Besifovir Dipivoxil Maleate 144-Week Treatment of Chronic Hepatitis B: An Open-Label Extensional Study of a Phase 3 Trial.

INTRODUCTION: Chronic hepatitis B (CHB) remains a major worldwide public health concern. Besifovir dipivoxil maleate (BSV) is a new promising treatment for CHB. However, long-term efficacy and safety have not yet been evaluated. Therefore, the goal of the study is to determine the antiviral efficacy and safety of BSV treatment over a 144-week duration (BSV-BSV) in comparison with those of a sequential treatment with tenofovir disoproxil fumarate (TDF) followed by a 96-week duration BSV administration (TDF-BSV). METHODS: After 48 weeks of a double-blind comparison between BSV and TDF treatments, patients continued the open-label BSV study. We evaluated antiviral efficacy and drug safety up to 144 weeks for BSV-BSV and TDF-BSV groups. The primary endpoint was a virological response (hepatitis B virus DNA < 69 IU/mL). RESULTS: Among the 197 patients enrolled, 170 and 158 patients entered the second-year and third-year open-label phase extensional study, respectively, whereas 153 patients completed the 144-week follow-up. The virological response rate over the 144-week period was 87.7% and 92.1% in BSV-BSV and TDF-BSV groups, respectively (P = 0.36). The rates of ALT normalization and HBeAg seroconversion were similar between the groups. No drug-resistant mutations to BSV were noted. Bone mineral density and renal function were well preserved in the BSV-BSV group and were significantly improved after switching therapy in TDF-BSV patients. DISCUSSION: This extensional study of a phase 3 trial (NCT01937806) suggests that BSV treatment is efficacious and safe for long-term use in treatment-naïve and TDF-experienced patients with CHB.

Efficacy and Safety of Besifovir Dipivoxil Maleate Compared With Tenofovir Disoproxil Fumarate in Treatment of Chronic Hepatitis B Virus Infection.

BACKGROUND & AIMS: Besifovir dipivoxil maleate (BSV) has activity against hepatitis B virus (HBV). We performed a phase 3 study to compare the antiviral efficacy and safety of BSV vs tenofovir disoproxil fumarate (TDF) in patients with chronic HBV infection in Korea. METHODS: We conducted a double-blind, non-inferiority trial of 197 patients with chronic HBV infection at 22 sites in South Korea, from November 2013 through February 2016. Patients were randomly assigned to groups given BSV (150 mg, n = 99) or TDF (300 mg, n = 98) for 48 weeks. We evaluated virologic responses to therapy (HBV DNA <69 IU/mL or 400 copies/ml), bone mineral density (BMD), and renal outcomes for safety analysis. The main efficacy endpoint was the proportion of patients with a virologic response at week 48. After 48 weeks, TDF was switched to BSV (150 mg) for an additional 48 weeks. RESULTS: After 48 weeks of treatment, 80.9% of patients given BSV and 84.9% of patients given TDF met the efficacy endpoint, indicating the non-inferiority of BSV to TDF. At week 96, 87.2% of patients in the BSV-BSV and 85.7% of patients in the TDF-BSV had a virologic response. At week 48, changes in hip and spine BMD differed significantly between the BSV and TDF groups, whereas the estimated glomerular filtration rate in the TDF group was significantly lower than that in the BSV group. However, at 96 weeks, there were no significant differences in BMD and estimated glomerular filtration rate between the BSV-BSV and TDF-BSV groups. CONCLUSIONS: BSV has antiviral efficacy comparable to that of TDF after 48 weeks of treatment, with durable effects for 96 weeks. BSV has a better safety profile than TDF, in terms of bone and renal outcomes. ClinicalTrials.gov no: NCT01937806.

Reduced Risk of Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Receiving Long-Term Besifovir Therapy.

