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Identification of HBV-DNA markers that are predictive of response to lamivudine therapy in patients infected with HBV precore variants
134
Poster Sessions
Conclusion: At week 48 of therapythe induction dose is more effective than the fixed dose in non-responders. The benefit of the induction regimen is more apparent in patients with prior IFN monotherapy and in those with genotype non-l infection.
I
458
IDENTIFICATION PREDICTIVE
OF HBV-DNA
OF RESPONSE
PATIENTS INFECTED
MARKERS
THAT ARE
TO LAMIVUDINE
WITH HBV PRECORE
THERAPY
IN
VARIANTS
A. Ciancio’,2, A. Smedile’, M. Rizzetto’, M. Lagget’, M. Abate’, .I. Gerin2, B.E. Korba2. ‘Dipartimento Di Gastroenterologia, Azienda Ospedaliera, SGiovanni Bat&a di Torino, Italy; 2Division Of Molecular Virology And Immunology, Georgetown University Medical Centec Rockville, MD, USA Lamivudine is initially highly effective in patients with hepatitis B e antigen-negative (HBeAg) chronic hepatitis B, but its long-term efficacy is burdened by high rates of virologic relapse. We analyzed the DNA sequence of HBV polymerase (domains A to E), and the HBV precore/core regions in 26 HBeAg-negative patients (genotype D, 16 with G1896A, 16 with A1762T/G1764A, 11 with both) treated for 21-48 months with lamivudine to determine if there was a relationship between specific HBV-DNA sequence patterns and long-term treatment response. After a minimum of 21 months of therapy, seven patients (27%) were responders (normal ALT, HBV-DNA-), 12 (46%) breakthroughs (following initial virologic response), and 7 (27%) non-responders (sustained elevated ALT, HBV-DNA+). Two HBV-DNA polymerase polymorphisms, present in the pretreatment serum samples, were correlated with extended treatment failures (breakthrough or non-response). Leucine was present at rt9 1 in 17 of 19 patients with long-term treatment failure, and a cysteine was present at rt2.56 in 13 of these 19 patients. All 7 long-term responders had an isoleucine at rt91 and a serine at rt2.56. Under therapy, reversion of A1762TIG1764A was observed in 4 of 13 patients (31%), and of G1896A in 3 of 12 (25%). YMDD Mutations (confirmed by INNOLiPAa) analysis) were found in 7/12 of the relapsing patients at the time of breakthrough. Our data suggest that specific HBV-DNA sequences present before treatment may predict long-term response to lamivudine, permitting therapy to be targeted to those individuals who are most likely to have sustained clinical benefit.
I
459
THE HEPATIC VENOUS
PRESSURE
PATIENTS WITH CHRONIC ASSOCIATED SEVERITY
GRADIENT
HEPATITIS
WITH THE EXTENT
tivariate analysis showed that the HVPG was independently associated with fibrosis, ascites and bilirubin levels (respective coefficients, 3.4, 2.4 and 1.4; intercept, -3.8). When this analysis was restricted to the cirrhosis group, only the degree of ascites and bilirubin levels (respective coefficients, 2.3, 1.2; intercept, 10.8) were independently significant in multiple linear regression. In conclusion, the HVPG mainly depends on the extent of liver fibrosis and the severity of liver disease in patients with hepatitis C.
