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Metformin proved useful in the treatment of nonalcoholic fatty liver disease (NAFLD), but its superiority over nutritional treatment and antioxidants has never been demonstrated. We aimed to compare the usefulness of metformin versus prescriptive diet or vitamin E. In an open label, randomized trial, nondiabetic NAFLD patients were given metformin (2 g/day; n = 55) for 12 months. The control cases were given either vitamin E (800 IU/day; n = 28) or were treated by a prescriptive, weight-reducing diet (n = 27). Outcome measures were liver enzymes, insulin resistance (homeostasis model assessment), parameters of the metabolic syndrome, and histology. Aminotransferase levels improved in all groups, in association with weight loss. The effects in the metformin arm were larger (p < 0.0001), and alanine aminotransferase normalized in 56% of cases (odds ratio (OR) versus. controls, 3.11; 95% confidence interval (CI), 1.56-6.20; p= 0.0013). In multivariate analysis, metformin treatment was associated with higher rates of aminotransferase normalization, after correction for age, gender, basal aminotransferases, and change in body mass index (OR, 5.98; 95% CI, 2.05-17.45). Differences were maintained when the two control groups were separately analyzed. The distribution of positive criteria for the metabolic syndrome was reduced only in the metformin arm (p= 0.001, signed rank test). A control biopsy in 17 metformin-treated cases (14 nonresponders) showed a significant decrease in liver fat (p= 0.0004), necroinflammation, and fibrosis (p= 0.012 for both). No side effects were observed during metformin treatment. Metformin treatment is better than a prescriptive diet or vitamin E in the therapy of NAFLD patients receiving nutritional counseling. Limited histological data support an association between improved aminotransferases and biopsy findings, which require confirmation in a double-blind trial with appropriate statistical power based on liver histology.

Non-alcoholic fatty liver disease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are impaired in this condition. We performed a two-step (1.5 and 6 pmol min(-1) kg(-1)) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2H2]glucose and [2H5]glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects. In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p<0.0001) at higher plasma insulin levels (p=0.05), due to impaired glucose oxidation (p=0.003) and glycogen synthesis (p<0.001). Compared with control subjects, glycerol appearance and lipid oxidation were significantly increased in NAFLD patients in the basal state, and were suppressed by insulin to a lesser extent (p<0.05-0.001). The lag phase of the in vitro copper-catalysed peroxidation of LDL particles was significantly shorter in the patients than in the control subjects (48+/-12 vs 63+/-13 min, p<0.04). Lipid oxidation was significantly related to endogenous glucose production, glucose disposal, the degree of hepatic steatosis, and LDL oxidisability. Insulin resistance appears to be an intrinsic defect in NAFLD, with the metabolic pattern observed indicating that adipose tissue is an important site.

In the second phase of a randomized, placebo-controlled trial of adefovir dipivoxil for the treatment of hepatitis B e antigen (HBeAg)–negative chronic hepatitis B, patients who had been treated with adefovir during the initial 48 weeks of the trial were randomly assigned to be switched to placebo or to continue to receive adefovir. Patients who were switched to placebo lost the benefits that had been gained during the initial 48 weeks of treatment, and patients randomly assigned to continue adefovir therapy maintained a response. Resistance mutations developed in 6 percent of the patients treated with adefovir dipivoxil for 144 weeks. Patients who were switched to placebo after 48 weeks lost the benefits that had been gained during initial treatment, and patients randomly assigned to continue adefovir therapy maintained a response. An estimated 400 million people worldwide are chronically infected with hepatitis B virus (HBV). One million die each year from complications of infection, including cirrhosis, hepatocellular carcinoma, or both. 1 Hepatitis B e antigen (HBeAg)–negative chronic hepatitis B represents a late phase in the course of HBV infection. 2 Mutations in the precore promoter regions, core promoter regions, or both, which prevent the formation of HBeAg, are selected during or after HBeAg loss and seroconversion to antibody to HBeAg (anti-HBe). HBeAg-negative chronic hepatitis B infection is characterized by intermittent periods of exacerbation and quiescence. It frequently follows an aggressive disease course, with . . .

