- Email: [email protected]
Two year results from a double-blind, randomized, placebo-controlled study of adefovir dipivoxil (ADV) for presumed precore mutant chronic hepatitis B
Category 6: Viral hepatitis: clinical aspects
I
490
PREVALENCE
OF HEPATITIS C VIRUS (HCV) INFECTION
NON-HODGKIN’S
LYMPHOMA
(NHL). SYSTEMATIC
IN
REVIEW
I
492
AND META-ANALYSIS
Aim: To conduct a systematic review of studies evaluating HCV prevalence in B-cell NHL (B-NHL), and to perform a meta-analysis of case-control studies comparing this prevalence with a reference group. Methods: All studies evaluating HCV prevalence in patients with BNHL were considered. Studies comparing HCV prevalence in B-NHL (cases) and in a reference group (controls) were included in the metaanalysis. Bibliographical searches were conducted in several electronic databases. Prevalence (weighted mean) of HCV infection was calculated. Meta-analysis was performed combining the Odds Ratios (OR). Results: 49 studies (including 5,629 patients) evaluating HCV were identified, with 14% mean prevalence of infection (95%CI: 13.15%). This figure was higher in countries as Italy (20%) and Japan (16%). Ten studies compared HCV prevalence in B-NHL (17%) and in blood donors or healthy subjects (1.5%) (OR: 10.8; 95%CI: 7.4.16), results being homogeneous. OR increased up to 14 when only Italian and Japanese studies were considered. Fifteen studies compared HCV prevalence in B-NHL (13%) and other haematological malignancies different from B-cell NHL (3%) (OR: 4.2; 95%CI: 2.5.7), also without heterogeneity. OThis figure increased up to 6 when subanalysis included only Italian and Japanese studies. Conclusion: HCV prevalence in patients with B-NHL is approximately 15%, higher than that reported not only in general population (1.5%) but also in patients with other haematological malignancies (3%), suggesting a role of the virus in the aetiology of B-NHL. The striking geographical variation in this association suggests that genetic and/or environmental factors are also involved in the pathogenesis of this disorder.
EPIDEMIOLOGICAL CHRONIC
CARRIERS
RANDOMIZED,
AND CLINICAL
PROFILE
OF HCV
IN THE AREA OF NORTHERN
We set up an observational prospective study to define the epidemiological and clinical profile of subjects with chronic HCV infection and normal ALT profile. We enrolled 90 cases with normal ALT measured 2-3 times in 6 months (M/F ratio 0.8; mean age 56+14,6yrs, BMI 25+4; disease duration 14, 5+9yrs; FU period 4+3yrs). All patients had persistent RNA viral replication. Quantitative HCV-RNA test (b-DNA) and viral genotype (HCV III) were performed at inclusion. We grouped the patients according to their ALT profile: group A (56 cases with normal ALT at each control); group B (34 cases with fluctuating ALT up to 1, 5 the standard values). 53 Patients underwent a needle biopsy for staging (Ishak), 16 of them had a further biopsy during a period of 5, 5+2, 8yrs. Demographical, epidemiological, biochemical, viral and histological parameters showed no difference between groups. Histological findings showed grading: 47% 14, 53% >4; staging: 92% 13, 8% >3; without differences between groups. A multiple regression analysis showed a significant relation between: age and staging (p=O.O02), age and grading (p=O.OOS) but not between staging and disease duration. The 16 cases with multiple biopsies analyzed by ANOVA confirmed a statistically relevant staging progression (p=O.O3) even if very slow (annual rate 0.1) The same analysis proved that no relation exists between staging progression and ALT profile, gender or genotype HCVl, HCV2. The distribution of viral genotype was clearly related with the age of patients: HCV3a and HCV4c/4d age under 45yrs, HCV2a/2c age over 5Oyrs (p=O.OOS). We conclude determining that in normal and quasi-normal ALT patients the fibrosis progression is extremely slow.
