Novel therapeutic strategy for Hepatitis C treatment 2011.3.25 Tatsuya Ide, M.D. Ph.D. Division of...

Novel therapeutic strategy for Hepatitis C treatment

2011.3.25Tatsuya Ide, M.D. Ph.D.

Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine

- Double Filtration Plasmapheresis and Interferon/Ribavirin combination Therapy -

6th International Symposium on Liver Failure and Artificial Liver 2011

Kurume University

Earthquake

Tokyo

Tohoku area

Prevalence of antibody to HCV in Japan 2.0 %

Age-specific prevalence of anti-HCV

Female

Male

Age

1996-20001996-2000 年年 1996-20001996-2000 年年

Mortality rate of hepatocellular carcinoma

FemaleMale

HCV genotype in Japan

1b 70 %

2a 20 %

2b 10 %

High (>5.0 log copy/ml)

Low (<5.0 log copy/ml)

90 %

10 %

Viral loadPoor response

to IFN therapy

Genotype 2a, 2bGenotype 1b

5.0 log copy/ml

(5.0 log copy/ml 100 ≒ KIU/ml 1 ≒ MEQ/ml)

Hig

h vi

ral

load

Low

vira

l lo

ad

PEG IFN/Rib48-72W

PEG IFN/Rib, 24W(PEG)IFN 24-48W

(PEG)IFN 24-48W (PEG)IFN 12-24W

(SVR ; HCV RNA in serum is negative at 6 month after IFN therapy)

Current IFN therapy ( for naïve) & SVR rate

70-90 % 70-90 %

70-90 %40-60 %

Predictability of sustained virologic response. PEG IFN + Ribavirin (48W) for gentype 1b and high viral load

Time of HCV RNA undetectable

Early viral disappearance in serum → SVR

0

20

40

60

80

100100%

71.1%

36.4%

0% 0%

4W 5〜 12W 13〜 24W 25〜 36W 37〜 48W

(23/23) (86/121) (12/33) (0/11) (0/4)

SV

R r

ate

(%)


(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.

a. Treatment concept

b. Outline of DFPP

c. Clinical Trial

d. Post-marketing surveillance study

e. Modified DFPP therapy

(PEG) IFN Ribavirin

Double Filtration Plasmapheresis (DFPP) +


HCV levels during and after Plasma Exchange(PE) therapy

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

Plasma Exchange

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

Even if the virus could be removed from blood, the virus continue to replicate in the liver.


b. Outline of DFPP

c. Clinical Trial



(PEG) IFN Ribavirin



Double Filtration Plasmapheresis （ DFPP ）

　　　　 anti-coagulant

Cascadeflo2nd filter

Plasmaflo1st filter

Plasma pump

Cell components

Plasma

HCV

0.5 μm0.5 μm

　 1st filter 　 1st filter

2nd filter2nd filter

0.5 μm0.5 μm

Large poreLarge pore

Small porePore size 30 nm

Small porePore size 30 nm

Morphology of 1st and 2nd filter for DFPP

HCV (55-65 nm)

0

1000

2000

3000

4000

5000

HC

V R

NA

leve

l（K

IU/m

L ,A

mpl

icor

e ）

Changes of HCV RNA levels before and after 2nd filter (n=14)

before After

Purified plasma

Plasma

Discard

2nd

fil

ter

・ 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)

Administrating conditions of DFPP


b. Outline of DFPP

c. Clinical Trial



(PEG) IFN Ribavirin



Ribavirin 600-800mg(daily, po)

DFPP (3 〜 5 session ）

24 weeks 24 weeks

IFN α-2b 6MU （ Daily for 2 w then 3 t/w,im ）

24 weeks

1) Treatment schedule of IFN/Ribavirin + DFPP (2003.1- 2004.11)


DFPP (3 〜 5 session ）

24 weeks

PEG IFNα-2b 1.5μg/kg （ weekly 、 sc ）

48 weeks

2) Treatment schedule of PEG IFN/Ribavirin + DFPP (2004.12-)


