Safety and efficacy of once-weekly efruxifermin versus placebo in non-alcoholic steatohepatitis (HARMONY): a multicentre, randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Fibroblast growth factor 21 (FGF21) regulates metabolism and protects cells against stress. Efruxifermin is a bivalent Fc-FGF21 analogue that replicates FGF21 agonism of fibroblast growth factor receptor 1c, 2c, or 3c. The aim of this phase 2b study was to assess its efficacy and safety in patients with non-alcoholic steatohepatitis (NASH) and moderate (F2) or severe (F3) fibrosis. METHODS: HARMONY is a multicentre, randomised, double-blind, placebo-controlled, 96-week, phase 2b trial that was initiated at 41 clinics in the USA. Adults with biopsy-confirmed NASH, defined by a non-alcoholic fatty liver disease activity score (NAS) of 4 or higher and scores of 1 or higher in each of steatosis, ballooning, and lobular inflammation, with histological stage F2 or F3 fibrosis, were randomly assigned (1:1:1), via an interactive response system, to receive placebo or efruxifermin (28 mg or 50 mg), subcutaneously once weekly. Patients, investigators, pathologists, site staff, and the sponsor were masked to group assignments during the study. The primary endpoint was the proportion of patients with improvement in fibrosis of at least 1 stage and no worsening of NASH, based on analyses of baseline and week 24 biopsies (liver biopsy analysis set [LBAS]). A sensitivity analysis evaluated the endpoint in the full analysis set (FAS), for which patients with missing biopsies were considered non-responders. This trial is registered with ClinicalTrials.gov, NCT04767529, and is ongoing. FINDINGS: Between March 22, 2021, and Feb 7, 2022, 747 patients were assessed for eligibility and 128 patients (mean age 54·7 years [SD 10·4]; 79 [62%] female and 49 male [38%]; 118 [92%] white; and 56 [41%] Hispanic or Latino) were enrolled and randomly assigned to receive placebo (n=43), efruxifermin 28 mg (n=42; two randomised patients were not dosed because of an administrative error), or efruxifermin 50 mg (n=43). In the LBAS (n=113), eight (20%) of 41 patients in the placebo group had an improvement in fibrosis of at least 1 stage and no worsening of NASH by week 24 versus 15 (39%) of 38 patients in the efruxifermin 28 mg group (risk ratio [RR] 2·3 [95% CI 1·1-4·8]; p=0·025) and 14 (41%) of 34 patients in the efruxifermin 50 mg group (2·2 [1·0-5·0]; p=0·036). Based on the FAS (n=128), eight (19%) of 43 patients in the placebo group met this endpoint versus 15 (36%) of 42 in the efruxifermin 28 mg group (RR 2·2 [95% CI 1·0-4·8]; p=0·033) and 14 (33%) of 43 in the efruxifermin 50 mg group (1·9 [0·8-4·3]; p=0·123). The most frequent efruxifermin-related adverse events were diarrhoea (16 [40%] of 40 patients in the efruxifermin 28 mg group and 17 [40%] of 43 patients in efruxifermin 50 mg group vs eight [19%] of 43 patients in the placebo group; all events except one were grade 1-2) and nausea (11 [28%] patients in the efruxifermin 28 mg group and 18 [42%] patients in the efruxifermin 50 mg group vs ten [23%] patients in the placebo group; all grade 1-2). Five patients (two in the 28 mg group and three in the 50 mg group) discontinued due to adverse events. Serious adverse events occurred in four patients in the 50 mg group; one was defined as drug related (ulcerative esophagitis in a participant with a history of gastro-oesophageal reflux disease). No deaths occurred. INTERPRETATION: Efruxifermin improved liver fibrosis and resolved NASH over 24 weeks in patients with F2 or F3 fibrosis, with acceptable tolerability, supporting further assessment in phase 3 trials. FUNDING: Akero Therapeutics.

Patient and endoscopic characteristics and clinical outcomes in subjects with non-variceal GI bleeding referred for transarterial embolization: a single-center experience.

