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Course of virologic breakthroughs (VBTs) under lamivudine (LAM) therapy in patients (PTS) with precore mutant HBV related chronic liver disease (CLD)
Category 6: Viral hepatitis: clinical aspects different T-cell populations but the level of T-cell induction is decisive for potential viral clearance.
~-0-~ CHRONIC HEPATITIS C AND TREATMENT OUTCOME: CORRELATIONS WITH APOPTOSIS, SOLUBLE HLA CLASS I AND SOLUBLE FAS LIGAND F. Torre l, N. Campo 1, p. Contini 1, R. Giusto 1, I. Comino 1, p. Ceppa 2, R. Fiocca 3, G. Icardi 2, E Indiveri 1, F. Puppo 1, A. Picciotto 1.
1Department of Internal Medicine, University of Genoa; 2Department of Health Science, University of Genoa; 3DICMI, University of Genoa, Italy Introduction: HCV clearance depends on the inhibition of viral replication and on infected cells elimination. Soluble HLA class I molecules is considered an indirect marker of immune activation. Soluble Fas ligand presents an apoptotic-inducing capacity and seems to down-regulates CTL Fas ligand mediated apoptotic activity. Aim: To evaluate apoptosis, indirect apoptotic and indirect immune activity indexes in relation to long term treatment response. Patients: 46 chronic hepatitis, C patients treated with IFN -2b, 3 MU tiw for 6-12 months with a follow up >2 years (range: 3-8 yrs). 23 were sustained biochemical and virological responders (SRs); 23 were non responders (NRs). Methods: HCV-RNA, soluble HLA class I and soluble Fas Ligand levels were evaluated at baseline, 1st mth, 3rd ruth, end of treatment, 6th mth of follow up, end of follow up. Apoptosis was detected in liver tissue by TUNEL technique an apoptotic index was calculated. Results: Apoptosis did not correlate with baseline ALT levels or virological characteristics. At baseline, a negative correlation was found between HCV-RNA levels and sFas-L levels (R: -0.389; p = 0.018). According to outcome, SRs presented a negative correlation between sFas-L vs fibrosis (R: -0.713; p = 0.004) and sFas-L vs apopt0sis; (R: -0.610; p = 0.026). A larger variability in sFas-L levels was present in SRs compared to NRs, with a progressive decrement that reach a significance at the end of follow up (Mann-Whitney, p = 0.001). In SRs, sHLA showed a significant point by point variation (Anova by ranks, p = 0.02) compare to the fiat, constant pattern of NRs. Conclusions: SRs seem to present a more activated immune system than NRs. In SR, the baseline inverse correlation of sFas-L vs apoptosis and viraemia may reflect the cell-immune activity and a preferential cytokines mediated antiviral activity.
~5-]
COURSE OF VIROLOGIC BREAKTHROUGHS (VBTs) UNDER LAMIVUDINE (LAM) THERAPY IN PATIENTS(PTS) WITH PRECORE MUTANT HBV RELATED CHRONIC LIVER DISEASE (CLD)
G.V. Papatheodoridis, E. Dimou, V. Papadimitropoulos, A. Laras, S. Hadziyannis. Academic Dept. of Medicine, Hippokration Hospital of
Athens, Greece YMDD mutants emerge in most of pts with HBeAg ( - ) CLD under long-term LAM, but their course remains unclear. We report the course of VBTs detected by a sensitive PCR in 30 pts with precore mutant HBV treated with long-term LAM. All pts had elevated ALT and HBV viremia before LAM; all achieved initial biochemical and virologic (neg. HBV DNA) response. LFFs were evaluated monthly and IgM anti-HBc (IMx, Abbott) and serum HBV DNA (Monitor, Roche; sens.400 cp/ml) every 3 mos and on every biochemical breakthrough (BBT). YMDD mutants were detected in all 30 pts in a median of 15 (6-48) mos after LAM start; M552I in 22 and M552V in 8 (+L528M in 6). Duration of LAM therapy after VBT (reappearance of HBV DNA) was 9 (0-33) mos; BBTs developed in 16 pts. The cumulative probability of BBT was 59% at 6, 69% at 12 and 100% at 24 mos after VBT. There was no difference in the characteristics at baseline or at VBT onset between pts
