- Email: [email protected]
93 Enhanced antiviral efficacy for valopicitabine (NM283) plus peg-interferon in hepatitis C patients with HCV genotype-1 infection: Results of a phase IIa multicenter trial
39
Sunday, April 17, 2005
General Session 4 & Closing: Hepatitis C
R E S PO O N S EL A N DO S A FG ETY O C O M E S IN [ ]T H EV I R I U TC R A P Y - N A I V E PATIENTS TREATED FOR C H R O N I C HEPATITIS C WITH V I R A M I D I N E IN C O M B I N A T I O N WITH PEGYLATED INTERFERON ~-2a
R.G. Gish 1, D. Nelson 2, S. Arora 3, M.W. Fried 4, K.R. Reddy 5, Y. Xu 6, B. Murphy ~, Study Group ~ . : Calijbrnia Pacific Medical Cente~ San
Francisco, CA, USA; 2University of Florida, Gainesville FL, USA; SUniversity of New Mexico, Albuquerque NM, USA," 4University of North Carolina, Chapel Hill, NC, USA; 5Hospital of the University of Pennsylvania, Philadelphia PA, USA; 6 Valeant Pharmaceuticals International, Costa Mesa, CA, USA Introduction: Dose-limiting anemia can be a prominent adverse event o f therapy with pegylated interferon and ribavirin. This dose-ranging study examined whether viramidine, a liver-targeting pro
[•
BINDING OF HCV E N V E L O P E PROTEIN E2 TO CD81 U P R E G U L A T E S MMP-2 IN H U M A N HEPATIC STELLATE CELLS B Y INCREASING A P - 2 / D N A BINDING ACTIVITY VIA ERK/MAPK PHOSPHORYLATION
B. Lottini 1, A. Mazzocca I , S. Cappadona Sciammetta I , V Carloni 1, L. Cosrni ~, T. Harada 2, S. Abrignani 2, M. Pinzani 1 . IDipartimento di
Medicina Interna, Universitd di Firenze, Firenze, Italy," 2Chiron Vaccines Research Cente~ Siena, Italy Background and Aim: The Hepatitis C virus (HCV) envelope ]/2 glycoprotein is a key molecule regulating the interaction of HCV with cell surface proteins. E2 binds the major extracellular loop of human CD81, a tewaspanin expressed on various cell types including hepatocytes and B lymphocytes. Regardless, information on tile biological functions originating from this interaction are largely unknown. Since human hepatic stellate cells (HSC) express high levels of CD81 at the cell surface, we investigated tile E2 CD81 interaction in human HSC and tile possible effects arising from this interaction. Methods and Results: Matrix metalloproteinase 2 0MMP-2, gelatinase A), a maj or enzyme involved in the degradation of normal hepatic extracellular matrix, was up-regulated following tile interaction between E2 and CD81. In particular, by employing zyrnography and western blot, we observed that the binding of E2 to CDS1 induces a time-dependent increase in the synthesis and activity of MMP-2. This effect was abolished by preincubating HSC with an anti-CD81 neutralizing antibody. Similar effects were detected in human CDS1-NIH3T3 transfected cells with identical time-course features. In addition, E2-CD81 interaction in human HSC induced the up-regulation of MMP-2 by increasing AP-2/DNA binding activity via ERKJMAPK phosphorylation. Finally, suppression of CD81 by RNA interference in human HSC completely abolished the described effects of E2 on these cells, indicating that CD81 is essential for the activation of the signaling pathway leading to tile upregulation of MMP-2. Conclusions: Taken together, these results suggest that HSC may represent a potential target for HCM The interaction of HCV envelope with CD81 on tile surface of human HSC induces an increased expression of MMP-2. Increased degradation of the normal hepatic ECM in areas where HCV is concentrated may favour itrlammatory infiltration and further parenchymal damage.
