
20
40
60
80
100Pooled T12/PR48 Pbo/PR48
n/N 24/59 1/18 16/38 0/9 7/50 1/10
Pol S et al. Hepatology 2011;54(Suppl. S1): 374A-375A.
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BOC in G1 null responders to PR
PROVIDE study: prospective, one arm PROVIDE study: prospective, one arm
Patients
Ν= 37 from SPRINT-2 (naive)
N= 11 from RESPOND-2
N= 42 HCV RNA >800.000 IU/ml
N=31 G1a
Duration of PR
discontinuation: 5-112 wks
Patients
Ν= 37 from SPRINT-2 (naive)
N= 11 from RESPOND-2
N= 42 HCV RNA >800.000 IU/ml
N=31 G1a
Duration of PR
discontinuation: 5-112 wks
Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A.
4738
16
0
20
40
60
80
100
EOT SVR Relapse
n/N= 20/43 16/42 3/19 n/N= 20/43 16/42 3/19
Pat
ien
ts,
%P
atie
nts
, %
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PROVIDE: SVR rates by baseline patient characteristics*
n/m (%) SVR, % (n/N)
MaleFemale
27 (4/15)44 (12/27)
BlackNon-black
27 (3/11)42 (13/31)
Age <50 yearsAge ≥50 years
50 (9/18)29 (7/24)
Weight <75 kgWeight ≥75 kg
25 (4/16)46 (12/26)
Baseline viral load ≤800,000 IU/mLBaseline viral load >800,000 IU/mL
67 (4/6)33 (12/36)
F0/1/2/3†
F4†38 (15/39)
50 (1/2)
Platelets† <200,000Platelets† ≥200,000
0 (0/8)48 (16/33)
ALT normalALT elevated
50 (5/10)34 (11/32)
HCV genotype 1a‡
HCV genotype 1b‡41 (11/27)33 (5/15)
Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A.
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Case 2 – GS – Question 2
If you retreat this patient with a triple
combination, do you think that the virological
response during a 4-week lead-in period with
only Peg-IFN+RBV might offer useful information
even in case of TPV based triple therapy?
1. No
2. Yes
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SVR rates of null responders to PR under BOC+PR in relation to virological response during the lead-in period
Vierling J et al. Hepatology 2011; 54 (Suppl. S1): 796A-797A.
34
50
3831
56
00
20
40
60
80
100Proportions of patients in each group
76% 24% 38% 38% 21% 3%Proportions of patients in each group
76% 24% 38% 38% 21% 3%
<1.0 ≥1.0 <0.5 0.5-<1.0 1.0-<1.5 1.5-2.0 <1.0 ≥1.0 <0.5 0.5-<1.0 1.0-<1.5 1.5-2.0
Reduction in HCV RNA at Week 4, log10 IU/mL
n/N= 11/32 5/10 6/16 5/16 5/9 0/1
SV
R (
%)
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REALIZE (telaprevir): SVR by Week 4 on-treatment response according to prior response category
SV
R (
%)
<1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase
≥1 log10 HCV RNA reduction after 4-week Peg-IFN/RBV lead-in phase
n/N =
Foster GR et al. J Hepatol 2011; 54 (Suppl.): S3.
Prior relapsers
8/13
Prior partial responders
10/18
Prior null responders
6/41
Prior relapsers
106/113
Prior partial responders
16/27
Prior null responders
15/28
6256
15
0
20
40
60
80
100 94
5954
P=0.001P=0.001
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SVR by Week 4 on-treatment response in the LI T12/PR48 arm in prior null responders
6
20
44
60
80
0
20
40
60
80
100
SV
R (
%)
Zeuzem S et al. Hepatology 2011; 54 (Suppl. S1): 986A-987A.
Reduction in HCV RNA at Week 4, log10 IU/mL
<0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.0<0.5 0.5-1.0 1.0-1.5 1.5-2.0 >2.0
n/N= 1/16 5/25 8/18 3/5 4/5
Proportions of patients in each group 23% 36% 26% 7% 7%
Proportions of patients in each group 23% 36% 26% 7% 7%
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Case 2 – GS – Question 3
Would you retreat this patient with?
1. BOC based triple therapy
2. TPV based triple therapy
3. Any of the above combinations
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BOC or TPV in G1 prior null responders
240 4812 364Weeks
TPV + PR PR
HCV RNA If >1000 IU/mL at Wk 4 or 12:discontinue all drugs
If detectable at Wk 24 or 36:discontinue PR
0 484 2412
PRlead-in
BOC + PR
If ≥100 IU/mL If detectable
Discontinue all drugs
HCV RNA
Weeks
Boceprevir, Telaprevir EU SmPC