8

ANTIVIRAL THERAPY PERI-LIVER TRANSPLANTATION

I A S G - ROMANIAN CHAPTER

BUCHAREST 11th April 2003

Liana GheorgheCenter of Gastroenterology & Hepatology

Fundeni Clinical InstituteBucharest, Romania

LIVER DISEASE IN ADULT TRANSPLANT RECIPIENTS

UNOS database 1987-1998; n=24,900 pts

adapted from Seaberg EC et al, Clinical Transplants 1998

Primary liver disease Number Percentage

Chronic hepatitis C 5,155 20.7 40Alcoholic liver disease 4,258 17.1ALD + HCV 1,106 4.4Chronic hepatitis B 1,368 5.5 10Cryptogenic cirrhosis 2,719 10.9Primary biliary cirrhosis 2,317 9.3Primary sclerosing cholangitis 2,178 8.7Autoimmune hepatitis 1,194 4.8Acute liver failure 1,555 6.2Malignancy 951 3.8Metabolic 923 3.7Other 1,050 4.2Unknown 126 0.5

SURVIVAL AFTER ADULT LTx BY DIAGNOSIS

Diagnosis 1 yr 4 yr 7 yrPrimary sclerosing cholangitis 91 84 78

Primary biliary cirrhosis 89 84 79

Autoimmune hepatitis 86 81 78

Chronic hepatitis C 86 75 67

Alcoholic liver disease 85 76 63

Cryptogenic cirrhosis 84 76 67

Chronic hepatitis B 83 71 63

Malignancy 72 43 34

UNOS database 1987-1998; n=24,900 pts

adapted from Seaberg EC et al, Clinical transplants 1998

THERAPEUTIC STRATEGIES IN PATIENTS WITH HBV, HDV, HCV INFECTION

UNDERGOING LTx Prevention of recurrent infection of the graft by

administration of antiviral agents prior (e.g. nucleoside analogues for HBV), at the time (e.g. hepatitis B immune globulin - HBIG), following LTx (e.g. nucleoside analogues+HBIG for HBV;

combination of IFN/PegIFN + RIBA for HCV), during all these phases

Treatment of the disease with antiviral agents if and when it occurs

89

67

40

32

17

0 20 40 60 80 100

HBV cirrhosisHBV(+)

HBV cirrhosisHBV(-)

FulminantHBV+HDV

HDV cirrhosis

Fulminanthepatitis B

PERCENTAGE OF REINFECTION RELATED TO LIVER DISEASE & HBV

REPLICATIVE STATUS

Samuel D, et al, N Engl J Med 1993

The huge spontaneous risk for HBV reinfection after LTx (around 80%) is related to

liver disease & HBV replication status at the time of LTx

RECURRENCE OF HBV INFECTION

NATURAL HISTORY OF HBV REINFECTION AFTER LTx

Spontaneous HBV reinfection occurs during the first 3 years post-LTx and is the consequence of circulating HBV particles, HBV particles coming from extrahepatic sites or both

Serological profile: HBsAg(+), HBeAg (+), high DNA HBV level

Almost all patients with HBV reinfection develop severe graft disease immunosuppressive therapy direct cytopathic effect

Samuel D & Roche B, NIH Consensus Conference 2002

I. PREVENTION OF HBV RECURRENCE AFTER LTx

Hepatitis B immune globulins (HBIG) polyclonal antibodies directed against HBV envelope, originally derived

from anti-HBs (+) donors they protects naïve hepatocytes from circulating HBV indefinite, high-dose immunoprophylaxis

Antiviral therapies interferon alpha new antiviral agents against HBV infection (lamivudine, adefovir

dipivoxil for lamivudine-resistant HBV)

