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Hepatitis C virus (HCV) is associated with the B-cell lymphoproliferative disorders mixed cryoglobulinemia (MC) and non-

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Objective Obesity and type 2 diabetes mellitus (T2DM) are risk factors for nonalcoholic fatty liver disease, including nonalcoholic steatohepatitis. This study assessed pegbelfermin (BMS‐986036), recombinant PEGylated human fibroblast growth factor 21 (FGF21), in patients with obesity and T2DM predisposed to fatty liver. Methods In this randomized, double‐blind, placebo‐controlled study, patients with T2DM and BMI of 30 to 50 kg/m2 received subcutaneous pegbelfermin (1, 5, or 20 mg daily or 20 mg weekly; n = 96) or placebo (n = 24) for 12 weeks. Primary end points were safety, tolerability, and change in HbA1c. Additional end points included insulin sensitivity, lipids, adiponectin, and disease progression biomarkers. Results There were no significant effects of pegbelfermin versus placebo on HbA1c. Pegbelfermin 20 mg/d significantly improved high‐density lipoprotein cholesterol (P = 0.015) and triglycerides (P = 0.037). All pegbelfermin regimens significantly increased adiponectin levels; 20‐mg daily and weekly regimens decreased serum PRO‐C3. Most adverse events were mild; the most frequent adverse events were injection‐site bruising and diarrhea. Conclusions Twelve‐week pegbelfermin treatment did not impact HbA1c concentrations, but QW and higher daily doses were associated with improved metabolic parameters and fibrosis biomarkers in patients with obesity and T2DM predisposed to fatty liver. These results support evaluation of pegbelfermin in patients with obesity‐related metabolic diseases (e.g., nonalcoholic steatohepatitis).

Hepatitis C virus (HCV) replication in primary liver cells is less robust than that in hepatoma cell lines, suggesting that innate antiviral mechanisms in primary cells may limit HCV replication or spread. Here, we analyzed expression of 47 genes associated with interferon (IFN) induction and signaling following HCV infection of primary human fetal liver cell (HFLC) cultures from 18 different donors. We report that cell culture-produced HCV (HCVcc) induced expression of Type III (λ) IFNs and of IFN-stimulated genes (ISGs). Little expression of Type I IFNs was detected. Levels of IFNλ and ISG induction varied among donors and, often, between adapted and non-adapted HCV chimeric constructs. Higher levels of viral replication were associated with greater induction of ISGs and of λ IFNs. Gene induction was dependent on HCV replication, as UV-inactivated virus was not stimulatory and an antiviral drug, 2′-C-methyladenosine, reduced induction of λ IFNs and ISGs. The level of IFNλ protein induced was sufficient to inhibit HCVcc infection of naïve cultures. Conclusion Together, these results indicate that despite its reported abilities to blunt the induction of an IFN response, HCV infection is capable of inducing antiviral cytokines and pathways in primary liver cell cultures. Induction of ISGs and λ IFNs may limit the growth and spread of HCV in primary cell cultures and in the infected liver. HCV infection of HFLC may provide a useful model for the study of gene induction by HCV in vivo.

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In this review we discuss the clinical manifestations, pathogenesis, and treatment of hepatitis C virus (HCV)-related cryoglobulinemia. HCV is a major cause of liver-related morbidity and is increasingly recognized as an instigator of B cell lymphoproliferative disorders such as mixed cryoglobulinemia and non-Hodgkin lymphoma. Cryoglobulinemia is characterized by the clonal expansion of rheumatoid factor-expressing B cells in the liver, lymph nodes and peripheral blood, resulting in the presence of cryoglobulins in the circulation. Cryoglobulins are cold-insoluble immune complexes containing rheumatoid factor, polyclonal IgG, and HCV RNA that precipitate and deposit on vascular endothelium, effecting a vasculitis in organs such as the skin, kidneys, and peripheral nerves. A subset of patients develops a low-grade lymphoma comprised of B cells that are immunophenotypically similar to the expanded B cells seen in cryoglobulinemia. HCV-related B cell lymphoproliferative disorders likely comprise a spectrum of disease, ranging from asymptomatic clonal B cell expansions to pathogenic cryoglobulinemia and lymphoma. It is unclear how B cells become dysregulated during the course of chronic HCV infection, and continued patient-centered research is necessary to elucidate the pathogenesis of HCV-related B cell dysregulation.