Jennifer E. Layden-Almer

Modelling how ribavirin improves interferon response rates in hepatitis C virus infection.

Nearly 200 million individuals worldwide are currently infected with hepatitis C virus (HCV). Combination therapy with pegylated interferon and ribavirin, the latest treatment for HCV infection, elicits long-term responses in only about 50% of patients treated. No effective alternative treatments exist for non-responders. Consequently, significant efforts are continuing to maximize response to combination therapy. However, rational therapy optimization is precluded by the poor understanding of the mechanism(s) of ribavirin action against HCV. Ribavirin alone induces either a transient early decline or no decrease in HCV viral load, but in combination with interferon it significantly improves long-term response rates. Here we present a model of HCV dynamics in which, on the basis of growing evidence, we assume that ribavirin decreases HCV infectivity in an infected individual in a dose-dependent manner. The model quantitatively predicts long-term response rates to interferon monotherapy and combination therapy, fits observed patterns of HCV RNA decline in patients undergoing therapy, reconciles conflicting observations of the influence of ribavirin on HCV RNA decline, provides key insights into the mechanism of ribavirin action against HCV, and establishes a framework for rational therapy optimization.

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. Demographic and clinical variables pertaining to the metabolic syndrome were collected retrospectively. Liver biopsies were evaluated according to the scoring system proposed by the Nonalcoholic Steatohepatitis Clinical Research Network and NASH was defined as a NASH activity score ≥5.RESULTS:African Americans had lower rates of steatosis than non-Hispanic whites (P<0.001) and Hispanics (P=0.03). Among patients with steatosis, African Americans had lower rates of NASH than non-Hispanic whites (P=0.05) and Hispanics (P=0.02) and lower rates of fibrosis score ≥F2 than non-Hispanic whites (P=0.002) and Hispanics (P=0.04). Ethnic differences in rates of NAFLD, NASH, and fibrosis ≥F2 persisted when controlling for demographic variables and features of the metabolic syndrome in logistic regression analysis. There were no significant differences in steatosis, NASH, or fibrosis ≥F2 between non-Hispanic whites and Hispanics.CONCLUSIONS:African-American obesity surgery patients have a lower rate of NAFLD, NASH, and less severe fibrosis than non-Hispanic whites and Hispanics.

p53, Ki-67, and serum alpha feto-protein as predictors of hepatocellular carcinoma recurrence in liver transplant patients.

Patients with hepatocellular carcinoma who undergo orthotopic liver transplantation (OLT) are at risk for post-transplant tumor recurrence. The aim of this study was to evaluate whether expression of p53 and Ki-67 in hepatocellular carcinoma lesions present in explanted liver tissue was associated with time to tumor recurrence after OLT. Subjects consisted of 20 consecutive patients who underwent OLT and were found to have hepatocellular carcinoma in the liver explant. Immunostaining for p53 and Ki-67 was performed by standard methods. The presence of nuclear immunostaining in >10% of the tumor tissue was considered positive. Time to recurrence of hepatocellular carcinoma after OLT was compared between patients with positive and negative immunostaining by the log rank test. Multivariate analysis was performed using a Cox regression model to control for potentially confounding clinical factors. Time to post-transplant hepatocellular carcinoma recurrence was significantly more rapid in p53+ (P=0.0007) and Ki-67+ cases (P=0.001). These associations remained significant in multivariate analysis. Furthermore, time to recurrent hepatocellular carcinoma was significantly shorter in patients with a serum alpha feto-protein (AFP) level ≥100 ng/ml at time of diagnosis, compared to those with an AFP level <100 ng/ml (P=0.003). In conclusion, expression of p53 and Ki-67 in hepatocellular carcinoma lesions, and a serum AFP level ≥100 ng/ml were associated with more rapid recurrence of hepatocellular carcinoma after OLT. Identification of patients at risk for early post-transplant recurrence could be used to guide surveillance and adjuvant treatment strategies.

