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Renal dysfunction (RD) following orthotopic liver transplantation (OLT): role of cyclosporine (CsA) elimination as provided by the neoral (NEO) formulation
Poster Sessions
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sally effective posttransplant prophylaxis. This study investigates whether this regimen may eradicate latent HBV infection posttransplant. 8 patients transplanted for HBV-cirrhosis were studied. Three were HBeAg+, 4 HBeAg neg/DNA+ and 1 HBeAg neg/DNA neg (HDV co-infection). All received pretransplant lamivudine 100 mg/day for at least 4 weeks and posttransplant lamivudine and IM HBIG 800 units/month. Serum and liver were collected at transplant and 12 months. Serum HBV DNA was detected by PCR (precore primers) and quantified by limiting dilution. Liver HBV cccDNA was detected by primers spanning the region of the HBV genome which is incomplete in non-cccDNA and quantified by real-time PCR using the LightCycler and hybridisation probes. Explant HBV cccDNA levels were higher in HBeAg+ compared to HBeAg negative patients (8.6 4- 5.0 vs 0.03 4- 0.01 copies/human genome equivalents (Geq); p = 0.018) and undetectable in the patient with HDV. After one year, serum in all patients was HBsAg negative, anti-HBs positive (65-1000 iu/ml) and HBV DNA negative. Liver HBV cccDNA levels were low (median 0.006 copies/GEq; range 0--0.018) compared to the explant (p = 0.04). HBV cccDNA levels were low in HBeAg negative (undetectable in 2/5) compared to HBeAg positive patients (0.002 4- 0.002 vs. 0.013 4- 0.004 copies/Geq; p = 0.05). Combination Lamivudine/low-dose IM HBIG suppresses HBV replication posttransplant and may eradicate latent HBV infection in HbeAg negative patients, cccDNA negative patients may be possible candidates for late HBIG withdrawal.
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PROPHYLACTIC BANDING LIGATION OF HIGH RISK ESOPHAGEAL VARICES IN PATIENTS ON THE WAITING LIST FOR LIVER TRANSPLANTATION: AN INTERIM REPORT
toxicity might be due to higher drug exposure in patients with RD than in patients without RD, therefore toxicity might decrease with switch to NEO C2 or dose reduction. CsA pharmacokinetics were evaluated in 14 patients with RD (creatinine clearance, C1 < 60 ml/min) and 12 matched patients without RD (C1 > 80 ml/min), while already on low Neo dosage. There was no difference between groups for age, time from OLT (54 + 8 vs 91 4- 24 months), and NEO dose (77 4- 7 vs 89 4- 19 mg/bid). Blood samples were obtained for CsA determination from 0 to 8 hrs following usual oral NEO dosage. Results: There was a significant difference between groups for C1, (46.7 4- 3.8 vs 98.5 4- 3.5 ml/min, p < 0.001). However there was no difference between groups for: CO (91.6 4- 15.9 vs 86.0 4- 7.7 nmol/L), area under curve (AUC) from 0 to 8 hrs, Cmax (761 4- 56 vs 687 4- 83 nmol/L), time to Cmax (1.5 4- 01 vs 1.9 4- 1.2 hrs), C2 (618 4- 47 vs 584 4- 71 nmol/L), absorption constant (ka), and apparent elimination constant (kel: 0.18 40.02 vs 1.23 4- 0.04). As expected, considering all patients, there was a significant correlation between AUC 0 to 8 h and C2 (r: 0.892, p < 0.001) and to a lesser extent with CO (r: 0669, p < 0.001). Conclusion: These findings indicate that CsA phannacokinetics are similar in matched patients with or without RD even when using reduced NEO doses and low C2 levels. In order to treat calcineurin inhibitor-induced RD, new strategies are needed.
