Modeling shows that the NS5A inhibitor daclatasvir has two modes of action and yields a shorter estimate of the hepatitis C virus half-life.

The nonstructural 5A (NS5A) protein is a target for drug development against hepatitis C virus (HCV). Interestingly, the NS5A inhibitor daclatasvir (BMS-790052) caused a decrease in serum HCV RNA levels by about two orders of magnitude within 6 h of administration. However, NS5A has no known enzymatic functions, making it difficult to understand daclatasvir's mode of action (MOA) and to estimate its antiviral effectiveness.

Racial differences in fibrosis progression after HCV-related liver transplantation.

Background: Black recipients undergoing liver transplantation (LT) for hepatitis C virus (HCV) have decreased patient and graft survival compared with white recipients, a finding that is primarily limited to black recipients of livers from white donors. The cause(s) for these discrepant outcomes are unclear but may be related to HCV disease recurrence. The rates of HCV-related disease recurrence and liver fibrosis progression among black and white liver transplant recipients have not been investigated.

Hepatitis C Viral Kinetics in the Era of Direct Acting Antiviral Agents and IL28B.

In the last decade hepatitis C virus (HCV) kinetics has become an important clinical tool for the optimization of therapy with (pegylated)-interferon-α (IFN) and ribavirin (RBV). Mathematical models have generated important insights into HCV pathogenesis, HCV- host dynamics, and IFN and RBV's modes of action. Clinical trials with direct acting agents (DAAs) against various steps of the HCV life cycle have revealed new viral kinetic patterns that have not been observed with IFN±RBV.

Pharmacodynamics of PEG-IFN-[alpha]-2a and HCV response as a function of IL28B polymorphism in HIV/HCV-coinfected patients.

We examined the association between IL28B single-nucleotide polymorphism rs12979860, hepatitis C virus (HCV) kinetic, and pegylated interferon alpha-2a pharmacodynamic parameters in HIV/HCV-coinfected patients from South America. Twenty-six subjects received pegylated interferon alpha-2a + ribavirin. Serum HCV-RNA and interferon concentrations were measured frequently during the first 12 weeks of therapy and analyzed using mathematical models.

Pharmacodynamics of PEG-IFN-alpha-2a in HIV/HCV co-infected patients: implications for treatment outcomes.

Background & Aims: The pharmacokinetics and pharmacodynamics of pegylated-interferon-alpha-2a (PEG-IFN) have not been described in HCV/HIV co-infected patients. We sought to estimate the pharmacokinetics and pharmacodynamics of PEG-IFN and determine whether these parameters predict treatment outcome.

Methods: Twenty-six HCV/human immunodeficiency virus (HIV)-co-infected patients were treated with a 48-week regimen of PEG-IFN (180 microg/week) plus ribavirin (11 mg/kg/day).

Liver Injury with Features Mimicking Autoimmune Hepatitis following the Use of Black Cohosh.

There are a growing number of cases detailing acute hepatic necrosis in patients taking black cohosh (Cimicifuga racemosa), an over-the-counter herbal supplement for management of menopausal symptoms. Our aim is to illustrate two cases of liver injury following the use of black cohosh characterized by histopathological features mimicking autoimmune hepatitis. Both patients reported black cohosh use for at least six months and had no evidence of another cause of liver disease.

Ethnicity and body mass index are associated with hepatitis C presentation and progression.

Background & Aims: Ethnicity and the metabolic syndrome are believed to affect progression of hepatitis C virus (HCV) infection, but the interaction between these factors is unknown. We evaluated the association between elements of the metabolic syndrome and ethnicity in the histologic progression of HCV in a large, diverse cohort.

Methods: We retrospectively evaluated clinical data and liver biopsy samples from 812 patients who had no cause of liver disease other than HCV infection.

Modelling hepatitis C virus kinetics: the relationship between the infected cell loss rate and the final slope of viral decay.

Background: Patients infected with hepatitis C virus (HCV) who respond to treatment with interferon-alpha plus ribavirin exhibit biphasic or triphasic viral load decreases. While the rapid first phase is indicative of the effectiveness of therapy in blocking viral production (epsilon), the slope of the final phase (lambda), that is, the second phase in biphasic decreases and the third phase in triphasic decreases, depends on the infected cell loss rate (delta). In standard models, lambda is approximately epsilondelta when the viral clearance rate c>>delta, as has been previously estimated.

Hepatitis B seroprevalence and disease characteristics in an urban Chinatown community.

Background & Aims: Chronic HBV infection is prevalent among Asian immigrants and is an important cause of cirrhosis and hepatocellular carcinoma. The aim of this study was to evaluate the HBsAg seroprevalence and to characterize hepatitis B in persons who presented to an urban Chinatown internal medicine practice.

Methods: Records were reviewed retrospectively from 4671 adult patients who had at least 1 office visit during a 2-year period.

A mathematical model of hepatitis C virus dynamics in patients with high baseline viral loads or advanced liver disease.

Background & Aims: Patients with baseline hepatitis C virus-RNA levels (bHCV-RNA)>6 log IU/mL or cirrhosis have a reduced probability of a sustained-virologic response (SVR). We examined the relation between bHCV-RNA, cirrhosis, and SVR with a mathematical model that includes the critical-drug efficacy (epsilonc; the efficacy required for a drug to clear HCV), the infection-rate constant (beta), and the percentage of HCV-infected hepatocytes (pi).

