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Antiviral therapy peri-liver transplantation

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  1. 1. 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
  2. 2. LIVER DISEASE IN ADULT TRANSPLANT RECIPIENTS UNOS database 1987-1998; n=24,900 pts adapted from Seaberg EC et al, Clinical Transplants 1998
  3. 3. SURVIVAL AFTER ADULT LTx BY DIAGNOSIS UNOS database 1987-1998; n=24,900 pts adapted from Seaberg EC et al, Clinical transplants 1998
  4. 4. THERAPEUTIC STRATEGIES IN PATIENTS WITH HBV, HDV, HCV INFECTION UNDERGOING LTx <ul><li>Prevention of recurrent infection of the graft by administration of antiviral agents </li></ul><ul><ul><li>prior (e.g. nucleoside analogues for HBV), </li></ul></ul><ul><ul><li>at the time (e.g. hepatitis B immune globulin - HBIG), </li></ul></ul><ul><ul><li>following LTx (e.g. nucleoside analogues+HBIG for HBV; combination of IFN/PegIFN + RIBA for HCV), </li></ul></ul><ul><ul><li>during all these phases </li></ul></ul><ul><li>Treatment of the disease with antiviral agents if and when it occurs </li></ul>
  5. 5. 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
  6. 6. NATURAL HISTORY OF HBV REINFECTION AFTER LTx <ul><li>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 </li></ul><ul><li>Serological profile: HBsAg(+), HBeAg (+), high DNA HBV level </li></ul><ul><li>Almost all patients with HBV reinfection develop severe graft disease </li></ul><ul><ul><li>immunosuppressive therapy </li></ul></ul><ul><ul><li>direct cytopathic effect </li></ul></ul>Samuel D & Roche B, NIH Consensus Conference 2002
  7. 7. I. PREVENTION OF HBV RECURRENCE AFTER LTx <ul><li>Hepatitis B immune globulins (HBIG) </li></ul><ul><ul><li>polyclonal antibodies directed against HBV envelope, originally derived from anti-HBs (+) donors </li></ul></ul><ul><ul><li>they protects naïve hepatocytes from circulating HBV </li></ul></ul><ul><ul><li>indefinite, high-dose immunoprophylaxis </li></ul></ul><ul><li>Antiviral therapies </li></ul><ul><ul><li>interferon alpha </li></ul></ul><ul><ul><li>new antiviral agents against HBV infection (lamivudine, adefovir dipivoxil for lamivudine-resistant HBV) </li></ul></ul><ul><li>Combination therapy </li></ul><ul><ul><li>HBIG + Lami </li></ul></ul>
  8. 8. FREQUENCY OF HBV RECURRENCE AFTER HBIG PROPHYLAXIS IN THE HBV LIVER TRANSPLANT SETTING
  9. 9. 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)
  10. 10. EFFICACY OF HBIG FOR PREVENTION OF HBV REINFECTION OF THE GRAFT - METAANALYSIS Total N = 422 Number of Studies: k = 5 <ul><li>Population effect size </li></ul><ul><li>r = 0.3883 </li></ul><ul><li>95% confidence interval of pop. effect size: from </li></ul><ul><li>0.23 to 0.54 </li></ul><ul><li>Explained variance </li></ul><ul><li>r-square = 0.15 </li></ul><ul><li>Corresponding Z in Normal Distribution = 8.28 </li></ul><ul><li>Significance </li></ul><ul><li>p  0 </li></ul><ul><li>Fail Safe N for critical r of 0.05 = 40 </li></ul><ul><li>Fail Safe N for critical r of 0.10 = 17 </li></ul>Percentage of observed variance accounted for by sampling error = 100.00 %  homogeneous Test of homogeneity Chi-square = 4.02  homogeneous Significance p = 0.54
  11. 11. HBIG PROPHYLAXIS: DRAWBACKS <ul><li>Drawbacks </li></ul><ul><ul><li>failure of efficacy in ~15-20% at 2 yr </li></ul></ul><ul><ul><ul><ul><ul><li>50% S gene escape mutation </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>50% other factors </li></ul></ul></ul></ul></ul><ul><ul><li>limited availability </li></ul></ul><ul><ul><li>high cost (3,000-4,700$/10,000 IU) </li></ul></ul><ul><ul><li>need for i.v.administration </li></ul></ul><ul><ul><li>side effects </li></ul></ul><ul><ul><li>heavy surveillance </li></ul></ul><ul><li>Reasons against discontinuation </li></ul><ul><ul><li>HBV DNA detected by highly sensitive molecular techniques in serum, liver, peripheral mononuclear cells of HBsAg(-) patients - suggesting that indefinite treatment is required </li></ul></ul>Berenguer M & Wright T, Transplantation of the Liver 2001
