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197NF-κB activation in liver allografts correlates with severity of histological disease & fibrosis in recurrent hepatitis C virus disease
Program Abstracts
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Evidence of serious damage induced by de n o v o HBV infection after o r t h o t o p i c liver transplantation (OLT).
THE DECLINING TITER OF ANTI-HBs IN ,'SERUM OF LIVER TRANSPLANT RECIPIENTS SWITCHED FROM IIEPATITIS B IMMUNOGLOBULINSTO LAMIVUDINE PROPHYLAXIS G Tisone. D Di Paolo. M Angalico. G Trinitu. G laria. E Tom. A Ansclruo, S. Mensi. C. Camplone. C.U. Casciani. Liver Transplant Ctr & Gasrro UniL Tor Ver,~la Universi~.. Rome. and Imruunoprophylaxis CIT. S. Eugenio Hospilal. Rome. Italy
R Segovia, A Sanchez-Fueyo, J Costa, C Soguero, L Grande, M Bruguera, A Rimola, Liver Transplant Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain, The occurrence of de novo HBV infection after OLT in patients who were HBsAg-negative pre-OLT has been increasingly observed in the last years and commonly described as a relatively benign condition. To report the incidence, clinical course and potential source of infection of de novo HBV infection after OLT, we reviewed the charts of 502 non-HBV related OLT performed in the last ten years at our institution, with at least 3 months survival, and we identified 19 of such cases (4%). De novo HBV infection, defined as the appearance of HBsAg after OLT, was detected a median of 9 months post-OLT (range: 4-81 months). At the end of follow-up (median of 25 months after the detection of the de novc HBV infection), 12 (63%) out of the 19 patients had a serious graft HBV-related damage (6 cirrhosis, 4 bridging chronic hepatitis, and 2 fulminant hepatic failure), whereas the remaining 7 patients had a less important lesion (6 mild to moderate chronic hepatitis, and 1 without any significant graft lesion; this patient spontaneously seroconverted to anti-HBs). Overall, 7 (37%) patients lost their grafts, and 4 (21%) died. All graft losses and deaths were directly related to the de novo HBV infection. In 12 out of 13 patients in whom possible sources of HBV infection could be tracked, evidences of past HBV infection (positive serum anti-HBc, determined by EIA, and/or positive serum or liver tissue HBV DNA, determined by heminested PCR) were found either in the donor (7 cases) or in the recipient (5 cases). Conclusions: 1) de novo HBV infection is associated with a high rate of morbidity and mortality. and 2) most of the de novo HBV infections can be attributed to the reactivation of a donor or recipient latent infection.
Background & aims. Long-tenn passive immunoprophylaxis with haman hepatitis B immunoglobulins (HBIG) is the standard approach to preveal HBV reinfection after liver transplantation for liBV-related liver disease. However, within few years the cost of this approach grcady exceeds thai of the transplant procedure. Lamwudine is highly effective in inhibiting HBV rcplination, thus being cxplored as an ahcrnativ¢ prophylaxis or a "HBIG-sparing" agent. The aim of this study was to investigale the kinetics of decay of I-IBsAb liter in a group of liver transplant recipiems who were switched from ruonthly e.v. HBIG Io lamivudine irumunoprophyl¢,,is. Methods. Fourteen patterns ( 12 M. 49.9-_ i0 yrs) transplanted for HBV-relaled cirrhosis 18-74 months earlier were sludind. All became HBsAg negative after transplant and all ware HBsAg and HBVDNA negative in senLru and HBcAg negative in a recetu liver biopsy. Lamivudine. 