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Pegylated 40KDA IFN alfa-2a plus amantadine (AMA) or ribavirin (RBV) in naives with chronic hepatitis C (CHC): the HIMPCT (Hepatitis Italian Multicenter Pegasys Amantadine Cooperative Trial)
112
•5-]
Poster Sessions WHAT CAN BE DONE FOR PATIENTS WITH CHRONIC HEPATITIS C, WHICH HAVE FAILEO TO RESPOND TO INTERFERON MONOTHERAPY?
Razvan lacob, Speranta lacob, Mircea Diculescu. Fundeni
Gastroenterology and Hepatology Center, Bucharest, Romania Background: Chronic hepatitis C is a major public health problem with a prevalence around 3%. Although interferon alpha (IFNa) monotherapy isn't the standard therapeutic regimen anymore, a large number of patients have been treated just with IFN in the past and only 15-20% of them have had a sustained response. It is important to evaluate the alternative treatment regimens available for IFN monotherapy non-responders (NRs) or relapsers (Rs), because eliminating the viral infection is an important goal. Methods: A recta-analysis was carried out of the studies related to this topic, published between 1997-2000. A total of 1857 patients with chronic hepatitis C (NRs or Rs after IFN monotherapy) who had participated to the trials included in the respective studies, were treated with: elevated doses of IFN, IFN + ribavirin, IFN + amantadine + ribavirin or Consensus interferon (CIFN). Follow-up after therapy was 6 or 12 month and sustained response (SR) was established depending on ALT normalization and HCV RNA negativity. Results: The meta-analysis indicates the following probability of SR for relapsers after IFN monotherapy: 16.5% after IFN in higher dose retreatment, 44.3% after IFN + ribavirin and 42.5% after CIFN. Regarding nonresponders, the SR after retreatment is: IFN in higher dose - 3.1%, IFN + ribavirin combination therapy - 12.7%, IFN + amantadine + ribavirin 40%, CIFN - 13%. Conclusions: Higher dose of IFNa for the retreatment of IFN previous non-responders has a very low rate of SR and should be avoided. IFN + ribavirin or CIF'N are viable alternative treatment regimens for the IFN monotherapy failure. Triple therapy with IFN, amantadine and ribavirin seems to be the treatment of choice for IFN monotherapy non-responders, but it needs further investigation. An individualized and aggressive therapy should be considered from the beginning. It should be modulated afterwards depending on the predictive markers of the treatment outcome.
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PEGYLATED 40KDA IFN alfa-2a PLUS AMANTADINE (AMA) OR RIBAVIRIN (RBV) IN NAIVES WITH CHRONIC HEPATITIS C (CHC): THE HIMPCT (HEPATITIS ITALIAN MULTICENTER PEGASYS AMANTADINE COOPERATIVE TRIAL)
Gaetano Ideo 1, Mario Angelico 2, A. Chirianni 3, Antonio Craxi 4, G. Di Perri 3, L. Minoli 3, Giuseppe Montalto 5, Antonio Picciotto 6, Mario Rizzctto 7, Giuseppe Ruggiero 8, A. Scalzini, Massimo Sarracino.
l Ospedale S. Giuseppe, Milano; 2Gastroenterology, University of Rome; 3Ospedale; 'tGastroenterology, University of Palermo; 5Internal Medicine, University of Palermo; 6Gastroenterology, University of Genoa; 7Gastroenterology, University of Turin; sInternal Medicine, University of Naples, Italy Background: The usefulness of AMA as an adjunct to IFN in treating nails with CHC is controversial Aim: To compare efficacy and tolerability of combination regimens of 40kDA PEG-IFN alfa-2a with RBV or AMA in a large randomized trial Patients and Methods" This multicenter study started 1/01 in 49 Italian centers. A total of 924 HCV-RNA positive naive patients with raised ALT and biopsy-proven CHC will be randomized to 180mcg once-weekly of 40kDA PEG-IFN alfa-2a with RBV (1-1.2 g/dally) or AMA (200 mg/daily) for 48 weeks, with a 24-weeks follow-up. Enrollment is still ongoing. Results: 101 subjects (M/F ratio 2:1, mean age 45 years, mean weight 72 kg, mean ALT 136 IU/L) have completed 12 weeks of therapy. 27% of them have cirrhosis, and 61% are infected by HCV genotype 1 or 4. Their mean baseline HCV-RNA is 846 logl0 copies/mL. ALT dropped from 146 to 55 IU/L under PEG-1FN+RBV and from 125 to 58 under PEG-IFN+AMA. No severe or unexpected adverse reactions were observed. The virological response is reported below.
