Epidemiology and Clinical Outcomes in the 20-Year HepCoVe Cohort: Progress Toward Elimination of HCV Infection in North-East Italy

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript reports a 20-year prospective, real-life cohort (HepCoVe) of patients with chronic hepatitis C enrolled in the Veneto Region (North-East Italy) and followed for a mean of 16.2 ± 8.4
years. The authors compare patients with parenteral exposure before vs. after 1995 (introduction of mandatory HCV testing) and describe two “waves” of HCV infection characterized by different risk factors, genotypes, and age distributions. They further contrast outcomes under Peg-IFN-based “standard of care” (SOC) vs. DAA therapy and evaluate long-term events such as HCC, transplantation and mortality. The topic is clinically important and fits well with the journal’s scope, and the dataset is rich and unique. With some clarifications on ethods, more precise wording in the interpretation, and polishing of the English and terminology.

1. The overall cohort structure is clear, but some aspects need to be more explicitly described up front. For instance, 3397 anti-HCV/HCV-RNA-positive patients were initially enrolled (2000–2005), of whom 2703 were included in the per-protocol analysis (1020 SOC, 940 DAA, 743 untreated), while 694 were classified as drop-outs or excluded for incomplete data. I suggest adding a simple flow diagram summarizing: number assessed/enrolled; numbers allocated to “untreated”, SOC, and DAA groups; numbers excluded (drop-outs, incomplete data, non-adherent) and the reasons. In the Methods, please clarify how follow-up time was handled for drop-outs and deaths (e.g., censoring date), and explicitly state that the main analysis is per-protocol rather than intention-to-treat. This is important for interpreting the HCC incidence and mortality results.
2. The description of “two epidemic waves” (pre-1995 vs. post-1995, and first vs. second outbreak wave) is a key result, but the terminology and structure are a bit difficult to follow. In Table 1 you mix several stratifications (before/after 1995 and first/second outbreak waves in the same table). I recommend clearly defining in the Methods what constitutes the “first outbreak wave” and “second outbreak wave” (e.g., which genotypes and risk factors, how you derived those definitions). In the Results, separate the description of “before vs. after 1995” and “first vs. second outbreak waves”, and explain the relationship between these groupings in a short, explicit paragraph. Ensure that figure and table captions also use consistent terms (“first outbreak wave”, “second outbreak wave”, “pre-1995 exposure”, etc.) so the reader does not get lost.
3. The Statistical Analysis section mentions Cox regression and Kaplan–Meier curves, and that only significant variables were retained as predictors of HCC onset. However, the main text does not clearly present hazard ratios (HRs) or confidence intervals for these predictors. It would strengthen the paper to: add a short table or paragraph summarizing the multivariable Cox model for HCC (e.g., age, fibrosis stage, treatment type, SVR vs. no SVR), including HRs and 95% CIs. Clarify whether “10-year risk of HCC was 0.81, 3.75, and 1.26 person-years” refers to incidence rates (per 100 person-years) or cumulative incidence. As written, “risk” and “person-years” are conflated and may confuse readers; please standardize terminology (e.g. “HCC incidence rate per 100 person-years”). In Figure 4, consider adding the number at risk at key timepoints, and specify in the legend that HCC curves start 12 weeks after end of therapy and how untreated patients were time-anchored.
4.  The Discussion appropriately notes that DAA therapy achieves high SVR rates and that HCC risk is reduced but not abolished. However, a few sentences could be more cautious, given the observational design and the presence of substantial differences among SOC-treated, DAA-treated, and untreated groups (age, fibrosis stage, genotype, comorbidities). I suggest rephrasing any language that could be interpreted as causal (e.g., “DAA therapy eradicated HCV infection in the older generation” or “DAA treatment changed mortality trends”) into more neutral observational wording (e.g., “was associated with high SVR rates” or “coincided with a marked decline in active HCV infection”). Explicitly acknowledging that residual confounding by indication and selection bias (e.g., the sickest or oldest patients remaining untreated or being ineligible for IFN) may influence the comparison between treated and untreated groups.