100 rug/daily, was started one month after the lasl e.v administration of HB|G (5000 UI). Patienls v,ere seen al 1-2 wenk intervals to determine the half-time (50% decrease from baseline) of HBsAb tiler and the time to reach a non-protective tiler (i.e .:100 [U.'rul) Resulls. All patients were swilchcd from HBIG to lamwudine without clinical or virological advars¢ effecls All remained HBsAg and HBV-DNA negative and with normal ALT The ruedian basal HBsAb tiler was 391 IU/ml (range 306-950). The decline o( HBsAg liter was highly variable The ruedian half-tirue was 5 weeks (range 2.512). The ruedien urue Io achieve a HBsAb liter ~ 100 UI was 8.5 weeks (range 4-18) The reduction of HBsAg tiler was biexponential, with an initial fast componenl (3-8 weeks) followed b) a slow coruponcnt (8-30 weeks). A protective liter was still present in 90% of patterns at week 5, in 75% m wcck 7 and in 25% al week I I after the lasl HBIG injection. Conclusions. The currenl recorurucndation of routine ruonthly administration of HBIG to prevent HBV recurrence is questionable More cosl-effcctive schedalcs of HBIG adruinislrazmn should bc lailorcd to individual patienls'characrerislics
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LAMIVUDINEMONOTHERAPYIN NON-VIREMICHBSAG+LIVERTRANSPLANT RECIPIENTS J.Nery, M.Serho,C.Nery-Avila,A.StaUer,D.Weppler,C.O'Bnen, E.Schiff,ATzakis Purpose:Development of HBV resistance during prevention or treatment of viral recurrence after liver transplant(LTx) has stirred a lot of interest in the developmentof new agents and multkdrug regimens. The aim of this study is to reviewour experience with non-viremic HBsAg+ LTx recipients in order to evaluate the need for combined agents or new antivirals in these pts. Patients/Methoda:Between Aug/94 and Dec/99 36 patients(pts)who underwentLTx due to HBsAg+cirrhosis without demonstrable preLTx HBeAg or HBVDNA received only lamivudine for prevention or treatment of HBV recurrence. The following conditions were present in 14 pts: HCC(5), co-infeclion by HCV (?) or HDV(2), and alcohol abuse(8). Post-LTx follow up has been 1-66 mos (median=41). In 15 pts lamivudine was stsded post-operatively(1-26rues, median=11) to replace HBIg or HBIg+famciclovir in the setting of viral recurrence(2) or economic constraints(13), and has been continued for 37-56mos(median=44). In 21pts the drug was staded 1dayto 10mospre.operatively(median=2mos), and those pts have been on the drug for 3-59mos(median=24) after LTx. All pts have been treated conUnuously, except two, who intenupted the (reatment at 12 and 24mos for complete seroconversion. Breakthroughcriteria was defined based on clinical, biochemical (24o 3-fold increment of Iransaminases), and serologic changes. 16 pts underwent 50 liver biopsies and the specimens were stained for H/E, and immunoperoxidase for surface and core antigens. Rosults:Pt and graft survivalare 97°/,,and 66%, rospectivsly.One pt died from recurrent HCC at 9mos, and 4 underwent early retx for primary graft nonfunction(3) and hepatic artery thrombesis{1). The most recent ALT and Direct Bilirubin levels are 40+5.3 IU/dl and 0.3 ¢,O.09mg/dl, respectively(mean:l:SEM).No evidenceof HBV infection was observed in any of the biopsies. Serologically,freedom of HBV recurrence was observedat all limos since introduction of lamivudine in 100%of the pts, with a single exception: the p( who discontinued the drug at 12mo~. He had viral reectivation 12mos later, was re-started on lamivudine, became serologically negative after 3mos, and has alternated betweennegativeand low levels of viremia for the past year. Conclusions: Lamivudine monotherepycontrols HBV recurrence in non.viremic pts undergoing LTx, and can obviate the use of combined agents or cumbersome immunoprophylaxis. We speculate that, low pre-LTx viral activity and RT enzyme blockade rosull in remarkably reduced loads of viral particles going from extrahepatic sites into the new liver and,conseduentiy, in lower selection pressure and mu(aUon rates. The 2pts rescued from S-mutant re-infec~on and the one with re-infection by lamivudine-sensitive strain can be al higher risk for recurrence. Breakthroughfollowing treatment interruption stresses the need for tests assuring viral eradication through the hepatocyteturnover,such as demonstration ol ccoONAelimination from the nuclei.
