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Famciclovir treatment of anti-HBE+ chronic hepatitis B: Results of a randomized, placebo-controlled study
Posters
P/C06/21
]
PREVALENCE AND CLINICAL SIGNIFICANCE OF ANTIPHOSPHOLIPID ANTIBODIES (APA) IN VIRAL CHRONIC LIVER DISEASE M. Romero-G6mez, A. Gull, E. Garcia-Diaz, L. Grande, E. Su~.rez, D. L6Dez Lacomba ~. M. Castro Digestive, Valme University Hospital, Seville, Spain. 1Hematology, Valme University Hospital, Seville, Spain. The progression from chronic hepatitis to liver cirrhosis could be explained by the ~ n of thrombotic events in portal and hepatic veins (Wanless. Hepatoiogy1995;21:1238). &INS: TO know the prevalence of APA in HCV and HBV related chronic.liver diseases. To analyse the relationship between APA and the progression of chronic hepat~s C. IRLerlBOIDS:One-hundred and forty-eight patients were enrolled: 133 with HCV infection (blopsy:Fl:47, 1=2:40 and F4:46) and 15 HBV drrhosis. A control group of 37 healthy people was also studied. No patient had received Interferon theraW. In HCV patients we analysed risk factors, the duration of the Illness and the daily consumption of alcohol, also, we determined platelet levels, ALT, RNAHCVin serum and liver. In the patients with liver cirrhosis the existenceof portal hypertension and the Chlld-Pugh stage were determined. We assayed lupus anticoagulant (LA), antlcardlollpln antibodies IgG (ACAIgG) and IgM (ACAIgH) by ELISA and anti132-gllcoproteln I also by EI.ISA in patients with ~ ACA. RESULTS: We found APA in 33 out of 133 (25%) HCV patient, mog'ly ACAIgG (29/133). We did not find differences in ALT, viremla or platelet levels in patients with or without ACAIgG, nor did we find a relationships with age, duration of the infection, alcohol consumption or risk factors. In 4 of 47 pauents (9%) with fibrosis F1, In 7 of 40 (18%) with 1=2and In 18 of 46 (39%) with drrhosis (F4) we found ACAIgG;Chi:11.22 p < 0,005. The presence of ACAIgG was related with a worse liver function (Chlld-Pugh: 5.6~1.2 Vs 5~0.4;p<0,005), and ~ portal hypertension -14/29 (48%) vs 20/104 (19%) ;p<0,05-. The prevalence of ACA-IgG was significantly higher In HCV cirrhosis (39%) than in HBV drrhosis 1/15 (6%),1o<0,05 and the control group 1/37(2,7%)p<0,005; without dlffererces in the presence of ACAIgH. We did not detect LA. The a~I32-GPI were detected In 9 of 22 ACA positive pat~,mts. CONCUJSIONS: The prevalence of ACAIgG increases as HCV progresses. These antlbedlas could be an autolrnmune epiphenomenen. Nevertheless,they could be implied In the the progression of HCV Infection, different to HBV. Apoptoslscould induce the appearance of these antibodiesthat would start these mlcrothrombotJcevents.
