Abstract
Background: Hepatitis B surface antigen (HBsAg) and viral load are important clinical indicators for antiviral therapy. Few studies have evaluated viral sequence biomarkers predicting the risk of hepatocellular carcinoma (HCC) in the stage, which show a low serological response (HBsAg < 100 IU/ml) and high viral levels (HBV DNA > 2,000 IU/ml). This study aims to determine the trend of the biological prevalence within the pre-S/S regions of special model of inactive CHB infection.Methods: We used Sanger sequencing, quantitative HBV serology (HBeAg and HBsAg), and liver function index to identify whether HBV genome sequences are associated with long-term risk of further HCC progression in special inactive CHB infection.Results: HBV sequencing analysis of 28 CHB patients with special infectious pattern showed higher genetic diversity among four opening reading frames (ORFs) (p < 0.001). However, dN/dS ratios of HBsAg and pre-C/C regions in the experimental group showed no significantly different from those in the HCC group (p = 0.06), while significantly lower in polymerase and HBxAg regions of the experimental group (p < 0.001). In addition, seven positively selected sites were identified in pre-S1, five in pre-S2, and four in S, in which five sites (128H/135Q/135R/139L/141P) were among “α” determinant.Conclusions: These mutations in the pre-S/S region might be associated with the HCC phenotype of low HBsAg expression, with the P region possibly impacting high viral loads. Increased viral diversity across the HBV genome is also associated with low levels of HBsAg. The cumulative evolutionary changes in the HBV pre-S/S regions shows that facilitate immune evasion should be monitored individually. Due to the similarity of evolutionary characteristics in HCC, low serological responses and high viremia may be associated with the risk of further disease progression.
Highlights
Hepatitis B virus (HBV) infection has a wide spectrum of clinical manifestations ranging from an asymptomatic carrier state to acute or chronic hepatitis, with progression to severe liver disease [1]
HBV-related hepatocellular carcinoma (HCC) sequences were present in the control group (HCC group)
We were interested in identifying molecular evolutionary characteristics specific to LR/RA chronic hepatitis B” (CHB), and employed population sequencing to analyze the relationship between LR CHB and HCC
Summary
Hepatitis B virus (HBV) infection has a wide spectrum of clinical manifestations ranging from an asymptomatic carrier state (immunotolerant state) to acute or chronic hepatitis, with progression to severe liver disease [1]. Lowering of serum HBsAg to an undetectable level may indicate that intrahepatic cccDNA has been eradicated, which is known as a “functional cure”; this state is difficult to achieve through current antiviral approaches [3, 4]. We focused on a special infectious pattern between the low replicative phase (LR, referred to as the “inactive HBsAg carrier” state) and the reactivation phase [RA, previously referred to as “HBeAg-negative/anti-HBe positive chronic hepatitis B” (CHB)] that is characterized by a low serological response (HBsAg < 100 IU/ml) and high viral levels (HBV DNA > 2,000 IU/ml), persistently normal aminotransferase levels and mild inflammation and minimal fibrosis in the liver; this pattern is referred to as LR/RA CHB. Hepatitis B surface antigen (HBsAg) and viral load are important clinical indicators for antiviral therapy. This study aims to determine the trend of the biological prevalence within the pre-S/S regions of special model of inactive CHB infection
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