Transcript Type of non response
Slide 1
Patrick
MARCELLIN
Slide 2
THE CHALLENGE OF TREATING
NON RESPONDERS
Patrick Marcellin
Service d’Hépatologie and INSERM CRB3
Hôpital Beaujon, Clichy
University of Paris
Slide 3
WHO TO RETREAT?
SYMPTOMS
GENOTYPE
MOTIVATION
SIDE EFFECTS
TOLERANCE
COST
FIBROSIS 2-4
FIBROSIS 0-1
PROS
CONS
Slide 4
HOW TO TREAT A NON RESPONDER?
Two strategies
- Viral eradication
- Maintenance therapy
Slide 5
HOW TO TREAT A NON RESPONDER?
Two strategies
- Viral eradication
- Maintenance therapy
Slide 6
The probability of viral eradication
depends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
Slide 7
The probability of viral eradication
depends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
Slide 8
Type of non response
7
Null non responder
Serum HCV RNA
6
1st phase
Partial non responder
5
4
Slow responder
2nd phase
3
Limit of detection
2
Rapid responder
1
0
1
2
3
14
7
21
28
Days
Neumann et al. 2000
Slide 9
Type of non response
7
Null non responder
Serum HCV RNA
6
1st phase
Partial non responder
5
4
Slow responder
2nd phase
3
Limit of detection
2
Rapid responder
1
0
1
2
3
14
7
21
28
Days
Neumann et al. 2000
Slide 10
The probability of viral eradication
depends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
Slide 11
Previous therapy
- Conventional interferon
- Standard combination
- Pegylated combination
Slide 12
HALT-C
SVR according to previous therapy
50
p<0.0001
%
40
30
28%
20
12%
10
0
IFN
IFN + RBV
(n=219)
(n=385)
Schiffman. Gastroenterology 2005
Slide 13
BEAUJON
SVR according to previous therapy
50
%
40
35%
30
20
10%
10
0
IFN
IFN + RBV
(n=49)
(n=50)
Ripault et al. DDW 2003
Slide 14
SVR to PEG IFN+RBV in NRs to IFN+RBV
According to Genotype
50
40
37%
30
%
20
10
0%
0
Genotype 2-3
SVR
Genotype 1
Moucari et al. J Hepatol in press
Slide 15
SVR to PEG IFN+RBV in NRs to IFN+RBV
According to Cirrhosis
50
40
32%
30
%
20
10
0%
0
No cirrhosis
SVR
Cirrhosis
Moucari et al. J Hepatol in press
Slide 16
RETREATMENT BY PEGYLATED COMBINATION OF 154
NON RESPONDERS TO STANDARD COMBINATION
HCV RNA (log10 copies/ml)
8
7
6
5
SVR (+)
4
SVR (-)
3
2
1
0
W0
W4*
W8*
W12
Treatment Week
Moucari et al. J Hepatol, in press
Slide 17
RETREATMENT FOR ERADICATION
Partial response
Genotype 2-3
No cirrhosis
PROS
Non response
Genotype 1
Cirrhosis
CONS
Slide 18
PROBABILITY OF SVR
TO RETREATMENT
P = P2 - P1
P is the probability of response to retreatment according
to the probability of response to the new treatment (P2)
minus the probability of response to the prior treatment (P1)
Slide 19
The probability of viral eradication
depends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
Slide 20
Cause(s) of non response
related to the patient:
To manage before retreatment
- Alcool:
- Overweight:
- Insulin resistance
- Iron overload:
- Psychologic:
stop
weight loss
treatment?
phlebotomy
prepare
Slide 21
Cause(s) of non response
related to reduced dosing:
To manage during retreatment
- Anemia:
- Neutropenia:
- Depression:
- Others …
EPO
GCSF
anti-depressive
Slide 22
PERSPECTIVES
- Optimise current therapy
- New drugs
Slide 23
PERSPECTIVES
- Optimize current therapy
- New drugs
Slide 24
OPTIMIZE CURRENT THERAPY
- Increase dose of PEG IFN
- Increase duration of therapy
- Better adjust dose of RBV according to
body weight
- Improve PEG IFN pharmacokinetic
(2 injections/week for PEG IFN a2b?)
