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Pegylated interferon alfa-2B (PEG-intron) mono-therapy is superior to interferon alfa-2B (intron A) for the treatment of chronic hepatitis C
GENERAL
SESSION 2
PEGYLATED INTERFERON ALFA-ZB (PEGINTRON) MONOTHERAPY IS SUPERIOR TO INTERFERON ALFA-2B (INTRON A) FOR THE TREATMENT OF CHRONIC HEPATITIS C
C. Treno’. K. Lindsav. C. Niederau. M. Shiffman, S. Gordon. .I. Hoefs. E. Schiff. I? Marcellin. B. Bacon, J. Fanez. J. Garaud. J. Albrecht. for the Henatitis Interventional Theraov Grouu ‘Hopital Hotel Dieu, Lyon, France. %chering-Plough Research Institute,
CHARACTERISATION OF DENDRITIC CELLS MIGRATED FROM HUMAN LIVER TISSUE REVEALS AN INTERMEDIATE PHENOTYPE WITH ABILITY TO INITIATE PRIMARY IMMUNE RE
SPONSES S. Goddard. S.G. Hubscher. P Lane. D.H. Adams MRC Centre for Immune Regulation, Queen Elizabeth Hospital, Edgbaston, Birmingham Dendritic & initiate
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.
L.mdiclurenhi&l~aIlvnalolvneluln-l8nd~mlmlHcvRNA
B30 2TH.
cells, DCs are able to present antigen to ndive T cells primary immune responses in viva After taking up
antigen in tissue, DCs migrate via lymphatics to lymph nodes where they activate T cells & determine the type of response. We have developed a novel method to isolate DCs from human liver in which thin pieces of liver tissue were cultured overnight allowing DCs to migrate out before being purified by density gradient centrifugation. The cells were phenotyped by immunohistochemistry & FACS & their ability to stimulate naiVe cord blood lymphocytes tested in a mixed lymphocyte reaction. In culture the cells had short processes initially & developed typical veils after tiher culture. Cells from normal liver were monocyte like & expressed CD14, CDllb but not CD68. They expressed CD83 & high HLA-DR, co-stimulatory molecules & CD1 lc. After culture cells developed a distinctive morphology, lost expression of CD1 lb & CD14 but increased CD83 & CD86, & gained 0X2. Cells derived from diseased liver contained a subset with a more mature morphology that expressed CD68 initially. Both types of cells were able to activate ndive T cells efficiently. In conclusion, DCs of intermediate maturity can be isolated from human liver with minimum manipulation. These cells can present Ag efficiently & will provide a useful tool for studying immune responses in the liver.
EVALUATION OF THE SAFETY AND EFFICACY OF ONCE-WEEKLY PEG/INTERFERON ALFA-2A (PEGASYSTM) FOR CHRONIC HEPATITIS C. A MULTINATIONAL, RANDOMIZED STUDY
THE E3BP (PROTEIN X) COMPONENT OF PYRUVATE DEHYDROGENASE COMPLEX (PDC) IS NOT A T-CELL AUTOANTIGEN IN PRIMARY BILIARY CIRRHOSIS (PBC)
S. Zeuzem’, S.V. Feinmar?. J. Rasenack3. E.J. Heathcote“, M.-Y. Lai5. E. Gane6. J. O’Gradv7. J. Reichen*. M.J. Brunda’ ‘Frankfurt, Germany. 2Toronto, Canada. 3Freiburg, Germany. 4Toronto, Canada. 5Taipei, Taiwan. 6Auckland, New Zealand. ‘London, United Kingdom. 8Bern, Switzerland. 9Nutley, NJ, USA, for the PEGASYS International Study Group. Pqnterleron alfa-2a (PEG[40K) -IFN&!a) is interferon aifa-la (IFNa-Pa) covalently
A. Robe’. J.M. Palmer’~z. S.J. Yeaman’,2. D.E.J. Jones’ ‘Centre for Liver Research, University of Newcastle, UK. *Department Biochemistry and Genetics, University of Newcastle, UK.
