IFNL4 rs368234815 and rs117648444 variants predict off-treatment HBsAg seroclearance in IFN-treated HBeAg-negative chronic hepatitis B patients

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/\u394G dinucleotide and rs117648444 nonsynonymous P70S polymorphisms in IFN lambda 4 (IFNL4) 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 IFNL4 rs368234815 and rs117648444 polymorphisms predict IFN-induced HBsAg clearance in CHB patients. METHODS: We sequenced the IFNL4 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 IFN\u3bb4 protein production, was comparable to that of 19 patients carrying the rs117648444 T allele predicted to produce an impaired IFN\u3bb4-S70 protein (39% vs 42%, P\u2009\u2009=\u2009\u2009.827). In contrast, these 81 patients, either not producing IFN\u3bb4 or producing an impaired IFN\u3bb4-S70 protein, had a significantly higher 15-year probability of HBsAg loss compared to the 45 subjects predicted to encode only the fully functional IFN\u3bb4-P70 (42% vs 11% P\u2009=\u2009.003). At multivariate analysis, combination of the rs368234815 and rs117648444 genotypes strongly predicted HBsAg clearance (HR 5.90, 95% CI 1.70-20.9, P\u2009=\u2009.006) together with pretreatment serum HBV DNA levels (HR 0.57, 95% CI 0.39-0.83, P\u2009=\u2009.003). CONCLUSION: IFNL4 rs368234815 and rs117648444 functional variants are worth to be investigated as pretreatment combined predictors of IFN response in HBeAg-negative CHB patients