Hepatitis B e antigen (HBeAg)–negative chronic hepatitis B is associated with progressive liver injury and is likely to require long-term therapy. In this trial, histologic liver abnormalities improved after 48 weeks of therapy with adefovir dipivoxil, and no resistance mutations were found. Separate reports show that adefovir dipivoxil is effective in both HBeAg-positive and HBeAg-negative disease. More than 350 million people worldwide are chronically infected with hepatitis B virus (HBV). Complications of chronic hepatitis B, such as cirrhosis, hepatocellular carcinoma, and end-stage liver disease, account for approximately 1 million deaths each year. 1 Liver injury seems to be particularly severe and rapidly progressive in patients with chronic hepatitis B who are negative for serum hepatitis B e antigen (HBeAg) and positive for antibodies against HBeAg (anti-HBe), but in whom clinically significant HBV replication persists. 2 For the most part, HBeAg-negative chronic hepatitis B is due to HBV mutations that suppress synthesis of HBeAg. Most patients with HBeAg-negative, anti-HBe–positive, . . .

Background: Insulin resistance is a significant risk factor for hepatic fibrosis in patients with both non-alcoholic fatty liver disease (NAFLD) and chronic hepatitis C (CHC), either directly or by favouring hepatic steatosis. Several methods are available to assess insulin resistance, but their impact on this issue has never been evaluated. Aims: To determine the relative contribution of steatosis, metabolic abnormalities and insulin resistance, measured by different basal and post-load parameters, to hepatic fibrosis in CHC and in NAFLD patients. Methods: In 90 patients with CHC and 90 pair-matched patients with NAFLD, the degree of basal insulin resistance (by the homeostasis model assessment, (HOMA)) and post-load insulin sensitivity (by the oral glucose insulin sensitivity (OGIS) index) was assessed, together with the features of the metabolic syndrome according to Adult Treatment Panel III definition. Data were correlated with hepatic histopathology. Results: The prevalence of basal insulin resistance (HOMA values >75th percentile of normal) was 23.3% in CHC patients and 57.8% in NAFLD, but it increased to 28.8 and 67.8% when measured by post-load insulin resistance (OGIS <25th percentile). In a multivariate model, after adjustment for age, gender and body mass index, OGIS was a predictor of severe fibrosis in CHC and in NAFLD patients, independently of steatosis. An OGIS value below the cut-off of the 25th percentile increased the likelihood ratio of severe fibrosis by a factor of 1.5–2 and proved to be a more sensitive and generally more specific test than HOMA-R for the identification of subjects with severe fibrosis both in NAFLD and in CHC. Conclusions: Post-load insulin resistance (OGIS <9.8 mg/kg/min) is associated with severe hepatic fibrosis in both NAFLD and CHC patients, and may help identify subjects at risk of progressive disease.

Long-term protection against clinically significant breakthrough hepatitis B (HB) virus infection and chronic carriage depends on immunological memory, which allows a protective anamnestic antibody response to antigen challenge. Memory seems to last for at least 15 years in immunocompetent individuals. To date there are no data to support the need for booster doses of HB vaccine in immunocompetent individuals who have responded to a primary course. All adequately vaccinated individuals have shown evidence of immunity in the form of persisting anti-HBs and/or in vitro B-cell stimulation or an anamnestic response to a vaccine challenge. Nonetheless several countries and individuals currently have a policy of administering booster doses to certain risk groups. Boosters may be used to provide reassurance of protective immunity against benign breakthrough infection. For immunocompromised patients, regular testing for anti-HBs, and a booster injection when the titre falls below 10 mIU/mL, is advised. Long-term monitoring should continue, to confirm the absence of clinically significant breakthrough episodes of hepatitis B and to find out if a carrier state develops after 15 years. Also, non-responders to a primary course should continue to be studied.