[•
E N H A N C E D A N T I V I R A L EFFICACY FOR V A L O P I C I T A B I N E (NM283) PLUS P E G - I N T E R F E R O N IN HEPATITIS C PATIENTS WITH HCV GENOTYPE-1 INFECTION: RESULTS OF A P H A S E Ila MULTICENTER TRIAL
N. Afdhal I , M. Rodriguez-Torres 2, E. Lawitz 3, E. Godofsky 4, G. Chat 5, B. Fielman5, S. Knox 5, N. Brown 5. :Department of Medicine, Beth
Israel Deaconess Medical Cente~ Boston, MA, USA," 2Fundacion de Investigacion de Diego, Santurce, PR, USA," 3Alamo Medical Research, San Antonio, TX, USA,"4Bach & Godofsky, Bradenton, FL, USA," ~Idenix Pharmaceuticals, Cambridge, MA, USA Background: Only 40-50% of HCV-1 infected hepatitis C patients respond to pegylated interferon (peg-IFN(0 plus ribavirin therapy. NM283 is a novel nucleoside analog that as monotherapy reduced serum HCV RigA by a mean 1.21og10 (94%) in a recent 15-day trial in HCV-1 patients, most of whom had previously failed antiviral therapy for HCV infection.
Sunday, April 17, 2005
40
NM107, the parent compound of NM283, and interferon o~ exhibit synergistic antiviral effects against BVDV models in vitro, prompting the current investigation of NM283 combined with peg-IFNc~ in treatment naive patients with chronic hepatitis C. Methods: A multicenter, open-label phase IIa trial is evaluating whether NM283 plus peg-IFNct-2b has enhanced antiviral activity compared to NM283 alone in HCV-1 infected patients. Key entry criteria are: HCV RNA >51og10 IU/ml, A L T < 5 × ULN, compensated liver disease, treatment naive. Eligible patients are randomized 2:3 to NM283 or pegIFNc~ + NM283 (combinationtLx). NM283 is dosed orally QD for24 weeks in both groups, escalating to 800mg/day over the first week and then continuing at that dose. The group randomized to cornbinationRx receives peg-IFNo,-2b (1.0~tg/kg weekly) starting on Day 8. Results: Presently 19 of 30 planned patients (age 22-65, 68% males) are enrolled and have received 10 or 12 weeks of treatment. Tolerance of both treatments has been satisfactory. Mean HCV RNA reductions (log10 IU/rnl) from baseline to the last patient visit are 1.0 for the NM283 monotherapy group and 3.2 for tile combinafiontLx group. Eleven of twelve combinationRx patients treated for at least 10 weeks have had substantial HCV RNA reductions (range 1.2-6.21og10), and 8 of 12 patients have achieved >21og10 decrease in HCV RNA, which has been associated with sustained response to current standard tLx. Presently 4 patients are PCR-negative (<10 IUhnl). 12-week early virological response data will be presented at tile meeting. Conclusions: NM283 combined with peg-IFNc~ shows consistent, rapid and marked anti-HCV activity in patients with HCV-1 infection, a historically difficult-to-treat group. Initial EVR rates with combinationRx are encouraging and support continued investigation of NM283 and NM283 + peg-IFN0t, which may offer improved efficacy and tolepability for patients with HCV-1 infection.
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4
]
IMMUNOLOGICAL CORRELATES OF PROTECTION IN HCV INFECTION: VIGOR, BREADTH AND SPECIFICITY OF THE T CELL RESPONSE
S. Urbarti I , P. Fisicaro 1, B. Arnadei 1, A. Bertolettl 2, C. Cavallo 1, G. Missale 1, C. Ferrari I . ILaboratorio di Immunopatologia ~3rale,
Dioisione Malattie Infettioe ed Epatologia, Azienda Ospedaliera Universitaria di Parma, Parma, Italy," 2Institute of Hepatology, UCL, London, UK A vigorous and long lasting cellular immune response to HCV proteins has been reported to be associated with successful control of HCV infection but still little is known about the hierarchy and the breadth of the T cell response during tile acute phase of hepatitis in relation to the final outcome of infection. To address this issue, the global profile of the HCV-specific T cell response was analyzed in 15 genotype 1-infected patients (5 selflimited and 10 with chronic evolution) using a panel of 601 15-met peptides overlapping by 10 residues and sparming tile entire HCV sequence ofgenotype 1, pooled in 60 mixtures of 10 peptides each. Direct ex vivo frequency of IFN-g producing T cells was determined longitudinally by ELISPOT assay from the time of acute illness. The results indicate that no more than 20% o f the peptide pools tested induced a T cell response in tile acute stage of infection in patients with chronic evolution of tile disease, whereas patients with a self-limited hepatitis showed a broader response directed towards 35-70% of all peptide pools tested. This different breadth of the T cell response was maintained throughout the follow-up. Responses were sustained by a mixed activation of both CD4 and CD8 T cell subsets as shown by depletion experiments and in vitro expansion of T cell lines by culture with tile stimulatory peptide pools. Moreover, NS3 was the most immunogenic protein for T cells, followed by core, NS4B and NS5B. In conclusion, these results provide additional information about the immunological correlates of protection in HCV infection and may be relevant to tile design of future immune therapies.
