patrick marcellin. the challenge of treating non responders patrick marcellin service...
TRANSCRIPT
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Patrick MARCELLIN
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THE CHALLENGE OF TREATING
NON RESPONDERS
Patrick Marcellin
Service d’Hépatologie and INSERM CRB3Hôpital Beaujon, Clichy
University of Paris
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WHO TO RETREAT?
SIDE EFFECTSTOLERANCECOST
FIBROSIS 0-1
PROS CONS
SYMPTOMSGENOTYPEMOTIVATION
FIBROSIS 2-4
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HOW TO TREAT A NON RESPONDER?
Two strategies
- Viral eradication
- Maintenance therapy
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HOW TO TREAT A NON RESPONDER?
Two strategies
- Viral eradication
- Maintenance therapy
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The probability of viral eradicationdepends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
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The probability of viral eradicationdepends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
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0 1 2 311
2
3
4
5
6
7
7 14 21 28
Limit of detection
Days
Ser
um
HC
V R
NA
1st phase
2nd phase
Partial non responder
Slow responder
Rapid responder
Null non responder
Neumann et al. 2000
Type of non response
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0 1 2 311
2
3
4
5
6
7
7 14 21 28
Limit of detection
Days
Ser
um
HC
V R
NA
1st phase
2nd phase
Partial non responder
Slow responder
Rapid responder
Null non responder
Neumann et al. 2000
Type of non response
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The probability of viral eradicationdepends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
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Previous therapy
- Conventional interferon
- Standard combination
- Pegylated combination
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HALT-CSVR according to previous therapy
28%
12%
0
10
20
30
40
50
%
IFN (n=219)
IFN + RBV (n=385)
p<0.0001
Schiffman. Gastroenterology 2005
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BEAUJON SVR according to previous therapy
35%
10%
0
10
20
30
40
50
%
IFN (n=49)
IFN + RBV (n=50)
Ripault et al. DDW 2003
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SVR to PEG IFN+RBV in NRs to IFN+RBVAccording to Genotype
0%
37%
0
10
20
30
40
50
SVR
%
Genotype 2-3 Genotype 1
Moucari et al. J Hepatol in press
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SVR to PEG IFN+RBV in NRs to IFN+RBVAccording to Cirrhosis
0%
32%
0
10
20
30
40
50
SVR
%
No cirrhosis Cirrhosis
Moucari et al. J Hepatol in press
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0
1
2
3
4
5
6
7
8
W0 W4* W8* W12
SVR (+)SVR (-)
HC
V R
NA
(lo
g10
co
pie
s/m
l)
Treatment Week
RETREATMENT BY PEGYLATED COMBINATION OF 154 NON RESPONDERS TO STANDARD COMBINATION
Moucari et al. J Hepatol, in press
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RETREATMENT FOR ERADICATION
Partial response Non response
Genotype 2-3 Genotype 1
No cirrhosis Cirrhosis
PROS CONS
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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)
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The probability of viral eradicationdepends on:
- Type of non response
- Previous therapy
- Cause(s) of non response
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Cause(s) of non responserelated to the patient:
To manage before retreatment
- Alcool: stop - Overweight: weight loss- Insulin resistance treatment?- Iron overload: phlebotomy- Psychologic: prepare
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Cause(s) of non responserelated to reduced dosing:
To manage during retreatment
- Anemia: EPO- Neutropenia: GCSF- Depression: anti-depressive- Others …
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PERSPECTIVES
- Optimise current therapy
- New drugs
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PERSPECTIVES
- Optimize current therapy
- New drugs
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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?)
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REPEATBackground
• Initial retreatment studies have suggested a benefit of induction doses and/or prolonged duration of treatment in previous non-responders
Jacobson. Hepatology 2005Strader. Hepatology 2004Diago. Hepatology 2003
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REPEATPatients
• Non-responders to ≥12 weeks’ treatment with standard-dose PEG IFN alfa-2b plus ribavirin
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Follow-up
Study Week0 4824 9612 36 60 72 84
Follow-up360 g Peg-IFN alpha2a + RBV
Follow-up360 g Peg-IFN alpha2a + RBV
180 g Peg-IFN alpha2a + RBV Follow-up
REPEAT study design950 patients randomized 2:1:1:2
A
B
C
D
180 g Peg-IFN alpha2a + RBV
Marcellin et al. AASLD 2005
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Virological Response at Week 12P
atie
nts
(%
)
<600 IU/mL <50 IU/mL≥2-log10 drop
25
42*
1320*
45
62*
p<0.0001 180 g (n=469)360 g (n=473)
HCV RNA
0
10
20
30
40
50
60
70
p<0.0001
p=0.0031
Marcellin et al. AASLD 2005
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PERSPECTIVES
- Optimise current therapy
- New drugs
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NEW DRUGS
• New “IFN”: Albuferon
Gene shuffled interferon
• New “ribavirins”: Levovirine
Merimepodib
Viramidine
• Enzyme inhibitors: Anti-polymerase
Anti-protease
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Merimepodib (VX 497) in non responders (IFN+RBV)
Weeks
2
3
4
5
6
7
8
0 4 8 12 16 20 24
Med
ian
HC
V R
NA
(lo
g 1
0)
PEG IFN + Riba PEG IFN + Riba + 25 mg VX 497
PEG IFN + Riba + 50 mg VX 497
Marcellin et al. EASL 2004
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ViramidineAnemia
Viramidine
Hemoglobine <10 g/dL
%
%
30%
25%
20%
15%
10%
5%
0%
400 mg 600 mg 800 mg
Ribavirin1000/1200 mg
0%2%
11%
27%
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Viramidine Phase 3 VISER 1 SVR
Viramidine 800mg Ribavirin 1000/1200 mg
52% 38%
.
