Because ISGs were shown to be a major mechanism of non-cytolytic inhibition of HBV replication in a transgenic mouse model [17] and IFN-λ2 (IL28A) inhibits HBV replication through upregulated ISGs in HCC cell lines [18], it is difficult to explain the negative correlation between major alleles of IL28B polymorphism and HBV spontaneous clearance given that IL28B stimulates ISGs, which play an important role in the immune response to HBV infection. This evidence concerns the gene IFNL2 and hepatocellular carcinoma.