Title: Anti-HBc: a significant host predictor of spontaneous HBsAg seroclearance in chronic
hepatitis B patients - a retrospective longitudinal study
Version: 1 Date: 17 Aug 2023
Reviewer:  Kaiping Jiang
Reviewer's report:
This study investigated the possibility of serum anti-HBc as a potential predictor of spontaneous
HBsAg seroclearance. Although several studies have explored the relationship between anti-
HBc and HBsAg seroclearance, this is the first study that shows a significant trend of decreasing
plasma anti-HBc levels before spontaneous HBsAg seroclearance in treatment-naive HBeAg-
negative CHB patients. Thus, the results of this study provide useful additional knowledge on
this field. It is suggested to revise the manuscript to better justify the study design and discuss
the findings in the context of existing studies, as follows.
Major comments#
1.There is a lack of data on baseline clinical characteristics in the study.
According to Table 1, only age, sex and baseline HBV DNA were collected to compare
differences in this study. Please collect additional laboratory data. For example, baseline HBsAg
level.
2.In the Materials and methods, a paragraph describing HBsAg testing methods is lacking.Please
add information on assay kit, lower and upper limits of detection, etc.
Minor comments#
1.In the abstract, specific experimental methods should be mentioned in the method.
2.In the third paragraph of the introduction, the authors state that "a non-neutralizing antibody
generated by host immune system in response to chronic hepatitis B infection", which appears to
be out of the blue. Therefore, the related description of anti-HBc should be added in the second
paragraph of the introduction.
3.In the first paragraph of the discussion, the authors state that “Our results showed that
lower plasma anti-HBc, presumably produced from dysfunctional B cells and without antiviral
effects, is independently associated with HBsAg seroclearance as early as 10 years before the
occurrence of the event”. The conclusion is overstated. The study does not prove that the two
are independently associated.
4.In the third paragraph of the Discussion section, the full name "CTL" is missing.
5.There are multiple missing references throughout the text, as follows.
"According to data from 2019, there are approximately 1.5 million new cases of chronic hepatitis
B each year and 296 million people, or 4% of the world's population, are living with chronic
hepatitis B. In the same year, hepatitis B was accountable for 820,000 deaths globally due to
cirrhosis and hepatocellular carcinoma (HCC)."
"Seroclearance of hepatitis B surface antigen (HBsAg) is a rare event that occurs at an annual
rate of 1% in which patients with CHB developed seroclearance of HBsAg."
"The number of samples in Hu's study was too small to show any significant trends in plasma
anti-HBc before HBsAg seroclearance."
"HBcAg can trigger humoral and cellular immune responses. The T cell response to HBcAg is
strong in acute self-limiting HBV infection, but is weak and quickly exhausted in chronic HBV
infection. CTLs specific to all viral antigens do exist in the liver of CHB patients, but in very
low levels. On the other hand, the antibody response to HBcAg comes off strong in chronically
infected patients but have almost no effect in inhibiting viral activity."
In addition to the examples above, there are a large number of statements in the full text that
lack references, please add references.
Title: Anti-HBc: a significant host predictor of spontaneous HBsAg seroclearance in chronic
hepatitis B patients - a retrospective longitudinal study
Version: 1 Date: 17 Aug 2023
Reviewer:  Kaiping Jiang
Reviewer's report:
This study investigated the possibility of serum anti-HBc as a potential predictor of spontaneous
HBsAg seroclearance. Although several studies have explored the relationship between anti-
HBc and HBsAg seroclearance, this is the first study that shows a significant trend of decreasing
plasma anti-HBc levels before spontaneous HBsAg seroclearance in treatment-naive HBeAg-
negative CHB patients. Thus, the results of this study provide useful additional knowledge on
this field. It is suggested to revise the manuscript to better justify the study design and discuss
the findings in the context of existing studies, as follows.
Major comments#
1.There is a lack of data on baseline clinical characteristics in the study.
According to Table 1, only age, sex and baseline HBV DNA were collected to compare
differences in this study. Please collect additional laboratory data. For example, baseline HBsAg
level.
2.In the Materials and methods, a paragraph describing HBsAg testing methods is lacking.Please
add information on assay kit, lower and upper limits of detection, etc.
Minor comments#
1.In the abstract, specific experimental methods should be mentioned in the method.
2.In the third paragraph of the introduction, the authors state that "a non-neutralizing antibody
generated by host immune system in response to chronic hepatitis B infection", which appears to
be out of the blue. Therefore, the related description of anti-HBc should be added in the second
paragraph of the introduction.
