Document6

LIVER TRANSPLANTATION FOR HCV DISEASE

John R. Lake, M.DMinneapolis, USA


OUTLINE

• The problem• Predictors of outcome• Impact of acute cellular rejection• Impact of immunosuppression• Impact of anti-viral treatment• Conclusions

C oh en J . S c ie n c e 1 9 9 9 ;2 8 5 :2 6 .

HEPATITIS C VIRUS INFECTION Worldwide prevalence

Decline among transfusion recipients

Decline among injection-drug users

Year

5

10

15

20

082 84 85 86 87 88 89 90 91 92 9383 94 95 96

Cas

es p

er 1

00 0

00Estimated incidence of HCV in the

USA, 1982-1996

HIV Prevention Measures

Centers for Disease Control and Prevention. Unpublished data.

Transplant Indication %

Cirrhosis 68.2 Hepatitis C 22.9 Alcoholic liver disease 15.8 Cryptogenic 11.4 Autoimmune 4.9 Hepatitis B 4.0 ALD + hepatitis C 7.4

Cholestatic liver disease 16.6 Primary biliary cirrhosis 7.9 Primary sclerosing cholangitis 8.0n = 12 908

Indications for adult liver transplantation, 1994-1998

Seaberg EC et al, 1999. Clinical Transplants 1998. Chapter 2.

Unknown causes : 1851 8%

Secondary Biliary : 271 1%

Primary Biliary : 295213% Others : 357

2%

Alcoholic : 693730%

Autoimmune : 9914%

Virus related : 956542%

Liver Transplantation in Europe: Indications Cirrhosis 01/1988 - 12/2001

Virus B : 241025%

Other virus : 841%

Virus BCD : 791%Virus BC : 380

4%

Virus BD : 6407%

Virus C : 597262%

Primary Indications of Liver Transplantationfor Virus related Cirrhosis in Europe

01/1988 - 12/2001

PREDICTORS OF OUTCOME OF TRANSPLANTATION FOR HEPATITIS C

2 (13%)13 (87%)15Berlin

9 (13%)60 (87%)69Paris

3 (3%)131 (97%)134LTD

2 (5%)39 (95%)41UCSF

ClearedRe-infectionnCenter

LIVER TRANSPLANTATION FOR HEPATITIS C

Re-infection

HCV POST TRANSPLANT:DIFFERENT PATTERNS OF RECURRENCE

• Minimal liver injury • Chronic HCV • Cholestatic HCV

CHOLESTATIC HCV

CHOLESTATIC HCV

• D ef in it ion– In cr ea s ed S A P ,G G T w it h

b ili.>1 0 0 u m /l

– >1 m on t h du r a t ion

– ba lloon in g /ch oles t a s is on b iop s y

– v ir a l loa d >1 x1 0 6

– occu r r in g >1 m on t h p os t t r a n s p la n t

Non-CholestaticNon-CholestaticPatientsPatients

2727 8989 180180 299299 502502 572572 10691069 15241524

PrePre 99 3232 5454 7272 152152 194194 243243 282282

2626 7070 9898 168168 308308 426426

Days post-transplantDays post-transplant



PrePre 6161 6868 7575 148148 162162 232232 442442 456456 519519

PrePre 88 1313 2121 2727 3030 7272 203203 632632



PrePre 88 2323 3737 6565 7575 8383 9595 122122


CholestaticCholestaticPatientsPatients

Lack of HCV T cell response in severe HCV (Cholestatic) recurrence

Immune-mediatedImmune-mediated tissue damagetissue damage

Escape from Escape from immune immune systemsystem

Very high viral loadsVery high viral loadsDirect tissue damageDirect tissue damageCholestatic hepatitisCholestatic hepatitis

No viral mutationNo viral mutation

Cell mediatedCell mediatedimmunityimmunity

Control of viral loadControl of viral load(no clearance)(no clearance)

Immune pressure on HCVImmune pressure on HCVviral mutationviral mutation

TH1 response

HCV persistenceHCV persistence HCV persistenceHCV persistence

No immune response

NON-CHOLESTATICNON-CHOLESTATIC CHOLESTATICCHOLESTATIC

HISTOLOGIC SEVERITY OF POST-OLT HEPATITIS C

612255747LTD (2 year)

1020234742Mayo

22474045Washington

1283554130London

381431860Paris

Norml(%)

Cirrhosis (%)

CAH (%)

CPH (%)

nCenter

PATIENT SURVIVAL BY DISEASE

0

20

40

60

80

100

0 1 2 3 4 5

cholnon B-CHCVmetabALDmaligHBV

Time post-OLT (years)

Cum

ulat

ive

surv

ival

(%)

LIVER TRANSPLANTATION FOR HEPATITIS CIs the Disease Becoming More Aggressive

• Is HCV re-infection leading to more aggressive liver disease?

