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Hepatitis C virus dynamics during induction with high PEG-IFN doses and ribavirin compared with low PEG-IFN doses plus ribavirin in naive patients with chronic hepatitis C, genotype 1
Working Party 2 - Cell biology
HBV (antiHBc+) and 1779 (58%) patients had no apparent previous contact to HBV (antiHBc-). HCV-RNA was detectable in serum by PCR in 2491 (82%) of the anti-HCV+ patients. There was no significant difference in HCV-RNA positivity between patients who had recovered from HBV (82% HCV-RNA-positive) and antiHBc-negative individuals (85% HCV-RNA-positive; p=O.O7), suggesting a minor impact of occult HBV infection on HCV replication. In contrast, HCV-RNA was found in only 63 of the 152 (41%) HBsAg+/anti-HCV+ patients (p
825 IZI
PREDICTIVE VALUE OF ALT LEVELS ON HISTOLOGICAL FINDINGS IN CHRONIC HEPATITIS C: A EUROPEAN COLLABORATIVE STUDY
P. Pradat, T. Poynard, A. Alberti, J.I. Esteban, P. Marcellin, 0. Weiland, S. Badalamenti, C. Trepo. Hepatology, Hotel-Dieu, Lyon, France Objective: To study the predictive value of ALT levels on histological
findings in HCV patients. Methods: Data on HCV RNA(+) patients were collected from six European Centers. ALT values were collected at the time of biopsy before any treatment. In a subset of patients, normal ALT values were defined as normal at serial testing during at least 6 months. Histological results were given using the METAVIR scoring system. Results: Data on 4728 patients were collected. In 3861 of them, ALT was assessed from a single value (group A) whereas in the remaining 867 patients, a normal ALT value meant “persistently” normal (group B). Within group A, the percentage of cases with at least Fl among patients with elevated ALT is about 92% against 87% among patients with normal ALT levels. Within group B, the percentage of cases with at least Fl among patients with elevated ALT reaches 99%. Among patients with “persistently normal” ALT values, still 65% have at least Fl. Conclusions: 1. Almost all HCV RNA(+) patients with elevated ALT present different degrees of fibrosis (>=Fl). 2. However, an important proportion of patients with ‘persistently normal” ALT also show histological signs of fibrosis, some of them even cirrhosis. This study suggests that patients with HCV RNA(+) and elevated ALT are a priori candidates for antiviral therapy. It also suggests that a significant proportion of cases with normal ALT may also benefit and that paradoxically, it is for them that liver biopsy may be most warranted.
I 993
HEPATITIS C VIRUS DYNAMICS DURING INDUCTION WITH HIGH PEG-IFN DOSES AND RIBAVIRIN COMPARED WITH LOW PEG-IFN DOSES PLUS RIBAVIRIN IN NAIVE PATIENTS WITH CHRONIC HEPATITIS C, GENOTYPE 1
J.F. Sanchez-Avila, M. Buti, Y. Lurie, M. Martell, R. Esteban, J. Guardia. Hospital Vu11d’tiebron, Barcelona, Spain PEG Interferon (PEG-IFN) plus ribavirin achieves a higher sustained response rate in genotype 1 patients with chronic hepatitis C, particularly when 1.5 pg/kg/weekly is used. Most sustained responders to standard combination therapy clear HCV-RNA during the first 12 weeks of therapy. Viral kinetics using PEG-IFN have not been extensively studied. AI: To study the dynamics of HCV replication during the first 24 weeks of therapy with a high dose of PEG-IFN plus Ribavirin compared
5
with a low dose of PEG-IFN plus ribavirin in untreated patients with chronic hepatitis C infected by genotype 1. Patients and Methods: 55 naive HCV (+), genotype 1 patients, (mean age: 42.8 yrs) with elevated ALT levels (mean: 90.04 f 42.23 WL) and HCV-RNA positive were randomized to receive PEG-IFN 3.0 wg/Kg qwk for one week, 1.5 PglKg qwk for 3 weeks and 1.0 &Kg for 44 weeks plus ribavirin 800 mg/day (27 patients) or 0.5 &Kg qwk plus Ribavirin 800 mg/day for 48 weeks (28 patients). HCV-RNA was detected by Real-time RT-PCR (LLD < 100 copies/ml) at baseline, every 24 hours during the first week and then at weeks, 2, 3,4,6,8, 12 and 24 of treatment. Results: Mean baseline HCV-RNA load was similar in both groups (5.17 log vs 5.32 log; p = ns.). 3 pg of PEG-IFN significantly inhibited HCV-RNA replication during the first two days of therapy compared with the low dose (2.39 f 1.14 log vs 1.1 f 0.82 log; p < O.OOl),but at day 7 before the following PEG-IFN dose, HCV-RNA levels were similar to those observed with 0.5 pg PEG-IFN (4.02 f 1.4 log vs 4.52 f 1.33 log; p = n.s.). Then during the first 24 weeks a progressive and slower viral decrease was observed with both doses but more dramatic with the high PEG-IFN dose (p: ns). HCV-RNA clearance was achieved faster and in a higher number of patients with the high PEG-IFN dose plus ribavirin during the whole period (22% vs. 7% at week 4, 56% vs 41% at week 8,56% vs 44% at week 12 and 69% vs. 63% at week 24). Conclusions: Initial high PEG-IFN doses plus ribavirin induce a more important viral decline during the first 2 days however by the end of the week both PEG-IFN doses achieve similar HCV reduction suggesting that a more frequent schedule of Peg-IFN should be considered.
