Efficacy and Safety of Sofosbuvir/Velpatasvir/Voxilaprevir for Hepatitis C Virus (HCV) NS5A-Inhibitor Experienced Patients With Difficult to Cure Characteristics.

BACKGROUND: In clinical trials, hepatitis C virus (HCV) salvage treatment with sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) achieved an SVR12 rate of >95% in NS5A-experienced participants. Lower SVR12 rates have been reported in real-world studies, particularly for genotype (GT)3 infection and cirrhosis. We determined the efficacy and safety of SOF/VEL/VOX in a large real-world cohort. METHODS: We assessed the efficacy of salvage SOF/VEL/VOX for HCV infection in NS5A-inhibitor experienced participants with cirrhosis and portal hypertension, prior liver transplantation (LT) or severe extra-hepatic manifestations. SOF/VEL/VOX was available via an early access program. The primary outcome was SVR12. Secondary outcome was frequency of adverse events (AE). FINDINGS: Ninety-seven participants were included. Median age was 58, 82% were male, 78% had cirrhosis, most with portal hypertension (61%, n = 46/76), and 18% had prior-LT. Of the cirrhotic participants, 96% were Child-Turcotte-Pugh class A, and 4% were class B. Of the 72% with GT3, 76% were also cirrhotic. By intention-to-treat analysis, SVR12 rate was 85% (n = 82/97). Per protocol, the SVR12 rate was 90%, including 91% in GT1 (GT1a n = 18/18, GT1b n = 2/4), 89% in GT3 (n = 59/66) and 100% in GT6 (n = 3/3). SVR12 in participants with GT3 and cirrhosis was 90%. No predictors of non-SVR12 were identified. There were 4 serious AEs including 1 death and 3 hepatic decompensation events. NS5A resistance-associated substitutions detected at baseline did not affect SVR12. CONCLUSIONS: This real-world study confirms high efficacy of SOF/VEL/VOX for the treatment of difficult-to-cure NS5A-inhibitor experienced patients, including those with GT3 and cirrhosis. Treatment was well tolerated in most; however, serious AEs can occur in those with advanced liver disease.

Response to endoscopic therapy for biliary anastomotic strictures in deceased versus living donor liver transplantation.

BACKGROUND: Endoscopic therapy has been successful in the management of biliary complications after both deceased donor liver transplantation (DDLT) and living donor liver transplantation (LDLT). LDLT is thought to be associated with higher rates of biliary complications, but there are few studies comparing the success of endoscopic management of anastomotic strictures between the two groups. This study aims to compare our experience in the endoscopic management of anastomotic strictures in DDLT versus LDLT. METHODS: This is a retrospective database review of all liver transplant patients undergoing endoscopic retrograde cholangiopancreatography (ERCP) after liver transplantation. The frequency of anastomotic stricture and the time to develop and to resolve anastomotic stricture were compared between DDLT and LDLT. The response of anastomotic stricture to endoscopic therapy was also analyzed. RESULTS: A total of 362 patients underwent liver transplantation between 2003 and 2011, with 125 requiring ERCP to manage biliary complications. Thirty-three (9.9%) cases of DDLT and 8 (27.6%) of LDLT (P=0.01) were found to have anastomotic stricture. When comparing DDLT and LDLT, there was no difference in the mean time to the development of anastomotic strictures (98+/-17 vs 172+/-65 days, P=0.11), likelihood of response to ERCP [22 (66.7%) vs 6 (75.0%), P=0.69], mean time to the resolution of anastomotic strictures (268+/-77 vs 125+/-37 days, P=0.34), and the number of ERCPs required to achieve resolution (3.9+/-0.4 vs 4.7+/-0.9, P=0.38). CONCLUSIONS: Endoscopic therapy is effective in the majority of biliary complications relating to liver transplantation. Anastomotic strictures occur more frequently in LDLT compared with DDLT, with equivalent endoscopic treatment response and outcomes for both groups.