Treatment options are limited for patients infected by hepatitis C virus (HCV) with advanced liver disease. We assessed the safety and efficacy of ledipasvir, sofosbuvir, and ribavirin in patients with HCV genotype 1 or 4 and advanced liver disease. We did an open-label study at 34 sites in Europe, Canada, Australia, and New Zealand. Cohort A included patients with Child-Turcotte-Pugh class B (CTP-B) or CTP-C cirrhosis who had not undergone liver transplantation. Cohort B included post-transplantation patients who had either no cirrhosis; CTP-A, CTP-B, or CTP-C cirrhosis; or fibrosing cholestatic hepatitis. Patients in each group were randomly assigned (1:1) using a computer-generated randomisation sequence to receive 12 or 24 weeks of ledipasvir (90 mg) and sofosbuvir (400 mg) once daily (combination tablet), plus ribavirin (600–1200 mg daily). The primary endpoint was the proportion of patients achieving a sustained virological response 12 weeks after treatment (SVR12). All patients who received at least one dose of study drug were included in the safety analysis and all patients who received at least one dose of study drug and did not undergo liver transplantation during treatment were included in the efficacy analyses. Estimates of SVR12 and relapse rates and their two-sided 90% CI (Clopper-Pearson method) were provided. This exploratory phase 2 study was not powered for formal comparisons among treatment groups; no statistical hypothesis testing was planned or conducted. The trial is registered with EudraCT (number 2013-002802-30) and ClinicalTrials.gov (number NCT02010255). Between Jan 14, 2014, and Aug 19, 2014, 398 patients were screened. Of 333 patients who received treatment, 296 had genotype 1 HCV and 37 had genotype 4 HCV. In cohort A, among patients with genotype 1 HCV, SVR12 was achieved by 20 (87%, 90% CI 70–96) of 23 CTP-B patients with 12 weeks of treatment; 22 (96%, 81–100) of 23 CTP-B patients with 24 weeks of treatment; 17 (85%, 66–96) of 20 CTP-C patients (12 weeks treatment); and 18 (78%, 60–91) of 23 CTP-C patients (24 weeks treatment). In cohort B, among patients with genotype 1 HCV, SVR12 was achieved by 42 (93%, 84–98) of 45 patients without cirrhosis (12 weeks treatment); 44 (100%, 93–100) of 44 patients without cirrhosis (24 weeks treatment); 30 (100%, 91–100) of 30 CTP-A patients (12 weeks treatment); 27 (96%, 84–100) of 28 CTP-A patients (24 weeks treatment); 19 (95%, 78–100) of 20 CTP-B patients (12 weeks treatment); 20 (100%, 86–100) of 20 CTP-B patients (24 weeks treatment); one (50%, 3–98) of two CTP-C patients (12 weeks treatment); and four (80%, 34–99) of five CTP-C patients (24 weeks treatment). All five patients with fibrosing cholestatic hepatitis achieved SVR12 (100%, 90% CI 55–100). Among all patients with genotype 4 HCV, SVR12 was achieved by 14 (78%, 56–92) of 18 patients (12 weeks treatment) and 16 (94%, 75–100) of 17 patients (24 weeks treatment). Seven patients (2%) discontinued ledipasvir–sofosbuvir prematurely due to adverse events. 17 patients died, mainly from complications of hepatic decompensation. Ledipasvir–sofosbuvir and ribavirin provided high rates of SVR12 for patients with advanced liver disease, including those with decompensated cirrhosis before or after liver transplantation. Gilead Sciences.

In patients with HCV infection and no previous treatment, the addition of telaprevir to peginterferon–ribavirin resulted in higher response rates than those achieved with peginterferon–ribavirin alone. High rates of response were achieved with only 24 weeks of treatment. Patients with chronic hepatitis C virus (HCV) infection are at risk for progressive hepatic fibrosis, cirrhosis, portal hypertension, hepatic failure, and hepatocellular carcinoma. 1 – 4 For the past decade, treatment with pegylated interferon (peginterferon alfa) and ribavirin has been associated with rates of sustained virologic response of 40 to 50% among patients with HCV genotype 1 who had received no previous treatment. 5 – 7 At least 48 weeks of treatment is required for most of these patients, and toxic effects may limit the extent of treatment in some patients. 5 – 7 Telaprevir, a linear peptidomimetic HCV NS3/4A serine protease inhibitor, was associated with . . .

