STAT4 rs7574865 polymorphism does not predict HBsAg loss in IFN treated genotype D HBeAg-negative patients with chronic Hepatitis B
AASLD LiverLearning®. Lampertico P. Nov 14, 2016; 144687
Topic: Treatment and Clinical Trials
Prof. Dr. Pietro Lampertico
Prof. Dr. Pietro Lampertico
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TITLE: STAT4 rs7574865 polymorphism does not predict HBsAg loss in IFN treated genotype D HBeAg-negative patients with chronic Hepatitis B

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Background and Aim: Interferon (IFN) is a well-established first line treatment for chronic hepatitis B (CHB) patients, although with a limited efficacy (20-30%) in genotype D patients. Recently, the polymorphism rs7574865 in the third intron of the STAT4 gene was reported to be a reliable predictor of response to IFNα therapy for HBeAg-positive Asian CHB patients. Aim of the study was to explore whether this STAT4 polymorphism could improve the predictive power of other genetic signatures such as IFNL4 variants on response to IFN-based treatment in genotype D HBeAg negative CHB patients. Materials and Methods: Genomic DNA extracted from whole blood of 126 HBeAg-negative CHB patients with compensated disease (age 46 years, 82% males, 90% genotype D, HBV-DNA 6.2 log10 copies/ml, ALT 132 IU/L, 40% with cirrhosis) that received (Peg)IFN alfa for 22 (6-48) months and followed for 11 (1-23) years with HBsAg clearance as a primary endpoint, was used either for TaqMan SNP Genotyping Assays (STAT4) than for Sanger sequencing (IFNL4). Results: The distribution of STAT4 rs7574865 genotype in our cohort was GG in 85 patients (68%), GT in 37 (29%) and TT in 4 (3%). The corresponding ones for the two IFNL4 variants were TT/TT in 62 (49%), TT/ΔG in 51 (40%) and ΔG/ΔG in 13 (11%) for rs368234815 and CC in 107 (85%), CT in 18 (14.2%) and TT in only 1 (0.8%) for rs117648444. Twenty-eight patients (22%) ultimately cleared HBsAg with a 15-year cumulative probability of 30%. However, the 15-year cumulative probability of HBsAg loss was similar in patients with different STAT4 genotypes (29% in GG; 29% in GT; 34% in TT; p=0.94). At multivariate analysis including also all the canonical pretreatment predictors of response (age, gender, cirrhosis, ALT, HBV-DNA and HBV genotype), the only independent baseline predictors of HBsAg seroclearance were the combined IFNL4 rs368234815 and rs117648444 genotypes (HR=4.3, 95%CI 1.5-12.3, p=0.007) and the pretreatment serum HBV-DNA levels (HR=0.61, 95%CI 0.43-0.87, p=0.007). Conclusions: The STAT4 rs7574865 variant does not predict the off-treatment HBsAg clearance in IFN-treated HBeAg negative CHB patients
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