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LIVER TRANSPLANTATION FOR HBV

Monoprophylaxis

Perrillo et al Hepatology 2001


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Markov model for cost-effectiveness analysis

LIVER TRANSPLANTATION FOR HBVCost-effective Prophylaxis


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Dan et al Liver Transplantation 2005


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Dan et al Liver Transplantation 2005US$ 6,000/yr

US$50,000/QALY


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HBsAg Carrier Rate


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>$15,000

Hong Kong Kuwait Taiwan

Israel Singapore UAE

Japan S. Korea

$10,001 to 15,000

Macau Saudi Arabia

Oman

$3,001 to 10,000

Indonesia Malaysia Thailand

Iran Sri Lanka

$1,000 to 3,000

Bangladesh Iraq Pakistan

Burma Laos Philippines

China Mongolia Vietnam

India Nepal


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Hepatocellular carcinoma, 90 (19%)

LIVER TRANSPLANTATION IN HONG KONG

Disease Indication: Overall

HBV

61%HCV5%

FHF

8%

polycystic disease

1%

others

10%

biliary atresia

8%

PBC

2%

Wilson

2%

retransplant

3%


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On list

NoYes

Lamivudine prophylaxis

OLT


Nucleoside/Nucleotide Analogue-Based Prophylaxis

Add-on adefovir prophylaxis

OLT

Monitor for mutant*

Monitor for mutant* NoYes

LamivudineAdd-on adefovir

Monitor for mutant*

* 3-monthly HBVDNA by Amplicor qPCR

and sequencing for mutants

On lamivudine Not on lamivudine


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HBsAg+

324

Pre-OLTno YMDD mutant

290

Pre-OLTYMDD mutant

33 (10.2%)

Lamivudine

291

Not recognised

1


Prophylaxis (1995 to 2006)

Add-on adefovir

33


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PRE-TRANSPLANT YMDD MUTANT

Add-on Adefovir Prophylaxis

0

10

20

30

40

50

60

70

80

90

100

0 6 12 18 24 30 36 42 48 54 60

Time months

Probilityo

fsurvival(%

pre-OLT mutant (n=33) no mutant (n=290)

84%

92%

88%

92%

93%

93%


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Lamivudine prophylaxis

290

no YMDD mutant258YMDD mutant32 (11.1%)

Retransplantation

2 (


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LIVER TRANSPLANATION FOR HBV

Lamivudine Prophylaxis

0

10

20

30

40

50

60

7080

90

100

0 6 12 18 24 30 36 42 48 54 60

Time (months)

Probi

lityofsurvival(%

with mutant (n=32) without mutant (n=258)

78%

84%

87%

91%

91%

100%


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YMDD Mutant Rate

4%10%10%

14%12%

0 6 12 18 24 30 36 42 48 54 60

Time (months)

0

40

80

100

ProbabilityofYMDDmutant(%)

20

60

Lo et al Am J Transplantation 2005


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No. at risk

Genotype B 43 39 37 31 23 20 17 14Genotype C 74 66 56 43 35 27 20 15

0 6 12 18 24 30 36 42

Time (months)

0

0.1

0.2

0.3

Probabilityoflam

ivudineresistance


Genotype and Lamivudine Resistance

Genotype B

Genotype C

4%

21%

P=0.017



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0.36016%

14%

14%

4%

9%

4%

HBV DNA (at OLT) Negative

Positive

0.33312%18%

8%14%

6%9%

HBV DNA (on listing) NegativePositive

0.74514%18%

11%12%

8%8%

HBeAg (at OLT) NegativePositive

0.94614%17%

11%12%

9%6%

HBeAg (on listing) NegativePositive

0.55211%18%

11%13%

6%9%

Core promoter variant NegativePositive

0.23120%11%17%11%10%6%Precore variant NegativePositive

0.0174%21%

0%18%

0%12%

HBV genotype BC

3-year2-year1-year

p valueRecurrence rate


Viral Factors and Lamivudine Resistance



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Sanchez-Fueyo Angelico Bienzle

(Barcelona) (Rome) (Berlin)

Number 22 17 20

Pre-OLT HBVDNA+ve 0 0 0OLT to vaccination (mth) 33 (18-76) 48 (25-85) 78 (24-156)

HBIG before vaccination Yes Yes Yes

HBIG during vaccination No No Yes

Seroconversion

>10 IU/L (%) 63.6 17.6 /

>100 IU/L (%) 23.5 11.8 /

>500 IU/L (%) 9.1 5.9 80

Max anti-HBs titer (IU/L) 47 (10-1,000) 258 (10-601) 25,344 (1255-83121)

Follow up after vaccination (mth) 41 (31-85) 66 (25-88) 13.5 (6-22)


Active Immunization- to Replace HBIG


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Active Immunization- In Addition to Lamivudine

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

time (months)

