All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database.

BACKGROUND: Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV-TARGET collects data in patients treated at tertiary academic and community centres. AIM: To assess efficacy of all-oral HCV therapy in advanced liver disease. METHODS: Between December 2013 and October 2014, 240 patients with a MELD score of ≥10 initiated HCV treatment with an all-oral regimen. Data from the 220 patients who completed 12-week follow-up were analysed. RESULTS: Genotype 1 (GT1) patients had higher sustained virological response (SVR) when treated with sofosbuvir plus simeprevir ± ribavirin than with sofosbuvir plus ribavirin (66-74% vs. 54%); GT1b vs GT1a (84% vs. 64%). SVR for GT2 was 72% with sofosbuvir plus ribavirin, while GT3 patients had a substantially lower response (35%). A decrease in MELD score was not clearly related to SVR over the short course of follow-up although some had improvements in MELD score, serum bilirubin and albumin. A predictor of virological response was albumin level while negative predictors were elevated bilirubin level and GT1a. Most patients with GT1 were treated with approximately 12-week duration of sofosbuvir and simeprevir ± ribavirin therapy while GT2 and GT3 patients were treated with approximately 12 and 24 weeks of sofosbuvir plus ribavirin respectively. CONCLUSIONS: All-oral therapies are effective among patients with advanced liver disease with high levels of success in GT2 and GT1b, and may serve to reduce the severity of liver disease after SVR. Treatment for GT3 patients remains an unmet need. Clinical trial number: NCT01474811.

Standardization of terminology of virological response in the treatment of chronic hepatitis C: panel recommendations.

The treatment paradigm for hepatitis C virus (HCV) infection is at a critical point in its evolution. The addition of a protease inhibitor to peginterferon plus ribavirin has become the new standard-of-care treatment for most patients. Data from clinical trials of new antivirals have been difficult to interpret and compare, partly because of heterogeneity in trial design, and partly because of inconsistencies in terminology used to define viral responses and the populations evaluated. Present definitions of viral responses for treatment with peginterferon and ribavirin are insufficient for novel treatment paradigms. Further, categorization of prior patient treatment experience in clinical trials, particularly of nonresponders to prior therapy, is inconsistent. Existing terms and definitions must be updated, standardized and/or redefined for easier interpretation of data and effective communication among clinicians. A panel of experts in HCV infection treatment met on 3 December 2009. Goals of the panel were to evaluate terms and definitions used traditionally in treatment with peginterferon and ribavirin, to refine and clarify definitions of existing terms that have varying meanings and to propose new terms and definitions appropriate for novel treatment paradigms emerging with development of new agents. A number of recommendations were accepted unanimously by the panel. Adoption of these terms would improve communication among investigators, enhance comparability among clinical trials, facilitate development of therapeutic guidelines and provide a standardized terminology for use in clinical practice.

The effects of midodrine on the natriuretic response to furosemide in cirrhotics with ascites.

BACKGROUND: Resistance to loop diuretics is common in patients with ascites. Diminished glomerular filtration rate (GFR) is thought to mediate resistance to loop diuretics. Midodrine, a commonly used alpha-1 agonist, has been shown to improve GFR in non-azotemic patients with cirrhosis. AIM: To conduct a randomized, double-blind, placebo-controlled, cross-over study to test the hypothesis that midodrine significantly increases natriuretic response of IV furosemide in non-azotemic cirrhotics with ascites. METHODS: All subjects participated in both phases, which were (i) furosemide IV infusion + oral midodrine 15 mg administered 30 min before furosemide (ii) furosemide IV infusion + oral placebo administered 30 min before furosemide. Primary outcomes were 6-h urine sodium excretion and 6-h total urine volume. RESULTS: A total of 15 patients (men: 8; age: 52.7 ± 7.6 years; serum creatinine: 1.06 ± 0.2 mg/dL) were studied. Total 6-h urine sodium excretion was 109 ± 42 mmol in the furosemide + midodrine treatment phase and was not significantly different from that in the furosemide + placebo treatment phase (126 ± 69 mmol, P = 0.6). Similarly, mean 6-h total urine volume was not significantly different between two groups (1770 ± 262 mL vs. 1962 ± 170 mL, P = 0.25). CONCLUSIONS: Oral midodrine does not increase the natriuretic response to furosemide in non-azotemic cirrhotic patients with ascites. Orally administered midodrine does not increase natriuretic response to furosemide in non-azotemic cirrhotic patients with ascites.

