- Email: [email protected]
Safety, tolerability and efficacy of interferon alfa 2b and Ribavirin combination therapy in HCV patients with cirrhosis
M1610
the sensitivity, specificity, positive and negative predictive value, and accuracy were 1.00, 0.95, 0.95,1.00, and 0.97 respectively. Conclusions; Our established formula might be useful to discriminate postoperative hepatic failure from reversible hyperbilirubinemia following digestive surgery.
ls There Any Relation Between CD81 Polymorphisms, HCV and the Presence of Cryoglobulinemia? Supriya Joshi, Joshua Schimmer, Elizabeth J. Heathcote, Robert Rottapel Background: Mixed cryogiobulinemia (MC) Is a complication of chronic hepatitis C virus (HCV) infection (detectable in 50% of patients) and may predispose to lymphoproliferative disSrders. Entry of HCV into hepatocytes and B lymphocytes may result from binding to CD81, a nonglycosylated tetraspanin protein that is widely expressed and involved in immune regulation, B cell stimulation, cell to cell interaction, and neuro-slgnaling. Hypothesis: Polymorphisms in the CD81 coding region may predispose patients with HCV to the development of MC. Methods: Forty-three patients with HCV were selected for invesngation. Patients with HCV +/- laboratory and clinical ewdence of MC were examined as well as 16 HCV-ve healthy controls (HC). A retrospective chart review assessed patient demographics, manifestations of MC, cryocrit, liver histology, genotype and viral load when available. Lymphocytes were collected from fresh blood samples and RNA was isolated. RT-PCR was used to create a cDNA library for each patient and the CD81 coding region was amplified by PCR, inserted into the pCR| 2.1 TOPO' vector and transformed into competent 1-shot E. coil bacteria. Four clones from each patient were selected for CD81 sequencing and reproducible mutations were identified. Results: Sequence analysis was completed for 59 individuals, 16 HC, 9 HCV+/MC- and 34 HCV+/MC+, 22 (64.7%) of whom were symptomatic. Nucleotide aberrancies were found in 5 pts, 4 HCV + / + MC ( 12 %), 0 HCV +/MC (0%) and 1 HC (6%). Manifestations of MC included 1 skin, 1 renal, 1 skin/neuropathy, 1 skin/renal and 1 skin/renal/arthntis. No patient had overt lymphoma. Of the 5 patients with a CD81 polymorphism, 4 had changes in the coding sequence for the second extracellular region of the protein, to which HCV is reported to bind. However, of those 5 patients, 3 had DNA changes that did not correspond with a change in amino acid coding. Conclusions: Polymorphisms of CDB1 may predispose to the development of MC in patients infected with HCV. As 3 out of 5 polymorphisms did not result in amino acid substitution, the question of a plausible mechanism underlying this association arises. The identified polymorphisms cannot explain why some individuals with HCV develop MC and others do not.
M1613 Safety, Tolerability And Efficacy Of Interferon Alfa 2h And Ribavirin Combination Therapy In HCV Patients With Cirrhosis Ravi Ravinuthala, Vosudesh Pal, Dilip Moonka, Kimberly Brown Introduction and Purpose: HCV infected patients with advanced liver disease are high risk for treatment with combination therapy with Interferon and Ribavirin due to tolerability ~nd safety issues. However, succesful treatment halts progression of the disease and reduces risk of HCC.We report our experience in treating this high risk group. Materials and Methods: Patients with cirrhosis or severe bridging fibrosis on liver biopsy were included in this study. All patients received standard combination therapy with Interferon 3 MU thnce-a-week and nbavirin 1000 or 1200 mg twice a day depending on the weight where possible. Side effects, laboratories were monitored monthly and dose was modified if necessary. HCV RNA was checked at the end of six months, one year and 18 months. Treatment was stopped if HCV RNA was positive at 6 months of treatment. If negative at 6 months, treatment was continued for 12 months. End of treatment response (ETR) was defined as negative HCV RNA at 12 months of treatment and sustained viral response (SVR) meant negative HCV RNA at 18 months. Results: 62 patients were included in the study. 2 (3%) patients did not complete the treatment due to side effects and were excluded from final analysis. 69% were Caucasian and 31% were African American. Male to female ratio was 7:3. Age ranged from 33-69 with a mean of 49.5. Cirrhosis was present in 32 (51%) and 30 (49%) had bridging fibrosis on biopsy. All patients were clinically Child's A class at the time of treatment although some had decompensation in the past. Majority were genotype 1. Platelet count ranged from 48402 with a mean of 161,000 and mean viral load was 664395 I.U. Dosage reduction was required in 9 (15%) patients and erythropoietin was required in 2 patients. ETR was seen in 24 (40%) with SVR in 13 (22%). SVR in previous non responders was 38% (6/16) as compared with 16% in naive patients. Conclusions: Combination therapy in patients with advanced liver disease is safe and well tolerated. Our discontinuation rate and dose reduction rates were 3% and 15% compared to 21% and 26% in the registration trials respectively SVR was achieved in 22% which is comparable to other trials in similar group of patients. Notably, the SVR in interferon non responders was 38% and higher than the total group These results suggest that patients with advanced liver disease which is compensated should be offered treatment for hepatitis C. Further follow up is needed to evaluate long-term benefits in patients with sustained viral clearance.