No information is available regarding the influence of besifovir (BSV), a new nucleotide analogue, on the occurrence of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B (CHB). This study evaluated the reduced risk of HCC in patients undergoing BSV treatment. A total of 188 patients with CHB were treated with BSV for up to 8 years. We prospectively assessed the incidence of HCC compared with the risk from prediction models. During the follow-up, 5 patients developed HCC: 1 of 139 patients with non-cirrhotic CHB, and 4 of 49 patients with liver cirrhosis. We compared the HCC incidence in non-cirrhotic and cirrhotic patients with the predicted number derived from the REACH-B (risk estimation for HCC in CHB) model and GAG-HCC (guide with age, gender, HBV DNA, core promotor mutation, and cirrhosis) model, respectively. The standardized incidence ratio (SIR) was 0.128 (p = 0.039) at 7 years in non-cirrhotic CHB patients, and the SIR was 0.371 (p = 0.047) at 7.5 years in cirrhotic patients, suggesting a significantly decreased HCC incidence in both groups. HCC prediction was available for BSV-treated patients using existing models. In conclusion, BSV decreased the risk of HCC in patients with CHB, and prediction models were applicable. Clinical trial registry website and trial number: ClinicalTrials.gov no: NCT01937806.

Usefulness of plasma epigenetic changes of five major genes involved in the pathogenesis of colorectal cancer.

PURPOSE: The purpose of present study was to investigate the methylation status of the promoter region in five genes (mothers against decapentaplegic homolog 4, fragile histidine triad protein, death-associated protein kinase 1, adenomatous polyposis coli (APC), and E-cadherin), which are known to be involved in the pathogenesis of colorectal cancer (CRC) and its clinicopathological significance. METHODS: The study subjects were 60 CRC patients, 40 patients with adenomatous colorectal polyp and 60 healthy control individuals. We further enrolled a total of 16 patients (two patients with Crohn's disease, two patients with ulcerative colitis, one patient with serrated adenoma, and 11 patients with colorectal cancer). The methylation states of the five genes were determined in peripheral blood plasma using methylation-specific polymerase chain reaction single-strand conformation polymorphism analysis. RESULTS: This study showed the most sensitive epigenetic markers, E-cadherin (60 %), followed by APC (57 %), for detecting CRC. E-cadherin and APC had similar specificities and amplified 84 and 86 %, respectively, of CRC patients compared to non-CRC patients. Additionally, APC was the only marker to be significantly increased (OR = 6.67, 95 % CI = 1.19-23.4, P = 0.045) and the most sensitive (57 %) and specific (89 %) marker in stage I CRC. Though we have not examined the paired cancer tissues and plasma, there was relatively high concordant rate (60-80 %) in our limited number of colorectal cancer patients. CONCLUSIONS: Five genes, promoter methylation, in plasma were statistically significant risk factors in CRC patients. In this study, E-cad and APC genes may be particularly useful epigenetic biomarkers in plasma for the detection of CRC. Additionally, APC may able to identify early potential CRC.

Clinical outcomes of palliative self-expandable metal stent placement in right- and left-sided malignant colon obstruction: A Honam Association for the Study of Intestinal Disease (HASID) multicenter study.

Self-expandable metal stent (SEMS) placement is commonly used for palliation of left-sided malignant colorectal obstruction (MCO). However, right-sided MCO is usually treated surgically. Recent studies that compared palliative SEMS insertion and emergency surgery in right-sided MCOs have reported conflicting results. This study aimed to compare the effectiveness of palliative SEMS placement in left-sided MCOs and right-sided MCOs and to investigate the predictive factors for clinical success and risk factors for complications. Data from 469 patients who underwent palliative SEMS placement for MCO at 6 hospitals in the Honam province of South Korea between 2009 and 2018 were reviewed. Among them, 69 patients with right-sided MCO and 400 patients with left-sided MCO who underwent SEMS placement for palliative purposes were enrolled. Clinical success, overall survival, complications, and predictive factors for clinical success and risk factors for complications were included as the main outcome measures. The clinical success rates were 97.1% (65/67) in right-sided MCO patients and 88.2% (353/400) in left-sided MCO patients. Complications including stent migration, tumor ingrowth, outgrowth, perforation, bacteremia/fever, and bleeding occurred in 10.1% (7/69) of right-sided MCO patients and 19.9% (79/400) of left-sided MCO patients. The mean overall survival of right-sided MCO was 28.02 months and 18.23 months for left-sided MCO. In multivariate logistic regression analysis, T3 stage tumors and the use of uncovered stents were significant factors for the clinical success of SEMS. The use of covered stents and performance status score of 0 to 2 were independent significant risk factors for complications. Palliative SEMS placement in right-sided MCO showed better clinical success rates than left-sided MCO. The use of uncovered stents is recommended for higher clinical success rates and lower complication rates.

