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Antiviral therapy peri-liver transplantation

Antiviral therapy peri-liver transplantation

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    8 8 Presentation Transcript

    • ANTIVIRAL THERAPY PERI-LIVER TRANSPLANTATION I A S G - ROMANIAN CHAPTER BUCHAREST 11 th April 2003 Liana Gheorghe Center of Gastroenterology & Hepatology Fundeni Clinical Institute Bucharest, Romania
    • LIVER DISEASE IN ADULT TRANSPLANT RECIPIENTS UNOS database 1987-1998; n=24,900 pts adapted from Seaberg EC et al, Clinical Transplants 1998
    • SURVIVAL AFTER ADULT LTx BY DIAGNOSIS 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
    • 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
    • EFFICACY OF HBIG FOR PREVENTION OF HBV REINFECTION OF THE GRAFT - METAANALYSIS Patients reinfected with HBV post LTx, according to pre-LTx status p value Replicating Non-replicating Number of patients  0 Yes - 38 (70%) No – 16 (30%) Yes – 31 (20%) No – 124 (80%) 209 Samuel D (1994) 0.09 (NS) Yes – 3 (75%) No – 1 (25%) Yes – 7 (33%) No – 16 (64%) 27 Devlin J (1994) 0.009 Yes – 11 (73%) No – 5 (27%) Yes – 8 (31%) No – 20 (69%) 44 Lemmens HP (1994)  0 Yes – 16 (63%) No – 7 (37%) Yes – 9 (11%) No – 78 (89%) 110 Samuel D (1991) 0.005 Yes – 9 (89%) No – 1 (11%) Yes – 4 (29%) No – 9 (71%) 23 Lauchart W (1987)
    • EFFICACY OF HBIG FOR PREVENTION OF HBV REINFECTION OF THE GRAFT - METAANALYSIS 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
    • 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 phase 1st 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 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 infection Gane E.J.; Hepatology 1998
    • Therapy with IFN / IFN-Riba of recurrent HCV disease
    • Samuel D.; Gastroenterology 2003
      • The first RCT of 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
    • Follow-up Follow-up PEGASYS ® 180 µg Monotherapy No Treatment Study Weeks 0 48 24 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 33 30 15 0 5 10 15 20 25 30 35 4 12 24 48 72 Responders (%) 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
    • 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