Simultaneous liver and pancreas transplantation in patients with cystic fibrosis.

BACKGROUND: Improved survival in patients with cystic fibrosis (CF) has led to an increased incidence of extrapulmonary complications of this disease. Of these, cirrhosis and pancreatic insufficiency, including CF-related diabetes (CFRD) and exocrine insufficiency, are significant causes of morbidity and mortality. Liver transplantation is the treatment of choice for cirrhosis in this setting, but the addition of an isolated simultaneous pancreas transplant in patients with CFRD has not been reported. METHODS: Two female patients with CF underwent simultaneous pancreas and liver transplantation. Both had pancreatic insufficiency, CFRD, cirrhosis, and preserved renal function. In each case, the liver and pancreas were procured from a single cadaveric donor. The liver transplant was performed first. A lower midline extension was added for improved exposure of the iliac vessels. The donor pancreas transplant was performed with systemic venous drainage and enteric exocrine drainage. Immunosuppression included rabbit anti-thymocyte globulin, tacrolimus, mycophenolate mofetil, and early steroid withdrawal. RESULTS: Both patients recovered well with normal liver function, resolution of portal hypertension, and normal blood glucoses independent of insulin. As a result of the enteric exocrine drainage of the pancreas, they are now independent of supplemental pancreatic enzymes. CONCLUSIONS: Simultaneous liver and pancreas transplantation in CF patients provides the advantages of normalization of glucose and improved nutrition for patients requiring liver transplantation and should be considered in CF patients with CFRD who require liver transplants.

Effect of food and food composition on alcohol elimination rates in healthy men and women.

Several studies have evaluated the effect of food on alcohol pharmacokinetics; however, most studies have used oral alcohol administration, which cannot separate the influence of food on absorption from its influence on alcohol elimination. Alcohol clamping uses intravenous alcohol and provides a direct measure of the alcohol elimination rate (AER). Two studies, using alcohol clamping at 50 mg %, were conducted to investigate the effect of food and food composition on AER (g/h) in healthymen and women. In the first study, 20 subjects underwent two clamping sessions, one after a 12-hour fast and another 1 hour after consuming a 530-calorie breakfast. In the second study, 8 subjects underwent four clamping sessions: one after a 12-hour fast and, in each of three "fed" sessions, 1 hour after a 550-calorie high-fat, high-protein, or high-carbohydrate breakfast. Comparison of AERs from the first study showed an average 25% increase following food compared to thatfollowingfasting. Men showed significantly higher AERs compared to women; however, the food effect was similar in both genders. In the second study, the AER showed a significant average 45% increase following the meal, regardless of composition, compared with that following fasting. These findings indicate that food intake results in increased alcohol elimination rates. The increase was similar for meals of different compositions, suggesting that the food effect is not due to specific interactions with meal constituents. Probable mechanisms for the increased alcohol elimination includefood-induced increases in hepatic blood flow and in the activity of alcohol-metabolizing enzymes.

Treatment of chronic hepatitis C in nonresponders to interferon monotherapy.

Sixty percent of patients fail to respond to interferon monotherapy. African-Americans with hepatitis C appear to respond less well to interferon monotherapy. Retreatment with a higher dose of consensus interferon for 48 weeks has led to a sustained virologic response rate of 13%. As a group, interferon nonresponders who breakthrough while on interferon monotherapy seem to have a more favorable response rate to a repeat course of treatment. Retreatment with interferon and ribavirin for 6 months in nonresponders led to a sustained virologic response rate of 21%. Preliminary results from two trials in the United States demonstrate similar treatment efficacy. There is now evidence that maintenance interferon therapy may also be beneficial in interferon monotherapy nonresponders.