Comparison of acoustic radiation force impulse imaging (ARFI) to liver biopsy histologic scores in the evaluation of chronic liver disease: A pilot study.

BACKGROUND AND AIMS: Acoustic Radiation Force Impulse Imaging (ARFI) is a novel non invasive technique studying the localized mechanical properties of tissue by utilising short, high intensity acoustic pulses (shear wave pulses) to assess the mechanical response (tissue displacement), providing a measure of tissue elasticity. The aim of this study is to investigate the feasibility of ARFI imaging as a non-invasive method for the assessment of liver fibrosis compared to liver biopsy scores. MATERIALS AND METHODS: A prospective blind comparison study of ARFI elastography (Virtual Touch Imaging., ACUSON S2000 Ultrasound Unit, Siemens, Mountain View CA) in a consecutive series of patients who underwent liver biopsy for assessment of fibrosis in chronic liver disease. ARFI shear-wave propagation velocity was measured in meters per second. Mean ARFI velocities were compared with both Batts-Ludwig (F0 to F4) and Modified Ishak scores (F0 to F4) for fibrosis in liver biopsy findings. Twenty-one patients with chronic liver disease (Hepatitis C (HCV) =16, Hepatitis B (HBV) = 1, both HCV and HBV = 1 Alcoholic liver disease (ALD) = 1, others = 2) underwent ARFI and liver biopsy on the same day. RESULTS: The Spearman correlation coefficients between the median values of the ARFI measurements and the histological fibrosis stage of the Modified Ishak score and Batts-Lud- (3) wig score were both highly significant (p < 0.01) with rho = 0.69 and rho = 0.72 respectively. The median ARFI (total 180 replications; minimum 5, maximum 10 measurements per patients) velocities for our study population range from 0.92 to 4.17 m/sec. Areas under the receiver operating characteristic curve for the accuracy of ARFI imaging was 1.00 and 0.35, for the diagnosis of moderate fibrosis (histologic fibrosis stage, F (3) 2) and 0.85 and 0.85 respectively for Ishak and Batts-Ludwig score, for the diagnosis of cirrhosis. CONCLUSION: ARFI imaging has a strong correlation with the fibrosis stage of both Batts-Ludwig and shak score in chronic liver disease. It.s accuracy in prediction of severe fibrosis and cirrhosis is maximal in comparison with earlier stages.

Spontaneous clearance of hepatitis C infection post-liver transplant: A rare but real phenomenon? A case report and review of the literature.

Recurrent hepatitis C virus (HCV) infection after liver transplantation is a significant cause of morbidity, mortality and graft loss. Spontaneous clearance of recurrent HCV after liver transplant is a rarely reported phenomenon. We report a case of a 66-year-old woman who underwent liver transplantation for HCV cirrhosis (treatment- naive genotype 2) under immunosuppression with tacrolimus, mycophenolate mofetil (MMF), and short-term corticosteroids. The patient developed histologically proved severe cholestatic recurrence of HCV hepatitis. Immunosuppression was reduced to tacrolimus monotherapy because of cytopenia. She subsequently became RNA negative at week 44 post- transplant while on tacrolimus and MMF despite no antiviral therapy. A spontaneous sustained virologic clearance was confirmed with subsequent HCV nucleotide testing. Only a few similar cases have been reported in the literature with uninterrupted immunosuppression and subsequent spontaneous clearance. Our experience, and the few other published cases in the literature, suggests that spontaneous clearance of HCV after liver transplantation is a rare but real phenomenon. Better understanding of this phenomenon may help to manage recurrent HCV disease after transplantation.

Methadone maintenance therapy in liver transplantation.

