Abstract
Background/AimsAlthough there have been a few reports regarding the effect of basal core promoter (BCP) double mutations (A1762T and G1764A) on hepatitis B viral loads, the association remains uncertain. We aim to determine the association after controlling for HBeAg – a strong confounding factor.MethodsWe selected randomly 190 individuals from a Chinese cohort of 2258 subjects for cross-sectional analysis and 56 of the 190 for longitudinal analysis of viral loads.ResultsIn multivariable analysis of the cross-sectional data, BCP double mutations are significantly associated with lower viral loads in HBeAg positive subjects but no difference was found in anti-HBe positive subjects. Triple mutations at nucleotide (nt) 1753, 1762 and 1764 and mutations between nt 1809 and 1817, precore stop mutation (nt 1896) and genotype are not associated with viral loads in either HBeAg or anti-HBe positive subjects. Analysis of the longitudinal data yielded similar results to the cross-sectional data. Viral loads differ significantly between individuals infected with wild-type and BCP double mutations prior to HBeAg seroconversion but this difference is lost after seroconversion.ConclusionsBCP double mutations are associated with lower viral loads in HBeAg positive individuals but have no effect on the viral loads of anti-HBe positive individuals.
Highlights
Hepatitis B virus (HBV) has a 3.2 kb circular DNA genome containing four partially overlapping open reading frames (ORFs): C, encoding the nucleocapsid protein (HBcAg) and secreted e antigen (HBeAg); P, the polymerase protein (Pol); S, the envelope proteins; and X, a transcriptional trans-activator protein
Whilst viral loads were significantly lower prior to HBeAg seroconversion in those with basal core promoter (BCP) double mutations than those without these mutations (P=0.01), the differences between the two groups were no longer significant after loss of HBeAg (P=0.27) (Fig. 2). This suggests that, whilst BCP double mutations are associated with lower viral loads in HBeAg positive individuals, they have no effect on the viral loads of HBeAg negative individuals
Viral loads may decline or increase after evolution of BCP mutations in individuals who remained HBeAg negative (Table 4). These results suggest that BCP double mutations have no effect on viral loads in anti-HBe positive individuals but determination of their effect in HBeAg positive individuals requires further study
Summary
Hepatitis B virus (HBV) has a 3.2 kb circular DNA genome containing four partially overlapping open reading frames (ORFs): C, encoding the nucleocapsid (core) protein (HBcAg) and secreted e antigen (HBeAg); P, the polymerase protein (Pol); S, the envelope proteins; and X, a transcriptional trans-activator protein. The core promoter located at nucleotides (nt) 1591-1822 plays a central role in virus replication, directing the synthesis of the pregenomic RNA, which, as well as being the template for genome synthesis, encodes HBcAg and Pol, and the precore RNA, which encodes HBeAg [1]. Studies involving transfection of human hepatoma cell lines and analysis of clinical samples showed that these double mutations suppress, but do not abolish, the synthesis of HBeAg and may and increase HBV DNA replication [2,7,8]
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