The relationships between IFNL4 genotype, intrahepatic interferon‐stimulated gene expression and interferon treatment response differs in HCV‐1 compared with HCV‐3. Issue 3 (1st June 2015) - Holmes, J. A.
Summary Background The biological mechanism underlying the association between IFNL4/IFNL3 polymorphism and peginterferon/ribavirin (PR) response in HCV‐1 is thought to involve differential intrahepatic interferon‐stimulated gene expression. HCV‐3 is more sensitive to PR, but there are no studies of the association between IFNL4 polymorphism, PR treatment response and liver interferon‐stimulated gene expression in HCV‐3. Aim We evaluated the association between IFNL4/IFNL3 genotypes, PR treatment outcomes and intrahepatic interferon‐stimulated gene expression, according to HCV genotype. Methods HCV‐1 and HCV‐3 patients who received PR therapy were identified. IFNL3 (rs12979860) and IFNL4 genotype (rs368234815) were determined. A second cohort with stored liver specimens was identified. Expression of ISGs was measured by rt‐PCR. Results Two hundred and fifty‐nine patients were identified: 55% HCV‐1, 45% HCV‐3. IFNL4 genotype frequency was TT/TT 44%, TT/ΔG 42% andΔG/ΔG 14%. Linkage disequilibrium with IFNL3 genotype was high (r2 = 0.98). The association between IFNL4 genotype and PR response was attenuated in HCV‐3 vs. HCV‐1 (HCV‐3: SVR 89% vs. 76% vs. 72% for TT/TT vs. TT/ΔG vs. ΔG/ΔG, P = 0.09; HCV‐1: SVR: 82% vs. 29% vs. 24%, P < 0.001). Intrahepatic ISG expression was evaluated in 92 patients; 61% HCV‐1. The association between IFNL4 genotype and liver ISG expression was significantly different for HCV‐3 vs. HCV‐1 (P‐value for interaction = 0.046), with levels of interferon‐stimulated gene expression being highest in HCV‐1 patients who carried a poor‐response IFNL4 genotype. Conclusions The relationship between IFNL4 genotype and PR treatment response as well as intrahepatic interferon‐stimulated gene expression differs between HCV‐1 and HCV‐3. These data suggest fundamental differences in host–virus interactions according to HCV genotype.