PURPOSE: Management of massive non-variceal upper gastrointestinal bleeding (NV-UGIB) can be challenging. Transarterial Embolization (TAE) is often the first therapeutic approach when endoscopic therapy fails before surgery. The purpose of this study is to analyze the technical success, and outcome for our patients with an NV-UGIB referred for TAE. METHOD: This retrospective analysis included 74 consecutive patients with an NV-UGIB in whom TAE was performed after endoscopic treatment between February 2016 to May 2019 at Prisma Health-Upstate Greenville Memorial Hospital. RESULTS: TAE was 98.7% technically successful, with a failure due to severe celiac stenosis, and 85.1% clinically successful. Most TAEs were performed empirically due to lack of extravasation yet were clinically as effective as targeted TAE. We noted a 30-day rebleeding rate and mortality rate of 14.8% and 13.5%, respectively. No complications were reported during the angiographic procedure. Subjects with coagulopathy had more rebleeding (45.5% vs. 17.5%, p = 0.040), and mortality (30% vs 7.4%, p = 0.012). Mortality was also associated with the number of transfused packed blood cells (13.6 ± 8.4 vs. 6.1 ± 5.4, p = 0.020) units and hypotension on admission (27.8% vs. 8.9%, p = 0.043). Interestingly, subjects that underwent left gastric artery (LGA) compared to non-LGA embolization had a higher rebleeding rate of (37.5% vs. 8.6%, p = 0.004) and a greater mortality rate of (37.5% vs. 6.9%, p = 0.002). CONCLUSION: TAE is clinically effective in the presence or absence of contrast extravasation to treat uncontrolled or high-risk NV-UGIB. Less effective clinical outcomes regarding TAE targeting the LGA warrant further investigation.

Cross-sectional examination of ultra-processed food consumption and adverse mental health symptoms.

OBJECTIVE: To explore whether individuals who consume higher amounts of ultra-processed food (UPF) have more adverse mental health symptoms. DESIGN: Using a cross-sectional design, we measured the consumption of UPF as a percentage of total energy intake in kilo-calories using the NOVA food classification system. We explored whether individuals who consume higher amounts of UPF were more likely to report mild depression, more mentally unhealthy days and more anxious days per month using multivariable analyses adjusting for potential confounding variables. SETTING: Representative sample from the United States National Health and Nutrition Examination Survey between 2007 and 2012. PARTICIPANTS: 10 359 adults aged 18+ without a history of cocaine, methamphetamine or heroin use. RESULTS: After adjusting for covariates, individuals with the highest level of UPF consumption were significantly more likely to report at least mild depression (OR: 1·81; 95 % CI1·09, 3·02), more mentally unhealthy (risk ratio (RR): 1·22; 95 % CI 1·18, 1·25) and more anxious days per month (RR: 1·19; 95 % CI 1·16, 1·23). They were also significantly less likely to report zero mentally unhealthy (OR: 0·60; 95 % CI 0·41, 0·88) or anxious days (OR: 0·65; 95 % CI 0·47, 0·90). CONCLUSIONS: Individuals reporting higher intakes of UPF were significantly more likely to report mild depression, more mentally unhealthy and more anxious days and less likely to report zero mentally unhealthy or anxious days. These data add important information to a growing body of evidence concerning the potential adverse effects of UPF consumption on mental health.

Risk stratification of adolescents for the screening of non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver conditions in adolescence are associated with premature mortality in adulthood. Effective screening could impact the population burden of this disease. OBJECTIVES: We sought to determine which adolescents should be screened for non-alcoholic fatty liver using vibration-controlled transient elastography. METHODS: We simulated a non-alcoholic fatty liver screening program of 938 adolescents from the National Health and Nutritional Examination Survey of 2017/2018. We stratified subjects by body mass index and metabolic parameters and analyzed our data using standard diagnostic statistical measures. RESULTS: The weighted prevalence of non-alcoholic fatty liver and non-alcoholic fatty liver disease was 24.4%, and 3.8%, respectively. For all subjects with obesity (21.8% of the population), screening identified 61.8% of the non-alcoholic fatty liver cases. In a category of all subjects with obesity and overweight subjects with metabolic abnormalities (26.7% of the population), screening identified 71.2% of non-alcoholic fatty liver cases. CONCLUSIONS: The two groups most likely to benefit by transient elastography screening are adolescents with obesity and overweight adolescents with one metabolic abnormality. These criteria reduce the number of individuals to be tested by approximately 80% (from an approximate 32 million adolescents to 6-7.5 million adolescents), while retaining a diagnostic accuracy of 84%-85%.