5. Many limitations are discussed throughout the text but are scattered. It would be helpful to add a concise paragraph (either late in the Discussion or as a separate “Limitations” subsection) explicitly stating: single-region, hepatology-center cohort (not population-based), which may limit generalizability. Per-protocol analysis with exclusion of drop-outs and incomplete cases. Changes in diagnostic practices, treatment eligibility, and surveillance intensity over 20 years, which may influence event detection (HCC, decompensation). Lack of granular data on comorbidities and competing causes of death in the main tables.
6. The title is informative but a bit long. Consider a small simplification, e.g.: “Epidemiology and Clinical Outcomes in the 20-year HepCoVe Cohort: Progress Toward Elimination of HCV Infection in North-East Italy.” The abstract is generally clear but quite dense. You might: explicitly state the total cohort size (n=2703 per-protocol) and follow-up duration. Clarify that HCC risk values are incidence rates (if that is the case) and not percentages.
7. Figure 1 (age bands and risk distribution) is useful but busy. Consider: simplifying the legend and clearly labeling the two waves. Ensuring that the green box representing the national screening campaign is explained in the caption for readers unfamiliar with the Italian context. Tables 1 and 2 contain a lot of information. To improve readability: align all percentages consistently and add a brief explanation of abbreviations directly beneath each table (e.g., SOC, DAA, PH, EV, GE). Double-check that percentages and denominators are consistent (e.g., percentages of F3–F4 fibrosis and post- ransfusion risk by group).
8. Some abbreviations are slightly non-standard or mis-expanded. For example: CI is listed as “confidential interval” instead of “confidence interval”. “standard of cure” (SOC) is unconventional; “standard of care” is the usual expression (you can keep the abbreviation SOC but define it clearly once). Please check that all abbreviations are defined at first use in the main text and that the abbreviations list matches what actually appears in the manuscript.
9. Overall, the English is understandable but would benefit from careful proofreading by a fluent speaker or professional editing service. Recurrent minor issues include: typographical errors and misspellings: e.g., “parental risk” instead of “parenteral risk”, “trasfusion” instead of “transfusion”, “hacient wave”, “cure effective intervention”, “cancelled the HCC occurrence risk”. Inconsistent tense and phrasing in Methods/Results. For example, prefer concise past tense: “Patients were followed for a mean of 16.2 ± 8.4 years” rather than “were then followed-up for 16.2 ± 8.4 years by a per protocol analysis.” Long, multi-clause sentences that could be split into two for clarity. Some non-idiomatic expressions, such as “hacient wave” (perhaps “ancient” or “earlier”), “older cohort is already extinct” (you could say “has largely disappeared”). It may help to go through the manuscript line by line and: shorten overly long sentences. Correct misspellings and minor grammar issues. Standardize key terms (e.g., “first epidemic wave”, “second epidemic wave”, “standard of care”, “person-years”).
10. The Discussion already references recent modeling studies on HCV prevalence and treatment uptake in Italy and Europe. You could modestly highlight how your long-term regional cohort complements these model-based estimates, emphasizing the real-world linkage between treatment eras (IFN vs. DAA), genotype shifts, and clinical outcomes (HCC, mortality). This is a valuable and timely cohort analysis, with long follow-up and a clear narrative around two “waves” of HCV infection and the impact of antiviral therapy in a well-defined region. The main findings are clinically relevant and, in my opinion, the data support the authors’ broad conclusions, provided that the limitations are clearly acknowledged and some wording is softened. I therefore recommend minor revision, focused on: clarifying the cohort structure and statistical reporting, tightening and standardizing terminology, and polishing the English language and phrasing.

This is a valuable and timely cohort analysis, with long follow-up and a clear narrative around two “waves” of HCV infection and the impact of antiviral therapy in a well-defined region. The main findings are clinically relevant and, in my opinion, the data support the authors’ broad conclusions, provided that the limitations are clearly acknowledged and some wording is softened. I therefore recommend minor revision, focused on: clarifying the cohort structure and statistical reporting, tightening and standardizing terminology, and polishing the English language and phrasing.