DFPP (3 〜 5 times ）

24 weeks 24 weeks

IFN α-2b 6MU （ Daily for 2 w then 3 t/w,im ）

24 weeks

1) Treatment schedule of IFN/Ribavirin + DFPP (2003.1- 2004.11)


DFPP (3 〜 5 times ）

24 weeks

PEG IFNα-2b 1.5μg/kg （ weekly 、 sc ）

48 weeks

2) Treatment schedule of PEG IFN/Ribavirin + DFPP (2004.12-)

Patient’s backgroudPEG/Rib +DFPP PEG/Rib

Male:Female 22:10 44:28

Age 54.9±7.8 54.7±9.7

Body Weight(kg) 68.3±9.8 64.2±10.4

Grading 0/1/2/3 1/15/12/1 0/26/39/1

Staging 0/1/2/3/4 2/11/12/3/1 0/24/20/14/8

naive 8(25.0%) 41(56.9%)

relapse 13(40.6%) 10(13.9%)

non-response 11(34.4%) 9(12.5%)

unknown 0(0%) 12(16.7%)

100-1300 10 26

>1300 22(68.8%) 46(63.9%)

ALT(IU/L) 72.7±44.6 88.8±64.1

Platelet(104 /μL) 16.4±4 15.9±4.2

Prior IFN therapy

HCV RNA(KIU/mL)

Sex

P<0.001

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.

Histology

Administration numbers of DFPP

5 sessions of DFPP at maximum during the 1st week of treatment

n = 32 (PEG IFN/Rib +DFPP ）

1,2,3,4,5(2)

5 session in 2 wk (1)

1,2,3,5(2)

1,2,4,5(2)

1,2,5,6(1)

1,3,5,6(1)

1,2,4(13)

1,2,5(6)

1,3,5(3)

1,2,3(1)

treatment day

(case)

35

64

233

casesession

average ： 3.4 sessions

21 4 8

HCV RNA negative(-) (-) (-)

12 24

DFPP

1 2 4

day Week

57 yrs 、 M 、 A2F2 、H

CV

RN

A le

vel (

KIU

/ml ,

Am

plic

ore)

0

200

400

600

800

1000

1200

1400

1600

Ribavirin 800 mg(daily, po)

PEG IFNα-2b 100 μg/kg （ weekly 、 sc ）

Changes of HCV RNA levels 　

-3.00

-2.50

-2.00

-1.50

-1.00

-0.50

0.00

2週後 4週後Δlog2 week 4 week

PEG/RBV

PEG/RBV + DFPP

-1.82(n=9)

-1.50(n=8)

-2.69(n=10)

-1.85(n=11)M

ea

n lo

g 1

0 r

edu

ctio

nfr

om

ba

selin

e in

vir

al l

oad

Mean HCV viral load reduction

10.2%( 6/ 59)

39.4%(26/ 66)

72.6%( 45/ 62)

7.4 %( 2/ 27)

62.1%(18/ 29)

82.8%( 24/ 29)

0

10

20

30

40

50

60

70

80

90

100

4 12 24

Per

cent

of p

atie

nts（％）

PEG/RBV

On- treatment virologic response rate(all cases ）A virologic response was defined as an undetectable of HCV RNA in serum

Week

PEG/RBV + DFPP

P=0.047

Sustained virological response rate in PEG/RBV (+ DFPP)

81.8 %(9/ 11)

60.0 %(3/ 5)

0

20

40

60

80

100S

VR

rat

e (%

)

naive relapse non-response

71.4%(5/ 7)

PEG/RBV + DFPP

Prior IFN

PEG/RBV50.0 %(18/36)

50.0 %(9/15)

28.6 %(2/7)


Adverse Event

Emerging period

Symptoms Case Session

During DFPP

Bad feeling 1 2

Fever 2 2

Chill 2 2

Vomit 2 2

Nausea 4 4

Slight nausea 1 1

Shock 1 1

Incidence of adverse event 　　 9/32 cases (28.1%) 　

