1. I A S G - ROMANIAN C HAPTER
BUC HARES T 1 1 th Ap ril 2 0 0 3
ANTIVIRAL THERAPYPERI-LIVER
TRANSPLANTATION
Liana Gheorghe
Center of Gastroenterology & Hepatology
Fundeni Clinical Institute
Bucharest, Romania

2. LIVER DISEASE IN ADULTTRANSPLANTRECIPIENTS
P rim a ry live r dis e a s e Num be r P e rc e nta g e
Chronic he pa titis C 5 ,1 5 5 2 0 .7→ 4 0
Alc oholic live r dis e a s e 4 ,2 5 8 1 7 .1
ALD + HCV 1 ,1 0 6 4 .4
Chronic he pa titis B 1 ,3 6 8 5 .5 → 1 0
Cryptoge nic c irrhos is 2 ,7 1 9 1 0 .9
P rim a ry bilia ry c irrhos is 2 ,3 1 7 9 .3
P rim a ry s c le ros ing c hola ngitis 2 ,1 7 8 8 .7
Autoim m une he pa titis 1 ,1 9 4 4 .8
Ac ute live r fa ilure 1 ,5 5 5 6 .2
Ma ligna nc y 951 3 .8
Me ta bolic 923 3 .7
Othe r 1 ,0 5 0 4 .2
Unknown 126 0 .5
UNOS database 1987-1998; n=24,900 pts
adapted from Seaberg EC et al, Clinical Transplants 1998

3. SURVIVAL AFTER ADULTLTxBYDIAGNOSIS
Dia g nos is 1 yr 4 yr 7 yr
P rim a ry s c le ros ing c hola ngitis 91 84 78
P rim a ry bilia ry c irrhos is 89 84 79
Autoim m une he pa titis 86 81 78
Chronic he pa titis C 86 75 67
Alc oholic live r dis e a s e 85 76 63
Cryptog e nic c irrhos is 84 76 67
Chronic he pa titis B 83 71 63
Ma ligna nc y 72 43 34
UNOS database 1987-1998; n=24,900 pts
adapted from Seaberg EC et al, Clinical transplants 1998

4. THERAPEUTIC STRATEGIES IN PATIENTS W HBV, HDV, HCV
ITH
INFECTION UNDERGOING LTx
s Prevention of recurrent infection of the graft by administration of antiviral
agents
s prior (e.g. nucleoside analogues for HBV),
s at the time (e.g. hepatitis B immune globulin - HBIG),
s following LTx(e.g. nucleoside analogues+HBIG for HBV; combination of
IFN/PegIFN + RIBA for HCV),
s during all these phases
s Treatment of the disease with antiviral agents if and when it occurs

5. RECURRENCE OF HBV INFECTION
PERCENTAGE OF REINFECTION RELATED TO LIVER
DISEASE & HBV REPLICATIVE STATUS
The huge spontaneous risk Fulminant 17
hepatitis B
for HBV reinfection after 32
HDV cirrhosis
LTx(around 80%) is
related to Fulminant 40
HBV+HDV
liver disease & HBV 67
HBV cirrhosis
replication status at the HBV(-)
time of LTx HBV cirrhosis 89
HBV(+)
0 20 40 60 80 100
Samuel D, et al, N Engl J Med 1993

6. NATURAL HISTORYOF HBV REINFECTION AFTER LTx
s 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
s Serological profile: HBsAg(+), HBeAg (+), high DNA HBV level
s Almost all patients with HBV reinfection develop severe graft disease
ª immunosuppressive therapy
ª direct cytopathic effect
Samuel D & Roche B, NIH Consensus Conference 2002

7. I. PREVENTION OF HBV RECURRENCE AFTER LTx
s 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
s Antiviral therapies
« interferon alpha
« newantiviral agents against HBV infection (lamivudine, adefovir dipivoxil for
lamivudine-resistant HBV)
s Combination therapy
« HBIG + Lami

8. FREQUENCYOF HBV RECURRENCE AFTER HBIG PROPHYLAXIS
IN THE HBV LIVER TRANSPLANTSETTING
A
uthor Year N pts.
o. R
egimen Recurrence A B
ntiHs
rate titer
Muller 1 991 23 6-1 2 mo 25% 1 yr > 1 00 IU
Samuel 1 991 110 Indefinite 59% 2 yr > 1 00 IU
Samuel 1 993 209 > 6 mo 33% 3 yr V ariable
Konig 1 994 27 I
ndefinite 48% 1 yr > 1 00 I
U
Devlin 1 994 44 I
ndefinite 39% 1 yr > 1 00 I
U
M ory
cG 1 996 27 I
ndefinite 1 1 % 2 yr > 500 I
U
Terrault 1 996 24 I
ndefinite 1 9% 2 yr > 500 I
U
Sam uel 1 998 1 20 I
ndefinite 37% 1 yr > 1 00 I
U
Lerut 1 999 60 I
ndefinite 30% 1 yr > 1 00 I
U

