Long-term open-label vebicorvir for chronic HBV infection: Safety and off-treatment responses.

Background & Aims: The investigational first-generation core inhibitor vebicorvir (VBR) demonstrated safety and antiviral activity over 24 weeks in two phase IIa studies in patients with chronic HBV infection. In this long-term extension study, patients received open-label VBR with nucleos(t)ide reverse transcriptase inhibitors (NrtIs). Methods: Patients in this study (NCT03780543) previously received VBR + NrtI or placebo + NrtI in parent studies 201 (NCT03576066) or 202 (NCT03577171). After receiving VBR + NrtI for ≥52 weeks, stopping criteria (based on the treatment history and hepatitis B e antigen status in the parent studies) were applied, and patients either discontinued both VBR + NrtI, discontinued VBR only, or continued both VBR + NrtI. The primary efficacy endpoint was the proportion of patients with HBV DNA <20 IU/ml at 24 weeks off treatment. Results: Ninety-two patients entered the extension study and received VBR + NrtI. Long-term VBR + NrtI treatment led to continued suppression of HBV nucleic acids and, to a lesser extent, HBV antigens. Forty-three patients met criteria to discontinue VBR + NrtI, with no patients achieving the primary endpoint; the majority of virologic rebound occurred ≥4 weeks off treatment. Treatment was generally well tolerated, with few discontinuations due to adverse events (AEs). There were no deaths. Most AEs and laboratory abnormalities were related to elevations in alanine aminotransferase and occurred during the off-treatment or NrtI-restart phases. No drug-drug interactions between VBR + NrtI and no cases of treatment-emergent resistance among patients who adhered to treatment were observed. Conclusions: Long-term VBR + NrtI was safe and resulted in continued reductions in HBV nucleic acids following completion of the 24-week parent studies. Following treatment discontinuation, virologic relapse was observed in all patients. This first-generation core inhibitor administered with NrtI for at least 52 weeks was not sufficient for HBV cure. Clinical trial number: NCT03780543. Impact and implications: Approved treatments for chronic hepatitis B virus infection (cHBV) suppress viral replication, but viral rebound is almost always observed after treatment discontinuation, highlighting an unmet need for improved therapies with finite treatment duration producing greater therapeutic responses that can be sustained off treatment. First-generation core inhibitors, such as vebicorvir, have mechanisms of action orthogonal to standard-of-care therapies that deeply suppress HBV viral replication during treatment; however, to date, durable virologic responses have not been observed after treatment discontinuation. The results reported here will help researchers with the design and interpretation of future studies investigating core inhibitors as possible components of finite treatment regimens for patients with cHBV. It is possible that next-generation core inhibitors with enhanced potency may produce deeper and more durable antiviral activity than first-generation agents, including vebicorvir.

Rare finding of a symptomatic epidermoid cyst of the diaphragm - a case report.

Cystic lesions of the diaphragm are rare and accordingly present a diagnostic challenge. Specific radiological features with which to clinch a diagnosis may be elusive. Herein we present the case of a patient who presented with symptoms attributable to a cyst in the left upper abdomen, irritating the diaphragm. Surgery was considered appropriate for diagnostic and symptomatic purposes. Final histology demonstrated an epidermoid cyst. Resolution of symptoms was reported after surgery. Diaphragmatic epidermoid cysts appear to be a rare entity with only three prior cases reported in the literature. Given the rarity of this lesion and the lack of unique features by which they can be characterized, accurately diagnosing epidermoid cysts of the diaphragm is likely to remain difficult without surgery, although they are presumed to have a benign behaviour.