Serum Alanine Transaminase Is an Inadequate Nonalcoholic Fatty Liver Screening Test in Adolescents: Results From the National Health and Nutrition Examination Survey 2017-2018.

Nonalcoholic fatty liver disease (NAFLD) is common in overweight adolescents, and screening with serum alanine transaminase (ALT) levels is recommended by the American Academy of Pediatrics. We sought to determine if ALT is an accurate adolescent screening measure for NAFLD in a nationally representative sample of overweight adolescents. Diagnosis of NAFLD was determined using vibration-controlled transient elastography. Analyses were performed to calculate the sensitivity, specificity, positive predictive value, negative predictive value, and Youden's index at various serum ALT cutoff levels. Receiver operating curves were generated in order to determine ALT's discrimination capability. Males and females were analyzed separately. While average measures (mean and median) of ALT were higher in subjects with NAFLD, ALT provided only minimal discrimination with AUROC (area under the receiver operating characteristic) values of .66 in males and .67 in females. In a nationally representative sample of overweight and obese adolescents, serum ALT level functioned inadequately as a screening test to detect NAFLD.

Cardiovascular Risk Factors in Young Adolescents: Results from the National Health and Nutrition Examination Survey 1988-2016.

OBJECTIVES: Lifestyle behaviors relevant to cardiovascular health are learned during childhood and continued into adulthood. Children and adolescents who participate in unhealthy behaviors have a higher lifetime risk of cardiovascular disease in adulthood. Public health institutions publish behavior and clinical recommendations designed for adolescents to reduce their lifetime cardiovascular risk. We assessed the prevalence and trends of cardiovascular-relevant behaviors and clinical tests among early adolescents using a nationally representative database. METHODS: In 2020, we compared the prevalence of cardiovascular risk factors among 1408 adolescents surveyed from 1988 to 1994 with that of 1812 adolescents surveyed from 2011 to 2016 by obtaining and comparing measures on physical activity, diet, body mass index, smoking status, cholesterol levels, hemoglobin A1c, sodium intake, and blood pressure. RESULTS: The prevalence of adherence to the current recommendations regarding physical activity, diet, and body weight declined over time. Conversely, the prevalence of adhering to recommendations to avoid smoking increased. Clinical indicators, including blood pressure control and normal measures of hemoglobin A1c and total serum cholesterol, showed mixed results, with more individuals showing signs of hyperglycemia, fewer showing signs of hypercholesterolemia, and the percentage of individuals with abnormal blood pressure remaining the same. The use of cardiometabolic medications also increased during the study period. Finally, the number of adolescents with all seven cardiovascular protective factors declined significantly during the study period, from 27.6% to 9.6%. CONCLUSIONS: Modern American teenagers aged 12 to 16 years have more cardiovascular risk factors relating mostly to diet, exercise, and obesity than those of a prior generation; however, smoking rates have also declined precipitously.

Healthy Behavior Adherence: The National Health and Nutrition Examination Survey, 2005-2016.

INTRODUCTION: Leading public health institutions recommend participation in several evidence-based behaviors, including exercise, a healthy diet, and maintenance of a normal BMI while simultaneously avoiding cigarette smoking and excessive alcohol consumption. The investigators attempted to evaluate the collective adherence to these recommendations and population trends in these behaviors by evaluating nationally representative surveys over a period of 12 years. METHODS: In 2019, the data from 26,194 National Health and Examination Survey participants who provided answers to survey questions regarding diet, physical activity, and usage of cigarettes and alcohol were analyzed. BMI was obtained from the examination data. Adherence to each behavior and the constellation of all 5 behaviors was assessed and tracked over a 12-year timeframe. RESULTS: The smoking rates (p=0.01) and adherence to a healthy BMI declined over time (p=0.03). The total percentage of subjects who participated in all 5 behaviors ranged from 4.4% to 6.3%, whereas subjects who performed 2 or fewer behaviors ranged from 45.4% to 48.3%. Greater education (p<0.0001), higher SES (p<0.0001), and being a female participant (p<0.0001) predicted higher behavior scores. CONCLUSIONS: Only 1 in 5 Americans engage in 4 or more healthy behaviors, whereas almost half of them participate in fewer than 3 healthy behaviors. Increased participation in numerous healthy behaviors can decrease premature mortality, decrease the burden of chronic diseases, improve life quality, and provide substantial economic benefits. A public health practice of targeting a constellation of behaviors as opposed to individual behaviors is needed.