Cirrhosis due to chronic infection with hepatitis C virus remains by far the most common reason for liver transplantation in North America. Currently, parenteral use of street drugs is the most common means of acquiring hepatitis C. Methadone maintenance therapy is an accepted form of treatment for chronic opiate (eg, heroin) addiction and, not surprisingly, a significant proportion of methadone-treated patients have chronic hepatitis C. The feasibility of liver transplant candidacy in hepatitis patients who require methadone maintenance therapy is controversial, and some transplant centers require patients to withdraw from such therapy in order for the transplant process to move forward. Thus stable patients with end-stage cirrhosis who are receiving methadone maintenance are left in a most difficult situation: discontinue methadone and accept the side effects of withdrawal with the risk of recidivism to use of street opiates, an absolute contraindication for transplantation, or continue methadone therapy and risk exclusion from the transplant process. The issue of methadone replacement therapy in end-stage cirrhosis and the posttransplant literature on the subject are explored in this paper.

Prevalence, risk factors and metabolic profile of the non-obese and obese non-alcoholic fatty liver disease in a rural community of South Asia.

INTRODUCTION: Since there is a paucity of data on the epidemiology of the non-alcoholic fatty liver disease (NAFLD), particularly in rural areas in Asia, we undertook such a study among the population of a rural community in Bangladesh with the aims to (1) determine the prevalence of non-obese and obese NAFLD, (2) compare the sociodemographic clinical and metabolic characteristics between non-obese and obese NAFLD subjects, and (3) determine the risk factors of NAFLD and no-nobese NAFLD. METHODS: In this door-to-door survey, clinical examination, anthropometric measurements, biochemical tests and ultrasonography were performed on the adult population (≥18 years) of three villages in Bangladesh. RESULTS: Of 1682, 1353 (80.44%) responded. After the exclusion of 48 subjects for alcohol consumption, HBsAg or anti-hepatitis C virus positivity, 1305 ((mean age 41.28±15.10 years, female 908 (69.6%)) were included in the final analysis. On ultrasonography, among the study population, 57 (4.4%) non-obese, 185 (14.2%) obese and, overall, 242 (18.5 %, (male 23.40%, female 16.4%, p=0. 003)) participants had NAFLD. NAFLD was detected in 57/804 (7.1%) of non-obese and 185/501 (36.93%) obese participants. Among the lean subjects, 24/592 (4.1%) had NAFLD. Among NAFLD subjects, 57 (23.55%) were non-obese, and 53 (22%) had raised alanine aminotransferase. On multivariate analysis, age >40 years, male gender, metabolic syndrome (MS), diabetes mellitus (DM), abdominal obesity, hypertension, dyslipidaemia and obesity were found as the risk factors for NAFLD. There were no differences in sociodemographic characteristics, DM, MS, abdominal obesity, hypertension and dyslipidaemia between non-obese and obese NAFLD (all p>0.05). CONCLUSION: In this community study in Bangladesh, NAFLD was present in 18.5% participants, one-quarter of whom were non-obese. Apart from body mass index, the metabolic profile was comparable between obese and non-obese NAFLD. Public health measures are needed to control and prevent NAFLD and MS and their adverse health consequences.

Late acute celiac and hepatic artery thrombosis with portal vein thrombosis resulting in hepatic infarction 12 years post orthotopic liver transplantation.

Hepatic artery thrombosis (HAT) is relatively infrequent, but possibly a devastating complication of orthotopic liver transplantation (OLT). It often requires urgent retransplantation. Two main forms of HAT are recognized as early and late HAT (diagnosis within or after 30 days following LT). Early HAT typically results in graft failure. Late HAT features biliary obstruction, cholangitis, and hepatic abscess formation. We report here the case of a patient of Wilson's disease who presented twelve years post-liver transplant symptoms typical of acute HAT and hepatic infarction. On diagnostic imaging, celiac axis and hepatic artery were thrombosed, resulting in ischemic necrosis of the left hepatic lobe. The resulting sepsis and transient hepatic insufficiency were managed conservatively, and repeat OLT was avoided. The patient remains stable more than one year later. To the best of our knowledge this case report is unique in the literature for the unusually long interval between OLT and late acute HAT, as well as celiac and portal vein occlusion. The acute presentation of sub massive hepatic necrosis is also uncharacteristic of late HAT and more typical of acute HAT. This report describes our experience in managing this and a literature review of the topic.

