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Cost-effectiveness of different strategies of cytomegalovirus (CMV) prophylaxis in recipients of orthotopic liver transplantation (OLT)
A1232 AASLDABSTRACTS
• L0134 COST-EFFECTIVENESS OF DIFFERENT STRATEGIES OF CYTOMEGALOVIRUS (CMV) PROPHYLAXIS IN RECIPIENTS OF ORTHOTOPIC LIVER TRANSPLANTATION (OLT). A Das. Division of Gastroenterology, University Hospitals of Cleveland, Cleveland, Ohio. Introduction: CMV is an important cause of mortality and morbidity in patients with OLT, particularly in the initial post-transplant period. Several different strategies of CMV prophylaxis are in practice but no cost effective analysis has been done to compare these strategies. Methods: A hypothetical cohort of recipients of OLT was considered in a Markov model constructed by using a decision analysis software. The cohort was followed for a year after transplantation as they made possible transitions from different stages of health ranging from no infection with CMV, primary or secondary infection with CMV, CMV disease and death over 12 Markov cycles (cycle length = 1 month). Different regimens of CMV prophylaxis were considered in this model and for each regimen two strategies were considered: prophylaxis in all patients and prophylaxis restricted to a high risk group (seronegative recipients of seropositive allografts and patients undergoing OKT3 therapy for steroid resistant rejection). Cost of management and quality adjusted life months (QALM) were the outcome measures compared for different strategies. Costs were obtained from a university hospital pharmacy, only direct costs were calculated and cost analysis was done with a societal perspective). Clinical probabilities were obtained by searching the available literature. Results: C/E (Cost / QALM) Regimen Strategy all/highrisk GCV* 10 mg/kg/d iv, 2 wks $4776/$5874 all/highrisk $4940/$5904 iv lg 200 mg/kg 2/wk + GCV 5/mg/kg/d iv, 3 wk ACV 5 mg/kg/d PO, 9 wk GCV 6 mg/kg/d, 30 d -5/wk, 70 d all/highrisk $5802/$6132 all/highrisk ACV * 2400 mg/d PO, 12 wk $6237/$5947 ACV 2400 mg/d PO, 24 wk all/highrisk $6403/$5988 ACV 30 mg/kg/d iv, 30 d - then all/highrisk $5981/$5635 2400 mg/d PO, 70 d CMVIg, 2/wk, 6 dose + ACV all/highrisk $6521/$6169 2400 mg/d, 12 wk *GCV = Ganciclover, ACV = Acyclovir Conclusion: In general, GCV based, short duration regimens are most costeffective. GCV based regimens yield higher cost-efficacy when prohylaxis is administered to all patients; in contrast ACV based regimens are more costeffective when restricted to the high risk group. Adding iv Ig/CMV Ig or extending prophylaxis beyond 3 months do not improve cost efficacy.
L0135 PLASMA HYDROXY METRONIDAZOLE / METRONIDAZOLE RATIO IN ANTI-HCV CARRIERS WITH AND WITHOUT APPARENT LIVER DISEASE. C.M.F. da Silva t, F.L. David l, M.N. Muscar~il, S.S. Sousal, J.G.P. Ferraz 2, G. de Nucci 3, N. C. Polimeno 4, J. Pedrazzoli Jr. 1. 1Clinical Pharmacology Unit, S~o Francisco University Medical School, Bragan~a Paulista, SP; 2Miguel Servet Clinical Pharmacology Unit, Department of Pharmacology, Faculty of Medical Sciences, UNICAMP, Campinas, SP; 3Department of Pharmacology, Institute of Biomedical Sciences, S~o Paulo University, S~o Panlo, SP; 4Hemocentro, S~o Francisco University Medical School, Braganqa Paulista, SP, Brazil. Aims: To evaluate plasma hydroxy-metronidazole/metronidazole ratio as a dynamic liver function test in HCV-infected individuals with/without liver disease, in the absence of liver cirrhosis. Methods: Metronidazole was intravenously administered for 20 min to healthy volunteers, asymptomatic anti-HCV-positive blood donors, and to chronic hepatitis C patients. Serology to HCV was determined by a second generation assay and confirmed by gelatin particle agglutination test using recombinant antigens C22-3 and C200. Plasma concentration of metronidazole and hydroxy-metronidazole was measured by high performance liquid chromatography in samples collected 5, 10, 20 and 30 min following the end of metronidazole infusion. Results: Chronic hepatitis C patients had abnormal liver enzymes, while healthy volunteers and anti-HCV-positive blood donors had normal liver biochemistry tests~ Plasma metronidazole concentration was similar in all groups studied. Plasma hydroxy-metronidazole/metronidazole ratio was significantly reduced in HCV-infected subjects, an effect observed 10 min after the end of drug infusion. Conclusions: Metronidazole clearance is impaired in anti-HCV-positive blood donors and chronic hepatitis C patients, indicating that HCV is capable of affecting liver function at early stages of the disease. The metronidazole clearance test can detect impaired liver function in HCV-infected individuals even in the absence of liver cirrhosis. Supported by grants from FAPESP and IPPEX.
