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Despite achieving sustained virologic response (SVR) to hepatitis C virus (HCV) therapy, there remains a post liver transplantation population with advanced fibrosis/cirrhosis. Emricasan is an orally active, pan-caspase inhibitor that suppresses apoptosis and inflammation, potentially decreasing hepatic inflammation and fibrosis. We aimed to determine the safety and efficacy of emricasan (IDN-6556-07) in a double-blind, randomized, placebo-controlled, multicenter study in reducing or preventing the progression of hepatic fibrosis in HCV liver transplant recipients with residual fibrosis or cirrhosis after achieving SVR. A total of 64 participants were randomly assigned to receive 25 mg twice daily of emricasan or placebo in a 2:1 ratio for 24 months. 41 participants were randomly assigned to emricasan and 23 to placebo; 32 participants in the emricasan group (78.0%) and 19 who took a placebo (82.6%) completed the study. There was no difference in the primary endpoint (Ishak fibrosis stages F2-F5, improvement in fibrosis or stability; Ishak fibrosis stage F6, improvement) between the emricasan (77.1%) and placebo groups (74.1%); P = NS. There was no difference between the emricasan (54.5%) and placebo (60.7%) arms in the rate of fibrosis improvement alone. However, those in the prespecified F3 to F5 subgroup had higher rates of stability or improvement in fibrosis in the emricasan group (95.2%) compared with placebo (54.6%) (P = 0.01). The tolerability and safety profiles were similar in both groups. In conclusion, overall stability in the Ishak fibrosis stage was similar between emricasan and placebo groups at 24 months. However, there was improvement and/or stability in fibrosis stage in the prespecified F3 to F5 subgroup with emricasan versus placebo, suggesting that patients with moderate fibrosis may benefit with emricasan., (Copyright © 2020 by the American Association for the Study of Liver Diseases.)

Background: Silymarin is the most commonly used herbal product for chronic liver disease; yet, whether silymarin protects against liver disease progression remains unclear., Aim: To assess the effects of silymarin use on subsequent liver disease progression in 1049 patients of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) trial who had advanced fibrosis or cirrhosis and had failed prior peginterferon plus ribavirin treatment., Methods: Patients recorded their use of silymarin at baseline and were followed up for liver disease progression (two point increase in Ishak fibrosis score across baseline, year 1.5, and year 3.5 biopsies) and over 8.65 years for clinical outcomes., Results: At baseline, 34% of patients had used silymarin, half of whom were current users. Use of silymarin was associated (P < 0.05) with male gender; oesophageal varices; higher ALT and albumin; and lower AST/ALT ratio, among other features. Baseline users had less hepatic collagen content on study biopsies and had less histological progression (HR: 0.57, 95% CI: 0.33-1.00; P-trend for longer duration of use=0.026). No effect was seen for clinical outcomes., Conclusions: Silymarin use among patients with advanced hepatitis C-related liver disease is associated with reduced progression from fibrosis to cirrhosis, but has no impact on clinical outcomes (Clinicaltrials.gov #NCT00006164)., (Published 2010. This article is a US Government work and is in the public domain in the USA.)

Background: Hepatitis C virus (HCV)/HIV coinfection treatment is suboptimal with low sustained viral response rates to standard therapies. A multicenter randomized clinical trial designed to assess the efficacy/safety of pegylated interferon maintenance therapy was performed by the National Institutes of Health-funded AIDS Clinical Trials Group network., Methods: HCV treatment-naive and nonresponding interferon-experienced subjects with confirmed HCV and HIV, CD4 >200 cells per cubic millimeter, and at least stage 1 fibrosis were enrolled and treated for 12 weeks with pegylated interferon alfa 2a 180 mcg per week (PEG) + weight-based ribavirin to determine response status. Nonresponder subjects (failure to clear HCV RNA or achieve 2-log drop) underwent liver biopsy and were randomized to receive full dose PEG or observation only for 72 weeks. Paired biopsies were evaluated by a central pathologist., Results: Three hundred thirty subjects were enrolled; median age was 48 years; 43% white, 37% black, non-Hispanic; 83% male; CD4+ 498 cells per cubic millimeter; 32% were interferon experienced; 74% had entry HIV RNA <50 copies per milliliter. early virologic responder was observed in 55.9% and 42.5% achieved complete Early Viral Response (cEVR). A planned interim analysis of occurred when 84 subjects were randomized. With data on 40 paired biopsies available, a safety monitoring board stopped the trial due to lack of fibrosis progression (median = 0 Metavir units/year) in the observation arm., Conclusions: Lack of fibrotic progression in the control arm was unexpected and may represent a short-term PEG/ribavirin therapy effect, high levels of HIV viral suppression, and use of antiretroviral regimens that may be less toxic than prior generations of therapy.