M1611 Lifestyle and Genetic Risk Factors for Progression of Hepatitis C Sara H. Olson, Nancy Lau, Sandy Iyer, Daniel Egan, Irene Orlow, Jay Cowan, Temima Markovits, Robert C. Kurtz, Marianne Berwick In patients with hepatitis C, previous studies have indicated that risk factors for progression and hepatocefiular carcinoma (HCC) include male gender, older age, and older age at infection. Some studies have reported slower progression in blacks than in whites. Individual differences in genes that are involved in the process of inflammation may also affect progression. We studied these and other potential risk factors in a hospital-based study in NYC. Our interviewers approach people in the clinics at Memorial Sloan-Kettering and North General Hospitals, obtain informed consent, administer a questionnaire, and collect mouthwash specimens for DNA. Participants fill out questionnaires on diet, family history, and quality of life. This analysis reports on 116 patients for whom data on stage based on liver biopsy were available, and includes 24 with hepatocellular carcinoma (HCC). Based on the questionnaire, we estimated route of infection (transfusion, intravenous drug use (IVDU), or other route), age at infection, and length of time infected. We studied the association of these variables, as well as age, gender, race, and GSTM1 genotype (null or present) with stage of disease. Stage of disease was dichotomized into early (stage 0, I, II, n = 58) and late (stage Ill, IV or HCC, n = 58). In univariate analysis, older age, higher number of years infected, infection at later ages (twenties or older), and infection through IVDU were significantly associated with increased risk of higher-stage disease. Odds ratios (ORs) were 6.3 for age > = 60; 2.6 for infected > = 35 years; 2.6 if infected in ones 20s vs earlier; and 2.6 if infected by IVDU. Older age remained a significant risk factor in all multivariate analyses and was a stronger factor than number of years infected or age at infection. Adjustment for age increased the strength of the association for IVDU (OR= 5.0). Gender and race were not significantly associated with stage. With stratification by age, however, male gender increased risk among younger patients (OR = 5.3), but not among older patients (OR = 1.2). In addition, risk associated with IVDU was higher among younger patients (OR= 7.6) than among older patients (OR= 1.9). Patients who had the null genotype of GSTM1 were at higher risk, with an odds ratio of 2.4 (p = .04) after controlhng for race. The number of patients with higher-stage liver disease is likely to increase as the infected population ages and as IVDU becomes a more prevalent mode of infection. Differences in genes involved in inflammation may affect individual risk.
