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Treatment of progenessive HCV recurrence post liver transplantation with combination interferon plus Ribavirin
A996 AASLD ABSTRACTS
1157 TREATMENT OF PROGRESSIVE HCV RECURRENCE POST LIVER TRANSPLANTATION WITH COMBINATION INTERFERON PLUS RIBA VIRIN. Deepak V. Gopal, John Rabkin, Brian S. Berk, Christopher L. Corless, Ali Olyaei, Susan L. Orloff, Hugo R. Rosen, Oregon Health Sci Univ, Portland, OR; Oregon Health Sci Univ & Portland VA Med Ctr, Portland, OR; Portland VA Med Ctr, Portland, OR. INTRODUCTION: HCV recurrence following OLT is common, although most cases are mild. However, a subset of recipients develops progressive allograft injury, including cirrhosis and allograft failure. Minimal data are available on the safety/efficacy of antiviral treatment in this group of patients. AIM: To review our experience in the treatment of moderate-tosevere HCV recurrence with combination interferon-ribavirin (IFN/RIB). METHODS: We treated 11 HCV+ OLT recipients (9 male: 2 Female; mean age 46 yrs) who had at least one of the following criteria: moderateto-severe inflammation (grade III-IV), bridging fibrosis, severe cholestasis attributable solely to HCV recurrence. 3/11 (27%) patients had severe cholestasis (total bili 2: IOmg/dL) at initiation of IFN/RIB treatment. Two patients had undergone retransplantation for HCV and had progressive HCV-related injury in their 2nd allografts. Appropriate dose reductions & initiation of G-CSF (granulocyte colony stimulating factor) for marked leukopenia were recorded. HCV quantitative viral loads were also followed during treatment. RESULTS: Three (27%) of the 11 pts became PCRnegative on treatment; I has relapsed after cessation of therapy for sideeffects. The mean serum bilirubin (mg/dL) for the II pts at initiation of treatment, 3mos into therapy, and most recent values were: 6.9, 3.5, & 1.1 , respectively. Start of therapy ranged from 60-1236 days post-OLT. The 3 patients initiated within the first 6 mos post OLT had significantly higher total bili(mg/dL): 13.0:!:4.1(@ start of Rx) vs. 2.8:!:1.0 (@ 3mo)(mean:!:SEM,p=0.02). All patients required dose reduction of both IFN/RIB. No pre-treatment variables were predictive of response. In 5 patients, GCSF was successfully used to treat leukopenia. One patient required treatment with EPO(erythropoietin) for anemia. One patient died of progressive allograft failure; another patient died of causes unrelated to HCV recurrence. No patients developed acute rejection. CONCLUSIONS: In this pilot of HCV + OLT recipients with progressive recurrence: 1) PCR-negativity was attained in 27% of pts; 2) Combination IFN/RIB treatment resulted in a decrease in total bilirubin; 3) IFNIRIB therapy at standard doses required dose reduction of both medications in all pts; use of GCSF in pts with leukopenia allowed resumption of therapy at standard or higher IFN doses; 4) Multicenter trials using combination therapy in the subset of patients with progressive HCV recurrence are required.