Inflammatory bowel disease in Waikato, New Zealand: incidence and prevalence.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) prevalence is rising globally; however, indigenous groups are underrepresented. Waikato, New Zealand, is a large region with a high proportion of Maori patients. In Canterbury in 2006, 1% of patients with IBD were Maori. We investigated the incidence and prevalence of IBD in Waikato over 10 years. METHODS: This was a retrospective cohort study assessing the incidence and prevalence of IBD between 2009 and 2019. The search strategy included pathology, radiology, Provation, ICD-10 coding and private clinics, using the keywords: Crohn's, Crohn, ileitis, colitis, ulcerative, inflammatory bowel disease and IBD. Collected data included current age and age at diagnosis, sex, ethnicity and IBD subtype. RESULTS: The IBD point prevalence on 31 December 2019 was 375.6/100 000 compared with 293.6/100 000 in 2010, increasing by 27.9%. The annualised incidence was static from 21.5/100 000 in 2010 to 17.5/100 000 in 2019. Female patients comprised 53.3% of the cohort. Ulcerative colitis (UC) made up 54.2% of cases, 43.8% had Crohn disease (CD) and 2.0% had indeterminate colitis. Sixty (3.7%) patients identified as Maori. In non-Maori patients, the average age at diagnosis was 36.2 years, compared with 33.0 years in Maori patients (P = 0.11). In Maori patients, 53.3% had UC and 45.0% had CD. Thirty-five percent of Maori patients lived 50 km or more from base hospital, compared with 41% of non-Maori patients (P = 0.33). CONCLUSION: IBD prevalence has increased substantially; however, the incidence has remained static. Maori IBD rates are higher than previously reported, in keeping with international indigenous trends. Maori patients were diagnosed at a similar age as non-Maori patients, with similar disease subtypes.

Conversion of locally advanced to resectable pancreatic body cancer aided by phosphorus-32 brachytherapy (OncoSil).

Nil.

Lessons learned from early experience of per oral endoscopic myotomy in children.

BACKGROUND/AIMS: Achalasia cardia (AC) is rare in children, and the standard treatment is open or Laparoscopic Heller's myotomy with or without fundoplication if pneumatic dilatation has failed. Per oral endoscopic myotomy (POEM) is a novel technique for management of achalasia with good results in adults. We report POEM in four children and the outcome with special emphasis on the technique and management of intra-operative complications. METHOD: Four children aged 7-15 years presenting with progressive dysphagia, cough, night-time aspirations, and weight loss of six months to one year were investigated with upper GI contrast study, flexible endoscopy and biopsy, oesophageal manometry, and a diagnosis of Type 1 & 2 AC was made. An experienced adult endoscopist in collaboration with the paediatric surgical team performed POEM. RESULTS: POEM was performed successfully using ERBE HYBRID knife setup and waterjet injection for the submucosal tunnelling. Operative time was 25-40 min (mean 31 min). The hospital stay was 3-8 days with last 3 patients discharged on day three. No major intraoperative or post-operative complications were seen. The Eckardt score changed from above 4 to 0 at one-month follow-up. All four are well at one year post-operatively and beyond. Two patients had subcutaneous emphysema post-operatively. One developed pneumoperitoneum intra-operatively. CONCLUSION: POEM was successfully performed with only minor adverse events in experienced hands. Anticipation and preparation for potential intraoperative complications and assigned responsibilities to each team helped the safe completion in the shortest time. Rectifying pneumoperitoneum concurrently without interruption of the operation exemplified teamwork. LEVEL OF EVIDENCE: III.