Slide 25
REPEAT
Background
• Initial retreatment studies have suggested a
benefit of induction doses and/or prolonged
duration of treatment in previous nonresponders
Jacobson. Hepatology 2005
Strader. Hepatology 2004
Diago. Hepatology 2003
Slide 26
REPEAT
Patients
• Non-responders to ≥12 weeks’ treatment with
standard-dose PEG IFN alfa-2b plus ribavirin
Slide 27
REPEAT study design
950 patients randomized 2:1:1:2
A
B
360 g
Peg-IFN alpha2a + RBV
360 g
Peg-IFN alpha2a + RBV
C
180 g
Peg-IFN alpha2a + RBV
D
180 g
Peg-IFN alpha2a + RBV
0
12
24
36
Follow-up
Follow-up
Follow-up
Follow-up
48
Study Week
60
72
84
96
Marcellin et al. AASLD 2005
Slide 28
Virological Response at Week 12
180 g (n=469)
360 g (n=473)
p<0.0001
70
62
*
Patients (%)
60
50
p<0.0001
45
42
*
40
p=0.0031
30
25
20
20
13 *
10
0
≥2-log10 drop
<600 IU/mL
HCV RNA
<50 IU/mL
Marcellin et al. AASLD 2005
Slide 29
PERSPECTIVES
- Optimise current therapy
- New drugs
Slide 30
NEW DRUGS
• New “IFN”:
Albuferon
Gene shuffled interferon
• New “ribavirins”:
Levovirine
Merimepodib
Viramidine
• Enzyme inhibitors: Anti-polymerase
Anti-protease
Slide 31
Merimepodib (VX 497)
in non responders (IFN+RBV)
Median HCV RNA (log 10)
8
7
6
PEG IFN + Riba
PEG IFN + Riba + 25 mg VX 497
5
PEG IFN + Riba + 50 mg VX 497
4
3
2
0
4
8
12
16
20
24
Weeks
Marcellin et al. EASL 2004
Slide 32
Viramidine
Anemia
Hemoglobine <10 g/dL
30%
27%
25%
20%
15%
11%
10%
5%
0%
0%
400 mg
2%
600 mg
Viramidine
800 mg
1000/1200 mg
Ribavirin
Slide 33
Viramidine Phase 3 VISER 1
SVR
100%
75%
50%
52%
38%
25%
0%
Viramidine 800mg
Ribavirin 1000/1200 mg
.
Slide 34
ENZYME INHIBITORS
• Anti-polymerase
• NM 283 (Idenix/Novartis)
• R1626 (Roche)
• HCV 796 (Wyeth)…
• Anti-protease
• VX 950 (Vertex)
• Schering 503034
• Others...
Slide 35
Valopicitabine (NM283)
HCV RNA
0.2
0
Placebo
50 mg x 1/j
-0.2
100 mg x 1/j
-0.4
200 mg x 1/j
400 mg x 1/j
-0.6
200 mg x 2/j
-0.8
Doses croissantes
100-800 mg
-1
Doses croissantes
400-800 mg +
anti-émetique
Traitement
-1.2
1
2
3
4
5
8
11
15 16 17
22
JDays
(Godofsky et al., DDW 2004)
Slide 36
R1626 (Roche)
Treatment
F-U
1
HCV RNA
0
Placebo
500 mg x 2/j
1500 mg x 2/j
-1
-2
-1,2 log10
3000 mg x 2/j
-3
-2,6 log10
4500 mg x 2/j
-4
-3,7 log10
-5
0
5
10
15
20
25
30
Days
(Roberts et al, AASLD 2006)
Slide 37
HCV 796 (Wyeth)
1
F-U
Treatment
HCV RNA
0
Placebo
50 mg
100 mg
250 mg
500 mg
1000 mg
1500 mg
-1
-2
-3
-1
2
5
8
11
14 17
Days
20
23
26
29
(Chandra et al, DDW 2006)
Slide 38
Slide 39
PegIFN-Ribavirine-VX 950
8
H C V R N A ( L o g1 0 IU /m L )
7
media
n
6
5
4
3
2
Limit of
Quantitation
Limit of
Detection
1
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Study Time (in Days)
Lawitz et al., DDW 2006
Slide 40
HCV RNA Levels Change
SCH 503034 ± IFN PEG a2b 1.5g/kg
HCV 1, IFN Non-Responders
0
-0,5
-1
PEG IFN
-1,5
PEG IFN +200 mg SCH
-2
PEG IFN + 400 mg SCH
)
-2,5
-3
0
1 2 3
Days
5
7
8
9 10 12 13
Slide 41
MAINTENANCE THERAPY
Slide 42
MAINTENANCE THERAPY
Reduce necro-inflam.