Comments on the Quality of English Language

Overall, the English is understandable but would benefit from careful proofreading by a fluent speaker or professional editing service. Recurrent minor issues include: typographical errors and misspellings: e.g., “parental risk” instead of “parenteral risk”, “trasfusion” instead of “transfusion”, “hacient wave”, “cure effective intervention”, “cancelled the HCC occurrence risk”. Inconsistent tense and phrasing in Methods/Results. For example, prefer concise past tense: “Patients were followed for a mean of 16.2 ± 8.4 years” rather than “were then followed-up for 16.2 ± 8.4 years by a per protocol analysis.” Long, multi-clause sentences that could be split into two for clarity. Some non-idiomatic expressions, such as “hacient wave” (perhaps “ancient” or “earlier”), “older cohort is already extinct” (you could say “has largely disappeared”). It may help to go through the manuscript line by line and: shorten overly long sentences. Correct misspellings and minor grammar issues. Standardize key terms (e.g., “first epidemic wave”, “second epidemic wave”, “standard of care”, “person-years”).

Author Response

REVIEWER_1 SUGGESTIONS & AUTHORS REPORT

Dear Reviewer, we thank you so much for your efforts and wise help in reviewing our article. Advising us on the most useful suggestions to improve it.

See below, we have responded point by point to your notes, trying to improve the form and presentation of our paper.

The English could be improved to more clearly express the research.

We have improved the English form throughout the manuscript. Please, follow in red characters the parts modified, and in particular we have shortened the introduction and modified the methods and results to simplify English text and gramma. We included a new figure (Figure S1: Flowchart, in supplementary material) and modified Fig. 1, 3 and 4, as you proposed.

COMMENTS TO ANSWER

This manuscript reports a 20-year prospective, real-life cohort (HepCoVe) of patients with chronic hepatitis C enrolled in the Veneto Region (North-East Italy) and followed for a mean of 16.2 ± 8.4
years. The authors compare patients with parenteral exposure before vs. after 1995 (introduction of mandatory HCV testing) and describe two “waves” of HCV infection characterized by different risk factors, genotypes, and age distributions. They further contrast outcomes under Peg-IFN-based “standard of care” (SOC) vs. DAA therapy and evaluate long-term events such as HCC, transplantation and mortality. The topic is clinically important and fits well with the journal’s scope, and the dataset is rich and unique. With some clarifications on methods, more precise wording in the interpretation, and polishing of the English and terminology.

1. The overall cohort structure is clear, but some aspects need to be more explicitly described up front. For instance, 3397 anti-HCV/HCV-RNA-positive patients were initially enrolled (2000–2005), of whom 2703 were included in the per-protocol analysis (1020 SOC, 940 DAA, 743 untreated), while 694 were classified as drop-outs or excluded for incomplete data. I suggest adding a simple flow diagram summarizing: number assessed/enrolled; numbers allocated to “untreated”, SOC, and DAA groups; numbers excluded (drop-outs, incomplete data, non-adherent) and the reasons. In the Methods, please clarify how follow-up time was handled for drop-outs and deaths (e.g., censoring date), and explicitly state that the main analysis is per-protocol rather than intention-to-treat. This is important for interpreting the HCC incidence and mortality results.

Thank you again for your kind consideration of our article, which is certainly an original and real data collection describing the epidemiological and clinical events regarding chronic hepatitis C in our region. We added a figure S1 with the flowchart of study description, which may also be included in the paper material and methods, instead of among the supplementary materials, if deemed more appropriate. This helped clarify and simplify the description of the study.

We have stated in several points of the manuscript, that we are reporting a population analyzed per protocol. Obviously cases with drop-out or death events were censored at the time of their last follow-up , being stopped from the group of at risk cases remaining in observation.

1. The description of “two epidemic waves” (pre-1995 vs. post-1995, and first vs. second outbreak wave) is a key result, but the terminology and structure are a bit difficult to follow. In Table 1 you mix several stratifications (before/after 1995 and first/second outbreak waves in the same table). I recommend clearly defining in the Methods what constitutes the “first outbreak wave” and “second outbreak wave” (e.g., which genotypes and risk factors, how you derived those definitions). In the Results, separate the description of “before vs. after 1995” and “first vs. second outbreak waves”, and explain the relationship between these groupings in a short, explicit paragraph. Ensure that figure and table captions also use consistent terms (“first outbreak wave”, “second outbreak wave”, “pre-1995 exposure”, etc.) so the reader does not get lost.

