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Objectives The aim of this study was to identify serum proteins with differential concentrations between hepatocellular carcinoma (HCC) patients and HBsAg asymptomatic carriers among individuals infected with hepatitis B virus (HBV) with basal core promoter (BCP) double mutations (A1762T, G1764A). Methods iTRAQ and liquid chromatography-tandem mass spectrometry were used to identify differentially expressed protein, and an ELISA test was used for the validation test. Results The total number of proteins identified was 1,125, of which 239 showed statistically significant differences in their expression. The relative concentrations of serum dihydrolipoyl dehydrogenase (DLD), which showed the most significant correlation with liver diseases and infection, were significantly lower in HCC patients than asymptomatic HBsAg carriers and individuals negative for HBsAg. However, only the difference between HCC patients with BCP double mutations and HBsAg-negative individuals could be confirmed by ELISA. Meanwhile, we found that the concentrations of serum DLD in those infected with HBV with BCP double mutations were significantly lower than in individuals with the wild-type BCP. However, the difference in the concentrations of serum DLD between individuals with wild-type BCP and those negative for HBsAg was not significant. Conclusions HBV with BCP double mutations are associated with lower concentrations of serum DLD.

Despite several studies regarding the correlation between serum HBsAg titers and viral loads, the association remains uncertain. Eighty‐nine individuals were selected randomly from a Chinese cohort of 2,258 subjects infected persistently with hepatitis B virus (HBV) for cross‐sectional and longitudinal analysis. Viral loads of mutant HBV are lower than those of wild type HBV. The serum HBsAg titers correlate positively with viral loads in both HBeAg positive and negative subjects (r = 0.449, P = 0.013; r = 0.300, P = 0.018, respectively). No correlation between serum HBsAg titer and viral loads was found in any of the four phases of chronic HBV infection. The serum HBsAg titers correlate positively with viral loads in the group with wild type sequences of the PreS/S, basal core promoter (BCP), and preC regions of HBV(r = 0.502, P = 0.040). However, the correlation was not seen in the group with mutations in these regions (r = 0.165, P = 0.257). The correlation between HBsAg titers and viral loads was seen in individuals with wild type PreS/S sequences but not in the subgroup with BCP double mutations or PreC stop mutation, although their sequences in the preS/S regions were wild type. All these findings were confirmed by the longitudinal analysis. In conclusion, the correlation between serum HBsAg levels and viral loads may not differ between HBeAg positive and negative individuals but may depend on wild‐type or mutated genomic sequences. Therefore, HBsAg quantitation may be used as a surrogate for viral loads in only wild‐type HBV infections. J. Med. Virol. 87:1351–1360, 2015. © 2015 The Authors. Journal of Medical Virology Published by Wiley Periodicals, Inc.

Highlights • The annual incidence rate of the basal core promoter (BCP) double mutations is 3.8%. • The incidence rate tends to decrease with age and the peak appeared early in the life. • Nucleotide (nt) 1762 is the favoured site of the first mutation. • Viruses with a single mutation at nt 1762 or 1764 are more prone to develop double mutations., Cross-sectional analyses showed that the prevalence of basal core promoter (BCP) double mutations (nt 1762T, 1764A) of hepatitis B virus (HBV) gradually increases with age. We aimed to determine the incidence rate of the mutations over 10 years. Study subjects were selected from the Long An cohort established in 2004, including 59 with HBV with single mutations at nt 1762 or 1764 in the BCP and 342 with wild type BCP sequences at baseline. Their serum samples for analysis were obtained at the 3rd and 10th annual visits, respectively. The results showed that the annual incidence rate of BCP double mutations is 3.8% (95% confidence interval [CI]: 1.4–6.2) and tends to decrease with age. The peak incidence is in the 30–34 years age-group. The incidence rate in HBeAg positive individuals (5.5%) is significantly higher than in those without HBeAg (3.4%) (P