[•
EFFECT OF MAINTENANCE PEG-INTRON T H E R A P Y ON PORTAL HYPERTENSION AND ITS COMPLICATIONS: RESULTS FROM THE COPILOT STUDY
M. Curry, A. C~xdenas, N.H. Afdhal. Liver Center, Beth Israel Deaconess
Medical Cente~ Boston, MA, USA The COPILOT clinical trial is evaluating maintenance therapy with PEGIntron 0.5~tg.~ weekly versus colchicine (COLC) 0 . r m g twice daily in 600 patients with HCV and advanced fibrosis who have failed prior interferon treatment. Clinical endpoints include death, liver failure, transplantation, variceal bleeding and liver cancer. The 2 year evaluation suggested an improved event free survival in patients on PEG compared to colchicine (Hepatology 2004; 40: 239A). We evaluated the role of portal hypertension (PHTN) on the clinical outcomes of maintenance therapy and the role of maintenance PEG-Intron on portal pressure. Patients and Methods: 537 patients are enrolled in the trial to date; 267 COLC and 270 PEG. 83% of patients in each group have cirrhosis and 40% have PHTN defined by varices or gastropathy. Endoscopy is performed every 2 years for development of new varices. A substudy evaluated portal pressure using HVPG measurements prior to PEG and after 24 weeks of PEG in 5 patients with varices who were not on B blockers. Clinical endpoints were evaluated in patients with and without PHTN. Results: 132 patients have had repeat endoscopy at 2 years and new varices were seen in 11 of 66 patients on COLC versus 5 of 66 patients on PEG (p=ns). All 5 patients had baseline elevated HVPG (Mean 15mmHg) and all had a reduction in HVPG after 24 weeks on PEG (Mean 6 mmHg; overall HVPG reduction 41%, mean reduction in HVPG 7mmHg). Primary event rate for patients with PHTN was 13.5% per year on COLC and 5.5% per year on PEG (p < 0.004). Primary event rate without PHTN was 3% in each treatment group. Variceal bleeding over 2 years occurred in 11 patients on COLC (9%) and 1 patient on PEG (1%). Ascites and liver failure was also more common in COLC (n 20) compared to tile group on PEG (n 13). Conclusion: Maintenance PEG therapy may retard varices development, reduces portal pressure and prevents variceal bleeding and complications of PHTN compared to COLC. Clinical endpoints are more common in patients with PHTN. PEG should be considered in patients with cirrhosis who fail interferon and ribavirin therapy.
[
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SUSTAINED VIROLOGIC RESPONSE (SVR) IN THE EPIC3 TRIAL: W E E K TWELVE VIROLOGY PREDICTS SVR IN PREVIOUS INTERFERON/RIBAVIRIN TREATMENT FAILURES RECEIVING PEG-INTRON/ REBETOL (PR) WEIGHT BASED DOSING (WBD)
T. PoynardI , E. Schiff2, R. Terg3, F. Goncales4, M. Diago 5, J. Reichen% R. Moreno 7, R Bedossa 8, M. Burroughs9, J. Albrecht 9. 1Service
d'Hepatologie, Hrpital Pitid-Salpgtri~re, Paris, France," 2University of Miami, School of Medicine, Miami, FL, USA," SHospital Municipal de Gastroenterologia D~ Bonorino Udaondo, Buenos Aires, Argentina," 4Hospital das Clinicas da Unicamp Cidade Universitaria Zefirina Vaz, Carnp#tas, Brazil," 5Hospital General Universitario de Valencia, Valencia, Spain," ~Institut fuer Klinische Pharmakologie, Bern, Switzerland," 7Hospital Universitario de la Princesa, Madrid, Spain," SService d'Anatomie Pathologique, H@ital Beaujon, Clichy, France," 9ScheringPlough Research Institute, Kenilworth, NJ, USA Introduction: EPIC3 is a large, prospective, controlled trial designed
to understand 1) the efficacy of treatment with PR for 48 weeks in previous treatment failures to interferon-a and ribavirin therapy (I/R) and 2) for non-responders (NR) to PR, to determine the efficacy of PEG-Intron 0.5 ~g/kg]wk compared to no treatment in either delaying progression of hepatic fibrosis or preventing end stage liver disease in cirrhofics.