  12. 12. I. PREVENTION OF HBV RECURRENCE AFTER LTx <ul><li>Hepatitis B immune globulins (HBIG) </li></ul><ul><ul><li>polyclonal antibodies directed against HBV envelope, originally derived from anti-HBs (+) donors </li></ul></ul><ul><ul><li>they protects naïve hepatocytes from circulating HBV </li></ul></ul><ul><ul><li>indefinite, high-dose immunoprophylaxis </li></ul></ul><ul><li>Antiviral therapies </li></ul><ul><ul><li>interferon alpha (Perillo R et al, 1995; Marcellin P et al, 1994, 1997) </li></ul></ul><ul><ul><li>lamivudine monotherapy (Naoumov NV et al, 1999) </li></ul></ul><ul><ul><li>adefovir dipivoxil for lamivudine-resistant HBV) </li></ul></ul><ul><li>Combination therapy </li></ul><ul><ul><li>HBIG + Lami </li></ul></ul>
  13. 13. PREVENTION OF HBV RECURRENCE AFTER LTx WITH COMBINATION THERAPY: LAMIVUDINE AND HBIG
  14. 14. 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
  15. 15. II. TREATMENT OF HEPATITIS B RECURRENCE POST-LTx <ul><li>3 categories of patients who are potential candidates for the treatment of hepatitis B disease of the graft: </li></ul><ul><ul><li>patients undergoing LTx in the pre-HBIG/lamivudine era </li></ul></ul><ul><ul><li>patients undergoing LTx in the post-HBIG/lamivudine era who have broken through treatment </li></ul></ul><ul><ul><li>patients with apparent “de novo” acquisition of HBV </li></ul></ul><ul><li>Alternatives: </li></ul><ul><ul><li>interferon </li></ul></ul><ul><ul><li>nucleoside analogues: </li></ul></ul><ul><ul><ul><ul><ul><li>Lamivudine </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>Adefovir dipivoxil in Lami-resistant mutants </li></ul></ul></ul></ul></ul>Samuel D & Roche B, Consensus Conference on Hepatitis B 2002
  16. 16. ADVANTAGES AND DISADVANTAGES OF NUCLEOSIDE ANALOGUES FOR THE TREATMENT OF HBV INFECTION POST-LTx Berenguer M & Wright T, Transplantation of the Liver 2001
  17. 17. DE NOVO HBV INFECTION OF THE GRAFT <ul><li>Rigurous utilization of anti-HBc (-) organs in candidates never exposed to hepatitis B </li></ul><ul><li>Vaccination prior to LTx, generally at the time of listing (accelerated regimen: 0,1,2 and 6 mo.) </li></ul><ul><li>Utilization of anti-HBc (+) organs only: </li></ul><ul><ul><li>for recipients already infected with HBV </li></ul></ul><ul><ul><li>in cases of emergency </li></ul></ul><ul><ul><li>borderline indication </li></ul></ul><ul><ul><li>using prophylaxis with HBIG and Lamivudine </li></ul></ul>Berenguer M & Wright T, Transplantation of the Liver 2001
  18. 18. RECURRENCE OF HCV INFECTION <ul><li>40-50% of adult LTx are performed for end-stage liver cirrhosis associated with hepatitis C virus (HCV) infection </li></ul><ul><li>Recurrence of HCV infection in transplant recipients for hepatitis C cirrhosis, defined as the presence of VHC replication in serum, is nearly universal </li></ul><ul><li>Recurrent infection represents a substantial source of morbidity, mortality and graft loss: </li></ul><ul><ul><li>8% to 30% of patients progress to cirrhosis in 5-7 yr </li></ul></ul><ul><ul><li>2--5% early graft failure due to fibrosing cholestatic hepatitis </li></ul></ul><ul><ul><li>15% of patients need retransplantation during the first 5 years </li></ul></ul>Gane E, Liver Transplant 2002
  19. 19. ANTIVIRAL THERAPY FOR RECURRENT HCV INFECTION <ul><li>Antiviral therapy for recurrent hepatitis C has become a growing problem facing adult LTx programs </li></ul><ul><li>Goals of antiviral therapy: </li></ul><ul><ul><li>prevention of allograft infection </li></ul></ul><ul><ul><li>eradication of established infection/disease </li></ul></ul><ul><li>Last decade: huge advances in antiviral therapy for chronic hepatitis C, confirmed by the improvement in SVR rates from 6% to 60% </li></ul>Gane E, Liver Transplant 2002