1

10

100

1000

anti-HBstiter(mIU

/mL)

Engerix

40ug IMI

Engerix

40ug IMI

52 patients on lamivudine prophylaxis 412 (370-2040) days post-OLT

Response rate 7.7%

Lo et al J Hepatology 2005


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Active Immunization- Pre-S containing VaccineSci-B-Vac

40ug IMI

Sci-B-Vac

40ug IMI

20 patients on lamivudine prophylaxis 570 (379-2160) days post-OLT

Response rate 50%

Lo et al Am J Transplantation (in press)

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

time (months)

1

10

100

1000

anti

-HBstiter(mIU/m

L)


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7

3

6

4

Interval since transplantation 1 3 years

> 3 years

67Living donor graft

67Donor anti-HBs+

10

0

8

2

Disease indication cirrhosis

cirrhosis with acute flare

5

2

1

2

HBVDNA positive on listing

at transplantation

1#7Age < 50 years54(35-60)*47.5 (36-57)Age in years, median (range)

78Male gender

Non-responder

(n=10)

Responder

(n=10)

*P = 0.05

#P = 0.02


Active Immunization- Pre-S containing Vaccine

Lo et al Am J Transplantation (in press)


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Karasu et al J Viral Hepatitis 2005

Patients (n=14)

pre-transplant HBV non-replicative

on lamivudine+HBIG without recurrence

14 months (12 to 50 months) after liver transplantVaccination protocol

pre-S containing vaccine (Genhavac B Pasteur)

double course of double dose (40ug) IM injection

1 month after HBIG discontinuationResults

only 1 patient responded (7%)

anti-HBs titer of 37 IU/L


Active Immunization- Pre-S containing Vaccine


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Time to develop: 8 (1-43) days

Time to disappear: 207 (24-414) days

1 7 14 30 60 90 120 150 180 210 240 270 300 330 360

post-transplant (days)

1

10

100

1000

10000

100000

anti-HBstiter(mIU/mL)

Peak titer no. median (range)

1,000 6 8,081 (1,000-121,000)

Lo et al Hepatology 2003

21 of 50 patients developed anti-HBs after liver transplantation


Adoptive Immunity Transfer


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Odd ratio 95% CI P-value

HBV immune donor 18.9 3.2-112.4 0.001

Lo et al Hepatology 2003


Adoptive Immunity Transfer


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Anti-HBs secreting B cell

2.7/10E6 lymphocytes

HBsAg specific IFN-secreting T cell


DONOR-DERIVED HBV IMMUNITY

HBV-specific Lymphocytes in Liver Graft

ELISPOT assay

HBcAg specific IFN-secreting T cell


Luo et al Liver Transplantation 2006


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HBsAg-specific T cells

0

2

4

6

8

10

12

Group 1 Group 2 Group3 Group 4

SFC/106i

ntrahepaticlymphocytes

HBcAg-specific T cells

0

2

4

6

8

10

Group 1 Group 2 Group 3 Group 4

SFC/106i

ntrahepaticlymphocytes

Anti-HBs-secreting B cells

0

1

2

3

4

5

6

Group 1 Group 2 Group 3 Group 4

SFC/10

6intrahepaticlymphocytes

DONOR-DERIVED HBV IMMUNITYIntragraft HBV-specific Lymphocytes


anti-HBs anti-HBc

Group 1 (22) + +Group 2 (10) + -

Group 3 (2) - +

Group 4 (7) - -


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DONOR-DERIVED HBV IMMUNITYAnti-HBs Seroconversion and Intragraft HBV-specific Lymphocytes


HBsAg-specific T cells

with anti-HBs production without anti-HBs production

0

2

4

6

8

10

12

SFC/10

6intrahepaticlympho

cytes

HBcAg-specific T cells


0

2

4

6

8

10

SFC/106intrahepaticlymphocytes

Anti-HBs-secreting B cells


0

1

2

3

4

5

6

SFC/106intrahepaticlymp

hocytes

P< 0.001

P= 0.082

P= 0.088


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T-cell Proliferation Response to Mitogen and Recall AntigenSerial monitoring in 54 patients on lamivudine prophylaxis

Day 0 Day 7 Day 14 Day 21 Day 28 Day 90 Day 180 Day 3600

20

40

60

80

100

120

140

*

Time after Liver Transplantation

StimulationIn

dex(median+interquartilerange)

a


2

4

6

8

10

12

14


StimulationIn

dex(median+interquartilerange)

b

PHA Tetanus Toxoid


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HBV-specific T cell ResponseSerial monitoring in 54 patients on lamivudine prophylaxis


2

4

6

8

10

12

14

16


NumberofIFN

-secretingTcells/2

105P

BMC

(mean+SD)


10

100

1000

10000

Time after transplantation

Seru

ma

nti-HBstiter(mIU/ml)


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HBV-specific T cell Response

