Transcript Slide 1

Individualisation of HCV
Therapy
Achieving an SVR
What is the evidence?
Dr Allister J Grant
Achieving an SVR
The ability to achieve SVR is the result of two
independent steps:
1. Achieving a virologic response
a. Interferon/peginterferon dose
b. The presence of ribavirin
2. Not relapsing
a. How fast the patient becomes HCV RNA
undetectable
b. How long the patient remains on treatment
c. Dose of ribavirin
Wk 12 PCR
“EVR”
Rx duration
Neg/2log drop
48 weeks
Genotype 1,4-6
Pos
Genotype 2,3
Stop
24 weeks
2004 Regimes
Genotype
1, 4, 5 and 6
Drug
Manufacturer
Pegasys (pegylated
interferon)
Roche
Copegus (ribavirin)
Roche
Viraferon (pegylated
interferon)
Schering
Plough
All
Rebetol (ribavirin)
Schering
Plough
< 65 kgs
65-85 kgs
> 85 kgs
Pegasys/Viraferon
2,3
Weight
All
< 75 kgs
≥75 kgs
Dose
180mcgs/week
1000mg
1200mg
1.5 mcgs/kg/week
800mg/day
1000mg/day
1200mg/day
As Above
Copegus(ribavirin)
Roche
All
Rebetol (ribavirin)
Schering
Plough
As Above
800mg/day
WIN-R trial
Weight based Interferon and Ribavirin Trial
AASLD 2005
• Ribavirin 800mg/d (FD)
vs 800-1400mg/d
• Community based US
study
• PEG IFN 2b
• 4913 patients
• G1 48wks
• G2/3 randomised to
24/48 wks
• G1 significant advantage
in WBD of RBV
• No advantage for G2/3
but…..
WIN-R Trial
• Analysis of SVR by
weight
60
50
44%
39%
34%
42%
47%
40
SVR
• More dose reductions
• No more
discontinuations
49%
45%
52%
<65kg
65-85kg
>85-105kg
>105kg
30
20
10
0
Flat dose
P<0.0001
WBD
p=0.11
WIN–R Trial
Sustained Virological Response
Ribavirin mg/d
All
G1
G1 HVL
G2,3
800-1400mg
44%
34%
32%
62%
800 mg FD
41%
29%
27%
60%
P value
0.02
0.004
0.047
0.26
G2 had a higher SVR and lower relapse rate than those with G3
(72% vs. 60% and 6% vs.10% respectively). Investigators concluded that higher
weight-based doses of ribavirin appear to be necessary to achieve similar
SVR rates in G3 patients
What is the clinical evidence to support the
value of EVR as a predictor of SVR?
EVR – Treatment Outcome (All Genotypes)
PEG IFN alfa-2a 180 g + ribavirin 1,000–1,200 mg
Start of study
Week 12
EVR
86%
(n=390/453)
Total study
population
(n=453)
No EVR
14%
(n=63/453)
Fried et al. NEJM 2002
Week 72
No SVR
35%
(n=137/390)
SVR
65%
(n=253/390)
SVR
3%
(n=2/63)
No SVR
97%
(n=61/63)
Overall
SVR
56%
(255/453)
EVR – Treatment Outcome (All Genotypes)
PEG IFN alfa-2b 1.5 g/kg + ribavirin 10.6 mg/kg
Start of study
Week 12
EVR
76%
(n=143/188)
Total study
population
(n=188)
No EVR
24%
(n=45/188)
Davis G, et al. Hepatology 2003
Week 72
No SVR
20%
(n=29/143)
SVR
80%
(n=114/143
SVR
0%
(n=0/45)
No SVR
100%
(n=45/45)
Overall
SVR
61%
(114/188)
But what about the difficult-to-treat Genotype 1
patients?
EVR – Week 12 in Genotype 1
(Patients HCV RNA negative and patients HCV RNA positive >2 Log at week 12)
PEG-IFN α-2a 180 g
+ ribavirin 1,000-1,200 mg
N=298
81%
Achieved EVR
N=240
19%
No EVR
N=58
58%
Achieve SVR
N=139
2%
Achieve SVR
N=1
PPV=58%
NPV=98%
Ferenci P et al. J Hepatol 2005;43(3):425-33.
EVR – Week 12 in Genotype 1
(Patients HCV RNA Negative and patients HCV RNA positive >2 Log at week 12)
PEG-IFN α-2a 180 g
+ ribavirin 1,000-1,200 mg
N=569
84%
Achieved EVR
N=477
16%
No EVR
N=58
58%
Achieve SVR
N=264
NA%
Achieve SVR
N=NA
PPV=58%
NPV=NA
Reddy K et al. DDW2005, Abstract # S1540
So are we able to push prediction back further?