Oral bismuth for chronic intractable diarrheal conditions?

OBJECTIVE: Bismuth has antidiarrheal, antibacterial, and anti-inflammatory properties. We report our single-center experience with oral colloidal bismuth subcitrate (CBS) treatment for patients with chronic intractable diarrhea. METHOD: We interrogated our web-based Inflammatory Bowel Disease Clinical and Research database to ascertain clinical details on all patients in our tertiary hospital gastroenterology service treated with CBS between 2000 and 2010. Treatment responses were based on prospective scoring of daily number of liquid stools. Responses were recorded prior to commencement of CBS and at follow-up visits over 12 months. RESULTS: Thirty-one patients, mean age 47 years (range 17-79 years) and a mean duration of diarrhea of 22 weeks (range 6-104 weeks), were prescribed CBS at doses ranging from 120 mg to 480 mg/day for ≥1 month. Of these, 23 patients (74%) had an initial clinical response and 12 (39%) who continued with this treatment had a sustained clinical response at 1 year. Twelve patients with pouchitis and four patients with indeterminate colitis had initial responses of 92% and 75%, respectively, and sustained responses of 50% and 75%, respectively. Ulcerative colitis patients (n = 5) responded poorly with respect to both initial and sustained responses. Three patients with microscopic colitis showed encouraging initial response of 100% but did not have any sustained benefit. Three of four patients with diarrhea-predominant irritable bowel syndrome (dIBS) had an initial response and two (50%) had good sustained responses. There were no serious adverse events. One patient stopped therapy because of nausea. CONCLUSION: This is the largest report of oral bismuth treatment in chronic intractable diarrhea. CBS is cheap and appears to have the potential to be effective for ameliorating diarrheal symptoms in indeterminate colitis, pouchitis, and dIBS. An appropriately powered, blinded, randomized, controlled study appears warranted to establish the position of oral bismuth in routine practice.

In a 'real-world', clinic-based community setting, sorafenib dose of 400 mg/day is as effective as standard dose of 800 mg/day in patients with advanced hepatocellular carcimona, with better tolerance and similar survival.

BACKGROUND: Sorafenib, an oral multityrosine kinase inhibitor, has been approved for treatment of unresectable hepatocellular carcinoma (HCC). British Columbia (BC) was the first province in Canada to provide drug coverage for sorafenib. OBJECTIVE: To review the BC experience with sorafenib to assess its effectiveness and tolerance in a 'real-world' clinical setting. METHODS: A retrospective clinic chart review identified 99 patients referred to the BC Cancer Agency from 2008 to 2010 with a diagnosis of HCC who qualified for treatment with sorafenib. RESULTS: Therapy with sorafenib was initiated and continued at a reduced dosage of 400 mg/day in 66 of 99 patients, with 22 patients requiring further dose reduction. Full- and reduced-dose group patients had similar baseline characteristics, except for a higher proportion of female patients (P=0.02) and individuals with alcoholic liver disease (P=0.04) in the full-dose group. The incidence of any grade of adverse effects was higher in the full-dose group (94% versus 77% in the reduced-dose group; P=0.04). Dose reduction rates were significantly higher in the full-dose group, occurring in 66% versus 24% of reduced-dose group patients (P=0.001). The overall survival rates were similar between the two groups: 7.8 months versus 7.1 months in full- versus reduced-dose groups (P=0.14), as were radiological progression rates and alpha-fetoprotein levels. CONCLUSIONS: In a review of 99 patients in a 'real-world' community setting, a sorafenib dose of 400 mg/day was better tolerated and had similar efficacy compared with a sorafenib dose of 800 mg/day with respect to survival and outcomes.