HCV-RNA 2-Log Drop from baseline (week 4) Negative (week 4) 2-Log Drop from baseline (week 12) Negative (week 12)
PEG-IFN + RBV (n = 52) 65.4 38.5 90.4 65.4
PEG-IFN+ AMA (n = 49) 63.5 34.7 69.4 57.1
Conclusions: Preliminary evidence suggests that in naive patients with CHC the early effects of combination regimens comprising 40kDA PEGIFN alfa-2a and RBV or AMA are comparable, both in terms of biochemical and virological changes and of safety. Further treatment and follow-up to assess the rate of sustained response primary response and to compare long term tolerability of the two regimens will allow to evaluate AMA as an alternative to RBV.
~ 7 " ] CLINICAL SIGNIFICANCE OF MIXED CRYOGLOBULINEMIA IN CHRONIC HEPATITIS C PATIENTS Zinaida Aprosina, Nickolay Muchin, Lidia Kozlovskaya, T. Ignatova.
Sechenov's Moscow Medical Academy, Clinic of Nephrology, Internal and Occupational Medicine, Moscow, Russia Aim: To assess the relationship between the presence of mixed cryoglobulinemia/CG/and some characteristics of the chronic hepatitis C/CH-C/. Patients and Methods: 207 patients (107 M and 100 F, mean age 38.2) with CH-C were studied. 88 (42.5%) of them were cryoglobulinemic /CG+/. We compared the clinical, histological (in 178 patients) characteristics and response to interferon-alpha/IFN/monotherapy (in 66 patients, 3ME, tiw) in CG+ and C G - groups of patients. Necroinflammatory activity and fibrosis were scored according to METAVIR. Results: CG+ was associated with female sex (p < 0.001), older age (p < 0.0001), longer disease duration (p < 0.0001) and liver cirrhosis (p < 0.0001). Stage of fibrosis was significantly higher in CG+ patients (p = 0.0001) whereas the activity grades and mean ALT levels were statistically similar in two groups. CG+ was associated with titer of rheumatoid factor, prevalence of extrahepatic manifestations ( C G - related vasculitis, some hematological and autoimmune syndromes). The sustained virological response rate to IFN was lower in CG+ patients (P < 0.05) and clinical improvement of C G - related symptoms was transient. But according to the results of presence of logistic regression analysis CG+ was not an independent negative predictive factor (age, disease stage were predictive). Conclusion: Patients with CG+ had increased fibrosis and incidence of cirrhosis. CG+ may be a cause or an effect of increased hepatic fibrosis. Fibrosis can influence the response rate to IFN treatment in this patients. Prognostic significance of CG in course of CH-C needs further evaluations.
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THE LONG-TERM OUTCOME OF LIVER TRANSPLANT RECIPIENTS WITH DE NOVO HEPATITIS B INFECTION WHO RECEIVED AN ANTI-HBC GRAFT
Sylvania Cauduro 1, David Douglas 2, Jorge Rakela 2, Rolland Dickson 3, Russell Wiesner 1, Charles Rosen 1, Ruud Krom 1, Michael Ishitani 1.
1Mayo Clinic, Rochester, MN 2Mayo Clinic, Scottsdale, AZ 3Mayo Clinic, Jacksonville, FL, USA A liver from a serum anti-HBC positive donor will transmit hepatitis B viral (HBV) infection to a high percentage of recipients. The clinical course of these patients ranges from an indolent to a rapid decline due to severe complications of HBV infection. Lamivudine appears to slow or stabilize the clinical course of HBV infection in these patients. Little information is available on the long-term clinical outcome of liver transplant recipients who develop de novo HBV infection after receiving a liver from an antiHBc positive donor. Methods: From 3/85-11/91, we performed 332 transplants before antiHBc donors were excluded from use in non-HBV infected patients. Nine
•5-]
Poster Sessions WHAT CAN BE DONE FOR PATIENTS WITH CHRONIC HEPATITIS C, WHICH HAVE FAILEO TO RESPOND TO INTERFERON MONOTHERAPY?