FibroSURE and elastography poorly predict the severity of liver fibrosis in Fontan-associated liver disease.

OBJECTIVE: As the population of patients with Fontan circulation surviving into adulthood increases, hepatic cirrhosis has grown to be a significant cause of morbidity and mortality. Early detection of advanced hepatic fibrosis is imperative for proper intervention and consideration for heart or combined heart/liver transplantation. Noninvasive biomarkers and elastography have been evaluated for their diagnostic utility with variable results in the Fontan population. DESIGN: The cohort included 14 patients age 26.4 SD 7.5 who underwent Fontan surgery. All patients were evaluated with FibroSURE, shear wave elastography (SWE), hepatic duplex sonography, and liver biopsy. Liver fibrosis on biopsy was evaluated according to the congestive hepatic fibrosis system. RESULTS: In our cohort, 100% of patients had fibrosis with 36% demonstrating advanced fibrosis. FibroSURE agreed with liver biopsy in only 5 out of 14 cases (36%): underestimating in 7 and overestimating in 2 individuals. SWE agreed with liver biopsy in 0% of cases: overestimating in 10 and underestimating in 4 cases. None of the duplex sonography indices predicted the presence or severity of liver fibrosis. CONCLUSION: This study demonstrates that children who have undergone a Fontan procedure universally develop some hepatic fibrosis and a significant number have advanced fibrosis by adulthood. The FibroSURE blood test, SWE, and hepatic duplex sonography were unable to accurately predict the presence or severity of hepatic fibrosis when compared with liver biopsy. Further studies are needed to investigate novel noninvasive methods and/or biomarkers that can adequately detect advanced hepatic fibrosis before the development of cirrhosis and hepatic decompensation.

Refractory Hepatic Hydrothorax: A Rare Complication of Systemic Sclerosis and Presinusoidal Portal Hypertension.

We report on a rare case of refractory hepatic hydrothorax in an individual with Scleroderma/CREST syndrome and noncirrhotic portal hypertension. Portal pressure measurements revealed a normal transjugular hepatic venous portal pressure gradient, mild pulmonary hypertension, and an unremarkable liver biopsy except for mild sinusoidal dilation. Pulmonary hypertension, cardiac diastolic dysfunction, and chronic kidney disease were determined to be the causes of his refractory pleural effusions and ascites. Over the year, he underwent 50 thoracenteses and 20 paracenteses averaging 10-12 liters/week. Repeat pulmonary evaluation determined his pulmonary pressures to be normal and a secondary review of the "unremarkable" liver biopsy noted mild venous outflow obstruction and possibly Nodular Regenerative Hyperplasia (NRH). Repeat portal pressures indirectly and directly confirmed the existence of presinusoidal portal hypertension that has been associated with NRH. A transjugular intrahepatic portal systemic shunt (TIPS) was placed and he has not required thoracentesis or paracentesis over the past 18 months.

Postmenopausal Deep Infiltrating Endometriosis of the Colon: Rare Location and Novel Medical Therapy.

We report an uncommon case of deep infiltrating endometriosis of the colon presenting as iron deficiency anemia nine years after hysterectomy with bilateral salpingo-oophorectomy. The endometrial implant was found at the hepatic flexure, an exceedingly rare location for endometriosis invasion with no cases distinctly reported in the literature. Additionally, the presentation of gastrointestinal endometriosis as iron deficiency anemia is not well documented in the literature. Instead of surgery, we prescribed a novel medical therapeutic approach using conjugated estrogen-bazedoxifene to antagonize the proliferative effects of estrogen on endometrial tissue. After five months of therapy and repeat colonoscopy, no evidence of endometrial tissue remained in the hepatic flexure.

Prevalence of HCV Infection in Adults with Congenital Heart Disease and Treatment with Direct Antiviral Agents.

