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A Comparative Study of Orthotopic Liver Transplant (OLTX) for Sclerosing Cholangitis in Patients With and Without Elevated Serum IgG4 Levels
tests and symptoms. Methods: Patients were given 1 gm of oral vancomycin twice daily for 52 weeks. Lab tests were done every 12 weeks throughout treatment. A liver biopsy and magnetic resonance cholangiopancreatography (MRCP) were both done at baseline and at study completion. Results: Ten patients were enrolled in the trial with 7 patients completing the full 52 weeks of treatment. The others completed between 24 and 48 weeks of treatment; one patient stopped due to abdominal pain at 36 weeks, a second stopped at 48 weeks in the midst of a flare of IBD, and the third was lost to follow-up at 24 weeks. All 7 patients who completed the full 52 weeks of therapy underwent pre- and post-liver biopsy and 9 patients had pre- and post-MRCP. The median age of the patients was 31.5 years (range 18-53). 9 subjects were male, 1 was female. At baseline the mean laboratory values were: alkaline phosphatase 343.5 ± 167.9; ALT 80.3 + 34.6; total bilirubin 0.69 + 0.45. At the end of the study mean laboratory values were: alkaline phosphatase 301.3 ± 231.5 (decreased in 8/10 patients, percent reduction range 13-50%) ; ALT 75.7 ± 45.4 (decreased in 5/10 patients, percent reduction range 14-59%). No overall improvement was seen in total bilirubin, though 2/10 patients saw a reduction between 30% and 60%. No patient normalized all values. The liver biopsies and MRCPs were reviewed in blinded fashion. Two patients of the seven who had paired biopsy specimens were judged to have improved histology while the remaining 5 were unchanged. None had progression. Four patients of the nine who had paired cholangiograms were judged to have an improved cholangiogram, 3 were worse, and 2 were the same. The improvements in LFTs did not predict histologic or MR improvement. No serious adverse events occurred and no patient developed vancomycin resistant enterococcus. Conclusion: Use of oral vancomycin in patients with PSC appears to be safe. In this short term trial it induced a mild improvement in alkaline phosphatase and transaminases. There was histologic and/or cholangiographic benefit seen in some patients. Contrary to the pediatric series, this study does not support a broadly positive effect of oral vancomycin in adults with PSC, although a subgroup of patients may benefit.
825 Maintenance Treatment is Necessary Even When Auto Immune Hepatitis is in Remission Nicole M. van Gerven, Bart J. Verwer, Chris J. Mulder, Maureen Guichelaar, Bart van Hoek, Martine Pronk, Minneke J. Coenraad, Henk R. van Buuren, Robert A. De Man, Karel J. Van Erpecum, Joost P. Drenth, Ulrich Beuers, Jannie den Ouden, Ger H. Koek, Johannes T. Brouwer, Karin van Nieuwkerk, Gerd Bouma Background: Autoimmune hepatitis (AIH) is a chronic inflammatory autoimmune disorder of the liver of unknown etiology. Treatment is aimed at suppressing the exaggerated inflammatory response and includes steroids and azathioprine. It is generally believed that discontinuation of therapy leads to rapid relapse of the disease, however literature to support this thesis is scarce. Aim: To determine the number of relapses in a cohort of AIH patients. Methods: We reviewed the charts of 800 patients (175.M; 625 F) that fulfilled the diagnostic criteria of AIH. In a group of 117 patients, treatment was reduced with the aim to eventually discontinue the treatment. Mean time after diagnosis was 5,68 years (range: 2-27 years). At the start of reduction therapy 22 patients (19%) used mono therapy azathioprine average dose 80 mg ; 30 patients (24%) mono therapy prednisone average 7.3 mg and 65 patients (57%) prednisone in combination with azathioprine average 6,75/85 mg. Relapse was defined as increasing aminotransferase levels above the upper limit of normal, with or without concomitant clinical symptoms. Results: In a group of 117 patients, treatment was discontinued due to longstanding (≥ 2 years) normal aminotransferases and no other clinical or biochemical abnormalities. In 17 of these patients (14,5 %) liver biopsy confirmed the absence of active inflammation. In 62 patients, all medication was discontinued. In 55 patients, medication was tapered, however not fully discontinued, because of a relapse. After a mean follow up of 7,61 years (range: 2-27), 104 out of 117 (89%) had a relapse requiring restarting of increasing immunosuppression. The thirteen patients (11%)who did not have a relapse had a follow-up mean of 6,6 years (1,6-16,5) without medication. A total of 49 (47,1%) of the relapse patients had no therapy when they got a relapse, while 55 patients (52,9%) got a relapse during tapering of the therapy. Conclusion: Relapse of AIH patients in remission occurs in virtually all patients when therapy is tapered or discontinued after a period of at least two years of maintenance therapy. These data indicate that AIH patients should therefore be kept on maintenance therapy.
