Genetic predictors of treatment outcomes in hepatitis C virus infection

© 2016 Dr. Jacinta Alison HolmesRecent data has identified IFNL3 polymorphism as a marker for treatment efficacy and ITPA polymorphism as a marker for treatment toxicity in patients treated with pegylated interferon-α plus ribavirin (PR) for chronic hepatitis C virus genotype 1 infection (HCV-1). This effect was attenuated in HCV genotype 3 (HCV-3) patients. The association between IFNL3 polymorphism and treatment response has been associated with intrahepatic interferon stimulated gene (ISG) expression, however the biological mechanisms are not understood. We retrospectively IFNL3 genotyped HCV-1/HCV-3 patients treated with PR and characterised liver ISG expression in HCV-1/HCV-3 patients. IFNL3 genotype was associated with both sustained virological response (SVR) and ISG expression, however the effect was attenuated in HCV-3. Multivariable analyses identified HCV genotype and IFNL3 genotype were both independent predictors of SVR and ISG expression. Interaction testing confirmed the novel finding that HCV genotype and IFNL3 genotype interact to alter treatment outcome and ISG expression, and demonstrates that host-viral interactions are critical. We also evaluated IFNL3 genotype in patients receiving interferon for another hepatotropic virus, chronic hepatitis B virus (CHB) infection. In contrast to HCV, IFNL3 genotype did not predict interferon responses, likely due to under-representation of non-C/C genotypes in the predominantly Asian CHB cohort. C/C patients demonstrate higher necroinflammation and faster HCV clearance during PR therapy, suggesting innate immunity may play a key role in mediating the IFNL3 effect. We performed detailed innate immune characterisation in HCV-1 patients before and during PR therapy. At baseline C/C patients demonstrated higher chemokine/cytokine and suppressor of cytokine signaling 1 levels ([SOCS1], a negative regulator of ISGs), which may explain the higher necroinflammation and lower ISG levels observed. In contrast, no difference was observed according to IFNL3 genotype in controls. Following commencement of PR therapy, C/C patients demonstrated early and potent induction of chemokines/cytokines and ISGs, and greater suppression of SOCS1, suggesting priming of the innate immune system in C/C patients, and weak dysregulated responses in non-C/C patients. To identify the cellular peripheral source of ISGs, we evaluated cell-specific ISG expression in peripheral blood mononuclear cells. ISG induction following stimulation was significantly greater in monocytes from both HCV patients and controls, particularly in C/C patients. This magnitude was greater in controls, demonstrating that HCV patients have impaired innate immune responses. These data provide novel insights into HCV-related immunopathogenesis and highlight the importance of host-viral interactions. Finally, we examined the complex relationships between anaemia, SVR, ITPA genotype and ribavirin exposure. We identified the mechanism underlying the association between anaemia and SVR is mediated through RBV pharmacokinetics, not ITPA genotype. In conclusion, there are complex host-viral relationships that determine induction of innate immune effectors both pre-treatment and in response to PR, which differ according to IFNL3 genotype that warrant further investigation. Detailed studies precisely defining the role of SOCS1 and similar characterisation of innate immunity in acute HCV and during direct-acting antiviral (DAA) therapy are planned. Understanding these differences may identify novel therapeutic strategies that may apply to other viruses and may be useful in the small but growing number of patients who do not achieve SVR with newer therapies