Hepatocellular Carcinoma in Delta Hepatitis Versus HBV Monoinfection: Spot the Differences

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Authors present an interesting study in HBV versus HBV-HDV impact on HCC. This articles provides novel insights into the different oncogenic pathways and clinical outcomes of these two subgroups. The study is clinically significant, highlighting the increased HCC prevalence in HDV infected patients. The presentation is clear, but minor refinements in data interpretation are needed. It will be of great interest to hepatologists and oncologists managing viral hepatitis-related HCC.
However, I have the following suggestions:
1. The molecular mechanisms of HDV-related carcinogenesis should be expanded.
2. The retrospective design’s limitations should be acknowledged.
3. The discussion should emphasize clinical implications, particularly screening and transplant candidacy.

Author Response

Authors present an interesting study in HBV versus HBV-HDV impact on HCC. This articles provides novel insights into the different oncogenic pathways and clinical outcomes of these two subgroups. The study is clinically significant, highlighting the increased HCC prevalence in HDV infected patients. The presentation is clear, but minor refinements in data interpretation are needed. It will be of great interest to hepatologists and oncologists managing viral hepatitis-related HCC.

A: Thank you for your kind words and for encouraging our research.

However, I have the following suggestions:
1. The molecular mechanisms of HDV-related carcinogenesis should be expanded.

A: I have expanded both HBV and HDV carcinogenesis into two large paragraphs in the manuscript.
2. The retrospective design’s limitations should be acknowledged.

A: I have added a new chapter, limitations, where I acknowledged the retrospective design of the study.

3. The discussion should emphasize clinical implications, particularly screening and transplant candidacy.

A: I have added two paragraphs in discussions, looking at the importance of individualized screening and transplant candidacy.

 

Reviewer 2 Report

Comments and Suggestions for Authors

There are some comments.
- It would be better to explain how to confirm the diagnosis of HCC.
- It would be better to explain how to confirm the disease stage and severity.
- It would be better to add a list of abbreviations.
- Please edit the tables and references according to the journal guidelines.

Comments on the Quality of English Language

Please check English grammar, spacing, and spelling
 For example, 
        desgamma-carboxy prothrombin -> des gamma-carboxy prothrombin
        Abbas et al -> Abbas et al.
       significat  -> significant
       particulary -> particularly

Author Response

A:Thank you for your time and effort and for considering our manuscript for publication.

There are some comments.
- It would be better to explain how to confirm the diagnosis of HCC.

A: I have added a whole paragraph on the HCC diagnosis in background section, but also in methodology. 
- It would be better to explain how to confirm the disease stage and severity.

A: I have added a paragraph regarding disease stage and severity in background section and I have also approached the topic in methodology.

- It would be better to add a list of abbreviations.

A: I have added a list of abbreviations at the end of the manuscript, before references.

- Please edit the tables and references according to the journal guidelines.

A: I have edited both the tables and references according to journal guidelines.

Please check English grammar, spacing, and spelling
 For example, 
        desgamma-carboxy prothrombin -> des gamma-carboxy prothrombin
        Abbas et al -> Abbas et al.
       significat  -> significant
       particulary -> particularly

A: Thank you very much for drawing attention to this and we apologise. I have  checked the spelling again and made the changes where needed.

Reviewer 3 Report

Comments and Suggestions for Authors

This manuscript presents a retrospective analysis comparing the characteristics of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) monoinfection versus HBV with hepatitis delta virus (HDV) co-infection. The study provides valuable insights into differences in HCC prevalence, tumor characteristics, and clinical outcomes between these two groups. The topic is relevant to the field of hepatology, and the findings have potential implications for disease monitoring and treatment strategies.

However, several areas require clarification and improvement. Below are specific comments regarding the study's methodology, statistical analysis, and interpretation of results.

 

Major Comments:

1. The inclusion criteria state that all HBsAg-positive patients were included. However, it would be beneficial to clarify whether any additional selection criteria (e.g., exclusion of patients with significant comorbidities, prior HCC treatment) were applied. Were patients matched for any confounding variables such as cirrhosis status, alcohol use, or metabolic dysfunction-associated liver disease? These factors could significantly influence HCC development and outcomes.
2. The study mentions that HDV-associated HCC is more likely to be detected at an earlier stage (smaller tumor size, lower AFP). Could this be due to closer monitoring of HDV-infected patients rather than a biological difference?
3. The findings suggest that HDV-associated HCC presents with smaller tumors and lower AFP levels. The authors attribute this to different molecular mechanisms. However, could this also be influenced by differences in surveillance frequency and access to healthcare?
4. Additional discussion is needed regarding the clinical implications of these findings. How should clinicians adjust screening protocols based on these results?
5. The study does not include an age- and gender-matched healthy control group. This limitation should be acknowledged and discussed.