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MOLECULAR ANALYSIS OF HEPATITIS B VIRUS DNA IN SERUM AND PERIPHERAL BLOOD MONONUCLEAR CELLS FROM HEPATITIS B SURFACE ANTIGEN-NEGATIVE CASES M. Cabrerizo 1. J. Bartolom6 ~, C. Caramelo, V. Carrefio Department of Hepatology and Nephrology, Fundaci6n Jim6nez Diaz, Madrid, Spain. ZFundaci6n para el Estudio de las Hepatitis virales, Madrid, Spain. We have analyzed the molecular bases of the persistence of HBV-DNA in serum and peripheral blood mononuclear cells (PBMC) in the absence of detectable HBsAg in 11 hemodialysis patients and 8 dialysis unit staff members who had suffered acute hepatitis B resolved previously. HBVDNA was found in both compartments by PCR using primers of pre-S/S region. Viral DNA was transcriptionally active in PBMC since all PBMC samples had HBV-RNA, although the eecHBV-DNA, the template for the viral RNA transcription, was only detected in 47% of the samples. HBsAg-negative cases had statistically lower levels of HBV-DNA in serum (median: 1.7x104 I-IBV copies/ml) than a control group of 12 chronic l-lBsAg carriers (median: 6.5x 107 I-IBV copies/ml) (p<0.001 ). We also studied the presence of immune complexes and the existence of mutations in the pre-S/S gene in order to explain the lack of detection of I-IBsAg in these cases. No serum I-IBsAg/antiHBs immune complexes or mutations in the "a" determinant of the S gene were found. However, all HBsAg-negative cases were infected by a mixture of the wild type HBVDNA and viral genomes habouring a deletion in the pre-S1 region. This deletion (amino acids 58-118) affects the S gene promoter and previous in vitro studies have shown that it produces a reduction in the HBsAg synthesis. In conclusion, in this work it has been shown that the lack of detection of HBsAg in the presence of low viral levels of replication may be dueto the existence of viral genomes harboring deletions in the pre-S1 region that affect the S promoter.
102
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P/C06/23 I
DECREASED PRODUCTION OF INTERFERON-? IN PATIENTS WITH CHRONIC HEPATITIS C TREATED WITH RIBAVIRIN IN COMBINATION WITH INTERFERON-ALPHA M. Cepparulo l, A. Bergamini 1, E Bolacchi l, E Demin l, I. Uccella l, B. Bon~iovanni 1, M. Capozzi l, D. Ombres2, E Angelico2, A. Liuti 2, M. Hurtov/t~, S. Francioso2, M. Angelico3, G. Rocchi 1, 1Dept. of Public Health, Chairs of Infectious Diseases, Rome, Italy. 2Terapia Medica Sistematica, Univ. of Rome "La Sapienza", Rome, Italy. 3Gastroenterology Univ. of Rome "Tot Vergata", Italy. J ~ It has been suggested that the effectof ribavirin in patients with chronic hepatitis C may be complex and not strictly antiviral. The present study was designed to examine the effect of ribavirin on eytokine production in patients with chronic hepatitis C. methods Cytokine production by activated T cells and serum cytokine levels were prospectively studied by FACS analysis and ELISA testing before and after ribavirin and IFN-cctreatment in 16 patients with chronic hepatitis C, unresponsive to IFN-~ and in 9 patients with chronic HCV hepatitis unresponsive to IFN-~ re-treated with IFN-~ alone. Results We found that treatment with ribavirin and IFN-cx was associated with a significant suppression of the production of IFN-y by T cells, with respect to initial values. The analysis of the "naive" and "memory" T cell subsets demonstrated a similar reduction of IFN-y production in either cell subsets after treatment with respect to before. Consistently, the blood levels of IFN-ywere significantly downregulatod in patients at the end of treatment as compared with pre-treatment values. In contrast, neither the expression ofinterleukin (IL)-2, IL-4 and IL-10 by T cells nor the blood levels of these cytokines were diffcnmt before with respect to after treatment. Finally, no modulation of cytokine production was seen in patients treated with IFN-c¢ alone. Conclusions In conclusion, we show here for the first time that ribavirin in conbination with IFN-(~ downmodulates IFN-T production in patients with chronic HCV infection. This is likely to favour an anti-inflammatory effect and may help reducing HCV-related T cell activation and liver damage. In addition, the results of this study do not support modulation of cytokine production in favour of a Thl phenotype as the mechanism by which rihavirin potentiate IFN-c¢ anti HCV activity.