STUDY OF
DIPIVOXIL (ADV) FOR PRESUMED
PRECORE
HEPATITIS B
S. Hadzivannis’, N. Tassopoulos2, J. Heathcote3, T.T. Chang4, G. Kitis’, M. Rizetto6, l? Marcellin7, S.G. Lim’, S.-S. Chen9, M. Wulfsohn9, M. Wollman9, J. Fry9, C. Brosgart9. ‘Henry Durant Hospital, Athens, Greece; 2 Western Attica Hospital, Athens, Greece; ‘Toronto Western, Toronto, Canada; 4National Cheng Kung Hospital, Taiwan, Taiwan; ‘Georgios Papanikolaou Hospital, Thessaloniki, Greece; 6Azienda Ospedaliera San Giovanni Bat&a, Torino, Italy; 7Hopital Beaujon, Clichy, Paris, France; ‘National University, Singapore, Singapore; ‘Gilead Sciences, Foster City, CA, USA
Patients were randomized (2:l) to ADV 1Omg or Placebo (PLB). After 48 weeks PLB patients received ADV, and ADV patients were re-randomized (2: 1) to ADV or PLB. Entry criteria: HBsAg+ > 6 months, HBeAg- and Anti-HBe+, HBV DNA > 100,000 copies/ml and ALT 1.5-15 x ULN. Treatment with ADV 1Omg over 48 weeks previously shown to result in significant histological, antiviral and biochemical improvement compared to PLB. Objective: To evaluate safety and efficacy of ADV in 184 patients randomized to treatment for 48 weeks and 80 randomized to treatment for 96 weeks. Results: 184 patients enrolled; 83% male, 66% Caucasian, 30% Asian, median age: 46 years. Median baseline HBV DNA was 6.76 log10 copies/ml, ALT was 83 IU/L. Nine patients (5%) discontinued ADV (3 due to adverse events). Most frequent AEs (>lO%); headache 21%, pharyngitis 20%, abdominal pain 17%, asthenia 12% and flu 12%. Median change in serum creatinine was 0.0 mg/dL and 0.1 mg/dL at weeks 48 and 96 respectively.
ADV 10 mg
HBV DNA
ITALY
A. Gottardo, E. Bemardinello, I. Mezzocolli, S. De Carlo, S. Luise, L. Chemello, A. Gatta, L. Cavalletto. ‘Department OfClinical And Experimental Medicine, Clinica Medica 5, University Of Padua, Padua, Italy
FROM A DOUBLE-BLIND,
PLACEBO-CONTROLLED
MUTANT CHRONIC
J.F! Gisbert, M.L. Garcia-Buey,
I 491
TWO YEAR RESULTS ADEFOVIR
J.M. Pajares, R. Moreno-Otero. ’Gastroenterology And Hepatology Unit, La Princesa University Hospital, Madrid, Spain
143
ALT
Median change in HBV DNA (loglo copies/ml) % undetectable by PCR (< 1000 copies/ml) Median change in ALT (IU/L) % normalized
Week 4X (n = 184)
Week 96 (n =X0)
-3.33 (n = 167) 69% (n = 115066) -4x (n = 166) 76% (n = 1111146)
-3.47 (n =70) 71% (n = 50/70) -60 (n = 166) 73% (n = 47164)
Conclusions: Treatment with ADV 1Omg over 96 weeks resulted in significant and persistent reductions in HBV DNA and ALT levels with increasing HBV DNA undetectability. The safety profile of ADV in the second year of treatment was comparable to the first year.