• Is HCV re-infection having a greater impact on long term patient and graft survival?

• What factors might be responsible for this?

HCV IN ORGAN TRANSPLANT RECIPIENTSRates of Fibrogenesis

• Berenguer, et al analyzed the change in fibrosis score (fibrosis progression/year) post-transplantation as an indicator of disease progression

• There was a linear association between change in fibrosis score and time from transplantation, with a median rate of fibrosis progression per year of 0.3 (0.004-2.19/year)

• Variables independently associated with post-transplantation progression included year of transplantation (p=0.0001), race (p=0.02), number of methyl-prednisolone boluses(p=0.03), and HCV RNA levels at transplantation (p=0.01)

Pre-OLT characteristics associated with increased mortality and graft loss in HCV-

infected recipients

Characteristic Patient survival Graft survival

RR 95% CI p RR 95% CI p

HCV RNA ≥ 1x106 vEq/ml

4.3 2.1-8.5 0.0001 3.6 2.0-6.6 0.0001

Non-Caucasian recipient

4.1 1.0-4.3 0.04 2.8 1.5-5.1 0.001

Recipient age (per year)

1.05 1.02-1.09 0.004 1.05 1.02-1.08 0.004

Recip pre-LT ugh score > 10

2.0 1.0-4.0 0.04

FACTORS ASSOCIATED WITH INCREASED RATE OF FIBROSIS IN HCV RECIPIENTS

• D on or a ge > 5 0 y ea r s

• B olu s S t er oids - r eject ion

• OK T 3 u s e

• In du ct ion w it h m y cop h en olic a cid

• S h or t du r a t ion p r edn is on e

• P a s t in t er f er on f a ilu r e

p value

0.0090.040.0020.002

0.00010.001

Berenguer, et al. Hepatology 2001;34:407A.

PATIENT SURVIVAL BY PRE-LT HCV RNA LEVEL

0102030405060708090

100

0 1 2 3 4 5Time post OLT (years)

Cum

ulat

ive

surv

ival

(%

)

RNA < 0.2 RNA 0.2-0.49RNA 0.5-0.99 RNA >1

IMPACT OF ACUTE CELLULAR REJECTION ON OUTCOME

INCIDENCE OF ACUTE HEPATIC ALLOGRAFT REJECTION

0

1020

3040

50

6070

80

HCV Non HCV

Inci

denc

e of

AR

(%

)

TotalEarly

IMPACT OF ACUTE REJECTION ON PATIENT SURVIVAL

Relative risk of death

Mortality

Non HCV (steroids)

0.5 p < 0.007

HCV (steroids) 2.9 p < 0.03

HCV (OKT3) 5.4 p < 0.003

Rejection and HCV Recurrence in TAC-Treated Patients

0

20

40

60

80

100

OverallRecurrence

No RejectionEpisodes

1 RejectionEpisode

>1 RejectionEpisodes

HCV Recurrence No HCV Recurrence

Singh N, et al. Surgery. 1996;119:452-456.

%

OKT3 Administration as a Predictor of HCV Recurrence

0102030405060708090

100

OKT3 No OKT3*

No HCV Recurrence

HCV Recurrence

%

*No episodes of steroid-resistant rejection or no episodes prior to diagnosis of recurrenceSheiner PA, et al. Hepatology. 1995;21:30-34.

P < 0.01


• Donor age > 50 years

• Bolus Steroids - rejection

• OKT3

• Induction with mycophenolic acid

• Short duration prednisone

• Past interferon failure

p value

0.0090.040.0020.002

0.00010.001


Gane EJ. Gastroenterology 1996; 110:167.