143
with or without BBT. In the 16 pts with BBT a) IgM anti-HBc and HBV DNA increased from the VBT onset to 6 (0.115 to 0.256, P = 0.01) and to 3 mos later (0.0034 to 0.596 Mcp/ml, P = 0.005) respectively; b) ALT exceeded baseline in 14 and reached acute hepatitis levels in 6; c) ALT peaked at the BBT onset in 13 or within the next 3 mos in 3. Compared to the BBT onset, ALT decreased after 6 mos (188 vs 123 IU/L, P = 0.015) but remained abnormal in all but 1 patient; HBV DNA relatively decreased after 6 (21 vs 2 Mcp/ml, P = 0.07) but increased again after 12 mos (15 Mcp/mi). Conclusions: In pts with precore mutant HBV CLD, VBTs are followed by increasing viremia levels culminating in development of BBTs in practically all pts. ALT and HBV DNA levels peak close to the BBT onset, decreasing thereafter but remaining abnormal with fluctuating levels. Thus, optimal monitoring with sensitive PCR assays permits early recognition of VBTs and may have therapeutic implications.
(-~
PEGYLATED (40 KDA) INTERFERON ALFA-2A (PEGASYS®) IN NEW COMBINATIONTHERAPIES: A REPORT OF A RANDOMIZED, MULTICENTER EFFICACY AND SAFETY STUDY
A.M. Di Bisceglie, D.E. Bernstein, V.R. Rustgi, N. Gitlin, L.J. Jeffers, D. Simon, J. Campagna, S.C. Pappas. St Louis University/Bethesda
Hospital., North Shore University Hospital, Manhasset, NY Georgetown University, Fairfax, VA, Atlanta Gastroenterology Associates, Atlanta, GA, University of Miami School of Medicine, Miami, FL, A., Jacobi Medical Center, Bronx, NY, Roche Laboratories lnc, Nutley, NJ, USA Background: Interferon (IFN) monotherapy in previously untreated patients with chronic hepatitis C (CHC) leads to a sustained virological response (SVR) in 10%-19% of treated patients; ribavirin (RBV) added to IFN monotherapy increases SVR. PEGASYS ® is also associated with higher SVR. Further increases in SVR may be possible by combining PEGASYS® with the antiviral and immunomodulatory agents RBV, amantadine, and mycophenolate mofefil (CellCept®). Objective: To investigate the efficacy and safety of PEGASYS ® when used in combination with antiviral and immunomodulatory agents. Methods: Previously untreated patients with CHC were randomized into one of 4 groups: A: IFN c~-2b+RBV (REBETRON TM) (n -- 55); B: PEGASYS®+mycophenolate (n = 58); C: PEGASYS®+amantadine (n = 21); D: PEGASYS®+amantadine+RBV (n = 19). Patients were stratified according to genotype and viral load (low vs. high). Treatment was for 48 weeks with 24 weeks of follow-up. The outcome of therapy was assessed as virological response (HCV RNA < 50 IU/mL and >2 log drop from baseline using the AMPLICOR MONITOR TM HCV Test v. 2.0) or biochemical response. Results: The baseline patient characteristics were: mean age 45 46.3 y, male 66%, mean ALT 109 4- 70.4 U/L, high viral load 67%, HCV genotype 1 73%. One hundred and forty patients (87.5%) have completed >24 weeks of treatment. No unexpected side effects related to the study medications have been noted. Group
A B C D
Therapy
IFN u-2b + RBV PEGASYS® + mycophenolate PEGASYS® + amantadine PEGASYS® + amantadine + RBV
Week 24 HCV RNA > 2 log drop
HCV RNA neg.
Normal ALT
34/52 37/54
31/52 30/54
39/50 29/55
16/17
13/17
9/17
15/17
11/17
13/17
Conclusions: These preliminary findings reveal a trend for the Week 24 antiviral effect of all 3 PEGASYS ® combinations to be similar to or greater than that with conventional combination therapy.