Endoscopic Full-Thickness Resection for Gastric Subepithelial Lesions Arising from the Muscularis Propria.

Most cases of gastric subepithelial lesions follow a good clinical course; however, some lesions progress to malignant tumors, and treatment of tumors with a high risk of malignancy is essential. Surgical excision has been the primary treatment for tumors originating from the propria muscle layer, but it has the disadvantages of being invasive and causing postoperative functional abnormalities. With the development of endoscopic techniques and instruments, the role of endoscopic resection, which is a less invasive method for the removal of gastric subepithelial lesions, has been attracting attention. We performed an endoscopic full-thickness resection for 8 patients with gastric subepithelial lesions originating from the muscularis propria. No fatal complications occurred. Our findings suggest the need to develop various devices for resection and closure and to accumulate further experience through additional studies to prevent complications and specimen loss.

Predictors of clinical outcomes of self-expandable metal stent treatment for malignant colorectal obstruction: A Honam Association for the Study of Intestinal Disease (HASID) multicenter study.

ABSTRACT: There has been increased use of self-expandable metal stents (SEMS) in treating malignant colorectal obstruction (MCO). The aim of this study was to investigate factors that are associated with the outcomes of SEMS placement for MCO.Clinical data from patients who underwent SEMS placement for MCO at 6 hospitals in Honam province of South Korea between 2009 and 2018 were reviewed retrospectively. Eight hundred two patients were identified and their data were analyzed. Technical success, clinical success, complications, and predictors of outcome were included as main outcome measures.Technical and clinical success rates were 98.8% (792/802) and 90.1% (723/802), respectively. Complications including stent migration, stent occlusion due to tumor ingrowth and outgrowth, perforation, bacteremia/fever, and bleeding occurred in 123 (15.3%) patients. In multivariate regression analyses, procedure time was significantly associated with the technical success of SEMS placement (P = .001). Longer length of obstruction, the use of covered stent, and longer procedure time were significant independent predictive factors for the clinical success of SEMS placement (odds ratio [OR] 0.974 (95% confidence interval [CI] 0.950-0.990); P = .043, OR 0.255 (95% CI 0.138-0.471); P < .001, and OR 0.957 (95% CI 0.931-0.984); P = .002, respectively). Stage IV colorectal cancer and the use of covered stent were significant independent predictive factors for the development of complications after SEMS placement (OR 2.428 (95% CI 1.407-4.188); P = .001 and OR 3.329 (95% CI 2.060-5.378); P < .001, respectively).Longer length of obstruction, the use of covered stent, and longer procedure time were associated with lower clinical success rates. Having stage IV colorectal cancer and the use of covered stents were associated with an increased risk of complications.

Continuing besifovir dipivoxil maleate versus switching from tenofovir disoproxil fumarate for treatment of chronic hepatitis B: Results of 192-week phase 3 trial.