CORTICOSTEROID TREATMENT

• Steroid bolus therapy is associated with an 4 to100-fold increase of HCV RNA

• Steroid bolus therapy is associated an increased frequency of acute hepatitis and earlier time to recurrence

• Higher HCV RNA levels are associated with increased histological severity of graft injury/hepatitis

IMPACT OF IMMUNOSUPPRESSIVE AGENTS

IMMUNOSUPPRESSIVE AGENTS MOST COMMONLY USED

Maintenance Therapy 2001• Calcineurin inhibitor

– Tacrolimus (83%)– Cyclosporine (12%)

• Corticosteroids (89%)

• Adjunct agents

– Azathioprine (3.1%)– Mycophenylate mofetil (48%)– Sirolimus (10%)

IMPACT OF SPECIFIC IMMUNOSUPPRESSIVE AGENTS

• Tacrolimus• Cyclosporine• Corticosteroids• Mycophenylate mofetil

US Multicenter Study 5-Year Patient Survival by Baseline HCV Status

HCV Positive

30405060708090

100

0 6 12 18 24 30 36 42 48 54Months

TAC CyA

n = 57

P = 0.041

n = 56

0

Wiesner RH. Transplantation. 1998;66:493-499.

%

US Multicenter Study 5-Year Patient Survival by Baseline HCV Status

HCV Negative

30405060708090

100

0 6 12 18 24 30 36 42 48 54Months

TAC CyA

n = 206

n = 210

P = 0.8620

Wiesner RH. Transplantation. 1998;66:493-499.

%



OPTIMAL IMMUNOSUPPRESSION

• Timing?

• Withdrawal (when), minimization, avoidance

• Assess benefits for the individual patient

• One “size” does not fit all

Steroid Withdrawal

HCV: STEROID AVOIDANCE

Thymo+TCR+MMF TCR+MMF+CS (n=60) (n=59) p

2-yr Surv 82% 83% NS

Rejection 23% 31% NS

Hep C 62%(29) 73%(33)NS

Stage 3-4 10% 21% NS

Eason et al Liver Transplantation 7:693, 2001




• OKT3




p value

0.0090.040.0020.002

0.00010.001




• Only two large controlled randomized trials in HCV positive patients

• No effect on the incidence of rejection, survival and severity of HCV recurrence

Wiesner et al. Liver Transplant 7:442, 2001.Jain et al. Liver Transplant 8: 40, 2002.

MMF AND HEPATITIS C: SALVE ON A WOUND OR GASOLINE ON FIRE ?

(Charlton 2002)

MMF AND HCV RECURRENCE

Rej or Graft loss 30.6 41.4 0.04Graft Loss 9.4 16.1 NSHepatitis C (6 mo) 18.5 29.1 NSRejction 30.6 41.4 NS

MMF AZA (n=108) (n=110) p-value




• OKT3




p value

0.0090.040.0020.002

0.00010.001


Histological course

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

prior MMF after MMF (24 months)

Stag

e

In fla m m a tio n

F ib ro s is

EFFECTIVENESS OF MMF IN THE LONG-TERM IN HCV POSITIVE PATIENTS AFTER OLT

Berlin, 40 patients, follow-up 24 months

HCV-RNA blood levels:No changes in viral load measured

by PCR during MMF treatment

Treatment of side effects:Reduction of nephrotoxic side

effects (n=3) with normalization of creatinine/ BUN

Switch from FK506 to MMF due to neurotoxic side-effects with improved symptoms (n=1)

MMF OUTCOMES

No MMF Low-dose MMF High-Dose MMFACR RS ACR RS

(96) (%) (8) (3) (13) (5) P

Grade

None (0) (22) (0) (33) (0) (40)

Inter (1-2) (54) (50) (33) (92) (60) .07

Sever(3-4) (22) (50) (33) (8) (0)

Stage

No fib(0) (43) (0) (33) (23) (80)

Inter (1-2) (33) (63) (67) (77) (20) .01

Sever(3-4) (24) (37) (0) (0) (0)


• Everolimus

• FTY

• FK 778

• New antibodies

• Tolerance induction

Agents on the Horizon

IMMUNOSUPPRESSION FOR HCV-INFECTED RECIPIENTS

Revised paradigms

• Recurrent hepatitis C is an increasing problem post-transplant

• It is difficult to determine if allo-immunity is also playing a role in post-tx hepatitis C

• Change in the degree of immunosuppression is “bad” for HCV-infected recipients

• Cortico-steroid “boluses” are “bad” for HCV-infected recipients

OPTIMAL IMMUNOSUPPRESSION HEPATITIS C

• Don’t make major changes!