I
493
LONG TERM FOLLOW-UP
OF GLYCYRRHIZIN
PATIENTS WITH CHRONIC NON-RESPONSE INDIVIDUAL
THERAPY
IN
HEPATITIS C AND
TO INTERFERON:
META-ANALYSIS
OF
PATIENT DATA
B.E. Hansen’, K. Ikeda2, B.J. Veldt’, E. Verheij I, H. Suzuki3, S.W. Schalm’. ‘Department Of Gastroenterology & Hepatology, Erasmus MC, University Medical Centec Rotterdam, Netherlands; 2Department Of Gastroenterology, Toranomon Hospital, Tokyo, Japan; ’Yamanashi Medical University, Yamanashi, Japan Background: Glycyrrhizin (SNMC) is used as a treatment for patients with hepatitis C in all academic units in Japan. However until now the long-term consequences of SNMC therapy have not been well documented. Aims: To determine the percentage of IFN non-responder patients with chronic hepatitis C and subsequent SNMC therapy that progress to HCC in comparison to IFN non-responders without SNMC treatment. Methods: Data were collected from 12 Japanese university and major general hospitals by well-trained professionals. All consecutive chronic
I
490
PREVALENCE
OF HEPATITIS C VIRUS (HCV) INFECTION
NON-HODGKIN’S
LYMPHOMA
(NHL). SYSTEMATIC
IN
REVIEW
I
492
AND META-ANALYSIS
Aim: To conduct a systematic review of studies evaluating HCV prevalence in B-cell NHL (B-NHL), and to perform a meta-analysis of case-control studies comparing this prevalence with a reference group. Methods: All studies evaluating HCV prevalence in patients with BNHL were considered. Studies comparing HCV prevalence in B-NHL (cases) and in a reference group (controls) were included in the metaanalysis. Bibliographical searches were conducted in several electronic databases. Prevalence (weighted mean) of HCV infection was calculated. Meta-analysis was performed combining the Odds Ratios (OR). Results: 49 studies (including 5,629 patients) evaluating HCV were identified, with 14% mean prevalence of infection (95%CI: 13.15%). This figure was higher in countries as Italy (20%) and Japan (16%). Ten studies compared HCV prevalence in B-NHL (17%) and in blood donors or healthy subjects (1.5%) (OR: 10.8; 95%CI: 7.4.16), results being homogeneous. OR increased up to 14 when only Italian and Japanese studies were considered. Fifteen studies compared HCV prevalence in B-NHL (13%) and other haematological malignancies different from B-cell NHL (3%) (OR: 4.2; 95%CI: 2.5.7), also without heterogeneity. OThis figure increased up to 6 when subanalysis included only Italian and Japanese studies. Conclusion: HCV prevalence in patients with B-NHL is approximately 15%, higher than that reported not only in general population (1.5%) but also in patients with other haematological malignancies (3%), suggesting a role of the virus in the aetiology of B-NHL. The striking geographical variation in this association suggests that genetic and/or environmental factors are also involved in the pathogenesis of this disorder.
EPIDEMIOLOGICAL CHRONIC
CARRIERS
RANDOMIZED,
AND CLINICAL
PROFILE
OF HCV
IN THE AREA OF NORTHERN
We set up an observational prospective study to define the epidemiological and clinical profile of subjects with chronic HCV infection and normal ALT profile. We enrolled 90 cases with normal ALT measured 2-3 times in 6 months (M/F ratio 0.8; mean age 56+14,6yrs, BMI 25+4; disease duration 14, 5+9yrs; FU period 4+3yrs). All patients had persistent RNA viral replication. Quantitative HCV-RNA test (b-DNA) and viral genotype (HCV III) were performed at inclusion. We grouped the patients according to their ALT profile: group A (56 cases with normal ALT at each control); group B (34 cases with fluctuating ALT up to 1, 5 the standard values). 53 Patients underwent a needle biopsy for staging (Ishak), 16 of them had a further biopsy during a period of 5, 5+2, 8yrs. Demographical, epidemiological, biochemical, viral and histological parameters showed no difference between groups. Histological findings showed grading: 47% 14, 53% >4; staging: 92% 13, 8% >3; without differences between groups. A multiple regression analysis showed a significant relation between: age and staging (p=O.O02), age and grading (p=O.OOS) but not between staging and disease duration. The 16 cases with multiple biopsies analyzed by ANOVA confirmed a statistically relevant staging progression (p=O.O3) even if very slow (annual rate 0.1) The same analysis proved that no relation exists between staging progression and ALT profile, gender or genotype HCVl, HCV2. The distribution of viral genotype was clearly related with the age of patients: HCV3a and HCV4c/4d age under 45yrs, HCV2a/2c age over 5Oyrs (p=O.OOS). We conclude determining that in normal and quasi-normal ALT patients the fibrosis progression is extremely slow.