I /co6 , ] FAMCICLOVIR TREATMENT OF ANTI-HBE+ CHRONIC HEPATITIS B: RESULTS OF A RANDOMIZED, PLACEBO-CONTROLLED STUDY N. Tassoooulos 1, S. Hadzivannis2, G. Idto 3, R. Jurewicz4, C. Young4, R. Saltzrnan4, C. Trepo5, E Bonino6, for the Famciclovir Anti-HBe+ Chronic Heoatitis B Study Group lWestern Attica Gen. Hosp., Athens, Greece. 2Hippokration Gen. Hosp., Athens, Greece. 3S. Giuseppe Hosp., Milan, Italy. 4SmithKline Beecham Pharmaceuticals, Collegeville, PA, USA. 5H6p. H6tel-Dieu, Lyon, France. 6Spedali Riuniti di S. Chiara, Pisa, Italy. Patients with chronic hepatitis B (CHB) without HBeAg (infected with HBeAg- mutants) experience periodic hepatic flares which can lead to cirrhosis and hepatocellular carcinoma. Famciclovir (FCV) significantly reduced HBV DNA in HBeAg+ patients; therefore, a study was undertaken to determine efficacy of treatment in HBeAg-/anti-HBe+ CHB patients. The co-primary endpoints were the proportion of patients with hepatic flares during therapy (i.e. 2-fold increase over baseline in HBV DNA and ALT) and changes in liver histology score. A total of 331 patients with documented anti-HBe profile and abnormal liver histology were randomized to receive FCV 500mg tid (n=l 11), FCV 1.5g daily (n=106) or placebo (PBO; n=114) for 12 months with a 12-munth follow-up. FCV significantly reduced the proportion of patients with on-dose hepatic flares (33% and 37% for FCV 500mg rid and 1.5g daily, respectively, vs. 52% for PBO; p<0.03). Median change in Ishak score was -2.0 points for FCV 500rag tid (p<0.001) and -1.0 point for FCV 1.5g daily (p=0.008) vs. +0.5 for PBO. Significantly more patients in the FCV 500rag tid (51%; p<0.001) and FCV 1.5g daily (38%; p=0.003) groups experienced ~ point improvement in Ishak score compared with PBO (17%). Between 21% and 25% of FCV-treated patients responded completely to treatment (undetectable HBV DNA [b-DNA], normal ALT and undetectable IgM anti-HBc for last 3 months of therapy) vs. 11% of PBO recipients (p<0.05). This response was not sustained during follow-up. AE and laboratory profiles showed FCV to be well tolerated both during and after cessation of therapy. In conclusion, FCV was well-tolerated and effective for treatment of patients with HBeAg-/anti-HBe+ CHB.
P/C06/21
]
PREVALENCE AND CLINICAL SIGNIFICANCE OF ANTIPHOSPHOLIPID ANTIBODIES (APA) IN VIRAL CHRONIC LIVER DISEASE M. Romero-G6mez, A. Gull, E. Garcia-Diaz, L. Grande, E. Su~.rez, D. L6Dez Lacomba ~. M. Castro Digestive, Valme University Hospital, Seville, Spain. 1Hematology, Valme University Hospital, Seville, Spain. The progression from chronic hepatitis to liver cirrhosis could be explained by the ~ n of thrombotic events in portal and hepatic veins (Wanless. Hepatoiogy1995;21:1238). &INS: TO know the prevalence of APA in HCV and HBV related chronic.liver diseases. To analyse the relationship between APA and the progression of chronic hepat~s C. IRLerlBOIDS:One-hundred and forty-eight patients were enrolled: 133 with HCV infection (blopsy:Fl:47, 1=2:40 and F4:46) and 15 HBV drrhosis. A control group of 37 healthy people was also studied. No patient had received Interferon theraW. In HCV patients we analysed risk factors, the duration of the Illness and the daily consumption of alcohol, also, we determined platelet levels, ALT, RNAHCVin serum and liver. In the patients with liver cirrhosis the existenceof portal hypertension and the Chlld-Pugh stage were determined. We assayed lupus anticoagulant (LA), antlcardlollpln antibodies IgG (ACAIgG) and IgM (ACAIgH) by ELISA and anti132-gllcoproteln I also by EI.ISA in patients with ~ ACA. RESULTS: We found APA in 33 out of 133 (25%) HCV patient, mog'ly ACAIgG (29/133). We did not find differences in ALT, viremla or platelet levels in patients with or without ACAIgG, nor did we find a relationships with age, duration of the infection, alcohol consumption or risk factors. In 4 of 47 pauents (9%) with fibrosis F1, In 7 of 40 (18%) with 1=2and In 18 of 46 (39%) with drrhosis (F4) we found ACAIgG;Chi:11.22 p < 0,005. The presence of ACAIgG was related with a worse liver function (Chlld-Pugh: 5.6~1.2 Vs 5~0.4;p<0,005), and ~ portal hypertension -14/29 (48%) vs 20/104 (19%) ;p<0,05-. The prevalence of ACA-IgG was significantly higher In HCV cirrhosis (39%) than in HBV drrhosis 1/15 (6%),1o<0,05 and the control group 1/37(2,7%)p<0,005; without dlffererces in the presence of ACAIgH. We did not detect LA. The a~I32-GPI were detected In 9 of 22 ACA positive pat~,mts. CONCUJSIONS: The prevalence of ACAIgG increases as HCV progresses. These antlbedlas could be an autolrnmune epiphenomenen. Nevertheless,they could be implied In the the progression of HCV Infection, different to HBV. Apoptoslscould induce the appearance of these antibodiesthat would start these mlcrothrombotJcevents.