828 A Comparative Study of Orthotopic Liver Transplant (OLTX) for Sclerosing Cholangitis in Patients With and Without Elevated Serum IgG4 Levels John Y. Nasr, Michael Nalesnik, Anthony J. Demetris, Mordechai Rabinovitz Background: Sclerosing Cholangitis is a chronic cholestatic liver disorder characterized by inflammation and fibrosis of the large and medium size intra and extrahepatic bile ducts. Sclerosing cholangitits can lead to biliary cirrhosis and liver transplantation. Recently, IgG4 associated cholangitis has been recognized as one of the causes of secondary sclerosing cholangitis. Our study aims at comparing patient characteristics and OLTx outcomes between sclerosing cholangitis patients with and without elevated serum IgG4 levels. Methods: We reviewed the records of all adult patients who underwent OLTx at the University of Pittsburgh Medical Center between March 1996 and April 2009. The diagnosis of sclerosing cholangitis was based on a combination of liver biochemistry tests, imaging studies and histology. Serum IgG4 levels were measured in stored sera of these patients. An IgG4 level of 90 mg/dl or higher was considered positive. Results: Of the entire cohort, we identified 72 patients who underwent OLTx for sclerosing cholangitis. 52 patients (72%) had normal serum IgG4 levels (range 6-82 mg/dl), and 20 patients (28%) had elevated IgG4 levels (range 91-539 mg/dl). Both groups were similar in regard to age (51 vs. 49 years), gender (male patients 58% vs. 80% (both p=0.065) and pre OLTx MELD score (16.9 vs. 17.4, (p=0.8), respectively. None of the patients of either group had evidence of cholangiocarcinoma in their explants. Average patient survival was 2172 days in the IgG4 negative group and 1867 days in the IgG4 positive group (p=0.13). ICU length of stay (LOS) was 13.3 days vs. 8.25 days (p=0.34) and total length of stay was 27.8 vs. 19.1 days (p=0.29), respectively. Rejection rates were 19/52 (37%) vs. 6/20 (30%) (p=0.4) and retransplantation rates were 13/52 (25%) vs. 3/ 20 (15%)(p=0.28) in the IgG4 negative and the IgG4 positive groups, respectively. At 1 year, 48 patients with IgG4 negative disease were alive (92%) compared to all patients with IgG4 positive disease (100%, p=0.26). At 3 years, patient survival was 87% vs. 100% respectively. Conclusions: In comparison of sclerosing cholangitis patients with normal levels of serum IgG4 who underwent OLTx, to those with elevated levels, there were no differences in LOS, patient survival, graft rejection, and retransplantaion rates between the two groups.