1158 AMBULATORY LONG·TERM IMMUNOPROPHYLAXIS WITH INTRAMUSCULAR ANTI-HBs IMMUNOGLOBULIN TO PREVENT HEPATITIS B REINFECTION AFTER ORTHOTOPIC LIVER TRANSPLANTATION. Dominik Faust, Holger Rabenau, Wolfgang F. Caspary, Stefan Zeuzem, 2nd Dept of Internal Medicine, J W Goethe Univ, Frankfurt/Main, Germany; Institute for Med Virology, J W Goethe Univ, Frankfurt/Main, Germany. Introduction: Hepatitis B virus (HBV)-infected patients receive an antiHBs immunoprophylaxis after orthotopic liver transplantation to prevent reinfection. Normally, the anti-HBs immunoglobulin (HBIG) is given intravenously every 2 weeks. Burbach et al. published a short-term study (Transplantation 1997;63:478-480) demonstrating that a switch from intravenous to intramuscular anti-HBs immunoprophylaxis had no disadvantage for anti-HBs serum titers. With regard to the high costs in the care of hepatitis B-positive liver transplant recipients, we investigated anti-HBs serum titers and patient outcome during immunoprophylaxis with intramuscular applications of 2000 IV HBIG every 4 weeks. Methods: Six out-patients who received transplants between 1996 and 1998 for HBVrelated end-stage liver disease (4 male, 2 female, mean age 48 :!: 7 years) and who received HBIG intravenously were switched to intramuscular HBIG (2000 IV Hepatitis-B-Immunglobulin Behring ®) every 4 weeks. At study entry, all patients were HBV-DNA- and HBs antigen-negative. Anti-HBs titers, HBs antigen, and HBV-DNA were measured at 4 week intervals (Axsym ELISA and HBV-DNA-Kit, Abbott). Results: Over the time period of 8 :!: I months, all patients on intramuscular HBIG therapy had mean anti-HBs titers of 173 :!: 23 mElmL. HBV-DNA and HBs antigen remained negative in all patients. No local or systemic side effects or signs of reinfection were observed, and the therapy was well tolerated.
GASTROENTEROLOGY Vol. 118, No.4
The monthly costs of immunoprophylaxis were 1503 Euros compared with 4124 Euros for intravenous applications of 2000 IV HBIG every 2 weeks. Conclusions: According to the generally accepted treatment criteria, intramuscular injections of 2000 IV HBIG every 4 weeks lead to sufficient anti-HBs titers (2: 100 mElmL) in hepatitis B-positive liver transplant recipients. With regard to the increasing costs in post transplant treatment, our study implies that intramuscular injection of HBIG is a sufficient long-term regimen to prevent reinfection in hepatitis B-positive liver transplant recipients, which saves approximately 65% of the costs of intravenous immunoprophylaxis.
1159 HIGH FREQUENCY OF THE H63D MUTATION OF THE HFE HEMOCHROMATOSIS GENE IN LIVER RECIPIENTS WITH FULMINANT NON-A-B-C HEPATITIS. Leena Halme, Tiina Helio, Judit Makinen, Krister Hckerstedt, Martti Farkkila, Aamo Palotie, Kimmo Kontula, Transplantation & Liver Surg, Univ Cent Hosp, Helsinki, Finland; Dept of Medicine, Univ Cent Hosp, Helsinki, Finland; Peijas Hosp, Vantaa, Finland; Dept of Biorned, Univ Cent Hosp, Helsinki, Finland. Background: The majority of patients with inherited hemochromatosis carry two mutant alleles of the HFE gene. It is possible that individuals heterozygous for the HFE mutation are predisposed to end-stage liver disease due to other causes. Methods: We determined the frequencies of the HFE gene mutations C282Y and H63D in DNA samples obtained from 189 consecutive patients after liver transplantation and 225 healthy Finnish blood donors. The HFE genotypes were associated with the etiology of the liver disease and the iron status of the 189 explanted liver specimens. Results: Of the 189 transplant recipients, 7 (5%) were heterozygotes and 1 (0.5%) homozygotes for the C282Y mutation while 31 (16%) were heterozygotes and 1 (0.5%) homozygotes for the H63D mutation. These figures were not significantly different from those in healthy blood donors of whom 11% were C282Y heterozygotes, and 16% H63D heterozygotes and 0.9 % H63D homozygotes. Among recipients with acute non A-C hepatitis (n = 32) the frequency of the H63D allele was higher than in controls (20% vs. 9.1%, p<0.05). Perl's stain for iron of explanted liver specimen was positive in 33 % of recipients with alcoholic liver disease, 28 % of patients with acute non A-C hepatitis and 14 % in the others. HFE genotypes did not correlate with the iron status. Conclusion: Individuals heterozygous for either the C282Y or H63D mutation of the hemochromatosis HFE gene are not at increased risk of developing chronic end-stage liver disease. However, subjects heterozygous for the H63D mutation may have an increased risk to develop fulminate non-A-B-C hepatitis. 