We have clarified these points by separating the description and definitions of the different groups, and now we hope it is clearer. Furthermore, the sentences have been shortened and focused more on specific description.

3. The Statistical Analysis section mentions Cox regression and Kaplan–Meier curves, and that only significant variables were retained as predictors of HCC onset. However, the main text does not clearly present hazard ratios (HRs) or confidence intervals for these predictors. It would strengthen the paper to: add a short table or paragraph summarizing the multivariable Cox model for HCC (e.g., age, fibrosis stage, treatment type, SVR vs. no SVR), including HRs and 95% CIs. Clarify whether “10-year risk of HCC was 0.81, 3.75, and 1.26 person-years” refers to incidence rates (per 100 person-years) or cumulative incidence. As written, “risk” and “person-years” are conflated and may confuse readers; please standardize terminology (e.g. “HCC incidence rate per 100 person-years”). In Figure 4, consider adding the number at risk at key timepoints, and specify in the legend that HCC curves start 12 weeks after end of therapy.

We clarified that our KM curves described a “HCC incidence rate per 100 person-years” and we added the number of cases at risk in the groups described in figure 4.

We also complete the result with presentation of hazard ratios (HRs), confidence intervals and p-levels obtained for parameters identified as predictors of HCC risk with the multivariable Cox model (see, Lines 278-283).

1. The Discussion appropriately notes that DAA therapy achieves high SVR rates and that HCC risk is reduced but not abolished. However, a few sentences could be more cautious, given the observational design and the presence of substantial differences among SOC-treated, DAA-treated, and untreated groups (age, fibrosis stage, genotype, comorbidities). I suggest rephrasing any language that could be interpreted as causal (e.g., “DAA therapy eradicated HCV infection in the older generation” or “DAA treatment changed mortality trends”) into more neutral observational wording (e.g., “was associated with high SVR rates” or “coincided with a marked decline in active HCV infection”). Explicitly acknowledging that residual confounding by indication and selection bias (e.g., the sickest or oldest patients remaining untreated or being ineligible for IFN) may influence the comparison between treated and untreated groups.

We changed some sentences to be into more neutral observational wording.

Certainly the untreated group included some patients who postponed therapy, for multiple personal reasons, but mainly due to the low chance of success with the IFN-based regimen or intolerance to IFN, or due to the presence of a still mild stage of fibrosis, which allowed patients to wait for the start of therapy.  The indications for IFN-based therapy were also different from those for DAA treatment and we have asserted these differences in our observational cohort.

5. Many limitations are discussed throughout the text but are scattered. It would be helpful to add a concise paragraph (either late in the Discussion or as a separate “Limitations” subsection) explicitly stating: single-region, hepatology-center cohort (not population-based), which may limit generalizability. Per-protocol analysis with exclusion of drop-outs and incomplete cases. Changes in diagnostic practices, treatment eligibility, and surveillance intensity over 20 years, which may influence event detection (HCC, decompensation). Lack of granular data on comorbidities and competing causes of death in the main tables.

For this We added in discussion the paragraph “4.1 Strengths and limitation of this study”

 

1. The title is informative but a bit long. Consider a small simplification, e.g.: “Epidemiology and Clinical Outcomes in the 20-year HepCoVe Cohort: Progress Toward Elimination of HCV Infection in North-East Italy.” The abstract is generally clear but quite dense. You might: explicitly state the total cohort size (n=2703 per-protocol) and follow-up duration. Clarify that HCC risk values are incidence rates (if that is the case) and not percentages.

Thanks, now we changed the title. We shortened the abstract and complete your suggestions.

1. Figure 1 (age bands and risk distribution) is useful but busy. Consider: simplifying the legend and clearly labeling the two waves. Ensuring that the green box representing the national screening campaign is explained in the caption for readers unfamiliar with the Italian context. Tables 1 and 2 contain a lot of information. To improve readability: align all percentages consistently and add a brief explanation of abbreviations directly beneath each table (e.g., SOC, DAA, PH, EV, GE). Double-check that percentages and denominators are consistent (e.g., percentages of F3–F4 fibrosis and post- ransfusion risk by group).