Safety and efficacy of vebicorvir administered with entecavir in treatment-naïve patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: Nucleos(t)ide reverse transcriptase inhibitors do not completely suppress HBV DNA in chronic HBV infection (cHBV). Vebicorvir (VBR) is an investigational core inhibitor that interferes with multiple aspects of HBV replication. This phase II trial evaluated the safety and efficacy of VBR in combination with entecavir (ETV) in treatment-naïve patients with cHBV. METHODS: HBeAg-positive, treatment-naïve patients without cirrhosis were randomised 1:1 in a double-blind manner to once-daily VBR 300 mg+ETV 0.5 mg or placebo (PBO)+ETV 0.5 mg for 24 weeks. The primary endpoint was change in mean log10 HBV DNA from Baseline to Week 12 and 24. RESULTS: All patients in both treatment groups (PBO+ETV: 12/12; VBR+ETV: 13/13) completed the study. At Week 12, VBR+ETV led to a greater mean (SD) reduction from Baseline in log10 IU/ml HBV DNA (-4.45 [1.03]) vs. PBO+ETV (-3.30 [1.18]; p = 0.0077). At Week 24, VBR+ETV led to a greater reduction from Baseline in log10 IU/ml HBV DNA (-5.33 [1.59]) vs. PBO+ETV (-4.20 [0.98]; p = 0.0084). Greater mean reductions in pregenomic RNA were observed at Week 12 and 24 in patients receiving VBR+ETV vs. PBO+ETV (p <0.0001 and p <0.0001). Changes in viral antigens were similar in both groups. No drug interaction between VBR and ETV was observed. Two patients experienced HBV DNA rebound during treatment, with no resistance breakthrough detected. The safety of VBR+ETV was similar to PBO+ETV. All treatment-emergent adverse events and laboratory abnormalities were Grade 1/2. There were no deaths, serious adverse events, or evidence of drug-induced liver injury. CONCLUSIONS: In this 24-week study, VBR+ETV provided additive antiviral activity over PBO+ETV in treatment-naïve patients with cHBV, with a favourable safety and tolerability profile. CLINICAL TRIAL NUMBER: NCT03577171 LAY SUMMARY: Hepatitis B is a long-lasting viral infection of the liver. Current treatments can suppress hepatitis B virus but do not offer the opportunity of cure, hence, new treatment approaches are required. Herein, we show that the combination of the novel core inhibitor vebicorvir with an existing antiviral (entecavir) in treatment-naïve patients chronically infected with hepatitis B virus demonstrated greater antiviral activity than entecavir alone. Additionally, vebicorvir was safe and well tolerated. Thus, further studies evaluating its potential role in the treatment of chronic hepatitis B are warranted.

Safety and efficacy of vebicorvir in virologically suppressed patients with chronic hepatitis B virus infection.

BACKGROUND & AIMS: HBV nucleos(t)ide reverse transcriptase inhibitors (NrtIs) do not completely suppress HBV replication. Previous reports indicate persistent viremia during NrtI treatment despite HBV DNA being undetectable. HBV core inhibitors may enhance viral suppression when combined with NrtIs. This phase II trial (NCT03576066) evaluated the efficacy and safety of the investigational core inhibitor, vebicorvir (VBR), in virologically- suppressed patients on NrtIs. METHODS: Non-cirrhotic, NrtI-suppressed patients with chronic HBV were randomised to VBR 300 mg once daily or matching placebo (PBO) for 24 weeks. Treatment was stratified by hepatitis B e antigen (HBeAg) status. The primary endpoint was change from Baseline in serum HBeAg or hepatitis B surface antigen (HBsAg) after 24 weeks. RESULTS: Of 73 patients enrolled, 47 were HBeAg positive and 26 were HBeAg negative. In HBeAg-positive and -negative patients, there were no differences in the change from Baseline at Week 24 for HBsAg or HBeAg. Using a novel, high-sensitivity assay to detect HBV DNA, a greater proportion of patients with detectable HBV DNA at Baseline achieved undetectable HBV DNA at Week 24 in the VBR+NrtI vs. PBO+NrtI group. In HBeAg-positive patients, a greater change from Baseline in HBV pregenomic (pg)RNA was observed at Week 24 with VBR+NrtI vs. PBO+NrtI. Treatment-emergent adverse events (TEAEs) in VBR+NrtI patients included upper respiratory tract infection, nausea, and pruritus. No serious adverse events, Grade 4 TEAEs, or deaths were reported. CONCLUSIONS: In this 24-week study, VBR+NrtI demonstrated a favourable safety and tolerability profile. While there were no significant changes in viral antigen levels, enhanced viral suppression was demonstrated by greater changes in DNA and pgRNA with the addition of VBR compared to NrtI alone. CLINICAL TRIALS NUMBER: NCT03576066. LAY SUMMARY: Core inhibitors represent a novel approach for the treatment of chronic hepatitis B virus (HBV) infection, with mechanisms of action distinct from existing treatments. In this study, vebicorvir added to existing therapy reduced HBV replication to a greater extent than existing treatment and was generally safe and well tolerated.

Drainage of pancreatic fluid collections using a lumen-apposing metal stent with an electrocautery-enhanced delivery system.