GASTROENTEROLOGYVol. 114, No. 4 L0136 PLASMA HYDROXY-METRONIDAZOLE RATIO IN ETHANOL ABUSERS. C.M.F. da Silva 1, M.N. Muscar~ l, S.S. Sousa1, J.G.P. Ferraz 2, G. de Nucci 3, N. C. Polimeno 4, J. Pedrazzoli Jr. 1. 1Clinical Pharmacology Unit, S~o Francisco University Medical School, Bragan~a Paulista, SP, Brazil; 2Miguel Servet Clinical Pharmacology Unit, Department of Pharmacology, Faculty of Medical Sciences, UNICAMP, Campinas, SP, Brazil; 3Department of Pharmacology, Institute of Biomedical Sciences, University of S~o Paulo, S~.o Paulo, SP, Brazil; and 4Hemocentro, S~o Francisco University Medical School, Bragan~a Paulista, SP, Brazil. Aims: To evaluate plasma hydroxy-metronidazole/metronidazole ratio as a dynamic liver function test in ethanol abusers with/without liver cirrhosis. Methods: Metronidazole was intravenously administered for 20 min to healthy volunteers, alcoholic hepatitis and alcoholic liver cirrhosis patients. Plasma concentration of metronidazole and hydroxy-metronidazole was measured by high performance liquid chromatography in samples collected 5, 10, 20 and 30 min following the end of metronidazole infusion. Results: Patients with alcoholic hepatitis had aminotransferase levels significantly elevated compared to healthy volunteers and Child A patients. Child-Pugh C patients had significantly prolonged prothrombin time when compared to healthy volunteers and alcoholic hepatitis patients. Metronidazole clearance, as measured by the OH-MET/MET ratio following intravenous administration of 500 mg metronidazole, was significantly impaired in all ethanol-abusing individuals, including the patients with alcoholic hepatitis. Conclusions: Metronidazole clearance is impaired in ethanol abusers, even in the absence of liver cirrhosis, indicating that ethanol is capable of affecting liver function at early stages of alcoholic liver disease. Supported by grants from FAPESP and IPPEX. L0137 HEPATIC CRYOABLATION INDUCES NF-~:B ACTIVATION, CYTOKINE PRODUCTION, AND LUNG INJURY IN A RAT MODEL. JP Debelak, DJ Schot, TS Blackwell+, JW Christman+, CW Pinson, P Williams, K Washington*, WC Chapman. Department of Surgery, Pulmonary Medicine+ and Pathology*, Vanderbilt University Medical Center, Nashville, TN. Hepatic cryoablation has been associated with significantly increased complication rates when 30-35% of the liver is cryoablated. Causative factors remain undefined. In this study, we investigated the effects of hepatic cryosurgery on NF-KB activation in the liver and lung, and cytokine production (TNF-a and MIP-2) and compared this to partial hepatectomy. Animals were anesthetized and underwent laparotomy with either resection (approximately 35% by weight) or cryoablation of a similar volume of the left lobe. Animals were sacrificed at 1, 2, and 24 hours and had blood obtained and necropsy performed. TNF-ct and MIP-2 levels were determined using monoclonal antibody techniques with results (mean +-SEM) analyzed by Student's t-test (*p<0.05, cryo vs. resection): I HR
Resect. N 3 TNF-ct(pg/mL) 0 MIP-2(pg/mL) 0 PCV(%) 44 Plts(xl03) 717
2 HR
Crvo. Resect. 8 4 311_+71"0 272 _+90* 0 42 42.5 468 706
24 HR Crvo. Resect. Crvo. 10 5 7 380_+110"25_+2 654_+304* 337 _+108" 0 NA 43.3 40.2 41.7 533 635 380
