8

ANTIVIRAL THERAPY PERI-LIVER TRANSPLANTATION

I A S G - ROMANIAN CHAPTER

BUC HARES T 1 1 th April 2 0 0 3

Liana GheorgheCenter of Gastroenterology & Hepatology

Fundeni Clinical InstituteBucharest, Romania

LIVER DISEASE IN ADULT TRANSPLANT RECIPIENTS

UNOS database 1987-1998; n=24,900 ptsadapted from Seaberg EC et al, Clinical Transplants 1998

P rim a ry live r dis e a s e Num be r P e rc e nta ge

Chronic he pa titis C 5 ,1 5 5 2 0 .7→ 4 0Alc oholic live r dis e a s e 4 ,2 5 8 1 7 .1ALD + HCV 1 ,1 0 6 4 .4Chronic he pa titis B 1 ,3 6 8 5 .5→ 1 0Cryptoge nic c irrhos is 2 ,7 1 9 1 0 .9P rima ry bilia ry c irrhos is 2 ,3 1 7 9 .3P rima ry s c le ros ing c hola ngitis 2 ,1 7 8 8 .7Autoimmune he pa titis 1 ,1 9 4 4 .8Ac ute live r fa ilure 1 ,5 5 5 6 .2Ma ligna nc y 9 5 1 3 .8Me ta bolic 9 2 3 3 .7Othe r 1 ,0 5 0 4 .2Unknown 1 2 6 0 .5

SURVIVAL AFTER ADULT LTx BY DIAGNOSIS

Dia g nos is 1 yr 4 yr 7 yrP rim a ry s c le ros ing c hola ngitis 9 1 8 4 7 8

P rim a ry bilia ry c irrhos is 8 9 8 4 7 9

Autoim m une he pa titis 8 6 8 1 7 8

Chronic he pa titis C 8 6 7 5 6 7

Alc oholic live r dis e a s e 8 5 7 6 6 3

Cryptog e nic c irrhos is 8 4 7 6 6 7

Chronic he pa titis B 8 3 7 1 6 3

Ma ligna nc y 7 2 4 3 3 4

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

8 9

6 7

4 0

3 2

1 7

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 SETTING

Author Year No. pts. Regimen Recurrencerate

AntiHBstiter

Muller 1 991 23 6-1 2 mo 25% 1 yr > 1 00 IUSamuel 1 991 1 1 0 Indefinite 59% 2 yr > 1 00 IUSamuel 1 993 209 > 6 mo 33% 3 yr VariableKonig 1 994 27 Indefinite 48% 1 yr > 1 00 IUDevlin 1 994 44 Indefinite 39% 1 yr > 1 00 IUMcGory 1 996 27 Indefinite 1 1 % 2 yr > 500 IUTerrault 1 996 24 Indefinite 1 9% 2 yr > 500 IUSamuel 1 998 1 20 Indefinite 37% 1 yr > 1 00 IULerut 1 999 60 Indefinite 30% 1 yr > 1 00 IU

EFFICACY OF 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

p va lueRe plic a tingNo n-re plic a tingNum b e r o f pa tie nts

→ 0Ye s - 3 8 (7 0 % )No – 1 6 (3 0 % )

Ye s – 3 1 (2 0 % )No – 1 2 4 (8 0 % )

2 0 9S am ue l D (1 9 9 4 )

0 .0 9 (NS)Ye s – 3 (7 5 % )No – 1 (2 5 % )

Ye s – 7 (3 3 % )No – 1 6 (6 4 % )

2 7De vlin J (1 9 9 4 )

0 .0 0 9Ye s – 1 1 (7 3 % )No – 5 (2 7 % )

Ye s – 8 (3 1 % )No – 2 0 (6 9 % )

4 4Le m m e ns HP (1 9 9 4 )

→ 0Ye s – 1 6 (6 3 % )No – 7 (3 7 % )

Ye s – 9 (1 1 % )No – 7 8 (8 9 % )

1 1 0S am ue l D (1 9 9 1 )

0 .0 0 5Ye s – 9 (8 9 % )No – 1 (1 1 % )

Ye s – 4 (2 9 % )No – 9 (7 1 % )

2 3Lauc hart W (1 9 8 7 )

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 ( - )

To ta l N = 422 Num b e r o f Studie s: k = 5• Po pula tio n e ffe c t size r = 0 .3 8 8 3• 9 5 % c o nfide nc e inte rva l o f po p. e ffe c t size : fro m 0 .2 3 to 0 .5 4• Expla ine d va ria nc e r-sq ua re = 0 .1 5• Co rre spo nding Z in No rm a l Distrib utio n = 8 .2 8• Signific a nc e p → 0• Fa il Sa fe N fo r c ritic a l r o f 0 .0 5 = 4 0• Fa il Sa fe N fo r c ritic a l r o f 0 .1 0 = 1 7

