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Ursodeoxycholic acid (UDCA) and interferon (IF) combined therapy of chronic viral C hepatitis: A meta-analysis
136
Poster Sessions
cholestatic syndromes are associated with HCV infection acquired during the post RT period. The aim of this study was to evaluate the natural cam-se of HCV infection acquired after RT. Patients and Methods: 17 RT pts had evidence of acquisition of HCV infection after RT [seroconversion or acute hepatitis (AH) at liver biopsy (LB)]. Biochemical abnormalities were first observed in a median (IQR) 7.8 months (2.4, 17) post RT. The pts, 13 males 4 females, mean (SD) age 49.1 (10.9) years, were followed up for mean (SD) 7.2 (4.2) years after RT. 1607 underwent more than 1 (2-4) consecutive LBs. Genotype and viral load were determined. Results: 4 pts developed fibrosing cholestatic hepatitis (FCH) 9.0 (4.7) months mean (SD) post RT. A cholestatic syndrome with bile duct damage presented in 6 pts (4 as progression from CH) 57.5 (33.5) months, mean (SD), post RT; later than the FCH pts (p=O.O2), ending up to vanishing bile duct syndrome (VBDS) in 3 of them. CH was observed in 7 pts (5 as progression from AH), showing yearly progression rate of fibrosis 0.84 per year (ratio between the fibrosing scores difference at two consecutive LBs divided by the interval time). 6 out of 17 pts died in a median (IQR) of 6.1 (1.5,7.1) years post RT, 4/6 due to hepatic failure (2 FCH, 1 VBDS, 1CH). Graft failure occurred in 607 pts (1 FCH, 2 VBDS, 3 CH) 5.9 (2.0) years, mean (SD), post RT. Genotype 1 was found in 7/9 (78%) of the FCH or VBDS pts and in 2/7 (29%) of CH pts (p=O.O5). HCV-RNA levels of FCH pts were 1 log10 higher (p=O.O6). Conclusions: HCV infection acquired after RT is frequently associated with a highly progressive course. Cholestatic syndromes present major complications manifesting as FCH in early and VBDS in late post RT period.
I467
URSODEOXYCHOLlC COMBINED
ACID (UDCA) AND INTERFERON
THERAPY
OF CHRONIC
(IF)
VIRAL C HEPATITIS: A
META-ANALYSIS
D.L. Dumitrascu’, V. Sandor2. ‘3rd Medical Dep., University Oj Medicine And Pharmacy, Cluj, Romania; 2Dept. Pharmacology, University Of Medicine And Pharmacology, Cluj, Romania Background and Aim: UDCA became an established treatment for chronic liver diseases in the last decade. A meta-analysis showed its effectiveness (Am .I Gastroenterol 1994, 89: 392). Recently UDCA was used in several trials in combination with IF in the therapy of chronic viral C hepatitis (CVCH). We looked for the therapeutical effect of this combination. Methods: A meta-analysis of the trials using UDCA and IF for CVCH was performed. All trials of these two drugs were identified on MEDLINE and the selected papers were pooled together and analyzed according to the methods of Cochran-Laird-Dersimonian and Mantel-Haenzel-Peto. Papers in inaccessible languages (i.e. Japanese) were discarded. Noncontrolled trials were also not retained for analysis. Results: Six papers remained for the meta-analysis. They included 192 patients with CVCH treated with UDCA+IF. UDCA was administered in doses of 300-600 mg/kg/day and IF in doses of 3-5 MU for 3-12 months. Controls were patients receiving either UDCA alone or IF alone. The metaanalysis detected a sustained improvement of transaminases in the group of UDCA+IF compared to IF alone. UDCA alone had a nonsignificant effect on liver function tests at long time follow-up. Conclusion: The association IF+UDCA is a promising therapy in CVCH.