~-0-~ CHRONIC HEPATITIS C AND TREATMENT OUTCOME: CORRELATIONS WITH APOPTOSIS, SOLUBLE HLA CLASS I AND SOLUBLE FAS LIGAND F. Torre l, N. Campo 1, p. Contini 1, R. Giusto 1, I. Comino 1, p. Ceppa 2, R. Fiocca 3, G. Icardi 2, E Indiveri 1, F. Puppo 1, A. Picciotto 1.
1Department of Internal Medicine, University of Genoa; 2Department of Health Science, University of Genoa; 3DICMI, University of Genoa, Italy Introduction: HCV clearance depends on the inhibition of viral replication and on infected cells elimination. Soluble HLA class I molecules is considered an indirect marker of immune activation. Soluble Fas ligand presents an apoptotic-inducing capacity and seems to down-regulates CTL Fas ligand mediated apoptotic activity. Aim: To evaluate apoptosis, indirect apoptotic and indirect immune activity indexes in relation to long term treatment response. Patients: 46 chronic hepatitis, C patients treated with IFN -2b, 3 MU tiw for 6-12 months with a follow up >2 years (range: 3-8 yrs). 23 were sustained biochemical and virological responders (SRs); 23 were non responders (NRs). Methods: HCV-RNA, soluble HLA class I and soluble Fas Ligand levels were evaluated at baseline, 1st mth, 3rd ruth, end of treatment, 6th mth of follow up, end of follow up. Apoptosis was detected in liver tissue by TUNEL technique an apoptotic index was calculated. Results: Apoptosis did not correlate with baseline ALT levels or virological characteristics. At baseline, a negative correlation was found between HCV-RNA levels and sFas-L levels (R: -0.389; p = 0.018). According to outcome, SRs presented a negative correlation between sFas-L vs fibrosis (R: -0.713; p = 0.004) and sFas-L vs apopt0sis; (R: -0.610; p = 0.026). A larger variability in sFas-L levels was present in SRs compared to NRs, with a progressive decrement that reach a significance at the end of follow up (Mann-Whitney, p = 0.001). In SRs, sHLA showed a significant point by point variation (Anova by ranks, p = 0.02) compare to the fiat, constant pattern of NRs. Conclusions: SRs seem to present a more activated immune system than NRs. In SR, the baseline inverse correlation of sFas-L vs apoptosis and viraemia may reflect the cell-immune activity and a preferential cytokines mediated antiviral activity.
~5-]
COURSE OF VIROLOGIC BREAKTHROUGHS (VBTs) UNDER LAMIVUDINE (LAM) THERAPY IN PATIENTS(PTS) WITH PRECORE MUTANT HBV RELATED CHRONIC LIVER DISEASE (CLD)
G.V. Papatheodoridis, E. Dimou, V. Papadimitropoulos, A. Laras, S. Hadziyannis. Academic Dept. of Medicine, Hippokration Hospital of
Athens, Greece YMDD mutants emerge in most of pts with HBeAg ( - ) CLD under long-term LAM, but their course remains unclear. We report the course of VBTs detected by a sensitive PCR in 30 pts with precore mutant HBV treated with long-term LAM. All pts had elevated ALT and HBV viremia before LAM; all achieved initial biochemical and virologic (neg. HBV DNA) response. LFFs were evaluated monthly and IgM anti-HBc (IMx, Abbott) and serum HBV DNA (Monitor, Roche; sens.400 cp/ml) every 3 mos and on every biochemical breakthrough (BBT). YMDD mutants were detected in all 30 pts in a median of 15 (6-48) mos after LAM start; M552I in 22 and M552V in 8 (+L528M in 6). Duration of LAM therapy after VBT (reappearance of HBV DNA) was 9 (0-33) mos; BBTs developed in 16 pts. The cumulative probability of BBT was 59% at 6, 69% at 12 and 100% at 24 mos after VBT. There was no difference in the characteristics at baseline or at VBT onset between pts
143
with or without BBT. In the 16 pts with BBT a) IgM anti-HBc and HBV DNA increased from the VBT onset to 6 (0.115 to 0.256, P = 0.01) and to 3 mos later (0.0034 to 0.596 Mcp/ml, P = 0.005) respectively; b) ALT exceeded baseline in 14 and reached acute hepatitis levels in 6; c) ALT peaked at the BBT onset in 13 or within the next 3 mos in 3. Compared to the BBT onset, ALT decreased after 6 mos (188 vs 123 IU/L, P = 0.015) but remained abnormal in all but 1 patient; HBV DNA relatively decreased after 6 (21 vs 2 Mcp/ml, P = 0.07) but increased again after 12 mos (15 Mcp/mi). Conclusions: In pts with precore mutant HBV CLD, VBTs are followed by increasing viremia levels culminating in development of BBTs in practically all pts. ALT and HBV DNA levels peak close to the BBT onset, decreasing thereafter but remaining abnormal with fluctuating levels. Thus, optimal monitoring with sensitive PCR assays permits early recognition of VBTs and may have therapeutic implications.