Reduce HCC?
Improve survival?
F3-F4
ALT decrease
PROS
Tolerability
Cost
Not proven
F1-F2
No ALT decrease
CONS
Slide 43
TREATMENT OF NON RESPONDERS
- The probability of SVR to ReTX depends on
type of non response, previous therapy and
characteristics of patients (genotype, cirrhosis)
-Viral eradication is rarely obtained (10%)
with pegylated combination
in NRs to optimal standard combination
- Viral eradication may be obtained
in NRs to sub-optimal combination (correct
causes of NR)
Slide 44
TREATMENT OF NON RESPONDERS
- The efficacy of new drugs
(anti-protease, anti-polymerase…) remains
to be demonstrated. Triple or double TX?
- Maintenance therapy is justified
In patients with severe liver disease, if it
induces a biochemical response (ALT<2N)
- Its modalities and the patients
who benefit need to be precised
Slide 45
IN PRACTICAL
Slide 46
Non Responder
Slide 47
Non Responder
False non Responder
Slide 48
Non Responder
False non Responder
Cause of non response?
Treat the cause
Slide 49
Non Responder
False non Responder
Cause of non response?
Treat the cause
ReTX
Response
Eradication
Slide 50
Non Responder
False non Responder
Cause of non response?
Treat the cause
Maintenance therapy
- if F3 or F4
- if biochemical response
- if tolerance OK
ReTX
Response
Eradication
Non response
Slide 51
Non Responder
False non Responder
True non Responder
Cause of non response?
Treat the cause
Maintenance therapy
- if F3 or F4
- if biochemical response
- if tolerance OK
ReTX
Response
Eradication
Non response
Slide 52
Non Responder
False non Responder
Trial
True non Responder
Cause of non response?
Treat the cause
Maintenance therapy
- if F3 or F4
- if biochemical response
- if tolerance OK
ReTX
Response
Eradication
Non response
Slide 53
Patrick
MARCELLIN
Slide 2
THE CHALLENGE OF TREATING
NON RESPONDERS
Patrick Marcellin
Service d’Hépatologie and INSERM CRB3
Hôpital Beaujon, Clichy
University of Paris
Slide 3
WHO TO RETREAT?
SYMPTOMS
GENOTYPE
MOTIVATION
SIDE EFFECTS
TOLERANCE
COST
FIBROSIS 2-4
FIBROSIS 0-1
PROS
CONS
Slide 4
HOW TO TREAT A NON RESPONDER?
Two strategies
- Viral eradication
- Maintenance therapy
Slide 5
HOW TO TREAT A NON RESPONDER?
Two strategies
- Viral eradication
- Maintenance therapy
Slide 6
The probability of viral eradication
depends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
Slide 7
The probability of viral eradication
depends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
Slide 8
Type of non response
7
Null non responder
Serum HCV RNA
6
1st phase
Partial non responder
5
4
Slow responder
2nd phase
3
Limit of detection
2
Rapid responder
1
0
1
2
3
14
7
21
28
Days
Neumann et al. 2000
Slide 9
Type of non response
7
Null non responder
Serum HCV RNA
6
1st phase
Partial non responder
5
4
Slow responder
2nd phase
3
Limit of detection
2
Rapid responder
1
0
1
2
3
14
7
21
28
Days
Neumann et al. 2000
Slide 10
The probability of viral eradication
depends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
Slide 11
Previous therapy
- Conventional interferon
- Standard combination
- Pegylated combination
Slide 12
HALT-C
SVR according to previous therapy
50
p<0.0001
%
40
30
28%
20
12%
10
0
IFN
IFN + RBV
(n=219)
(n=385)
Schiffman. Gastroenterology 2005
Slide 13
BEAUJON
SVR according to previous therapy
50
%
40
35%
30
20
10%
10
0
IFN
IFN + RBV
(n=49)