1160 GLUCOSIDASE AND MANNOSIDASE INHIBITORS MEDIATE INCREASED SECRETION OF A·I-ANTRITRYPSIN Z. Nancy Y. Marcus, David H. Perlmutter, Washington Univ Sch of Medicine, St. Louis, MO. In (l(, antitrypsin deficiency, retention of misfolded (l(, antitrypsin Z (ATZ) in the ER of liver cells is associated with liver injury and hepatocellular carcinoma and the lack of its secretion into the blood is associated with pulmonary emphysema. Some deficient individuals are protected from liver injury by efficient degradation of the misfolded ATZ protein in the ER and recent studies indicate that post-translational trimming of oligosaccharide side chains plays a role in determining ER degradation. Thus, in this study, we examined the effect of inhibiting oligosaccharide side chain trimming on the fate of ATZ in the ER in model cell culture systems. Indeed, the fate of ATZ was altered by both glucosidase and mannosidase inhibitors. Surprisingly, one glucosidase inhibitor, castanospermine (CST), the (l( mannosidase 1 inhibitor kifunensine (KIF) and the (l( mannosidase I & IT inhibitor deoxymannojirimycin (DMJ), mediated marked increases in secretion of ATZ. In each case, the ATZ that was secreted was partially functionally active. Although KIF and DMJ are probably not candidates for chemoprophylaxis because they also inhibit ER degradation of ATZ, CST mediates its marked positive effect on secretion of ATZ without affecting its degradation. These surprising results have important implications for the role of glucosidases and mannosidases in the quality control mechanism of the ER and show that CST, or compounds based on CST, constitute candidates for chemoprophylaxis of both liver and lung disease in ATZ deficiency.
1157 TREATMENT OF PROGRESSIVE HCV RECURRENCE POST LIVER TRANSPLANTATION WITH COMBINATION INTERFERON PLUS RIBA VIRIN. Deepak V. Gopal, John Rabkin, Brian S. Berk, Christopher L. Corless, Ali Olyaei, Susan L. Orloff, Hugo R. Rosen, Oregon Health Sci Univ, Portland, OR; Oregon Health Sci Univ & Portland VA Med Ctr, Portland, OR; Portland VA Med Ctr, Portland, OR. INTRODUCTION: HCV recurrence following OLT is common, although most cases are mild. However, a subset of recipients develops progressive allograft injury, including cirrhosis and allograft failure. Minimal data are available on the safety/efficacy of antiviral treatment in this group of patients. AIM: To review our experience in the treatment of moderate-tosevere HCV recurrence with combination interferon-ribavirin (IFN/RIB). METHODS: We treated 11 HCV+ OLT recipients (9 male: 2 Female; mean age 46 yrs) who had at least one of the following criteria: moderateto-severe inflammation (grade III-IV), bridging fibrosis, severe cholestasis attributable solely to HCV recurrence. 3/11 (27%) patients had severe cholestasis (total bili 2: IOmg/dL) at initiation of IFN/RIB treatment. Two patients had undergone retransplantation for HCV and had progressive HCV-related injury in their 2nd allografts. Appropriate dose reductions & initiation of G-CSF (granulocyte colony stimulating factor) for marked leukopenia were recorded. HCV quantitative viral loads were also followed during treatment. RESULTS: Three (27%) of the 11 pts became PCRnegative on treatment; I has relapsed after cessation of therapy for sideeffects. The mean serum bilirubin (mg/dL) for the II pts at initiation of treatment, 3mos into therapy, and most recent values were: 6.9, 3.5, & 1.1 , respectively. Start of therapy ranged from 60-1236 days post-OLT. The 3 patients initiated within the first 6 mos post OLT had significantly higher total bili(mg/dL): 13.0:!:4.1(@ start of Rx) vs. 2.8:!:1.0 (@ 3mo)(mean:!:SEM,p=0.02). All patients required dose reduction of both IFN/RIB. No pre-treatment variables were predictive of response. In 5 patients, GCSF was successfully used to treat leukopenia. One patient required treatment with EPO(erythropoietin) for anemia. One patient died of progressive allograft failure; another patient died of causes unrelated to HCV recurrence. No patients developed acute rejection. CONCLUSIONS: In this pilot of HCV + OLT recipients with progressive recurrence: 1) PCR-negativity was attained in 27% of pts; 2) Combination IFN/RIB treatment resulted in a decrease in total bilirubin; 3) IFNIRIB therapy at standard doses required dose reduction of both medications in all pts; use of GCSF in pts with leukopenia allowed resumption of therapy at standard or higher IFN doses; 4) Multicenter trials using combination therapy in the subset of patients with progressive HCV recurrence are required.