NF-IcB ACTIVATION IN LIVER ALLOGRAFTS CORRELATES WITH SEVERITY OF HISTOLOGICAL DISEASE & FIBROSIS IN RECURRENT HEPATITIS C VIRUS DISEASE. G Cheifec I, AS Gawcco I, RI-I Wiesner2, VK Rustgi ~, M Poreyko z, S Yong I, J Harig I, KD McClatchey I, DH Van Thiel I. Loyola Univ Chicago Med Ctr I, Maywood, [L; Mayo Clinic 2, Rochester, MN & Georgetown Univ Med Ctr3, Washington, DC Nuclear factor Y,.B L"NF-Y~B] is activated during viral infection and is central to the regulation of host immune responses. The NF-KB activation status and its morphological sources were assessed by irnmanohistochemistry in allograft biopsies o f orthotopic liver transplantation [OLTx] patients with recurrent HCV disease. NF-KB immunostaining was detected in hepatocytas compared to non-transplant (P<0.001) or transplant (P=0.006) controls which correlated with the number of NF-Y~+ hepatocytes (P=0.01) and contrasted to the absent to weak staining of non-transplant (P-0.001) and transplant (P-0.009) controls. Enhanced NF-~:B staining of cytokcratin 19-positive bile ducts and proliferating ducmles in the HCV group was in contrast to controls. Strong NF-KB immunorcectivity was detected in CD68+ Kupffer cells and macrophages o f all HCV spocimans compared to a few non-transplant (P<0.001) or Iz'ansplant (P=-0.001) controls which contrasted to the weak staining of non-transplant (P<0.001) and transplant (P=0.001) controls. The weak HF-KB+ immunoreactivity o f TCRoJ[3+ lymphocytcs was not observed in controls. The staining intensity and fi'equcncy of NF-Y,.B+ cells within morphological compartments assessed was higher in HCV+ allografis with histologic evidence of nccroinflammatury acitivity and fibrosis and in those obtained fi'oru patients under tacroliruus- compared to cyclosporine-based immunosuppression. The NF-Y~B staining intensity o f hepatocytcs and lymphocytes positively correlated with the severity of Iobular inflammation (hepatocyles:P=0.013; infiltrates:P=-0.025), portal inflammation (hcpatucytcs:P=0.031 ), piecemeal necrosis (hepatocytes:P=O.027) and fibrosis (hcpatocytes:P=0.037; infiltrates:P=0.040); and of Kupffer cells within the tacrolimus group which correlated with tacroliruus levels (P=0.0t 7). These data implicate an immunoregulatory role of local NF-Y,.B activation in the pathogeaasis and progression o f post-txansplant HCV disease recurrence.
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Evidence of serious damage induced by de n o v o HBV infection after o r t h o t o p i c liver transplantation (OLT).
THE DECLINING TITER OF ANTI-HBs IN ,'SERUM OF LIVER TRANSPLANT RECIPIENTS SWITCHED FROM IIEPATITIS B IMMUNOGLOBULINSTO LAMIVUDINE PROPHYLAXIS G Tisone. D Di Paolo. M Angalico. G Trinitu. G laria. E Tom. A Ansclruo, S. Mensi. C. Camplone. C.U. Casciani. Liver Transplant Ctr & Gasrro UniL Tor Ver,~la Universi~.. Rome. and Imruunoprophylaxis CIT. S. Eugenio Hospilal. Rome. Italy
R Segovia, A Sanchez-Fueyo, J Costa, C Soguero, L Grande, M Bruguera, A Rimola, Liver Transplant Unit, Hospital Clinic, IDIBAPS, Barcelona, Spain, The occurrence of de novo HBV infection after OLT in patients who were HBsAg-negative pre-OLT has been increasingly observed in the last years and commonly described as a relatively benign condition. To report the incidence, clinical course and potential source of infection of de novo HBV infection after OLT, we reviewed the charts of 502 non-HBV related OLT performed in the last ten years at our institution, with at least 3 months survival, and we identified 19 of such cases (4%). De novo HBV infection, defined as the appearance of HBsAg after OLT, was detected a median of 9 months post-OLT (range: 4-81 months). At the end of follow-up (median of 25 months after the detection of the de novc HBV infection), 12 (63%) out of the 19 patients had a serious graft HBV-related damage (6 cirrhosis, 4 bridging chronic hepatitis, and 2 fulminant hepatic failure), whereas the remaining 7 patients had a less important lesion (6 mild to moderate chronic hepatitis, and 1 without any significant graft lesion; this patient spontaneously seroconverted to anti-HBs). Overall, 7 (37%) patients lost their grafts, and 4 (21%) died. All graft losses and deaths were directly related to the de novo HBV infection. In 12 out of 13 patients in whom possible sources of HBV infection could be tracked, evidences of past HBV infection (positive serum anti-HBc, determined by EIA, and/or positive serum or liver tissue HBV DNA, determined by heminested PCR) were found either in the donor (7 cases) or in the recipient (5 cases). Conclusions: 1) de novo HBV infection is associated with a high rate of morbidity and mortality. and 2) most of the de novo HBV infections can be attributed to the reactivation of a donor or recipient latent infection.