826 Optimizing Biochemical Markers as Endpoints for Clinical Trials in Primary Biliary Cirrhosis Njideka Momah, Marina Silveira, Roberta A. Jorgensen, Emmanouil Sinakos, Keith D. Lindor Biochemical tests have been recommended as endpoints for clinical trials in primary biliary cirrhosis (PBC) because the use of outcomes such as liver transplantation and death in therapeutic trials in ursodeoxycholic acid (UDCA) treated patients is unfeasible. However, the best cut-off values for including patients in trials and for demonstrating treatment success have not been defined. Our aim was to determine the most appropriate biochemical values for inclusion of patients into therapeutic trials and to also define values for treatment success in these trials. We performed a retrospective record review of 73 patients with PBC treated with UDCA followed over at least 36 months. Levels of serum alkaline phosphatase (ALP), aspartate aminotransaminase (AST), bilirubin and albumin were evaluated quarterly. Following one year of UDCA therapy, the likelihood of developing clinical endpoints of varices, ascites, encephalopathy, death or transplantation over the ensuing two years, based on degrees of elevation of biochemical markers, was analyzed using chi-square or Fisher's exact test. Patients with ALP > 2 X upper limit of normal (ULN) had a 2-fold greater likelihood of developing endpoints compared to patients with lower values (23% versus 11%), (p<0.05). Patients with bilirubin > 1 mg/dL were 4 times more likely to develop endpoints compared to those with lower values (33% versus 8%), (p=0.02). These values help determine the patient population for adjunctive therapy trials. Patients with ALP < 1.67 X ULN and bilirubin < 1mg/dL demonstrated the least likelihood of reaching adverse clinical endpoints and can be used to define treatment success. Conclusion: ALP > 2 X ULN or bilirubin > 1 mg/dL at 12 months of UDCA therapy are appropriate biochemical criteria for enrollment in adjunctive therapy trials. Treatment success can be defined as ALP < 1.67 X ULN and bilirubin < 1mg/dL. These values define appropriate biochemical criteria for patient selection and defining treatment success in future clinical trials in patients with PBC.
829 Similar SVR Rates in IL28B CC, CT or TT Prior Relapser, Partial- or NullResponder Patients Treated With Telaprevir/Peginterferon/Ribavirin: Retrospective Analysis of the Realize Study Zobair M. Younossi, Jeroen Aerssens, Stanislas Pol, Paul Pockros, Eric J. Lawitz, Stefan Zeuzem, Pietro Andreone, Stuart K. Roberts, Graham Foster, Roberto Focaccia, Andrzej Horban, Rolf van Heeswijk, Sandra De Meyer, Don Luo, Martyn C. Botfield, Maria Beumont-Mauviel, Gaston Picchio Background and Aims: IL28B polymorphisms are linked to differences in SVR rates in HCV treatment-naïve patients treated with pegylated interferon (P) and ribavirin (R). REALIZE is a Phase 3 study that compared the efficacy, safety and tolerability of telaprevir (T), with or without a Lead-in (L-I), in combination with PR against PR alone in prior treatmentfailure patients including relapsers, partial responders and null responders (NR). Both T/ PR arms were superior to control in all three patient categories. The relationship between IL28B genotype and SVR was investigated retrospectively. Methods: 527/662 (80%) patients enrolled in REALIZE consented to genetic testing. This represented 72%, 76% and 98% of the total relapsers, partial responders, and NR, respectively. Genotype rs12979860 was determined using a TaqMan allelic discrimination assay validated against Sanger sequencing on 50 independent samples. This was a retrospective study based on patients who consented to genetic testing prior to the discovery of IL28B, thus, sample size was not based on formal statistical considerations. Results: Overall, 94% were Caucasian and 4% were Black. Eighteen percent of patients were IL28B CC, 61% CT and 21 % TT. By prior response category, the highest proportion of IL28B TT patients was among prior NR (28%) while the highest frequency of CC patients occurred among prior relapsers (27%). The observed IL28B genotype frequencies indicated that the population was not in Hardy-Weinberg equilibrium (Chi2=28, P<0.0001). IL28B genotypes were well-balanced across all arms with exception of a higher frequency of TTs in the placebo arm. Since no differences were observed between
827 An Open Label Pilot Trial of Oral Vancomycin in Primary Sclerosing Cholangitis - Results of the VIP Trial Daniel Pratt, Sheela Agarwal, Sanjay Saini, Joseph Misdraji, Joshua R. Korzenik Background: Primary sclerosing cholangitis (PSC), a condition frequently associated with inflammatory bowel disease (IBD), is characterized by chronic suppurative destruction of the intrahepatic and extrahepatic bile ducts and inevitable progression to biliary cirrhosis and liver failure. There is no proven medical therapy for PSC and limited experience in the use of antibiotics to treat PSC. Oral vancomycin has been advanced as a promising therapy. A small uncontrolled series of oral vancomycin in 14 children showed improvement in liver
S-907
AASLD Abstracts
AASLD Abstracts
(95% CI 0.40-2.04) for PBC and 4.63 (95% CI 2.97-6.89) for PSC. After adjusting for hepatobiliary cancer, standardized morbidity ratios for malignancy were 2.08 (95% CI 1.353.07) for AIH, 1.01 (95% CI 0.41-2.07) for PBC and 2.36 (95% CI 1.22-4.11) for PSC. Conclusion: This is the first mortality analysis comparing population-based AIH, PBC and PSC cohorts from the same region. PSC had the worst outcome. The standardized mortality ratios for all three cohorts were significantly higher than those of the general population, suggesting that better treatment strategy is desperately needed for these conditions. AIH and PSC were associated with significantly more cases of malignancy, even after adjusting for hepatobiliary cancer.