9. EFFICACYOF HBIG FOR PREVENTION OF HBV
REINFECTION OF THE GRAFT- METAANALYSIS
P a tie n ts re in fe c te d w ith HB V p o s t LTx ,
a c c o rd in g to p re -LTx s ta tu s
N b e r o f N n-re plica ting
um o R plica ting
e p va lue
pa tie nts
Lauc ha rt W 23 Y s – 4 (2 9 % )
e Y s – 9 (8 9 % )
e 0 .0 0 5
(1 9 8 7 ) N – 9 (7 1 % )
o N – 1 (1 1 % )
o
S am ue l D 110 Y s – 9 (1 1 % )
e Y s – 1 6 (6 3 % )
e →0
(1 9 9 1 ) N – 7 8 (8 9 % )
o N – 7 (3 7 % )
o
Le m m e ns 44 Y s – 8 (3 1 % )
e Y s – 1 1 (7 3 % )
e 0 .0 0 9
HP (1 9 9 4 ) N – 2 0 (6 9 % )
o N – 5 (2 7 % )
o
De vlin J 27 Y s – 7 (3 3 % )
e Y s – 3 (7 5 % )
e 0 .0 9 (NS)
(1 9 9 4 ) N – 1 6 (6 4 % )
o N – 1 (2 5 % )
o
S am ue l D 209 Y s – 3 1 (2 0 % )
e Y s - 3 8 (7 0 % )
e →0
(1 9 9 4 ) N – 1 2 4 (8 0 % )
o N – 1 6 (3 0 % )
o

10. EFFICACYOF HBIG FOR PREVENTION OF HBV
REINFECTION OF THE GRAFT- METAANALYSIS
To tal N = 422 N b e r o f S
um tudie s: k = 5
• Po pula tio n e ffe ct size
r = 0 .3 8 8 3 90 80.8
• 9 5 % co nfide nce inte rval o f po p. 80 71.9
e ffe ct size : fro m 70
0 .2 3 to 0 .5 4 60
•E xplaine d variance
50
r-sq uare = 0 .1 5
• C rre spo nding Z N rm al
o in o 40
D istrib utio n = 8 .2 8 30 19.2 20.1
•S ignificance 20
p→ 0 10
• Fa il S Nfo r critical r o f 0 .0 5
afe 0
= 40 Non-replicating Replicating
• Fa il S Nfo r critical r o f 0 .1 0
afe
= 17 Reinfection (+) Reinfection ( - )
Pe rce ntage o f o b se rve d variance acco unte d fo r b y sam pling e rro r =
1 0 0 .0 0 % → homogeneous
Te st o f ho m o ge ne ity Chi-sq ua re = 4 .0 2 → homogeneous
S ignificance p = 0 .5 4

11. HBIG PROPHYLAXIS: DRAWBACKS
s 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
s 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

12. I. PREVENTION OF HBV RECURRENCE AFTER LTx
s 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
s 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)
s Combination therapy
« HBIG + Lami

13. PREVENTION OF HBV RECURRENCE AFTER LTxWITH
COMBINATION THERAPY: LAMIVUDINE AND HBIG
A
uthor N pts
o. P T
re-Lx P T
ost-Lx R
ecurrence
rate
M arkowitz 14 L 3 mo
ami L + HI i.v
ami BG 0
1 998
Y oshida 7 Lami L + HI i.m
ami BG 0
1 999
A ngus 37 L 3.2 mo
ami L + HI i.m
ami BG 1 (2.7%)
2000
M arzano 26 L 4.6 mo
ami L + HI i.v
ami BG 1 (4%)
2001
M aughan
cC 9 0 L + HI i.m
ami BG 0
1 999
R osenau 21 L 4.6 mo
ami L + HI i.v
ami BG 2 (9.5%)
2001
R oche 15 L 4.6 mo
ami L + HI i.v
ami BG 1 (6.6%)
1 999
H an 59 Lami L + HI i.v
ami BG 0
2001