SO9 Working Party 2 - Cell biology
I627
ANTI-FIBROTIC EFFECTS OF A NEW LIVER SPECIFIC NO DONOR IN BILE DUCT LIGATED RATS
F. Moal, E. Vuillemin, J. Wang, N. Veal, F. Oberti, Y. Gallois, E. Barriere, D. Rousselot, P. Cales. University ofAngers, HIFIH Laboratory, France
Hepatic NO production is decreased in cirrhosis. NO could act as an antifibrotic factor. Aim: To assess the antifibrotic effects of V-PYRRO/NO chronic administration in bile duct ligated (BDL) rats. Methods: This study was performed in 43 rats, divided in 4 groups: Group 1: n=9, sham rats with saline; group 2: n=12, sham rats with V-PYRROMO (0.53 pmol.kg-l.h-1); group 3: n=12, BDL rats with saline; group 4: n=lO, BDL rats with V-PYRRO/NO (same dosage). Treatment was administred by osmotic pump during 24 days. Liver fibrosis evaluation included the area of fibrosis and hydroxyproline content. Lipid peroxydation was assessed by liver malonedialdehyde (MDA). The liver specificity of V-PYRRO/NO was evaluated by liver cGMP and NOS activity. Results: V-PYRRO/NO significantly reduced the area of fibrosis in BDL rats (8.4 f 3.6 vs 12.1 f 0.7%, piO.05). In BDL rats, it significantly lowered hepatic hydroxyproline content compared to placebo (295f112 vs 371f88 &g prot, p
HBV (antiHBc+) and 1779 (58%) patients had no apparent previous contact to HBV (antiHBc-). HCV-RNA was detectable in serum by PCR in 2491 (82%) of the anti-HCV+ patients. There was no significant difference in HCV-RNA positivity between patients who had recovered from HBV (82% HCV-RNA-positive) and antiHBc-negative individuals (85% HCV-RNA-positive; p=O.O7), suggesting a minor impact of occult HBV infection on HCV replication. In contrast, HCV-RNA was found in only 63 of the 152 (41%) HBsAg+/anti-HCV+ patients (p
825 IZI
PREDICTIVE VALUE OF ALT LEVELS ON HISTOLOGICAL FINDINGS IN CHRONIC HEPATITIS C: A EUROPEAN COLLABORATIVE STUDY
P. Pradat, T. Poynard, A. Alberti, J.I. Esteban, P. Marcellin, 0. Weiland, S. Badalamenti, C. Trepo. Hepatology, Hotel-Dieu, Lyon, France Objective: To study the predictive value of ALT levels on histological
findings in HCV patients. Methods: Data on HCV RNA(+) patients were collected from six European Centers. ALT values were collected at the time of biopsy before any treatment. In a subset of patients, normal ALT values were defined as normal at serial testing during at least 6 months. Histological results were given using the METAVIR scoring system. Results: Data on 4728 patients were collected. In 3861 of them, ALT was assessed from a single value (group A) whereas in the remaining 867 patients, a normal ALT value meant “persistently” normal (group B). Within group A, the percentage of cases with at least Fl among patients with elevated ALT is about 92% against 87% among patients with normal ALT levels. Within group B, the percentage of cases with at least Fl among patients with elevated ALT reaches 99%. Among patients with “persistently normal” ALT values, still 65% have at least Fl. Conclusions: 1. Almost all HCV RNA(+) patients with elevated ALT present different degrees of fibrosis (>=Fl). 2. However, an important proportion of patients with ‘persistently normal” ALT also show histological signs of fibrosis, some of them even cirrhosis. This study suggests that patients with HCV RNA(+) and elevated ALT are a priori candidates for antiviral therapy. It also suggests that a significant proportion of cases with normal ALT may also benefit and that paradoxically, it is for them that liver biopsy may be most warranted.
