Transcript DFPP

6th International Symposium on Liver
Failure and Artificial Liver 2011
Novel therapeutic strategy for
Hepatitis C treatment
- Double Filtration Plasmapheresis and
Interferon/Ribavirin combination Therapy -
2011.3.25
Tatsuya Ide, M.D. Ph.D.
Division of Gastroenterology, Department of Medicine,
Kurume University School of Medicine
Tohoku area
Earthquake
Kurume
University
Tokyo
Prevalence of antibody to HCV in Japan
2.0 %
Age-specific prevalence of anti-HCV
Male
Female
Age
Mortality rate of hepatocellular carcinoma
Female
Male
1996-2000年
1996-2000年
HCV genotype in Japan
Viral load
1b 70 %
2a 20 %
2b 10 %
High (>5.0 log copy/ml)
90 %
Low (<5.0 log copy/ml)
10 %
Poor response
to IFN therapy
Low viral load High viral load
Current IFN therapy ( for naïve) & SVR rate
PEG IFN/Rib
48-72W
40-60 %
5.0
PEG IFN/Rib, 24W
(PEG)IFN 24-48W
70-90 %
log copy/ml
(PEG)IFN 24-48W
70-90 %
Genotype 1b
(PEG)IFN 12-24W
70-90 %
Genotype 2a, 2b
(5.0 log copy/ml≒100 KIU/ml ≒ 1 MEQ/ml)
(SVR ; HCV RNA in serum is negative at 6 month after IFN therapy)
Predictability of sustained virologic response.
PEG IFN + Ribavirin (48W) for gentype 1b and high viral load
100%
SVR rate (%)
100
Early viral disappearance in serum → SVR
80
71.1%
60
36.4%
40
0%
20
(23/23)
0
4W
(86/121)
5〜12W
(12/33)
13〜24W
0%
(0/11)
25〜36W
(0/4)
37〜48W
Time of HCV RNA undetectable
(SVR ; HCV RNA in serum is negative at 6 month after IFN therapy)
(PEG) IFN Ribavirin
+
Double Filtration Plasmapheresis (DFPP)
for patients with genotype 1b and high viral load.
This therapy has been approved in Japan, April 2008.
(PEG) IFN Ribavirin
+
Double Filtration Plasmapheresis (DFPP)
for patients with genotype 1b and high viral load.
a. Treatment concept
b. Outline of DFPP
c. Clinical Trial
d. Post-marketing surveillance study
e. Modified DFPP therapy
HCV levels during and after Plasma Exchange(PE) therapy
Plasma Exchange
Manzin et al,
J Hepatol 31;389-393, 1999
・PE was performed 3 patients with hepatitis C
・Immediate after completion of PE：HCV-RNA was reduced to 50 ~ 90% of
the initial level
・ 4 ~ 6 hours after completion of PE：rebound to the initial level
⇒Viral level can be reduced by extracorporeal therapy
Even if the virus could be removed from blood,
the virus continue to replicate in the liver.
Is physical viral reduction in peripheral blood
effective as treatment of chronic hepatitis?
⇒ Induce early viral reduction
⇒ Prevent reinfection of HCV to liver cells
⇒ Cytotoxic T cell activation
(PEG) IFN Ribavirin
+
Double Filtration Plasmapheresis (DFPP)
for patients with genotype 1b and high viral load.
a. Treatment concept
b. Outline of DFPP
c. Clinical Trial
d. Post-marketing surveillance study
e. Modified DFPP therapy
Double Filtration Plasmapheresis （DFPP）
Cell components
anti-coagulant
Plasma
HCV
Cascadeflo
2nd filter
Plasmaflo
1st filter
Plasma pump
Morphology of 1st and 2nd filter for DFPP
1st filter
Large pore
0.5 μm
2nd filter
Small pore
Pore size 30 nm
HCV
(55-65 nm)
0.5 μm
5000
Plasma
4000
3000
2000
2nd filter
HCV RNA level（KIU/mL ,Amplicore ）
Changes of HCV RNA levels before and after 2nd filter (n=14)
1000
Purified
plasma
0
before
After
Discard
Administrating conditions of DFPP
・Flow rate: Blood 100 mL/min, Plasma 30 mL/min
・Desired plasma process volume: 50 mL/kg (3000ml/body)
・Operation time: 2 - 6 hrs
・Postpone if fibrinogen level in the morning of DFPP
is less than 100 mg/mL
・Anticoagulant: nafamostat mesilate / heparine
・Substitutional fluid: Use in a vial of 25 % Albumin (50 mL)
diluted with saline solution (200 mL)
(PEG) IFN Ribavirin
+
Double Filtration Plasmapheresis (DFPP)
for patients with genotype 1b and high viral load.