825 Maintenance Treatment is Necessary Even When Auto Immune Hepatitis is in Remission Nicole M. van Gerven, Bart J. Verwer, Chris J. Mulder, Maureen Guichelaar, Bart van Hoek, Martine Pronk, Minneke J. Coenraad, Henk R. van Buuren, Robert A. De Man, Karel J. Van Erpecum, Joost P. Drenth, Ulrich Beuers, Jannie den Ouden, Ger H. Koek, Johannes T. Brouwer, Karin van Nieuwkerk, Gerd Bouma Background: Autoimmune hepatitis (AIH) is a chronic inflammatory autoimmune disorder of the liver of unknown etiology. Treatment is aimed at suppressing the exaggerated inflammatory response and includes steroids and azathioprine. It is generally believed that discontinuation of therapy leads to rapid relapse of the disease, however literature to support this thesis is scarce. Aim: To determine the number of relapses in a cohort of AIH patients. Methods: We reviewed the charts of 800 patients (175.M; 625 F) that fulfilled the diagnostic criteria of AIH. In a group of 117 patients, treatment was reduced with the aim to eventually discontinue the treatment. Mean time after diagnosis was 5,68 years (range: 2-27 years). At the start of reduction therapy 22 patients (19%) used mono therapy azathioprine average dose 80 mg ; 30 patients (24%) mono therapy prednisone average 7.3 mg and 65 patients (57%) prednisone in combination with azathioprine average 6,75/85 mg. Relapse was defined as increasing aminotransferase levels above the upper limit of normal, with or without concomitant clinical symptoms. Results: In a group of 117 patients, treatment was discontinued due to longstanding (≥ 2 years) normal aminotransferases and no other clinical or biochemical abnormalities. In 17 of these patients (14,5 %) liver biopsy confirmed the absence of active inflammation. In 62 patients, all medication was discontinued. In 55 patients, medication was tapered, however not fully discontinued, because of a relapse. After a mean follow up of 7,61 years (range: 2-27), 104 out of 117 (89%) had a relapse requiring restarting of increasing immunosuppression. The thirteen patients (11%)who did not have a relapse had a follow-up mean of 6,6 years (1,6-16,5) without medication. A total of 49 (47,1%) of the relapse patients had no therapy when they got a relapse, while 55 patients (52,9%) got a relapse during tapering of the therapy. Conclusion: Relapse of AIH patients in remission occurs in virtually all patients when therapy is tapered or discontinued after a period of at least two years of maintenance therapy. These data indicate that AIH patients should therefore be kept on maintenance therapy.