　　　　　　　　　 14/108 session (13.0%) 　　　

After extracting catheter

Bleeding 1 1

0

500

1000

1500

2000

2500

3000

day 1 day 2 day 3 day 4 day 5 day 6 week 2

Lym

phoc

yte（

/μL）

0

5

10

15

20


Hem

oglo

bin

（g/

dL）

0

1

2

3

4

5


Alb

min

（g/

dL）

0

5

10

15

20

25


Pla

tele

t （

×10

4 /μ

L)Changes of laboratory data

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.


b. Outline of DFPP

c. Clinical Trial



(PEG) IFN Ribavirin



北海道大学病院

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

名古屋医療センター名鉄病院岐阜市民病院

久留米大学病院福岡赤十字病院長田病院藤元早鈴病院

Participating HospitalsParticipating Hospitals 　　（（ 36 Hp36 Hp ））

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

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

PEG-IFN/RBV (n=73)Other IFN therapy (n=48)

naive (n=60)

Collected patients (n=239)

Efficacy evaluation (genotype 1, high viral load)

Safety Analysis (n=239)

PEG-IFN/RBV+DFPP (n=181)

Excluded patietns 　 (n=58)

Genotype 2 　 (n=7)

HCV RNA level < 5 Log IU/mL 　 (n=15)

lost follow-up 　 (n=11)

IFN β 　 inductuoin (n=25)

Prior IFN

　　 Patient disposition Patient disposition FlowchartFlowchart

Patients’ backgroundPatients’ background　　

Sex （ M/F ） 90/91Age 59 (24-75) †

Weight (kg) 59.0 (38.0-108.0) †

Live biopsy Activity (0/1/2/3) 2/30/36/7 Fibrosis (0/1/2/3/4) 3/20/35/13/4

HCV RNA level (LogIU/mL) 6.4 (5.0-7.7) †

AST (IU/L) 47 (12-225) †

ALT (IU/L) 47 (10-294) †

Platelet (×104/μL ） 14.1 (4.4-36.8) †

Fibrinogen (mg/dL) 234 (121-430) †

Treatment history 、 n (%) naive 60 (33.1) relapse 35 (19.3) non-response 62 (34.3) unknown 24 (13.2)

†Median (min-max)

PEG-IFN/RBV+DFPP (n=181)PEG-IFN/RBV+DFPP (n=181)

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.

4w 12w

DFPP

PEG-IFN/RBV+DFPP（ n=181）

Efficacy Efficacy evaluationevaluation

Ribavirin PEG IFNα

Treatment response at 4 and 12 Treatment response at 4 and 12 weeks weeks

PEG-IFN/RBV+DFPP PEG-IFN/RBV+DFPP （（ n=181n=181 ））

　　　： HCV RNA negative at 4 weeks


0

20

40

60

80

100

All patients

(%)

57.5% (104/181)

14.9% (27/181)

Per

cent

of p

atie

nts（％

）

39.4% (26/66)

10.2% (6/59)

PEG-IFN/RBV (non DFPP) PEG-IFN/RBV (non DFPP) （（ n=66n=66 ））Hepatology Research 2007 ; 37 701-710 　

Treatment response at 4 and 12 Treatment response at 4 and 12 weeks by treatment historyweeks by treatment history

PEG-IFN/RBV+DFPP PEG-IFN/RBV+DFPP （（ n=181n=181 ））



0

20

40

60

80

100

All patients

(%)

57.5% (104/181)

14.9% (27/181)

Per

cent

of p

atie

nts（％

）

naive relapse non-response

41.9% (26/62)

12.9% (8/62)

57.1% (20/35)

70.0% (42/60)

20.0% (12/60)

8.6% (3/35)

Treatment history

Prior　therapy

PEG　IFN/RBV　　　　　73　cases

Other　IFN　　　　　33　cases　

0

20

40

60

80

100

(%)

relapse non-response

18.9% (7/37)

5.4% (2/37)

63.0% (17/27)

7.4% (2/27)

41.1% (30/73)

8.2% (6/73)

Treatment response at 4 and 12 Treatment response at 4 and 12 weeks weeks

(prior IFN therapy : PEG IFN /RBV)(prior IFN therapy : PEG IFN /RBV)



Per

cent

of p

atie

nts（％

）

All patients

0

50

100

150

200

250

300

350

DFPP1 session

Changes of fibrinogen Changes of fibrinogen levels.levels.Changes of fibrinogen Changes of fibrinogen levels.levels.

