Toll-IL1 receptor-mediated innate immune responses vary across HBV genotype and predict treatment response to pegylated-IFN in HBeAg-positive CHB patients.

Patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) have suppressed TLR2 expression, function and cytokine production. The aim of this study was to explore the importance of hepatitis B virus (HBV) genotype in innate immune responses and investigate whether Toll-like receptor (TLR) expression/function has potential roles as predictive biomarkers of successful therapy with pegylated interferon (Peg-IFN) therapy of HBeAg seroconversion in HBeAg-positive patients. We showed that as early as 4 weeks after initiation of Peg-IFN, future HBeAg seroconverters had significantly elevated levels of TLR2 expression on monocytes. TLR2-associated IL-6 production at baseline and week 4 of therapy and TLR4 IL-6 production at week 4 were also markedly elevated in HBeAg seroconverters. HBV genotype also influenced treatment response, with genotypes A and B more likely to seroconvert than D. We were able to demonstrate that these differences were due in part to the interaction of the specific HBeAg proteins with TLR pathway adaptor molecules, and these interactions were genotype dependent. HBeAg-mediated modulation of TLR signalling was also observed in Huh7 cells, following stimulation with Pam3Cys. Importantly, the addition of IFN-α to TLR2-stimulated cells cotransfected with an HBeAg expression plasmid reversed HBeAg-mediated suppression of hepatocytes. These findings demonstrate that patients with an activated inflammatory response are much more likely to respond to IFN therapy, with TLR responses showing promise as potential biomarkers of HBeAg seroconversion in this setting. Furthermore, our findings suggest there is differential genotype-specific HBeAg suppression of innate signalling pathways which may account for some of the clinical differences observed across the CHB spectrum.

Grazoprevir plus peginterferon and ribavirin in treatment-naive patients with hepatitis C virus genotype 1 infection: a randomized trial.

UNLABELLED: Grazoprevir (MK-5172, Merck & Co., Inc.) is a selective inhibitor of the hepatitis C virus (HCV) NS3/4a protease. The aim of this study was to evaluate the safety and efficacy of grazoprevir at doses of 25-100 mg/day in combination with peginterferon and ribavirin (PEG-IFN/RBV). In this randomized, dose-ranging, multicentre trial, treatment-naive adults with chronic HCV genotype 1 infection received once-daily grazoprevir 25 mg, 50 mg or 100 mg plus PEG-IFN/RBV for 12 weeks. Patients with quantifiable HCV RNA (≥25 IU/mL) at week 4 received an additional 12 weeks of PEG-IFN/RBV. The primary endpoint was sustained virologic response (HCV RNA <25 IU/mL 12 weeks after completing therapy [SVR12]). Eighty-seven patients were randomly assigned and received ≥1 dose of therapy. Median time to undetectable HCV RNA was 16 days in the 100-mg arm and 22 days in the 25- and 50-mg arms. All patients except one had HCV RNA undetectable or unquantifiable at week 4 and received 12 weeks of therapy. SVR12 was achieved by 13 of 24 (54.2%), 21 of 25 (84.0%) and 23 of 26 (88.5%) patients in the 25-, 50- and 100-mg arms, respectively (per-protocol analysis). Three patients discontinued as a result of nonserious adverse events (AEs) and three patients experienced serious AEs. Transaminase elevations occurred in two patients (one each in the 25- and 100-mg arms). CONCLUSION: These data support further study of the grazoprevir 100-mg dose. Phase 3 studies of grazoprevir 100 mg in combination with elbasvir are currently ongoing (NCT01710501; protocol P038).

Incidence of upper gastrointestinal haemorrhage in Maori and New Zealand European ethnic groups, 2001-2010.

BACKGROUND: To date no incidence figures for upper gastrointestinal haemorrhage (UGIH) in New Zealand have been published. AIMS: To determine the incidence of UGIH in a demographically defined population, and to assess variation in incidence associated with demographic parameters. METHODS: Between 17 March 2001 and 12 October 2010, all patients presenting to Waikato Hospital with UGIH were prospectively ascertained, and clinical, epidemiological and laboratory data were collected. Incidence rates were calculated, and were age adjusted to the World Health Organization world standard population. Parameters associated with trends in incidence were examined. RESULTS: There were 1360 UGIH events, yielding a crude incidence of 59.2 per 100,000 adults (age ≥ 15 years) per year (all quoted incidence figures per 100,000 adults per year), and an age-adjusted incidence (AAI) of 46.4. AAI was higher for Maori compared with New Zealand Europeans (91.3 vs 37.0, rate ratio (RR) = 2.47, P < 0.001). Maori were more likely to have a gastric ulcer at endoscopy (odds ratio (OR) = 2.21, P < 0.001). For those tested for Helicobacter pylori (n = 702), Maori were more likely to be infected (OR = 2.12, P < 0.001). AAI was higher for males (61.1 vs 33.6, RR = 1.82, P < 0.001). Males were more likely to have a duodenal ulcer at endoscopy (OR = 1.79, P < 0.001). AAI incidence decreased from the first to the second half of the study period (53.6 vs 45.8, RR = 1.17, P < 0.001). CONCLUSION: AAI of UGIH in the Waikato region was 46.4. This was significantly higher in Maori and in males, and decreased over the study period. These data will provide a comparison for future assessment of trends in UGIH.