M1614 Severity of Liver Disease in HCV Infected Dialysis Patients Awaiting Renal Transplantation Renee Pozza, Else Alhanese, Karel Biando, Erik Wahlstrom, Tarek Hassanein BACKGROUND: Hepatitis C viral infection (HCV) is common in patients with end stage renal disease. 20-40% of patients on hemodialysis are infected with HCV. HCV viremia and disease activity is expected to increase as a result of immune suppression post-renal transplantation. Liver histology is crucial in evaluating patients for transplantation to avoid post-trausplantation liver decompensation and failure. METHODS: 31 patients seropositive for anti-HCV with chronic end-stage renal failure receiving dialytic therapy were included in the study. All patients were awaiting renal transplantation. As part of their transplant workup, patients underwent lab chemistry testing, HCV PCR and genotype testing. A liver biopsy was performed to detenmne severity of liver disease. Liver biopsy results were scored according to the METAVIR score. The scoring is based on the presence of inflammation (04) and fibrosis (0-4). RESULTS: 19(61%) were males and 12(39%) were female. 29% Caucasian, 34% Hispanic, 22% African American and 12% other. Mean age was 52.2 years 84% were on hemodialysis while 16% were on peritoneal dialysis. 73% of patients have a viral titer ~ 1 million copies/ml and 27% ~ 1 million copies/ml using the superquant assay. 18% of the patients were HCV-RNA negative by PCR. 56% were genotype la/lb, 19% 2b, 19% 3a and 6% were genotype 4. The mean ALT and AST levels were 61 and 40 iu/ dl respectively. Histologically 0% had severe inflammation, however, mild and moderate inflammation was detected in 62.5% and 37.5% of the biopsies respectively. Fibrosis scores were 0,1,2,3,4, in 33%, 38%, 12%, 17% and 0% respectively. Iron staining was positive in 82% of the biopsies. Severe iron deposition was seen in only 18% of the patients. All patients were considered candidates for renal transplantation. CONCLUSION: Patients with ESRD on dialysis have mild histological disease. 0% of our cohort had advanced disease while 71% had mild and 29% had moderate disease. Therefore a liver biopsy is essential in evaluating HCV infected patients for renal transplantation. Since HCV disease progression is relatively slow even with immunosuppression, the majority of HCV-infected patients in our cohort were candidates for renal transplantation.
M1612 Postoperative Hyperbilirubinemia; How Can We Discriminate Fetal Hepatic Failure from Reversible Hyperbilirubonemia Following Digestive Surgery? Ikuo Nagashima, Tadahiro Takada, shinichiro Morofuji, Kota Okinaga Purpose; Hyperbilirabinemia following digestive surgery is sometimes a sign of fatal hepatic failure. In order to start an early intensive therapy, it is important to discriminate fetal hepatic failure from reversible hyperbilirubinemia. We tried to establish a formula to discriminate fetal hepatic failure. Methods; We retrospectively reviewed 39 patients who revealed hyperbilirubinemia (Total bilirubin_> 5mg/di) following digestive surgery between 1981 and 2000. Twenty of 39 (51%) died of hepatic failure. We compared 15 clinical and laboratory variables between 20 died patients and 19 recovered patients using uni- and multi-variate analysis. At last we established a discrimination formula. Results; 1) By univariate analysis, chronic hepatitis or cirrhosis (CH/LC), bacteremia, low alkalinephosphatase(ALP), low hemoglobin, and low platelet(PLT) were significant risk factors of hepatic failure. 2) By multivariate analysis, CH/LC (p=0.008), hacteremla (p=0.004), low ALP (p=0.0008), and low PLT (p=0.0014) were significant. 3) Using these 4 variables, we established the following discrimination formula: Y= 3.9970+ 0.0729 x ALP(U/ml)+ 0.5743 x PLT(xlO4) - 19.6373 x CH/LC-25.6132 x hacteremia. A negative Y value indicated hepatic failure. Therefore,
M1615 Systematic Review: Does the Evidence Support an Association Between Cryptogenic Cirrhosis (CC) and Non-alcoholic Steatohepatitis (NASH)? Terence L. Angtnaco, Vivek Raj, Florinela G. Oprescu, Jill C. Beisel, John D. Moore, Brady D. Russell, Jennifer M. Co, Colin W. Howden Purpose: To assess, by systematic review, the strength of current evidence supporting the association of CC and NASH. Methods: We searched Medtine for English articles using the following keywords: cryptogenic cirrhosis, cirrhosis, steatohepatitis, NASH, NAFLD, fatty liver, and liver transplant. Bibliographies of articles were used to augment our search. Results: 22 relevant publications were reviewed - 1 cohort study (Co) comparing CC patients with cirrhotics of known cause, 9 longitudinal studies (LS), 7 case-control studies (CCS), 1 ease series (CS) and 4 case reports (CR). Only 12 studies defined significant alcohol use. Hepatitis
A-383
AGA Abstracts
the sensitivity, specificity, positive and negative predictive value, and accuracy were 1.00, 0.95, 0.95,1.00, and 0.97 respectively. Conclusions; Our established formula might be useful to discriminate postoperative hepatic failure from reversible hyperbilirubinemia following digestive surgery.
