1
HEPATOLOGY Vol. 34, No. 4, Pt. 2, 2001 AASLD ABSTRACTS 577A 1619 PEGYLATED INTERFERON AND RIBAVIRIN FOR THE TREATMENT OF HCV INFECTED PATIENTS WHO FAILED PREVIOUS THERAPY. Paul J Gaglio, Fredric Regenstein, Dellainna Bartholomew, Marianne Vlacos, Tulane University Medical School, New Orleans, LA Introduction: Treatment strategies designed to maximize Hepatitis C (HCV) viral clear- ance are required. The present prospective study is designed to determine the efficacy and safety of treatment with PEG-lntron (polyethylene glycol interferon alfa-2b) and Pdbavirin in a group of previously treated patients who failed to clear HCV following therapy. Methods: 266 patients are presently enrolled in this multi-centered study. All patients are viremic (quantitative HCV RNA positive), and have histologic evidence of hepatitis C on liver biopsy performed within 36 months of enrollment. AlI eligible patients were carefully screened prior to therapy and met standard inclusion and exclusion criteria. The first 250 enrolled patients were treated with 1.5 mg/kg of PEG-Intron sc q week, and Ribavirin 800 mg po qd. The next 250 patients will be treated with a similar close of PEG-lntron but a weight based dose of Ribavirin (13 + 2 mg/kg). The intended duration of treatment is 48 weeks. 207 patients have been treated for at least 24 weeks, and 6 patients have been treated for 48 weeks. Patient characteristics: Mean age 45, 65% male, 35% female, 74% White, 19% AA, 7% other. Results (see table)Dose reduction was required in 71 of 254 pts (28%) due to: Leukopenia (41%) Anemia (21%) thrombocytopenia (14%) weight loss (14%), depres- sion (4%) flu sx's (2%), abdominal pain (2%), dyspnea (2%). Permanent discontinuation of therapy was required in 10 of 254 pts (4%) due to: Psychotic reaction (2 pts), major depression (1 pt), retinal hemorrhage (l pt), intractable flu sx's (2 pts), neutropenia (1 pt), colitis (I pt), new onset diabetes, pancreatitis (1 pt).Treatlnent was temporarily discontin- ued in 13 of 254 pts (5%) due to:Pneumonia (2 pts), thromboeytopenia (2 pts), fatigue (1 pt), leuckopenia (2 pts), anemia (2 pts), bronchitis (1 pt), abdominal pain (1 pt), cystitis (1 pt); hypokalemia (1 pt). 1 death occurred in a patient who succumbed to ceiIulitis and muhi-organ failure. Conclusions:in this group of HCV infected patients who failed therapy or relapsed following previous therapy, preliminary results using PEG-Intron and Ribavi- fin are encouraging. In patients who were treated for at least 24 weeks; 41% ofpts are HCV negative; 31% of Genotype 1A and 49% of Oenotype 1B pts, 22°/0 of previous not respond- ers, 25% African Americans are HCV neg. Of the patients who were treated for 48 weeks, 1/6 patients (the only pt with an ETR) received a weight appropriate dose of Rihavirin and "80,80~80" of their therapy. It is hoped that a change to a "weight based" Ribavirin dosing schedule and a more liberal use of Neupogen and Epogen to allow patients to receive 80% of their PEGfRibavirin dose for at least 80% of their treatment course will achieve HCV eradication in a greater percentage of patients. Baseline Week 12 Week 24 Week 48 207 ptst28%HCV- 132 ptet41%HC¥. 6 pte/16%HCV- Gen I (85%) 2t% HCV- 37% HCV- 16%HCV- Gen2 (6%) 82% HCV- 100%HCV. Gen3 (8%) 86% HCV- 63%HCV- __~n 4 (1%) 0% HCV- 1620 EFFECTIVENESS OF DAILY-DOSE TREATMENT WITH ALFACON-1 VS ALPHA-2A RECOMBINANT INTERFERON IN NAIVE PATIENTS WITH CHRONIC HEPATITIS C VIRUS INFECTION: A PILOT STUDY. Gaetano Scotto, Infectious Diseases University, Foggia Italy; Fazio Vincertzina, II Lab- oratory OORR, Foggia Italy Hepatitis C virus (HCV)is the most common cause of viral hepatitis in the world, the current approved therapies consist of the alpha-interferons. Alia- con-1 (CIFN)is a non-naturally occurrring