BACKGROUND AND AIM: Our aim was to evaluate the efficacy and safety of a lumen-apposing metal stent with an electrocautery-enhanced delivery system (EDS-LAMS) for endoscopic ultrasound (EUS)-guided drainage of pancreatic fluid collections (PFCs) in regular clinical practice. METHODS: A retrospective and subsequent prospective analysis was undertaken of all patients who underwent EUS-guided drainage of their PFCs using the EDS-LAMS at 17 tertiary therapeutic endoscopy centers. RESULTS: Two hundred eight cases of EDS-LAMS deployment were attempted in 202 patients (mean age 52.9 years) at time of evaluation. Ninety-seven patients had pancreatic pseudocysts (PPs), 75 walled-off pancreatic necrosis (WOPN), 10 acute peripancreatic fluid collections (APFCs), 6 acute necrotic collections (ANCs), and 14 postoperative collections (POCs). Procedural technical success was achieved in 202/208 cases (97.1%). Maldeployment occurred in 7/208 cases (3.4%). Clinical success was achieved in 142/160 (88.8%) patients (PP 90%, WOPN 85.2%, APFC 100%, ANC 75%, POC 100%). Delayed adverse events included stent migration in 15/202 (7.4%), stent occlusion and infection in 16/202 (7.9%), major bleeding in 4/202 (2%), and buried EDS-LAMS in 2/202 (1%). PFC recurrence occurred in 13/142 (9.2%) patients; 9/202 (4.5%) required surgical or radiological intervention for PFC management after EDS-LAMS insertion. CONCLUSIONS: This large international multicenter study evaluating the EDS-LAMS for drainage of PFCs in routine clinical practice suggests that the EDS-LAMS are safe and effective for drainage of all types of PFCs; however, further endoscopic therapy is often required for WOPN. Major bleeding was a rare complication in our cohort.

Safety and outcomes of endoscopic ultrasound-guided drainage for malignant biliary obstruction using cautery-enabled lumen-apposing metal stent.

Background and study aims There is increasing evidence to suggest that EUS-guided biliary drainage (EUS-BD) is a safe and effective treatment alternative for patients with malignant biliary obstructions (MBOs) after failed endoscopic retrograde cholangiopancreatography. Patients and methods We performed a retrospective analysis of data prospectively collected from patients with MBO who underwent choledochoduodenostomy (CDS) or gallbladder drainage (GBD) between August 2016 and June 2020 using the electrocautery-enabled lumen-apposing metal stents (ECE-LAMS). The primary endpoint was technical and clinical success. Secondary endpoints were adverse events (AEs) and reinterventions. Results A total of 60 patients were included in the study, with 56 CDS and 4 GBD. Median age was 76 years with 57 % male (34/60). The most common indication for EUS-BD was pancreatic cancer (78 %). Technical success was achieved in 100 % of cases, with a clinical success rate of 91.7 %. Mean total bilirubin pre-procedure was 202 umol/L (normal < 20 umol/L) and 63.8 umol/L post procedure ( P  < .001). Twenty-one patients had bilirubin recorded at 2 weeks post EUS-BD with 20 of 21 patients demonstrating > 50 % reduction in bilirubin (mean bilirubin reduction 75 %). AEs occurred in 12 of 60 patients (20 %), all of which were mild. The reintervention rate was 11.7 % (7/60). Stent occlusion occurred in 10 of 60 patients (16.7 %) with a mean time to stent occlusion of 46.2 days (3-133). Stent patency of 83.3 % was observed with a mean follow up of 7.9 months. Conclusion EUS-CDS and GBD using ECE-LAMS are effective EUS-based techniques for managing patients with MBO. AEs are usually mild and resolved by reintervention.

Antiviral Activity, Safety, and Pharmacokinetics of Capsid Assembly Modulator NVR 3-778 in Patients with Chronic HBV Infection.

