Rhys Vaughan

Resistance to adefovir dipivoxil therapy associated with the selection of a novel mutation in the HBV polymerase

BACKGROUND & AIMS Adefovir dipivoxil effectively inhibits both hepatitis B virus (HBV) replication and disease activity in patients with chronic hepatitis B. Resistance to treatment was not observed in 2 recent large placebo-controlled 48-week studies with this drug. The aim of this study was to characterize adefovir resistance in a patient who developed clinical and virologic evidence of breakthrough during a 96-week course of treatment. METHODS HBV DNA was PCR amplified and sequenced. Phenotypic studies used patient-derived HBV as well as specific mutations created by site-directed mutagenesis of a HBV/baculovirus recombinant. RESULTS Following the commencement of treatment with adefovir dipivoxil, the patient initially responded with a 2.4 log(10) decrease in serum HBV DNA and normalization of alanine aminotransaminase levels by week 16. During the second year of treatment, however, serum HBV DNA rose progressively, eventually returning to near-pretreatment levels. This increase in viral replication was associated with a marked increase in alanine aminotransferase and mild changes in bilirubin, albumin, and prothrombin time. Comparison of pretreatment and posttreatment HBV DNA by polymerase chain reaction sequencing identified a novel asparagine to threonine mutation at residue rt236 in domain D of the HBV polymerase. In vitro testing of a laboratory strain encoding the rtN236T mutation and testing of patient-derived virus confirmed that the rtN236T substitution caused a marked reduction in susceptibility to adefovir. CONCLUSIONS The development of this novel mutation in the HBV polymerase confers resistance to adefovir dipivoxil. The patient responded to subsequent lamivudine therapy, achieving normalization of alanine aminotransferase and a significant decrease in serum HBV DNA.

Right-sided adenoma detection with retroflexion versus forward-view colonoscopy.

BACKGROUND Colonoscopy and polypectomy can prevent up to 80% of colon cancer; however, a significant adenoma miss rate still exists, particularly in the right side of the colon. OBJECTIVE To assess whether retroflexion in the right side of the colon significantly improves the adenoma detection rate (ADR) over forward-view assessment. DESIGN Multicenter prospective cohort study. SETTING Three tertiary care public and 2 private hospitals. PATIENTS A total of 1351 consecutive adult patients undergoing elective colonoscopy. INTERVENTION Withdrawal from the cecum was performed in the forward view initially and identified polyps removed. Once the hepatic flexure was reached, the cecum was reintubated and the right side of the colon was assessed in the retroflexed view to the hepatic flexure. MAIN OUTCOME MEASUREMENTS ADR in the retroflexed view when compared with forward-view examination of the right side of the colon. RESULTS Retroflexion was successful in 95.9% of patients, with looping the predominant (69.6%) reason for failure. Forward-view assessment of the right side of the colon identified 642 polyps, of which 531 were adenomas yielding a polyp and ADR of 28.57% and 24.64%, respectively. Retroflexion identified a further 84 polyps of which 75 were adenomas, improving the polyp and ADR to 30.57% and 26.4%, respectively. LIMITATIONS Observational study. CONCLUSION Right-sided retroflexion was successful in most of our cohort with a statistically significant but small increase in ADR. Right-sided retroflexion is safe when performed by experienced endoscopists with no adverse events observed in this cohort. ( CLINICAL TRIAL REGISTRATION Australian New Zealand Clinical Trials Registry, ACTRN12613000424707.).

Intestinal transplantation: Current status and future directions

Three decades after the first intestinal transplant was performed in humans, this life‐saving procedure has come of age and now offers hope of long‐term survival in a small group of patients with life‐threatening complications of intestinal failure and parenteral nutrition. Success rates have greatly improved, largely through advances in immunosuppression protocols, improved surgical technique and postoperative care, and accumulated experience. Management of the intestinal transplant recipient entails careful surveillance, prevention, and treatment of rejection and infection, as well as optimization of feeding and nutrition. With this approach, survival and quality of life are demonstrably improved, such that intestinal transplantation is now an established and accepted procedure for this very select group of highly‐complex patients.

Evidence for altered vascular responses to exogenous endothelin-1 in patients with advanced cirrhosis with restoration of the normal vasoconstrictor response following successful liver transplantation