Sunday, April 17, 2005
General Session 4 & Closing: Hepatitis C
R E S PO O N S EL A N DO S A FG ETY O C O M E S IN [ ]T H EV I R I U TC R A P Y - N A I V E PATIENTS TREATED FOR C H R O N I C HEPATITIS C WITH V I R A M I D I N E IN C O M B I N A T I O N WITH PEGYLATED INTERFERON ~-2a
R.G. Gish 1, D. Nelson 2, S. Arora 3, M.W. Fried 4, K.R. Reddy 5, Y. Xu 6, B. Murphy ~, Study Group ~ . : Calijbrnia Pacific Medical Cente~ San
Francisco, CA, USA; 2University of Florida, Gainesville FL, USA; SUniversity of New Mexico, Albuquerque NM, USA," 4University of North Carolina, Chapel Hill, NC, USA; 5Hospital of the University of Pennsylvania, Philadelphia PA, USA; 6 Valeant Pharmaceuticals International, Costa Mesa, CA, USA Introduction: Dose-limiting anemia can be a prominent adverse event o f therapy with pegylated interferon and ribavirin. This dose-ranging study examined whether viramidine, a liver-targeting pro
[•
BINDING OF HCV E N V E L O P E PROTEIN E2 TO CD81 U P R E G U L A T E S MMP-2 IN H U M A N HEPATIC STELLATE CELLS B Y INCREASING A P - 2 / D N A BINDING ACTIVITY VIA ERK/MAPK PHOSPHORYLATION
B. Lottini 1, A. Mazzocca I , S. Cappadona Sciammetta I , V Carloni 1, L. Cosrni ~, T. Harada 2, S. Abrignani 2, M. Pinzani 1 . IDipartimento di
Medicina Interna, Universitd di Firenze, Firenze, Italy," 2Chiron Vaccines Research Cente~ Siena, Italy Background and Aim: The Hepatitis C virus (HCV) envelope ]/2 glycoprotein is a key molecule regulating the interaction of HCV with cell surface proteins. E2 binds the major extracellular loop of human CD81, a tewaspanin expressed on various cell types including hepatocytes and B lymphocytes. Regardless, information on tile biological functions originating from this interaction are largely unknown. Since human hepatic stellate cells (HSC) express high levels of CD81 at the cell surface, we investigated tile E2 CD81 interaction in human HSC and tile possible effects arising from this interaction. Methods and Results: Matrix metalloproteinase 2 0MMP-2, gelatinase A), a maj or enzyme involved in the degradation of normal hepatic extracellular matrix, was up-regulated following tile interaction between E2 and CD81. In particular, by employing zyrnography and western blot, we observed that the binding of E2 to CDS1 induces a time-dependent increase in the synthesis and activity of MMP-2. This effect was abolished by preincubating HSC with an anti-CD81 neutralizing antibody. Similar effects were detected in human CDS1-NIH3T3 transfected cells with identical time-course features. In addition, E2-CD81 interaction in human HSC induced the up-regulation of MMP-2 by increasing AP-2/DNA binding activity via ERKJMAPK phosphorylation. Finally, suppression of CD81 by RNA interference in human HSC completely abolished the described effects of E2 on these cells, indicating that CD81 is essential for the activation of the signaling pathway leading to tile upregulation of MMP-2. Conclusions: Taken together, these results suggest that HSC may represent a potential target for HCM The interaction of HCV envelope with CD81 on tile surface of human HSC induces an increased expression of MMP-2. Increased degradation of the normal hepatic ECM in areas where HCV is concentrated may favour itrlammatory infiltration and further parenchymal damage.
[•
E N H A N C E D A N T I V I R A L EFFICACY FOR V A L O P I C I T A B I N E (NM283) PLUS P E G - I N T E R F E R O N IN HEPATITIS C PATIENTS WITH HCV GENOTYPE-1 INFECTION: RESULTS OF A P H A S E Ila MULTICENTER TRIAL
N. Afdhal I , M. Rodriguez-Torres 2, E. Lawitz 3, E. Godofsky 4, G. Chat 5, B. Fielman5, S. Knox 5, N. Brown 5. :Department of Medicine, Beth
Israel Deaconess Medical Cente~ Boston, MA, USA," 2Fundacion de Investigacion de Diego, Santurce, PR, USA," 3Alamo Medical Research, San Antonio, TX, USA,"4Bach & Godofsky, Bradenton, FL, USA," ~Idenix Pharmaceuticals, Cambridge, MA, USA Background: Only 40-50% of HCV-1 infected hepatitis C patients respond to pegylated interferon (peg-IFN(0 plus ribavirin therapy. NM283 is a novel nucleoside analog that as monotherapy reduced serum HCV RigA by a mean 1.21og10 (94%) in a recent 15-day trial in HCV-1 patients, most of whom had previously failed antiviral therapy for HCV infection.