Treatment Of Chronic HCV
Predicting SVR Over Time
SVR (%)
100
PEG-IFN-2a
+ Ribavirin
91
80
66
60
45
40
20
The later a patient becomes HCV RNA
0
undetectable,
regardless of EVR the
lower the chance
for SVR.12
4
2
24
Week Became HCV RNA (-)
P Ferrenci et al.
J Hepatology 2005; 43:425-33.
HCV RNA +
at week 24
Relapse Rate Relationship to First Time HCV
RNA Negativity
Week 4 Neg
Week 12 Neg
Week 24 Neg
100%
Relapse %
80%
60%
40%
20%
0%
IFN α-2b 24
wks
IFN α-2b 48
wks
PEG-IFN α-2b
1.5 48 wks
IFN α-2b +
riba 24 wks
IFN α-2b +
riba 48 wks
Data on file Schering-Plough Corp. Adapted Poynard T. et al, Lancet 1998, McHutchison JG, NEJM, 1998,
Lindsay K. et al, Hepatology 2001
RAPID VIROLOGIC RESPONSE
100
91
93
92
• Rapid virologic
SVR (%)
80
60
•
40
20
0
PEG/RBV
PEG
P Ferrenci et al.
J Hepatology 2005; 43:425-33.
IFN/RVN
response (RVR)
defined as HCV RNA
(-) by week 4
Occurs regardless of
the interferon type or if
ribavirin utilised or not
RVR- Effect Of Genotype
SVR (%)
100
91
91
89
1
2
3
80
60
40
20
0
GENOTYPE
P Ferrenci et al. J Hepatology 2005; 43:425-33.
ML Shiffman et al. EASL 2006.
RVR- Frequency
SVR (%)
100
80
70
63
60
40
20
15
0
1
2
GENOTYPE
P Ferrenci et al. J Hepatology 2005; 43:425-33
ML Shiffman et al. EASL 2006.
3
Individualisation of Therapy According to
HCV Genotype and Viral Load
Zeuzem et al J.Hepatol 2006
Open multicentre, historical
controlled trial to test whether
HCV-1 patients with low viral load
can be treated with 24 weeks
therapy
(PEG IFN 2b +Ribavirin 8001400mg/)
100
81% 74%
50% 71%
89% 85%
90
80
70
SVR(%)
•
60
24wks
50
48 wks
Manns et al 2001
40
•
30
724 patients screened and 235
enrolled
20
10
0
EOT
SVR
RVR
Virologic response in patients with HCV-1 and HCV
RNA < 600,000 IU/mL
90
Patients (%)
80
70
SVR
Relapse
89%
80%
75%
60
50
40
30
50%
37%
20
25%
10
0
All patients
Zeuzem et al., J Hepatol 2006
8%
Week 4
(47%)
17%
Week 12
(26%)
Week 24/EOT
(10%)
Time to first negative HCV RNA
PEG-IFN a-2b + RBV
Shorter treatment in HCV-2 and HCV-3 ?
Peginterferon alfa-2a 180 µg qw +
Ribavirin 1000-1200 mg qd
HCV-RNA
N = 71
A
< 600 IU/mL
N = 153
 600 IU/mL
0
4
8
N = 69
B
N = 13
C
12
16
20
weeks
24
follow-up period 48
v. Wagner, Gastroenterology 2005
End-of-treatment (EOT) and sustained virologic
response (SVR)
- HCV genotypes 2 and 3 combined -
Virologic response (%)
SVR B vs C: P = 0.003
100%
94%
82%
80%
EOT
SVR
86% 81%
69%
60%
39%
40%
20%
67/71 58/71
59/69 56/69
Group A
Group B
9/13
5/13
0%
(16 weeks)
(24 weeks)
Group C
(24 weeks)
v. Wagner et al, Gastroenterology 2005
SHORTENING TREATMENT FOR G2-3
RAPID VIROLOGIC RESPONDERS
% HCV RNA (-)
100
80
94
85
82
80
End-of-Treatment
SVR
Relapse
60
40
13
20
6
0
16
24
Weeks of Treatment
M Von Wagner et al.
Gastroenterology. 2005;129:522-527.