I468
ANTIVIRAL TREATMENT
ACTIVITY
AND SAFETY
WITH ACH-126,443
TREATMENT-NAVE
OF 12 WEEKS
(BETA-L-FD4C)
PATIENTS WITH CHRONIC
OF ORAL IN
HBV
INFECTION J.C. Pottage Jr’, S.C. Oshana’,
PT. Yen’, D. Delic2, V. Rehak’, S. Plisek4, G.M. Mechkov3, L.M. Dunkle’. ‘Achillion Pharmaceuticals, Inc, New Haven, CT USA; 2 University Of Belgrade School Of Medicine, Clinical Ctr Of Serbia, Serbia, Yugoslavia; ‘5th Clinical City Hospital, Sojia, Bulgatia; 4 University Hospital, Hradec Kralove, Czech Republic; ‘NZZ DI: Svobody ‘s Clinic, Private Hospital, Prague, Czech Republic
Background: ACH-126,443 (b-L-Fd4C) is an L-nucleoside cytosine analog with potent in vitro activity against both wild-type and lamivudineresistant Hepatitis B Virus (HBV). Previously, a 14.day treatment with ACH-126, 443 (5mg-100mg orally once daily as buffered solution) resulted in 1.5-2.5 log10 declines in HBV-DNA in treatment-nave chronic HBV patients. A new enteric-coated tablet has been shown to have dose proportional, linear pharmacokinetics with exposures well in excess of in vitro anti-HBV activity. Methods: A randomized, double-blind, placebo-controlled trial was conducted at 18 centers in Central and Eastern Europe. 87 patients with chronic HBV, +HBeAg, and no prior treatment were randomized to receive: ACH126, 443 5mg, 20 mg, or 50 mg, lamivudine lOOmg, or placebo, (in a 3: 3: 3: 2: 1 ratio, respectively), all given orally once daily. Patients were treated for 12 weeks and followed for an additional 8 weeks off therapy. Safety evaluations and plasma HBV-DNA (Roche COBASaassay) were performed at weeks 0,2,4, 8, 12, 16, and 20. Results: Baseline characteristics: Male 78%, Female 22%; mean age: 39.3 years; mean baseline HBV-DNA: 9.38 loglO; mean baseline ALT: 120.6 U/L. After 12 weeks of therapy, blinded pooled HBV-DNA data from all patients showed a mean 3.15 log10 decline from baseline. Data unblinded by treatment group will be presented. There were no grade 3 or 4 adverse events or laboratory abnormalities attributed to ACH-126, 443. Conclusions: All three doses of ACH-126, 443 were well tolerated and demonstrated potent anti-HBV activity over 12 weeks in treatment-na ve chronic HBV natients.
Poster Sessions
cholestatic syndromes are associated with HCV infection acquired during the post RT period. The aim of this study was to evaluate the natural cam-se of HCV infection acquired after RT. Patients and Methods: 17 RT pts had evidence of acquisition of HCV infection after RT [seroconversion or acute hepatitis (AH) at liver biopsy (LB)]. Biochemical abnormalities were first observed in a median (IQR) 7.8 months (2.4, 17) post RT. The pts, 13 males 4 females, mean (SD) age 49.1 (10.9) years, were followed up for mean (SD) 7.2 (4.2) years after RT. 1607 underwent more than 1 (2-4) consecutive LBs. Genotype and viral load were determined. Results: 4 pts developed fibrosing cholestatic hepatitis (FCH) 9.0 (4.7) months mean (SD) post RT. A cholestatic syndrome with bile duct damage presented in 6 pts (4 as progression from CH) 57.5 (33.5) months, mean (SD), post RT; later than the FCH pts (p=O.O2), ending up to vanishing bile duct syndrome (VBDS) in 3 of them. CH was observed in 7 pts (5 as progression from AH), showing yearly progression rate of fibrosis 0.84 per year (ratio between the fibrosing scores difference at two consecutive LBs divided by the interval time). 6 out of 17 pts died in a median (IQR) of 6.1 (1.5,7.1) years post RT, 4/6 due to hepatic failure (2 FCH, 1 VBDS, 1CH). Graft failure occurred in 607 pts (1 FCH, 2 VBDS, 3 CH) 5.9 (2.0) years, mean (SD), post RT. Genotype 1 was found in 7/9 (78%) of the FCH or VBDS pts and in 2/7 (29%) of CH pts (p=O.O5). HCV-RNA levels of FCH pts were 1 log10 higher (p=O.O6). Conclusions: HCV infection acquired after RT is frequently associated with a highly progressive course. Cholestatic syndromes present major complications manifesting as FCH in early and VBDS in late post RT period.