OBJECTIVES: Hepatitis C virus (HCV) infection affects >3% of the US population, which over time can lead to cirrhosis and hepatocellular carcinoma. The lack of a reliable screening method for HCV before 1992 resulted in a higher prevalence of the virus in adults with congenital heart disease who underwent corrective surgery that required blood transfusions. Direct-acting antiviral agents such as sofosbuvir/ledipasvir have significantly increased the efficacy of HCV therapy, although use of these medications in adults with congenital heart disease has not been described. METHODS: Ours was a retrospective study of 188 adults with congenital heart conditions who had cardiac surgery before 1992. These patients were screened for HCV using HCV antibody followed by HCV RNA if the screening test was positive. RESULTS: Of the 188 adults, 116 (43% male patients, 24-70 years) were screened for the HCV antibody, demonstrating that 104 individuals were negative and 12 subjects were positive for the virus. Subsequently, further testing for the presence of HCV demonstrated 11 of 12 were infected, with an overall prevalence of 9.5%. Five individuals chose to be treated with sofosbuvir/ledipasvir and 5 of 5 have successfully cleared the virus and are considered cured. CONCLUSIONS: Adults with congenital heart disease who underwent cardiac surgery before 1992 warrant being screened for HCV, and, if testing positive, may be considered for therapy using direct-acting antiviral agents with close monitoring for cardiac complications.

LOGIQ E9 Shear Wave Elastrography for Detection of Liver Fibrosis in Patients with Chronic Hepatitis C Virus.

OBJECTIVES: Shear wave elastography (SWE) is an emerging technology that assesses hepatic fibrosis. The aim of our study was to determine the diagnostic accuracy of General Electric (GE) Healthcare's LOGIQ E9 SWE in patients with chronic hepatitis C virus using liver biopsy as the reference standard. METHODS: The liver stiffness of 43 subjects with hepatitis C virus was assessed using LOGIQ E9 SWE immediately before they underwent liver biopsy. The Fibrosis-4 Index (FIB-4) and Aspartate Aminotransferase-to-Platelet Index (APRI) were calculated, and the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were determined. RESULTS: Mild hepatic fibrosis (F0-F2) was noted in 30 of the 43 (69.7%) patients and advanced disease (F3-F4) was seen in 13 of the 43 (30.3%) individuals. Using the GE LOGIQ E9 SWE proposed cutoff value of ≥9.4 kPa for advanced fibrosis, the sensitivity, specificity, PPV, and NPV were only 69.2%, 73.3%, 52.9%, and 84.6%, respectively. The post hoc analysis identified best cutoff values of <9.4 and ≥12 kPa, thereby classifying 76% of patients with an NPV of 84.6% and a PPV of 85.7%. The Aminotransferase-to-Platelet Index results were as follows: 83.3%, sensitivity, 95.2% specificity, 83.3% PPV, and 95.2% NPV in 27 of the individuals (37% remained unclassifiable). The FIB-4 Index demonstrated 100% sensitivity, 76.9% specificity, 66.6% PPV, and 100% NPV; however, 24 (56%) of the patients were classified within the indeterminate range. CONCLUSIONS: In our cohort, the proposed GE LOGIQ value of ≥9.4 kPa did not adequately discriminate subjects with advanced fibrosis. Further prospective evaluation of our post hoc analyses is warranted to identify the ideal cutoff values for the LOGIQ E9 system.

Randomized study of asunaprevir plus pegylated interferon-α and ribavirin for previously untreated genotype 1 chronic hepatitis C.

BACKGROUND: Asunaprevir is a selective NS3 protease inhibitor with in vitro activity against HCV genotypes 1 and 4. METHODS: In this Phase IIa double-blind study, treatment-naive HCV genotype-1-infected patients in the United States and France were randomly assigned 1:1:1:1 to placebo or asunaprevir 200 mg twice daily, 600 mg twice daily or 600 mg once daily in combination with pegylated interferon (PEG-IFN)-α2a and ribavirin for 48 weeks. The primary efficacy end point was undetectable HCV RNA at weeks 4 and 12 (extended rapid virological response [eRVR]). Other end points included safety and undetectable HCV RNA at 24 weeks post-treatment (24-week sustained virological response [SVR24]). RESULTS: A total of 47 patients were randomized and treated. eRVR was achieved by 75% (9/12), 75% (9/12) and 92% (11/12) of patients in the asunaprevir 200 mg twice-daily, 600 mg twice-daily and 600 mg once-daily groups, respectively, versus 0% (0/11) in the placebo group. Corresponding SVR24 rates were 83% (10/12), 83% (10/12) and 92% (11/12) in the asunaprevir groups and 46% (5/11) in the placebo group. There was no virological breakthrough in any asunaprevir group. Following the 12-week analysis, the 600 mg doses were reduced to 200 mg twice daily because of a greater frequency of transaminase elevations at the 600 mg dose. The most common grade 3-4 laboratory abnormalities were consistent with those reported for PEG-IFN and ribavirin. CONCLUSIONS: Asunaprevir plus PEG-IFN and ribavirin achieved higher response rates than placebo plus PEG-IFN and ribavirin, with a tolerable adverse event profile at the 200 mg twice-daily dose. This dose is being evaluated in the Phase IIb and Phase III studies.