(HVPG) IN
C IS ONLY
OF FIBROSIS
I
460
LACK OF INFLUENCE
OF ACTIVE INTRAVENOUS
ON THE MANAGEMENT CHRONIC
DRUG USE
QUALITY OF PATIENTS WITH
HEPATITIS C
M. Cournot2, F. Castel’, F. Druart’, T. Morin’, V. Lauwers-Cances2, K. Imani ‘, A. Glibert I. ‘DepartmentOf Hepatogastroenterology, Tarbes Hospital, Tarbes, France; 2Department Of Epidemiology, INSERM lJ558, Toulouse, France Background: Recent guidelines regarding chronic Hepatitis C virus (HCV) infection support that the anti HCV therapy of active intravenous drug users (AIVDU) should be the same as in the other patients. The aim of this study was to compare methods used to manage hepatitis C and clinical outcome after treatment between AIVDU and non-AIVDU when AIVDU patients are offered cares concerning both the addictions and the HCV Infection. Methods: Four hundred and thirty five naive HCV seropositive patients were followed up during a mean period of 2.5 years (SD 1 year), 116 of them were AIVDU at the beginning of the study. Social, clinical, biological and histological data were collected. HCV management and responses to eventual treatments were compared among AIVDU and non AIVDU. Results: We found no statistical significant difference between AIVDU and non-AIVDU concerning HCV management: realization of a PCR (85% versus 67%), realization of a liver biopsy when indicated (81.6% versus 86.6%), starting a treatment for HC when indicated (66.2% versus 74.9%), rate of loss to follow up during therapy (14.4% vs 9.7.%). The sustained viral response rate (SVR) was not significantly different between AIVDU (29.4%) and non-AIVDU (28.9%). Using multivariate analysis, factors independently associated with a SVR were female sex, genotype 3, weak virus load, low fibrosis score, high transaminases level, bitherapy treatment. Conclusion: This study emphasize the lack of influence of intravenous drug use on the patient’s compliance to management as well as on the viral response to the treatment.
AND THE
OF LIVER DISEASE
Y. Consienv’,
A. Plessier’, A. Gervais’, D. Cazals-Hatem2, C. Degott2, R. Moreau’, D. Valla’, D. Lebrec’. ‘ZNSERM U-481 AndService D’Hepatologie, Hopital Beaujon, Clichy, France; 2Service D’Anatomie Et Cytologic Pathologiques, Hopital Beaujon, Clichy, France
The HVPG has been shown to reflect portal pressure and to be a good prognostic factor in cirrhosis from hepatitis C virus. However, factors affecting HVPG values have not been clearly elucidated in hepatitis C, although it is probable that histological, hemodynamic and biological factors probably play a role. The aim of this prospective study was to evaluate the histological, systemic hemodynamic, clinical and biological factors that affect the HVPG in patients with hepatitis C. 297 patients (63% men; mean age 50) who underwent transjugular liver biopsy for chronic hepatitis C were evaluated. Fibrosis and activity of hepatitis were assessed by the Metavir score. Multivariate linear regression analysis was performed to select variables that were significantly associated with the HVPG, first in all patients, and then in the 142 cirrhotic patients. Fibrosis, disease activity, ascites, bilirubin levels, prothrombin time, alanine aminotransferase activity and arterial pressure were significantly correlated with the HVPG in univariate analysis but not cardiac output. Mul-
I
461
SHORTTREATMENT INTERFERON TREATMENT
(14 WEEKS)
ALPHA-2B
WITH PEGYLATED
AND RIBAVIRIN
OF HEPATITIS
C GENOTYPE
FOR THE 2/3 INFECTION
0. Dalgard’,
K. Skaug2, S. Ritland3, B. Myrvang4, K. Hellurn’, K. Bjoro6, H. Bell’. ‘Medical Department, Aker University Hospital, Oslo, Norway; 2National Institute Of Public Health, Oslo, Norway; ‘Medical Department, Buskerud Hospital, Oslo, Norway; 4Medical Department, Ullevaal University Hospital, Oslo, Norway; ‘Medical Department, Akershus University Hospital, Oslo, Norway; 6Medical Department, National Hospital, Oslo, Norway Aim: To determine the virological response rate after 14 weeks of combination treatment in patients with hepatitis C virus (HCV) genotype 213 who experience early HCV clearance. Methods: In a multicenter trial 82 HCV RNA positive patients with genotype 2 or 3 have been included. All patients are treated with pegylated interferon alfa-2b 1, 5 kg/kg once weekly and ribavirin (800-1200 mg) daily. Treatment is stopped at week 14 in patients who are HCV RNA negative (Cobas Amplicor HCV monitor test, lower detection limit 100 copies/ml) at week 4 and 8. The remaining patients continue treatment until week 24.