828 A Comparative Study of Orthotopic Liver Transplant (OLTX) for Sclerosing Cholangitis in Patients With and Without Elevated Serum IgG4 Levels John Y. Nasr, Michael Nalesnik, Anthony J. Demetris, Mordechai Rabinovitz Background: Sclerosing Cholangitis is a chronic cholestatic liver disorder characterized by inflammation and fibrosis of the large and medium size intra and extrahepatic bile ducts. Sclerosing cholangitits can lead to biliary cirrhosis and liver transplantation. Recently, IgG4 associated cholangitis has been recognized as one of the causes of secondary sclerosing cholangitis. Our study aims at comparing patient characteristics and OLTx outcomes between sclerosing cholangitis patients with and without elevated serum IgG4 levels. Methods: We reviewed the records of all adult patients who underwent OLTx at the University of Pittsburgh Medical Center between March 1996 and April 2009. The diagnosis of sclerosing cholangitis was based on a combination of liver biochemistry tests, imaging studies and histology. Serum IgG4 levels were measured in stored sera of these patients. An IgG4 level of 90 mg/dl or higher was considered positive. Results: Of the entire cohort, we identified 72 patients who underwent OLTx for sclerosing cholangitis. 52 patients (72%) had normal serum IgG4 levels (range 6-82 mg/dl), and 20 patients (28%) had elevated IgG4 levels (range 91-539 mg/dl). Both groups were similar in regard to age (51 vs. 49 years), gender (male patients 58% vs. 80% (both p=0.065) and pre OLTx MELD score (16.9 vs. 17.4, (p=0.8), respectively. None of the patients of either group had evidence of cholangiocarcinoma in their explants. Average patient survival was 2172 days in the IgG4 negative group and 1867 days in the IgG4 positive group (p=0.13). ICU length of stay (LOS) was 13.3 days vs. 8.25 days (p=0.34) and total length of stay was 27.8 vs. 19.1 days (p=0.29), respectively. Rejection rates were 19/52 (37%) vs. 6/20 (30%) (p=0.4) and retransplantation rates were 13/52 (25%) vs. 3/ 20 (15%)(p=0.28) in the IgG4 negative and the IgG4 positive groups, respectively. At 1 year, 48 patients with IgG4 negative disease were alive (92%) compared to all patients with IgG4 positive disease (100%, p=0.26). At 3 years, patient survival was 87% vs. 100% respectively. Conclusions: In comparison of sclerosing cholangitis patients with normal levels of serum IgG4 who underwent OLTx, to those with elevated levels, there were no differences in LOS, patient survival, graft rejection, and retransplantaion rates between the two groups.
826 Optimizing Biochemical Markers as Endpoints for Clinical Trials in Primary Biliary Cirrhosis Njideka Momah, Marina Silveira, Roberta A. Jorgensen, Emmanouil Sinakos, Keith D. Lindor Biochemical tests have been recommended as endpoints for clinical trials in primary biliary cirrhosis (PBC) because the use of outcomes such as liver transplantation and death in therapeutic trials in ursodeoxycholic acid (UDCA) treated patients is unfeasible. However, the best cut-off values for including patients in trials and for demonstrating treatment success have not been defined. Our aim was to determine the most appropriate biochemical values for inclusion of patients into therapeutic trials and to also define values for treatment success in these trials. We performed a retrospective record review of 73 patients with PBC treated with UDCA followed over at least 36 months. Levels of serum alkaline phosphatase (ALP), aspartate aminotransaminase (AST), bilirubin and albumin were evaluated quarterly. Following one year of UDCA therapy, the likelihood of developing clinical endpoints of varices, ascites, encephalopathy, death or transplantation over the ensuing two years, based on degrees of elevation of biochemical markers, was analyzed using chi-square or Fisher's exact test. Patients with ALP > 2 X upper limit of normal (ULN) had a 2-fold greater likelihood of developing endpoints compared to patients with lower values (23% versus 11%), (p<0.05). Patients with bilirubin > 1 mg/dL were 4 times more likely to develop endpoints compared to those with lower values (33% versus 8%), (p=0.02). These values help determine the patient population for adjunctive therapy trials. Patients with ALP < 1.67 X ULN and bilirubin < 1mg/dL demonstrated the least likelihood of reaching adverse clinical endpoints and can be used to define treatment success. Conclusion: ALP > 2 X ULN or bilirubin > 1 mg/dL at 12 months of UDCA therapy are appropriate biochemical criteria for enrollment in adjunctive therapy trials. Treatment success can be defined as ALP < 1.67 X ULN and bilirubin < 1mg/dL. These values define appropriate biochemical criteria for patient selection and defining treatment success in future clinical trials in patients with PBC.
