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Antiviral therapy peri-liver transplantation
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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