Combination therapy HBIG + Lami

FREQUENCY OF HBV RECURRENCE AFTER HBIG PROPHYLAXIS IN THE HBV LIVER

TRANSPLANT SETTINGAuthor Year No. pts. Regimen Recurrence

rateAntiHBs

titerMuller 1991 23 6-12 mo 25% 1 yr >100 IU

Samuel 1991 110 Indefinite 59% 2 yr >100 IU

Samuel 1993 209 >6 mo 33% 3 yr Variable

Konig 1994 27 Indefinite 48% 1 yr >100 IU

Devlin 1994 44 Indefinite 39% 1 yr >100 IU

McGory 1996 27 Indefinite 11% 2 yr >500 IU

Terrault 1996 24 Indefinite 19% 2 yr >500 IU

Samuel 1998 120 Indefinite 37% 1yr >100 IU

Lerut 1999 60 Indefinite 30% 1yr >100 IU

EFFICACY OF HBIG FOR PREVENTION OF HBV REINFECTION OF THE GRAFT -

METAANALYSISPatients reinfected with HBV post LTx,

according to pre-LTx status

p valueReplicatingNon-replicating

Number of patients

0Yes - 38 (70%)No – 16 (30%)

Yes – 31 (20%)No – 124 (80%)

209Samuel D (1994)

0.09 (NS)Yes – 3 (75%)No – 1 (25%)

Yes – 7 (33%)No – 16 (64%)

27Devlin J (1994)

0.009Yes – 11 (73%)No – 5 (27%)

Yes – 8 (31%)No – 20 (69%)

44Lemmens HP (1994)

0Yes – 16 (63%)No – 7 (37%)

Yes – 9 (11%)No – 78 (89%)

110Samuel D (1991)

0.005Yes – 9 (89%)No – 1 (11%)

Yes – 4 (29%)No – 9 (71%)

23Lauchart W (1987)

EFFICACY OF HBIG FOR PREVENTION OF HBV REINFECTION OF THE GRAFT -

METAANALYSIS

19.2

80.871.9

20.1

0102030405060708090

Non-replicating Replicating

Reinfection (+) Reinfection ( - )

Total N = 422 Number of Studies: k = 5• Population effect size r = 0.3883• 95% confidence interval of pop. effect size: from 0.23 to 0.54• Explained variance r-square = 0.15• Corresponding Z in Normal Distribution = 8.28• Significance p 0• Fail Safe N for critical r of 0.05 = 40• Fail Safe N for critical r of 0.10 = 17

Percentage of observed variance accounted for by sampling error = 100.00 % homogeneous Test of homogeneity Chi-square = 4.02 homogeneous Significance p = 0.54

HBIG PROPHYLAXIS: DRAWBACKS Drawbacks

failure of efficacy in ~15-20% at 2 yr 50% S gene escape mutation 50% other factors

limited availability high cost (3,000-4,700$/10,000 IU) need for i.v.administration side effects heavy surveillance

Reasons against discontinuation HBV DNA detected by highly sensitive molecular techniques in serum, liver,

peripheral mononuclear cells of HBsAg(-) patients - suggesting that indefinite treatment is required

Berenguer M & Wright T, Transplantation of the Liver 2001

I. PREVENTION OF HBV RECURRENCE AFTER LTx

Hepatitis B immune globulins (HBIG) polyclonal antibodies directed against HBV envelope, originally derived

from anti-HBs (+) donors they protects naïve hepatocytes from circulating HBV indefinite, high-dose immunoprophylaxis

Antiviral therapies interferon alpha (Perillo R et al, 1995; Marcellin P et al, 1994, 1997) lamivudine monotherapy (Naoumov NV et al, 1999) adefovir dipivoxil for lamivudine-resistant HBV)

Combination therapy HBIG + Lami

PREVENTION OF HBV RECURRENCE AFTER LTx WITH COMBINATION THERAPY:

LAMIVUDINE AND HBIG Author No. pts Pre-LTx Post-LTx Recurrence

rateMarkowitz1998

14 Lami 3 mo Lami + HBIG i.v 0

Yoshida1999

7 Lami Lami + HBIG i.m 0

Angus2000

37 Lami 3.2 mo Lami + HBIG i.m 1 (2.7%)

Marzano2001

26 Lami 4.6 mo Lami + HBIG i.v 1 (4%)

McCaughan1999

9 0 Lami + HBIG i.m 0

Rosenau2001

21 Lami 4.6 mo Lami + HBIG i.v 2 (9.5%)

Roche1999

15 Lami 4.6 mo Lami + HBIG i.v 1 (6.6%)

Han2001

59 Lami Lami + HBIG i.v 0

GUIDELINE FOR PREVENTION OF HBV RECURRENCE AFTER LTx

HBsAg (+)

HBV DNA (-)

HBsAg (+)

