- Email: [email protected]
IIA, double-blind, randomized, placebo-controlled trial of a novel antiviral agent, LB80380 in Chinese patients with chronic hepatitis B infection
Category 5c assess the efficacy and safety of adefovir-dipivoxil (Gilead Sciences, Foster City, CA), 46 patients with lamivudine resistance (43 men, 53 years, 42 HBeAg negative, 37 cirrhotics, 89% with HBV DNA >6 log10 copies/ml by HBV Roche Amplicor Monitor) were also given adefovir-dipivoxil 10 mg/daily for 5 to 30 months (median 7). Results: At month 5, HBV-DNA levels decreased from a median of 7.6 (range 3.8-9.3) to 3.7 log10 copies/ml. HBV-DNA was <2.3 log10 copies/ml in 21 (46%) patients, between 2.3 and 5.3 in 12 (26%) and >5.3 log in 13 (28%). 29 (63%) patients had normal ALT. Patients with undetectable serum HBV-DNA at month 5 had pre-treatment lower HBV-DNA and higher levels of ALT than those with detectable HBV-DNA (6.7 vs 8.2 logs, p=0.011; 174 vs 74 U/l, p=0.045). None of the patients showed a >1 log rebound of serum HBV-DNA. In two patients who had >4 log HBV-DNA despite 12 months of therapy, the adefovir-resistance associated rtN236T and rtA181V mutations were not identified. Child-Pugh score improved by at least 2 points in 9 of 13 Child-Pugh B/C patients. None of the patients had significant changes of renal function. Conclusions: Adefovir dipivoxil resulted in a significant reduction of serum HBV DNA in 72% of patients with lamivudine resistant HBV after 5 months of therapy. High ALT and low HBV-DNA predicted a faster response to treatment.
449 CHANGES OF VIRAL QUASI-SPECIES IN CHRONIC
133
doses with 30mg, 60mg, 120mg and 240mg daily for 4 weeks. Patients were monitored till week 16. The median age and male:female ratio were 27.5 years and 20:8 respectively. The median follow-up was 8.9 weeks. HBV DNA reductions are depicted in the figure. HBV DNA reduction was greater with 60mg dose and above. HBV DNA returned to the pretreatment levels at a slower rate with higher doses. No serious adverse events were observed.
In conclusion, four-week treatment of LB80380 was safe and associated with a reduction of HBV DNA levels greater than those observed with lamivudine and adefovir.
HEPATITIS D: IMMUNE EPITOPES AND FUNCTIONAL DOMAINS ASSOCIATED WITH SELECTION
J.C. Wu 1 , S.Y. Wang 1 , Y.H. Huang 1 , I.J. Sheen 1 , T.Y. Chiang 2 . 1 Division of Gastroenterology and Institute of Clinical Medicine, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan; 2 Department of Biology, Cheng-Kung University, Tainan, Taiwan The mechanism for the selection of hepatitis D virus (HDV) quasi-species is obscure. To study immunogenic or functional domains of hepatitis delta antigen associated with selection, serum HDV genomes were analyzed at different time points from seven patients. Three showed selections in the helper T-cell epitope from aa 26 to 41, three showed selections within the epitope from aa 66 to 81, and five showed selections within the epitope from aa 106 to 121. Of potential cytotoxic T cell epitopes associated with selection, the epitope from aa 26-34 overlaps with cryptic RNA binding domain (CRBD) and coil-coil structure (CCS) and a CD4+ T cell epitope, the epitope from aa 43 - 51 overlaps with CCS and a CD4+ T cell epitope, and the epitope from aa 114-122 overlaps with helix-loop-helix (HLH) and a CD4+ T cell epitope. Four to six patients showed selections within these three epitopes. The peptide from aa 8 to 16 overlapping with CRBD was associated with aa selection in 7 patients, and the peptide from aa 173 to 182 overlapping with B cell epitopes was associated with selection in 5. Two dominant variants cloned before and after acute exacerbations were transfected into the Huh7 human hepatoma cell line. The replication of the novel dominant variant was lower than that of the original one. In summary, the emergence of novel dominant variant is not due to growth advantage, but more likely resulted from the selection by multi-specific CD8+ T cell and CD4+ T cell responses.