14. GUIDELINE FOR PREVENTION OF HBV RECURRENCE AFTER LTx
H sA (+)
B g H sA (+)
B g
Status
H V N (-)
BDA H V N (+)
BDA
L ivudine 1 0 0 m g > 4 wks
am
N pre L a ntiviral the rapy
o Tx
Pre -LTx
A fo vir dipivo xil fo r L i
de am
re sistant pts
A he patic phase
ne 1 0 0 0 0 I H I i.v
U BG
1 st po stL we e k
Tx 1 0 0 0 0 I /day H I i.v
U BG
10 000 IU HBIG i.v. for 10 000 IU HBIG i.v. for
Po st-LTx
antiHBs>100-150 IU/l*** antiHBs>500 IU/l +
L ivudine /A fo vir
am de
Consensus Conference on Hepatitis B, Geneva 2002

15. II. TREATMENTOF HEPATITIS B RECURRENCE POST-LTx
s 3 categories of patients who are potential candidates for the treatment of
hepatitis B disease of the graft:
‚ patients undergoing LTxin the pre-HBIG/lamivudine era
— patients undergoing LTxin the post-HBIG/lamivudine era who have broken
through treatment
˜ patients with apparent “de novo” acquisition of HBV
s Alternatives:
ª interferon
ª nucleoside analogues:
ª Lamivudine
ª Adefovir dipivoxil in Lami-resistant mutants
Samuel D & Roche B, Consensus Conference on Hepatitis B 2002

16. ADVANTAGES AND DISADVANTAGES OF NUCLEOSIDE ANALOGUES FOR
THE TREATMENTOF HBV INFECTION POST-LTx
Adva nta g e s
Hig h bioa va ila bility by ora l route
Re la tive la c k of a dve rs e e ffe c ts (hig h tole ra bility)
L a c k of e ffe c t on the im m une s ys te m
P os ible c a pa bility of bloc king s upe rc oille d HB V DNA
(a de fovir, fa m c ic lovir)
E ffe c tive a g a ins t othe r virus e s
Dis a dva nta ge s
Ne e d for prolong e d the ra py (inde finite )
De ve lopm e nt of drug -re s is ta nt vira l m uta nts
Berenguer M & Wright T, Transplantation of the Liver 2001

17. DE NOVO HBV INFECTION OF THE GRAFT
s Rigurous utilization of anti-HBc (-) organs in candidates never exposed to
hepatitis B
s Vaccination prior to LTx, generally at the time of listing (accelerated
regimen: 0,1,2 and 6 mo.)
s 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

18. RECURRENCE OF HCV INFECTION
s 40-50% of adult LTxare performed for end-stage liver cirrhosis associated
with hepatitis C virus (HCV) infection
s Recurrence of HCV infection in transplant recipients for hepatitis C cirrhosis,
defined as the presence of VHC replication in serum, is nearly universal
s 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

19. ANTIVIRAL THERAPYFOR RECURRENTHCV INFECTION
s Antiviral therapy for recurrent hepatitis C has become a growing problem
facing adult LTxprograms
s Goals of antiviral therapy:
s prevention of allograft infection
s eradication of established infection/disease
s 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

20. BASELINE NEGATIVE PREDICTORS FOR VIROLOGICAL
RESPONSE
s higher pre-treatment viremia level
s high prevalence of genotype 1
s concomitent immunosuppression
s coexistence of other viral infections (CMV, EBV, HSV)
s susceptibility of LTx recipients to hematological side effects of
interferon-α because of hypersplenism, myelosuppressive drugs

21. ISSUES TO OPTIMIZE THE ANTIVIRAL THERAPYFOR HCV IN
PATIENTS UNDERGOING LTx
s Which antiviral regimen to choose ?
s When to start the treatment ?
s W to treat ?
ho

22. Which antiviral regimen to choose ?
Antiviral regimens in recurrent hepatitis C are based on interferon-α
and, recently, on pegylated interferon
® interferon monotherapy
® combination interferon + ribavirine
® pegylated interferon monotherapy
® combination pegylated interferon + ribavirine