Predictors of large esophageal varices in patients with cirrhosis.

OBJECTIVE: Recent guidelines recommend that all cirrhotics undergo screening upper endoscopy to identify those patients at risk for bleeding from varices. However, this practice may not be cost effective as large esophageal varices are seen only in 9-36% of these patients. The aim of this study was to determine whether clinical variables were predictive of the presence of large esophageal varices. METHODS: This is a retrospective analysis of cirrhotics who had a screening upper endoscopy during an evaluation for liver transplantation at three different centers and who had not previously bled from varices. A multivariate model was derived on the combined cohort using logistic regression. Three hundred forty-six patients were eligible for the study. RESULTS: The prevalence of large esophageal varices was 20%. On multivariate analysis, splenomegaly detected by computed tomographic scan (odds ratio: 4.3; 95% confidence interval: 1.6-11.5) or by physical examination (odds ratio: 2.0; 95% confidence interval: 1.1-3.8), and low platelet count were independent predictors of large esophageal varices. On the basis of these variables, cirrhotics were stratified into high- and low-risk groups for the presence of large esophageal varices. Patients with a platelet count of > or = 88,000/mm3 (median value) and no splenomegaly by physical examination had a risk of large esophageal varices of 7.2%. Those with splenomegaly or platelet count < 88,000/mm3 had a risk of large esophageal varices of 28% (p < 0.0001). CONCLUSIONS: Our data show that clinical predictors could be used to stratify cirrhotic patients for the risk of large esophageal varices and such stratification could be used to improve the cost effectiveness of screening endoscopy.

Vaccination against hepatitis B in patients with chronic liver disease awaiting liver transplantation.

BACKGROUND: Most transplant centers in the United States immunize patients awaiting liver transplantation against hepatitis B to prevent acquisition of hepatitis B through transplantation (de novo hepatitis B). A recent study showed that only 16% of patients with cirrhosis awaiting liver transplantation responded to single-dose recombinant vaccine. METHODS: We studied the immunogenicity of double-dose recombinant vaccine in patients with cirrhosis awaiting liver transplantation. RESULTS: Over a 4-year period (January 1994 to December 1997), 140 patients with cirrhosis without past or current hepatitis B infection were given double-dose recombinant vaccine (40 microg of Engerix B; SmithKline Beecham, Philadelphia, PA) at 0, 1 to 2, and 2 to 4 months. Hepatitis B surface antibody (HBsAb) was measured 1 to 3 months after completing vaccination. The response rate was 37%. However, HBsAb titers became undetectable in 35% of the responders during the post-transplant follow-up period. One hundred and thirty-seven patients underwent 144 liver transplantation procedures during the study period, and 3 patients developed de novo hepatitis B (2.2%). Livers transplanted from hepatitis B core antibody (HBcAb)-positive donors was the source of de novo hepatitis B in all cases. Two of the 3 patients who developed de novo hepatitis B were immunized before transplantation and one of them was a responder. CONCLUSION: Although the response rate to double-dose recombinant vaccines is higher than the previously reported response to single-dose vaccine, it still is less than optimal.

Screening for hepatocellular carcinoma in patients with advanced cirrhosis.

