on behalf of the CHARIOT Study GroupOn-treatment anemia is associated with higher sustained virological response (SVR) rates during peginterferon plus ribavirin (RBV) therapy. Inosine triphosphatase (ITPA) variants causing ITPase deficiency have been shown to protect against RBV-induced anemia. However, ITPase activity has not been associated with SVR. To study this discrepancy, we examined the relationships between ITPase activity, on-treatment anemia, SVR, and RBV levels in hepatitis C virus genotype 1 (HCV-1) patients from the CHARIOT study. ITPA genotype (rs7270101, rs1127354) was used to define ITPase activity in 546 patients. Plasma RBV levels were measured using high-performance liquid chromatography (HPLC). Relationships between ITPase activity, on-treatment hemoglobin (Hb) levels, RBV levels, and SVR were tested using regression modeling, survival analysis, and locally weighted scatterplot smoothing (LOWESS) plot analysis. Hb decline was independently associated with SVR (P < 0.0001). ITPase deficiency was present in 35%. ITPase deficiency strongly protected against Hb decline (P < 0.0001), but was not associated with SVR (P 5 0.28). The probability of SVR increased with lower nadir Hb for both wild-type and deficient ITPase activity, but the association curve shifted to describe a parallel relationship at higher Hb levels in patients with ITPase deficiency. In a subset (n 5 203), we tested the hypothesis that the association between Hb decline and SVR reflected RBV levels rather than actual Hb level. RBV levels were associated with on-treatment Hb decline and SVR, but not ITPase activity. In regression models, adjustment for RBV levels attenuated the association between Hb decline and SVR. Conclusion: ITPase deficiency protects against RBV-induced anemia, but is not associated with SVR. Our data suggest that the relationship between Hb decline and SVR is not mechanistic, but is linked to RBV levels. (HEPATOLOGY 2014;59:2152-2160

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In the context of a small possible effect size and high frequency in Asian populations, IL28B genotyping is likely to have, at best, limited clinical utility for predicting peg-IFN treatment outcome for CHB patients in the Asia-Pacific region.

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.

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