Pe rc e nta g e o f o b se rve d va ria nc e a c c o unte d fo r b y sa m pling e rro r = 1 0 0 .0 0 % → homogeneous Te st o f ho m o g e ne ity Chi-sq ua re = 4 .0 2 → homogeneous Sig nific a nc e p = 0 .5 4

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 Recurrencerate

Markowitz1 998

1 4 Lami 3 mo Lami + HBIG i.v 0

Yoshida1 999

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%)

McCaughan1 999

9 0 Lami + HBIG i.m 0

Rosenau2001

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

Roche1 999

1 5 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 (-)

HBs Ag (+)

HBV DNA (+)

La m ivudine 1 0 0 m g > 4 wks

Ade fo vir dipivo xil fo r La m i re sista nt pts

Sta tus

Consensus Conference on Hepatitis B, Geneva 2002

No pre LTx a ntivira l the ra pyPre -LTx

1 0 0 0 0 IU HBIG i.v

1 0 0 0 0 IU/ da y HBIG i.v

Ane he pa tic pha se

1 st po stLTx we e k

Po st-LTx 10 000 IU HBIG i.v. for antiHBs>100-150 IU/l***

10 000 IU HBIG i.v. for antiHBs>500 IU/l + La m ivudine / Ade fo vir

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:❶ patients undergoing LTx in the pre-HBIG/lamivudine era

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

➌ 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

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

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-α 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-α 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. ptsRe g im e n Tim e

fromL Tx

His tologicre c urre nc e

Diffe re nc ein s urviva l

Re je c tionra te

S ingh/’9 8n=2 4 (C, R)

IF N ∝ 2 b 2 wk 4 2 % vs5 0 %

No 5 0 % vs 4 2 %

S he ine r/’9 8n=3 8(C, R)

IF N ∝ 2 b 2 wk 2 5 % vs5 3 %

Ye s 5 6 % vs 5 6 %

Ma zza fe rro/’9 8n=2 1 (UC)

IF N+RIB A 3 wk 5 7 % NA Nodiffe re nc ein re je ctionra te

43

93

21

64

43 3646

17

0

20

40

60

80

100

Normal ALTs Decreased HAI Increased F HCV RNA -

Comparing IFN vs Riba for hepatitis C reccurence a fter LTx

Interferon Ribavirin

Gane E.J.; He pato lo gy 1 9 9 8

Author/yrNo. pts

Re g im e n E OT - B RE OT - VR

S B RS VR

His tologyim prove m e nt

Re je ctionra te

Wright/’9 4n=1 8 (UC)

IF N ∝2 b 2 8 %0 .0 5 %

2 2 %0

2 8 % 0 .0 5 %

F e ra y/’9 5n=4 6(C, R)

IF N ∝2 b 2 2 %2 2 %

1 1 %1 1 %vs 0 inc trl

2 2 % vs 0 3 5 % vs3 %

Ga ne /’9 8 IF N+RIB A 4 3 % vs8 5 %6 % vs 0

NA Noim prove m e ntin HAI/F B

Nodiffe re nc einre je c tionra te

28%

Therapy with IFN / IFN-Riba of recurrent HCV disease

Los s of s erum HCV RNA at various time points

21.4

3225

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 -2b (3 MUx3/week) + Riba 1000-1200 mg/day 48 weeksα• Sustained virological response in 21 % of treated vs. 0% of controls

Follow-up

Follow-up

PEGASYS® 180 µg Monotherapy

No Treatment

Study Weeks0 4824 72

Randomization

n=33

n=32

Wolfgang Vogel, AASLD 2002 Oral Presentation

Monotherapy with pegylated IFN α2a of recurrent HCV disease

weeks

0 0 0 0 0

12

33 3330

15

05

101520253035

4 12 24 48 72

Res

pond

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 α2a 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 α2b 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

■ Whic h a ntivira l re g im e n ?■ Whe n to sta rt the tre a tm e nt ?■ Who to tre a t ?

When to start therapy ?

■ Pre e m ptive pre -LTx the ra py➤ g o a ls: - supre ss vira l re plic a tio n & the risk o f po st-LTx HCV re c urre nc e - sta b ilize / im pro ve he pa tic c o nd itio nso the ne e d fo r LTx m a y b e

de la ye d■ Pre e m ptive po st-LTx the ra py■ Tre a tm e nt o f g ra ft dise a se re la te d to he pa titis C

➨ IFN / IFN+RIBA➨ Pe g yla te d IFN / Pe g yla te d IFN + RIBA➨ HCV im m uno glo b ulins

ISSUES TO OPTIMIZE THE ANTIVIRAL THERAPY FOR HCV IN PATIENTS UNDERGOING LTx

■ Whic h a ntivira l re g im e n ?■ Whe n to sta rt the tre a tm e nt ?■ Who to tre a t ?

Who to treat ?

■ pa tie nts with hig h HCV RNA le ve ls prio r o r in the e a rly po st-LTx pe rio d

■ g e no type 1 ■ se ve re a nd e a rly a c ute he pa titis■ stro ng im m uno suppre ssio n

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