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. Model predictions were compared with clinical data from 170 noncirrhotic and 75 cirrhotic patients. RESULTS The ranges chosen for beta and the viral production rate (p) resulted in bHCV-RNA levels that were in agreement with the distribution observed in US patients. With these beta and p values, higher bHCV-RNA levels led to higher epsilonc, resulting in lower SVR rates. However, higher beta values resulted in lower bHCV-RNA levels but higher pi and (epsilonc), predicting lower rates of SVR. Cirrhotic patients had lower bHCV-RNA levels than noncirrhotic patients (P=.013), and more had bHCV-RNA levels<6 log IU/mL (P<.001). Even cirrhotic patients with lower bHCV-RNA levels had lower SVR rates. An increase in beta could explain the results observed in cirrhotic patients. CONCLUSIONS Our model predicts that higher bHCV-RNA levels lead to higher epsilonc, reducing the chance of achieving SVR; cirrhotic patients have lower SVR rates because of large pi values, caused by increased rates of hepatocyte infection.

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. The HCV NS5A region from 21 treated patients with HCV genotype 1a was sequenced and analyzed. White patients displayed more mutations in the V3 region (mean+/-SD, 4.5+/-1.4 vs. 2.9+/-1.6; P=.016), and treatment responders tended to have more mutations in this region than did nonresponders. There was a significant positive correlation between IFN effectiveness and the number of mutations in the V3 region (P=.03). There was no clustering of strains by race, treatment response, or IFN effectiveness in phylogenetic analyses. The results of this study, in conjunction with those of a previous study illustrating the impaired IFN effectiveness in African Americans, suggest a role for host-related factors.

Ethnic differences in the presentation of chronic hepatitis C

Summary.  Hispanics comprise 13% of the population in the United States and are the fastest growing minority group. Features of hepatitis C in Hispanics have not been well characterized. The aims of this study were to compare features of hepatitis C among Hispanics, Whites, and African–Americans and to characterize hepatitis C infection in Hispanics. A retrospective analysis was performed on 1225 consecutive patients with hepatitis C seen at the University of Illinois at Chicago including 227 Hispanics, 508 Whites, and 490 African–Americans. Data collection consisted of demographic variables, risk factors for hepatitis C, history of alcohol use, laboratory parameters and liver histology. Pair‐wise comparisons showed that Hispanics had higher aminotransferase levels than Whites and African–Americans. Hispanics had higher portal inflammation scores on liver biopsy than African–Americans (P = 0.002) and Whites (P = 0.043). Hispanics had a higher frequency of cirrhosis than African–Americans (P < 0.001) and a trend towards more cirrhosis than Whites (P = 0.165). There was a trend towards a higher prevalence of cirrhosis in Hispanic women (56%) than in Hispanic men (45%) [P = 0.14]. A cross‐sectional analysis of patients at our liver center showed that Hispanics with hepatitis C had higher aminotransferase levels, more portal inflammation than Whites and African–Americans, and a higher prevalence of cirrhosis than African–Americans.

Viral kinetics in the treatment of chronic hepatitis C

Summary.  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. Mathematic modelling of viral dynamics has shown the importance of optimal doses of drug, with early virologic response at week 12 predictive of sustained virologic response. Maintaining INF concentration above a therapeutically effective level is necessary to prevent viral rebound and subsequent treatment failure. Once‐weekly dosing with peg‐INF‐α2a, which has a longer half‐life than other forms of INF, plus daily dosing with ribavirin, has been shown to be effective in reducing viral load.

Measurement of liver fat content using selective saturation at 3.0 T

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.

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. Methods. Subjects consisted of 27 hepatitis C-infected liver transplant recipients who had liver biopsy specimens available from 49 protocol liver biopsies. Paraffin embedded liver tissue sections were stained for 8-hydroxy-2′ deoxyguanosine (8-OHdG), an indicator of hydroxyl radical mediated tissue damage. The percentage of cells staining for 8-OHdG in a histologic section was categorized as high (>66%) versus low score (≤66%). Fibrosis index was calculated as fibrosis score (0–4)/ years posttransplant. Time to bridging fibrosis or cirrhosis (F3–4) was compared as a function of PTDM and 8-OHdG score. Results. Considering all 49 biopsies, fibrosis index was higher in cases with PTDM (P<0.001) and high 8-OHdG score (P=0.004). High 8-OHdG score was associated with PTDM (P=0.012). In time to event analyses, time to F3–4 was more rapid in patients with PTDM (P=0.02) and in those with high 8-OHdG scores (P<0.001). Conclusions. This study confirmed a relationship between PTDM and hepatitis C fibrosis progression and found that oxidative damage in liver biopsy specimens was associated with PTDM and more rapid development of advanced fibrosis.