100%
75%
50%
25%
0%
%
%
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ENZYME INHIBITORS
• Anti-polymerase• NM 283 (Idenix/Novartis)
• R1626 (Roche)
• HCV 796 (Wyeth)…
•Anti-protease• VX 950 (Vertex)
• Schering 503034
• Others...
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Valopicitabine (NM283)
HCV RNA
-1.2
-1
-0.8
-0.6
-0.4
-0.2
0
0.2
1 3 5 8 11 1615 17 22
JDays
Placebo
50 mg x 1/j
100 mg x 1/j
200 mg x 1/j
400 mg x 1/j
200 mg x 2/j
Doses croissantes100-800 mg
Doses croissantes400-800 mg + anti-émetiqueTraitement
2 4
(Godofsky et al., DDW 2004)
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R1626 (Roche)
(Roberts et al, AASLD 2006)(Roberts et al, AASLD 2006)
PlaceboPlacebo
500 mg x 2/j500 mg x 2/j
1500 mg x 2/j1500 mg x 2/j
3000 mg x 2/j3000 mg x 2/j
4500 mg x 2/j4500 mg x 2/j
TreatmentTreatment F-UF-U
DaysDays
00 55 1010 1515 2020 2525 3030
HC
V R
NA
HC
V R
NA
-5-5
-4-4
-3-3
-2-2
-1-1
00
11
-2,6 log-2,6 log1010
-3,7 log-3,7 log1010
-1,2 log-1,2 log1010
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HCV 796 (Wyeth)
(Chandra et al, DDW 2006)(Chandra et al, DDW 2006)
--11 22 55 88 1111 1144 1177 2200 2233 2266 2299--33
--22
--11
00
11
PPllaacceebboo5500 mmgg110000 mmgg225500 mmgg550000 mmgg11000000 mmgg11550000 mmgg
DaysDays
HC
V R
NA
HC
V R
NA
TreatmentTreatment F-UF-U
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PegIFN-Ribavirine-VX 950
0
1
2
3
4
5
6
7
8
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
HC
V R
NA
(L
og
10 I
U/m
L)
Study Time (in Days)
median
Limit of Quantitation
Limit of Detection
Lawitz et al., DDW 2006Lawitz et al., DDW 2006
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SCH 503034 ± IFN PEG a2b 1.5g/kg HCV 1, IFN Non-Responders
-3
-2,5
-2
-1,5
-1
-0,5
0
0 1 2 3 5 7 8 9 10 12 13 Days
HC
V R
NA
Le
vel
s C
han
ge
PEG IFN PEG IFN +200 mg SCH PEG IFN + 400 mg SCH )
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MAINTENANCE THERAPY
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MAINTENANCE THERAPY
Reduce necro-inflam. Tolerability
Reduce HCC? Cost
Improve survival? Not proven
F3-F4 F1-F2
ALT decrease No ALT decrease
PROS CONS
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- The probability of SVR to ReTX depends ontype 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)
TREATMENT OF NON RESPONDERS
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- The efficacy of new drugs(anti-protease, anti-polymerase…) remains to be demonstrated. Triple or double TX?- Maintenance therapy is justifiedIn patients with severe liver disease, if it induces a biochemical response (ALT<2N)- Its modalities and the patients who benefit need to be precised
TREATMENT OF NON RESPONDERS
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IN PRACTICAL
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Non Responder
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Non Responder
False non Responder
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Non Responder
False non Responder
Cause of non response?
Treat the cause
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Non Responder
False non Responder
Cause of non response?
Treat the cause
ReTX
Response
Eradication
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Non Responder
False non Responder
Cause of non response?
Treat the cause
ReTX
Response
Maintenance therapy- if F3 or F4- if biochemical response- if tolerance OK
Eradication
Non response
![Page 51: Patrick MARCELLIN. THE CHALLENGE OF TREATING NON RESPONDERS Patrick Marcellin Service d’Hépatologie and INSERM CRB3 Hôpital Beaujon, Clichy University](https://reader036.vdocuments.net/reader036/viewer/2022081519/56649c765503460f9492ae99/html5/thumbnails/51.jpg)
Non Responder
False non Responder True non Responder
Cause of non response?
Treat the cause
ReTX
Response
Maintenance therapy- if F3 or F4- if biochemical response- if tolerance OK
Eradication
Non response
![Page 52: Patrick MARCELLIN. THE CHALLENGE OF TREATING NON RESPONDERS Patrick Marcellin Service d’Hépatologie and INSERM CRB3 Hôpital Beaujon, Clichy University](https://reader036.vdocuments.net/reader036/viewer/2022081519/56649c765503460f9492ae99/html5/thumbnails/52.jpg)
Non Responder
False non Responder True non Responder
Cause of non response?
Treat the cause
ReTX
Response
Maintenance therapy- if F3 or F4- if biochemical response- if tolerance OK
Eradication
Non response
Trial
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