Limited data suggest that low T-helper cell levels may be observed in hepatitis C virus (HCV) monoinfected patients with decompensated liver disease. We sought to determine the distribution and relationship of T-helper cells (CD4) to liver fibrosis in HCV-monoinfected patients before and during pegylated interferon (PegIFN) therapy. CD4 populations were prospectively determined using flow cytometry. All subjects had compensated liver disease. Baseline and subsequent CD4 counts at treatment weeks 12, 24, 36 and 48 and at two time points following treatment discontinuation (weeks 60 and 72) were evaluated. Ishak score was determined by a central pathologist. At baseline, data from 267 subjects were available. Mean age was 50 and 68% were male/Caucasian. HCV viral load was >800 000 IU/mL in 55%. Nearly half (48%) were Ishak 4-6 with all stages represented. Mean CD4 count was 1004 cells/mm(3) + or - 400, and 6% had counts <500. There was a trend towards lower CD4 counts among cirrhotic subjects (P = 0.07). A CD4 decrease was noted following PegIFN initiation. Mean CD4 decline was 38.9% and was statistically significant for all fibrosis stages compared with baseline levels, but not between fibrosis levels. CD4 counts <500 cells/mm(3) are seen in <10% of HCV-monoinfected subjects. A trend towards lower CD4 counts in subjects with advanced fibrosis was observed. However, at baseline and during/after PegIFN therapy, no significant differences were observed between groups. CD4 counts declined during PegIFN treatment, but returned to baseline after completion. The significance of these findings in terms of disease progression and treatment response requires further evaluation.

Background & Aims: Although the incidence of hepatocellular carcinoma (HCC) is increasing in the United States, data from large prospective studies are limited. We evaluated the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis (HALT-C) cohort for the incidence of HCC and associated risk factors., Methods: Hepatitis C virus-positive patients with bridging fibrosis or cirrhosis who did not respond to peginterferon and ribavirin were randomized to groups that were given maintenance peginterferon for 3.5 years or no treatment. HCC incidence was determined by Kaplan-Meier analysis, and baseline factors associated with HCC were analyzed by Cox regression., Results: 1,005 patients (mean age, 50.2 years; 71% male; 72% white race) were studied; 59% had bridging fibrosis, and 41% had cirrhosis. During a median follow-up of 4.6 years (maximum, 6.7 years), HCC developed in 48 patients (4.8%). The cumulative 5-year HCC incidence was similar for peginterferon-treated patients and controls, 5.4% vs 5.0%, respectively (P= .78), and was higher among patients with cirrhosis than those with bridging fibrosis, 7.0% vs 4.1%, respectively (P= .08). HCC developed in 8 (17%) patients whose serial biopsy specimens showed only fibrosis. A multivariate analysis model comprising older age, black race, lower platelet count, higher alkaline phosphatase, esophageal varices, and smoking was developed to predict the risk of HCC., Conclusions: We found that maintenance peginterferon did not reduce the incidence of HCC in the HALT-C cohort. Baseline clinical and laboratory features predicted risk for HCC. Additional studies are required to confirm our finding of HCC in patients with chronic hepatitis C and bridging fibrosis.

Persons with non-A, non-B hepatitis (cases) identified in 5 transfusion studies in the early 1970s have been followed ever since and compared for outcome with matched, transfused, non-hepatitis controls from the same studies. Previously, we reported no difference in all-cause mortality but slightly increased liver-related mortality between these cohorts after 18 years follow-up. We now present mortality and morbidity data after approximately 25 years of follow-up, restricted to the 3 studies with archived original sera. All-cause mortality was 67% among 222 hepatitis C-related cases and 65% among 377 controls (P = NS). Liver-related mortality was 4.1% and 1.3%, respectively (P =.05). Of 129 living persons with previously diagnosed transfusion-associated hepatitis (TAH), 90 (70%) had proven TAH-C, and 39 (30%), non-A-G hepatitis. Follow-up of the 90 TAH-C cases revealed viremia with chronic hepatitis in 38%, viremia without chronic hepatitis in 39%, anti-HCV without viremia in 17%, and no residual HCV markers in 7%. Thirty-five percent of 20 TAH-C patients biopsied for biochemically defined chronic hepatitis displayed cirrhosis, representing 17% of all those originally HCV-infected. Clinically evident liver disease was observed in 86% with cirrhosis but in only 23% with chronic hepatitis alone. Thirty percent of non-A, non-B hepatitis cases were unrelated to hepatitis viruses A,B,C, and G, suggesting another unidentified agent. In conclusion, all-cause mortality approximately 25 years after acute TAH-C is high but is no different between cases and controls. Liver-related mortality attributable to chronic hepatitis C, though low (<3%), is significantly higher among the cases. Among living patients originally HCV-infected, 23% have spontaneously lost HCV RNA.