450 INTERIM REPORT ON A PHASE I/IIA, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF A NOVEL ANTIVIRAL AGENT, LB80380 IN CHINESE PATIENTS WITH CHRONIC HEPATITIS B INFECTION
M.F. Yuen 1 , J. Kim 2 , D.K.H. Wong 1 , V.W.S. Ngai 1 , J.C.H. Yuen 1 , C.L. Lai 1 . 1 Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong; 2 Clinical Development, LG Life Sciences, Seoul, Korea To investigate the safety and antiviral activity of LB80380, a novel guanosine analogue, in HBeAg-positive HBV patients, 28 patients in 4 cohorts (7 per group with 6:1 ratio of LB80380: placebo) were given escalating
451 COMPARISON OF LIVER FUNCTIONAL PARAMETERS WITH SERUM FIBROSIS MARKERS AS PREDICTORS OF SEVERE NECRO-INFLAMMATION IN PATIENTS WITH CHRONIC HEPATITIS B AND D
C. Yurdaydin 1,4 , M. Toruner 1 , H. Bozkaya 1,4 , A. Okcu-Heper 2 , M. Voelker 3 , E. Erden 2 , M.A. Bozdayi 4 , O. Uzunalimoglu 4 , D. Schuppan 5 . 1 Gastroenterology Department, University of Ankara Medical School, Ankara, Turkey; 2 Pathology Department, University of Ankara Medical School, Ankara, Turkey; 3 Bayer Research, Wuppertal, Germany; 4 Hepatology Institute, University of Ankara, Ankara, Turkey; 5 Department of Gastroenterology and Hepatology, University of Erlangen, Erlangen, Germany Predictive value of serum markers in 112 adult patients(evaluated for treatment protocols) with chronic hepatitis B(CHB) and D (CHD) was assessed. 40 patients had HBeAg(+) and 39 HBeAg(-)CHB and 33 had CHD. Platelet count, ALT,AST,ALP,GGT, bilirubin, albumin, prothrombin time, and 8 serum fibrosis markers (TIMP-1, tenascin, collagen IV and VI, procollagen III aminoterminal propeptide(PIIINP), MMP-2, laminin, hyaluronan) were determined. Fibrosis markers were quantified using monoclonal antibodies in sandwich immunoassays performed in an automated analyser (Bayer Immuno1 TM immunoassay system). Histology was assessed according to METAVIR (significant inflammation ≥ stage A2. Predictive power was calculated by receiver operating statistics(ROC-curves), followed by univariate and multistep logistic regression analysis. Patients with severe necro-inflammation were older, had lower platelets and higher TIMP-1, PIIINP, laminin, hyaluronan and collagen IV levels. Routine parameters were less useful to predict severe inflammation (age, GGT, platelets, prothrombin time and albumin with area under curves (AUC) of 0.653, 0.676, 0.661, 0.644 and 0.635, respectively), compared to fibrosis markers (TIMP-1, hyaluronan, collagen IV, laminin, PIIINP and MMP-2 with AUC’s of 0.747, 0.733, 0.699, 0.673, 0.657 and 0.601, respectively). Using multistep logistic regression analysis, TIMP-1 and hyluronan arose as two independent fibrosis markers for prediction of marked inflammation (Odd’s ratios of 7.86 and 4.25, respectively). Sensitivities and specificities to diagnose marked necro-inflammation at cut-off values of 623ng/ml and 49ng/ml were 82 and 62% and 60 and 72% for TIMP-1 and hyaluranon, respectively. In conclusion, significant liver inflammation in CHB and CHD may correctly be predicted by combined TIMP-1 and hyaluronan measurements.
449 CHANGES OF VIRAL QUASI-SPECIES IN CHRONIC
133
doses with 30mg, 60mg, 120mg and 240mg daily for 4 weeks. Patients were monitored till week 16. The median age and male:female ratio were 27.5 years and 20:8 respectively. The median follow-up was 8.9 weeks. HBV DNA reductions are depicted in the figure. HBV DNA reduction was greater with 60mg dose and above. HBV DNA returned to the pretreatment levels at a slower rate with higher doses. No serious adverse events were observed.
In conclusion, four-week treatment of LB80380 was safe and associated with a reduction of HBV DNA levels greater than those observed with lamivudine and adefovir.