• Steroids: either avoid or do not taper

• MMF: use or don’t use

• Avoid antibody induction

• Avoid treating rejection with steroid boluses; avoid antibody therapy

ANTI-VIRAL THERAPY OF POST-TRANSPLANT HEPATITIS C

TREATMENT STATEGIES

• Observation • Preemptive Treatment• Treatment of Recurrence

– Acute– Chronic

INTERFERON FOR ESTABLISHED DISEASE

28

0

12

0

36

0

13

0

20

2.5

0

10

20

30

40

50

Wright n=18 Feray n=16 Gane n=28 Cotler n=12 Shakil n=40

ETR

SVR

PREEMPTIVE INTERFERON

020406080

100120140160180

HCV RNA Recurrence Survival Rejection

SheinerControlSinghControl

POST-TRANSPLANT HEPATITIS CInterferon and ribavirin

0

10

20

30

40

50

60

Bizzilionn=20

Bellatin=122

Zambonin=45

Ahmadn=20

Davisn=54

Albertin=18

Samueln=28

ETRSVR

40-kDa branched PEG-IFN: Sustained therapeutic serum concentrations over a one-week period

0 25 50 75 100 125 150

0.20.40.60.8

11.21.41.61.8

5-kDa linear PEG-IFN α-2a once weekly

Time (hours over one week)25 50 75 100 125 150

510152025

40-kDa branched PEG-IFN α-2a once weekly

PE

G-IF

N (n

g/m

l)

25 50 75 100 125 150

2

68

1214

Interferon 3 MIU TIW

Time (hours over one week)

IFN

(U/m

L)

M T T F S SW

10

4Nieforth et al, Clin Pharmacol Ther 1996; 59:636-46. Xu J et al, Hepatology 1998;

Time (hours over one week)

M T T F S SWM T T F S SW

0

000

0

10

20

30

40

50

60

Week 4 Week 12 Week 24

Res

pons

e (%

) HCV RNA 2-log drop onlyHCV RNA Negative

37%41%

50%

16%

41%

31%

PEG-IFN α-2aRecurrent HCV post-OLT

Riely C et al, Am J Transplant 2001; 1 (Suppl 1):158 (A89).

PEG-IFN α-2aRecurrent HCV post-OLT

525Headache1415Abd pain530Pyrexia

1420Diarrhea2430Nausea1445Fatigue

UntreatedPEG-IFN α-2aAdverse event

Riely C et al, Am J Transplant 2001; 1 (Suppl 1):158 (A89).

Patie

nts

(%)

01020304050607080

Genotype 1 Genotype 2, 3

n = 285n = 298

37%

21%

46%

n = 145

n = 145n = 140

61%45%

76%

n = 69

SUSTAINED VIROLOGIC RESPONSE & GENOTYPE

PEG-IFN α-2a + ribavirinPEG-IFN α-2a + placeboIFN α-2b + RBV

PEG-IFN α-2a + RBV

p = 0.001

p = 0.054 p = 0.008p = 0.001

p = 0.001 p = 0.016

Fried MW et al, NEJM, 2002

POST-TRANSPLANT HEPATITIS CPegylated interferon and ribavirin

0102030405060708090

100

Chicagon=10

MayoScottn=23

Miamin=33

Omahan=31

HCV RNA (-)

HCV IN ORGAN TRANSPLANT RECIPIENTS

HCV Treatment

• Using standard dose interferon, sustained response rates are poor, significant risk of rejection in non-liver recipients

• Pre-emptive treatment is difficult but may yield the best chance to impact post-transplant liver disease

• Newer regimens, i.e. with pegylated interferons and/or ribavirin will likely lead to better results

TREATMENT OF RECURRENT HCV POST-OLT

• Sustained virologic and histologic data with pegylated IFN are forthcoming

• Studies of PEG-IFN + ribavirin represent the future

• True anti-viral agents are sorely needed

CHRONIC HEPATITIS C Advances in therapy

N o t r ea t m en tIF N ( 6 m on t h s )

IF N ( 1 2 m on t h s )

IF N + r iba v ir in( 1 2 m on t h s )

P egin t er f er on( 1 2 m on t h s )

P egin t er f er on +r iba v ir in

?

?

?

1 9 9 1 1 9 9 8 2 0 0 0

1 0 0

5 0

?

Su

stai

ned

vir

olo

gic

resp

on

se r

ate

(%)

Health & Medicine

Document6