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Background and Aims Seroclearance of hepatitis B surface antigen (HBsAg) is regarded as the functional cure of chronic hepatitis B (CHB). The relationship between human leukocyte antigen (HLA) variants, hepatitis B virus genotype, and longitudinal HBsAg serodecline remains to be explored. Methods A total of 2498 HBeAg-seronegative CHB patients of the community-based REVEAL-HBV cohort were genotyped for rs1710 (HLA-G) and rs2770 (HLA-B) using TaqMan assay. Cox proportional hazard regression and generalized linear mixed models were used to analyze the association of HLA genetic variants with the rate of HBsAg seroclearance and longitudinal HBsAg serodecline. Results Rs1710 G allele was differentially associated with the HBsAg seroclearance in genotype B [aRR (95% CI)=0.74 (0.56-0.98)] and genotype C [aRR (95%CI)=1.43 (1.08-1.88)] infection. Rs2770 G allele was associated with HBsAg seroclearance only in genotype B infection [aRR (95% CI)=0.69 (0.52-0.91)]. The alleles associated with HBsAg seroclearance were significant predictors for the serodecline of HBsAg levels in an HBV genotype-dependent manner (genotype B infection: rs1710, p=0.013; rs2770, p=0.0081; genotype C infection: rs1710, P=0.0452). Conclusions Our results suggest both spontaneous HBsAg seroclearance and serodecline are modified by the interaction between HLA variants and HBV genotype.

In chronic hepatitis B virus (HBV) infection, earlier seroclearance of hepatitis B e antigen (HBeAg) is associated with more favorable outcomes. Soluble programmed cell death 1 (sPD-1) has been implicated in higher viral load and hepatocellular carcinoma. We investigated the association between sPD-1 levels and spontaneous HBeAg seroclearance.Baseline serum samples from 488 HBeAg-seropositive patients in the REVEAL-HBV cohort were tested for sPD-1 levels. Among them, 329 with available follow-up serum samples were further assayed. Multivariate Cox regression analysis was used to estimate the adjusted rate ratio (aRR) and 95% confidence interval (CI) with adjustment of host and viral factors. The 66th percentile and an annual reduction of ≥ 10% were used as the cut-off point for baseline sPD-1 levels (high/low) and sPD-1 trajectory (decline/no decline), respectively.Lower baseline sPD-1 levels [aRR (95% CI): 2.19 (1.47-3.27)] and long-term decline in sPD-1 levels [aRR (95% CI): 4.08 (2.79-5.97)] were both independent predictors for HBeAg seroclearance. However, further stratification analysis by HBV genotype showed that lower baseline sPD-1 levels were significantly associated with HBeAg seroclearance only in genotype C infection [aRR (95% CI): 4.47 (2.38-8.37)] but not in genotype B infection. On the other hand, long-term decline in sPD-1 levels was predictive for HBeAg seroclearance regardless of HBV genotype with aRR (95% CI) of 4.62 (2.71-7.88) and 2.95 (1.68-5.17), respectively, for genotypes B and C.Serum sPD-1 levels may serve as a novel immunological predictor for spontaneous HBeAg seroclearance in patients with chronic hepatitis B.