Sofosbuvir in combination with peginterferon alfa-2a and ribavirin for non-cirrhotic, treatment-naive patients with genotypes 1, 2, and 3 hepatitis C infection: a randomised, double-blind, phase 2 trial.

BACKGROUND: Protease inhibitors have improved treatment of infection with hepatitis C virus (HCV), but dosing, a low barrier to resistance, drug interactions, and side-effects restrict their use. We assessed the safety and efficacy of sofosbuvir, a uridine nucleotide analogue, in treatment-naive patients with genotype 1-3 HCV infection. METHODS: In this two-cohort, phase 2 trial, we recruited treatment-naive patients with HCV genotypes 1-3 from 22 centres in the USA. All patients were recruited between Aug 16, 2010, and Dec 13, 2010, and were eligible for inclusion if they were aged 18-70 years, had an HCV RNA concentration of 50,000 IU/mL or greater, and had no cirrhosis. We randomly allocated all eligible patients with HCV genotype 1 (cohort A) to receive sofosbuvir 200 mg, sofosbuvir 400 mg, or placebo (2:2:1) for 12 weeks in combination with peginterferon (180 µg per week) and ribavirin (1000-1200 mg daily), after which they continued peginterferon and ribavirin for an additional 12 weeks or 36 weeks (depending on viral response). Randomisation was done by use of a computer-generated randomisation sequence and patients and investigators were masked to treatment allocation until week 12. Patients with genotypes 2 or 3 (cohort B) received open-label sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks. Our primary outcomes were safety and tolerability. Secondary efficacy analyses were by intention to treat and endpoints included sustained virological response, defined as undetectable HCV RNA at post-treatment weeks 12 and 24. This study is registered with ClinicalTrials.gov, number NCT01188772. FINDINGS: In cohort A, 122 patients were assigned 200 mg sofosbuvir (48 patients), 400 mg sofosbuvir (48), or placebo (26). We enrolled 25 patients into cohort B. The most common adverse events--fatigue, headache, nausea, and chills--were consistent with those associated with peginterferon and ribavirin. Eight patients discontinued treatment due to adverse events, two (4%) receiving sofosbuvir 200 mg, three (6%) receiving sofosbuvir 400 mg, and three (12%) receiving placebo. In cohort A, HCV RNA was undetectable at post-treatment week 12 in 43 (90%; 95% CI 77-97) of 48 patients in the 200 mg sofosbuvir group; 43 (91%; 80-98) of 47 patients in the 400 mg sofosbuvir group, and 15 (58%; 37-77) of 26 patients in the placebo group. In cohort B, 23 (92%) of 25 patients had undetectable HCV RNA at post-treatment week 12. INTERPRETATION: Our findings lend support to the further assessment, in phase 2 and 3 trials, of sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks in treatment-naive patients with HCV genotype-1. FUNDING: Gilead Sciences.

Daclatasvir for previously untreated chronic hepatitis C genotype-1 infection: a randomised, parallel-group, double-blind, placebo-controlled, dose-finding, phase 2a trial.