I467
URSODEOXYCHOLlC COMBINED
ACID (UDCA) AND INTERFERON
THERAPY
OF CHRONIC
(IF)
VIRAL C HEPATITIS: A
META-ANALYSIS
D.L. Dumitrascu’, V. Sandor2. ‘3rd Medical Dep., University Oj Medicine And Pharmacy, Cluj, Romania; 2Dept. Pharmacology, University Of Medicine And Pharmacology, Cluj, Romania Background and Aim: UDCA became an established treatment for chronic liver diseases in the last decade. A meta-analysis showed its effectiveness (Am .I Gastroenterol 1994, 89: 392). Recently UDCA was used in several trials in combination with IF in the therapy of chronic viral C hepatitis (CVCH). We looked for the therapeutical effect of this combination. Methods: A meta-analysis of the trials using UDCA and IF for CVCH was performed. All trials of these two drugs were identified on MEDLINE and the selected papers were pooled together and analyzed according to the methods of Cochran-Laird-Dersimonian and Mantel-Haenzel-Peto. Papers in inaccessible languages (i.e. Japanese) were discarded. Noncontrolled trials were also not retained for analysis. Results: Six papers remained for the meta-analysis. They included 192 patients with CVCH treated with UDCA+IF. UDCA was administered in doses of 300-600 mg/kg/day and IF in doses of 3-5 MU for 3-12 months. Controls were patients receiving either UDCA alone or IF alone. The metaanalysis detected a sustained improvement of transaminases in the group of UDCA+IF compared to IF alone. UDCA alone had a nonsignificant effect on liver function tests at long time follow-up. Conclusion: The association IF+UDCA is a promising therapy in CVCH.
I468
ANTIVIRAL TREATMENT
ACTIVITY
AND SAFETY
WITH ACH-126,443
TREATMENT-NAVE
OF 12 WEEKS
(BETA-L-FD4C)
PATIENTS WITH CHRONIC
OF ORAL IN
HBV
INFECTION J.C. Pottage Jr’, S.C. Oshana’,
PT. Yen’, D. Delic2, V. Rehak’, S. Plisek4, G.M. Mechkov3, L.M. Dunkle’. ‘Achillion Pharmaceuticals, Inc, New Haven, CT USA; 2 University Of Belgrade School Of Medicine, Clinical Ctr Of Serbia, Serbia, Yugoslavia; ‘5th Clinical City Hospital, Sojia, Bulgatia; 4 University Hospital, Hradec Kralove, Czech Republic; ‘NZZ DI: Svobody ‘s Clinic, Private Hospital, Prague, Czech Republic
Background: ACH-126,443 (b-L-Fd4C) is an L-nucleoside cytosine analog with potent in vitro activity against both wild-type and lamivudineresistant Hepatitis B Virus (HBV). Previously, a 14.day treatment with ACH-126, 443 (5mg-100mg orally once daily as buffered solution) resulted in 1.5-2.5 log10 declines in HBV-DNA in treatment-nave chronic HBV patients. A new enteric-coated tablet has been shown to have dose proportional, linear pharmacokinetics with exposures well in excess of in vitro anti-HBV activity. Methods: A randomized, double-blind, placebo-controlled trial was conducted at 18 centers in Central and Eastern Europe. 87 patients with chronic HBV, +HBeAg, and no prior treatment were randomized to receive: ACH126, 443 5mg, 20 mg, or 50 mg, lamivudine lOOmg, or placebo, (in a 3: 3: 3: 2: 1 ratio, respectively), all given orally once daily. Patients were treated for 12 weeks and followed for an additional 8 weeks off therapy. Safety evaluations and plasma HBV-DNA (Roche COBASaassay) were performed at weeks 0,2,4, 8, 12, 16, and 20. Results: Baseline characteristics: Male 78%, Female 22%; mean age: 39.3 years; mean baseline HBV-DNA: 9.38 loglO; mean baseline ALT: 120.6 U/L. After 12 weeks of therapy, blinded pooled HBV-DNA data from all patients showed a mean 3.15 log10 decline from baseline. Data unblinded by treatment group will be presented. There were no grade 3 or 4 adverse events or laboratory abnormalities attributed to ACH-126, 443. Conclusions: All three doses of ACH-126, 443 were well tolerated and demonstrated potent anti-HBV activity over 12 weeks in treatment-na ve chronic HBV natients.