Serial monitoring in 54 patients on lamivudine prophylaxisHBcAg-specific IFN- Response


2

4

6

8

10

12

14

16

18

20

22

24

26

28without anti-HBs response

with anti-HBs response

*

** *

**

* *

Time after transplantation

NumberofIFN-secretingTcells/21

05P

BMC

(median+interquartilerange)

*P < 0.05 by Mann-Whitney U test

Serial monitoring in 54 patients on lamivudine prophylaxis


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Lamivudine prophylaxis with adefovir rescue is highlyeffective in preventing recurrent hepatitis B withexcellent graft survival and is most cost-effective

There is adoptive transfer of both humoral and cellularimmunity through liver transplantation which mayrepresent the interplay between donors and recipientsimmunocompetent cells

Restoration of host immunity to hepatitis B mayprovide the ultimate solution for long term recurrence-free and medication-free survival


Conclusions


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Adefovir Prophylaxis

Lo et al Liver Transplantation 2005

0

50

100

150

200

250

pre-lamivudine pre-adefovir pre-transplant last follow-up

Cenncean(mLmin


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YMDD Mutant Rate

4%10%10%

14%12%

0 6 12 18 24 30 36 42 48 54 60

Time (months)

0

40

80

100

ProbabilityofYMDDmutant

(%)

20

60



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0 1 2 3 4 5-1

Time (weeks)

1

10

100

1000

10000

ant

i-HBstiter(mIU/mL)

0

5

10

15

20

25anti-HBssecretingBcell(/1

0E6PBMC)

booster vaccine

anti-HBs

anti-HBs

anti-HBs secreting B cell

anti-HBs secreting B cell

Donor

Recipient

DONOR-DERIVED HBV IMMUNITY

Booster Pre-S Containing Vaccine in Living donor


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Immunotherapy

Passive immunoprophylaxis (HBIg)

Interferon

Active immunisation

Adoptive immunity transfer

Nucleoside analogue

Lamivudine

adefovir

famciclovir

ganciclovir

entecavir

lobucavir

emtricitabine


Prophylaxis


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HBIg prophylaxis (Terrault et al, Hepatology 1996)

high cost, parenteral administration, toxicity, s-mutant Lamivudine prophylaxis (Grellier et al, Lancet 1996)

drug resistance due to viral mutant

Lamivudine + HBIg (Markowitz et al, Hepatology 1998)

effective

disadvantages of HBIg


Prophylaxis


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Intravenous HBIG

Target anti-HBs:

>100 IU/L (non-replicative)

>500 IU/L (replicative)

Recurrence rate:

0 to 15% (non-replicative)

16-35% (replicative)

Disadvanges: Recurrence due to escape mutants

High cost

Parenteral administration

Toxicity


Passive Immunoprophylaxis


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Improving HBV ProphylaxisHow: Additional prophylaxis

Other anti-viral agents

Adefovir Entecavir

Restoration of host immunity

Active immunisation

Adoptive immunity transferWhen: Selective Pre-OLT escape mutants Other high-risk patients


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Samuel et al, New Engl J Med 1993

0 12 24 36 48 60

Months

0

20

40

60

80

100

R

iskofrecurrence(%)

HBV DNA+ve

HBeAg+ve HBV DNA-ve

HBeAg -ve HBV DNA-ve


Recurrence


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CYC, M/37


Retransplantation for Fibrosing Cholestatic Hepatitis

Aug1997

Sep1997

Oct1997

Nov1997

Dec1997

Jan1998

Feb1998

Mar1998

Apr1998

May1998

Jun1998

Jul1998

Aug1998

Sep1998

Oct1998

Nov1998

Dec1998

Jan1999

Feb1999

Mar1999

Apr1999

May1999

Jun1999

Jul1999

Aug1999

Sep1999

Oct1999

Nov1999

Dec1999

Jan2000

0

200

400

600

800

1000

1200

ALT/totalbilirubin

1.00E+01

1.00E+02

1.00E+03

1.00E+04

1.00E+05

1.00E+06

1.00E+07

1.00E+08

1.00E+09

1.00E+10

1.00E+11

HBVDNA(copies/mL

)

ALT (IU/L)

total bilirubin (umol/L)

HBV DNA


YIDD


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No. of patients 16

M:F 15:1

Age (yr) 48 (31-66)Lamivudine pre-OLT (days) 738 (400-1799)

HBeAg+ 11

HBVDNA >10,000 copies/ml 14

Mutant

rt M204I 13

rt M204V 2

rt M204I and rt M204V 1


Adefovir Prophylaxis



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No. of patients 265

M:F 225:40Age (yr) 47 9 (17-68)

HBeAg+ 83

HBVDNA (bDNA)+ 77

Lamivudine pre-OLT (days) 137 373 (0-4000)Liver graft

cadaver 87

living 178


Primary Lamivudine Prophylaxis

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