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RELATIONSHIP BETWEEN ALCOHOLIC RELAPSE, NON COMPLIANCE AND HISTOLOGICAL LESIONS AFTER LIVER TRANSPLANTATION (LT) FOR ALCOHOLIC CIRRHOSIS (AC)
Cristian Gheorghe 1, Liana Gheorghe 1, Roxana Vadan I , Doina Hrehoret 2, Irinel Popescu 2. 1Center of Gastroenterology and Hepatology, Fundeni
Monika Hurtova, Jean-Charles Duclos-Vallee, Valerie Delvart, Vincent Karam, Faouzi Saliba, Philippe Ichai, Cyrille Feray, Catherine Guettier, Henri Bismuth, Didier Samuel. Hepato-Biliary Center,
Clinical Institute, Bucharest; 2Department of Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
Paul Brousse Hospital, Villejuif, France
Background/Aim: Primary prophylactic endoscopic ligation of high risk esophageal varices in cirrhotic patients on the waiting list (WL) has not yet been evaluated. We developed a study designed to determine the efficacy of prophylactic endoscopic variceal ligation (EVL) on the first episode of gastrointestinal bleeding and related mortality in cirrhotic patients with high risk esophageal varices on the WL. Material and Methods: From the 89 patients on WL, 53 cirrhotic patients with endoscopically assessed high risk esophageal varices {more than 5 mm, red signs, Child-Pugh B or C) but no history of variceal bleeding were randomized to receive either Propranolol or EVL. Ligation was performed at 3 week interval untill variceal obliteration was achieved, using a sixshutter Saed Ligator. Results: During a median follow-up of 14.89 months (SD 4- 6.22), 3 out of 25 patients (12%) in the EVL group and 13 out of 28 patients (46.4%) in the Propranolol group experienced variceal bleeding (p = 0.04). One patient (4%) in the ligation group and 5 patients (17.8%) in the Propranolol group died (p = 0.1). Conclusion: This interim report showed that EVL significantly reduces the incidence of first episode of variceal bleeding in cirrhotic patients with high-risk varices on WL. Furthermore, there was a trend of reducing mortality from variceal bleeding in patients receiving EVL.
51 RENAL DYSFUNCTION (RD) FOLLOWING ORTHOTOPIC LIVER TRANSPLANTATION (OLT): ROLE OF CYCLOSPORINE (CsA) ELIMINATION AS PROVIDED BY THE NEORAL (NEO) FORMULATION R-Michel Huet 1, Denis Marleau l , Wendy Hauck 2. 1Department of Medicine, Centre Hospitalier de l'Universitd de MontrdaL Montrdal, Qudbec; 2Novartis Pharma Canada, Montrdal, Qudbec, Canada Objectives: RD is well recognized in OLT patients and has been related to long term use of calcineurin inhibitors. With NEO CO monitoring, renal
Although good results of LT for AC have been reported, consequences of alcoholic relapse after LT have to be evaluated. Aim: Evaluate (1) the alcohol relapse rate in patients transplanted for alcoholic liver disease (ALD) (2), the influence of alcohol relapse on the post-LT course. Methods: We retrospectively examined charts of 110 patients, (94 males, 16 females), 50.8 4- 8.6 yrs at LT (31-68). Alcohol recurrence was detected by interviews, anonymous questionnaries, clinical, biological indicators of alcohol intake and histological examination. Abstinence was defined by absence of any alcohol drink, social drink by less than 14 units/week, heavy drinking by more than 14 units/week and/or periods of time with more than 4 units/day. Routine biopsies were performed at 1, 2, 5 and 10 years. Results: 24 patients (21.8%) (18 M, 6 F) relapsed alcoholism and 15 had a heavy relapse. Mean delay of relapse was 2.1 yrs (0.3-6 yrs) and occurred during the first 3 years in 67% of cases. Neither sex nor preLT abstinence period was a predictive for alcohol relapse. Acute alcoholic hepatitis appeared in 6 patients (25%); moderate to severe steatosis was found more frequent in the relapser group (66.7% vs 23%, p < 0.001). Fibrosis was more frequent in the relapser group (25% vs 8.2%, p = 0.03). Chronic rejection was more frequent in the group with heavy relapse after LT (53.5% vs 20.5%, p = 0.008). Three relapsers discontinued immunosuppressive therapy. Survival rate at 1 and 5 yrs was 85.8% and 62.2%, respectively (n.s.). Conclusions: The observed relapse rate is 22% and the main consequence of alcoholism relapse is steatosis and/or fibrosis on liver graft. Chronic rejection occurs frequently particularly in heavy relapsers and may influence long-term patient and graft survival rate.