a. Treatment concept
b. Outline of DFPP
c. Clinical Trial
d. Post-marketing surveillance study
e. Modified DFPP therapy
1) Treatment schedule of IFN/Ribavirin + DFPP (2003.1- 2004.11)
DFPP (3〜5 session）
IFN α-2b 6MU（Daily for 2 w then 3 t/w,im）
Ribavirin 600-800mg(daily, po)
24 weeks
24 weeks
24 weeks
2) Treatment schedule of PEG IFN/Ribavirin + DFPP (2004.12-)
DFPP (3〜5 session）
PEG IFNα-2b 1.5μg/kg （weekly、sc）
Ribavirin 600-1000mg(daily, po)
48 weeks
24 weeks
1) Treatment schedule of IFN/Ribavirin + DFPP (2003.1- 2004.11)
DFPP (3〜5 times）
IFN α-2b 6MU（Daily for 2 w then 3 t/w,im）
Ribavirin 600-800mg(daily, po)
24 weeks
24 weeks
24 weeks
2) Treatment schedule of PEG IFN/Ribavirin + DFPP (2004.12-)
DFPP (3〜5 times）
PEG IFNα-2b 1.5μg/kg （weekly、sc）
Ribavirin 600-1000mg(daily, po)
48 weeks
24 weeks
Patient’s backgroud
PEG/Rib +DFPP
Male:Female
Sex
Age
Body Weight(kg)
Grading
Histology
Staging
Prior IFN therapy
HCV RNA(KIU/mL)
ALT(IU/L)
4
Platelet(10 /μL)
0/1/2/3
0/1/2/3/4
naive
relapse
non-response
unknown
100-1300
>1300
22:10
PEG/Rib
44:28
54.9±7.8
68.3±9.8
1/15/12/1
2/11/12/3/1
54.7±9.7
64.2±10.4
0/26/39/1
0/24/20/14/8
8(25.0%)
13(40.6%)
11(34.4%)
0(0%)
41(56.9%)
10(13.9%)
9(12.5%)
12(16.7%)
10
22(68.8%)
P<0.001
26
46(63.9%)
72.7±44.6
88.8±64.1
16.4±4
15.9±4.2
Relapse : Reversion to an HCV RNA-positive state after HCV RNA negative while on prior IFN treatment.
Non-response : Failure to achieve HCV RNA-negative at any time point during prior IFN treatment.
Administration numbers of DFPP
5 sessions of DFPP at maximum during the 1st week of treatment
n = 32 (PEG IFN/Rib +DFPP）
session
3
4
5
case
treatment day
(case)
23
1,2,4(13)
1,2,5(6)
1,3,5(3)
1,2,3(1)
6
1,2,3,5(2)
1,2,4,5(2)
1,2,5,6(1)
1,3,5,6(1)
3
1,2,3,4,5(2)
5 session in 2 wk (1)
average：3.4 sessions
Changes of HCV RNA levels
57 yrs、M、A2F2、
HCV RNA level (KIU/ml ,Amplicore)
PEG IFNα-2b 100 μg/kg （weekly、sc）
Ribavirin 800 mg(daily, po)
DFPP
1600
1400
1200
1000
800
600
400
200
HCV RNA negative
(-)
(-) (-)
0
12
day
4
1
2
4
8
Week
12
24
Mean HCV viral load reduction
Δlog
22週後
week
44週後
week
Mean log 10 reduction
from baseline in viral load
0.00
-0.50
-1.00
-1.50
(n=8)
-1.82
-1.50
(n=9)
-2.00
-1.85
(n=11)
-2.50
PEG/RBV
-3.00
PEG/RBV
+ DFPP
-2.69
(n=10)
On- treatment virologic response rate(all cases）
A virologic response was defined as an undetectable of HCV RNA in serum
100
P=0.047
Percent of patients（％）
90
80
82.8%
( 24/ 29)
72.6%
( 45/ 62)
62.1%
(18/ 29)
70
60
39.4%
(26/ 66)
50
PEG/RBV
40
PEG/RBV
+ DFPP
30
20
10
10.2% 7.4 %
( 6/ 59) ( 2/ 27)
0
4
12
Week
24
Sustained virological response rate in PEG/RBV (+ DFPP)
SVR rate (%)
100
80
60
81.8 %
(9/ 11)
60.0 %
(3/ 5)
50.0 %
(18/36)
50.0 %
(9/15)
71.4%
(5/ 7)
PEG/RBV +
DFPP
PEG/RBV
28.6 %
(2/7)
40
20
0
naive
relapse non-response
Prior IFN
(SVR ; HCV RNA in serum is negative at 6 month after IFN therapy)
Adverse Event
Incidence of adverse event
9/32 cases
(28.1%)
14/108 session (13.0%)
Emerging
period
During DFPP
After extracting
catheter
Symptoms
Case
Session
Bad feeling
1
2
Fever
2
2
Chill
2
2
Vomit
2
2
Nausea
4
4
Slight nausea
1
1
Shock
1
1
Bleeding
1
1
Lymphocyte（/μL）
Platelet （×104/μL)
Changes of laboratory data
25
20
15
10
5
0
day 2
day 3
day 4 day 5
2500
2000
1500
1000
500
0
day 6 week 2
day 1 day 2 day 3
20
day 4 day 5 day 6 week 2
5
Albmin （g/dL）
Hemoglobin （g/dL）
day 1
3000
15
10
5
0
4
3
2
1
0
day 1
day 2
day 3
day 4
day 5
day 6 week 2
day 1
day 2
day 3
day 4
day 5
day 6
week 2
Summary of results
１） Mean Log10 reduction of viral load are
more than 2 log at 4 week in DFPP group.