OBJECTIVE: Most available data on screening for hepatocellular carcinoma (HCC) in patients with cirrhosis originate from Asia and Europe. These data may not be applicable to patients from the United States because of geographic variation in the underlying etiology and other factors. Our aim was to assess the risk of HCC in U.S. patients with cirrhosis undergoing standardized screening. METHODS: All cirrhotic patients evaluated for liver transplantation at our institution from January 1, 1994-December 31, 1997 were included in this study. The screening strategy included initial screening, which was offered to all patients and consisted of alpha-fetoprotein (AFP), abdominal ultrasound, and computed tomography (CT) scan, and extended screening, which was performed only on transplant-eligible patients and consisted of semiannual AFP and ultrasound. RESULTS: During the study period, 285 patients with cirrhosis were evaluated for transplantation and underwent initial screening. Of these, 166 were eligible for transplantation and underwent extended screening during a median follow-up of 15 months (range 6-42 months). Twenty-seven HCC were found, 22 during initial screening and five during extended screening. The cancer-free proportions of the cohort who underwent extended screening at 1, 2, and 3.5 yr were 98.6% +/- 1.4%, 96.4 +/- 1.8%, and 77.1% +/- 1.7%, respectively (mean +/- SE). Hepatitis C, either alone or in part, was the etiology in 63% of patients with HCC. The sensitivity of CT scan (88%) was significantly higher than AFP >20 ng/ml (62%) and ultrasound (59%) for detecting HCC (p < 0.001). CONCLUSIONS: In patients with established cirrhosis, the risk of detecting HCC is maximal at the baseline screening (7%). Hepatitis C was the most common etiology for cirrhosis in study. In U.S. patients with established cirrhosis, CT scan exhibited higher sensitivity for detecting HCC than ultrasound or AFP.

Gender differences in alcohol metabolism: relationship to liver volume and effect of adjusting for body mass.

BACKGROUND & AIMS: Alcoholic liver disease purportedly develops more readily in women than in men. Some studies have demonstrated faster rates of alcohol elimination in women. This study examined whether gender differences in alcohol metabolism are related to differences in liver volume and/or differences in lean body mass. METHODS: Ten men and 10 women had alcohol elimination rates determined by clamping of the breath alcohol concentration at 50 mg/dL by means of a constant rate of intravenous infusion of 6% ethanol. Liver volume was determined by computed tomography. RESULTS: Mean alcohol elimination rate and mean computed liver volume were not significantly different in men and women. Lean body mass was 42% greater in men than in women. Consequently, the calculated alcohol elimination rate and liver volume per kilogram of lean body mass were 33% and 38% higher in women than in men, respectively. When the alcohol elimination rate was calculated per unit liver volume, no gender-related difference was found. CONCLUSIONS: Women have greater clearance of ethanol per unit lean body mass, confirming previous oral alcohol administration studies. Women have approximately the same liver volume as men, explaining the equivalent alcohol elimination rates seen when men and women are compared on the basis of liver size.

The sequence and phylogenetic analysis of a novel hepatitis E virus isolated from a patient with acute hepatitis reported in the United States.

A variant of hepatitis E virus (HEV), designated HEV US-1, was identified in a hepatitis patient in the United States (US); the patient had no history of travel to areas where HEV is endemic. Nucleotide sequences were obtained from the 5' end of open reading frame (ORF) 1 (1418 nt), the 3' end of ORF1 (1359 nt), the entire ORF2 and ORF3 regions, and the 3'-untranslated region (2127 nt). The HEV US-1 strain is significantly divergent from other human HEV isolates with nucleotide identities ranging from 76.8 to 77.5%. Phylogenetic analyses indicate that HEV US-1 and a recently discovered HEV variant from swine may represent separate isolates of a new strain of HEV, significantly divergent from the Mexican and Burmese strains. Synthetic peptides derived from the carboxyl amino acids of ORF2 and ORF3 were shown to be useful for detecting exposure to HEV. In addition, IgM class antibodies directed against HEV US-1 synthetic peptides were detected in the US patient infected with HEV US-1, but were absent using synthetic peptides from the Burmese or Mexican strains of HEV. A preferential reactivity to HEV US-1 specific peptides has lead to the identification of a second isolate of this virus also from a patient with acute hepatitis from the US. The discovery of these HEV variants may be important in understanding the worldwide distribution of HEV infection.

Acute hepatitis E by a new isolate acquired in the United States.

OBJECTIVE: To report the first case of acute hepatitis E by a novel isolate acquired in the United States and confirmed by nucleotide sequencing. MATERIAL AND METHODS: We describe the clinical manifestations and the results of associated laboratory studies in a man who was found to have acute hepatitis E infection. RESULTS: A 62-year-old man was hospitalized because of fever, abdominal pain, and jaundice. After an initial evaluation did not provide a cause, his serum was found to be positive for IgG anti-hepatitis E virus (HEV) by three antibody assays. Serum was also positive for HEV RNA by reverse transcriptase polymerase chain reaction (PCR). Sequencing results from the PCR products demonstrated substantial differences at the nucleotide level between this strain and the known Mexican and Burmese strains. CONCLUSION: On the basis of this initial report, HEV should be considered an etiologic agent in patients with acute non-ABC hepatitis in the United States.

