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The long—term outcome of liver transplantation recipients with de novo hepatitis B infection who received an anti—HBC graft
642A
AASLD ABSTRACTS
HEPATOLOGYOctober 2001
1879
1880
LIVER TRANSPLANTATION IN HEPATITIS B PATIENTS W I T H PREOPERATIVE RESISTANCE FORMATION DURING LAMIVUDINE TREATMENT. Daniel Seehofer, Nada Rayes, Thomas Steinm~ller, Uta Naumann, Utz
STEROID OR NO STEROID FOR PRIMARY BILIARY CIRRHOSIS (PBC), PRIMARY SCLEROSING CHOLANGITIS (PSC) AND AUTOIMMUNE HEPATITIS (AIR) UNDEER TACROLIMUS AFTER LIVER TRANSPLANTATION AND LONG-TERM SURVIVAL. Ashok B Jain, Randeep S Kashyap,
Settmacher, Andrea R M~ller, Peter Neuhaus, Charit~ Campus Virchow, Berlin Germany Objective: Due to increasing lamivudine use in chronic hepatitis B, pre-transplant lamivudine resistance is an evolving problem in potential liver transplant recipients. Since clinical data are lacking on this problem, we have characterised the perioperative course of six patients, who receiveda liver transplant after having evolved clinical lamivudine resistance. Methods: Between August 1998 and February 2001, in total 6 patients with pre-existing lamiwudine resistance undervcent liver transplantation at our centre. Four of them had primary transplantations and two retransplantations. In all patients except the last, lamivudine was continued until transplantation. Passive immunopropylaxis was started with application of 10.000 units HBIg intraoperatively and every following day under HBsAg and anti-HBs titre control. Lamivudine was continued postoperatively and combined with famciclovir during the postoperative course. Results: All patients had high viral replication preoperatively (92 - 6858 pg/ml), 5 were HBeAg positive, one was negative. Four of six patients (67%) developed early hepatitis B recurrence between day I and 120 with high viral replication but only mildly elevated liver enzymes. The remaining two (one after primary and one after secondary transplantation) are reinfection free under HBIg, lamivudine and famciclovir prophylaxis at present. All patients with primary transplantation are alive and well 11.5 months (range 1 to 17 months) after OLT. One patient with HBV recurrence after retransplantation died after 4.5 months due to sepsis and multi or-gan failure, the other patient is recurrence free 13 months after retransplantation. Liver biop-sies revealed low hepatitic activity in the patients with reinfection alive and no signs of recur-rence in the recurrence free patients. Conclusion.: Preoperative lamivudine resistance predicts high reinfection rates after liver transplantation. Using antiviral combination treatment, in most cases a relatively mild course was observed. Therefore liver transplantation in patients with lamivudine resistance seems to be justifiable, although the optimal management has to be evaluated yet.
Bijan Eghtesad, Shakeel Obaid, Asham Emad, John J Fung, T E Starzl Transplantation Institute, Pittsburgh, PA Recurrence of autoimmune process after liver transplantation (LTx) has been documented. Use of steroids has been suggested to prevent the recurrence of disease. Aim: To examine the long-term outcome after LTx for PBC, PSC and AT under tacrolimus and the need to use steroid with baseline immunosuppression. Material and Methods: Between August '89 to Dec '92, 168 patients underwent LTx for PBC (n=83), PSC (n=60), and AI (n=25). All patients were followed up to March 2000. Mean follow -up 8.8+ 0.7 year (median 8.9, range 7.2 to 10.5). Their postoperative course and base line immunosuppression was retrospectively reviewed. Results: Deaths: Total 43 patients died and 26 underwent retransplantation for PNF (n= 14), HAT (n=4) Biliary complications (n=4), rejection, acute/chronic rejection (n=3) and denovo HCV (n= 1). Survival: Overall patient survival was 74.9% at mean follow up of 9 years. Patient survival for PBC at 1, 3, 5, and 9 year was 84%, 82%, 79%, and 75%, for PSC, 98%, 92%, 82%, and 73% and for AIH 84%, 84%, 84%, and 80%. Liver functions: Current mean bilirubin is 0.6, 0.6 and 0.7, mean AST is 43.8, 32.3, and 32, mean ALT is 50, 49, and 38, mean ALKPo4 is 170, 172 and 119, mean GGTP is 113, 94, and 132 for PBC, PSC, and AIH respectively. Steroid Withdrawal: In all patients, steroid was withdrawn at some time point after LTx. Steroid reintroduction: However in 31 (24.8%) it was reintroduced for recurrence of disease. Rate of reintroduction was 18 (29%) for PBC, 6 (30%) for AI and 7(16.2%) for PSC. All patients showed improvement in biochemical profile upon reintroduction of steroid. In addition 6 (13%) patients with PSC received steroid to control colitis. Conclusion: 9-year actuarial patient survival for PBC, PSC and AI hepatitis is 76.7%, 73.2% and 80% respectively. Maintenance of steroid is not necessary in all patients. 24.8% of patients may require re-introduction of steroid with recurrent autoimmune process with a satisfactory biochemical response without any risk to allograft.