Minor Comments:

1. Some references appear outdated or lack sufficient detail. Consider incorporating more recent studies on HDV-related HCC to strengthen the discussion.
2. Ensure consistency in reference formatting. For example, all references should include issue and page numbers, many of which are currently missing.
3. The discussion on future research is relevant but would benefit from a more specific proposal for prospective studies, including potential biomarkers or therapeutic targets for HDV-related HCC.

Author Response

This manuscript presents a retrospective analysis comparing the characteristics of hepatocellular carcinoma (HCC) in patients with hepatitis B virus (HBV) monoinfection versus HBV with hepatitis delta virus (HDV) co-infection. The study provides valuable insights into differences in HCC prevalence, tumor characteristics, and clinical outcomes between these two groups. The topic is relevant to the field of hepatology, and the findings have potential implications for disease monitoring and treatment strategies.

A: Thank you for your kind words and for considering our manuscript for publication.

However, several areas require clarification and improvement. Below are specific comments regarding the study's methodology, statistical analysis, and interpretation of results.

 

Major Comments:

1. The inclusion criteria state that all HBsAg-positive patients were included. However, it would be beneficial to clarify whether any additional selection criteria (e.g., exclusion of patients with significant comorbidities, prior HCC treatment) were applied. Were patients matched for any confounding variables such as cirrhosis status, alcohol use, or metabolic dysfunction-associated liver disease? These factors could significantly influence HCC development and outcomes.

A: We have not done matching for confounding factors unfortunately, but I added this at the limitations section of the manuscript and at the future research section as well. Thank you for the suggestion. No other exclusion criteria than the one mentioned in the methodology has been used in the study.

 

1. The study mentions that HDV-associated HCC is more likely to be detected at an earlier stage (smaller tumor size, lower AFP). Could this be due to closer monitoring of HDV-infected patients rather than a biological difference?

A:yes, definitely. I have highlighted where I mentioned it before, but after your suggestion I insisted more on the topic at the end of the discussion section.

 

1. The findings suggest that HDV-associated HCC presents with smaller tumors and lower AFP levels. The authors attribute this to different molecular mechanisms. However, could this also be influenced by differences in surveillance frequency and access to healthcare?

A: yes, we are a tertiary care centre and we have plenty of HDV patients refered to us for liver transplantation, HBV patients usually are managed in primary and secondary care. I have insisted on the topic at the end of discussions section

 

1. Additional discussion is needed regarding the clinical implications of these findings. How should clinicians adjust screening protocols based on these results?

A: I have added a paragraph regarding this topic at the end of discussions section.

 

1. The study does not include an age- and gender-matched healthy control group. This limitation should be acknowledged and discussed.

A: Thank you for your suggestion. I have added this to the limitations section.

Minor Comments:

1. Some references appear outdated or lack sufficient detail. Consider incorporating more recent studies on HDV-related HCC to strengthen the discussion.

A: Thank you for your suggestion. I have added roughly 10 new references, many of them being reviews published in  2024

 

1. Ensure consistency in reference formatting. For example, all references should include issue and page numbers, many of which are currently missing.

A: I have re-formatted the references using Mendeley and I have selected all the reference details on the author guidelines

 

1. The discussion on future research is relevant but would benefit from a more specific proposal for prospective studies, including potential biomarkers or therapeutic targets for HDV-related HCC.

A: thank you for your suggestion, I have added this to the future research section.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript was well-revised.

1. It would be better to add how many liver biopsies were performed.

2. Please ensure the tables conform to the journal’s formatting guidelines.
For example, list all abbreviations in the footnotes to enhance clarity and consistency.

Comments on the Quality of English Language

Please check English grammar and spelling.
 For example, oxigen  -> oxygen 
                       prooved -> proved 

Author Response

The manuscript was well-revised.

A: Thank you for your positive feedback and for your recommendations. We truly appreciate it. 

1. It would be better to add how many liver biopsies were performed. A: I have added this to the revised manuscript. Thank you.

2. Please ensure the tables conform to the journal’s formatting guidelines.
For example, list all abbreviations in the footnotes to enhance clarity and consistency.

A: Thank you for your suggestion and for explaining it. I have added an abbreviation list to each table.

A: regarding English and grammar - I have checked spelling and grammar again, thank you for your recommendation.

Reviewer 3 Report

Comments and Suggestions for Authors

No further comments.

Author Response

Dear Reviewer, 

Thank you for your recommendations and for the time allocated to read our manuscript. 

All the best, 

Mirela