Endoscopic ultrasound-guided drainage of pancreatic fluid collections with indeterminate adherence using temporary covered metal stents.

Transenteric drainage of a pancreatic fluid collection (PFC) with poor adherence to the bowel wall risks leakage and perforation. Elimination of tract dilation and the use of a fully covered self-expanding metal stent (FCSEMS) may improve safety. We evaluated endoscopic ultrasound (EUS)-guided drainage of PFCs using a one-step access device followed by placement of a FCSEMS. Eighteen patients (12 males; median age 50) with PFCs (median size 135 mm) meeting the criteria for indeterminate adherence were enrolled. After 7 - 10 days, the FCSEMSs were removed and exchanged for double-pigtail stents. When indicated, tract dilation and endoscopy-guided cyst debridement was performed. FCSEMS placement was technically successful in all patients without complications. Median procedure time was 37.5 minutes. Cystgastrostomy dilation resulted in dehiscence in one patient and was treated with repeat FCSEMS placement. Cyst resolution was achieved in 78 % of patients. FCSEMS placement without tract dilation enables safe initial drainage of PFCs with indeterminate adherence.

Endoscopic ultrasound-guided anterograde treatment of biliary stones following gastric bypass.

Endoscopic treatment of bile duct stones in gastric bypass patients is challenging. We describe a novel method involving endoscopic ultrasound (EUS)-guided anterograde interventions. After prior experience with EUS-guided rendezvous endoscopic retrograde cholangiopancreatography (ERCP) and direct EUS-guided anterograde stenting for malignant biliary obstruction, we have attempted EUS-guided treatment of biliary stones as first-line therapy following gastric bypass. Our approach involves: (i) EUS-fine needle aspiration (FNA) puncture into an intrahepatic bile duct; (ii) EUS-guided cholangiography; (iii) guide wire advancement across the ampulla; (iv) catheter dilation of the transhepatic-transgastric access tract; (v) anterograde balloon sphincteroplasty; and (vi) anterograde advancement of stones across the ampulla using a balloon catheter. We reviewed outcomes and complications of this technique. Six patients with previous Roux-en-Y gastric bypass were referred for treatment of symptomatic choledocholithiasis. EUS-guided transhepatic puncture and cholangiography was successful in 100 %, and revealed choledocholithiasis in all patients. Tract dilation, anterograde balloon sphincteroplasty, and stone extraction were successful in four (67 %). Anterograde sphincteroplasty failed in two patients due to inability to advance the transhepatic dilation catheters. In both cases, wires were advanced down the afferent limb, and rendezvous ERCP using double-balloon enteroscopy was successful. Five patients experienced no complications. One patient in whom EUS anterograde therapy failed due to difficulty in advancing the transhepatic dilation catheter, developed a subcapsular hepatic hematoma. This was managed conservatively. Direct EUS-guided treatment of biliary stones after gastric bypass appears safe and feasible. Further studies are needed to confirm the safety and efficacy of this technique.

Stool antigen testing for the diagnosis and confirmation of eradication of Helicobacter pylori infection: a prospective blinded trial.

BACKGROUND AND AIMS: Helicobacter pylori is an established pathogen for a wide spectrum of gastroduodenal diseases. We investigated the usefulness of H. pylori stool antigen test (HpSA) before and after eradication therapy on patients referred for gastroscopy. METHODS: Over a 12-month period, 127 adult patients (47% males) underwent HpSA and gastroscopy with dual biopsies from the antrum and proximal body of the stomach for urease and histology. The positive patients (histology, urease or combined positive) received triple therapy consisting of clarithromycin 500 mg, amoxycillin 1 g and omeprazole 20 mg, each given twice daily for 7 days. Six weeks post-therapy, eradication was verified with the 13C-urea breath test (UBT) and the HpSA results compared on a second stool sample. RESULTS: Pre-therapy, 23/113 patients were positive by urease test, 22/112 by histology and 22/112 were combined positive. For the HpSA, compared to combined urease and histology as the reference standards, the sensitivity and specificity were 79 and 92% while the positive and negative predictive values (PPV and NPV) were 68 and 96%, respectively. Post-therapy, UBT was adopted as the reference standard and 18 paired samples were available for analysis: three were positive and 15 were negative. Sensitivity and specificity were 67 and 100% while the PPV and NPV were 100 and 94%, respectively. CONCLUSIONS: In this prospective study, HpSA was found to be a reasonably useful diagnostic test for H. pylori infection. Post-eradication, it was highly specific and similar to UBT in terms of PPV and NPV. The test is non-invasive and cheaper than the urease test or the UBT, making it a candidate in the investigation of dyspepsia.