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sally effective posttransplant prophylaxis. This study investigates whether this regimen may eradicate latent HBV infection posttransplant. 8 patients transplanted for HBV-cirrhosis were studied. Three were HBeAg+, 4 HBeAg neg/DNA+ and 1 HBeAg neg/DNA neg (HDV co-infection). All received pretransplant lamivudine 100 mg/day for at least 4 weeks and posttransplant lamivudine and IM HBIG 800 units/month. Serum and liver were collected at transplant and 12 months. Serum HBV DNA was detected by PCR (precore primers) and quantified by limiting dilution. Liver HBV cccDNA was detected by primers spanning the region of the HBV genome which is incomplete in non-cccDNA and quantified by real-time PCR using the LightCycler and hybridisation probes. Explant HBV cccDNA levels were higher in HBeAg+ compared to HBeAg negative patients (8.6 4- 5.0 vs 0.03 4- 0.01 copies/human genome equivalents (Geq); p = 0.018) and undetectable in the patient with HDV. After one year, serum in all patients was HBsAg negative, anti-HBs positive (65-1000 iu/ml) and HBV DNA negative. Liver HBV cccDNA levels were low (median 0.006 copies/GEq; range 0--0.018) compared to the explant (p = 0.04). HBV cccDNA levels were low in HBeAg negative (undetectable in 2/5) compared to HBeAg positive patients (0.002 4- 0.002 vs. 0.013 4- 0.004 copies/Geq; p = 0.05). Combination Lamivudine/low-dose IM HBIG suppresses HBV replication posttransplant and may eradicate latent HBV infection in HbeAg negative patients, cccDNA negative patients may be possible candidates for late HBIG withdrawal.
~-1
PROPHYLACTIC BANDING LIGATION OF HIGH RISK ESOPHAGEAL VARICES IN PATIENTS ON THE WAITING LIST FOR LIVER TRANSPLANTATION: AN INTERIM REPORT
toxicity might be due to higher drug exposure in patients with RD than in patients without RD, therefore toxicity might decrease with switch to NEO C2 or dose reduction. CsA pharmacokinetics were evaluated in 14 patients with RD (creatinine clearance, C1 < 60 ml/min) and 12 matched patients without RD (C1 > 80 ml/min), while already on low Neo dosage. There was no difference between groups for age, time from OLT (54 + 8 vs 91 4- 24 months), and NEO dose (77 4- 7 vs 89 4- 19 mg/bid). Blood samples were obtained for CsA determination from 0 to 8 hrs following usual oral NEO dosage. Results: There was a significant difference between groups for C1, (46.7 4- 3.8 vs 98.5 4- 3.5 ml/min, p < 0.001). However there was no difference between groups for: CO (91.6 4- 15.9 vs 86.0 4- 7.7 nmol/L), area under curve (AUC) from 0 to 8 hrs, Cmax (761 4- 56 vs 687 4- 83 nmol/L), time to Cmax (1.5 4- 01 vs 1.9 4- 1.2 hrs), C2 (618 4- 47 vs 584 4- 71 nmol/L), absorption constant (ka), and apparent elimination constant (kel: 0.18 40.02 vs 1.23 4- 0.04). As expected, considering all patients, there was a significant correlation between AUC 0 to 8 h and C2 (r: 0.892, p < 0.001) and to a lesser extent with CO (r: 0669, p < 0.001). Conclusion: These findings indicate that CsA phannacokinetics are similar in matched patients with or without RD even when using reduced NEO doses and low C2 levels. In order to treat calcineurin inhibitor-induced RD, new strategies are needed.