synthetic recombinant type-1 in- terferon, derived by assigning the most commonly observed aminoacid se- quences of several natural alpha-interferon subtypes. Some studies have demonstrated that when compared on a mass base, the in vitro antiviral, anti- proliferative and NK stimulating activity of CIFN was to be higher than the ones observed with the other recombinant IFNs. The aim of this study, follow- ing the last theories on the kinetics of HCV, has been to evaluate th effective- ness and tulerabilty in daily-dose of 9 microg. CIFN vs. 3MU of alpha-2a recombinant IFN in the treatment of naive patients with chronic hepatitis C with high viral titres. SUBJECTS and METHODS: Fourty-two naive patients with chronic hepatitis C were randomly assigned in equal numbers to two groups; all patients presented similar baseline characteristcs (age, sex, geno- type, viral load, HAI score). A) Received CIFN subcutaneous; B) Received alpha-2a IFN subcutaneous. The period of therapy both with CIFN and al- pha-2a IFN was of 52 weeks; the treatment was then stopped, and patients were observed for an additional 24 weeks. RESULTS:Two patients of gr.A and one of gr.B required withdrawals due to adverse events. The treatment was inter- rupted, between the III and VI month, in five patients of gr.A and eight ofgr.B, because non-responders, or breakthrough. At the end of the treatment period, complete response (biochemical and virological) with normalization of serum alanine-aminotransferase levels and HCVRNA non detectable was seen in 11/21 (52.4%)of gr.A and in 10/21 (47.6%)of gr.B; partial response was seen in 3/21 (14.3%) of gr.A and in 2/21 (9.5%)of gr.B. At the end of follow-up 8/21 (38. l%)patients of gr.A and 5/21 (23.8%)of gr.B presented complete sustained response; 1/21 (4.8%)both gr.A and gr.B presented partial biochemical and virological response. CONCLUSIONS:The results emerging from this study have indicated that a 52-week course of treatment daily-dose with CIFN offers a better response vs. alpha-2a recombinant IFN, both in complete and in partial response at the end of treatment and in inducing prolonged remission. Adverse events are similar in the two groups without different statistical significativity; thrombocytopenia was the most common laboratory anormality observed. 1621 HIGH c~2B-IFN DOSES IN COMBINATION WITH RIBAVIRIN LEAD TO A HIGHER PERCENTAGE OF BIOCHEMICAL AND VIROLOGICAL SUS- TAINED RESPONSE. Silvia Giovanelli, Giovanni Nigro, Stefania Lira, Francesco Ferrara, Anna Miracolo, Maria FrancescaJaboli, Francesco Azzaroli, Costanza Mazzeo, Sabrina Marchetto, Andrea Grilli, Enrico Roda, Giuseppe Mazzella, Ospedale Sant'Orsola-Malpighi, Bologna Italy Standard treatment for hepatitis C is IFN 3MU/tiw plus ribavirin for 24-48 weeks. Aim of this study was to evaluate primary (48th week) and sustained (72th week) biochemical and virological response in 239 subjects with chronic active hepatitis C (155 previously treated with IFN and 84 naive, equally distributed in the two groups) who received IFN-a2b plus Ribavirin (12 m~ kg/d.ay) for 12 months. Patients were randomised to receive IFN 3MU/tiw (groupl - 116 subjects) or 6MU/day for 4 weeks followed by 6 MU/tiw for 20 weeks and then 3MU IFN/tiw for further 24 weeks (group2 - 123 subjects). Intention to treat analysis was used for statistical purpose. There were no differences in response rate of naive and retreated patients, therefore the two groups were considered as one for statistical analysis. Sustained response in patients infected with genotype l or 4 was obtained in 9% and in 22.5% of group 1 and 2 patients, respectively (p=0.004). In the group of patients in- fected by other genotypes, sustained response was obtained in 51.2% and in 61.6% patients of group 1 and 2, respectively (p=ns). Within the two groups, in a subset of patients with hepatic fibrosis (Scheuer score > 3) a sustained response was obtained in 9.9% of subjects of group 1 and in 45.8% of group 2 (p=0.001). At multivariate analysis, genotype 1 and 4, and high pre-treatment TGT values were correlated with a poor response, while higher IFN dose was related to a better treatment outcome. Anemia, fever and mild depression were the most common side effects: 12 subjects withdrawn from therapy, and 15 required dose modification (of IFN). High IFN-a2b doses in combination with ribavirin lead to a higher percentage of biochemical and virological sustained response. Patients with genotype 1 or 4 and with hepatic fibrosis benefit from higher doses of IPN in the combination therapy. BIOCHEMICAL AND VIROLOGICAL RESPONSE ALT normalisation HCV.RNA clearance 48th w e e k 72thweek 48th week 72th week Group1 901116 (78%) 22/116(19%) 106/~16(92%) 22/tt6 (19%) Group2 112/t23 {91%) 64t123(52%) 1051123 (86%) 50/123(41%) p= 0,004 0,0005 as 0,0005 1622 EFFICACY OF HIGH DOSE CONSENSUS INTERFERON FOR THE TREATMENT OF CHRONIC HEPATITIS C NON RESPONDERS TO IN- TERFERON ALPHA 2B AND RIBAVIRIN. David N Moskovitz, Pooma Ma- noharan, Jenny Heathcote, University Health Network, Toronto, ON Canada Introduction The current standard of care for the treatment of chronic hepatitis C is a combination of interferon (IFN) alpha 2b and ribavirin. However there are more non-responders than responders to therapy. Consensus interferon (CIFN) is a genetically engineered molecule derived by aligning the sequences of known interferon alpha and assigning the most cmnmonly observed amino acid in each sequence. Previous studies indicate that CIFN is more efficacious than IFN alpha 2b in those with high viral loads and in those with genotype l infection, features common to non-responders to all antiviral therapies. The aim of our study was to evaluate the efficacy of treatment with a high dose of CIFN (15micrograms/d) in patients with chronic HCV infection who had failed previous therapy with a full course (80:80:80) of interferon alpha 2b combined with ribavirin. Methods To be eligible for the study patients had to be positive for HCV RNA and have serum ALT concentration at least 1.5 times the upper limit of normal. Patients were administered 15mcg/d CIFN daily. In those whose serum HCVRNA remained detectable after 12 weeks of treatment, treatment was stopped. In those with undetectable HCVRNA 12 weeks into therapy, treatment was continued at 15mcg/d three times per week for a further 36 weeks. The Roche Amplicor assay was used to measure HCV RNA. Results Of the 24 patients enrolled, 18 were infected with genotype 1, 1 with genotype 2, 1 with genotype 3, and 4 with genotype 4. Twenty (83%) were male and 4 (17%) were female. Their mean age was 49 years. Six patients (25%) withdrew from the study prior to 12 weeks because of side effects to CIFN. Of the 18 patients who completed 12 weeks of therapy 9 (38%) had undetectable HCV RNA at this time. Seven of the 9 patients who were HCV RNA negative at week 12 completed 48 weeks of treatment, two withdrew early because of intolerable side effects. At 48 weeks, HCV RNA remained undetectable in 3 (13%). After 6 months of follow up off treatment, 2 (8%) remained with no detectable HCV RNA in their sera, one had been infected with genotype 1 and the other with genotype 4. Conchtsion This study indicates that high dose CIFN mono- therapy may induce a sustained virological response in individuals who have previously failed full course IFN alpha 2b and ribavirin. This suggests that treatment with long acting interferon's with or without ribavirin may also be effective in individuals who are non responders to a full course of IFN alpha 2b and ribavirin.