ls There Any Relation Between CD81 Polymorphisms, HCV and the Presence of Cryoglobulinemia? Supriya Joshi, Joshua Schimmer, Elizabeth J. Heathcote, Robert Rottapel Background: Mixed cryogiobulinemia (MC) Is a complication of chronic hepatitis C virus (HCV) infection (detectable in 50% of patients) and may predispose to lymphoproliferative disSrders. Entry of HCV into hepatocytes and B lymphocytes may result from binding to CD81, a nonglycosylated tetraspanin protein that is widely expressed and involved in immune regulation, B cell stimulation, cell to cell interaction, and neuro-slgnaling. Hypothesis: Polymorphisms in the CD81 coding region may predispose patients with HCV to the development of MC. Methods: Forty-three patients with HCV were selected for invesngation. Patients with HCV +/- laboratory and clinical ewdence of MC were examined as well as 16 HCV-ve healthy controls (HC). A retrospective chart review assessed patient demographics, manifestations of MC, cryocrit, liver histology, genotype and viral load when available. Lymphocytes were collected from fresh blood samples and RNA was isolated. RT-PCR was used to create a cDNA library for each patient and the CD81 coding region was amplified by PCR, inserted into the pCR| 2.1 TOPO' vector and transformed into competent 1-shot E. coil bacteria. Four clones from each patient were selected for CD81 sequencing and reproducible mutations were identified. Results: Sequence analysis was completed for 59 individuals, 16 HC, 9 HCV+/MC- and 34 HCV+/MC+, 22 (64.7%) of whom were symptomatic. Nucleotide aberrancies were found in 5 pts, 4 HCV + / + MC ( 12 %), 0 HCV +/MC (0%) and 1 HC (6%). Manifestations of MC included 1 skin, 1 renal, 1 skin/neuropathy, 1 skin/renal and 1 skin/renal/arthntis. No patient had overt lymphoma. Of the 5 patients with a CD81 polymorphism, 4 had changes in the coding sequence for the second extracellular region of the protein, to which HCV is reported to bind. However, of those 5 patients, 3 had DNA changes that did not correspond with a change in amino acid coding. Conclusions: Polymorphisms of CDB1 may predispose to the development of MC in patients infected with HCV. As 3 out of 5 polymorphisms did not result in amino acid substitution, the question of a plausible mechanism underlying this association arises. The identified polymorphisms cannot explain why some individuals with HCV develop MC and others do not.
M1613 Safety, Tolerability And Efficacy Of Interferon Alfa 2h And Ribavirin Combination Therapy In HCV Patients With Cirrhosis Ravi Ravinuthala, Vosudesh Pal, Dilip Moonka, Kimberly Brown Introduction and Purpose: HCV infected patients with advanced liver disease are high risk for treatment with combination therapy with Interferon and Ribavirin due to tolerability ~nd safety issues. However, succesful treatment halts progression of the disease and reduces risk of HCC.We report our experience in treating this high risk group. Materials and Methods: Patients with cirrhosis or severe bridging fibrosis on liver biopsy were included in this study. All patients received standard combination therapy with Interferon 3 MU thnce-a-week and nbavirin 1000 or 1200 mg twice a day depending on the weight where possible. Side effects, laboratories were monitored monthly and dose was modified if necessary. HCV RNA was checked at the end of six months, one year and 18 months. Treatment was stopped if HCV RNA was positive at 6 months of treatment. If negative at 6 months, treatment was continued for 12 months. End of treatment response (ETR) was defined as negative HCV RNA at 12 months of treatment and sustained viral response (SVR) meant negative HCV RNA at 18 months. Results: 62 patients were included in the study. 2 (3%) patients did not complete the treatment due to side effects and were excluded from final analysis. 69% were Caucasian and 31% were African American. Male to female ratio was 7:3. Age ranged from 33-69 with a mean of 49.5. Cirrhosis was present in 32 (51%) and 30 (49%) had bridging fibrosis on biopsy. All patients were clinically Child's A class at the time of treatment although some had decompensation in the past. Majority were genotype 1. Platelet count ranged from 48402 with a mean of 161,000 and mean viral load was 664395 I.U. Dosage reduction was required in 9 (15%) patients and erythropoietin was required in 2 patients. ETR was seen in 24 (40%) with SVR in 13 (22%). SVR in previous non responders was 38% (6/16) as compared with 16% in naive patients. Conclusions: Combination therapy in patients with advanced liver disease is safe and well tolerated. Our discontinuation rate and dose reduction rates were 3% and 15% compared to 21% and 26% in the registration trials respectively SVR was achieved in 22% which is comparable to other trials in similar group of patients. Notably, the SVR in interferon non responders was 38% and higher than the total group These results suggest that patients with advanced liver disease which is compensated should be offered treatment for hepatitis C. Further follow up is needed to evaluate long-term benefits in patients with sustained viral clearance.