Sunday, April 17, 2005
40
NM107, the parent compound of NM283, and interferon o~ exhibit synergistic antiviral effects against BVDV models in vitro, prompting the current investigation of NM283 combined with peg-IFNc~ in treatment naive patients with chronic hepatitis C. Methods: A multicenter, open-label phase IIa trial is evaluating whether NM283 plus peg-IFNct-2b has enhanced antiviral activity compared to NM283 alone in HCV-1 infected patients. Key entry criteria are: HCV RNA >51og10 IU/ml, A L T < 5 × ULN, compensated liver disease, treatment naive. Eligible patients are randomized 2:3 to NM283 or pegIFNc~ + NM283 (combinationtLx). NM283 is dosed orally QD for24 weeks in both groups, escalating to 800mg/day over the first week and then continuing at that dose. The group randomized to cornbinationRx receives peg-IFNo,-2b (1.0~tg/kg weekly) starting on Day 8. Results: Presently 19 of 30 planned patients (age 22-65, 68% males) are enrolled and have received 10 or 12 weeks of treatment. Tolerance of both treatments has been satisfactory. Mean HCV RNA reductions (log10 IU/rnl) from baseline to the last patient visit are 1.0 for the NM283 monotherapy group and 3.2 for tile combinafiontLx group. Eleven of twelve combinationRx patients treated for at least 10 weeks have had substantial HCV RNA reductions (range 1.2-6.21og10), and 8 of 12 patients have achieved >21og10 decrease in HCV RNA, which has been associated with sustained response to current standard tLx. Presently 4 patients are PCR-negative (<10 IUhnl). 12-week early virological response data will be presented at tile meeting. Conclusions: NM283 combined with peg-IFNc~ shows consistent, rapid and marked anti-HCV activity in patients with HCV-1 infection, a historically difficult-to-treat group. Initial EVR rates with combinationRx are encouraging and support continued investigation of NM283 and NM283 + peg-IFN0t, which may offer improved efficacy and tolepability for patients with HCV-1 infection.
•
4
]
IMMUNOLOGICAL CORRELATES OF PROTECTION IN HCV INFECTION: VIGOR, BREADTH AND SPECIFICITY OF THE T CELL RESPONSE
S. Urbarti I , P. Fisicaro 1, B. Arnadei 1, A. Bertolettl 2, C. Cavallo 1, G. Missale 1, C. Ferrari I . ILaboratorio di Immunopatologia ~3rale,
Dioisione Malattie Infettioe ed Epatologia, Azienda Ospedaliera Universitaria di Parma, Parma, Italy," 2Institute of Hepatology, UCL, London, UK A vigorous and long lasting cellular immune response to HCV proteins has been reported to be associated with successful control of HCV infection but still little is known about the hierarchy and the breadth of the T cell response during tile acute phase of hepatitis in relation to the final outcome of infection. To address this issue, the global profile of the HCV-specific T cell response was analyzed in 15 genotype 1-infected patients (5 selflimited and 10 with chronic evolution) using a panel of 601 15-met peptides overlapping by 10 residues and sparming tile entire HCV sequence ofgenotype 1, pooled in 60 mixtures of 10 peptides each. Direct ex vivo frequency of IFN-g producing T cells was determined longitudinally by ELISPOT assay from the time of acute illness. The results indicate that no more than 20% o f the peptide pools tested induced a T cell response in tile acute stage of infection in patients with chronic evolution of tile disease, whereas patients with a self-limited hepatitis showed a broader response directed towards 35-70% of all peptide pools tested. This different breadth of the T cell response was maintained throughout the follow-up. Responses were sustained by a mixed activation of both CD4 and CD8 T cell subsets as shown by depletion experiments and in vitro expansion of T cell lines by culture with tile stimulatory peptide pools. Moreover, NS3 was the most immunogenic protein for T cells, followed by core, NS4B and NS5B. In conclusion, these results provide additional information about the immunological correlates of protection in HCV infection and may be relevant to tile design of future immune therapies.
