Soon-Ho Um

Twenty‐four‐week clevudine therapy showed potent and sustained antiviral activity in HBeAg‐positive chronic hepatitis B

Clevudine is a pyrimidine analogue with potent and sustained antiviral activity against HBV. The present study evaluated the safety and efficacy of 30 mg clevudine once daily for 24 weeks and assessed the durable antiviral response for 24 weeks after cessation of dosing. A total of 243 hepatitis B e antigen (HBeAg)‐positive chronic hepatitis B patients were randomized (3:1) to receive clevudine 30 mg once daily (n = 182) or placebo (n = 61) for 24 weeks. Patients were followed for a further 24 weeks off therapy. Median serum HBV DNA reductions from baseline at week 24 were 5.10 and 0.27 log10 copies/mL in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained off therapy, with 3.73 log10 reduction at week 34 and 2.02 log10 reduction at week 48. At week 24, 59.0% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (less than 300 copies/mL). The proportion of patients who achieved normalization of alanine aminotransferase (ALT) levels was 68.2% in the clevudine group and 17.5% in the placebo group at week 24 (P < 0.0001). ALT normalization in the clevudine group was well maintained during post‐treatment follow‐up period. The incidence of adverse events (AEs) was similar between the clevudine group and the placebo group. No resistance to clevudine was detected with 24 weeks of administration of drug. Conclusion: A 24‐week clevudine therapy was well tolerated and showed potent and sustained antiviral effect without evidence of viral resistance during treatment period in HBeAg‐positive chronic hepatitis B. (HEPATOLOGY 2007;45:1172–1178.)

Clevudine is highly efficacious in hepatitis B e antigen‐negative chronic hepatitis B with durable off‐therapy viral suppression

Clevudine is a pyrimidine analog with potent and sustained antiviral activity against HBV. In the present study, we evaluated the safety and efficacy of clevudine 30 mg daily for 24 weeks and assessed the durability of antiviral response for 24 weeks after cessation of dosing in hepatitis B e antigen (HBeAg)‐negative chronic hepatitis B (e‐CHB). We randomized a total of 86 patients (3:1) to receive clevudine 30 mg (n = 63) or placebo (n = 23) daily for 24 weeks. We followed patients for an additional 24 weeks after withdrawal of treatment. The median changes in HBV DNA from baseline were −4.25 and −0.48 log10 copies/mL at week 24 in the clevudine and placebo groups, respectively (P < 0.0001). Viral suppression in the clevudine group was sustained after withdrawal of therapy, with 3.11 log10 reduction at week 48. At week 24 and week 48, 92.1% and 16.4% of patients in the clevudine group had undetectable serum HBV DNA levels by Amplicor PCR assay (<300 copies/mL). The proportion of patients who achieved ALT normalization was 74.6% and 33.3% in the clevudine and placebo groups at week 24, respectively (P = 0.0006). ALT normalization in the clevudine group was well‐maintained during the post‐treatment follow‐up period. The incidence of adverse events was similar in the 2 groups. No resistance to clevudine was detected during treatment. Conclusion: A 24‐week clevudine therapy was well‐tolerated and showed potent and sustained antiviral effect without evidence of viral resistance in e‐CHB patients. However, treatment for longer than 24 weeks would be needed to achieve durable remission. (HEPATOLOGY 2007.)

Factors that affect the diagnostic accuracy of liver fibrosis measurement by Fibroscan in patients with chronic hepatitis B

Aliment Pharmacol Ther 2010; 32: 498–505

Pharmacokinetics of oltipraz and its major metabolite (RM) in patients with liver fibrosis or cirrhosis: Relationship with suppression of circulating TGF-Β1

Oltipraz is a potential candidate drug for the treatment of liver fibrosis (LF) and liver cirrhosis (LC). The pharmacokinetics of oltipraz and its major rearranged metabolite (7‐methyl‐6,8‐bis(methylthio)H‐pyrrolo[1,2‐a]pyrazine (RM)) were evaluated after single‐dose (30−90 mg) and multiple‐dose (60 mg b.i.d. or 90 mg q.d. for 24 weeks) oral administration of oltipraz to patients with LF or LC. Oltipraz was safe and well tolerated in both studies. In the single‐dose study, the area under the plasma concentration–time curve (AUC), peak plasma concentration (Cmax), and terminal half‐life (t1/2) of oltipraz as well as the AUC of its RM were dose dependent. Oltipraz was rapidly absorbed; the time to reach Cmax (Tmax) was 2–4 h. The conversion of oltipraz to RM was also rapid and substantial (AUC of RM from time 0 to the last measured concentration (AUClast, RM)/AUClast, oltipraz, 42−61%). In the multiple‐dose study, the level of transforming growth factor‐β1 (TGF‐β1) (a blood fibrosis marker) was suppressed at steady‐state plasma concentrations of _20−60 ng/ml of oltipraz or of _60−140 ng/ml of oltipraz plus RM. Overall, the pharmacokinetics, safety, and efficacy of oltipraz suggest that it may be helpful in the treatment of patients with LF or LC, at an optimal dosing regimen.

