Title: Changes in liver stiffness values assessed using transient elastography in chronic hepatitis
B patients treated with tenofovir disoproxil fumarate: a prospective observational study
Version: 3 Date: 03 May 2023
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
No - there are minor issues
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
Yes - the author's interpretation is reasonable
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: Overall this manuscript is well-written and summarizes the findings
of a carefully designed prospective observational cohort study of patients with chronic HBV
infection treated with TDF tenofovir at a single center between 2015-2020 who undergo
protocol assessments of liver stiffness measurement (LSM) using transient elastography over
the course of 144 weeks at times 0 (baseline), 48, 96, and 144 weeks. The authors report that
TDF antiviral therapy was associated with a statistically and clinically significant decrease
in median liver stiffness. The methodology used for defining the study population, inclusion/
exclusion criteria, outcome measures, and statistical methods are reasonable. The authors have
satisfactorily addressed the comments raised by prior reviewers. The major concerns with this
manuscript are largely non-modifiable - the study population is very small (n=36), there is
no comparator treatment group (e.g. alternative antiviral or no treatment) or comparator gold
standard assessment of fibrosis (e.g. liver biopsy) or assessment of liver clinical outcomes (e.g.
cirrhosis, hepatic decompensation, HCC, mortality).  On this basis, the results are generally
predictable and do not significantly add to the existing literature, and is largely underpowered
to answer clinical questions of interest.
REQUESTED REVISIONS:
Objective: the authors' stated objective to ""investigate the changes in LS values during the 144-
week TDF therapy in treatment-naïve CHB patients"" is clear, but is not novel as it's already
been studied and published in far larger cohorts, and with higher validity assessments of fibrosis
such as liver biopsy - clear but unsure of significance.  Design: main concern is the absence of
clear comparator groups.  Execution: reasonable overall given intrinsic limitations of study size
and design - largely descriptive statistics.  Statistics: reasonable given limitations as outlined.
Interpretation: The authors' conclusions are accurate and sound given the results and overall
I have no major concerns with the validity of this report, but am uncertain regarding impact/
novelty.
ADDITIONAL REQUESTS/SUGGESTIONS:
1) Materials and methods, patients: inclusion criteria #3 states that ""clinically diagnosed liver
cirrhosis"" was an inclusion criteria yet in Table 1 only 22% had cirrhosis - please clarify as
this appears to be incorrect or at minimum misleading; 2) Materials and methods, patients: why
restrict to patients with LSM >5.5 kPa? 3) Materials and methods, patients: was hepatocellular
carcinoma (HCC) an exclusion criteria? This could certainly influence results; 5) Materials
and methods, patients: was HDV coinfection an exclusion criteria? 6) Materials and methods,
patients: how was NAFLD/obesity handled as a variable given influence on LSM? 7) Results,
changes in LS values and FIB-4 scores during follow-up: please define comparisons to determine
statistical differences between LSM groups at all timepoints - can we assume baseline LSM was
reference as there is no defined comparator group?"
Title: Changes in liver stiffness values assessed using transient elastography in chronic hepatitis
B patients treated with tenofovir disoproxil fumarate: a prospective observational study
Version: 3 Date: 03 May 2023
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
No - there are minor issues
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
Yes - the author's interpretation is reasonable
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: Overall this manuscript is well-written and summarizes the findings
of a carefully designed prospective observational cohort study of patients with chronic HBV
infection treated with TDF tenofovir at a single center between 2015-2020 who undergo
protocol assessments of liver stiffness measurement (LSM) using transient elastography over
the course of 144 weeks at times 0 (baseline), 48, 96, and 144 weeks. The authors report that
TDF antiviral therapy was associated with a statistically and clinically significant decrease
in median liver stiffness. The methodology used for defining the study population, inclusion/
exclusion criteria, outcome measures, and statistical methods are reasonable. The authors have
satisfactorily addressed the comments raised by prior reviewers. The major concerns with this
manuscript are largely non-modifiable - the study population is very small (n=36), there is
no comparator treatment group (e.g. alternative antiviral or no treatment) or comparator gold
standard assessment of fibrosis (e.g. liver biopsy) or assessment of liver clinical outcomes (e.g.
cirrhosis, hepatic decompensation, HCC, mortality).  On this basis, the results are generally
predictable and do not significantly add to the existing literature, and is largely underpowered
to answer clinical questions of interest.
