The relationships between IFNL4 genotype, intrahepatic interferon‐stimulated gene expression and interferon treatment response differs in HCV‐1 compared with HCV‐3

Abstract

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.

Impact of Interferon Lambda 4 Genotype on Interferon‐Stimulated Gene Expression During Direct‐Acting Antiviral Therapy for Hepatitis C

“…The findings above represent an extrapolation of data that is already available regarding the impact of host genotype on response to HCV . However, the most unexpected and challenging findings came in the analyses of the dynamic changes in responses on therapy.…”

Dynamic changes in innate immune responses during direct‐acting antiviral therapy for HCV infection

“…During IFN‐based therapy, HCV‐GT1 and HCV‐GT2/3 demonstrated markedly different IFN sensitivity, with HCV‐GT2/3 patients experiencing twofold higher SVR rates with a shorter duration of treatment (70‐80% vs. 40% for HCV‐GT3 and HCV‐GT‐1, respectively) . In addition, the degree of ISG upregulation has been shown to differ in HCV‐GT1 compared to HCV‐GT3, and an interaction between HCV genotype and host IL28B genotype that determines ISG expression has been reported . Together, these data demonstrate similar dynamic changes in ISG expression are also observed in HCV‐GT3 during DAA therapy; however, restriction of the findings to HCV‐GT3 C/C IL28B genotype cirrhotic patients suggests the importance of host‐viral interactions that partially modulate IFN responses with less potent DAA (and IFN‐based) regimens in difficult‐to‐treat patient populations.…”

“…Firstly, the former study exclusively enrolled HCV‐GT2‐ and HCV‐GT3‐infected patients, while our study only enrolled patients with HCV‐GT1a infection. ISG expression levels have previously been demonstrated to be determined by both IFNL3 genotype and HCV genotype, whereby ISG expression is higher in HCV‐GT1 patients compared to HCV‐GT3 patients. IFNL3 genotype was also important in determining ISG expression level, with a greater influence in HCV‐GT1 infection than HCV‐GT3 infection .…”

“…ISG expression levels have previously been demonstrated to be determined by both IFNL3 genotype and HCV genotype, whereby ISG expression is higher in HCV‐GT1 patients compared to HCV‐GT3 patients. IFNL3 genotype was also important in determining ISG expression level, with a greater influence in HCV‐GT1 infection than HCV‐GT3 infection . Secondly, their study included patients with compensated cirrhosis (~20%) who are well recognized to have immune dysregulation, which may ultimately affect ISG and cytokine/chemokine levels.…”

“…The endogenous IFN system plays an important role during IFN‐based therapy for CHC, whereby lower pre‐treatment intrahepatic ISG expression and rapid normalization of peripheral ISG levels are associated with a sustained virologic response (SVR) during IFN‐based therapy. Furthermore, baseline intrahepatic ISG expression strongly correlates with IL28B genotype, the strongest pre‐treatment predictor of outcome during IFN‐based therapy . These associations have not been consistently associated with baseline peripheral ISG expression …”