Poster Sessions
Conclusion: At week 48 of therapythe induction dose is more effective than the fixed dose in non-responders. The benefit of the induction regimen is more apparent in patients with prior IFN monotherapy and in those with genotype non-l infection.
I
458
IDENTIFICATION PREDICTIVE
OF HBV-DNA
OF RESPONSE
PATIENTS INFECTED
MARKERS
THAT ARE
TO LAMIVUDINE
WITH HBV PRECORE
THERAPY
IN
VARIANTS
A. Ciancio’,2, A. Smedile’, M. Rizzetto’, M. Lagget’, M. Abate’, .I. Gerin2, B.E. Korba2. ‘Dipartimento Di Gastroenterologia, Azienda Ospedaliera, SGiovanni Bat&a di Torino, Italy; 2Division Of Molecular Virology And Immunology, Georgetown University Medical Centec Rockville, MD, USA Lamivudine is initially highly effective in patients with hepatitis B e antigen-negative (HBeAg) chronic hepatitis B, but its long-term efficacy is burdened by high rates of virologic relapse. We analyzed the DNA sequence of HBV polymerase (domains A to E), and the HBV precore/core regions in 26 HBeAg-negative patients (genotype D, 16 with G1896A, 16 with A1762T/G1764A, 11 with both) treated for 21-48 months with lamivudine to determine if there was a relationship between specific HBV-DNA sequence patterns and long-term treatment response. After a minimum of 21 months of therapy, seven patients (27%) were responders (normal ALT, HBV-DNA-), 12 (46%) breakthroughs (following initial virologic response), and 7 (27%) non-responders (sustained elevated ALT, HBV-DNA+). Two HBV-DNA polymerase polymorphisms, present in the pretreatment serum samples, were correlated with extended treatment failures (breakthrough or non-response). Leucine was present at rt9 1 in 17 of 19 patients with long-term treatment failure, and a cysteine was present at rt2.56 in 13 of these 19 patients. All 7 long-term responders had an isoleucine at rt91 and a serine at rt2.56. Under therapy, reversion of A1762TIG1764A was observed in 4 of 13 patients (31%), and of G1896A in 3 of 12 (25%). YMDD Mutations (confirmed by INNOLiPAa) analysis) were found in 7/12 of the relapsing patients at the time of breakthrough. Our data suggest that specific HBV-DNA sequences present before treatment may predict long-term response to lamivudine, permitting therapy to be targeted to those individuals who are most likely to have sustained clinical benefit.
I
459
THE HEPATIC VENOUS
PRESSURE
PATIENTS WITH CHRONIC ASSOCIATED SEVERITY
GRADIENT
HEPATITIS
WITH THE EXTENT
tivariate analysis showed that the HVPG was independently associated with fibrosis, ascites and bilirubin levels (respective coefficients, 3.4, 2.4 and 1.4; intercept, -3.8). When this analysis was restricted to the cirrhosis group, only the degree of ascites and bilirubin levels (respective coefficients, 2.3, 1.2; intercept, 10.8) were independently significant in multiple linear regression. In conclusion, the HVPG mainly depends on the extent of liver fibrosis and the severity of liver disease in patients with hepatitis C.