Background and aims: There is evidence that dampened responses to endogenous vasoconstrictors contribute to the hyperdynamic circulation that is characteristic of advanced cirrhosis. The aim of this study was to determine whether there is an altered vascular responsiveness to the endothelium derived constricting factor endothelin-1 (ET-1) in patients with decompensated chronic liver disease which might contribute to this abnormal circulatory state, and whether normal endothelin responses are restored following liver transplantation. Methods: Using forearm plethysmography, we studied the vascular response to an intra-arterial ET-1 infusion in six patients with end stage cirrhosis, before and after liver transplantation, compared with six normal control subjects. Responses to the selective endothelin A (ETA) receptor subtype antagonist, BQ123, were also examined. Results: The forearm vessels of patients with cirrhosis vasodilated in response to ET-1 infusion while in healthy controls a marked vasoconstriction response was observed (p<0.0001, area under the curve time-blood flow was normal compared with the cirrhosis groups, ANOVA). Prior to commencement of liver transplant surgery, cirrhotic patients were confirmed to have a hyperdynamic circulation with a high cardiac index (4.07 (0.23) l/min/m2 (normal range 2.8–3.6 l/min/m2)) and low systemic vascular resistance index (1284 (115) dyn×s/cm5/m2 (normal range 1760–2600 dyn×s/cm5/m2)). Following transplantation, normal vasoconstrictor responses to ET-1 were restored. Responses to BQ123 were not different in patients with advanced cirrhosis compared with controls. Conclusion: In patients with end stage cirrhosis, ET-1 produces vasodilatation at a dose that causes marked vasoconstriction in normal control subjects. This effect is not attributable to impairment of ETA receptor responses. Our findings suggest that altered endothelin responses may contribute to the generalised dilatation of the circulation that occurs in patients with advanced liver disease.

Norfloxacin and trimethoprim–sulfamethoxazole therapy have similar efficacy in prevention of spontaneous bacterial peritonitis

Background and Aim:  Although norfloxacin (N) is widely accepted as the drug of choice for spontaneous bacterial peritonitis (SBP) prophylaxis, there is data to suggest that trimethoprim–sulfamethoxazole (TS) may be similarly effective. However, no studies have compared the efficacy and safety of N and TS in SBP prophylaxis. The aim of this retrospective analysis was to compare outcomes in patients who received either N or TS for the prevention of SBP.

Predictors of improvement in renal function after calcineurin inhibitor withdrawal for post-liver transplant renal dysfunction.

Abstract:  Background:  Renal dysfunction after liver transplantation is a major management problem. Predictors of improvement in renal dysfunction after calcineurin inhibitor therapy (CNI) withdrawal and replacement with either mycophenolate mofetil (MMF) or azathioprine (AZA) have not previously been examined.

Risk stratification of upper GI bleeding with an esophageal capsule

BACKGROUND Analysis of upper GI bleeding (UGIB) presentations to our institutions suggests that many patients admitted for endoscopic investigation could be managed safely as outpatients. OBJECTIVE To learn whether an esophageal capsule could identify a low-risk group of patients with UGIB who could safely wait for elective EGD. DESIGN Diagnostic, nonrandomized, single-blind (investigator) study. SETTING Three tertiary-care referral centers. PATIENTS Eighty-three consecutive adult patients referred for management of UGIB. INTERVENTION A capsule endoscopy (CE) was performed before EGD for the investigation and management of UGIB. MAIN OUTCOME MEASUREMENTS Detection rates of UGIB source and identification of a low-risk group of patients who would have been suitable for outpatient EGD based on CE findings. RESULTS In total, 62 of 83 patients (75%) had a cause for bleeding identified. Findings were concordant across both modalities in 34 patients (55%). Twenty-one patients (38%) with positive EGD results had negative CE results, 7 of whom were due to lack of duodenal visualization alone. However, 7 of 28 patients (25%) with normal EGD results had positive CE results. The subgroup of patients with duodenal visualization on CE, 23 of 25 (92%), were concordant with EGD for low-risk lesions that would have been suitable for outpatient management. LIMITATIONS Low duodenal visualization rates with CE and low concordance between EGD and CE. CONCLUSION Although CE is not currently ready to be used as a triage tool, when duodenal visualization was achieved CE correlated well with EGD findings and identified 92% of patients who may have been managed as outpatients.

A prospective multicenter evaluation of a new side-port endoscopic ultrasound-fine-needle aspiration in solid upper gastrointestinal lesions

Background and Study Aims:  Diagnostic yield of endoscopic ultrasound (EUS)‐fine‐needle aspiration (FNA) varies depending on the equipment used and the site targeted. Multiple needle passes are usually required to obtain a diagnosis. A new needle incorporating a side‐port carries a theoretical advantage regarding acquisition of cytological material. The aim of the study was to demonstrate the safety and efficacy of the Olympus side‐port needle in solid upper gastrointestinal indications.

Vasoconstrictor responses are normal but prostanoid-mediated vasodilatation is enhanced in human cirrhotic mesenteric arteries

Background and Aims:  The mechanisms responsible for mesenteric vasodilatation in cirrhosis have not been fully elucidated. The aim of the present study was to examine whether there is altered intrinsic vascular reactivity of human mesenteric vessels in cirrhosis, which might contribute to vasodilatation in vivo.

A randomized controlled study of trimethoprim-sulfamethoxazole versus norfloxacin for the prevention of infection in cirrhotic patients.

To prospectively compare norfloxacin (N) with trimethoprim‐sulfamethoxazole (T‐S) in preventing infection in cirrhotic patients.