1353 A PHASE IIB STUDY OF THE EFFICACY AND SAFETY OF LB80380 VS ENTECAVIR IN TREATMENT-NAIVE PATIENTS WITH CHRONIC HEPATITIS B

1353 A PHASE IIB STUDY OF THE EFFICACY AND SAFETY OF LB80380 VS ENTECAVIR IN TREATMENT-NAIVE PATIENTS WITH CHRONIC HEPATITIS B C.L. Lai, S.H. Ahn, K.S. Lee, S.H. Um, M. Cho, S.K. Yoon, J.W. Lee, N.W. Park, Y.O. Kwon, J.H. Sohn, J.Y. Lee, H.E. Park, J.A. Kim, K.H. Han, M.F. Yuen. The University of Hong Kong, Queen Mary Hospital, Hong Kong, Hong Kong S.A.R., China; College of Medicine, Yonsei University, College of Medicine, Korea University, Seoul, College of Medicine, Pusan National University, Pusan, College of Medicine, The Catholic University of Korea, Seoul, College of Medicine, Inha University, Incheon, College of Medicine, University of Ulsan, Ulsan, College of Medicine, Kyungpook National University, Daegu, College of Medicine, Hanyang University, LG Life Sciences Ltd, Seoul, Republic of Korea E-mail: hrmelcl@hkucc.hku.hk

Efficacy and safety of entecavir versus lamivudine over 5 years of treatment: A randomized controlled trial in Korean patients with hepatitis B e antigen-negative chronic hepatitis B.

Background/Aims Long-term data on antiviral therapy in Korean patients with hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) are limited. This study evaluated the efficacy and safety of entecavir (ETV) and lamivudine (LAM) over 240 weeks. Methods Treatment-naive patients with HBeAg-negative CHB were randomized to receive ETV 0.5 mg/day or LAM 100 mg/day during the 96 week double-blind phase, followed by open-label treatment through week 240. The primary endpoint was the proportion of patients with virologic response (VR; hepatitis B virus [HBV] DNA<300 copies/mL) at week 24. Secondary objectives included alanine aminotransferase (ALT) normalization and emergence of ETV resistance (week 96), VR and log reduction in HBV DNA levels (week 240), and safety evaluation. Results In total, 120 patients (>16 years old) were included (ETV, n=56; LAM, n=64). Baseline characteristics were comparable between the two groups. A significantly higher proportion of ETV-treated patients achieved VR compared to LAM at week 24 (92.9% vs. 67.2%, P=0.0006), week 96 (94.6% vs. 48.4%, P<0.0001), and week 240 (95.0% vs. 47.6%, P<0.0001). At week 96, ALT normalization was observed in 87.5% and 51.6% of ETV and LAM patients, respectively (P<0.0001). Virologic breakthrough occurred in one patient (1.8%) receiving ETV and 26 patients (42.6%) receiving LAM (P<0.0001) up to week 96. Emergence of resistance to ETV was not detected. The incidence of serious adverse events was low and unrelated to the study medications. Conclusions Long-term ETV treatment was superior to LAM, with a significantly higher proportion of patients achieving VR. Both treatments were well tolerated.

145 CLINICAL FEATURES OF AUTOIMMUNE HEPATITIS IN KOREAN PATIENTS; A NATIONWIDE, MULTICENTER STUDY

144 ASPARTATE AMINOTRANSFERASE TO PLATELET RATIO INDEX (APRI) IS ASSOCIATED WITH IN-HOSPITAL LIVER DISEASE SEVERITY AND MORTALITY C.R. Jayasekera, M. Lee, E.S. Echevarria, M.M. Kagimu, E. Seremba, C.K. Opio, P. Ocama, A. Ahmed. Internal Medicine, Gastroenterology and Hepatology, Stanford University Medical Center, Stanford, CA, Boston University School of Medicine, Boston, MA, USA; Gastroenterology, Makerere University School of Medicine, Kampala, Uganda E-mail: crj@stanford.edu