BACKGROUND & AIMS: NVR 3-778 is a first-in-class hepatitis B virus (HBV) capsid assembly modulator that can inhibit HBV replication. We performed a proof-of-concept study to examine the safety, pharmacokinetics, and antiviral activity of NVR 3-778 in patients with chronic HBV infection. METHODS: We performed a phase 1 study in 73 hepatitis B envelope antigen (HBeAg)-positive patients with chronic HBV infection without cirrhosis. In a 2-part study (part 1 in New Zealand and part 2 in Hong Kong, Singapore, Taiwan, Korea, and the United States), patients were randomly assigned to groups that were given oral NVR 3-778 (100 mg, 200 mg, or 400 mg daily or 600 mg or 1000 mg twice daily) or placebo for 4 weeks. Additional groups received combination treatment with pegylated interferon (pegIFN) and NVR 3-778 (600 mg twice daily) or pegIFN with placebo. RESULTS: Reductions in serum levels of HBV DNA and HBV RNA were observed in patients receiving ≥1200 mg/d NVR 3-778. The largest mean reduction in HBV DNA was observed in the group given NVR 3-778 plus pegIFN (1.97 log10 IU/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.43 log10 IU/mL and 1.06 log10 IU/mL, respectively). The mean reduction in HBV RNA was also greatest in the group given NVR 3-778 plus pegIFN (2.09 log10 copies/mL), compared with the groups given NVR 3-778 or pegIFN alone (1.42 log10 copies/mL and 0.89 log10 copies/mL, respectively). There was no significant mean reduction in HBsAg during the 4-week treatment period. There were no discontinuations and no pattern of dose-related adverse effects with NVR 3-778. CONCLUSIONS: In a phase 1 study of HBeAg-positive patients with chronic HBV infection without cirrhosis, NVR 3-778 was well tolerated and demonstrated antiviral activity. The agent reduced serum levels of HBV DNA and HBV RNA, to the greatest extent in combination with pegIFN. The observed reductions in HBV RNA confirmed the novel mechanism of NVR 3-778. Clinicaltrials.gov no. NCT02112799 (single-center) and NCT02401737 (multicenter).

Glecaprevir/pibrentasvir for hepatitis C virus genotype 3 patients with cirrhosis and/or prior treatment experience: A partially randomized phase 3 clinical trial.

This study assessed the efficacy and safety of ribavirin-free coformulated glecaprevir/pibrentasvir (G/P) in patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis, a patient population with limited treatment options. SURVEYOR-II, Part 3 was a partially randomized, open-label, multicenter, phase 3 study. Treatment-experienced (prior interferon or pegylated interferon ± ribavirin or sofosbuvir plus ribavirin ± pegylated interferon therapy) patients without cirrhosis were randomized 1:1 to receive 12 or 16 weeks of G/P (300 mg/120 mg) once daily. Treatment-naive or treatment-experienced patients with compensated cirrhosis were treated with G/P for 12 or 16 weeks, respectively. The primary efficacy endpoint was the percentage of patients with sustained virologic response at posttreatment week 12 (SVR12). Safety was evaluated throughout the study. There were 131 patients enrolled and treated. Among treatment-experienced patients without cirrhosis, SVR12 was achieved by 91% (20/22; 95% confidence interval [CI], 72-97) and 95% (21/22; 95% CI, 78-99) of patients treated with G/P for 12 or 16 weeks, respectively. Among those with cirrhosis, SVR12 was achieved by 98% (39/40; 95% CI, 87-99) of treatment-naive patients treated for 12 weeks and 96% (45/47; 95% CI, 86-99) of patients with prior treatment experience treated for 16 weeks. No adverse events led to discontinuation of study drug, and no serious adverse events were related to study drug. Conclusion: Patients with hepatitis C virus genotype 3 infection with prior treatment experience and/or compensated cirrhosis achieved high SVR12 rates following 12 or 16 weeks of treatment with G/P. The regimen was well tolerated. (Hepatology 2018;67:514-523).

Cyanoacrylate glue for gastrointestinal bleeding.

PURPOSE OF REVIEW: Cyanoacrylate (CYA) therapy has become an important component of the therapeutic toolbox of the interventional endoscopists with direct endoscopic injection accepted as first-line therapy of gastric varices. However, its generalized use has been cautioned by its serious adverse event profile. RECENT FINDINGS: Endoscopic ultrasound guided therapy has several conceptual advantages over free-hand injection, particularly as it ensures intravascular delivery of therapy. This has allowed innovation with the use of vascular coils with or without CYA therapy, and very encouraging long-term results are now published showing reduced serious adverse events and low rebleeding rates. SUMMARY: Direct endoscopic ultrasound guided intravascular injection of CYA is gaining widespread acceptance and offers reduced complication rates and significantly lower rebleeding rates. Data are supportive of CYA use both for primary and secondary prophylaxis of gastric varices.