REQUESTED REVISIONS:
Objective: the authors' stated objective to ""investigate the changes in LS values during the 144-
week TDF therapy in treatment-naïve CHB patients"" is clear, but is not novel as it's already
been studied and published in far larger cohorts, and with higher validity assessments of fibrosis
such as liver biopsy - clear but unsure of significance.  Design: main concern is the absence of
clear comparator groups.  Execution: reasonable overall given intrinsic limitations of study size
and design - largely descriptive statistics.  Statistics: reasonable given limitations as outlined.
Interpretation: The authors' conclusions are accurate and sound given the results and overall
I have no major concerns with the validity of this report, but am uncertain regarding impact/
novelty.
ADDITIONAL REQUESTS/SUGGESTIONS:
1) Materials and methods, patients: inclusion criteria #3 states that ""clinically diagnosed liver
cirrhosis"" was an inclusion criteria yet in Table 1 only 22% had cirrhosis - please clarify as
this appears to be incorrect or at minimum misleading; 2) Materials and methods, patients: why
restrict to patients with LSM >5.5 kPa? 3) Materials and methods, patients: was hepatocellular
carcinoma (HCC) an exclusion criteria? This could certainly influence results; 5) Materials
and methods, patients: was HDV coinfection an exclusion criteria? 6) Materials and methods,
patients: how was NAFLD/obesity handled as a variable given influence on LSM? 7) Results,
changes in LS values and FIB-4 scores during follow-up: please define comparisons to determine
statistical differences between LSM groups at all timepoints - can we assume baseline LSM was
reference as there is no defined comparator group?"
Please review this paper.
user
Title: Changes in liver stiffness values assessed using transient elastography in chronic hepatitis
B patients treated with tenofovir disoproxil fumarate: a prospective observational study
Version: 3 Date: 03 May 2023
Reviewer's report:
"PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
Yes - there is a clear objective
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
No - there are minor issues
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are minor issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
Yes - appropriate statistical analyses have been used in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
Yes - the author's interpretation is reasonable
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Probably - with minor revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: Overall this manuscript is well-written and summarizes the findings
of a carefully designed prospective observational cohort study of patients with chronic HBV
infection treated with TDF tenofovir at a single center between 2015-2020 who undergo
protocol assessments of liver stiffness measurement (LSM) using transient elastography over
the course of 144 weeks at times 0 (baseline), 48, 96, and 144 weeks. The authors report that
TDF antiviral therapy was associated with a statistically and clinically significant decrease
in median liver stiffness. The methodology used for defining the study population, inclusion/
exclusion criteria, outcome measures, and statistical methods are reasonable. The authors have
satisfactorily addressed the comments raised by prior reviewers. The major concerns with this
manuscript are largely non-modifiable - the study population is very small (n=36), there is
no comparator treatment group (e.g. alternative antiviral or no treatment) or comparator gold
standard assessment of fibrosis (e.g. liver biopsy) or assessment of liver clinical outcomes (e.g.
cirrhosis, hepatic decompensation, HCC, mortality).  On this basis, the results are generally
predictable and do not significantly add to the existing literature, and is largely underpowered
to answer clinical questions of interest.
REQUESTED REVISIONS:
Objective: the authors' stated objective to ""investigate the changes in LS values during the 144-
week TDF therapy in treatment-naïve CHB patients"" is clear, but is not novel as it's already
been studied and published in far larger cohorts, and with higher validity assessments of fibrosis
such as liver biopsy - clear but unsure of significance.  Design: main concern is the absence of
clear comparator groups.  Execution: reasonable overall given intrinsic limitations of study size
and design - largely descriptive statistics.  Statistics: reasonable given limitations as outlined.
Interpretation: The authors' conclusions are accurate and sound given the results and overall
I have no major concerns with the validity of this report, but am uncertain regarding impact/
novelty.
ADDITIONAL REQUESTS/SUGGESTIONS:
1) Materials and methods, patients: inclusion criteria #3 states that ""clinically diagnosed liver
cirrhosis"" was an inclusion criteria yet in Table 1 only 22% had cirrhosis - please clarify as
this appears to be incorrect or at minimum misleading; 2) Materials and methods, patients: why
restrict to patients with LSM >5.5 kPa? 3) Materials and methods, patients: was hepatocellular
carcinoma (HCC) an exclusion criteria? This could certainly influence results; 5) Materials
and methods, patients: was HDV coinfection an exclusion criteria? 6) Materials and methods,
patients: how was NAFLD/obesity handled as a variable given influence on LSM? 7) Results,
changes in LS values and FIB-4 scores during follow-up: please define comparisons to determine
statistical differences between LSM groups at all timepoints - can we assume baseline LSM was
reference as there is no defined comparator group?"
assistant