Tables 1 and 2 have been improved as suggested by changing the group abbreviations and adding them to the table legend. We checked and found no errors in the rates of F3-F4 fibrosis and post-transfusion risk by group in the tables.

1. Some abbreviations are slightly non-standard or mis-expanded. For example: CI is listed as “confidential interval” instead of “confidence interval”. “standard of cure” (SOC) is unconventional; “standard of care” is the usual expression (you can keep the abbreviation SOC but define it clearly once). Please check that all abbreviations are defined at first use in the main text and that the abbreviations list matches what actually appears in the manuscript.

Thanks, we complete all suggestions and used standard and correct expressions.

1. Overall, the English is understandable but would benefit from careful proofreading by a fluent speaker or professional editing service. Recurrent minor issues include: typographical errors and misspellings: e.g., “parental risk” instead of “parenteral risk”, “trasfusion” instead of “transfusion”, “hacient wave”, “cure effective intervention”, “cancelled the HCC occurrence risk”. Inconsistent tense and phrasing in Methods/Results. For example, prefer concise past tense: “Patients were followed for a mean of 16.2 ± 8.4 years” rather than “were then followed-up for 16.2 ± 8.4 years by a per protocol analysis.” Long, multi-clause sentences that could be split into two for clarity. Some non-idiomatic expressions, such as “hacient wave” (perhaps “ancient” or “earlier”), “older cohort is already extinct” (you could say “has largely disappeared”). It may help to go through the manuscript line by line and: shorten overly long sentences. Correct misspellings and minor grammar issues. Standardize key terms (e.g., “first epidemic wave”, “second epidemic wave”, “standard of care”, “person-years”).

Thanks. We improved the English form in the text of paper and corrected all the tipo and mistakes.

1. The Discussion already references recent modeling studies on HCV prevalence and treatment uptake in Italy and Europe. You could modestly highlight how your long-term regional cohort complements these model-based estimates, emphasizing the real-world linkage between treatment eras (IFN vs. DAA), genotype shifts, and clinical outcomes (HCC, mortality). This is a valuable and timely cohort analysis, with long follow-up and a clear narrative around two “waves” of HCV infection and the impact of antiviral therapy in a well-defined region. The main findings are clinically relevant and, in my opinion, the data support the authors’ broad conclusions, provided that the limitations are clearly acknowledged and some wording is softened. I therefore recommend minor revision, focused on: clarifying the cohort structure and statistical reporting, tightening and standardizing terminology, and polishing the English language and phrasing.

Comments on the Quality of English Language

Overall, the English is understandable but would benefit from careful proofreading by a fluent speaker or professional editing service. Recurrent minor issues include: typographical errors and misspellings: e.g., “parental risk” instead of “parenteral risk”, “trasfusion” instead of “transfusion”, “hacient wave”, “cure effective intervention”, “cancelled the HCC occurrence risk”. Inconsistent tense and phrasing in Methods/Results. For example, prefer concise past tense: “Patients were followed for a mean of 16.2 ± 8.4 years” rather than “were then followed-up for 16.2 ± 8.4 years by a per protocol analysis.” Long, multi-clause sentences that could be split into two for clarity. Some non-idiomatic expressions, such as “hacient wave” (perhaps “ancient” or “earlier”), “older cohort is already extinct” (you could say “has largely disappeared”). It may help to go through the manuscript line by line and: shorten overly long sentences. Correct misspellings and minor grammar issues. Standardize key terms (e.g., “first epidemic wave”, “second epidemic wave”, “standard of care”, “person-years”).

We  tried to make the text more fluid, which was shortened and made clearer. We really hope you like it.

We wanted to thank you once again for your help and expertise in improving our paper.

Best regards. Liliana Chemello and Luisa Cavalletto

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Abstract

• Line 18–22: The first sentence is fragmented (“rhosis and hepatocellular carcinoma…”). Please revise for clarity and correct broken words.

• Line 20–21: Consider rephrasing “has, s 2000” → “has, since 2000”.

• Line 24–26: “track the changes induced by antiviral treatments…”—this is too long and grammatically unclear. Split into two sentences.