bonded to a 40 kilodatton branched polyethylene glycol nwiety (PEG) for st~ctural modifzdkm and enhanced pharmacologic es well as dinical performance. Phase II trials of PEG(40K>IFNw2a revealed improved effcacy for boh non-cirrhotic and cirrh&ic patients witi chronic hepatitis C mmpamd to treatment with 3MIU IFNa-2a thrice weekly. Obiectlve: To evaluate and compare the safely and efT=cy of wee weekiy PEG(40K)_ IFNa-2a with IFNw2a. three time weekly, in a phase Ill multinetkmal randomized trial of IFN-na.ive patients with chronic hepatitis C. Methods: In a mui?i.xnter. intematicaal study (Genany, Canada. UK. Spain. Taiwan, New Zealand. Swilzerlacd, Mexico. and Australia). 531 IFN-naTve adult patients with chrcnic hepatitis C were randomized in an open-label trial Of the 531 patients. 254 were randomized to treatment with IFNw2a subcuteneously three times weekly (6 MIU for 12 mteks, foIlawed by 3 MIU for 36 weeks) and 267 wire randomized to receive PEG(40K)_ IFNw2a subxtanewsly onca weekly (180 ,,g for 48 weeks). &g!& Treated patients were predominantly male (67%) and Caucasian (85%), with a mean age of 41 years The percanlage of patients with HCV genotype 1 was 60% in the IFNa-2a groups and 63% in the PEG(40K)-IFNw2a group. Mean HCV RNAtitere were 8.2 and 7.4 million copies/ml in the IFNa-2e and PEG(40K)_IFN&a groups, respectively. Patients with cirrhosis or transitii to cinhmis Comprised 14% of those randombed to receive IFNa-2a and 12% of those randomized to receive PEG(40K)_ IFNa-2a. End of treatment (week 48) vira!agic response rates (AMPLICORN II: cut-off of ~100 copies/ml) for all randomized patients were 27% (IFNu-Pa grwp) and 66% (PEG[40K)-lFNw2a group). Sustained virologic responses (week 72) were obtained in 19% of pabents treated with IFNa-2a and in 39% of patients treated with PEG(40K)IFNada. Types and frequencies of adverse events were similar fw bofJ~groups. Dose modification wae required for neutroopenie in 7% and 11%. for thmmbocytopenia m 2% and 3%. and for all other adverse events !n 12% and 8% of patiente in the IFNa-2a and PEG(40KbtFNw2a groups. reswctively. Discontinual+an rates for drug intolerance were 10% I” the IFNw2a group and 7% in the PEG(40K)_IFN&?e group. Conclurions: For patients with chmnic hepatitis C. once weekly subcutaneous injection of PEG(40K)-IFNw2a is significantly more eKcaaws than thrii weekly IFNada and has a” acceptable safety profile
of
PBC is characterised by serum auto-antibody responses reactive with the E2 and E3BP components of PDC. These responses have recently been shown to be fully cross-reactive, a finding which explains earlier observations that antibody responses to PDC-EP and EBBP always co-exist in PBC patients. The degree of crossreactivity between PDC-E2 andE3BP at the B-cell level has meant that these studies have failed to answer the critical question - which antigen does the critical breakdown of self-tolerance in PBC occur to. To address this question we have studied T-cell responses to full length recombinant (r) human PDC-E2 and E3BP in PBC patients (n=12). We have previously demonstrated peripheral blood T-cell proliferative responses to a preparation of PDC-E2 and EBBP (which co-purify when derived from tissue) which are present in the majority of PBC patients but absent from controls. Positive proliferative responses to rE2 were seen in 1 l/l 2 PBC patients. A (marginal) positive response to rE3BP was, in contrast, only seen in 1112 of the PBC patients (p=O.OOOl). Median stimulation index to rE2 was markedly higher than that to rE3BP (6.48 [1.6-18.21 v 1.0 [0.64-2.11, pcO.0001. Comparison of culture supematant IFN7 and IL-10 levels in response to rE2 and rE3BP and in control wells showed significant secretion of both cytokines in response to rE2, but no response to rE3BP. Conclusion: T-cell responses to PDC-ESBP are not seen in PBC patients. This finding suggests that the breakdown of T-cell tolerance to PDC in PBC is to the E2 component with subsequent cross-reactivity with E3BP at the B-cell but not T-cell level.