No deaths occurred in the resected group, but 50% of 24 hr. cryoablated group expired within 20 hours with pulmonary histology showing significant lung injury and interstitial infiltrate not present in resection animals. NF-KB activation assessed by electrophoretic mobility shift assay demonstrated marked increases in NF-IcB by 1 hour in both liver and lung tissue in cryoablation animals with a return to baseline by 2 hours. In partial hepatectomy animals, no increase in NF-KB was found at any time. These data demonstrate that hepatic cyrosurgery induces overproduction of NF-nB dependent cytokines. We speculate that lung injury and death in this model are mediated by an exaggerated systemic inflammatory response to cryosurgery. L0138 IDENTIFICATION OF A NOVEL NEGATIVE-ACTING CYTOKINE RESPONSE ELEMENT IN THE RAT LIVER SODIUM-DEPENDENT BILE ACID COTRANSPORTER GENE PROMOTER. L.A. Denson, M.H. McClure, S.J. Karpen, Dept. of Ped., Yale U. Sch. of Med., New Haven, CT. Several lines of evidence have implicated endotoxin and associated cytokines in the pathogenesis of sepsis-associated cholestasis. Administration of endotoxin to rats leads to down-regulation of hepatobiliary transport, including significant reduction in the transcription and function of the basolateral sodium-dependent Na+/taurocholate cotransporter protein, ntcp (Hepatol. 26: 262A, 1997; Gastro. 112: 214, 1997). We hypothesize that cytokines mediate negative effects on transcription of the ntcp gene through reductions in quantities of key positive-acting transcription factors. HepG2 ceils were transiently transfected with rat ntcp promoter-driven luciferase constructs and treated with cytokines at various doses for differing lengths of time. Activities of promoter constructs were assayed by standard luciferase
• L0134 COST-EFFECTIVENESS OF DIFFERENT STRATEGIES OF CYTOMEGALOVIRUS (CMV) PROPHYLAXIS IN RECIPIENTS OF ORTHOTOPIC LIVER TRANSPLANTATION (OLT). A Das. Division of Gastroenterology, University Hospitals of Cleveland, Cleveland, Ohio. Introduction: CMV is an important cause of mortality and morbidity in patients with OLT, particularly in the initial post-transplant period. Several different strategies of CMV prophylaxis are in practice but no cost effective analysis has been done to compare these strategies. Methods: A hypothetical cohort of recipients of OLT was considered in a Markov model constructed by using a decision analysis software. The cohort was followed for a year after transplantation as they made possible transitions from different stages of health ranging from no infection with CMV, primary or secondary infection with CMV, CMV disease and death over 12 Markov cycles (cycle length = 1 month). Different regimens of CMV prophylaxis were considered in this model and for each regimen two strategies were considered: prophylaxis in all patients and prophylaxis restricted to a high risk group (seronegative recipients of seropositive allografts and patients undergoing OKT3 therapy for steroid resistant rejection). Cost of management and quality adjusted life months (QALM) were the outcome measures compared for different strategies. Costs were obtained from a university hospital pharmacy, only direct costs were calculated and cost analysis was done with a societal perspective). Clinical probabilities were obtained by searching the available literature. Results: C/E (Cost / QALM) Regimen Strategy all/highrisk GCV* 10 mg/kg/d iv, 2 wks $4776/$5874 all/highrisk $4940/$5904 iv lg 200 mg/kg 2/wk + GCV 5/mg/kg/d iv, 3 wk ACV 5 mg/kg/d PO, 9 wk GCV 6 mg/kg/d, 30 d -5/wk, 70 d all/highrisk $5802/$6132 all/highrisk ACV * 2400 mg/d PO, 12 wk $6237/$5947 ACV 2400 mg/d PO, 24 wk all/highrisk $6403/$5988 ACV 30 mg/kg/d iv, 30 d - then all/highrisk $5981/$5635 2400 mg/d PO, 70 d CMVIg, 2/wk, 6 dose + ACV all/highrisk $6521/$6169 2400 mg/d, 12 wk *GCV = Ganciclover, ACV = Acyclovir Conclusion: In general, GCV based, short duration regimens are most costeffective. GCV based regimens yield higher cost-efficacy when prohylaxis is administered to all patients; in contrast ACV based regimens are more costeffective when restricted to the high risk group. Adding iv Ig/CMV Ig or extending prophylaxis beyond 3 months do not improve cost efficacy.