  20. 20. BASELINE NEGATIVE PREDICTORS FOR VIROLOGICAL RESPONSE <ul><li>higher pre-treatment viremia level </li></ul><ul><li>high prevalence of genotype 1 </li></ul><ul><li>concomitent immunosuppression </li></ul><ul><li>coexistence of other viral infections (CMV, EBV, HSV) </li></ul><ul><li>susceptibility of LTx recipients to hematological side effects of interferon-  because of hypersplenism, myelosuppressive drugs </li></ul>
  21. 21. ISSUES TO OPTIMIZE THE ANTIVIRAL THERAPY FOR HCV IN PATIENTS UNDERGOING LTx <ul><li>Which antiviral regimen to choose ? </li></ul><ul><li>When to start the treatment ? </li></ul><ul><li>Who to treat ? </li></ul>
  22. 22. Which antiviral regimen to choose ? <ul><li>Antiviral regimens in recurrent hepatitis C are based on interferon-  and, recently, on pegylated interferon </li></ul><ul><li>interferon monotherapy </li></ul><ul><li>combination interferon + ribavirine </li></ul><ul><li>pegylated interferon monotherapy </li></ul><ul><li>combination pegylated interferon + ribavirine </li></ul>
  23. 23. Preemptive postLTx therapy for recurrent HCV infection Gane E.J.; Hepatology 1998
  24. 24. Therapy with IFN / IFN-Riba of recurrent HCV disease
  25. 25. Samuel D.; Gastroenterology 2003 <ul><li>The first RCT of combination therapy with IFN + Riba in LTx recipiens </li></ul><ul><li>Infected with HCV </li></ul><ul><li>Regimen: IFN α-2b (3 MUx3/week) + Riba 1000-1200 mg/day 48 weeks </li></ul><ul><li>Sustained virological response in 21 % of treated vs. 0% of controls </li></ul>
  26. 26. 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
  27. 27. 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
  28. 28. On-treatment results of combined therapy with pegylated IFN  2b and Riba for rec . HCV hepatitis Khatib MA & Vargas H, DDW 2002 Oral Presentation
  29. 29. ISSUES TO OPTIMIZE THE ANTIVIRAL THERAPY FOR HCV IN PATIENTS UNDERGOING LTx <ul><li>Which antiviral regimen ? </li></ul><ul><li>When to start the treatment ? </li></ul><ul><li>Who to treat ? </li></ul>
  30. 30. When to start therapy ? <ul><li>Preemptive pre-LTx therapy </li></ul><ul><ul><li>goals: - supress viral replication & the risk of post-LTx HCV recurrence </li></ul></ul><ul><ul><li>- stabilize/improve hepatic conditionso the need for LTx may be delayed </li></ul></ul><ul><li>Preemptive post-LTx therapy </li></ul><ul><li>Treatment of graft disease related to hepatitis C </li></ul><ul><ul><li>IFN / IFN+RIBA </li></ul></ul><ul><ul><li>Pegylated IFN / Pegylated IFN + RIBA </li></ul></ul><ul><ul><li>HCV immunoglobulins </li></ul></ul>
  31. 31. ISSUES TO OPTIMIZE THE ANTIVIRAL THERAPY FOR HCV IN PATIENTS UNDERGOING LTx <ul><li>Which antiviral regimen ? </li></ul><ul><li>When to start the treatment ? </li></ul><ul><li>Who to treat ? </li></ul>
  32. 32. Who to treat ? <ul><li>patients with high HCV RNA levels prior or in the early post-LTx period </li></ul><ul><li>genotype 1 </li></ul><ul><li>severe and early acute hepatitis </li></ul><ul><li>strong immunosuppression </li></ul>
  33. 33. CONCLUSIONS ANTIVIRAL THERAPY - A GROWING PROBLEM FACING LTx PROGRAMS <ul><li>In the absence of specific therapy, viral reinfection of the graft is the rule </li></ul><ul><li>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%) </li></ul><ul><li>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 </li></ul><ul><li>Antiviral agents developed for this approach: improve histology, graft/patients survival, acceptable side effect profile, acceptable cost </li></ul>

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