Transient improvement of acquired hepatocerebral degeneration with parkinsonian symptoms after failed liver transplant: case report and literature review.

OBJECTIVES: Acquired (non-Wilsonian) hepato-cerebral degeneration is an infrequent neurologic disorder in patients with liver dysfunction and longstanding portal-systemic shunting. The clinical manifestations include dysarthria, ataxia, tremor, and cognitive dysfunction. Typically, patients with acquired hepatocerebral degeneration respond poorly to medical therapy as the underlying end-stage liver disease remains. Information regarding the effect of orthotopic liver transplant on acquired hepatocerebral degeneration, however, is limited and conflicting. MATERIALS AND METHODS: We conducted a review of literature via a PubMed search to summarize the effect of orthotopic liver transplant on acquired hepatocerebral degeneration. RESULTS: We present a 56-year-old man with compensated hepatitis C cirrhosis who developed acquired hepatocerebral degeneration with Parkinsonian symptoms refractory to conventional Parkinson medical therapy. Orthotopic liver transplant led to marked clinical improvement of the acquired hepatocerebral degeneration. However, the patient developed recurrence of acquired hepatocerebral degeneration 6-week postorthotopic liver transplant as he developed graft failure from aggressive progressive hepatitis C recurrence. Our review found a heterogeneous group of case series, suggesting that the experience with orthotopic liver transplant is variable. CONCLUSIONS: Our experience demonstrates that orthotopic liver transplant may lead to resolution of acquired hepatocerebral degeneration; however, acquired hepatocerebral degeneration may return with recurrent liver disease. Future studies with long-term follow-up are needed.

Gastric polyps in patients with portal hypertension.

OBJECTIVES: Gastric hyperplastic polyps are usually associated with chronic gastritis including Helicobacter pylori gastritis and postantrectomy stomachs. Here, we report on a series of 12 patients with portal hypertension secondary to liver cirrhosis, who were found to have a unique histological type of gastric polyp on endoscopy. METHODS: Retrospective chart review of 12 patients with portal hypertension, who presented with histologically diagnosed gastric hyperplastic polyps. These polyps were reviewed and compared with hyperplastic polyps from 21 patients who did not have portal hypertension. RESULTS: The endoscopic appearances of portal hypertension-associated polyps varied considerably, with sizes ranging up to 18 mm. They were sessile or pedunculated, singular or multiple, found in the antrum or body of the stomach, and endoscopically appeared to be typical hyperplastic polyps. Histopathological examination, however, showed mucosal hyperplasia and extensive vascular proliferation and granulation tissue formation. CONCLUSION: The unique histological appearance of gastric hyperplastic polyps in patients with portal hypertension polyps is described. The exact pathogenetic mechanism of polyp formation is unclear although it seems possible that the underlying cause is mucosal injury that is vascular in nature rather than being secondary to surface inflammation. Although there is an emerging evidence of the neoplastic potential of usual hyperplastic polyps, the natural history of portal hypertension-associated polyps is unknown. Identification and management of portal hypertension-associated gastric polyps present a particular dilemma, as these patients often have coagulopathies and vascular ectasias. Therefore, the natural history and endoscopic features of gastric polyps arising in portal hypertensive patients warrants further exploration.

Central pontine myelinolysis after orthotopic liver transplant-a rare complication.

Central pontine myelinolysis is a rare but devastating cause of morbidity and mortality after orthotopic liver transplant. The exact cause of central pontine myelinolysis is uncertain. However, rapid correction of hyponatremia has been described as a major factor. We describe a patient with central pontine myelinolysis after orthotopic liver transplant in the absence of significant hyponatremia. Although rapid correction of hypernatremia has been reported in association with central pontine myelinolysis, to our knowledge, in this case, where the serum sodium went from normal to hypernatremic, later diagnosis of central pontine myelinolysis in a postliver transplant setting is unique. We also discuss factors that may contribute to the development of central pontine myelinolysis after orthotopic liver transplant and its pathophysiology.