I
]
MOLECULAR ANALYSIS OF HEPATITIS B VIRUS DNA IN SERUM AND PERIPHERAL BLOOD MONONUCLEAR CELLS FROM HEPATITIS B SURFACE ANTIGEN-NEGATIVE CASES M. Cabrerizo 1. J. Bartolom6 ~, C. Caramelo, V. Carrefio Department of Hepatology and Nephrology, Fundaci6n Jim6nez Diaz, Madrid, Spain. ZFundaci6n para el Estudio de las Hepatitis virales, Madrid, Spain. We have analyzed the molecular bases of the persistence of HBV-DNA in serum and peripheral blood mononuclear cells (PBMC) in the absence of detectable HBsAg in 11 hemodialysis patients and 8 dialysis unit staff members who had suffered acute hepatitis B resolved previously. HBVDNA was found in both compartments by PCR using primers of pre-S/S region. Viral DNA was transcriptionally active in PBMC since all PBMC samples had HBV-RNA, although the eecHBV-DNA, the template for the viral RNA transcription, was only detected in 47% of the samples. HBsAg-negative cases had statistically lower levels of HBV-DNA in serum (median: 1.7x104 I-IBV copies/ml) than a control group of 12 chronic l-lBsAg carriers (median: 6.5x 107 I-IBV copies/ml) (p<0.001 ). We also studied the presence of immune complexes and the existence of mutations in the pre-S/S gene in order to explain the lack of detection of I-IBsAg in these cases. No serum I-IBsAg/antiHBs immune complexes or mutations in the "a" determinant of the S gene were found. However, all HBsAg-negative cases were infected by a mixture of the wild type HBVDNA and viral genomes habouring a deletion in the pre-S1 region. This deletion (amino acids 58-118) affects the S gene promoter and previous in vitro studies have shown that it produces a reduction in the HBsAg synthesis. In conclusion, in this work it has been shown that the lack of detection of HBsAg in the presence of low viral levels of replication may be dueto the existence of viral genomes harboring deletions in the pre-S1 region that affect the S promoter.