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SESSION 2
PEGYLATED INTERFERON ALFA-ZB (PEGINTRON) MONOTHERAPY IS SUPERIOR TO INTERFERON ALFA-2B (INTRON A) FOR THE TREATMENT OF CHRONIC HEPATITIS C
C. Treno’. K. Lindsav. C. Niederau. M. Shiffman, S. Gordon. .I. Hoefs. E. Schiff. I? Marcellin. B. Bacon, J. Fanez. J. Garaud. J. Albrecht. for the Henatitis Interventional Theraov Grouu ‘Hopital Hotel Dieu, Lyon, France. %chering-Plough Research Institute,
CHARACTERISATION OF DENDRITIC CELLS MIGRATED FROM HUMAN LIVER TISSUE REVEALS AN INTERMEDIATE PHENOTYPE WITH ABILITY TO INITIATE PRIMARY IMMUNE RE
SPONSES S. Goddard. S.G. Hubscher. P Lane. D.H. Adams MRC Centre for Immune Regulation, Queen Elizabeth Hospital, Edgbaston, Birmingham Dendritic & initiate
-
.
L.mdiclurenhi&l~aIlvnalolvneluln-l8nd~mlmlHcvRNA
B30 2TH.
cells, DCs are able to present antigen to ndive T cells primary immune responses in viva After taking up
antigen in tissue, DCs migrate via lymphatics to lymph nodes where they activate T cells & determine the type of response. We have developed a novel method to isolate DCs from human liver in which thin pieces of liver tissue were cultured overnight allowing DCs to migrate out before being purified by density gradient centrifugation. The cells were phenotyped by immunohistochemistry & FACS & their ability to stimulate naiVe cord blood lymphocytes tested in a mixed lymphocyte reaction. In culture the cells had short processes initially & developed typical veils after tiher culture. Cells from normal liver were monocyte like & expressed CD14, CDllb but not CD68. They expressed CD83 & high HLA-DR, co-stimulatory molecules & CD1 lc. After culture cells developed a distinctive morphology, lost expression of CD1 lb & CD14 but increased CD83 & CD86, & gained 0X2. Cells derived from diseased liver contained a subset with a more mature morphology that expressed CD68 initially. Both types of cells were able to activate ndive T cells efficiently. In conclusion, DCs of intermediate maturity can be isolated from human liver with minimum manipulation. These cells can present Ag efficiently & will provide a useful tool for studying immune responses in the liver.
EVALUATION OF THE SAFETY AND EFFICACY OF ONCE-WEEKLY PEG/INTERFERON ALFA-2A (PEGASYSTM) FOR CHRONIC HEPATITIS C. A MULTINATIONAL, RANDOMIZED STUDY
THE E3BP (PROTEIN X) COMPONENT OF PYRUVATE DEHYDROGENASE COMPLEX (PDC) IS NOT A T-CELL AUTOANTIGEN IN PRIMARY BILIARY CIRRHOSIS (PBC)
S. Zeuzem’, S.V. Feinmar?. J. Rasenack3. E.J. Heathcote“, M.-Y. Lai5. E. Gane6. J. O’Gradv7. J. Reichen*. M.J. Brunda’ ‘Frankfurt, Germany. 2Toronto, Canada. 3Freiburg, Germany. 4Toronto, Canada. 5Taipei, Taiwan. 6Auckland, New Zealand. ‘London, United Kingdom. 8Bern, Switzerland. 9Nutley, NJ, USA, for the PEGASYS International Study Group. Pqnterleron alfa-2a (PEG[40K) -IFN&!a) is interferon aifa-la (IFNa-Pa) covalently
A. Robe’. J.M. Palmer’~z. S.J. Yeaman’,2. D.E.J. Jones’ ‘Centre for Liver Research, University of Newcastle, UK. *Department Biochemistry and Genetics, University of Newcastle, UK.