Objective: Hepatic histological evaluation is currently the gold standard to determine the degree of liver injury in chronic hepatitis C. It is unclear whether degree of serum ALT elevation or quantitative hepatitis C virus (HCV) RNA can predict level of histological damage., Methods: Fifty nine biopsies from 44 patients with chronic hepatitis C were reviewed. The amount of liver damage was quantified using the Histology Activity Index (HAI) and was compared with serum ALT and, in 26 biopsies, quantitative HCV RNA (branched DNA amplification, Quantiplex, Chiron)., Results: A statistically significant linear relationship was noted between degree of ALT elevation and amount of liver injury based on HAI score (p < 0.05) although this relationship was not statistically strong (rs = 0.4900). No significant correlation was noted between serum ALT and HCV RNA titer (rs = 0.4044) or between quantitative HCV RNA titer and HAI score (rs = 0.3506). No individual component of the HAI correlated with ALT or HCV RNA., Conclusions: Although there is a correlation between serum ALT and degree of hepatic injury based on HAI score, this relationship is weak and probably of no clinical use. There is no significant correlation between HCV RNA and serum ALT or HCV RNA and degree of hepatic injury in individual patients. Hepatic histological evaluation continues to be required for clinical assessment of patients with chronic hepatitis C.

Objectives: The presence of talc crystals in the liver has been associated with prior history of i.v. drug abuse (IVDA). Patients with hepatitis C virus (HCV) infection often deny IVDA, and many patients have no other identifiable risk factors. To evaluate the role of prior surreptitous IVDA in patients with chronic HCV infection and to assess the role of talc identification in liver tissue, an epidemiological evaluation was performed., Methods: One hundred and nine patients with chronic HCV (ALT abnormal > 6 months, HCV ELISA and recombinant immunoblot assay positive) underwent careful evaluation for risk factors potentially associated with HCV infection. All patients then had liver biopsy. Liver biopsies were reviewed by two observers to determine histological stage and were then examined by polarized light microscopy to reveal the presence or absence of typical talc crystals. Patients with discordance between history and histological findings were re-interviewed and were confronted with the information., Results: Patient interviews revealed the following risk factors: IVDA, 17.1%; blood transfusion, 24.3%; possible household/occupational exposure, 14.4%; and tattoos, 15.3%. No identifiable risk factors were noted in 28.8% of the cohort. Talc crystals were seen in 9/109 (8.3%) of liver specimens. Of this group, only two patients admitted to prior history of IVDA. Seventeen patients with an IVDA history did not have identifiable talc crystals. Follow-up phone interviews were possible with five out of seven patients with liver talc who had previously denied IVDA history. Of the five patients, three admitted to prior IVDA but only after being confronted with the liver biopsy evidence., Conclusions: The findings of talc crystals in liver biopsy specimens appears to be a specific, but not a sensitive, marker for prior IVDA. Identification of talc crystals from liver tissue may contribute to categorization of risk factors in patients with community-acquired HCV infection. Tattoos are an important, and frequently unrecognized, risk factor for HCV infection. Despite these findings, a significant proportion of patients still have no identifiable risk factor for HCV acquisition.

Hepatitis C can cause a range of hepatic histopathology. The virus may cause an acute hepatitis indistinguishable from any other acute viral hepatitis, but it is more likely to be associated with steatosis, bile duct injury, and portal lymphoid aggregates. Chronic infection with hepatitis C can range from mild nonspecific changes, presumably representing a hepatitis C carrier state, to end-stage liver disease with cirrhosis and hepatocellular carcinoma. Between these are chronic hepatitis of varying severity. Steatosis, portal lymphoid aggregates, and bile duct injury, while not specific, are very characteristic of chronic hepatitis C. Reputed precursors of hepatocellular carcinoma, including liver cell dysplasia and adenomatous hyperplasia, frequently follow the development of cirrhosis and are presumed to predispose to the development of malignancy. New techniques for localizing the virus in liver tissue will undoubtedly lead to greater understanding of the pathogenesis of hepatitis C-related diseases.

We have evaluated the clinical and histopathological outcomes of patients who contracted chronic non A, non B hepatitis as a result of transfusions administered during heart surgery at the National Institutes of Health. Posttransfusion hepatitis developed in 65 of 1,070 (6.1%) patients and became chronic in 45 (69%) of those cases. Antibody to hepatitis C virus was detectable in 53 patients (82%) with posttransfusion non A, non B hepatitis. Thirty-three patients with chronic non A, non B hepatitis agreed to liver biopsy (group 1). In addition, six other patients with chronic posttransfusion non A, non B hepatitis were evaluated (group 2). These 39 patients were followed between 1 and 24 yr (mean = 9.7 yr). Cirrhosis developed in 8 patients (20%) between 1.5 and 16 yr after blood transfusion. Of the 33 patients in group 1, 11 (33%) died during follow-up. In two cases (6%), this was related to liver failure. At this writing, two additional patients (6%) have decompensated cirrhosis and one (3%) had debilitating fatigue. Twenty of 33 patients (61%) with histological evidence of chronic active hepatitis or cirrhosis are asymptomatic and have no clinical evidence of liver disease. Thus chronic non A, non B posttransfusion hepatitis appeared to be due to hepatitis C virus infection in most cases. It was associated with the development of cirrhosis in approximately 20% of cases and end-stage liver disease in 12% of patients followed prospectively. Most patients with histological evidence of cirrhosis or chronic active hepatitis, however, had minimal clinical evidence of liver disease within the time frame of this study.