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HEPATOLOGY Vol. 34, No. 4, Pt. 2, 2001 AASLD ABSTRACTS 5 7 7 A

1619

PEGYLATED INTERFERON AND RIBAVIRIN FOR THE TREATMENT OF HCV INFECTED PATIENTS WHO FAILED PREVIOUS THERAPY. Paul J Gaglio, Fredric Regenstein, Dellainna Bartholomew, Marianne Vlacos, Tulane University Medical School, New Orleans, LA

Introduction: Treatment strategies designed to maximize Hepatitis C (HCV) viral clear- ance are required. The present prospective study is designed to determine the efficacy and safety of treatment with PEG-lntron (polyethylene glycol interferon alfa-2b) and Pdbavirin in a group of previously treated patients who failed to clear HCV following therapy. Methods: 266 patients are presently enrolled in this multi-centered study. All patients are viremic (quantitative HCV RNA positive), and have histologic evidence of hepatitis C on liver biopsy performed within 36 months of enrollment. AlI eligible patients were carefully screened prior to therapy and met standard inclusion and exclusion criteria. The first 250 enrolled patients were treated with 1.5 mg/kg of PEG-Intron sc q week, and Ribavirin 800 mg po qd. The next 250 patients will be treated with a similar close of PEG-lntron but a weight based dose of Ribavirin (13 + 2 mg/kg). The intended duration of treatment is 48 weeks. 207 patients have been treated for at least 24 weeks, and 6 patients have been treated for 48 weeks. Patient characteristics: Mean age 45, 65% male, 35% female, 74% White, 19% AA, 7% other. Results (see table)Dose reduction was required in 71 of 254 pts (28%) due to: Leukopenia (41%) Anemia (21%) thrombocytopenia (14%) weight loss (14%), depres- sion (4%) flu sx's (2%), abdominal pain (2%), dyspnea (2%). Permanent discontinuation of therapy was required in 10 of 254 pts (4%) due to: Psychotic reaction (2 pts), major depression (1 pt), retinal hemorrhage (l pt), intractable flu sx's (2 pts), neutropenia (1 pt), colitis (I pt), new onset diabetes, pancreatitis (1 pt).Treatlnent was temporarily discontin- ued in 13 of 254 pts (5%) due to:Pneumonia (2 pts), thromboeytopenia (2 pts), fatigue (1 pt), leuckopenia (2 pts), anemia (2 pts), bronchitis (1 pt), abdominal pain (1 pt), cystitis (1 pt); hypokalemia (1 pt). 1 death occurred in a patient who succumbed to ceiIulitis and muhi-organ failure. Conclusions:in this group of HCV infected patients who failed therapy or relapsed following previous therapy, preliminary results using PEG-Intron and Ribavi- fin are encouraging. In patients who were treated for at least 24 weeks; 41% ofpts are HCV negative; 31% of Genotype 1A and 49% of Oenotype 1B pts, 22°/0 of previous not respond- ers, 25% African Americans are HCV neg. Of the patients who were treated for 48 weeks, 1/6 patients (the only pt with an ETR) received a weight appropriate dose of Rihavirin and "80,80~80" of their therapy. It is hoped that a change to a "weight based" Ribavirin dosing schedule and a more liberal use of Neupogen and Epogen to allow patients to receive 80% of their PEGfRibavirin dose for at least 80% of their treatment course will achieve HCV eradication in a greater percentage of patients.

Baseline Week 12 Week 24 Week 48 207 ptst28% HCV- 132 ptet41% HC¥. 6 pte/16% HCV-

Gen I (85%) 2t% HCV- 37% HCV- 16% HCV- Gen 2 (6%) 82% HCV- 100% HCV. Gen 3 (8%) 86% HCV- 63% HCV-

__~n 4 (1%) 0% HCV-

1620

EFFECTIVENESS OF DAILY-DOSE TREATMENT WITH ALFACON-1 VS ALPHA-2A RECOMBINANT INTERFERON IN NAIVE PATIENTS WITH CHRONIC HEPATITIS C VIRUS INFECTION: A PILOT STUDY. Gaetano Scotto, Infectious Diseases University, Foggia Italy; Fazio Vincertzina, II Lab- oratory OORR, Foggia Italy