Razvan lacob, Speranta lacob, Mircea Diculescu. Fundeni
Gastroenterology and Hepatology Center, Bucharest, Romania Background: Chronic hepatitis C is a major public health problem with a prevalence around 3%. Although interferon alpha (IFNa) monotherapy isn't the standard therapeutic regimen anymore, a large number of patients have been treated just with IFN in the past and only 15-20% of them have had a sustained response. It is important to evaluate the alternative treatment regimens available for IFN monotherapy non-responders (NRs) or relapsers (Rs), because eliminating the viral infection is an important goal. Methods: A recta-analysis was carried out of the studies related to this topic, published between 1997-2000. A total of 1857 patients with chronic hepatitis C (NRs or Rs after IFN monotherapy) who had participated to the trials included in the respective studies, were treated with: elevated doses of IFN, IFN + ribavirin, IFN + amantadine + ribavirin or Consensus interferon (CIFN). Follow-up after therapy was 6 or 12 month and sustained response (SR) was established depending on ALT normalization and HCV RNA negativity. Results: The meta-analysis indicates the following probability of SR for relapsers after IFN monotherapy: 16.5% after IFN in higher dose retreatment, 44.3% after IFN + ribavirin and 42.5% after CIFN. Regarding nonresponders, the SR after retreatment is: IFN in higher dose - 3.1%, IFN + ribavirin combination therapy - 12.7%, IFN + amantadine + ribavirin 40%, CIFN - 13%. Conclusions: Higher dose of IFNa for the retreatment of IFN previous non-responders has a very low rate of SR and should be avoided. IFN + ribavirin or CIF'N are viable alternative treatment regimens for the IFN monotherapy failure. Triple therapy with IFN, amantadine and ribavirin seems to be the treatment of choice for IFN monotherapy non-responders, but it needs further investigation. An individualized and aggressive therapy should be considered from the beginning. It should be modulated afterwards depending on the predictive markers of the treatment outcome.
F
3
•
-
]
PEGYLATED 40KDA IFN alfa-2a PLUS AMANTADINE (AMA) OR RIBAVIRIN (RBV) IN NAIVES WITH CHRONIC HEPATITIS C (CHC): THE HIMPCT (HEPATITIS ITALIAN MULTICENTER PEGASYS AMANTADINE COOPERATIVE TRIAL)
Gaetano Ideo 1, Mario Angelico 2, A. Chirianni 3, Antonio Craxi 4, G. Di Perri 3, L. Minoli 3, Giuseppe Montalto 5, Antonio Picciotto 6, Mario Rizzctto 7, Giuseppe Ruggiero 8, A. Scalzini, Massimo Sarracino.
l Ospedale S. Giuseppe, Milano; 2Gastroenterology, University of Rome; 3Ospedale; 'tGastroenterology, University of Palermo; 5Internal Medicine, University of Palermo; 6Gastroenterology, University of Genoa; 7Gastroenterology, University of Turin; sInternal Medicine, University of Naples, Italy Background: The usefulness of AMA as an adjunct to IFN in treating nails with CHC is controversial Aim: To compare efficacy and tolerability of combination regimens of 40kDA PEG-IFN alfa-2a with RBV or AMA in a large randomized trial Patients and Methods" This multicenter study started 1/01 in 49 Italian centers. A total of 924 HCV-RNA positive naive patients with raised ALT and biopsy-proven CHC will be randomized to 180mcg once-weekly of 40kDA PEG-IFN alfa-2a with RBV (1-1.2 g/dally) or AMA (200 mg/daily) for 48 weeks, with a 24-weeks follow-up. Enrollment is still ongoing. Results: 101 subjects (M/F ratio 2:1, mean age 45 years, mean weight 72 kg, mean ALT 136 IU/L) have completed 12 weeks of therapy. 27% of them have cirrhosis, and 61% are infected by HCV genotype 1 or 4. Their mean baseline HCV-RNA is 846 logl0 copies/mL. ALT dropped from 146 to 55 IU/L under PEG-1FN+RBV and from 125 to 58 under PEG-IFN+AMA. No severe or unexpected adverse reactions were observed. The virological response is reported below.