(n=50)
Ripault et al. DDW 2003
Slide 14
SVR to PEG IFN+RBV in NRs to IFN+RBV
According to Genotype
50
40
37%
30
%
20
10
0%
0
Genotype 2-3
SVR
Genotype 1
Moucari et al. J Hepatol in press
Slide 15
SVR to PEG IFN+RBV in NRs to IFN+RBV
According to Cirrhosis
50
40
32%
30
%
20
10
0%
0
No cirrhosis
SVR
Cirrhosis
Moucari et al. J Hepatol in press
Slide 16
RETREATMENT BY PEGYLATED COMBINATION OF 154
NON RESPONDERS TO STANDARD COMBINATION
HCV RNA (log10 copies/ml)
8
7
6
5
SVR (+)
4
SVR (-)
3
2
1
0
W0
W4*
W8*
W12
Treatment Week
Moucari et al. J Hepatol, in press
Slide 17
RETREATMENT FOR ERADICATION
Partial response
Genotype 2-3
No cirrhosis
PROS
Non response
Genotype 1
Cirrhosis
CONS
Slide 18
PROBABILITY OF SVR
TO RETREATMENT
P = P2 - P1
P is the probability of response to retreatment according
to the probability of response to the new treatment (P2)
minus the probability of response to the prior treatment (P1)
Slide 19
The probability of viral eradication
depends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
Slide 20
Cause(s) of non response
related to the patient:
To manage before retreatment
- Alcool:
- Overweight:
- Insulin resistance
- Iron overload:
- Psychologic:
stop
weight loss
treatment?
phlebotomy
prepare
Slide 21
Cause(s) of non response
related to reduced dosing:
To manage during retreatment
- Anemia:
- Neutropenia:
- Depression:
- Others …
EPO
GCSF
anti-depressive
Slide 22
PERSPECTIVES
- Optimise current therapy
- New drugs
Slide 23
PERSPECTIVES
- Optimize current therapy
- New drugs
Slide 24
OPTIMIZE CURRENT THERAPY
- Increase dose of PEG IFN
- Increase duration of therapy
- Better adjust dose of RBV according to
body weight
- Improve PEG IFN pharmacokinetic
(2 injections/week for PEG IFN a2b?)
Slide 25
REPEAT
Background
• Initial retreatment studies have suggested a
benefit of induction doses and/or prolonged
duration of treatment in previous nonresponders
Jacobson. Hepatology 2005
Strader. Hepatology 2004
Diago. Hepatology 2003
Slide 26
REPEAT
Patients
• Non-responders to ≥12 weeks’ treatment with
standard-dose PEG IFN alfa-2b plus ribavirin
Slide 27
REPEAT study design
950 patients randomized 2:1:1:2
A
B
360 g
Peg-IFN alpha2a + RBV
360 g
Peg-IFN alpha2a + RBV
C
180 g
Peg-IFN alpha2a + RBV
D
180 g
Peg-IFN alpha2a + RBV
0
12
24
36
Follow-up
Follow-up
Follow-up
Follow-up
48
Study Week
60
72
84
96
Marcellin et al. AASLD 2005
Slide 28
Virological Response at Week 12
180 g (n=469)
360 g (n=473)
p<0.0001
70
62
*
Patients (%)
60
50
p<0.0001
45
42
*
40
p=0.0031
30
25
20
20
13 *
10
0
≥2-log10 drop
<600 IU/mL
HCV RNA
<50 IU/mL
Marcellin et al. AASLD 2005
Slide 29
PERSPECTIVES
- Optimise current therapy
- New drugs
Slide 30
NEW DRUGS
• New “IFN”:
Albuferon
Gene shuffled interferon
• New “ribavirins”:
Levovirine
Merimepodib
Viramidine
• Enzyme inhibitors: Anti-polymerase
Anti-protease
Slide 31
Merimepodib (VX 497)
in non responders (IFN+RBV)
Median HCV RNA (log 10)
8
7
6
PEG IFN + Riba
PEG IFN + Riba + 25 mg VX 497
5
PEG IFN + Riba + 50 mg VX 497
4
3
2
0
4
8
12
16
20
24
Weeks
Marcellin et al. EASL 2004
Slide 32
Viramidine
Anemia
Hemoglobine <10 g/dL
30%
27%
25%
20%
15%
11%
10%
5%
0%
0%
400 mg
2%
600 mg
Viramidine
800 mg
1000/1200 mg
Ribavirin
Slide 33
Viramidine Phase 3 VISER 1
SVR
100%
75%
50%
52%
38%
25%
0%
Viramidine 800mg
Ribavirin 1000/1200 mg
.