1881
1882
CHARACTERISATION OF REVERSE TRANSCRIPTASE HBV MUTANTS IN OLT PATIENTS TREATED W I T H LAMIVUDINE OR LAMIVUDINE PLUS FAMCICLOVIR. Francesco Torre, University of Genoa, Genoa Italy;
THE LONCr--TERM OUTCOME OF LIVER TRANSPLANT RECIPIENTS WITH DE NOVO HEPATITIS B INFECTION VCHO RECEIVED AN A N T I - HBC GRAFT. Michael B Ishitani, Mayo Clinic, Rochester, MN; David D Doug-
Ivo Graziadei, University of Innsbruck, lnnsbruck Austria; Andrea Delfino, University of Genoa, Genoa Italy; Wolfgang Vogel, University of Innsbruck, Innsbruck Austria; Antonino Picciotto, University of Genoa, Genoa Italy
las, Jorge Rakela, Mayo Clinic Scottsdale, Scottsdale, AZ; Rolland D Dickson, Mayo Clinic Jacksonville, Jacksonville, FL; Russell H Wiesner, Charles B Rosen, Ruud A Krom, Mayo Clinic, Rochester, MN
Background: Recurrence of hepatitis B virus (HBV) is a major problem in patients transplanted for HBV related cirrhosis. Nucleoside analogues, such as famciclovir and lamivudine, efficiently inhibit HBV replication and have been used to treat HBV recurrence after OLT. Although effective, their efficacy is hampered by viral breakthrough due to the emergence of HBV drug-resistant strains. Mutations appear mainly in the YMDD motif (M552I or M552V) and are frequently associated with another mutation at aa position 528 (L528M), which seems to confer resistance also to famciclovir. Methods: Forty-one patients (7 female) transplanted for end-stage HBV related liver disease between 1985 and 2000 were studied for a mean follow up of 3.4 years (range: 0.2-14.0 years). All of them received the usual immuno-suppressive treatment and steroids were discontinued within 3 months post OLT. Thirty-five of them received HBIg immunoprophylaxis. Fourteen patients out of 41 presented with HBV recurrence and were treated: 3 with famciclovir, 7 with lamivudine alone and 4 with famciclovir and lamivudine together. Two patients on famciclovir were switched: one to lamivudine and the other one to famciclovir plus lamivudine because of treatment inefficacy. Six of them presented with viral breakthrough. Two patients were put on adefovir dipivoxil which completely suppressed viral replication. Seventy eight serum samples have been collected accordingly to clinical history: earliest sample available, soon after OLT, at the time of recurrence and at the time of viral breakthrough. All samples have been screened by nested PCR and the positive ones have been evaluated for reverse transcriptase mutant strains by the newly developed HBV DR InnoLiPa kit (kindly donated by Innogenetics). Results: All samples before OLT were positive at the PCR, excepted in 2 patients, and all were bearing a wild type virus. At recurrence (14 patients) wild type HBV was also present. At the time of viral breakthrough the M552V mutation was present in all 6 cases, and in all of them was associated with the M528L mutation. Conclusions: Management of viral breakthrough from nucleoside analogues represents the major issue in this group of OLT patients. These data clearly show how even the association of famciclovir and lamivudine was unable to prevent this outbreak. At this time, adefovir dipivoxil seems to represent the only effective treatment available in this subgroup of patients.