L0135 PLASMA HYDROXY METRONIDAZOLE / METRONIDAZOLE RATIO IN ANTI-HCV CARRIERS WITH AND WITHOUT APPARENT LIVER DISEASE. C.M.F. da Silva t, F.L. David l, M.N. Muscar~il, S.S. Sousal, J.G.P. Ferraz 2, G. de Nucci 3, N. C. Polimeno 4, J. Pedrazzoli Jr. 1. 1Clinical Pharmacology Unit, S~o Francisco University Medical School, Bragan~a Paulista, SP; 2Miguel Servet Clinical Pharmacology Unit, Department of Pharmacology, Faculty of Medical Sciences, UNICAMP, Campinas, SP; 3Department of Pharmacology, Institute of Biomedical Sciences, S~o Paulo University, S~o Panlo, SP; 4Hemocentro, S~o Francisco University Medical School, Braganqa Paulista, SP, Brazil. Aims: To evaluate plasma hydroxy-metronidazole/metronidazole ratio as a dynamic liver function test in HCV-infected individuals with/without liver disease, in the absence of liver cirrhosis. Methods: Metronidazole was intravenously administered for 20 min to healthy volunteers, asymptomatic anti-HCV-positive blood donors, and to chronic hepatitis C patients. Serology to HCV was determined by a second generation assay and confirmed by gelatin particle agglutination test using recombinant antigens C22-3 and C200. Plasma concentration of metronidazole and hydroxy-metronidazole was measured by high performance liquid chromatography in samples collected 5, 10, 20 and 30 min following the end of metronidazole infusion. Results: Chronic hepatitis C patients had abnormal liver enzymes, while healthy volunteers and anti-HCV-positive blood donors had normal liver biochemistry tests~ Plasma metronidazole concentration was similar in all groups studied. Plasma hydroxy-metronidazole/metronidazole ratio was significantly reduced in HCV-infected subjects, an effect observed 10 min after the end of drug infusion. Conclusions: Metronidazole clearance is impaired in anti-HCV-positive blood donors and chronic hepatitis C patients, indicating that HCV is capable of affecting liver function at early stages of the disease. The metronidazole clearance test can detect impaired liver function in HCV-infected individuals even in the absence of liver cirrhosis. Supported by grants from FAPESP and IPPEX.
GASTROENTEROLOGYVol. 114, No. 4 L0136 PLASMA HYDROXY-METRONIDAZOLE RATIO IN ETHANOL ABUSERS. C.M.F. da Silva 1, M.N. Muscar~ l, S.S. Sousa1, J.G.P. Ferraz 2, G. de Nucci 3, N. C. Polimeno 4, J. Pedrazzoli Jr. 1. 1Clinical Pharmacology Unit, S~o Francisco University Medical School, Bragan~a Paulista, SP, Brazil; 2Miguel Servet Clinical Pharmacology Unit, Department of Pharmacology, Faculty of Medical Sciences, UNICAMP, Campinas, SP, Brazil; 3Department of Pharmacology, Institute of Biomedical Sciences, University of S~o Paulo, S~.o Paulo, SP, Brazil; and 4Hemocentro, S~o Francisco University Medical School, Bragan~a Paulista, SP, Brazil. Aims: To evaluate plasma hydroxy-metronidazole/metronidazole ratio as a dynamic liver function test in ethanol abusers with/without liver cirrhosis. Methods: Metronidazole was intravenously administered for 20 min to healthy volunteers, alcoholic hepatitis and alcoholic liver cirrhosis patients. Plasma concentration of metronidazole and hydroxy-metronidazole was measured by high performance liquid chromatography in samples collected 5, 10, 20 and 30 min following the end of metronidazole infusion. Results: Patients with alcoholic hepatitis had aminotransferase levels significantly elevated compared to healthy volunteers and Child A patients. Child-Pugh C patients had significantly prolonged prothrombin time when compared to healthy volunteers and alcoholic hepatitis patients. Metronidazole