<italic>IFNL4</italic> rs368234815 and rs117648444 variants predict off‐treatment HBsAg seroclearance in IFN‐treated HBeAg‐negative chronic hepatitis B patients.

Abstract: Background & Aim: Robust baseline predictors of interferon (IFN) response in HBeAg‐negative chronic hepatitis B (CHB) patients are not currently available. The recently described rs368234815 TT/ΔG dinucleotide and rs117648444 nonsynonymous P70S polymorphisms in IFN lambda 4 (<italic>IFNL4</italic>) gene, which are strongly associated with response to IFN in hepatitis C virus (HCV) infection, could be also useful in IFN‐treated CHB patients. Here we assessed whether <italic>IFNL4</italic> rs368234815 and rs117648444 polymorphisms predict IFN‐induced HBsAg clearance in CHB patients. Methods: We sequenced the <italic>IFNL4</italic> gene on genomic DNA collected from 126 HBeAg‐negative CHB patients treated with IFN and followed up for a median of 11 (1‐23) years. Results: The 15‐year cumulative probability of HBsAg loss in the 62 carriers of the rs368234815 TT/TT genotype, which abolishes the IFNλ4 protein production, was comparable to that of 19 patients carrying the rs117648444 T allele predicted to produce an impaired IFNλ4‐S70 protein (39% vs 42%, <italic>P</italic>  =  .827). In contrast, these 81 patients, either not producing IFNλ4 or producing an impaired IFNλ4‐S70 protein, had a significantly higher 15‐year probability of HBsAg loss compared to the 45 subjects predicted to encode only the fully functional IFNλ4‐P70 (42% vs 11% <italic>P</italic> = .003). At multivariate analysis, combination of the rs368234815 and rs117648444 genotypes strongly predicted HBsAg clearance (HR 5.90, 95% CI 1.70‐20.9, <italic>P</italic> = .006) together with pretreatment serum HBV DNA levels (HR 0.57, 95% CI 0.39‐0.83, <italic>P</italic> = .003). Conclusion: <italic>IFNL4</italic> rs368234815 and rs117648444 functional variants are worth to be investigated as pretreatment combined predictors of IFN response in HBeAg‐negative CHB patients. [ABSTRACT FROM AUTHOR]