Factors associated with the response to interferon-based antiviral therapies for chronic hepatitis C

Abstract

Hepatitis C virus (HCV) infection is a major health concern worldwide. Interferon-α (IFN-α) therapy has been the main antiviral treatment for more than 20 years. Because of its established antitumor effects, IFNbased treatments for chronic HCV infection still have a clinical impact, particularly for patients with high risk conditions of developing hepatocellular carcinoma, such as older age and advanced liver fibrosis. As a result of exhaustive research, several viral factors, including NS5A amino acid mutations such as the IFN sensitivitydetermining region and the IFN/ribavirin resistancedetermining region, and mutations of amino acids in the core protein region (core 70 and 91) were shown to be associated with the response to IFN-α treatment. In addition, among the host factors related to the response to IFN-α treatment, polymorphisms of the interleukin-28B gene were identified to be the most important factor. In this article, we review the factors associated with the efficacy of IFN-α treatment for chronic HCV infection. In addition, our recent findings regarding the possible involvement of anti-IFN-α neutralizing antibodies in a non-response to pegylated-IFN-α treatment are also described. Core tip: Interferon-α (IFN-α) therapy has been playing a central role in anti-hepatitis C virus (HCV) strategies, and several viral and host factors related to the treatment efficacy have been identified. After the development of pegylated-IFN-α (Peg-IFN-α), the clinical impact of anti-IFN-α neutralizing antibodies in the treatment for HCV infection has not been sufficiently addressed. We recently found that anti-IFN-α neutralizing antibodies were associated with a non-response to Peg-IFN-α treatment. Our findings provide important information for the treatment of chronic hepatitis C in the clinical setting. MINIREVIEWSSubmit a

Type I interferon pathway in CNS homeostasis and neurological disorders

“…Further mutations linked to HSV-associated encephalitis in humans include mutations in the unc-93 homolog B1 (Unc93b1), toll like receptor 3 (Tlr3), TNF receptor-associated factor 3 (Traf3), TIR-domain-containing adapter-inducing interferon-b (Trif), serine/threonine-protein kinase (Tbk1), signal transducer and activator of transcription 1 (Stat1), and NF-kappa-B essential modulator (Nemo) genes (Zhang, Abel, & Casanova, 2013a). While in patients recombinant IFN-b is a first line treatment for relapsing-remitting multiple sclerosis (Fogarty, Schmitz, Tubridy, Walsh, & Barry, 2016;Sormani & Bruzzi, 2015), recombinant IFN-a is used to treat cancer (Parker, Rautela, & Hertzog, 2016), chronic hepatitis C (Enomoto & Nishiguchi, 2015) and hepatitis (Antonelli, Scagnolari, Moschella, & Proietti, 2015). Extended type I interferon signaling is also the basis for neuroinflammatory events in models of Alzheimer's disease.…”

Type-I Interferon Responses: From Friend to Foe in the Battle against Chronic Viral Infection

“…In the perspective of human infection, the role of IFN responses is particularly important based on the widespread use of IFN therapy against chronic viral diseases such as HCV (4), HIV (5–8, 72), and more broadly in clinical setting such as systemic lupus erythematosus (9), melanoma, and other neoplastic indications [(11–13), reviewed in Ref. (10)].…”

“…Whereas the protective role of IFNs has been widely characterized, emerging lines of evidence illustrate a deleterious effect borne by IFN-associated immunopathology (2, 3). These characterizations bear particular importance given the historic use and ongoing studies on IFN therapy in the treatment of chronic viral infections [e.g., HCV (4) and HIV (5–8)], autoimmune diseases [e.g., systemic lupus erythematosus (9)], and cancer (10–13). Whereas the advent of new therapies has spurred a trend toward IFN-free treatments in HCV, HIV, and oncology, IFN therapy is still considered to be a significant therapeutic agent due to its efficacy against HCV-associated complications [e.g., hepatocellular carcinoma (4)] and combinatorial effect in cancer therapy (14).…”

Immunological dynamics associated with rapid virological response during the early phase of type I interferon therapy in patients with chronic hepatitis C

“…Since the degree of virological response upon type I IFN treatment is variable and determined by a variety of host and viral factors, and the early kinetics of virological response are the major predictors of sustained virological response (SVR) [13,31], the immunological programs established by chronic HCV infection might play a pivotal role in the efficient viral clearance upon exogenous type I IFN. To elucidate the regulatory mechanisms of the innate cytokines in altering antiviral immunity, we investigated the early dynamics of diverse immunological parameters from baseline to one week treatment with type I IFN.…”