1158 AMBULATORY LONG·TERM IMMUNOPROPHYLAXIS WITH INTRAMUSCULAR ANTI-HBs IMMUNOGLOBULIN TO PREVENT HEPATITIS B REINFECTION AFTER ORTHOTOPIC LIVER TRANSPLANTATION. Dominik Faust, Holger Rabenau, Wolfgang F. Caspary, Stefan Zeuzem, 2nd Dept of Internal Medicine, J W Goethe Univ, Frankfurt/Main, Germany; Institute for Med Virology, J W Goethe Univ, Frankfurt/Main, Germany. Introduction: Hepatitis B virus (HBV)-infected patients receive an antiHBs immunoprophylaxis after orthotopic liver transplantation to prevent reinfection. Normally, the anti-HBs immunoglobulin (HBIG) is given intravenously every 2 weeks. Burbach et al. published a short-term study (Transplantation 1997;63:478-480) demonstrating that a switch from intravenous to intramuscular anti-HBs immunoprophylaxis had no disadvantage for anti-HBs serum titers. With regard to the high costs in the care of hepatitis B-positive liver transplant recipients, we investigated anti-HBs serum titers and patient outcome during immunoprophylaxis with intramuscular applications of 2000 IV HBIG every 4 weeks. Methods: Six out-patients who received transplants between 1996 and 1998 for HBVrelated end-stage liver disease (4 male, 2 female, mean age 48 :!: 7 years) and who received HBIG intravenously were switched to intramuscular HBIG (2000 IV Hepatitis-B-Immunglobulin Behring ®) every 4 weeks. At study entry, all patients were HBV-DNA- and HBs antigen-negative. Anti-HBs titers, HBs antigen, and HBV-DNA were measured at 4 week intervals (Axsym ELISA and HBV-DNA-Kit, Abbott). Results: Over the time period of 8 :!: I months, all patients on intramuscular HBIG therapy had mean anti-HBs titers of 173 :!: 23 mElmL. HBV-DNA and HBs antigen remained negative in all patients. No local or systemic side effects or signs of reinfection were observed, and the therapy was well tolerated.
GASTROENTEROLOGY Vol. 118, No.4
The monthly costs of immunoprophylaxis were 1503 Euros compared with 4124 Euros for intravenous applications of 2000 IV HBIG every 2 weeks. Conclusions: According to the generally accepted treatment criteria, intramuscular injections of 2000 IV HBIG every 4 weeks lead to sufficient anti-HBs titers (2: 100 mElmL) in hepatitis B-positive liver transplant recipients. With regard to the increasing costs in post transplant treatment, our study implies that intramuscular injection of HBIG is a sufficient long-term regimen to prevent reinfection in hepatitis B-positive liver transplant recipients, which saves approximately 65% of the costs of intravenous immunoprophylaxis.