Shortening
therapy even in
patients with
RVR doubles
the relapse rate
Peginterferon alfa-2b 1.0 µg/kg+
Ribavirin 1000-1200 mg qd
A
N = 70
HCV-RNA
-
N = 133
B
N = 80
C
N = 213
+
0
4
8
12
weeks
16
20
24
follow-up period 48
Mangia et al, N Engl J Med 2005
Sustained virologic response (SVR) according to
HCV genotype
Rx: PEG-IFN alfa-2b 1.0 µg/kg + RBV 1000-1200 mg
100%
SVR (%)
80%
87%
76% 76%
77%
HCV-2
HCV-3
72%
60%
41%
40%
20%
40/53 13/17
89/102 24/31
42/58 9/22
Group A
Group B
Group C
(24 weeks)
(12 weeks)
(24 weeks)
0%
Mangia et al, N Engl J Med 2005
HCV Genotypes 2 & 3
ACCELERATE TRIAL
N=1469
PEGASYS 180 mcg/wk
Ribavirn 800 mg/d
PEGASYS 180 mcg/wk
Ribavirin 800 mg/day
0
4
12
Weeks
ML Shiffman et al.
EASL 2006.
16
24
48
HCV Genotypes 2 & 3
ACCELERATE TRIAL
% OF PATIENTS
100
80
60
N=1469
94 92
*
68 65
76
65
16 Weeks
24 Weeks
40
30
20
*
18
0
Week 4
ML Shiffman et al.
EASL 2006.
EOT
EOFu
REL
HCV Genotypes 2 & 3
Impact Of Rapid Response
100
SVR (%)
80
90
82
Rapid Virologic
Response:
60
*
49
40
20
*
27
0
16 Weeks
ML Shiffman et al.
EASL 2006.
24 Weeks
Yes
No
Viral load
at baseline
Wk 4 PCR
Rx duration
Neg/2log drop*
48 weeks
Pos
Pos
Low
Wk 12 PCR
Neg
Stop
24 weeks
PPV 89%
Genotype 1,4-6
High
48 weeks
Neg
PPV75-85% / 46-72%
Pos
Neg/2log drop*
Pos
Low
Genotype 2,3
48 weeks
Stop
Pos
24G2(48G3)
Neg
16G2/24G3
PPV 82-90%
High
Low= <600,000 IUml
<3x106 cpm
Neg
24 weeks
Pos
24G2(48G3)
* If 2 log drop then PCR at 24 weeks
HCV Treatment in 2007
Genotype
Drug
Manufacturer
Pegasys (pegylated interferon)
Roche
Copegus (ribavirin)
Roche
Viraferon (pegylated
interferon)
Schering
Plough
1,3, 4 to 6
Rebetol (ribavirin)
Pegasys/Viraferon
Schering
Plough
Roche/Schering
Plough
Weight
All
< 65 kgs
65-85 kgs
85-105 kgs
>105kg
All
< 65 kgs
65-85 kgs
85-105 kgs
>105kg
Dose
180mcgs/week
800mg/day
1000mg/day
1200mg/day
1400mg/day
1.5 mcgs/kg/week
800mg/day
1000mg/day
1200mg/day
1400mg/day
As Above
2
Copegus/Rebetol(ribavirin)
Roche/Schering
Plough
All
800mg/day
SUMMARY OF RECOMMENDATIONS
Shorten duration of therapy for
Genotype 1 LVL with RVR………………24 weeks instead of 48
Genotype 2 LVL with RVR………………16 weeks instead of 24
Consider lengthening duration of therapy for
Genotype 3 who do not have RVR……..48 weeks instead of 24
Do PCR at
4 weeks for everyone
If 4 week PCR negative then no need for further PCR till 24 weeks post Rx
If 4 week PCR positive then do PCR at 12 weeks.
If PCR positive at 12 weeks stop therapy
If PCR shows 2 log drop at 12 weeks do PCR at 24 weeks
EXTENDING TREATMENT DURATION
HCV RNA (+)
48 weeks
N=165
Pegasys 180 mg QW
Ribavirin 800 mg/d
N=162
72 weeks
0
4
Weeks
JM Sanchez-Tapias et al.
Gastroenterology 2006; 131: 451-460.
48
72
96
EXTENDING THERAPY
% HCV RNA (-)
80
60
End-of-Treatment
61
SVR
52
40
45
Extending the
duration of
therapy reduced
relapse from 47%
to 13%
32
20
0
48
P=0.014
72
Weeks of Treatment
JM Sanchez-Tapias et al.
Gastroenterology 2006; 131: 451-460.
G1 without RVR
SVR 28%(48w) vs 44%(72w)
Urgent Treatment Recommended For
• Acute HCV
• Stable compensated cirrhotics
• HCV with cryoglobulinaemia/renal involvement
• Occupation where HCV infection is hazardous