235±52

149±37（ -36.2% ）

155±51（ -32.8% ）

182±58（ -21.1% ）

142±41（ -38.5% ）

（ 177 ）（ 157 ）（ 176 ）（ 170 ）（ 146 ）

DFPP2 session

DFPP3 session

DFPP4 session

DFPP5 session

Fib

rinog

en

level

　（

mg/d

L）

*** ******

***

*** ： P<0.001 （ vs.1 session ）

： P<0.001 （ vs.1 session ）

0

5

10

15

20

（ 45 ）（ 38 ）（ 43 ）（ 44 ）（ 40 ）

13.8±4.5

10.8±3.7 9.5±3.19.5±3.7 9.5±3.8

****** *** ***

***Pla

tele

t co

un

t　

（×

10

4/μ

L）

(-23.3% ）

(-28.9% ） (-30.

9% ）(-30.0% ）

Changes of Platelet Changes of Platelet countcount

DFPP1 session

DFPP2 session

DFPP3 session

DFPP4 session

DFPP5 session


b. Outline of DFPP

c. Clinical Trial



(PEG) IFN Ribavirin



IFNβ 3MU twice a day

PEG IFN RBV

Viral kinetics of IFNβ 3MU twice a day &PEG IFN/RBV

Asahina et al Hepatology 2007;34:377-384

　　　　　　

　　　　

HC

V R

NA

leve

l (L

og I

U/m

l)　　

Hepatogastroenterology 2006;53:94-9. Ebinuma H et al

DigDis Sci 2001:46:516-23 Izumi et al.

J Hepatol 2003 ;39:421-7 Asahina Y et al

IFNβ(3M) Twice a day

M

1st week 2nd week

E

3rd week 4th ・・・

DFPP 　

Modified DFPP therapy 　

Ribavirin

PEG IFN

・・・・

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)14.9±5.1 (9.0 ～

30.7)

HCV RNA level (logCopy/ml) 6.8±0.5 (5.7 ～ 7.3)

Prior IFN (naive ：ＩＦＮ mono)

1 : 10

0

2

4

6

8

HC

V R

NA

level (L

og

IU

/ml)

HC

V R

NA

level (L

og

IU

/ml)

(week)(week)

Changes of HCV RNA levelsChanges of HCV RNA levels

Ribavirin

PEG IFNIFNβ(3M) 　Twice a dayIFNβ(3M) 　Twice a day

0 4 8 12 16

BDFPP 　

Discontinued by ribavirin side effectDiscontinued by ribavirin side effect

1.2

2420

HCV RNA levelBefore IFN

Weeks of HCV RNA negative ISDR Core 70 IL28B Result

6.9 8 1 W SVR 7.2 8 0 W SVR 6.2 12 0 W Major Homo SVR 5.1 12 1 M Minor Homo SVR 7.3 12 1 W Discontinued

7 12 0 W ongoing

6.8 16 0 M SVR 5.9 24 0 W Major Homo SVR 6.6 24 0 M Major Homo ongoing

7.6 Non response 1 M Minor Hetero ongoing

6.7 Discontinued

HCV mutation No

1

2

3

4

5

6

7

8

9

10

11

Mutations & ResultMutations & Result

(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)

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

Conclusion 　

Thank you for your attention!

Chronic Hepatitis C

1) Standard IFN treatment in Japan

2) DFPP / IFN combination therapy

Novel therapeutic strategy for Hepatitis C treatment 2011.3.25 Tatsuya Ide, M.D. Ph.D. Division of...

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