Abstract
Soluble CD14 (sCD14) and IL-18 are markers and mediators of the innate immune response, and their plasma levels candidate biomarkers of HCV treatment effects and outcome. Here, we retrospectively studied sCD14 and IL-18 over the course of interferon-based treatment of HCV genotype 1 infection, with the aim to investigate the impact of direct-acting antivirals (DAAs) on the dynamics and relationships between these biomarkers and treatment effects and outcome. Two cohorts were followed longitudinally; one treated with standard dual therapy of pegylated IFNα and ribavirin, and one cohort receiving triple therapy including Telaprevir. sCD14 and IL-18 were measured before and during treatment and analyzed in relation to treatment effects. The initial analysis confirmed two patterns previously observed in patients with HCV/HIV-1 co-infection: Baseline levels of sCD14 were significantly lower in patients that went on to clear HCV infection in response to IFNα and ribavirin, and sCD14 levels were strongly induced during the course of this treatment. Interestingly, baseline levels of sCD14 and IL-18 in combination predicted treatment outcome in dual therapy better than either marker alone. Notably, these associations were weaker with the addition of Telaprevir to the treatment regimen, suggesting that the relationships between innate immune activation and outcome were altered and diminished by inclusion of a DAA in the treatment. In triple therapy, the dynamic increase of sCD14 in response to treatment was higher in patients clearing the virus, suggesting that the innate response to interferon is still significantly associated with outcome in patients treated with DAA-containing regimens. These results support the notion that levels of innate immune activation before and during treatment are associated with interferon-based treatment outcome. Furthermore, the addition of Telaprevir significantly alters the dynamics and relationships between innate immune biomarkers and treatment effects and outcome.
Highlights
Chronic Hepatitis C virus (HCV) infection is treated to prevent progression to cirrhosis and development of hepatocellular cancer
The results indicate that baseline levels, as well as the on-treatment dynamics, of innate immune activation as measured by plasma Soluble CD14 (sCD14) and IL-18 are associated with treatment outcome
Given the role of sCD14 and IL-18 as markers and mediators of the innate immune response, we were interested to evaluate their plasma levels as candidate biomarkers of HCV treatment effects and outcome. sCD14 and IL-18 were measured in plasma samples drawn at treatment baseline, at 4 weeks of treatment, and at 12 weeks of treatment, and the dynamics of these proteins were analyzed
Summary
Chronic Hepatitis C virus (HCV) infection is treated to prevent progression to cirrhosis and development of hepatocellular cancer. Until recently the standard of care for treatment of HCV has consisted of a combination of pegylated interferon a (peg-IFNa) and ribavirin, which clears the virus in a significant fraction of patients, but at a high cost in terms of side effects. IFNa mobilizes a number of antiviral mechanisms, such as enhancement of MHC class I-mediated antigen presentation, activation of innate cellular immunity and increased transcription of IFN-stimulated genes [1,2,3,4,5]. The addition of first generation HCV protease inhibitors to peg-IFNa and ribavirin enhances response rates, leading the way towards substantial improvement in treatment of HCV disease [6,7,8]. The use of peg-IFNa continues until the efficacy, safety, and cost effectiveness of IFN-
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