Background & aims. Long-tenn passive immunoprophylaxis with haman hepatitis B immunoglobulins (HBIG) is the standard approach to preveal HBV reinfection after liver transplantation for liBV-related liver disease. However, within few years the cost of this approach grcady exceeds thai of the transplant procedure. Lamwudine is highly effective in inhibiting HBV rcplination, thus being cxplored as an ahcrnativ¢ prophylaxis or a "HBIG-sparing" agent. The aim of this study was to investigale the kinetics of decay of I-IBsAb liter in a group of liver transplant recipiems who were switched from ruonthly e.v. HBIG Io lamivudine irumunoprophyl¢,,is. Methods. Fourteen patterns ( 12 M. 49.9-_ i0 yrs) transplanted for HBV-relaled cirrhosis 18-74 months earlier were sludind. All became HBsAg negative after transplant and all ware HBsAg and HBVDNA negative in senLru and HBcAg negative in a recetu liver biopsy. Lamivudine. 100 rug/daily, was started one month after the lasl e.v administration of HB|G (5000 UI). Patienls v,ere seen al 1-2 wenk intervals to determine the half-time (50% decrease from baseline) of HBsAb tiler and the time to reach a non-protective tiler (i.e .:100 [U.'rul) Resulls. All patients were swilchcd from HBIG to lamwudine without clinical or virological advars¢ effecls All remained HBsAg and HBV-DNA negative and with normal ALT The ruedian basal HBsAb tiler was 391 IU/ml (range 306-950). The decline o( HBsAg liter was highly variable The ruedian half-tirue was 5 weeks (range 2.512). The ruedien urue Io achieve a HBsAb liter ~ 100 UI was 8.5 weeks (range 4-18) The reduction of HBsAg tiler was biexponential, with an initial fast componenl (3-8 weeks) followed b) a slow coruponcnt (8-30 weeks). A protective liter was still present in 90% of patterns at week 5, in 75% m wcck 7 and in 25% al week I I after the lasl HBIG injection. Conclusions. The currenl recorurucndation of routine ruonthly administration of HBIG to prevent HBV recurrence is questionable More cosl-effcctive schedalcs of HBIG adruinislrazmn should bc lailorcd to individual patienls'characrerislics
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LAMIVUDINEMONOTHERAPYIN NON-VIREMICHBSAG+LIVERTRANSPLANT RECIPIENTS J.Nery, M.Serho,C.Nery-Avila,A.StaUer,D.Weppler,C.O'Bnen, E.Schiff,ATzakis Purpose:Development of HBV resistance during prevention or treatment of viral recurrence after liver transplant(LTx) has stirred a lot of interest in the developmentof new agents and multkdrug regimens. The aim of this study is to reviewour experience with non-viremic HBsAg+ LTx recipients in order to evaluate the need for combined agents or new antivirals in these pts. Patients/Methoda:Between Aug/94 and Dec/99 36 patients(pts)who underwentLTx due to HBsAg+cirrhosis without demonstrable preLTx HBeAg or HBVDNA received only lamivudine for prevention or treatment of HBV recurrence. The following conditions were present in 14 pts: HCC(5), co-infeclion by HCV (?) or HDV(2), and alcohol abuse(8). Post-LTx follow up has been 1-66 mos (median=41). In 15 pts lamivudine was stsded post-operatively(1-26rues, median=11) to replace HBIg or HBIg+famciclovir in the setting of viral recurrence(2) or economic constraints(13), and has been continued for 37-56mos(median=44). In 21pts the drug was staded 1dayto 10mospre.operatively(median=2mos), and those pts have been on the drug for 3-59mos(median=24) after LTx. All pts have been treated conUnuously, except two, who intenupted the (reatment at 12 and 24mos for complete seroconversion. Breakthroughcriteria was defined based on clinical, biochemical (24o 3-fold increment of Iransaminases), and serologic changes. 