M1611 Lifestyle and Genetic Risk Factors for Progression of Hepatitis C Sara H. Olson, Nancy Lau, Sandy Iyer, Daniel Egan, Irene Orlow, Jay Cowan, Temima Markovits, Robert C. Kurtz, Marianne Berwick In patients with hepatitis C, previous studies have indicated that risk factors for progression and hepatocefiular carcinoma (HCC) include male gender, older age, and older age at infection. Some studies have reported slower progression in blacks than in whites. Individual differences in genes that are involved in the process of inflammation may also affect progression. We studied these and other potential risk factors in a hospital-based study in NYC. Our interviewers approach people in the clinics at Memorial Sloan-Kettering and North General Hospitals, obtain informed consent, administer a questionnaire, and collect mouthwash specimens for DNA. Participants fill out questionnaires on diet, family history, and quality of life. This analysis reports on 116 patients for whom data on stage based on liver biopsy were available, and includes 24 with hepatocellular carcinoma (HCC). Based on the questionnaire, we estimated route of infection (transfusion, intravenous drug use (IVDU), or other route), age at infection, and length of time infected. We studied the association of these variables, as well as age, gender, race, and GSTM1 genotype (null or present) with stage of disease. Stage of disease was dichotomized into early (stage 0, I, II, n = 58) and late (stage Ill, IV or HCC, n = 58). In univariate analysis, older age, higher number of years infected, infection at later ages (twenties or older), and infection through IVDU were significantly associated with increased risk of higher-stage disease. Odds ratios (ORs) were 6.3 for age > = 60; 2.6 for infected > = 35 years; 2.6 if infected in ones 20s vs earlier; and 2.6 if infected by IVDU. Older age remained a significant risk factor in all multivariate analyses and was a stronger factor than number of years infected or age at infection. Adjustment for age increased the strength of the association for IVDU (OR= 5.0). Gender and race were not significantly associated with stage. With stratification by age, however, male gender increased risk among younger patients (OR = 5.3), but not among older patients (OR = 1.2). In addition, risk associated with IVDU was higher among younger patients (OR= 7.6) than among older patients (OR= 1.9). Patients who had the null genotype of GSTM1 were at higher risk, with an odds ratio of 2.4 (p = .04) after controlhng for race. The number of patients with higher-stage liver disease is likely to increase as the infected population ages and as IVDU becomes a more prevalent mode of infection. Differences in genes involved in inflammation may affect individual risk.