•I
RELATIONSHIP BETWEEN ALCOHOLIC RELAPSE, NON COMPLIANCE AND HISTOLOGICAL LESIONS AFTER LIVER TRANSPLANTATION (LT) FOR ALCOHOLIC CIRRHOSIS (AC)
Cristian Gheorghe 1, Liana Gheorghe 1, Roxana Vadan I , Doina Hrehoret 2, Irinel Popescu 2. 1Center of Gastroenterology and Hepatology, Fundeni
Monika Hurtova, Jean-Charles Duclos-Vallee, Valerie Delvart, Vincent Karam, Faouzi Saliba, Philippe Ichai, Cyrille Feray, Catherine Guettier, Henri Bismuth, Didier Samuel. Hepato-Biliary Center,
Clinical Institute, Bucharest; 2Department of Surgery and Liver Transplantation, Fundeni Clinical Institute, Bucharest, Romania
Paul Brousse Hospital, Villejuif, France
Background/Aim: Primary prophylactic endoscopic ligation of high risk esophageal varices in cirrhotic patients on the waiting list (WL) has not yet been evaluated. We developed a study designed to determine the efficacy of prophylactic endoscopic variceal ligation (EVL) on the first episode of gastrointestinal bleeding and related mortality in cirrhotic patients with high risk esophageal varices on the WL. Material and Methods: From the 89 patients on WL, 53 cirrhotic patients with endoscopically assessed high risk esophageal varices {more than 5 mm, red signs, Child-Pugh B or C) but no history of variceal bleeding were randomized to receive either Propranolol or EVL. Ligation was performed at 3 week interval untill variceal obliteration was achieved, using a sixshutter Saed Ligator. Results: During a median follow-up of 14.89 months (SD 4- 6.22), 3 out of 25 patients (12%) in the EVL group and 13 out of 28 patients (46.4%) in the Propranolol group experienced variceal bleeding (p = 0.04). One patient (4%) in the ligation group and 5 patients (17.8%) in the Propranolol group died (p = 0.1). Conclusion: This interim report showed that EVL significantly reduces the incidence of first episode of variceal bleeding in cirrhotic patients with high-risk varices on WL. Furthermore, there was a trend of reducing mortality from variceal bleeding in patients receiving EVL.
51 RENAL DYSFUNCTION (RD) FOLLOWING ORTHOTOPIC LIVER TRANSPLANTATION (OLT): ROLE OF CYCLOSPORINE (CsA) ELIMINATION AS PROVIDED BY THE NEORAL (NEO) FORMULATION R-Michel Huet 1, Denis Marleau l , Wendy Hauck 2. 1Department of Medicine, Centre Hospitalier de l'Universitd de MontrdaL Montrdal, Qudbec; 2Novartis Pharma Canada, Montrdal, Qudbec, Canada Objectives: RD is well recognized in OLT patients and has been related to long term use of calcineurin inhibitors. With NEO CO monitoring, renal
Although good results of LT for AC have been reported, consequences of alcoholic relapse after LT have to be evaluated. Aim: Evaluate (1) the alcohol relapse rate in patients transplanted for alcoholic liver disease (ALD) (2), the influence of alcohol relapse on the post-LT course. Methods: We retrospectively examined charts of 110 patients, (94 males, 16 females), 50.8 4- 8.6 yrs at LT (31-68). Alcohol recurrence was detected by interviews, anonymous questionnaries, clinical, biological indicators of alcohol intake and histological examination. Abstinence was defined by absence of any alcohol drink, social drink by less than 14 units/week, heavy drinking by more than 14 units/week and/or periods of time with more than 4 units/day. Routine biopsies were performed at 1, 2, 5 and 10 years. Results: 24 patients (21.8%) (18 M, 6 F) relapsed alcoholism and 15 had a heavy relapse. Mean delay of relapse was 2.1 yrs (0.3-6 yrs) and occurred during the first 3 years in 67% of cases. Neither sex nor preLT abstinence period was a predictive for alcohol relapse. Acute alcoholic hepatitis appeared in 6 patients (25%); moderate to severe steatosis was found more frequent in the relapser group (66.7% vs 23%, p < 0.001). Fibrosis was more frequent in the relapser group (25% vs 8.2%, p = 0.03). Chronic rejection was more frequent in the group with heavy relapse after LT (53.5% vs 20.5%, p = 0.008). Three relapsers discontinued immunosuppressive therapy. Survival rate at 1 and 5 yrs was 85.8% and 62.2%, respectively (n.s.). Conclusions: The observed relapse rate is 22% and the main consequence of alcoholism relapse is steatosis and/or fibrosis on liver graft. Chronic rejection occurs frequently particularly in heavy relapsers and may influence long-term patient and graft survival rate.