HEPATITIS D: IMMUNE EPITOPES AND FUNCTIONAL DOMAINS ASSOCIATED WITH SELECTION
J.C. Wu 1 , S.Y. Wang 1 , Y.H. Huang 1 , I.J. Sheen 1 , T.Y. Chiang 2 . 1 Division of Gastroenterology and Institute of Clinical Medicine, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan; 2 Department of Biology, Cheng-Kung University, Tainan, Taiwan The mechanism for the selection of hepatitis D virus (HDV) quasi-species is obscure. To study immunogenic or functional domains of hepatitis delta antigen associated with selection, serum HDV genomes were analyzed at different time points from seven patients. Three showed selections in the helper T-cell epitope from aa 26 to 41, three showed selections within the epitope from aa 66 to 81, and five showed selections within the epitope from aa 106 to 121. Of potential cytotoxic T cell epitopes associated with selection, the epitope from aa 26-34 overlaps with cryptic RNA binding domain (CRBD) and coil-coil structure (CCS) and a CD4+ T cell epitope, the epitope from aa 43 - 51 overlaps with CCS and a CD4+ T cell epitope, and the epitope from aa 114-122 overlaps with helix-loop-helix (HLH) and a CD4+ T cell epitope. Four to six patients showed selections within these three epitopes. The peptide from aa 8 to 16 overlapping with CRBD was associated with aa selection in 7 patients, and the peptide from aa 173 to 182 overlapping with B cell epitopes was associated with selection in 5. Two dominant variants cloned before and after acute exacerbations were transfected into the Huh7 human hepatoma cell line. The replication of the novel dominant variant was lower than that of the original one. In summary, the emergence of novel dominant variant is not due to growth advantage, but more likely resulted from the selection by multi-specific CD8+ T cell and CD4+ T cell responses.
450 INTERIM REPORT ON A PHASE I/IIA, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED TRIAL OF A NOVEL ANTIVIRAL AGENT, LB80380 IN CHINESE PATIENTS WITH CHRONIC HEPATITIS B INFECTION
M.F. Yuen 1 , J. Kim 2 , D.K.H. Wong 1 , V.W.S. Ngai 1 , J.C.H. Yuen 1 , C.L. Lai 1 . 1 Department of Medicine, The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong; 2 Clinical Development, LG Life Sciences, Seoul, Korea To investigate the safety and antiviral activity of LB80380, a novel guanosine analogue, in HBeAg-positive HBV patients, 28 patients in 4 cohorts (7 per group with 6:1 ratio of LB80380: placebo) were given escalating
451 COMPARISON OF LIVER FUNCTIONAL PARAMETERS WITH SERUM FIBROSIS MARKERS AS PREDICTORS OF SEVERE NECRO-INFLAMMATION IN PATIENTS WITH CHRONIC HEPATITIS B AND D
C. Yurdaydin 1,4 , M. Toruner 1 , H. Bozkaya 1,4 , A. Okcu-Heper 2 , M. Voelker 3 , E. Erden 2 , M.A. Bozdayi 4 , O. Uzunalimoglu 4 , D. Schuppan 5 . 1 Gastroenterology Department, University of Ankara Medical School, Ankara, Turkey; 2 Pathology Department, University of Ankara Medical School, Ankara, Turkey; 3 Bayer Research, Wuppertal, Germany; 4 Hepatology Institute, University of Ankara, Ankara, Turkey; 5 Department of Gastroenterology and Hepatology, University of Erlangen, Erlangen, Germany Predictive value of serum markers in 112 adult patients(evaluated for treatment protocols) with chronic hepatitis B(CHB) and D (CHD) was assessed. 40 patients had HBeAg(+) and 39 HBeAg(-)CHB and 33 had CHD. Platelet count, ALT,AST,ALP,GGT, bilirubin, albumin, prothrombin time, and 8 serum fibrosis markers (TIMP-1, tenascin, collagen IV and VI, procollagen III aminoterminal propeptide(PIIINP), MMP-2, laminin, hyaluronan) were determined. Fibrosis markers were quantified using monoclonal antibodies in sandwich immunoassays performed in an automated analyser (Bayer Immuno1 TM immunoassay system). Histology was assessed according to METAVIR (significant inflammation ≥ stage A2. Predictive power was calculated by receiver operating statistics(ROC-curves), followed by univariate and multistep logistic regression analysis. Patients with severe necro-inflammation were older, had lower platelets and higher TIMP-1, PIIINP, laminin, hyaluronan and collagen IV levels. Routine parameters were less useful to predict severe inflammation (age, GGT, platelets, prothrombin time and albumin with area under curves (AUC) of 0.653, 0.676, 0.661, 0.644 and 0.635, respectively), compared to fibrosis markers (TIMP-1, hyaluronan, collagen IV, laminin, PIIINP and MMP-2 with AUC’s of 0.747, 0.733, 0.699, 0.673, 0.657 and 0.601, respectively). Using multistep logistic regression analysis, TIMP-1 and hyluronan arose as two independent fibrosis markers for prediction of marked inflammation (Odd’s ratios of 7.86 and 4.25, respectively). Sensitivities and specificities to diagnose marked necro-inflammation at cut-off values of 623ng/ml and 49ng/ml were 82 and 62% and 60 and 72% for TIMP-1 and hyaluranon, respectively. In conclusion, significant liver inflammation in CHB and CHD may correctly be predicted by combined TIMP-1 and hyaluronan measurements.