7191 Electron microscopic study of association between helicobacter pylori and gsatric epithelial cells.

Backgrounds: To study pathophysiologic roles of Helicobacter pylori, we investigate the ultrastructural relation of Helicobacter pylori to the gastric epithelial cells. Subjects and Methods: Endoscopic biopsy of gastric antrum and body were performed from thirty-one patients(18men and 13women) with chronic gastritis. These specimens were processed and observed by transmission and scanning electron microscope(Hitachi H-600, Hitachi S- 450). Results: 1) Helicobacter pylori were spiral, coccoid, and intermediate or un-defined forms. 2)Most of the Helicobacter pylori were present in the mucus gel layer, on the surface of gastric epithelium and were common at the area around the junctional complexes. 3)Coccoid forms were most common in the mucosal layer. 4)The gastric epithelial cells show increased cytoplasmic electron density, few microvilli, disruption of apical membrane, presence of cell fragments in intercellular space and mucosal layer. Junctional complexes were frequently observed deep in the intercellular space between the cytoplasmic elevation filled with secretory granules. Complete destruction of junctional complex was not common. Conclusions: Helicobacter pylori had variable relations to the gastric epithelial cells in human stomach. These features may contribute to the pathogenic action of the organism.

4728 Classification of gastric stromal tumor according to immunohistochemical phenotype.

Backgrounds: Gastrointestinal stromal tumor(GIST) is a mesenchymal tumor which originates from the GI tracts. Although recent immunohistochemical study has helped classifying mesenchymal tumor and forming diagnostic criteria for benign and malignant tumors according to cells origin and differentiation, it is yet to be settled. This study has classified gastric stromal tumor by using immunohistochemical staining. Materials and Methods: Immunohistochemical staining was performed on the gastric stromal tumor specimens attained by endoscopic resection and surgery. Smooth muscle actin, Desmin, Neuron-specific enolase, S-100, CD 34 and Vimentin has been used as immunohistochemical antibodies and the guideline for Ackermans surgical pathology has been used as criteria for diagnosing malignancy(Ackermans surgical pathology 8th ed, 1996). Smooth muscle type was classified as benign, borderline and malignant according to the size and number of mitosis. Neural type was classified as malignant, and combined smooth muscle-neural type and uncommitted type were classified as either potentially malignant or malignant. Results: Subjects consisted of 12 males and 26 females with average age being 53 ± 12.8 years old. 22 cases has been endoscopically resected, 16 surgically removed, with the mean length of tumor being 25.3 ± 18.1 mm. The results of immunohistochemical staining showed 12 cases(31.6%) of smooth muscle type, 7 cases(18.4%) of neural type, 1 case(2.6%) of combined smooth muscle-neural type and 18 cases(47.4%) of uncommitted type. On the basis of above immunohistochemical results and histologic findings, 12 cases(31.6%) were regarded as benign, 17 cases(44.7%) as potentially malignant or malignant, and 9 cases(23.7%) as malignant(Table). Conclusion: When classified by immunohistochemical staining, 68.4% of gastric stromal tumor proved to be potentially malignant or malignant.

⁎4727 Reassessment of usefulness of eus in differentiation of benign and malignant gastric stromal tumors which were diagnosed according to pathologic guidelines of ackerman's surgical pathology.

Backgrounds: GISTs originate from mesenchymal tissue within the GI tract, and it is difficult to differentiate between benign and malignancy by endoscopy. Although recent development of EUS allows a trial of differentiation from benign and malignant stromal tumors, its diagnostic accuracy is controversial. The aim of this study is to determine whether EUS can differentiate between benign and malignant gastric stromal tumors. Materials and Methods: EUS was performed prior to endoscopic resection or surgical resection of 38 gastric stromal tumors. EUS features such as tumor size(diameter>4 cm), irregular extraluminal border, echogenic foci, and cystic spaces, which were proposed by Chak A et al. as EUS findings of malignant GISTs(Gastrointest Endosc 1997) were evaluated. Pathologic diagnosis was based on guidelines of Ackermans surgical pathology (Ackermans surgical pathology 8th ed, 1996). Results: Subjects consisted of 12 males and 26 females. 22 cases has been endoscopically resected, 16 cases surgically removed. The results of immunohistochemical staining showed 12 cases of smooth muscle type, 7 cases of neural type, 1 case of mixed type and 18 cases of uncommitted type. On the basis of above immunohistochemical results and histologic findings, 12 cases were regarded as benign, 17 cases as potentially malignant or malignant, and 9 cases as malignant. Analyses of EUS features according to the criteria of Chak et al. are shown in the following table. Conclusion: When gastric stromal tumors were diagnosed with criteria from Ackermans surgical pathology, EUS features, which were proposed by Chak et al, were assessed to be less useful in differentiating between benign and malignant stromal tumors.