BACKGROUND/AIMS: Besifovir dipivoxil maleate (BSV), an acyclic nucleotide phosphonate, shows potent antiviral activity against hepatitis B virus. Our previous 48-week trial revealed that BSV has comparable antiviral efficacy to tenofovir disoproxil fumarate (TDF) and better safety profiles in terms of improved renal and bone safety. This extension study evaluated the prolonged efficacy and safety of BSV in treatment-naive chronic hepatitis B patients. METHODS: Patients continued to participate in an open-label BSV study after an initial 48-week double-blind comparison of BSV and TDF treatment. The antiviral efficacy and drug safety was evaluated up to 192 weeks in two groups: patients continuing BSV treatment (BSV-BSV) and patients switching from TDF to BSV after 48 weeks (TDF-BSV). RESULTS: Among 197 patients receiving randomized treatments, 170 (86%) entered the open-label phase and 152 (77%) entered the 192-week extension study. Virological response rates over 192 weeks were 92.50% and 93.06% in the BSV-BSV and TDF-BSV groups, respectively (P=0.90). Hepatitis B envelop antigen seroconversion and alanine aminotransferase normalization rates were similar between the groups (P=0.75 and P=0.36, respectively). There were no drug-resistant mutations to BSV. Bone mineral density and renal function were well preserved in the BSV-BSV group, whereas these initially worsened then recovered after switching therapy in the TDF-BSV group. CONCLUSION: BSV maintained potent antiviral efficacy after 192 weeks and showed no evidence of drug resistance. BSV was safe, well tolerated, and effective in patients who switched from TDF to BSV. Trial Registration Number: NCT01937806 (date: 10 Sep 2013).

[Clinical characteristics and gestational complications associated with acute hepatitis a in pregnancy].

BACKGROUND/AIMS: Acute hepatitis A was recently significant increased among women with gestational age in Korea. However, the clinical course and gestational complications have not been fully elucidated in pregnant patients with acute hepatitis A. We evaluated the clinical impact of acute HAV infection in pregnancy. METHODS: Twelve pregnant women out of 85 female patients with acute hepatitis A during 6 years were retrospectively reviewed. RESULTS: The median age of the pregnant group was 26.5 years old. The number of patient with acute hepatitis A were 5 cases in the 1st trimester, 3 cases in the 2nd and 4 cases in the 3rd. 4 cases had significant gestational complications. One case experienced the abortion in 1st trimester and one fetal distress was noted in 3rd trimester. The latter case was delivered of a low birth weight infant (2,390 g) caused by premature rupture of membrane in 36 weeks of gestational age. Other two cases experienced premature contraction and they had been required tocolytic treatment. But, all mothers featured full recovery from HAV infection. Except one aborted fetus and one premature birth, Newborn babies were not affected by maternal hepatitis A. CONCLUSIONS: Acute HAV infection during pregnancy may be associated with the risk of gestational complications. HAV serology and vaccination for women with gestation age should be considered at high prevalence area of acute hepatitis A.

A Case of Endoscopically Treated Laryngopharyngitis Resulting from Clinostomum complanatum Infection.

A 46-year-old woman visited our hospital presenting throat pain and globus sensation. The symptoms occurred seven days after eating raw perch and mullet. An endoscopy under sedation showed a fluke-with an approximate length of 4.8 mm and width of 1.5 mm-on the left aryepiglottic fold, with active motility on the mucosa. It was extracted from the larynx using biopsy forceps and was identified as Clinostomum complanatum. To the best of our knowledge, this is the second reported case of human infection with Clinostomum complanatum diagnosed and treated by an endoscopy in Korea. Endoscopy is a useful tool in the diagnosis and treatment of patients at risk for parasitic infections complaining of throat pain.

A case of endoscopic removal of a giant appendicolith combined with stump appendicitis.

Stump appendicitis is an acute inflammation of the residual appendix and is a rare complication after appendectomy. The physician should be aware of the possibility of stump appendicitis in patients with right lower abdominal pain after appendectomy so that delayed diagnosis and treatment can be prevented. Stump appendicitis is usually treated by surgical resection, and endoscopic treatment has not been reported previously. A 48-year-old man who had undergone appendectomy 35 years earlier presented to the hospital because of right lower quadrant discomfort. A computed tomography scan showed a large stone in the residual appendix. Colonoscopic findings revealed a large, smooth, protruding lesion at the cecum with a stone inside the appendiceal orifice. Endoscopic removal after incision of the appendiceal orifice was performed successfully.

A case of enteritis cystica profunda in the ampulla of vater mimicking choledochocele.