• Line 30–33: Some parentheses are incomplete and several sentences are interrupted; please revise for grammar and continuity.

• Line 37–42: The conclusions contain multiple grammar issues (“eli…”, “widespread through drug addiction in youngers”). Rewrite for clarity and scientific tone.

Introduction

• Line 48–50: Correct repeated word breaks (“ci rhosis”, “car cinoma”).

• Line 51–54: Prevalence figures should be updated to consistent decimal formatting (0.96–3% → perhaps 0.96–3.0%).

• Line 55–58: Sentence beginning “Chronic hepatitis C (CHC), especially when…” is very long; consider dividing it for readability.

• Line 59–63: The causal chain (“has led to the hypothesis…”) should be clarified—specify which findings support which hypothesis.

• Line 64–70: Several lines break mid-sentence; unify fragments for readability.

• Line 74–82: Consider condensing the description of previous Italian studies; currently verbose and repetitive.

• Line 83–87: The logic connecting age-related prevalence to the disappearance of older cohorts needs clearer explanation.

• Line 88–92: Sentence starting with “Aware of these events…” is overly long; break into shorter segments.

• Line 93–103: Historical timeline of antiviral treatments is accurate but would benefit from clearer transitions and consistent tense.

• Line 106–108: The statement on national screening should specify the law more succinctly.

Materials and Methods

• Line 121–128: Remove repeated phrases and clarify that data were collected prospectively.

• Line 130–136: The selection criteria are described but could be formatted as bullet points for clarity.

• Line 141–146: “Parental risk” should be corrected to parenteral risk consistently throughout.

• Line 147–158: Consider reorganizing the description of treated/untreated/drop-out groups to improve flow.

• Line 160–174: Grammar needs improvement in several sentences; e.g., “were used, if α-2a at a flat dose…” → “Peg-IFN α-2a was administered at a fixed dose…”.

• Line 169–174: Include a clearer explanation of dosing regimens (α-2a vs α-2b LD/HD).

• Line 175–182: Define RBV at first mention; ensure consistent units (e.g., mg/kg/day).

• Line 184–196: Laboratory description is complete, but consider summarizing to avoid excessive detail.

• Line 197–211: Statistical methods are appropriate; however, ensure consistent p-value formatting and software citation styles.

Results

• Line 213–232: Table 1 is informative, but text repeats many table values; consider reducing redundancy.

• Line 219–221: “showing a different epidemiologic and clinical pattern” is vague—specify key differences.

• Line 233–238: “the hacient” appears to be a typo; likely meant “the ancient wave”.

• Line 244–255: Figure 1 caption is clear but age ranges in text and figure should match.

• Line 257–268: Table 2 description is clear; however, avoid repeating numerical values already in the table.

• Line 272–284: Viral load comparisons need clearer explanation of the clinical relevance.

• Line 287–303: Figure 3 panel descriptions are detailed but could be streamlined.

• Line 309–329: The presentation of outcomes (deaths, HCC) is good but complex; consider reorganizing with subsections.

• Line 323–327: Ensure consistency in units (“person-years”).

• Line 329–330: Clarify timepoints for HCC risk calculations.

Discussion

• Line 336–343: Introductory paragraph repeats parts of the Introduction; consider shortening.

• Line 350–365: The comparison between the two waves is valuable but lengthy—consider concisely summarizing.

• Line 369–374: Improve grammar and fix word breaks (“prob abilistic”).

• Line 376–381: Avoid speculative statements unless supported by references.

• Line 385–400: Discussion on untreated cases needs clearer connection to clinical implications.

• Line 401–420: The interpretation of genotype-specific response should be clarified; some claims appear overly general.

• Line 431–437: Present HCC incidence more concisely.

• Line 438–453: Recommendations for elimination strategies should be more structured.

Conclusion

• Line 455–462: Conclusion is clear but contains small grammar issues (“cancelled” → “does not cancel”).

• Consider adding a sentence on public health implications.

Comments on the Quality of English Language

The manuscript would benefit from a thorough English language revision. Several sections contain grammatical errors, fragmented or incomplete sentences, inconsistent verb tenses, and word break issues (likely introduced during manuscript preparation). These issues occasionally obscure the meaning and reduce readability. A careful professional language edit is recommended to improve clarity, sentence structure, and overall fluency, ensuring that the scientific content is conveyed with precision.