clearance, as measured by the OH-MET/MET ratio following intravenous administration of 500 mg metronidazole, was significantly impaired in all ethanol-abusing individuals, including the patients with alcoholic hepatitis. Conclusions: Metronidazole clearance is impaired in ethanol abusers, even in the absence of liver cirrhosis, indicating that ethanol is capable of affecting liver function at early stages of alcoholic liver disease. Supported by grants from FAPESP and IPPEX. L0137 HEPATIC CRYOABLATION INDUCES NF-~:B ACTIVATION, CYTOKINE PRODUCTION, AND LUNG INJURY IN A RAT MODEL. JP Debelak, DJ Schot, TS Blackwell+, JW Christman+, CW Pinson, P Williams, K Washington*, WC Chapman. Department of Surgery, Pulmonary Medicine+ and Pathology*, Vanderbilt University Medical Center, Nashville, TN. Hepatic cryoablation has been associated with significantly increased complication rates when 30-35% of the liver is cryoablated. Causative factors remain undefined. In this study, we investigated the effects of hepatic cryosurgery on NF-KB activation in the liver and lung, and cytokine production (TNF-a and MIP-2) and compared this to partial hepatectomy. Animals were anesthetized and underwent laparotomy with either resection (approximately 35% by weight) or cryoablation of a similar volume of the left lobe. Animals were sacrificed at 1, 2, and 24 hours and had blood obtained and necropsy performed. TNF-ct and MIP-2 levels were determined using monoclonal antibody techniques with results (mean +-SEM) analyzed by Student's t-test (*p<0.05, cryo vs. resection): I HR
Resect. N 3 TNF-ct(pg/mL) 0 MIP-2(pg/mL) 0 PCV(%) 44 Plts(xl03) 717
2 HR
Crvo. Resect. 8 4 311_+71"0 272 _+90* 0 42 42.5 468 706
24 HR Crvo. Resect. Crvo. 10 5 7 380_+110"25_+2 654_+304* 337 _+108" 0 NA 43.3 40.2 41.7 533 635 380
No deaths occurred in the resected group, but 50% of 24 hr. cryoablated group expired within 20 hours with pulmonary histology showing significant lung injury and interstitial infiltrate not present in resection animals. NF-KB activation assessed by electrophoretic mobility shift assay demonstrated marked increases in NF-IcB by 1 hour in both liver and lung tissue in cryoablation animals with a return to baseline by 2 hours. In partial hepatectomy animals, no increase in NF-KB was found at any time. These data demonstrate that hepatic cyrosurgery induces overproduction of NF-nB dependent cytokines. We speculate that lung injury and death in this model are mediated by an exaggerated systemic inflammatory response to cryosurgery. L0138 IDENTIFICATION OF A NOVEL NEGATIVE-ACTING CYTOKINE RESPONSE ELEMENT IN THE RAT LIVER SODIUM-DEPENDENT BILE ACID COTRANSPORTER GENE PROMOTER. L.A. Denson, M.H. McClure, S.J. Karpen, Dept. of Ped., Yale U. Sch. of Med., New Haven, CT. Several lines of evidence have implicated endotoxin and associated cytokines in the pathogenesis of sepsis-associated cholestasis. Administration of endotoxin to rats leads to down-regulation of hepatobiliary transport, including significant reduction in the transcription and function of the basolateral sodium-dependent Na+/taurocholate cotransporter protein, ntcp (Hepatol. 26: 262A, 1997; Gastro. 112: 214, 1997). We hypothesize that cytokines mediate negative effects on transcription of the ntcp gene through reductions in quantities of key positive-acting transcription factors. HepG2 ceils were transiently transfected with rat ntcp promoter-driven luciferase constructs and treated with cytokines at various doses for differing lengths of time. Activities of promoter constructs were assayed by standard luciferase