BACKGROUND: Several direct-acting antivirals for chronic hepatitis C virus (HCV) infection are available, but they are limited by tolerability and dosing schedules. Once-daily daclatasvir, a potent NS5A replication complex inhibitor, was generally well tolerated in phase 1 studies. We assessed daclatasvir in combination with pegylated interferon (peginterferon) and ribavirin for chronic HCV. METHODS: In this double-blind, parallel-group, dose-finding, phase 2a study, treatment-naive patients with HCV genotype-1 infection (without cirrhosis) from 14 centres in the USA and France were randomly assigned (1:1:1:1) to receive peginterferon alfa-2a (180 µg per week) and ribavirin (1000-1200 mg daily) plus placebo or 3 mg, 10 mg, or 60 mg of daclatasvir taken once daily, for 48 weeks. The primary efficacy endpoint was undetectable HCV RNA at 4 weeks and 12 weeks after start of treatment (extended rapid virological response, eRVR). Analysis was of all participants who received one dose of study drug. We used descriptive analyses to compare results. This study is registered with ClinicalTrials.gov, number NCT00874770. FINDINGS: 48 patients were randomly assigned (12 per group); all received at least one dose of study drug. 15 patients discontinued treatment before week 48. Five of 12 patients (42%, 80% CI 22-64%) who received 3 mg daclatasvir achieved eRVR, compared with ten of 12 (83%, 61-96%) who received 10 mg daclatasvir, nine of 12 (75%, 53-90%) who received 60 mg daclatasvir, and one of 12 (8%, 1-29%) who received placebo. Adverse events and discontinuations as a result of adverse events occurred with similar frequency across groups. INTERPRETATION: Daclatasvir seems to be a potent NS5A replication complex inhibitor that increases the antiviral potency of peginterferon and ribavirin. Our findings support the further development of regimens containing 60 mg daclatasvir for the treatment of chronic genotype-1 HCV infection. FUNDING: Bristol-Myers Squibb.

Chronic exposure to a high-fat diet induces hepatic steatosis, impairs nitric oxide bioavailability, and modifies the mitochondrial proteome in mice.

Obesity-related pathologies, such as nonalcoholic fatty liver disease, are linked to mitochondrial dysfunction and nitric oxide (NO) deficiency. Herein, we tested the hypothesis that a high-fat diet (HFD) modifies the liver mitochondrial proteome and alters proteins involved in NO metabolism, namely arginase 1 and endothelial NO synthase. Male C57BL/6 mice were fed a control or HFD and liver mitochondria were isolated for proteomics and reactive oxygen species measurements. Steatosis and hepatocyte ballooning were present in livers of HFD mice, with no pathology observed in the controls. HFD mice had increased serum glucose and decreased adiponectin. Mitochondrial reactive oxygen species was increased after 8 weeks in the HFD mice, but decreased at 16 weeks compared with the control, which was accompanied by increased uncoupling protein 2. Using proteomics, 22 proteins were altered as a consequence of the HFD. This cohort consists of oxidative phosphorylation, lipid metabolism, sulfur amino acid metabolism, and chaperone proteins. We observed a HFD-dependent increase in arginase 1 and decrease in activated endothelial NO synthase. Serum and liver nitrate + nitrite were decreased by HFD. In summary, these data demonstrate that a HFD causes steatosis, alters NO metabolism, and modifies the liver mitochondrial proteome; thus, NO may play an important role in the processes responsible for nonalcoholic fatty liver disease.

Comparative evaluation of whole body and hepatic insulin resistance using indices from oral glucose tolerance test in morbidly obese subjects with nonalcoholic Fatty liver disease.

Nonalcoholic Fatty Liver Disease (NAFLD) is the hepatic manifestation of metabolic syndrome and is a marker of Insulin Resistance (IR). Euglycemic-hyperinsulinemic clamp is the gold standard for measuring whole body IR (hepatic + peripheral IR). However, it is an invasive and expensive procedure. Homeostasis Model Assessment Index for Insulin Sensitivity (HOMA-IS), Quantitative Insulin Sensitivity Check Index (QUICKI) for hepatic IR and Insulin Sensitivity Index (ISI(0,120)), and Whole Body Insulin Sensitivity Index (WBISI) for whole body IR are the indices calculated after Oral Glucose Tolerance Test (OGTT). We used these indices as noninvasive methods of IR (inverse of insulin sensitivity) estimation and compared hepatic/peripheral components of whole body IR in NAFLD. Methods. 113 morbidly obese, nondiabetic subjects who underwent gastric bypass surgery and intraoperative liver biopsy were included in the study. OGTT was performed preoperatively and the indices were calculated. Subjects were divided into closely matched groups as normal, fatty liver (FL) and Non-Alcoholic Steatohepatitis (NASH) based on histology. Results. Whole body IR was significantly higher in both FL and NASH groups (NAFLD) as compared to Normal, while hepatic IR was higher only in NASH from Normal. Conclusions. FL is a manifestation of peripheral IR but not hepatic IR.