Enteritis cystica profunda is a very rare disease in which a mucin-filled cystic space is surrounded partially with nonneoplastic columnar epithelium in the submucosa of the small intestine. Most of the cases are accompanied by intestinal diseases, and the disease usually occurs in the jejunum and the ileum and there has been no report of a case that occurred in the ampulla of Vater. A 58-year-old healthy female patient without any particular symptom visited the hospital to get additional examination for a mass found on the ampulla of Vater by accident. In esophagogastroduodenoscopy, a cystic mass showing a positive pillow sign was found on the ampulla of Vater. Endoscopic retrogradecholangiopancreatography was conducted as choledochocele was suspected, but no abnormality was found in the biliary system. In endoscopic ultrasonography, multiseptated cystic structures were detected in the submucosal layer of the duodenum. The lesion was resected completely through endoscopic snare polypectomy and the case was histologically diagnosed as enteritis cystica profunda.

Paclitaxel-incorporated nanoparticles of hydrophobized polysaccharide and their antitumor activity.

The aim of this study was to characterize paclitaxel-incorporated polysaccharide nanoparticles and evaluate their antitumor activity in vitro and in vivo. Pullulan was hydrophobically modified using acetic anhydride to make the paclitaxel-incorporated nanoparticles. Pullulan acetate (PA) was used to encapsulate paclitaxel using the nanoprecipitation method. The particles had spherical shapes under electron microscopy with sizes <100 nm. The sizes of paclitaxel-incorporated nanoparticles increased to >100 nm, and higher drug feeding induced higher particle size and drug content. Initial drug burst release was observed until 2 days and then the drug was continuously released over 1 week. Intrinsic cytotoxicity of empty PA nanoparticles was tested with RAW264.7 macrophage cells for biocompatibilty. The viability of RAW264.7 cells was >93% at all concentrations of empty PA nanoparticles, indicating that the PA nanoparticles are not acutely cytotoxic to normal human cells. The nanoparticles showed lower antitumor activity in vitro against HCT116 human colon carcinoma cells than that of paclitaxel itself, indicating the sustained release properties of nanoparticles. An in vivo study using HCT116 human colon carcinoma-bearing mice showed that paclitaxel-incorporated PA nanoparticles reduced tumor growth more than that of paclitaxel itself. These results indicate that PA paclitaxel-incorporated nanoparticles are a promising candidate for antitumor drug delivery.

Combination of paclitaxel- and retinoic acid-incorporated nanoparticles for the treatment of CT-26 colon carcinoma.

The aim of this study was to evaluate the antitumor effect of combinatorial targeted therapy with paclitaxel and all-trans retinoic acid (ATRA) nanoparticles in vitro. Paclitaxel-incorporated pullulan acetate (PA) nanoparticles were prepared by the nanoprecipitation-solvent evaporation method. ATRA-incorporated nanoparticles were prepared by dialysis using a methoxy poly(ethylene glycol)-grafted chitosan (ChitoPEG) copolymer. Particle sizes of paclitaxel-incorporated nanoparticles and ATRA-incorporated nanoparticles were about 160 nm and 60 nm, respectively. Nanoparticles were reconstituted in various aqueous media such as deionized water, phosphate-buffered saline, and fetal bovine serum-supplemented cell culture media. The combination of paclitaxel + ATRA (10 + 10 µg/mL) delivered by nanoparticles showed a synergistic antiproliferative effect against CT26 cells that was not observed with other combinations. Furthermore, the activity of MMP-2, a key enzyme in tumor cell invasion, was significantly decreased in cells treated with the combination of paclitaxel and ATRA while other combinations and single agents did not significantly affect its activity. A matrigel assay supported these results, indicating that paclitaxel/ATRA combination nanoparticles are effective for the inhibition of the invasion of tumor cells. The results of the present study suggest that combination treatment with paclitaxel and ATRA could be an effective treatment for the inhibition of tumor cell proliferation and invasion, and that nanoparticles are promising candidates for antitumor drug delivery.