16 pts underwent 50 liver biopsies and the specimens were stained for H/E, and immunoperoxidase for surface and core antigens. Rosults:Pt and graft survivalare 97°/,,and 66%, rospectivsly.One pt died from recurrent HCC at 9mos, and 4 underwent early retx for primary graft nonfunction(3) and hepatic artery thrombesis{1). The most recent ALT and Direct Bilirubin levels are 40+5.3 IU/dl and 0.3 ¢,O.09mg/dl, respectively(mean:l:SEM).No evidenceof HBV infection was observed in any of the biopsies. Serologically,freedom of HBV recurrence was observedat all limos since introduction of lamivudine in 100%of the pts, with a single exception: the p( who discontinued the drug at 12mo~. He had viral reectivation 12mos later, was re-started on lamivudine, became serologically negative after 3mos, and has alternated betweennegativeand low levels of viremia for the past year. Conclusions: Lamivudine monotherepycontrols HBV recurrence in non.viremic pts undergoing LTx, and can obviate the use of combined agents or cumbersome immunoprophylaxis. We speculate that, low pre-LTx viral activity and RT enzyme blockade rosull in remarkably reduced loads of viral particles going from extrahepatic sites into the new liver and,conseduentiy, in lower selection pressure and mu(aUon rates. The 2pts rescued from S-mutant re-infec~on and the one with re-infection by lamivudine-sensitive strain can be al higher risk for recurrence. Breakthroughfollowing treatment interruption stresses the need for tests assuring viral eradication through the hepatocyteturnover,such as demonstration ol ccoONAelimination from the nuclei.
NF-IcB ACTIVATION IN LIVER ALLOGRAFTS CORRELATES WITH SEVERITY OF HISTOLOGICAL DISEASE & FIBROSIS IN RECURRENT HEPATITIS C VIRUS DISEASE. G Cheifec I, AS Gawcco I, RI-I Wiesner2, VK Rustgi ~, M Poreyko z, S Yong I, J Harig I, KD McClatchey I, DH Van Thiel I. Loyola Univ Chicago Med Ctr I, Maywood, [L; Mayo Clinic 2, Rochester, MN & Georgetown Univ Med Ctr3, Washington, DC Nuclear factor Y,.B L"NF-Y~B] is activated during viral infection and is central to the regulation of host immune responses. The NF-KB activation status and its morphological sources were assessed by irnmanohistochemistry in allograft biopsies o f orthotopic liver transplantation [OLTx] patients with recurrent HCV disease. NF-KB immunostaining was detected in hepatocytas compared to non-transplant (P<0.001) or transplant (P=0.006) controls which correlated with the number of NF-Y~+ hepatocytes (P=0.01) and contrasted to the absent to weak staining of non-transplant (P-0.001) and transplant (P-0.009) controls. Enhanced NF-~:B staining of cytokcratin 19-positive bile ducts and proliferating ducmles in the HCV group was in contrast to controls. Strong NF-KB immunorcectivity was detected in CD68+ Kupffer cells and macrophages o f all HCV spocimans compared to a few non-transplant (P<0.001) or Iz'ansplant (P=-0.001) controls which contrasted to the weak staining of non-transplant (P<0.001) and transplant (P=0.001) controls. The weak HF-KB+ immunoreactivity o f TCRoJ[3+ lymphocytcs was not observed in controls. The staining intensity and fi'equcncy of NF-Y,.B+ cells within morphological compartments assessed was higher in HCV+ allografis with histologic evidence of nccroinflammatury acitivity and fibrosis and in those obtained fi'oru patients under tacroliruus- compared to cyclosporine-based immunosuppression. The NF-Y~B staining intensity o f hepatocytcs and lymphocytes positively correlated with the severity of Iobular inflammation (hepatocyles:P=0.013; infiltrates:P=-0.025), portal inflammation (hcpatucytcs:P=0.031 ), piecemeal necrosis (hepatocytes:P=O.027) and fibrosis (hcpatocytes:P=0.037; infiltrates:P=0.040); and of Kupffer cells within the tacrolimus group which correlated with tacroliruus levels (P=0.0t 7). These data implicate an immunoregulatory role of local NF-Y,.B activation in the pathogeaasis and progression o f post-txansplant HCV disease recurrence.