A liver from a donor who is serum anti--HBc positive will result in hepatitis B viral (HBV) infection in a high percentage of recipients. The clinical course of these patients ranges from a largely indolent course to a rapid decline due to severe complications of HBV infection. Lamivudine appears to slow or stabilize the clinical course of HBV infection in these patients. Little information is available on the long--term clinical outcome of liver transplant recipients who develop de novo HBV infection after receiving a liver from an anti--HBc positive donor. Methods: From 3/85-11/91, we performed 332 transplants before anti--HBe donors were excluded from use in non--HBV infected patients. Nine patients received anti--HBc grafts; five developed de novo HBV. All patients received standard immunosuppression with CSA/AZA/Prednisone. Data: Four patients are alive and well with a mean follow--up of 13.5 years (range 11.1-16.3 years). One patient died of metastatic squamous cell carcinoma unrelated to her liver disease 78 months following liver transplant. Two of four patients received lamivudine (LAM),one beginning 11 years after transplant and one beginning 5 years after transplant. One patient developed a mutant strain and famciclovirwas added to her regimen with good response. Conclusions: Patients who develop de novo HBV after receiving an anti--HBcAg graft generally pursue an indolent course. In those with more active disease, anti--viral therapy appears to halt progression. Long--term survival with excellent graft function can be expected.
Pt 1
Dx PBC
Follow HBV DNA HBeAg Antivir~l hepatitis/ •up (pre/post) (pre/post) Tx(yrs) fibrosis)
(yrs)
16.3
.
.
.
-~
.
.
.
.
.
.
.
.
.
J+
--'-
÷ (4.8 2
PSC
15,5
-/+
d_
3 4
PBC PBC
11.7 11.1
-~ d-
J÷ j+
5
PSC
6.5
J+
J+
Clinical Course
.
yrs/LAM + FAM) + (6.0 yrs/LAM)
'A~ymptoma~e Asymptomatic. Active hepatitis/fil~osis prior to ../severe LAM. FAM added for breakthrough 2 yrs later ~Asymptomatic mild/Asymptomatlc.HBeA9 negative after LAM Asympfomatic. Death due to -/metastatic squamous cell carcinoma of the vulva
AASLD ABSTRACTS
HEPATOLOGYOctober 2001
1879
1880
LIVER TRANSPLANTATION IN HEPATITIS B PATIENTS W I T H PREOPERATIVE RESISTANCE FORMATION DURING LAMIVUDINE TREATMENT. Daniel Seehofer, Nada Rayes, Thomas Steinm~ller, Uta Naumann, Utz
STEROID OR NO STEROID FOR PRIMARY BILIARY CIRRHOSIS (PBC), PRIMARY SCLEROSING CHOLANGITIS (PSC) AND AUTOIMMUNE HEPATITIS (AIR) UNDEER TACROLIMUS AFTER LIVER TRANSPLANTATION AND LONG-TERM SURVIVAL. Ashok B Jain, Randeep S Kashyap,
Settmacher, Andrea R M~ller, Peter Neuhaus, Charit~ Campus Virchow, Berlin Germany Objective: Due to increasing lamivudine use in chronic hepatitis B, pre-transplant lamivudine resistance is an evolving problem in potential liver transplant recipients. Since clinical data are lacking on this problem, we have characterised the perioperative course of six patients, who receiveda liver transplant after having evolved clinical lamivudine resistance. Methods: Between August 1998 and February 2001, in total 6 patients with pre-existing lamiwudine resistance undervcent liver transplantation at our centre. Four of them had primary transplantations and two retransplantations. In all patients except the last, lamivudine was continued until transplantation. Passive immunopropylaxis was started with application of 10.000 units HBIg intraoperatively and every following day under HBsAg and anti-HBs titre control. Lamivudine was continued postoperatively and combined with famciclovir during the postoperative course. Results: All patients had high viral replication preoperatively (92 - 6858 pg/ml), 5 were HBeAg positive, one was negative. Four of six patients (67%) developed early hepatitis B recurrence between day I and 120 with high viral replication but only mildly elevated liver enzymes. The remaining two (one after primary and one after secondary transplantation) are reinfection free under HBIg, lamivudine and famciclovir prophylaxis at present. All patients with primary transplantation are alive and well 11.5 months (range 1 to 17 months) after OLT. One patient with HBV recurrence after retransplantation died after 4.5 months due to sepsis and multi or-gan failure, the other patient is recurrence free 13 months after retransplantation. Liver biop-sies revealed low hepatitic activity in the patients with reinfection alive and no signs of recur-rence in the recurrence free patients. Conclusion.: Preoperative lamivudine resistance predicts high reinfection rates after liver transplantation. Using antiviral combination treatment, in most cases a relatively mild course was observed. Therefore liver transplantation in patients with lamivudine resistance seems to be justifiable, although the optimal management has to be evaluated yet.