1159 HIGH FREQUENCY OF THE H63D MUTATION OF THE HFE HEMOCHROMATOSIS GENE IN LIVER RECIPIENTS WITH FULMINANT NON-A-B-C HEPATITIS. Leena Halme, Tiina Helio, Judit Makinen, Krister Hckerstedt, Martti Farkkila, Aamo Palotie, Kimmo Kontula, Transplantation & Liver Surg, Univ Cent Hosp, Helsinki, Finland; Dept of Medicine, Univ Cent Hosp, Helsinki, Finland; Peijas Hosp, Vantaa, Finland; Dept of Biorned, Univ Cent Hosp, Helsinki, Finland. Background: The majority of patients with inherited hemochromatosis carry two mutant alleles of the HFE gene. It is possible that individuals heterozygous for the HFE mutation are predisposed to end-stage liver disease due to other causes. Methods: We determined the frequencies of the HFE gene mutations C282Y and H63D in DNA samples obtained from 189 consecutive patients after liver transplantation and 225 healthy Finnish blood donors. The HFE genotypes were associated with the etiology of the liver disease and the iron status of the 189 explanted liver specimens. Results: Of the 189 transplant recipients, 7 (5%) were heterozygotes and 1 (0.5%) homozygotes for the C282Y mutation while 31 (16%) were heterozygotes and 1 (0.5%) homozygotes for the H63D mutation. These figures were not significantly different from those in healthy blood donors of whom 11% were C282Y heterozygotes, and 16% H63D heterozygotes and 0.9 % H63D homozygotes. Among recipients with acute non A-C hepatitis (n = 32) the frequency of the H63D allele was higher than in controls (20% vs. 9.1%, p<0.05). Perl's stain for iron of explanted liver specimen was positive in 33 % of recipients with alcoholic liver disease, 28 % of patients with acute non A-C hepatitis and 14 % in the others. HFE genotypes did not correlate with the iron status. Conclusion: Individuals heterozygous for either the C282Y or H63D mutation of the hemochromatosis HFE gene are not at increased risk of developing chronic end-stage liver disease. However, subjects heterozygous for the H63D mutation may have an increased risk to develop fulminate non-A-B-C hepatitis. 1160 GLUCOSIDASE AND MANNOSIDASE INHIBITORS MEDIATE INCREASED SECRETION OF A·I-ANTRITRYPSIN Z. Nancy Y. Marcus, David H. Perlmutter, Washington Univ Sch of Medicine, St. Louis, MO. In (l(, antitrypsin deficiency, retention of misfolded (l(, antitrypsin Z (ATZ) in the ER of liver cells is associated with liver injury and hepatocellular carcinoma and the lack of its secretion into the blood is associated with pulmonary emphysema. Some deficient individuals are protected from liver injury by efficient degradation of the misfolded ATZ protein in the ER and recent studies indicate that post-translational trimming of oligosaccharide side chains plays a role in determining ER degradation. Thus, in this study, we examined the effect of inhibiting oligosaccharide side chain trimming on the fate of ATZ in the ER in model cell culture systems. Indeed, the fate of ATZ was altered by both glucosidase and mannosidase inhibitors. Surprisingly, one glucosidase inhibitor, castanospermine (CST), the (l( mannosidase 1 inhibitor kifunensine (KIF) and the (l( mannosidase I & IT inhibitor deoxymannojirimycin (DMJ), mediated marked increases in secretion of ATZ. In each case, the ATZ that was secreted was partially functionally active. Although KIF and DMJ are probably not candidates for chemoprophylaxis because they also inhibit ER degradation of ATZ, CST mediates its marked positive effect on secretion of ATZ without affecting its degradation. These surprising results have important implications for the role of glucosidases and mannosidases in the quality control mechanism of the ER and show that CST, or compounds based on CST, constitute candidates for chemoprophylaxis of both liver and lung disease in ATZ deficiency.