829 Similar SVR Rates in IL28B CC, CT or TT Prior Relapser, Partial- or NullResponder Patients Treated With Telaprevir/Peginterferon/Ribavirin: Retrospective Analysis of the Realize Study Zobair M. Younossi, Jeroen Aerssens, Stanislas Pol, Paul Pockros, Eric J. Lawitz, Stefan Zeuzem, Pietro Andreone, Stuart K. Roberts, Graham Foster, Roberto Focaccia, Andrzej Horban, Rolf van Heeswijk, Sandra De Meyer, Don Luo, Martyn C. Botfield, Maria Beumont-Mauviel, Gaston Picchio Background and Aims: IL28B polymorphisms are linked to differences in SVR rates in HCV treatment-naïve patients treated with pegylated interferon (P) and ribavirin (R). REALIZE is a Phase 3 study that compared the efficacy, safety and tolerability of telaprevir (T), with or without a Lead-in (L-I), in combination with PR against PR alone in prior treatmentfailure patients including relapsers, partial responders and null responders (NR). Both T/ PR arms were superior to control in all three patient categories. The relationship between IL28B genotype and SVR was investigated retrospectively. Methods: 527/662 (80%) patients enrolled in REALIZE consented to genetic testing. This represented 72%, 76% and 98% of the total relapsers, partial responders, and NR, respectively. Genotype rs12979860 was determined using a TaqMan allelic discrimination assay validated against Sanger sequencing on 50 independent samples. This was a retrospective study based on patients who consented to genetic testing prior to the discovery of IL28B, thus, sample size was not based on formal statistical considerations. Results: Overall, 94% were Caucasian and 4% were Black. Eighteen percent of patients were IL28B CC, 61% CT and 21 % TT. By prior response category, the highest proportion of IL28B TT patients was among prior NR (28%) while the highest frequency of CC patients occurred among prior relapsers (27%). The observed IL28B genotype frequencies indicated that the population was not in Hardy-Weinberg equilibrium (Chi2=28, P<0.0001). IL28B genotypes were well-balanced across all arms with exception of a higher frequency of TTs in the placebo arm. Since no differences were observed between
827 An Open Label Pilot Trial of Oral Vancomycin in Primary Sclerosing Cholangitis - Results of the VIP Trial Daniel Pratt, Sheela Agarwal, Sanjay Saini, Joseph Misdraji, Joshua R. Korzenik Background: Primary sclerosing cholangitis (PSC), a condition frequently associated with inflammatory bowel disease (IBD), is characterized by chronic suppurative destruction of the intrahepatic and extrahepatic bile ducts and inevitable progression to biliary cirrhosis and liver failure. There is no proven medical therapy for PSC and limited experience in the use of antibiotics to treat PSC. Oral vancomycin has been advanced as a promising therapy. A small uncontrolled series of oral vancomycin in 14 children showed improvement in liver
S-907
AASLD Abstracts
AASLD Abstracts
(95% CI 0.40-2.04) for PBC and 4.63 (95% CI 2.97-6.89) for PSC. After adjusting for hepatobiliary cancer, standardized morbidity ratios for malignancy were 2.08 (95% CI 1.353.07) for AIH, 1.01 (95% CI 0.41-2.07) for PBC and 2.36 (95% CI 1.22-4.11) for PSC. Conclusion: This is the first mortality analysis comparing population-based AIH, PBC and PSC cohorts from the same region. PSC had the worst outcome. The standardized mortality ratios for all three cohorts were significantly higher than those of the general population, suggesting that better treatment strategy is desperately needed for these conditions. AIH and PSC were associated with significantly more cases of malignancy, even after adjusting for hepatobiliary cancer.