(HVPG) IN
C IS ONLY
OF FIBROSIS
I
460
LACK OF INFLUENCE
OF ACTIVE INTRAVENOUS
ON THE MANAGEMENT CHRONIC
DRUG USE
QUALITY OF PATIENTS WITH
HEPATITIS C
M. Cournot2, F. Castel’, F. Druart’, T. Morin’, V. Lauwers-Cances2, K. Imani ‘, A. Glibert I. ‘DepartmentOf Hepatogastroenterology, Tarbes Hospital, Tarbes, France; 2Department Of Epidemiology, INSERM lJ558, Toulouse, France Background: Recent guidelines regarding chronic Hepatitis C virus (HCV) infection support that the anti HCV therapy of active intravenous drug users (AIVDU) should be the same as in the other patients. The aim of this study was to compare methods used to manage hepatitis C and clinical outcome after treatment between AIVDU and non-AIVDU when AIVDU patients are offered cares concerning both the addictions and the HCV Infection. Methods: Four hundred and thirty five naive HCV seropositive patients were followed up during a mean period of 2.5 years (SD 1 year), 116 of them were AIVDU at the beginning of the study. Social, clinical, biological and histological data were collected. HCV management and responses to eventual treatments were compared among AIVDU and non AIVDU. Results: We found no statistical significant difference between AIVDU and non-AIVDU concerning HCV management: realization of a PCR (85% versus 67%), realization of a liver biopsy when indicated (81.6% versus 86.6%), starting a treatment for HC when indicated (66.2% versus 74.9%), rate of loss to follow up during therapy (14.4% vs 9.7.%). The sustained viral response rate (SVR) was not significantly different between AIVDU (29.4%) and non-AIVDU (28.9%). Using multivariate analysis, factors independently associated with a SVR were female sex, genotype 3, weak virus load, low fibrosis score, high transaminases level, bitherapy treatment. Conclusion: This study emphasize the lack of influence of intravenous drug use on the patient’s compliance to management as well as on the viral response to the treatment.
AND THE
OF LIVER DISEASE
Y. Consienv’,
A. Plessier’, A. Gervais’, D. Cazals-Hatem2, C. Degott2, R. Moreau’, D. Valla’, D. Lebrec’. ‘ZNSERM U-481 AndService D’Hepatologie, Hopital Beaujon, Clichy, France; 2Service D’Anatomie Et Cytologic Pathologiques, Hopital Beaujon, Clichy, France
The HVPG has been shown to reflect portal pressure and to be a good prognostic factor in cirrhosis from hepatitis C virus. However, factors affecting HVPG values have not been clearly elucidated in hepatitis C, although it is probable that histological, hemodynamic and biological factors probably play a role. The aim of this prospective study was to evaluate the histological, systemic hemodynamic, clinical and biological factors that affect the HVPG in patients with hepatitis C. 297 patients (63% men; mean age 50) who underwent transjugular liver biopsy for chronic hepatitis C were evaluated. Fibrosis and activity of hepatitis were assessed by the Metavir score. Multivariate linear regression analysis was performed to select variables that were significantly associated with the HVPG, first in all patients, and then in the 142 cirrhotic patients. Fibrosis, disease activity, ascites, bilirubin levels, prothrombin time, alanine aminotransferase activity and arterial pressure were significantly correlated with the HVPG in univariate analysis but not cardiac output. Mul-
I
461
SHORTTREATMENT INTERFERON TREATMENT
(14 WEEKS)
ALPHA-2B
WITH PEGYLATED
AND RIBAVIRIN
OF HEPATITIS
C GENOTYPE
FOR THE 2/3 INFECTION
0. Dalgard’,
K. Skaug2, S. Ritland3, B. Myrvang4, K. Hellurn’, K. Bjoro6, H. Bell’. ‘Medical Department, Aker University Hospital, Oslo, Norway; 2National Institute Of Public Health, Oslo, Norway; ‘Medical Department, Buskerud Hospital, Oslo, Norway; 4Medical Department, Ullevaal University Hospital, Oslo, Norway; ‘Medical Department, Akershus University Hospital, Oslo, Norway; 6Medical Department, National Hospital, Oslo, Norway Aim: To determine the virological response rate after 14 weeks of combination treatment in patients with hepatitis C virus (HCV) genotype 213 who experience early HCV clearance. Methods: In a multicenter trial 82 HCV RNA positive patients with genotype 2 or 3 have been included. All patients are treated with pegylated interferon alfa-2b 1, 5 kg/kg once weekly and ribavirin (800-1200 mg) daily. Treatment is stopped at week 14 in patients who are HCV RNA negative (Cobas Amplicor HCV monitor test, lower detection limit 100 copies/ml) at week 4 and 8. The remaining patients continue treatment until week 24.