Since the major established risk factors explain the pathogenesis of ischemic heart disease (IHD) in a proportion of cases, it is crucial to search for other causal mechanisms. The possible link between IHD and Helicobacter pylori (H.pylori) infection has been reported. However, the precise mechanism of this potential relationship, by a proinflammatory activity or metabolic disorder, is unclear. In order to investigate this issue, the authors assessed changes in clinical and biochemical parameters related to IHD after bacterial eradication. A total of 496 patients (281 males; mean age 59.7+/-2.3) with H.pylori-positive dyspepsia and/or peptic ulcer were studied after cure of the bacterium. H.pylori status was determined by histology or 13C-urea breath testing. Examinations for body mass index, diastolic blood pressure and blood testing (C-reactive protein, fibrinogen, triglycerides, total cholesterol, high-density and low-density lipoprotein cholesterol, fasting glucose) were performed before eradication and annually for up to five years thereafter. For statistical analyses, the Student's t test was performed. HDL-C increased (P=0.02) while C-reactive protein and fibrinogen levels diminished (P<0.0001) significantly. BMI and diastolic blood pressure increased in a significant (P=0.032 and P=0.039 respectively) manner compared to baseline. H.pylori eradication is associated with modification of some clinical and biochemical parameters related to IHD during a follow-up of five years. There is a need for large interventional randomized studies in order to prove a causal association.

BackgroundHDV depends on HBsAg for its infectivity. HBsAg can derive from cccDNA and also from the integration of the so-called linear HBV-DNA in the genome of infected hepatocytes. Here, we elucidate the contribution of HBsAg production from linear HBV-DNA integration in sustaining HDV activity and its pathogenetic potential.Material and Methods70 liver biopsies from eAg-negative individuals (74% NUC-treated) were included: 35 with CHB and 35 with CHD. Droplet-digital PCR was used to quantify intrahepatic levels of cccDNA, pgRNA, HDV-RNA and HBs transcripts from cccDNA and from integrated HBV-DNA (Grudda, 2022). Next-generation sequencing by Illumina was applied to assess the integration of linear HBV-DNA in hepatocytes’ genome (in 22 CHB and 32 CHD).ResultsIndividuals with CHD and CHB had comparable age and NUC-treatment duration. CHD was characterized by lower cccDNA and pgRNA than CHB (median [IQR]: 1 [0.02–12] vs 24 [8–93] copies (cps)/1000 cells and 8 [1–147] vs 518 [57–3,894] cps/1000cells, P<0.0001 for both). In CHD, no correlation was observed between cccDNA and intrahepatic HDV-RNA, supporting that HDV replicative activity is not strictly related to the extent of HBV reservoir.At least 1 event of linear HBV-DNA integration was observed in 100% and 78.1% (25/32) of individuals with CHB and CHD (total number of unique HBV-integration events: 847 in CHB and 427 in CHD). Furthermore, in both CHB and CHD, a comparable production of HBs transcripts was observed, with >99% of them from integrated HBV-DNA (median [IQR] cps/1000cells: 12,776 [4,570–55,977] in CHB and 6,041 [323–29,446] in CHD).Among the 427 HBV-integration events observed in CHD, 180 involved coding regions of the hepatocytes’ genome, corresponding to a median (IQR) number of 5 (2–10) unique events per patient. Notably, the number of HBV-integration events in coding regions showed a positive correlation with the amount of integration-derived HBsAg transcripts and with serum HBsAg (Rho=0.54 and 0.64, P<0.01 for both). Even more, HBV-integration events were significantly more frequent in individuals with CHD characterized by higher serum HBsAg levels (median [IQR] number of unique HBV-integration events: 10 [7–16] in people with vs 2 [1–7] in people without serum HBsAg >4 logIU/ml; P=0.01).In 19/25 individuals with CHD characterized by >1 HBV-integration event, HBV-DNA integrants localised in human genes regulating cell proliferation. Among the 60 genes identified, 40 genes are already known to be specifically involved in hepatocarcinogenesis.ConclusionsHDV persistence is independent from the intrahepatic HBV reservoir and is sustained by HBsAg production from integrated HBV-DNA. Higher HBsAg levels (>4logIU/ml) can reflect an enrichment of HBV-DNA integration events in coding regions of hepatocytes’ genome.Localization of HBV integrants suggests that these events may potentially induce hepatocytes proliferation, paving the way for carcinogenesis.