2) On- treatment virologic response rate is higher
in DFPP group.
3) DFPP combination therapy have high SVR rate.
(PEG) IFN Ribavirin
+
Double Filtration Plasmapheresis (DFPP)
for patients with genotype 1b and high viral load.
a. Treatment concept
b. Outline of DFPP
c. Clinical Trial
d. Post-marketing surveillance study
e. Modified DFPP therapy
Participating Hospitals
（36 Hp）
北海道大学病院
金沢大学附属病院
日本赤十字社和歌山 医療センター
大阪市立総合医療センター
大阪労災病院
兵庫県立西宮病院
三木山陽病院
神戸朝日病院
市立奈良病院
近江八幡市立総合医療センター
久留米大学病院
福岡赤十字病院
長田病院
藤元早鈴病院
聖隷佐倉市民病院
新潟市民病院
済生会新潟第二病院
三愛記念病院
谷津保健病院
山王病院
能代山本医師会病院
黒石病院
いわき市立総合磐城共立病院
日本医科大学付属多摩 永山病院
東戸塚記念病院
佐々総合病院
沼津市立病院
共立蒲原総合病院
香川県立中央病院
香川大学医学部附属病院
愛媛大学病院
福山市民病院
下関厚生病院
名古屋医療センター
名鉄病院
岐阜市民病院
Patient disposition Flowchart
Collected patients (n=239)
Safety Analysis
(n=239)
Excluded patietns (n=58)
Genotype 2 (n=7)
HCV RNA level < 5 Log IU/mL
lost follow-up (n=11)
IFN β inductuoin (n=25)
(n=15)
Efficacy evaluation (genotype 1, high viral load)
PEG-IFN/RBV+DFPP
(n=181)
naive (n=60)
PEG-IFN/RBV (n=73)
Other IFN therapy (n=48)
Prior IFN
Patients’ background
PEG-IFN/RBV+DFPP (n=181)
Sex （M/F）
Age
Weight (kg)
Live biopsy
Activity (0/1/2/3)
Fibrosis (0/1/2/3/4)
HCV RNA level (LogIU/mL)
AST (IU/L)
ALT (IU/L)
4
Platelet (×10 /μL）
Fibrinogen (mg/dL)
Treatment history 、n (%)
naive
relapse
non-response
unknown
90/91
59 (24-75) †
59.0 (38.0-108.0)
2/30/36/7
3/20/35/13/4
6.4 (5.0-7.7) †
47 (12-225) †
47 (10-294) †
14.1 (4.4-36.8)
234 (121-430) †
60
35
62
24
†
†
(33.1)
(19.3)
(34.3)
(13.2)
†Median
(min-max)
Relapse : Reversion to an HCV RNA-positive state after HCV RNA negative while prior IFN treatment.
Non-response : Failure to achieve HCV RNA-negative at any time point during prior IFN treatment.
Efficacy evaluation
PEG-IFN/RBV+DFPP（n=181）
DFPP
PEG IFNα
Ribavirin
4w
12w
Treatment response at 4 and 12 weeks
PEG-IFN/RBV+DFPP （n=181）
(%)
100
：HCV RNA negative at 4 weeks
Percent of patients（％）
：HCV RNA negative at 12 weeks
80
60
57.5%
(104/181)
39.4%
(26/66)
40
PEG-IFN/RBV (non DFPP) （n=66）
Hepatology Research 2007 ; 37 701-710
20
0
14.9%
(27/181)
10.2%
(6/59)
All patients
Treatment response at 4 and 12 weeks
by treatment history
PEG-IFN/RBV+DFPP （n=181）
(%)
：HCV RNA negative at 4 weeks
100
Percent of patients（％）
：HCV RNA negative at 12 weeks
70.0%
(42/60)
80
60
57.1%
(20/35)
57.5%
(104/181)
41.9%
(26/62)
40
20
14.9%
(27/181)
20.0%
(12/60)
8.6%
(3/35)
12.9%
(8/62)
0
All patients
naive
relapse
Treatment history
non-response
Prior
therapy
PEG IFN/RBV
73 cases
Other IFN
33 cases
Treatment response at 4 and 12 weeks
(prior IFN therapy : PEG IFN /RBV)
(%)
：HCV RNA negative at 4 weeks
Percent of patients（％）
100
：HCV RNA negative at 12 weeks
80
63.0%
(17/27)
60
41.1%
(30/73)
40
20
0
8.2%
(6/73)
All patients
7.4%
(2/27)
relapse
5.4%
(2/37)
18.9%
(7/37)
non-response
Changes of fibrinogen levels.