Bijan Eghtesad, Shakeel Obaid, Asham Emad, John J Fung, T E Starzl Transplantation Institute, Pittsburgh, PA Recurrence of autoimmune process after liver transplantation (LTx) has been documented. Use of steroids has been suggested to prevent the recurrence of disease. Aim: To examine the long-term outcome after LTx for PBC, PSC and AT under tacrolimus and the need to use steroid with baseline immunosuppression. Material and Methods: Between August '89 to Dec '92, 168 patients underwent LTx for PBC (n=83), PSC (n=60), and AI (n=25). All patients were followed up to March 2000. Mean follow -up 8.8+ 0.7 year (median 8.9, range 7.2 to 10.5). Their postoperative course and base line immunosuppression was retrospectively reviewed. Results: Deaths: Total 43 patients died and 26 underwent retransplantation for PNF (n= 14), HAT (n=4) Biliary complications (n=4), rejection, acute/chronic rejection (n=3) and denovo HCV (n= 1). Survival: Overall patient survival was 74.9% at mean follow up of 9 years. Patient survival for PBC at 1, 3, 5, and 9 year was 84%, 82%, 79%, and 75%, for PSC, 98%, 92%, 82%, and 73% and for AIH 84%, 84%, 84%, and 80%. Liver functions: Current mean bilirubin is 0.6, 0.6 and 0.7, mean AST is 43.8, 32.3, and 32, mean ALT is 50, 49, and 38, mean ALKPo4 is 170, 172 and 119, mean GGTP is 113, 94, and 132 for PBC, PSC, and AIH respectively. Steroid Withdrawal: In all patients, steroid was withdrawn at some time point after LTx. Steroid reintroduction: However in 31 (24.8%) it was reintroduced for recurrence of disease. Rate of reintroduction was 18 (29%) for PBC, 6 (30%) for AI and 7(16.2%) for PSC. All patients showed improvement in biochemical profile upon reintroduction of steroid. In addition 6 (13%) patients with PSC received steroid to control colitis. Conclusion: 9-year actuarial patient survival for PBC, PSC and AI hepatitis is 76.7%, 73.2% and 80% respectively. Maintenance of steroid is not necessary in all patients. 24.8% of patients may require re-introduction of steroid with recurrent autoimmune process with a satisfactory biochemical response without any risk to allograft.
1881
1882
CHARACTERISATION OF REVERSE TRANSCRIPTASE HBV MUTANTS IN OLT PATIENTS TREATED W I T H LAMIVUDINE OR LAMIVUDINE PLUS FAMCICLOVIR. Francesco Torre, University of Genoa, Genoa Italy;
THE LONCr--TERM OUTCOME OF LIVER TRANSPLANT RECIPIENTS WITH DE NOVO HEPATITIS B INFECTION VCHO RECEIVED AN A N T I - HBC GRAFT. Michael B Ishitani, Mayo Clinic, Rochester, MN; David D Doug-
Ivo Graziadei, University of Innsbruck, lnnsbruck Austria; Andrea Delfino, University of Genoa, Genoa Italy; Wolfgang Vogel, University of Innsbruck, Innsbruck Austria; Antonino Picciotto, University of Genoa, Genoa Italy
las, Jorge Rakela, Mayo Clinic Scottsdale, Scottsdale, AZ; Rolland D Dickson, Mayo Clinic Jacksonville, Jacksonville, FL; Russell H Wiesner, Charles B Rosen, Ruud A Krom, Mayo Clinic, Rochester, MN
Background: Recurrence of hepatitis B virus (HBV) is a major problem in patients transplanted for HBV related cirrhosis. Nucleoside analogues, such as famciclovir and lamivudine, efficiently inhibit HBV replication and have been used to treat HBV recurrence after OLT. Although effective, their efficacy is hampered by viral breakthrough due to the emergence of HBV drug-resistant strains. Mutations appear mainly in the YMDD motif (M552I or M552V) and are frequently associated with another mutation at aa position 528 (L528M), which seems to confer resistance also to famciclovir. Methods: Forty-one patients (7 female) transplanted for end-stage HBV related liver disease between 1985 and 2000 were studied for a mean follow up of 3.4 years (range: 0.2-14.0 years). All of them received the usual immuno-suppressive