New Endoscopic Technologies and Procedural Advances for Endoscopic Hemostasis.

Endoscopic interventions are first-line therapy for upper and lower gastrointestinal bleeding. Injection therapy in combination with a second endoscopic modality has reduced re-bleeding, need for surgery and mortality in non-variceal bleeding. For variceal bleeding endoscopic banding or cyanoacrylate injection techniques are recommended interventions. However, despite ease of application and general acceptance of these techniques, there is an ongoing re-bleeding rate associated with significant in-hospital mortality. We discuss current literature on new advances in endoscopic technologies and procedural techniques that have emerged to improve patient outcomes.

EUS-guided treatment of gastric fundal varices with combined injection of coils and cyanoacrylate glue: a large U.S. experience over 6 years (with video).

BACKGROUND AND AIMS: Conventional endoscopic treatment of gastric fundal varices (GFV) with cyanoacrylate (CYA) glue may be complicated by embolization and rebleeding. We evaluated the long-term outcomes of EUS-guided injection of coils and CYA glue for therapy of GFV. METHODS: A retrospective chart review of patients treated for GFV was performed. The main outcomes measured were hemostasis, obliteration on surveillance EUS, post-treatment bleeding rate, and adverse events. RESULTS: From March 2009 to 2015, 152 patients with GFV were treated. Seven (5%) had active hemorrhage, 105 (69%) had recent bleeding, and 40 (26%) were treated for primary prophylaxis. Treatment was technically successful in 151 patients (>99%). Mean number of coils was 1.4 (range, 1-4 coils), and mean volume of CYA was 2 mL (range, 0.5-6). Follow-up was available for 125 patients with treated GFV (mean, 436 days; range, 30-2043). Among 100 patients with follow-up EUS examinations, complete obliteration (on Doppler study) of GFV was confirmed in 93 (93%). Post-treatment bleeding from obliterated GFV occurred in 3 of 93 patients (3%). Twenty-five patients who had clinical and/or EGD follow-up had 3 post-treatment bleeding episodes after a median follow-up of 324 days (range, 41-486). Among the 40 patients treated for primary prophylaxis, 28 underwent follow-up EUS and 27 (96%) had confirmed obliteration. Mild postprocedure abdominal pain occurred in 4 of 125 patients (3%), and clinical signs of pulmonary embolization were seen in 1 patient (1%). Another 4 of 125 patients (3%) presented with minor delayed upper GI bleeding from coil/glue extrusion. CONCLUSIONS: EUS-guided combined coil and CYA glue injection of high-risk GFV appears to be highly effective for hemostasis in active bleeding and primary and secondary bleeding prophylaxis. Once obliteration was achieved, post-treatment bleeding from GFV occurred in only 3% during long-term follow-up. Combination therapy appears safe and may reduce the risk of CYA embolization.

Endoscopic Ultrasound-Assisted Pancreaticobiliary Access.

Endoscopic retrograde cholangiopancreatography (ERCP) is the primary approach to drain an obstructed pancreatic or biliary duct. Failed biliary drainage is traditionally referred for percutaneous transhepatic biliary drainage or surgical bypass, which carry significantly higher morbidity and mortality rates compared with ERCP and transpapillary drainage. Endoscopic ultrasound provides a real-time imaging platform to access and deliver therapy to organs and tissues outside of the bowel lumen. The bile and pancreatic ducts can be directly accessed from the stomach and duodenum, offering an alternative to ERCP when this fails or is not feasible.

Endoscopic management of gastric variceal bleeding.

Expert knowledge of endoscopic management of gastric varices is essential, as these occur in 20% of patients with portal hypertension. Bleeding is relatively uncommon, but carries significant mortality when this occurs. Inability to directly target intravascular injections and the potential complication related to glue embolization has resulted in the development of novel techniques. Direct visualization of the varix lumen using endoscopic ultrasound (EUS) allows targeted therapy of feeder vessels with real-time imaging. EUS-guided combination therapy with endovascular coiling and cyanoacrylate injections promise to provide reduced complication rates, increased obliteration of varices, and reduced long-term rebleeding rates.