Methods: The relation between baseline factors and SVR was evaluated in 1000 in silico HCV-infected patients, generated by random assignment of realistic host and viral kinetic parameters.

Hepatitis C Viral Kinetics in Special Populations.

Mathematical models of hepatitis C viral (HCV) kinetics provide a means of estimating the antiviral effectiveness of therapy, the rate of virion clearance and the rate of loss of HCV-infected cells. They have also proved useful in evaluating the extrahepatic contribution to HCV plasma viremia and they have suggested mechanisms of action for both interferon-α and ribavirin. Viral kinetic models can explain the observed HCV RNA profiles under treatment, e.

The histologic spectrum of liver disease in African-American, non-Hispanic white, and Hispanic obesity surgery patients.

Objectives: Non-alcoholic fatty liver disease (NAFLD) is a prominent cause of chronic liver disease in African Americans, non-Hispanic whites, and Hispanics. The aim of this study was to evaluate ethnic differences in the prevalence of NAFLD and non-alcoholic steatohepatitis (NASH) and to compare the severity of histologic features of NASH in obesity surgery patients.

Methods: Subjects consisted of 238 patients who had a routine liver biopsy at the time of obesity surgery.

Does nonalcoholic fatty liver disease predispose patients to hepatocellular carcinoma in the absence of cirrhosis?

Context: Hepatocellular carcinoma (HCC) is recognized as a complication of cirrhosis related to nonalcoholic fatty liver disease (NAFLD). Diabetes and the metabolic syndrome are also associated with HCC. However, it is not clear whether NAFLD predisposes patients to HCC in the absence of cirrhosis.

Diabetes and hepatic oxidative damage are associated with hepatitis C progression after liver transplantation.

Background: Posttransplant diabetes mellitus (PTDM) is common after liver transplantation and was recently identified as a risk factor for hepatitis C progression. Increased levels of oxidative stress have been identified in diabetes and hepatitis C. The aim of this study was to evaluate the relationship among PTDM, oxidative damage in liver biopsy specimens, and fibrosis progression posttransplant.

Immunohistochemical expression of components of the Akt-mTORC1 pathway is associated with hepatocellular carcinoma in patients with chronic liver disease.

Unlabelled: Activation of the Akt-mTORC1 signaling pathway was evaluated in premalignant and hepatocellular carcinoma (HCC) lesions by assessing the expression of pS6, an Akt effector, and PTEN, an Akt suppressor.

Methods: Immunohistochemical staining for pS6 and PTEN was performed on liver tissue from 52 patients with cirrhosis, with and without HCC. Two pathologists independently evaluated pS6 staining on a semiquantitative scale and categorized PTEN staining as present or absent.

A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C.

Unlabelled: Clinical factors such as age, gender, alcohol use, and age-at-infection influence the progression to cirrhosis but cannot accurately predict the risk of developing cirrhosis in patients with chronic hepatitis C (CHC). The aim of this study was to develop a predictive signature for cirrhosis in Caucasian patients. All patients had well-characterized liver histology and clinical factors; DNA was extracted from whole blood for genotyping.

Measurement of liver fat content using selective saturation at 3.0 T.

Purpose: To validate an MRI technique for measuring liver fat content by calibrating MRI readings with liver phantoms and comparing MRI measurements in human subjects with estimates of liver fat content on liver biopsy specimens.

Materials And Methods: The MRI protocol consisted of fat and water imaging by selective saturation using a 3.0-T scanner.

Viral kinetics in the treatment of chronic hepatitis C.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis and hepatic fibrosis, and chronic infection can frequently progress to cirrhosis, end-stage liver disease and hepatocellular carcinoma. Treatment with pegylated interferons (INFs) plus ribavirin has been shown to be more effective than pegylated INFs alone or standard INFs with or without ribavirin. The early response of HCV to treatment with peg-INF has been used to predict treatment outcomes in infected patients, emphasizing the importance of viral kinetics and genotyping in their treatment.

Peliosis hepatis in a living related liver transplantation donor candidate.

Peliosis hepatis is a rare benign condition histologically characterized by multiple cystic blood-filled spaces distributed throughout the liver parenchyma. Peliosis hepatis has been associated with malignancies, immunosuppression, infections and medications. We report a case of peliosis hepatis in a candidate for living liver donation, which regressed with restitutio ad integrum, after the noxious stimulus was stopped.

Identification of two gene variants associated with risk of advanced fibrosis in patients with chronic hepatitis C.

Background & Aims: Previously identified clinical risk factors such as sex, alcohol consumption, and age at infection do not accurately predict which patients with chronic hepatitis C (CHC) will develop advanced fibrosis (bridging fibrosis and cirrhosis). The aim of this study was to identify genetic polymorphisms that can predict the risk of advanced fibrosis in patients with CHC.

Methods: A total of 916 subjects with CHC was enrolled from 2 centers.

Hepatitis C virus genotype 1a NS5A pretreatment sequence variation and viral kinetics in African American and white patients.

In hepatitis C virus (HCV) infection, race is a determinant of treatment response and interferon (IFN) effectiveness. Here, we investigated whether there were differences in the pretreatment viral strains between African American patients and white patients and whether these differences correlated with viral kinetics. IFN effectiveness was calculated using a viral kinetic model.