Hepatitis C virus (HCV)is the most common cause of viral hepatitis in the world, the current approved therapies consist of the alpha-interferons. Alia- con-1 (CIFN)is a non-naturally occurrring synthetic recombinant type-1 in- terferon, derived by assigning the most commonly observed aminoacid se- quences of several natural alpha-interferon subtypes. Some studies have demonstrated that when compared on a mass base, the in vitro antiviral, anti- proliferative and NK stimulating activity of CIFN was to be higher than the ones observed with the other recombinant IFNs. The aim of this study, follow- ing the last theories on the kinetics of HCV, has been to evaluate th effective- ness and tulerabilty in daily-dose of 9 microg. CIFN vs. 3MU of alpha-2a recombinant IFN in the treatment of naive patients with chronic hepatitis C with high viral titres. SUBJECTS and METHODS: Fourty-two naive patients with chronic hepatitis C were randomly assigned in equal numbers to two groups; all patients presented similar baseline characteristcs (age, sex, geno- type, viral load, HAI score). A) Received CIFN subcutaneous; B) Received alpha-2a IFN subcutaneous. The period of therapy both with CIFN and al- pha-2a IFN was of 52 weeks; the treatment was then stopped, and patients were observed for an additional 24 weeks. RESULTS:Two patients of gr.A and one of gr.B required withdrawals due to adverse events. The treatment was inter- rupted, between the III and VI month, in five patients of gr.A and eight ofgr.B, because non-responders, or breakthrough. At the end of the treatment period, complete response (biochemical and virological) with normalization of serum alanine-aminotransferase levels and HCVRNA non detectable was seen in 11/21 (52.4%)of gr.A and in 10/21 (47.6%)of gr.B; partial response was seen in 3/21 (14.3%) of gr.A and in 2/21 (9.5%)of gr.B. At the end of follow-up 8/21 (38. l%)patients of gr.A and 5/21 (23.8%)of gr.B presented complete sustained response; 1/21 (4.8%)both gr.A and gr.B presented partial biochemical and virological response. CONCLUSIONS:The results emerging from this study have indicated that a 52-week course of treatment daily-dose with CIFN offers a better response vs. alpha-2a recombinant IFN, both in complete and in partial response at the end of treatment and in inducing prolonged remission. Adverse events are similar in the two groups without different statistical significativity; thrombocytopenia was the most common laboratory anormality observed.

1621

HIGH c~2B-IFN DOSES IN COMBINATION WITH RIBAVIRIN LEAD TO A HIGHER PERCENTAGE OF BIOCHEMICAL AND VIROLOGICAL SUS- TAINED RESPONSE. Silvia Giovanelli, Giovanni Nigro, Stefania Lira, Francesco Ferrara, Anna Miracolo, Maria FrancescaJaboli, Francesco Azzaroli, Costanza Mazzeo, Sabrina Marchetto, Andrea Grilli, Enrico Roda, Giuseppe Mazzella, Ospedale Sant'Orsola-Malpighi, Bologna Italy

