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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
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
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
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
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
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.
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
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
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%
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
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
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
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
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
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.
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
, %
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.
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
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 (
%)
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
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%
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
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