23. Preemptive postLTxtherapy for recurrent HCV infection
Author/yr Re g im e n Tim e His tologic Diffe re nc e Re je c tion
No. pts from re c urre nc e in s urviva l ra te
L Tx
S ingh/’9 8 IF N ∝ 2 b 2 wk 4 2 % vs No 5 0 % vs 4 2 %
n=2 4 (C, R) 50%
S he ine r/’9 8 IF N ∝ 2 b 2 wk 2 5 % vs Ye s 5 6 % vs 5 6 %
n=3 8 53%
(C, R)
Ma zza fe rro/ IF N+RIB A 3 wk 5 7 % NA No
’9 8 diffe re nc e
n=2 1 (UC) in re je ction
ra te
Comparing IFN vs Riba for hepatitis C
reccurence a fter LTx
93
100
80 64
60 43 43 46 Ga ne E.J.; He p a to lo gy 1 9 9 8
36
40
21 17
20
0
Normal ALTs Decreased HAI Increased F HCV RNA -
Interferon Ribavirin

24. Therapy with IFN / IFN-Riba of recurrent HCV disease
Author/yr Re g im e n E OT - B R S B R His tology Re je ction
No. pts E OT - VR S VR im prove m e nt ra te
Wright/’9 4 IF N ∝ b
2 28% 22% 28% 0 .0 5 %
n=1 8 (UC) 0 .0 5 % 0
F e ra y/’ 9 5 IF N ∝ b
2 22% 11% 2 2 % vs 0 3 5 % vs
n=4 6 22% 11% 3%
(C, R) vs 0 in
c trl
Ga ne /’9 8 IF N+RIB A 4 3 % vs NA No No
85% im prove m e nt diffe re nc e
6 % vs 0 in HAI/F B in
re je c tion
28%
ra te

25. Los s of s erum HCV RNA a t va rious time
points
Week 24 of follow-up 21.4
End of treatment 32
Week 48 25
Week 24 28.6
Week 12 17.9
Week 4 10.7
0 20 40 60 80 100
IFN+Riba
• The first RCTof combination therapy with IFN + Riba in LTx recipiens
Infected 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
Samuel D.; Gastroenterology 2003

26. Monotherapy with pegylated IFN α2a of recurrent HCV disease
n=33 PEGASYS® 180 µg Monotherapy Follow-up
n=32 No Treatment Follow-up
0 24 48 72
Study Weeks
Randomization
Wolfgang Vogel, AASLD 2002 Oral Presentation

27. Monotherapy with pegylated IFN α2a of recurrent HCV disease
35 33 33
30
30 Untreated
Responders (%)
25 PEGASYS®
20
15
15 12
10
5
0 0 0 0 0
0
4 12 24 48 72
weeks
ITT = 33 33 33 33 27
n = 33 31 28 23 15
Wolfgang Vogel, AASLD 2002 Oral Presentation

28. On-treatment results of combined therapy with pegylated IFN
α2b and Riba for rec. HCV hepatitis
10
8
5
6 8
4
5
2
2
0
decreased negative
non-responders responders
Khatib MA & Vargas H, DDW 2002 Oral Presentation

29. ISSUES TO OPTIMIZE THE ANTIVIRAL THERAPYFOR HCV IN
PATIENTS UNDERGOING LTx
s Which antivira l re gim e n ?
s W n to sta rt the tre a tm e nt ?
he
s W to tre at ?
ho

30. W to start therapy ?
hen
s Pre e m ptive pre -L the rapy
Tx
® go a ls: - supre ss viral re plicatio n & the risk o f po st-L H V curre nce
Tx C re
- stab ilize /im pro ve he patic co nditio nso the ne e d fo r L m a y b e
Tx
de la ye d
s Pre e m ptive po st-L the rapy
Tx
s Tre atm e nt o f graft dise ase re la te d to he patitis C
² I / I +RB
FN FN I A
² Pe gylate d I / Pe gyla te d I + RB
FN FN I A
² H V m uno glo b ulins
C im

31. ISSUES TO OPTIMIZE THE ANTIVIRAL THERAPYFOR HCV IN
PATIENTS UNDERGOING LTx
s Which antivira l re gim e n ?
s W n to sta rt the tre a tm e nt ?
he
s W to tre at ?
ho

32. W to treat ?
ho
s pa tie nts with high H VR Ale ve ls prio r o r in the e arly po st-L
C N Tx
pe rio d
s ge no type 1
s se ve re and e arly acute he patitis
s stro ng im m uno suppre ssio n

33. CONCLUSIONS
ANTIVIRAL THERAPY- A GROW PROBLEM FACING LTx
ING
PROGRAMS
s In the absence of specific therapy, viral reinfection of the graft is the rule
s 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%)
s The inability of curently available therapies to eliminate HCV/HBV in the
setting of LTxleads to the need of indefinite treatment designed to suppress
viral replication
s Antiviral agents developed for this approach: improve histology,
graft/patients survival, acceptable side effect profile, acceptable cost