bonded to a 40 kilodatton branched polyethylene glycol nwiety (PEG) for st~ctural modifzdkm and enhanced pharmacologic es well as dinical performance. Phase II trials of PEG(40K>IFNw2a revealed improved effcacy for boh non-cirrhotic and cirrh&ic patients witi chronic hepatitis C mmpamd to treatment with 3MIU IFNa-2a thrice weekly. Obiectlve: To evaluate and compare the safely and efT=cy of wee weekiy PEG(40K)_ IFNa-2a with IFNw2a. three time weekly, in a phase Ill multinetkmal randomized trial of IFN-na.ive patients with chronic hepatitis C. Methods: In a mui?i.xnter. intematicaal study (Genany, Canada. UK. Spain. Taiwan, New Zealand. Swilzerlacd, Mexico. and Australia). 531 IFN-naTve adult patients with chrcnic hepatitis C were randomized in an open-label trial Of the 531 patients. 254 were randomized to treatment with IFNw2a subcuteneously three times weekly (6 MIU for 12 mteks, foIlawed by 3 MIU for 36 weeks) and 267 wire randomized to receive PEG(40K)_ IFNw2a subxtanewsly onca weekly (180 ,,g for 48 weeks). &g!& Treated patients were predominantly male (67%) and Caucasian (85%), with a mean age of 41 years The percanlage of patients with HCV genotype 1 was 60% in the IFNa-2a groups and 63% in the PEG(40K)-IFNw2a group. Mean HCV RNAtitere were 8.2 and 7.4 million copies/ml in the IFNa-2e and PEG(40K)_IFN&a groups, respectively. Patients with cirrhosis or transitii to cinhmis Comprised 14% of those randombed to receive IFNa-2a and 12% of those randomized to receive PEG(40K)_ IFNa-2a. End of treatment (week 48) vira!agic response rates (AMPLICORN II: cut-off of ~100 copies/ml) for all randomized patients were 27% (IFNu-Pa grwp) and 66% (PEG[40K)-lFNw2a group). Sustained virologic responses (week 72) were obtained in 19% of pabents treated with IFNa-2a and in 39% of patients treated with PEG(40K)IFNada. Types and frequencies of adverse events were similar fw bofJ~groups. Dose modification wae required for neutroopenie in 7% and 11%. for thmmbocytopenia m 2% and 3%. and for all other adverse events !n 12% and 8% of patiente in the IFNa-2a and PEG(40KbtFNw2a groups. reswctively. Discontinual+an rates for drug intolerance were 10% I” the IFNw2a group and 7% in the PEG(40K)_IFN&?e group. Conclurions: For patients with chmnic hepatitis C. once weekly subcutaneous injection of PEG(40K)-IFNw2a is significantly more eKcaaws than thrii weekly IFNada and has a” acceptable safety profile
of
PBC is characterised by serum auto-antibody responses reactive with the E2 and E3BP components of PDC. These responses have recently been shown to be fully cross-reactive, a finding which explains earlier observations that antibody responses to PDC-EP and EBBP always co-exist in PBC patients. The degree of crossreactivity between PDC-E2 andE3BP at the B-cell level has meant that these studies have failed to answer the critical question - which antigen does the critical breakdown of self-tolerance in PBC occur to. To address this question we have studied T-cell responses to full length recombinant (r) human PDC-E2 and E3BP in PBC patients (n=12). We have previously demonstrated peripheral blood T-cell proliferative responses to a preparation of PDC-E2 and EBBP (which co-purify when derived from tissue) which are present in the majority of PBC patients but absent from controls. Positive proliferative responses to rE2 were seen in 1 l/l 2 PBC patients. A (marginal) positive response to rE3BP was, in contrast, only seen in 1112 of the PBC patients (p=O.OOOl). Median stimulation index to rE2 was markedly higher than that to rE3BP (6.48 [1.6-18.21 v 1.0 [0.64-2.11, pcO.0001. Comparison of culture supematant IFN7 and IL-10 levels in response to rE2 and rE3BP and in control wells showed significant secretion of both cytokines in response to rE2, but no response to rE3BP. Conclusion: T-cell responses to PDC-ESBP are not seen in PBC patients. This finding suggests that the breakdown of T-cell tolerance to PDC in PBC is to the E2 component with subsequent cross-reactivity with E3BP at the B-cell but not T-cell level.
29