STUDY OF
DIPIVOXIL (ADV) FOR PRESUMED
PRECORE
HEPATITIS B
S. Hadzivannis’, N. Tassopoulos2, J. Heathcote3, T.T. Chang4, G. Kitis’, M. Rizetto6, l? Marcellin7, S.G. Lim’, S.-S. Chen9, M. Wulfsohn9, M. Wollman9, J. Fry9, C. Brosgart9. ‘Henry Durant Hospital, Athens, Greece; 2 Western Attica Hospital, Athens, Greece; ‘Toronto Western, Toronto, Canada; 4National Cheng Kung Hospital, Taiwan, Taiwan; ‘Georgios Papanikolaou Hospital, Thessaloniki, Greece; 6Azienda Ospedaliera San Giovanni Bat&a, Torino, Italy; 7Hopital Beaujon, Clichy, Paris, France; ‘National University, Singapore, Singapore; ‘Gilead Sciences, Foster City, CA, USA
Patients were randomized (2:l) to ADV 1Omg or Placebo (PLB). After 48 weeks PLB patients received ADV, and ADV patients were re-randomized (2: 1) to ADV or PLB. Entry criteria: HBsAg+ > 6 months, HBeAg- and Anti-HBe+, HBV DNA > 100,000 copies/ml and ALT 1.5-15 x ULN. Treatment with ADV 1Omg over 48 weeks previously shown to result in significant histological, antiviral and biochemical improvement compared to PLB. Objective: To evaluate safety and efficacy of ADV in 184 patients randomized to treatment for 48 weeks and 80 randomized to treatment for 96 weeks. Results: 184 patients enrolled; 83% male, 66% Caucasian, 30% Asian, median age: 46 years. Median baseline HBV DNA was 6.76 log10 copies/ml, ALT was 83 IU/L. Nine patients (5%) discontinued ADV (3 due to adverse events). Most frequent AEs (>lO%); headache 21%, pharyngitis 20%, abdominal pain 17%, asthenia 12% and flu 12%. Median change in serum creatinine was 0.0 mg/dL and 0.1 mg/dL at weeks 48 and 96 respectively.
ADV 10 mg
HBV DNA
ITALY
A. Gottardo, E. Bemardinello, I. Mezzocolli, S. De Carlo, S. Luise, L. Chemello, A. Gatta, L. Cavalletto. ‘Department OfClinical And Experimental Medicine, Clinica Medica 5, University Of Padua, Padua, Italy
FROM A DOUBLE-BLIND,
PLACEBO-CONTROLLED
MUTANT CHRONIC
J.F! Gisbert, M.L. Garcia-Buey,
I 491
TWO YEAR RESULTS ADEFOVIR
J.M. Pajares, R. Moreno-Otero. ’Gastroenterology And Hepatology Unit, La Princesa University Hospital, Madrid, Spain
143
ALT
Median change in HBV DNA (loglo copies/ml) % undetectable by PCR (< 1000 copies/ml) Median change in ALT (IU/L) % normalized
Week 4X (n = 184)
Week 96 (n =X0)
-3.33 (n = 167) 69% (n = 115066) -4x (n = 166) 76% (n = 1111146)
-3.47 (n =70) 71% (n = 50/70) -60 (n = 166) 73% (n = 47164)
Conclusions: Treatment with ADV 1Omg over 96 weeks resulted in significant and persistent reductions in HBV DNA and ALT levels with increasing HBV DNA undetectability. The safety profile of ADV in the second year of treatment was comparable to the first year.
I
493
LONG TERM FOLLOW-UP
OF GLYCYRRHIZIN
PATIENTS WITH CHRONIC NON-RESPONSE INDIVIDUAL
THERAPY
IN
HEPATITIS C AND
TO INTERFERON:
META-ANALYSIS
OF
PATIENT DATA
B.E. Hansen’, K. Ikeda2, B.J. Veldt’, E. Verheij I, H. Suzuki3, S.W. Schalm’. ‘Department Of Gastroenterology & Hepatology, Erasmus MC, University Medical Centec Rotterdam, Netherlands; 2Department Of Gastroenterology, Toranomon Hospital, Tokyo, Japan; ’Yamanashi Medical University, Yamanashi, Japan Background: Glycyrrhizin (SNMC) is used as a treatment for patients with hepatitis C in all academic units in Japan. However until now the long-term consequences of SNMC therapy have not been well documented. Aims: To determine the percentage of IFN non-responder patients with chronic hepatitis C and subsequent SNMC therapy that progress to HCC in comparison to IFN non-responders without SNMC treatment. Methods: Data were collected from 12 Japanese university and major general hospitals by well-trained professionals. All consecutive chronic