M1614 Severity of Liver Disease in HCV Infected Dialysis Patients Awaiting Renal Transplantation Renee Pozza, Else Alhanese, Karel Biando, Erik Wahlstrom, Tarek Hassanein BACKGROUND: Hepatitis C viral infection (HCV) is common in patients with end stage renal disease. 20-40% of patients on hemodialysis are infected with HCV. HCV viremia and disease activity is expected to increase as a result of immune suppression post-renal transplantation. Liver histology is crucial in evaluating patients for transplantation to avoid post-trausplantation liver decompensation and failure. METHODS: 31 patients seropositive for anti-HCV with chronic end-stage renal failure receiving dialytic therapy were included in the study. All patients were awaiting renal transplantation. As part of their transplant workup, patients underwent lab chemistry testing, HCV PCR and genotype testing. A liver biopsy was performed to detenmne severity of liver disease. Liver biopsy results were scored according to the METAVIR score. The scoring is based on the presence of inflammation (04) and fibrosis (0-4). RESULTS: 19(61%) were males and 12(39%) were female. 29% Caucasian, 34% Hispanic, 22% African American and 12% other. Mean age was 52.2 years 84% were on hemodialysis while 16% were on peritoneal dialysis. 73% of patients have a viral titer ~ 1 million copies/ml and 27% ~ 1 million copies/ml using the superquant assay. 18% of the patients were HCV-RNA negative by PCR. 56% were genotype la/lb, 19% 2b, 19% 3a and 6% were genotype 4. The mean ALT and AST levels were 61 and 40 iu/ dl respectively. Histologically 0% had severe inflammation, however, mild and moderate inflammation was detected in 62.5% and 37.5% of the biopsies respectively. Fibrosis scores were 0,1,2,3,4, in 33%, 38%, 12%, 17% and 0% respectively. Iron staining was positive in 82% of the biopsies. Severe iron deposition was seen in only 18% of the patients. All patients were considered candidates for renal transplantation. CONCLUSION: Patients with ESRD on dialysis have mild histological disease. 0% of our cohort had advanced disease while 71% had mild and 29% had moderate disease. Therefore a liver biopsy is essential in evaluating HCV infected patients for renal transplantation. Since HCV disease progression is relatively slow even with immunosuppression, the majority of HCV-infected patients in our cohort were candidates for renal transplantation.
M1612 Postoperative Hyperbilirubinemia; How Can We Discriminate Fetal Hepatic Failure from Reversible Hyperbilirubonemia Following Digestive Surgery? Ikuo Nagashima, Tadahiro Takada, shinichiro Morofuji, Kota Okinaga Purpose; Hyperbilirabinemia following digestive surgery is sometimes a sign of fatal hepatic failure. In order to start an early intensive therapy, it is important to discriminate fetal hepatic failure from reversible hyperbilirubinemia. We tried to establish a formula to discriminate fetal hepatic failure. Methods; We retrospectively reviewed 39 patients who revealed hyperbilirubinemia (Total bilirubin_> 5mg/di) following digestive surgery between 1981 and 2000. Twenty of 39 (51%) died of hepatic failure. We compared 15 clinical and laboratory variables between 20 died patients and 19 recovered patients using uni- and multi-variate analysis. At last we established a discrimination formula. Results; 1) By univariate analysis, chronic hepatitis or cirrhosis (CH/LC), bacteremia, low alkalinephosphatase(ALP), low hemoglobin, and low platelet(PLT) were significant risk factors of hepatic failure. 2) By multivariate analysis, CH/LC (p=0.008), hacteremla (p=0.004), low ALP (p=0.0008), and low PLT (p=0.0014) were significant. 3) Using these 4 variables, we established the following discrimination formula: Y= 3.9970+ 0.0729 x ALP(U/ml)+ 0.5743 x PLT(xlO4) - 19.6373 x CH/LC-25.6132 x hacteremia. A negative Y value indicated hepatic failure. Therefore,
M1615 Systematic Review: Does the Evidence Support an Association Between Cryptogenic Cirrhosis (CC) and Non-alcoholic Steatohepatitis (NASH)? Terence L. Angtnaco, Vivek Raj, Florinela G. Oprescu, Jill C. Beisel, John D. Moore, Brady D. Russell, Jennifer M. Co, Colin W. Howden Purpose: To assess, by systematic review, the strength of current evidence supporting the association of CC and NASH. Methods: We searched Medtine for English articles using the following keywords: cryptogenic cirrhosis, cirrhosis, steatohepatitis, NASH, NAFLD, fatty liver, and liver transplant. Bibliographies of articles were used to augment our search. Results: 22 relevant publications were reviewed - 1 cohort study (Co) comparing CC patients with cirrhotics of known cause, 9 longitudinal studies (LS), 7 case-control studies (CCS), 1 ease series (CS) and 4 case reports (CR). Only 12 studies defined significant alcohol use. Hepatitis
A-383
AGA Abstracts