HBV DNA (+)

Lamivudine 100 mg > 4 wks

Adefovir dipivoxil for Lami resistant pts

Status

Consensus Conference on Hepatitis B, Geneva 2002

No preLTx antiviral therapy

Pre-LTx

10 000 IU HBIG i.v

10 000 IU/day HBIG i.v

Anehepatic phase1st postLTx week

Post-LTx

10 000 IU HBIG i.v. for antiHBs>100-

150 IU/l***

10 000 IU HBIG i.v. for antiHBs>500 IU/l + Lamivudine/Adefovir

II. TREATMENT OF HEPATITIS B RECURRENCE POST-LTx

3 categories of patients who are potential candidates for the treatment of hepatitis B disease of the graft:patients undergoing LTx in the pre-HBIG/lamivudine era

patients undergoing LTx in the post-HBIG/lamivudine era who have broken through treatment

patients with apparent “de novo” acquisition of HBV

Alternatives: interferon nucleoside analogues:

Lamivudine Adefovir dipivoxil in Lami-resistant mutants

Samuel D & Roche B, Consensus Conference on Hepatitis B 2002

Advantages

High bioavailability by oral route

Relative lack of adverse effects (high tolerability)

Lack of effect on the immune system

Posible capability of blocking supercoilled HBV DNA(adefovir, famciclovir)Effective against other viruses

Disadvantages

Need for prolonged therapy (indefinite)

Development of drug-resistant viral mutants

ADVANTAGES AND DISADVANTAGES OF NUCLEOSIDE ANALOGUES FOR THE TREATMENT

OF HBV INFECTION POST-LTx

Berenguer M & Wright T, Transplantation of the Liver 2001

DE NOVO HBV INFECTION OF THE GRAFT

Rigurous utilization of anti-HBc (-) organs in candidates never exposed to hepatitis B

Vaccination prior to LTx, generally at the time of listing (accelerated regimen: 0,1,2 and 6 mo.)

Utilization of anti-HBc (+) organs only: for recipients already infected with HBV in cases of emergency borderline indication

using prophylaxis with HBIG and Lamivudine

Berenguer M & Wright T, Transplantation of the Liver 2001

RECURRENCE OF HCV INFECTION

40-50% of adult LTx are performed for end-stage liver cirrhosis associated with hepatitis C virus (HCV) infection

Recurrence of HCV infection in transplant recipients for hepatitis C cirrhosis, defined as the presence of VHC replication in serum, is nearly universal

Recurrent infection represents a substantial source of morbidity, mortality and graft loss:

8% to 30% of patients progress to cirrhosis in 5-7 yr 2--5% early graft failure due to fibrosing cholestatic hepatitis 15% of patients need retransplantation during the first 5 years

Gane E, Liver Transplant 2002

ANTIVIRAL THERAPY FOR RECURRENT HCV INFECTION Antiviral therapy for recurrent hepatitis C has become a

growing problem facing adult LTx programs

Goals of antiviral therapy: prevention of allograft infection eradication of established infection/disease

Last decade: huge advances in antiviral therapy for chronic hepatitis C, confirmed by the improvement in SVR rates from

6% to 60%

Gane E, Liver Transplant 2002

BASELINE NEGATIVE PREDICTORS FOR VIROLOGICAL RESPONSE

higher pre-treatment viremia level

high prevalence of genotype 1 concomitent immunosuppression coexistence of other viral infections (CMV, EBV, HSV) susceptibility of LTx recipients to hematological side

effects of interferon- because of hypersplenism, myelosuppressive drugs

ISSUES TO OPTIMIZE THE ANTIVIRAL THERAPY FOR HCV IN PATIENTS

UNDERGOING LTx

Which antiviral regimen to choose ?

When to start the treatment ? Who to treat ?

Which antiviral regimen to choose ?