(-~
PEGYLATED (40 KDA) INTERFERON ALFA-2A (PEGASYS®) IN NEW COMBINATIONTHERAPIES: A REPORT OF A RANDOMIZED, MULTICENTER EFFICACY AND SAFETY STUDY
A.M. Di Bisceglie, D.E. Bernstein, V.R. Rustgi, N. Gitlin, L.J. Jeffers, D. Simon, J. Campagna, S.C. Pappas. St Louis University/Bethesda
Hospital., North Shore University Hospital, Manhasset, NY Georgetown University, Fairfax, VA, Atlanta Gastroenterology Associates, Atlanta, GA, University of Miami School of Medicine, Miami, FL, A., Jacobi Medical Center, Bronx, NY, Roche Laboratories lnc, Nutley, NJ, USA Background: Interferon (IFN) monotherapy in previously untreated patients with chronic hepatitis C (CHC) leads to a sustained virological response (SVR) in 10%-19% of treated patients; ribavirin (RBV) added to IFN monotherapy increases SVR. PEGASYS ® is also associated with higher SVR. Further increases in SVR may be possible by combining PEGASYS® with the antiviral and immunomodulatory agents RBV, amantadine, and mycophenolate mofefil (CellCept®). Objective: To investigate the efficacy and safety of PEGASYS ® when used in combination with antiviral and immunomodulatory agents. Methods: Previously untreated patients with CHC were randomized into one of 4 groups: A: IFN c~-2b+RBV (REBETRON TM) (n -- 55); B: PEGASYS®+mycophenolate (n = 58); C: PEGASYS®+amantadine (n = 21); D: PEGASYS®+amantadine+RBV (n = 19). Patients were stratified according to genotype and viral load (low vs. high). Treatment was for 48 weeks with 24 weeks of follow-up. The outcome of therapy was assessed as virological response (HCV RNA < 50 IU/mL and >2 log drop from baseline using the AMPLICOR MONITOR TM HCV Test v. 2.0) or biochemical response. Results: The baseline patient characteristics were: mean age 45 46.3 y, male 66%, mean ALT 109 4- 70.4 U/L, high viral load 67%, HCV genotype 1 73%. One hundred and forty patients (87.5%) have completed >24 weeks of treatment. No unexpected side effects related to the study medications have been noted. Group
A B C D
Therapy
IFN u-2b + RBV PEGASYS® + mycophenolate PEGASYS® + amantadine PEGASYS® + amantadine + RBV
Week 24 HCV RNA > 2 log drop
HCV RNA neg.
Normal ALT
34/52 37/54
31/52 30/54
39/50 29/55
16/17
13/17
9/17
15/17
11/17
13/17
Conclusions: These preliminary findings reveal a trend for the Week 24 antiviral effect of all 3 PEGASYS ® combinations to be similar to or greater than that with conventional combination therapy.