5-year incidence of adenomas after negative colonoscopy in asymptomatic average-risk persons [see comment].

BACKGROUND & AIMS: Cost-effectiveness of colorectal cancer screening will be maximized by selecting the widest screening intervals that effectively prevent cancer mortality. However, data on the incidence of neoplasia in persons with no abnormal findings on initial examination are limited. The aim of this study was to describe the incidence of colonic neoplasia 5 years after negative screening colonoscopy in asymptomatic average-risk persons. METHODS: We previously reported the results of screening colonoscopy in 496 asymptomatic average-risk persons, 368 of whom had no neoplasia identified. Colonoscopy to the cecum was performed in 154 of these persons at a mean of 66 months after the initial negative colonoscopy. RESULTS: Forty-one (27%) had at least one adenoma, but only 1 person had an adenoma > or = 1 cm and none had cancer, severe dysplasia, or villous or tubulovillous histology. Hyperplastic polyps at the initial examination did not predict incident adenomas. Regular nonsteroidal anti-inflammatory drug use was associated with a decreased rate of incident adenomas. CONCLUSIONS: In average-risk persons, the interval between screening examinations can be safely expanded beyond 5 years, provided the initial examination is a carefully performed complete colonoscopy that is negative for colonic adenomas or cancer.

Endoscopic esophageal manometry.

OBJECTIVE: We performed through-the-scope-manometry of the esophagus on 12 patients referred for esophageal symptoms. METHODS: A 3-lumen polyvinyl tube was passed through the biopsy channel of a standard video-endoscope. All patients underwent esophagogastroduodenoscopy with through-the-scope-manometry as well as a conventional laboratory-based manometric study; the sequence of the procedures was randomized. RESULTS: Mean lower esophageal sphincter pressure was 18 +/- 11 mm of mercury by both methods. In the lower esophagus, mean wave amplitude was 60 +/- 25 mm of mercury by through-the-scope manometry and 82 +/- 28 by laboratory testing. In the upper esophagus, mean wave amplitude was 50 +/- 26 mm of mercury by through-the-scope manometry and 63 +/- 20 by laboratory testing. Wave duration tended to be lower by through-the-scope manometry than by laboratory testing in the lower and upper esophagus. In nine patients with normal esophageal motility, 54% of swallows resulted in a peristaltic wave by the endoscopic study versus 100% for the laboratory test. CONCLUSION: Through-the-scope-manometry was able to accurately measure lower esophageal sphincter pressure compared with laboratory-based manometry. Peristaltic wave amplitude by through-the-scope manometry was reduced compared with laboratory-based manometry, most likely because of the use of dry swallows. Through-the-scope-manometry has promise as a screening test for esophageal motility disorders.

Nonsteroidal anti-inflammatory drug-induced enteropathy: case discussion and review of the literature.

The adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) on the upper gastrointestinal tract are well described. Evidence also shows that NSAIDs can be harmful to the small intestine. The use of NSAIDs has been associated with small intestinal strictures, ulcerations, perforations, diarrhea, and villous atrophy. Herein we present a case of NSAID-induced enteropathy with multiple diaphragm-like strictures that involved the distal 35 cm of ileum and review the literature of other cases of NSAID-induced enteropathy in which biopsy specimens were obtained for histologic analysis to rule out other causes. The prevalence of NSAID-induced enteropathy is unknown. Diagnosis can be made by endoscopy or at abdominal exploration. The role of radionuclide scans for diagnosis remains unclear. The pathogenesis is likely multifactorial. Mucosal diaphragms may be specific for NSAID-related disease. Treatment options for NSAID-induced enteropathy are discussed.