Standard treatment for hepatitis C is IFN 3MU/tiw plus ribavirin for 24-48 weeks. Aim of this study was to evaluate primary (48th week) and sustained (72th week) biochemical and virological response in 239 subjects with chronic active hepatitis C (155 previously treated with IFN and 84 naive, equally distributed in the two groups) who received IFN-a2b plus Ribavirin (12 m ~ kg/d.ay) for 12 months. Patients were randomised to receive IFN 3MU/tiw (groupl - 116 subjects) or 6MU/day for 4 weeks followed by 6 MU/tiw for 20 weeks and then 3MU IFN/tiw for further 24 weeks (group2 - 123 subjects). Intention to treat analysis was used for statistical purpose. There were no differences in response rate of naive and retreated patients, therefore the two groups were considered as one for statistical analysis. Sustained response in patients infected with genotype l or 4 was obtained in 9% and in 22.5% of group 1 and 2 patients, respectively (p=0.004). In the group of patients in- fected by other genotypes, sustained response was obtained in 51.2% and in 61.6% patients of group 1 and 2, respectively (p=ns) . Within the two groups, in a subset of patients with hepatic fibrosis (Scheuer score > 3) a sustained response was obtained in 9.9% of subjects of group 1 and in 45.8% of group 2 (p=0.001). At multivariate analysis, genotype 1 and 4, and high pre-treatment TGT values were correlated with a poor response, while higher IFN dose was related to a better treatment outcome. Anemia, fever and mild depression were the most common side effects: 12 subjects withdrawn from therapy, and 15 required dose modification (of IFN). High IFN-a2b doses in combination with ribavirin lead to a higher percentage of biochemical and virological sustained response. Patients with genotype 1 or 4 and with hepatic fibrosis benefit from higher doses of IPN in the combination therapy.

BIOCHEMICAL AND VIROLOGICAL RESPONSE ALT normalisation HCV.RNA clearance

48th w e e k 72thweek 48th week 72th week Group1 901116 (78%) 22/116 (19%) 106/~16(92%) 22/tt6 (19%) Group2 112/t23 {91%) 64t123(52%) 1051123 (86%) 50/123(41%) p= 0,004 0,0005 as 0,0005

1622

EFFICACY OF HIGH DOSE CONSENSUS INTERFERON FOR THE TREATMENT OF CHRONIC HEPATITIS C NON RESPONDERS TO IN- TERFERON ALPHA 2B AND RIBAVIRIN. David N Moskovitz, Pooma Ma- noharan, Jenny Heathcote, University Health Network, Toronto, ON Canada

Introduction The current standard of care for the treatment of chronic hepatitis C is a combination of interferon (IFN) alpha 2b and ribavirin. However there are more non-responders than responders to therapy. Consensus interferon (CIFN) is a genetically engineered molecule derived by aligning the sequences of known interferon alpha and assigning the most cmnmonly observed amino acid in each sequence. Previous studies indicate that CIFN is more efficacious than IFN alpha 2b in those with high viral loads and in those with genotype l infection, features common to non-responders to all antiviral therapies. The aim of our study was to evaluate the efficacy of treatment with a high dose of CIFN (15micrograms/d) in patients with chronic HCV infection who had failed previous therapy with a full course (80:80:80) of interferon alpha 2b combined with ribavirin. Methods To be eligible for the study patients had to be positive for HCV RNA and have serum ALT concentration at least 1.5 times the upper limit of normal. Patients were administered 15mcg/d CIFN daily. In those whose serum HCVRNA remained detectable after 12 weeks of treatment, treatment was stopped. In those with undetectable HCVRNA 12 weeks into therapy, treatment was continued at 15mcg/d three times per week for a further 36 weeks. The Roche Amplicor assay was used to measure HCV RNA. Results Of the 24 patients enrolled, 18 were infected with genotype 1, 1 with genotype 2, 1 with genotype 3, and 4 with genotype 4 . Twenty (83%) were male and 4 (17%) were female. Their mean age was 49 years. Six patients (25%) withdrew from the study prior to 12 weeks because of side effects to CIFN. Of the 18 patients who completed 12 weeks of therapy 9 (38%) had undetectable HCV RNA at this time. Seven of the 9 patients who were HCV RNA negative at week 12 completed 48 weeks of treatment, two withdrew early because of intolerable side effects. At 48 weeks, HCV RNA remained undetectable in 3 (13%). After 6 months of follow up off treatment, 2 (8%) remained with no detectable HCV RNA in their sera, one had been infected with genotype 1 and the other with genotype 4. Conchtsion This study indicates that high dose CIFN mono- therapy may induce a sustained virological response in individuals who have previously failed full course IFN alpha 2b and ribavirin. This suggests that treatment with long acting interferon's with or without ribavirin may also be effective in individuals who are non responders to a full course of IFN alpha 2b and ribavirin.