Reduced ITPase activity and favorable IL28B genetic variant protect against ribavirin-induced anemia in interferon-free regimens

Genetic variants of inosine triphosphatase (ITPA) that confer reduced ITPase activity are associated with protection against ribavirin(RBV)-induced hemolytic anemia in peginterferon(IFN)/RBV-based treatment of hepatitis C virus (HCV). Patients with reduced ITPase activity showed improved treatment efficacy when treated with IFN/RBV. In addition, a genetic polymorphism near the IL28B gene is associated with an improved response to IFN/RBV treatment. RBV has been an important component of IFN-containing regimens, and is currently recommended in combination with several IFN-free regimens for treatment of harder to cure HCV infections. To evaluate whether genetic variations that reduce ITPase activity impact RBV-induced anemia in IFN-free/RBV regimens. In this study, genetic analyses were conducted in the PEARL-IV trial to investigate the effect of activity-reducing ITPA variants as well as IL28B polymorphism on anemia, platelet (PLT) counts, and virologic response in HCV genotype1a-infected patients treated with the direct-acting antiviral (DAA) regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir±RBV. Reduction in ITPase activity and homozygosity for the IL28Brs12979860 CC genotype protected against RBV-induced anemia. In patients receiving RBV, reduced ITPase activity was associated with reduced plasma RBV concentration and higher PLT counts. ITPase activity had no impact on response to DAA treatment, viral kinetics, or baseline IP-10 levels. Our study demonstrates that genetics of ITPA and IL28B may help identify patients protected from RBV-induced anemia when treated with IFN-free regimens. Our work demonstrates for the first time that IL28B genetics may also have an impact on RBV-induced anemia. This may be of particular significance in patients with difficult-to-cure HCV infections, such as patients with decompensated cirrhosis where RBV-containing regimens likely will continue to be recommended.