treatment and steroids were discontinued within 3 months post OLT. Thirty-five of them received HBIg immunoprophylaxis. Fourteen patients out of 41 presented with HBV recurrence and were treated: 3 with famciclovir, 7 with lamivudine alone and 4 with famciclovir and lamivudine together. Two patients on famciclovir were switched: one to lamivudine and the other one to famciclovir plus lamivudine because of treatment inefficacy. Six of them presented with viral breakthrough. Two patients were put on adefovir dipivoxil which completely suppressed viral replication. Seventy eight serum samples have been collected accordingly to clinical history: earliest sample available, soon after OLT, at the time of recurrence and at the time of viral breakthrough. All samples have been screened by nested PCR and the positive ones have been evaluated for reverse transcriptase mutant strains by the newly developed HBV DR InnoLiPa kit (kindly donated by Innogenetics). Results: All samples before OLT were positive at the PCR, excepted in 2 patients, and all were bearing a wild type virus. At recurrence (14 patients) wild type HBV was also present. At the time of viral breakthrough the M552V mutation was present in all 6 cases, and in all of them was associated with the M528L mutation. Conclusions: Management of viral breakthrough from nucleoside analogues represents the major issue in this group of OLT patients. These data clearly show how even the association of famciclovir and lamivudine was unable to prevent this outbreak. At this time, adefovir dipivoxil seems to represent the only effective treatment available in this subgroup of patients.
A liver from a donor who is serum anti--HBc positive will result in hepatitis B viral (HBV) infection in a high percentage of recipients. The clinical course of these patients ranges from a largely indolent course to a rapid decline due to severe complications of HBV infection. Lamivudine appears to slow or stabilize the clinical course of HBV infection in these patients. Little information is available on the long--term clinical outcome of liver transplant recipients who develop de novo HBV infection after receiving a liver from an anti--HBc positive donor. Methods: From 3/85-11/91, we performed 332 transplants before anti--HBe donors were excluded from use in non--HBV infected patients. Nine patients received anti--HBc grafts; five developed de novo HBV. All patients received standard immunosuppression with CSA/AZA/Prednisone. Data: Four patients are alive and well with a mean follow--up of 13.5 years (range 11.1-16.3 years). One patient died of metastatic squamous cell carcinoma unrelated to her liver disease 78 months following liver transplant. Two of four patients received lamivudine (LAM),one beginning 11 years after transplant and one beginning 5 years after transplant. One patient developed a mutant strain and famciclovirwas added to her regimen with good response. Conclusions: Patients who develop de novo HBV after receiving an anti--HBcAg graft generally pursue an indolent course. In those with more active disease, anti--viral therapy appears to halt progression. Long--term survival with excellent graft function can be expected.
Pt 1
Dx PBC
Follow HBV DNA HBeAg Antivir~l hepatitis/ •up (pre/post) (pre/post) Tx(yrs) fibrosis)
(yrs)
16.3
.
.
.
-~
.
.
.
.
.
.
.
.
.
J+
--'-
÷ (4.8 2
PSC
15,5
-/+
d_
3 4
PBC PBC
11.7 11.1
-~ d-
J÷ j+
5
PSC
6.5
J+
J+
Clinical Course
.
yrs/LAM + FAM) + (6.0 yrs/LAM)
'A~ymptoma~e Asymptomatic. Active hepatitis/fil~osis prior to ../severe LAM. FAM added for breakthrough 2 yrs later ~Asymptomatic mild/Asymptomatlc.HBeA9 negative after LAM Asympfomatic. Death due to -/metastatic squamous cell carcinoma of the vulva