102
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P/C06/23 I
DECREASED PRODUCTION OF INTERFERON-? IN PATIENTS WITH CHRONIC HEPATITIS C TREATED WITH RIBAVIRIN IN COMBINATION WITH INTERFERON-ALPHA M. Cepparulo l, A. Bergamini 1, E Bolacchi l, E Demin l, I. Uccella l, B. Bon~iovanni 1, M. Capozzi l, D. Ombres2, E Angelico2, A. Liuti 2, M. Hurtov/t~, S. Francioso2, M. Angelico3, G. Rocchi 1, 1Dept. of Public Health, Chairs of Infectious Diseases, Rome, Italy. 2Terapia Medica Sistematica, Univ. of Rome "La Sapienza", Rome, Italy. 3Gastroenterology Univ. of Rome "Tot Vergata", Italy. J ~ It has been suggested that the effectof ribavirin in patients with chronic hepatitis C may be complex and not strictly antiviral. The present study was designed to examine the effect of ribavirin on eytokine production in patients with chronic hepatitis C. methods Cytokine production by activated T cells and serum cytokine levels were prospectively studied by FACS analysis and ELISA testing before and after ribavirin and IFN-cctreatment in 16 patients with chronic hepatitis C, unresponsive to IFN-~ and in 9 patients with chronic HCV hepatitis unresponsive to IFN-~ re-treated with IFN-~ alone. Results We found that treatment with ribavirin and IFN-cx was associated with a significant suppression of the production of IFN-y by T cells, with respect to initial values. The analysis of the "naive" and "memory" T cell subsets demonstrated a similar reduction of IFN-y production in either cell subsets after treatment with respect to before. Consistently, the blood levels of IFN-ywere significantly downregulatod in patients at the end of treatment as compared with pre-treatment values. In contrast, neither the expression ofinterleukin (IL)-2, IL-4 and IL-10 by T cells nor the blood levels of these cytokines were diffcnmt before with respect to after treatment. Finally, no modulation of cytokine production was seen in patients treated with IFN-c¢ alone. Conclusions In conclusion, we show here for the first time that ribavirin in conbination with IFN-(~ downmodulates IFN-T production in patients with chronic HCV infection. This is likely to favour an anti-inflammatory effect and may help reducing HCV-related T cell activation and liver damage. In addition, the results of this study do not support modulation of cytokine production in favour of a Thl phenotype as the mechanism by which rihavirin potentiate IFN-c¢ anti HCV activity.
I /co6 , ] FAMCICLOVIR TREATMENT OF ANTI-HBE+ CHRONIC HEPATITIS B: RESULTS OF A RANDOMIZED, PLACEBO-CONTROLLED STUDY N. Tassoooulos 1, S. Hadzivannis2, G. Idto 3, R. Jurewicz4, C. Young4, R. Saltzrnan4, C. Trepo5, E Bonino6, for the Famciclovir Anti-HBe+ Chronic Heoatitis B Study Group lWestern Attica Gen. Hosp., Athens, Greece. 2Hippokration Gen. Hosp., Athens, Greece. 3S. Giuseppe Hosp., Milan, Italy. 4SmithKline Beecham Pharmaceuticals, Collegeville, PA, USA. 5H6p. H6tel-Dieu, Lyon, France. 6Spedali Riuniti di S. Chiara, Pisa, Italy. Patients with chronic hepatitis B (CHB) without HBeAg (infected with HBeAg- mutants) experience periodic hepatic flares which can lead to cirrhosis and hepatocellular carcinoma. Famciclovir (FCV) significantly reduced HBV DNA in HBeAg+ patients; therefore, a study was undertaken to determine efficacy of treatment in HBeAg-/anti-HBe+ CHB patients. The co-primary endpoints were the proportion of patients with hepatic flares during therapy (i.e. 2-fold increase over baseline in HBV DNA and ALT) and changes in liver histology score. A total of 331 patients with documented anti-HBe profile and abnormal liver histology were randomized to receive FCV 500mg tid (n=l 11), FCV 1.5g daily (n=106) or placebo (PBO; n=114) for 12 months with a 12-munth follow-up. FCV significantly reduced the proportion of patients with on-dose hepatic flares (33% and 37% for FCV 500mg rid and 1.5g daily, respectively, vs. 52% for PBO; p<0.03). Median change in Ishak score was -2.0 points for FCV 500rag tid (p<0.001) and -1.0 point for FCV 1.5g daily (p=0.008) vs. +0.5 for PBO. Significantly more patients in the FCV 500rag tid (51%; p<0.001) and FCV 1.5g daily (38%; p=0.003) groups experienced ~ point improvement in Ishak score compared with PBO (17%). Between 21% and 25% of FCV-treated patients responded completely to treatment (undetectable HBV DNA [b-DNA], normal ALT and undetectable IgM anti-HBc for last 3 months of therapy) vs. 11% of PBO recipients (p<0.05). This response was not sustained during follow-up. AE and laboratory profiles showed FCV to be well tolerated both during and after cessation of therapy. In conclusion, FCV was well-tolerated and effective for treatment of patients with HBeAg-/anti-HBe+ CHB.