Antiviral regimens in recurrent hepatitis C are based on interferon- and, recently, on pegylated interferon

interferon monotherapy combination interferon + ribavirine pegylated interferon monotherapy combination pegylated interferon + ribavirine

Preemptive postLTx therapy for recurrent HCV infectionAuthor/yr

No. ptsRegimen Time

fromLTx

Histologicrecurrence

Differencein survival

Rejectionrate

Singh/’98n=24 (C,R)

IFN 2b 2 wk 42% vs50%

No 50% vs 42%

Sheiner/’98n=38(C, R)

IFN 2b 2 wk 25% vs53%

Yes 56% vs 56%

Mazzaferro/’98n=21 (UC)

IFN+RIBA 3 wk 57% NA Nodifferencein rejectionrate

43

93

21

64

4336

46

17

0

20

40

60

80

100

Normal ALTs Decreased HAI Increased F HCV RNA -

Comparing IFN vs Riba for hepatitis C reccurence after LTx

Interferon Ribavirin

Gane E.J.; Hepatology 1998

Author/yrNo. pts

Regimen EOT - BREOT - VR

SBRSVR

Histologyimprovement

Rejectionrate

Wright/’94n=18 (UC)

IFN 2b 28%0.05%

22%0

28% 0.05%

Feray/’95n=46(C, R)

IFN 2b 22%22%

11%11%vs 0 inctrl

22% vs 0 35% vs3%

Gane/’98 IFN+RIBA 43% vs85%6% vs 0

NA Noimprovementin HAI/FB

Nodifferenceinrejectionrate

28%

Therapy with IFN / IFN-Riba of recurrent HCV disease

Loss of serum HCV RNA at various time points

21.4

32

25

28.6

17.9

10.7

0 20 40 60 80 100

Week 4

Week 12

Week 24

Week 48

End of treatment

Week 24 of follow-up

IFN+Riba

Samuel D.; Gastroenterology 2003

• The first RCT of combination therapy with IFN + Riba in LTx recipiensInfected with HCV• Regimen: IFN α-2b (3 MUx3/week) + Riba 1000-1200 mg/day 48 weeks• Sustained virological response in 21 % of treated vs. 0% of controls

Follow-up

Follow-up

PEGASYS® 180 µg Monotherapy

No Treatment

Study Weeks

0 4824 72

Randomization

n=33

n=32

Wolfgang Vogel, AASLD 2002 Oral Presentation

Monotherapy with pegylated IFN 2a of recurrent HCV disease

weeks

0 0 0 0 0

12

33 3330

15

0

5

10

15

20

25

30

35

4 12 24 48 72

Res

po

nd

ers

(%) Untreated

PEGASYS®

ITT = 33 33 33 33 27 n = 33 31 28 23 15

Wolfgang Vogel, AASLD 2002 Oral Presentation

Monotherapy with pegylated IFN 2a of recurrent HCV disease

2

8

5

5

0

2

4

6

8

10

decreased negative

non-responders responders

On-treatment results of combined therapy with pegylated IFN 2b and Riba for rec.

HCV hepatitis

Khatib MA & Vargas H, DDW 2002 Oral Presentation

ISSUES TO OPTIMIZE THE ANTIVIRAL THERAPY FOR HCV IN PATIENTS

UNDERGOING LTx

Which antiviral regimen ? When to start the

treatment ? Who to treat ?

When to start therapy ?

Preemptive pre-LTx therapy goals: - supress viral replication & the risk of post-

LTx HCV recurrence - stabilize/improve hepatic conditionso the

need for LTx may be delayed Preemptive post-LTx therapy Treatment of graft disease related to

hepatitis C IFN / IFN+RIBA Pegylated IFN / Pegylated IFN + RIBA HCV immunoglobulins

ISSUES TO OPTIMIZE THE ANTIVIRAL THERAPY FOR HCV IN PATIENTS

UNDERGOING LTx

Which antiviral regimen ? When to start the

treatment ? Who to treat ?

Who to treat ?

patients with high HCV RNA levels prior or in the early post-LTx period

genotype 1 severe and early acute hepatitis strong immunosuppression

CONCLUSIONS

ANTIVIRAL THERAPY - A GROWING PROBLEM FACING LTx PROGRAMS

In the absence of specific therapy, viral reinfection of the graft is the rule

Although prophylactic therapy with HBIG has proved to be highly beneficial for HBV infection, there are no similar approaches for HCV infection (current strategies have limited efficacy ~20%)

The inability of curently available therapies to eliminate HCV/HBV in the setting of LTx leads to the need of indefinite treatment designed to suppress viral replication

Antiviral agents developed for this approach: improve histology, graft/patients survival, acceptable side effect profile, acceptable cost