Slide 34
ENZYME INHIBITORS
• Anti-polymerase
• NM 283 (Idenix/Novartis)
• R1626 (Roche)
• HCV 796 (Wyeth)…
• Anti-protease
• VX 950 (Vertex)
• Schering 503034
• Others...
Slide 35
Valopicitabine (NM283)
HCV RNA
0.2
0
Placebo
50 mg x 1/j
-0.2
100 mg x 1/j
-0.4
200 mg x 1/j
400 mg x 1/j
-0.6
200 mg x 2/j
-0.8
Doses croissantes
100-800 mg
-1
Doses croissantes
400-800 mg +
anti-émetique
Traitement
-1.2
1
2
3
4
5
8
11
15 16 17
22
JDays
(Godofsky et al., DDW 2004)
Slide 36
R1626 (Roche)
Treatment
F-U
1
HCV RNA
0
Placebo
500 mg x 2/j
1500 mg x 2/j
-1
-2
-1,2 log10
3000 mg x 2/j
-3
-2,6 log10
4500 mg x 2/j
-4
-3,7 log10
-5
0
5
10
15
20
25
30
Days
(Roberts et al, AASLD 2006)
Slide 37
HCV 796 (Wyeth)
1
F-U
Treatment
HCV RNA
0
Placebo
50 mg
100 mg
250 mg
500 mg
1000 mg
1500 mg
-1
-2
-3
-1
2
5
8
11
14 17
Days
20
23
26
29
(Chandra et al, DDW 2006)
Slide 38
Slide 39
PegIFN-Ribavirine-VX 950
8
H C V R N A ( L o g1 0 IU /m L )
7
media
n
6
5
4
3
2
Limit of
Quantitation
Limit of
Detection
1
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28
Study Time (in Days)
Lawitz et al., DDW 2006
Slide 40
HCV RNA Levels Change
SCH 503034 ± IFN PEG a2b 1.5g/kg
HCV 1, IFN Non-Responders
0
-0,5
-1
PEG IFN
-1,5
PEG IFN +200 mg SCH
-2
PEG IFN + 400 mg SCH
)
-2,5
-3
0
1 2 3
Days
5
7
8
9 10 12 13
Slide 41
MAINTENANCE THERAPY
Slide 42
MAINTENANCE THERAPY
Reduce necro-inflam.
Reduce HCC?
Improve survival?
F3-F4
ALT decrease
PROS
Tolerability
Cost
Not proven
F1-F2
No ALT decrease
CONS
Slide 43
TREATMENT OF NON RESPONDERS
- The probability of SVR to ReTX depends on
type of non response, previous therapy and
characteristics of patients (genotype, cirrhosis)
-Viral eradication is rarely obtained (10%)
with pegylated combination
in NRs to optimal standard combination
- Viral eradication may be obtained
in NRs to sub-optimal combination (correct
causes of NR)
Slide 44
TREATMENT OF NON RESPONDERS
- The efficacy of new drugs
(anti-protease, anti-polymerase…) remains
to be demonstrated. Triple or double TX?
- Maintenance therapy is justified
In patients with severe liver disease, if it
induces a biochemical response (ALT<2N)
- Its modalities and the patients
who benefit need to be precised
Slide 45
IN PRACTICAL
Slide 46
Non Responder
Slide 47
Non Responder
False non Responder
Slide 48
Non Responder
False non Responder
Cause of non response?
Treat the cause
Slide 49
Non Responder
False non Responder
Cause of non response?
Treat the cause
ReTX
Response
Eradication
Slide 50
Non Responder
False non Responder
Cause of non response?
Treat the cause
Maintenance therapy
- if F3 or F4
- if biochemical response
- if tolerance OK
ReTX
Response
Eradication
Non response
Slide 51
Non Responder
False non Responder
True non Responder
Cause of non response?
Treat the cause
Maintenance therapy
- if F3 or F4
- if biochemical response
- if tolerance OK
ReTX
Response
Eradication
Non response
Slide 52
Non Responder
False non Responder
Trial
True non Responder
Cause of non response?
Treat the cause
Maintenance therapy
- if F3 or F4
- if biochemical response
- if tolerance OK
ReTX
Response
Eradication
Non response
Slide 53