*** ： P<0.001（vs.1 session）
350
Fibrinogen level
（mg/dL）
300
235±52
250
149±37
（-36.2%）
200
***
150
155±51
（-32.8%）
***
182±58
（-21.1%）
***
142±41
（-38.5%）
***
100
50
0
（177）
（157）
（176）
（170）
（146）
DFPP
1 session
DFPP
2 session
DFPP
3 session
DFPP
4 session
DFPP
5 session
Platelet count （×104/μL）
Changes of Platelet count
20
***
： P<0.001（vs.1 session）
15
***
***
10
***
***
13.8±4.5
5
10.8±3.7
(-23.3%）
0
9.5±3.1
(-28.9%）
（45）
（38）
（43）
DFPP
1 session
DFPP
2 session
DFPP
3 session
9.5±3.7
9.5±3.8
(-30.9%）
(-30.0%）
（44）
（40）
DFPP
4 session
DFPP
5 session
(PEG) IFN Ribavirin
+
Double Filtration Plasmapheresis (DFPP)
for patients with genotype 1b and high viral load.
a. Treatment concept
b. Outline of DFPP
c. Clinical Trial
d. Post-marketing surveillance study
e. Modified DFPP therapy
Viral kinetics of
IFNβ 3MU twice a day &PEG IFN/RBV
PEG IFN RBV
IFNβ 3MU twice a day
DigDis Sci 2001:46:516-23 Izumi et al.
Hepatogastroenterology 2006;53:94-9. Ebinuma H et al
J Hepatol 2003 ;39:421-7 Asahina Y et al
Asahina et al Hepatology 2007;34:377-384
Modified DFPP therapy
DFPP
1st week
2nd week
3rd week
IFNβ(3M) Twice a day
4th
・・・
PEG IFN
・・・・
M
Ribavirin
E
DigDis Sci 2001:46:516-23 Izumi et al.
Hepatology 2001;34:377-84.Asahina et al
Hepatogastroenterology 2006;53:94-9. Ebinuma H et al
J Hepatol 2003 ;39:421-7 Asahina Y et al
48 week
Patients’ Background
Sex (M:F)
6:5
Age
59.4±8.4 (39～67)
Platelet
(×104/μL)
HCV RNA level
(logCopy/ml)
Prior IFN (naive ： ＩＦＮ mono)
14.9±5.1 (9.0～30.7)
6.8±0.5 (5.7～7.3)
1 : 10
Changes of HCV RNA levels
DFPP
PEG IFN
B
HCV RNA level (Log IU/ml)
IFNβ(3M)
Twice a day
Ribavirin
8
6
Discontinued by ribavirin side effect
4
2
0
1.2
0
4
8
12
16
20
24 (week)
Mutations & Result
No
HCV mutation
HCV RNA level
Before IFN
Weeks of HCV
RNA negative
ISDR
Core 70
1
6.9
8
1
W
2
7.2
8
0
W
3
6.2
12
0
W
Major Homo
4
5.1
12
1
M
Minor Homo
5
7.3
12
1
W
Discontinued
6
7
12
0
W
ongoing
7
6.8
16
0
M
8
5.9
24
0
W
Major Homo
SVR
SVR
9
6.6
24
0
M
Major Homo
ongoing
10
7.6
Non response
1
M
Minor Hetero
ongoing
11
6.7
Discontinued
IL28B
Result
SVR
SVR
SVR
SVR
(ISDR ; Interferon sensitivity determining region, W; Wild, M;Mutant, IL28B ;Interluekin 28B (SNPs)
SVR ; HCV RNA in serum is negative at 6 month after IFN therapy)
Conclusion
DFPP plus IFN/Rib combination therapy produced a great
reduction of HCV-RNA load during the early stage of treatment,
suggesting that this combination therapy may be a new modality
for chronic hepatitis C patients with genotype 1b, high viral load.
Hepatology Research. 37:701-10, 2007
Thank you for your attention!
Chronic Hepatitis C
1) Standard IFN treatment in Japan
2) DFPP / IFN combination therapy