I 993
HEPATITIS C VIRUS DYNAMICS DURING INDUCTION WITH HIGH PEG-IFN DOSES AND RIBAVIRIN COMPARED WITH LOW PEG-IFN DOSES PLUS RIBAVIRIN IN NAIVE PATIENTS WITH CHRONIC HEPATITIS C, GENOTYPE 1
J.F. Sanchez-Avila, M. Buti, Y. Lurie, M. Martell, R. Esteban, J. Guardia. Hospital Vu11d’tiebron, Barcelona, Spain PEG Interferon (PEG-IFN) plus ribavirin achieves a higher sustained response rate in genotype 1 patients with chronic hepatitis C, particularly when 1.5 pg/kg/weekly is used. Most sustained responders to standard combination therapy clear HCV-RNA during the first 12 weeks of therapy. Viral kinetics using PEG-IFN have not been extensively studied. AI: To study the dynamics of HCV replication during the first 24 weeks of therapy with a high dose of PEG-IFN plus Ribavirin compared
5
with a low dose of PEG-IFN plus ribavirin in untreated patients with chronic hepatitis C infected by genotype 1. Patients and Methods: 55 naive HCV (+), genotype 1 patients, (mean age: 42.8 yrs) with elevated ALT levels (mean: 90.04 f 42.23 WL) and HCV-RNA positive were randomized to receive PEG-IFN 3.0 wg/Kg qwk for one week, 1.5 PglKg qwk for 3 weeks and 1.0 &Kg for 44 weeks plus ribavirin 800 mg/day (27 patients) or 0.5 &Kg qwk plus Ribavirin 800 mg/day for 48 weeks (28 patients). HCV-RNA was detected by Real-time RT-PCR (LLD < 100 copies/ml) at baseline, every 24 hours during the first week and then at weeks, 2, 3,4,6,8, 12 and 24 of treatment. Results: Mean baseline HCV-RNA load was similar in both groups (5.17 log vs 5.32 log; p = ns.). 3 pg of PEG-IFN significantly inhibited HCV-RNA replication during the first two days of therapy compared with the low dose (2.39 f 1.14 log vs 1.1 f 0.82 log; p < O.OOl),but at day 7 before the following PEG-IFN dose, HCV-RNA levels were similar to those observed with 0.5 pg PEG-IFN (4.02 f 1.4 log vs 4.52 f 1.33 log; p = n.s.). Then during the first 24 weeks a progressive and slower viral decrease was observed with both doses but more dramatic with the high PEG-IFN dose (p: ns). HCV-RNA clearance was achieved faster and in a higher number of patients with the high PEG-IFN dose plus ribavirin during the whole period (22% vs. 7% at week 4, 56% vs 41% at week 8,56% vs 44% at week 12 and 69% vs. 63% at week 24). Conclusions: Initial high PEG-IFN doses plus ribavirin induce a more important viral decline during the first 2 days however by the end of the week both PEG-IFN doses achieve similar HCV reduction suggesting that a more frequent schedule of Peg-IFN should be considered.
SO9 Working Party 2 - Cell biology
I627
ANTI-FIBROTIC EFFECTS OF A NEW LIVER SPECIFIC NO DONOR IN BILE DUCT LIGATED RATS
F. Moal, E. Vuillemin, J. Wang, N. Veal, F. Oberti, Y. Gallois, E. Barriere, D. Rousselot, P. Cales. University ofAngers, HIFIH Laboratory, France
Hepatic NO production is decreased in cirrhosis. NO could act as an antifibrotic factor. Aim: To assess the antifibrotic effects of V-PYRRO/NO chronic administration in bile duct ligated (BDL) rats. Methods: This study was performed in 43 rats, divided in 4 groups: Group 1: n=9, sham rats with saline; group 2: n=12, sham rats with V-PYRROMO (0.53 pmol.kg-l.h-1); group 3: n=12, BDL rats with saline; group 4: n=lO, BDL rats with V-PYRRO/NO (same dosage). Treatment was administred by osmotic pump during 24 days. Liver fibrosis evaluation included the area of fibrosis and hydroxyproline content. Lipid peroxydation was assessed by liver malonedialdehyde (MDA). The liver specificity of V-PYRRO/NO was evaluated by liver cGMP and NOS activity. Results: V-PYRRO/NO significantly reduced the area of fibrosis in BDL rats (8.4 f 3.6 vs 12.1 f 0.7%, piO.05). In BDL rats, it significantly lowered hepatic hydroxyproline content compared to placebo (295f112 vs 371f88 &g prot, p