[•
EFFECT OF MAINTENANCE PEG-INTRON T H E R A P Y ON PORTAL HYPERTENSION AND ITS COMPLICATIONS: RESULTS FROM THE COPILOT STUDY
M. Curry, A. C~xdenas, N.H. Afdhal. Liver Center, Beth Israel Deaconess
Medical Cente~ Boston, MA, USA The COPILOT clinical trial is evaluating maintenance therapy with PEGIntron 0.5~tg.~ weekly versus colchicine (COLC) 0 . r m g twice daily in 600 patients with HCV and advanced fibrosis who have failed prior interferon treatment. Clinical endpoints include death, liver failure, transplantation, variceal bleeding and liver cancer. The 2 year evaluation suggested an improved event free survival in patients on PEG compared to colchicine (Hepatology 2004; 40: 239A). We evaluated the role of portal hypertension (PHTN) on the clinical outcomes of maintenance therapy and the role of maintenance PEG-Intron on portal pressure. Patients and Methods: 537 patients are enrolled in the trial to date; 267 COLC and 270 PEG. 83% of patients in each group have cirrhosis and 40% have PHTN defined by varices or gastropathy. Endoscopy is performed every 2 years for development of new varices. A substudy evaluated portal pressure using HVPG measurements prior to PEG and after 24 weeks of PEG in 5 patients with varices who were not on B blockers. Clinical endpoints were evaluated in patients with and without PHTN. Results: 132 patients have had repeat endoscopy at 2 years and new varices were seen in 11 of 66 patients on COLC versus 5 of 66 patients on PEG (p=ns). All 5 patients had baseline elevated HVPG (Mean 15mmHg) and all had a reduction in HVPG after 24 weeks on PEG (Mean 6 mmHg; overall HVPG reduction 41%, mean reduction in HVPG 7mmHg). Primary event rate for patients with PHTN was 13.5% per year on COLC and 5.5% per year on PEG (p < 0.004). Primary event rate without PHTN was 3% in each treatment group. Variceal bleeding over 2 years occurred in 11 patients on COLC (9%) and 1 patient on PEG (1%). Ascites and liver failure was also more common in COLC (n 20) compared to tile group on PEG (n 13). Conclusion: Maintenance PEG therapy may retard varices development, reduces portal pressure and prevents variceal bleeding and complications of PHTN compared to COLC. Clinical endpoints are more common in patients with PHTN. PEG should be considered in patients with cirrhosis who fail interferon and ribavirin therapy.
[
•
SUSTAINED VIROLOGIC RESPONSE (SVR) IN THE EPIC3 TRIAL: W E E K TWELVE VIROLOGY PREDICTS SVR IN PREVIOUS INTERFERON/RIBAVIRIN TREATMENT FAILURES RECEIVING PEG-INTRON/ REBETOL (PR) WEIGHT BASED DOSING (WBD)
T. PoynardI , E. Schiff2, R. Terg3, F. Goncales4, M. Diago 5, J. Reichen% R. Moreno 7, R Bedossa 8, M. Burroughs9, J. Albrecht 9. 1Service
d'Hepatologie, Hrpital Pitid-Salpgtri~re, Paris, France," 2University of Miami, School of Medicine, Miami, FL, USA," SHospital Municipal de Gastroenterologia D~ Bonorino Udaondo, Buenos Aires, Argentina," 4Hospital das Clinicas da Unicamp Cidade Universitaria Zefirina Vaz, Carnp#tas, Brazil," 5Hospital General Universitario de Valencia, Valencia, Spain," ~Institut fuer Klinische Pharmakologie, Bern, Switzerland," 7Hospital Universitario de la Princesa, Madrid, Spain," SService d'Anatomie Pathologique, H@ital Beaujon, Clichy, France," 9ScheringPlough Research Institute, Kenilworth, NJ, USA Introduction: EPIC3 is a large, prospective, controlled trial designed
to understand 1) the efficacy of treatment with PR for 48 weeks in previous treatment failures to interferon-a and ribavirin therapy (I/R) and 2) for non-responders (NR) to PR, to determine the efficacy of PEG-Intron 0.5 ~g/kg]wk compared to no treatment in either delaying progression of hepatic fibrosis or preventing end stage liver disease in cirrhofics.