Viral Factors Correlate With HBeAg Seroconverson in Chronic Hepatitis B
Viral Factors Correlate With HBeAg Seroconverson in Chronic Hepatitis B
Background/Aims: Seroconversion (SC) from hepatitis B envelope antigen (HBeAg) to anti-HBe usually indicates lower viral loads, resolved hepatitis activity and improved long-term outcomes. However, the role of viral factors in the development of SC remains largely unknown. We thus comprehensively studied these factors in 25 patients with sustained HBeAg SC and seven control patients with sustained loss of HBeAg.
Methods: We determined viral factors in serum samples obtained 1 year before, 6 months before, 3 months before, at the time of, 6 months after and 1 year after HBeAg SC or HBeAg loss. Precore A1896 and basal core promoter T1762/A1764 mutants were determined by polymerase chain reaction (PCR)-based assays. Serum HBV levels were determined by a real-time PCR assay.
Results: We found that decline of serum viral load, frequently accompanied by hepatitis exacerbation, occurred within 1 year before HBeAg SC. The proportions of precore and BCP mutations also increased gradually throughout the process of HBeAg SC. The virologic features were similar between HBeAg SC group and HBeAg loss group. Before HBeAg SC or loss, genotype B patients had higher serum viral loads and lower proportions of BCP mutation compared with genotype C patients.
Conclusion: Our findings suggested that viral factors correlate with the development of sustained HBeAg SC or loss.
Hepatitis B envelope antigen (HBeAg) and an antibody to HBeAg (anti-HBe) are closely related to the level of hepatitis B virus (HBV) replication and thus frequently used in assessing the activity of liver disease and monitoring the responses to antiviral therapy in patients with chronic HBV infection. Seroconversion (SC) from HBeAg to anti-HBe, either spontaneous or after antiviral therapy, usually indicates lower viral loads, resolved hepatitis activity and improved long-term outcomes. Therefore, it is important to identify factors associated with the development of HBeAg SC in patients with HBeAg-positive chronic hepatitis B.
However till now, the molecular basis of HBeAg SC is only partly clarified. From the viral replication's point of view, when the precore region and core gene in HBV DNA are transcribed and translated, HBeAg is produced and secreted into the circulation. A point mutation from G to A at nucleotide (nt) 1896 (A1896) converts codon 28 in the precore region from TGG for tryptophan to TAG for a stop codon, and aborts the synthesis of HBeAg at the translation level. Likewise, a double mutation in the basal core promoter (BCP) changing nt 1762 and 1764 from A to T and G to A (T1762/A1764), respectively, reduces the production of HBeAg by downregulating the transcription of precore mRNAs. Convincing lines of evidence have indicated a close association of HBeAg SC with the appearance of precore and BCP mutations as well as a decrease in serum viral load. Another study revealed that precore 1896 wild vs. mutant strain ratio also played a role in the SC of HBeAg and severity of disease activity. Our previous study further suggested that non-sustained HBeAg SC might be due to the lack of sustained precore and BCP mutations after SC.
Although some viral factors contributing to the development of HBeAg SC had been disclosed, there are limitations in previous studies. First, only few studies followed up these mutations closely during SC. To clarify the effects of viral factors on the development and durability of SC, relevant viral factors before, at and after the SC, should be investigated. Second, the viral load was not assessed by sensitive polymerase chain reaction (PCR)-based assays in previous studies. Currently, it is well known that viral load in the low range (<10) copies/ml could still affect the treatment outcomes and the progression of liver cirrhosis and HCC. Thus, it is important to evaluate the dynamics and influence of viral load on the pre- and post-SC clinical course. To that end, sensitive PCR-based assays should be adopted. To address these issues, we prospectively collected 25 patients with sustained HBeAg SC and seven patients with sustained loss of HBeAg as controls, and then comprehensively studied viral factors including serum viral load, genotype, precore A1896 mutation, and BCP di-nucleotide T1762/A1764 mutation.
Abstract and Introduction
Abstract
Background/Aims: Seroconversion (SC) from hepatitis B envelope antigen (HBeAg) to anti-HBe usually indicates lower viral loads, resolved hepatitis activity and improved long-term outcomes. However, the role of viral factors in the development of SC remains largely unknown. We thus comprehensively studied these factors in 25 patients with sustained HBeAg SC and seven control patients with sustained loss of HBeAg.
Methods: We determined viral factors in serum samples obtained 1 year before, 6 months before, 3 months before, at the time of, 6 months after and 1 year after HBeAg SC or HBeAg loss. Precore A1896 and basal core promoter T1762/A1764 mutants were determined by polymerase chain reaction (PCR)-based assays. Serum HBV levels were determined by a real-time PCR assay.
Results: We found that decline of serum viral load, frequently accompanied by hepatitis exacerbation, occurred within 1 year before HBeAg SC. The proportions of precore and BCP mutations also increased gradually throughout the process of HBeAg SC. The virologic features were similar between HBeAg SC group and HBeAg loss group. Before HBeAg SC or loss, genotype B patients had higher serum viral loads and lower proportions of BCP mutation compared with genotype C patients.
Conclusion: Our findings suggested that viral factors correlate with the development of sustained HBeAg SC or loss.
Introduction
Hepatitis B envelope antigen (HBeAg) and an antibody to HBeAg (anti-HBe) are closely related to the level of hepatitis B virus (HBV) replication and thus frequently used in assessing the activity of liver disease and monitoring the responses to antiviral therapy in patients with chronic HBV infection. Seroconversion (SC) from HBeAg to anti-HBe, either spontaneous or after antiviral therapy, usually indicates lower viral loads, resolved hepatitis activity and improved long-term outcomes. Therefore, it is important to identify factors associated with the development of HBeAg SC in patients with HBeAg-positive chronic hepatitis B.
However till now, the molecular basis of HBeAg SC is only partly clarified. From the viral replication's point of view, when the precore region and core gene in HBV DNA are transcribed and translated, HBeAg is produced and secreted into the circulation. A point mutation from G to A at nucleotide (nt) 1896 (A1896) converts codon 28 in the precore region from TGG for tryptophan to TAG for a stop codon, and aborts the synthesis of HBeAg at the translation level. Likewise, a double mutation in the basal core promoter (BCP) changing nt 1762 and 1764 from A to T and G to A (T1762/A1764), respectively, reduces the production of HBeAg by downregulating the transcription of precore mRNAs. Convincing lines of evidence have indicated a close association of HBeAg SC with the appearance of precore and BCP mutations as well as a decrease in serum viral load. Another study revealed that precore 1896 wild vs. mutant strain ratio also played a role in the SC of HBeAg and severity of disease activity. Our previous study further suggested that non-sustained HBeAg SC might be due to the lack of sustained precore and BCP mutations after SC.
Although some viral factors contributing to the development of HBeAg SC had been disclosed, there are limitations in previous studies. First, only few studies followed up these mutations closely during SC. To clarify the effects of viral factors on the development and durability of SC, relevant viral factors before, at and after the SC, should be investigated. Second, the viral load was not assessed by sensitive polymerase chain reaction (PCR)-based assays in previous studies. Currently, it is well known that viral load in the low range (<10) copies/ml could still affect the treatment outcomes and the progression of liver cirrhosis and HCC. Thus, it is important to evaluate the dynamics and influence of viral load on the pre- and post-SC clinical course. To that end, sensitive PCR-based assays should be adopted. To address these issues, we prospectively collected 25 patients with sustained HBeAg SC and seven patients with sustained loss of HBeAg as controls, and then comprehensively studied viral factors including serum viral load, genotype, precore A1896 mutation, and BCP di-nucleotide T1762/A1764 mutation.
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