3.In the first paragraph of the discussion, the authors state that “Our results showed that
lower plasma anti-HBc, presumably produced from dysfunctional B cells and without antiviral
effects, is independently associated with HBsAg seroclearance as early as 10 years before the
occurrence of the event”. The conclusion is overstated. The study does not prove that the two
are independently associated.
4.In the third paragraph of the Discussion section, the full name "CTL" is missing.
5.There are multiple missing references throughout the text, as follows.
"According to data from 2019, there are approximately 1.5 million new cases of chronic hepatitis
B each year and 296 million people, or 4% of the world's population, are living with chronic
hepatitis B. In the same year, hepatitis B was accountable for 820,000 deaths globally due to
cirrhosis and hepatocellular carcinoma (HCC)."
"Seroclearance of hepatitis B surface antigen (HBsAg) is a rare event that occurs at an annual
rate of 1% in which patients with CHB developed seroclearance of HBsAg."
"The number of samples in Hu's study was too small to show any significant trends in plasma
anti-HBc before HBsAg seroclearance."
"HBcAg can trigger humoral and cellular immune responses. The T cell response to HBcAg is
strong in acute self-limiting HBV infection, but is weak and quickly exhausted in chronic HBV
infection. CTLs specific to all viral antigens do exist in the liver of CHB patients, but in very
low levels. On the other hand, the antibody response to HBcAg comes off strong in chronically
infected patients but have almost no effect in inhibiting viral activity."
In addition to the examples above, there are a large number of statements in the full text that
lack references, please add references.
Please review this paper.
user
Title: Anti-HBc: a significant host predictor of spontaneous HBsAg seroclearance in chronic
hepatitis B patients - a retrospective longitudinal study
Version: 1 Date: 17 Aug 2023
Reviewer:  Kaiping Jiang
Reviewer's report:
This study investigated the possibility of serum anti-HBc as a potential predictor of spontaneous
HBsAg seroclearance. Although several studies have explored the relationship between anti-
HBc and HBsAg seroclearance, this is the first study that shows a significant trend of decreasing
plasma anti-HBc levels before spontaneous HBsAg seroclearance in treatment-naive HBeAg-
negative CHB patients. Thus, the results of this study provide useful additional knowledge on
this field. It is suggested to revise the manuscript to better justify the study design and discuss
the findings in the context of existing studies, as follows.
Major comments#
1.There is a lack of data on baseline clinical characteristics in the study.
According to Table 1, only age, sex and baseline HBV DNA were collected to compare
differences in this study. Please collect additional laboratory data. For example, baseline HBsAg
level.
2.In the Materials and methods, a paragraph describing HBsAg testing methods is lacking.Please
add information on assay kit, lower and upper limits of detection, etc.
Minor comments#
1.In the abstract, specific experimental methods should be mentioned in the method.
2.In the third paragraph of the introduction, the authors state that "a non-neutralizing antibody
generated by host immune system in response to chronic hepatitis B infection", which appears to
be out of the blue. Therefore, the related description of anti-HBc should be added in the second
paragraph of the introduction.
3.In the first paragraph of the discussion, the authors state that “Our results showed that
lower plasma anti-HBc, presumably produced from dysfunctional B cells and without antiviral
effects, is independently associated with HBsAg seroclearance as early as 10 years before the
occurrence of the event”. The conclusion is overstated. The study does not prove that the two
are independently associated.
4.In the third paragraph of the Discussion section, the full name "CTL" is missing.
5.There are multiple missing references throughout the text, as follows.
"According to data from 2019, there are approximately 1.5 million new cases of chronic hepatitis
B each year and 296 million people, or 4% of the world's population, are living with chronic
hepatitis B. In the same year, hepatitis B was accountable for 820,000 deaths globally due to
cirrhosis and hepatocellular carcinoma (HCC)."
"Seroclearance of hepatitis B surface antigen (HBsAg) is a rare event that occurs at an annual
rate of 1% in which patients with CHB developed seroclearance of HBsAg."
"The number of samples in Hu's study was too small to show any significant trends in plasma
anti-HBc before HBsAg seroclearance."
"HBcAg can trigger humoral and cellular immune responses. The T cell response to HBcAg is
strong in acute self-limiting HBV infection, but is weak and quickly exhausted in chronic HBV
infection. CTLs specific to all viral antigens do exist in the liver of CHB patients, but in very
low levels. On the other hand, the antibody response to HBcAg comes off strong in chronically
infected patients but have almost no effect in inhibiting viral activity."
In addition to the examples above, there are a large number of statements in the full text that
lack references, please add references.
assistant