HCV-RNA 2-Log Drop from baseline (week 4) Negative (week 4) 2-Log Drop from baseline (week 12) Negative (week 12)
PEG-IFN + RBV (n = 52) 65.4 38.5 90.4 65.4
PEG-IFN+ AMA (n = 49) 63.5 34.7 69.4 57.1
Conclusions: Preliminary evidence suggests that in naive patients with CHC the early effects of combination regimens comprising 40kDA PEGIFN alfa-2a and RBV or AMA are comparable, both in terms of biochemical and virological changes and of safety. Further treatment and follow-up to assess the rate of sustained response primary response and to compare long term tolerability of the two regimens will allow to evaluate AMA as an alternative to RBV.
~ 7 " ] CLINICAL SIGNIFICANCE OF MIXED CRYOGLOBULINEMIA IN CHRONIC HEPATITIS C PATIENTS Zinaida Aprosina, Nickolay Muchin, Lidia Kozlovskaya, T. Ignatova.
Sechenov's Moscow Medical Academy, Clinic of Nephrology, Internal and Occupational Medicine, Moscow, Russia Aim: To assess the relationship between the presence of mixed cryoglobulinemia/CG/and some characteristics of the chronic hepatitis C/CH-C/. Patients and Methods: 207 patients (107 M and 100 F, mean age 38.2) with CH-C were studied. 88 (42.5%) of them were cryoglobulinemic /CG+/. We compared the clinical, histological (in 178 patients) characteristics and response to interferon-alpha/IFN/monotherapy (in 66 patients, 3ME, tiw) in CG+ and C G - groups of patients. Necroinflammatory activity and fibrosis were scored according to METAVIR. Results: CG+ was associated with female sex (p < 0.001), older age (p < 0.0001), longer disease duration (p < 0.0001) and liver cirrhosis (p < 0.0001). Stage of fibrosis was significantly higher in CG+ patients (p = 0.0001) whereas the activity grades and mean ALT levels were statistically similar in two groups. CG+ was associated with titer of rheumatoid factor, prevalence of extrahepatic manifestations ( C G - related vasculitis, some hematological and autoimmune syndromes). The sustained virological response rate to IFN was lower in CG+ patients (P < 0.05) and clinical improvement of C G - related symptoms was transient. But according to the results of presence of logistic regression analysis CG+ was not an independent negative predictive factor (age, disease stage were predictive). Conclusion: Patients with CG+ had increased fibrosis and incidence of cirrhosis. CG+ may be a cause or an effect of increased hepatic fibrosis. Fibrosis can influence the response rate to IFN treatment in this patients. Prognostic significance of CG in course of CH-C needs further evaluations.
[-~
THE LONG-TERM OUTCOME OF LIVER TRANSPLANT RECIPIENTS WITH DE NOVO HEPATITIS B INFECTION WHO RECEIVED AN ANTI-HBC GRAFT
Sylvania Cauduro 1, David Douglas 2, Jorge Rakela 2, Rolland Dickson 3, Russell Wiesner 1, Charles Rosen 1, Ruud Krom 1, Michael Ishitani 1.
1Mayo Clinic, Rochester, MN 2Mayo Clinic, Scottsdale, AZ 3Mayo Clinic, Jacksonville, FL, USA A liver from a serum anti-HBC positive donor will transmit hepatitis B viral (HBV) infection to a high percentage of recipients. The clinical course of these patients ranges from an indolent to a rapid decline due to severe complications of HBV infection. Lamivudine appears to slow or stabilize the clinical course of HBV infection in these patients. Little information is available on the long-term clinical outcome of liver transplant recipients who develop de novo HBV infection after receiving a liver from an antiHBc positive donor. Methods: From 3/85-11/91, we performed 332 transplants before antiHBc donors were excluded from use in non-HBV infected patients. Nine