In vitro Blood Cell Responsiveness to IFN-alpha Predicts Clinical Response Independently of IL28B in Hepatitis C Virus Genotype 1 Infected Patients.
Item Type:Journal Article
Citation:Bourke NM, O'Neill M, Sarwar S, Norris S, Stewart S, Hegarty JE, Stevenson NJ and O'Farrelly C., In vitro Blood Cell Responsiveness to IFN-alpha Predicts Clinical Response Independently of IL28B in Hepatitis C Virus Genotype 1 Infected Patients., Journal of Translational Medicine, 2014, 204-
1479-5876-12-206.pdf (Published (author's copy) - Peer Reviewed) 685.7Kb
BACKGROUND: Treatment with interferon-alpha (IFN-α) and ribavirin successfully clears hepatitis C virus (HCV) infection in 50% of patients infected with genotype 1. Addition of NS3-4A protease inhibitors (PIs) increases response rates but results in additional side effects and significant economic costs. Here, we hypothesised that in vitro responsiveness of peripheral blood mononuclear cells (PBMCs) to IFN-α stimulation would identify patients who achieved sustained virological response (SVR) on dual therapy alone and thus not require addition of PIs. METHODS: PBMCs were isolated from HCV infected patients (n = 42), infected with either HCV genotype 1 or genotype 3, before commencing therapy and stimulated in vitro with IFN-α. Expression of the IFN stimulated genes (ISGs) PKR, OAS and MxA was measured and correlated with subsequent treatment response and IL28B genotype. RESULTS: Genotype 1 infected patients who achieved SVR had significantly higher pre-treatment expression of PKR (p = 0.0148), OAS (p = 0.0019) and MxA (p = 0.0019) in IFN-α stimulated PBMCs, compared to genotype 1 infected patients who did not achieve SVR or patients infected with genotype 3, whose in vitro ISG expression did not correlate with clinical responsiveness. IL28B genotype (rs12979860) did not correlate with endogenous or IFN-α stimulated ISG responsiveness. CONCLUSIONS: In vitro responsiveness of PBMCs to IFN-α from genotype 1 infected patients predicts clinical responsiveness to dual therapy, independently of IL28B genotype. These results indicate that this sub-group of HCV infected patients could be identified pre-treatment and successfully treated without PIs, thus reducing adverse side effects and emergence of PI resistant virus while making significant economic savings.
Health Research Board (HRB)
Science Foundation Ireland (SFI)
Type of material:Journal Article
Series/Report no:Journal of Translational Medicine
Availability:Full text available
Keywords:IL28B genotype, Host predictive markers, Protease inhibitors, Interferon stimulated genes;
Subject (TCD):Genes & Society , Immunology, Inflammation & Infection , ANTIVIRAL ACTIVITY , HEPATITIS C VIRUS , Immune system , Immunology, Immunotherapy , Molecular Biology , SIGNAL-TRANSDUCTION PATHWAYS