Author Response

REVIEWER_2 SUGGESTIONS & AUTHORS REPORT

Dear Reviewer, we thanks so much for your efforts and wise help in reviewing our article. Advising us on the most useful suggestions to improve it.

Please see below, we responded point by point to your notes.

The English and Methods could be improved to more clearly express the research.

We have improved the English form throughout the manuscript (please, follow in red characters the parts modified), and in particular we have shortened the introduction and modified the methods to simplify them, including through the insertion of a new figure (Figure S1: Flowchart, in supplementary material).

COMMENTS TO ANSWER - Abstract

• Line 18–22: The first sentence is fragmented (“rhosis and hepatocellular carcinoma…”). Please revise for clarity and correct broken words.

Unfortunately, Livers' editing system doesn't allow sentence justification on each line and, to save space, uses the (-) symbol at line breaks, breaking words. I agree that it's not nice, but we can't do anything about these "broken words," I'm sorry.

• Line 20–21: Consider rephrasing “has, s 2000” → “has, since 2000”.

It has been revised and edited

• Line 24–26: “track the changes induced by antiviral treatments…”—this is too long and grammatically unclear. Split into two sentences.

We shortened the sentences.

• Line 30–33: Some parentheses are incomplete and several sentences are interrupted; please revise for grammar and continuity.

We split the results of abstract into more shorter sentences

• Line 37–42: The conclusions contain multiple grammar issues (“eli…”, “widespread through drug addiction in youngers”). Rewrite for clarity and scientific tone.

The conclusions, but also the entire abstract, have been extensively revised and shortened.

COMMENTS TO ANSWER - Introduction

• Line 48–50: Correct repeated word breaks (“ci rhosis”, “car cinoma”).

Unfortunately, Livers' editing system doesn't allow sentence justification on each line and, to save space, uses the (-) symbol at line breaks, breaking words. I agree that it's not nice, but we can't do anything about these "broken words," I'm sorry.  We will ensure that no significant imperfections appear in the final version of the article, if it is published.

• Line 51–54: Prevalence figures should be updated to consistent decimal formatting (0.96–3% → perhaps 0.96–3.0%).

OK thanks, it was done.

• Line 55–58: Sentence beginning “Chronic hepatitis C (CHC), especially when…” is very long; consider dividing it for readability.

We have split the sentences

• Line 59–63: The causal chain (“has led to the hypothesis…”) should be clarified—specify which findings support which hypothesis.

We changed and simplified the sentence.

• Line 64–70: Several lines break mid-sentence; unify fragments for readability.

We apologize and have tried to improve readability.

• Line 74–82: Consider condensing the description of previous Italian studies; currently verbose and repetitive.

We shortened and simplify the paragraph

• Line 83–87: The logic connecting age-related prevalence to the disappearance of older cohorts needs clearer explanation.

We have revised this entire paragraph, and now we hope it has become clearer

• Line 88–92: Sentence starting with “Aware of these events…” is overly long; break into shorter segments.

This paragraph was shortened and divided in clear periods.

• Line 93–103: Historical timeline of antiviral treatments is accurate but would benefit from clearer transitions and consistent tense.

OK, It was done

• Line 106–108: The statement on national screening should specify the law more succinctly.

OK, It was completed

COMMENTS TO ANSWER - Materials and Methods

• Line 121–128: Remove repeated phrases and clarify that data were collected prospectively.

We did these suggestion in the text

• Line 130–136: The selection criteria are described but could be formatted as bullet points for clarity.

we shortened the paragraph and it seemed clearer

• Line 141–146: “Parental risk” should be corrected to parenteral risk consistently throughout.

Thanks, we corrected the sentence

• Line 147–158: Consider reorganizing the description of treated/untreated/drop-out groups to improve flow.

We have added a new Figure S1 in supplementary material with the flowchart of the study. Now the progress of the study appears clearer

• Line 160–174: Grammar needs improvement in several sentences; e.g., “were used, if α-2a at a flat dose…” → “Peg-IFN α-2a was administered at a fixed dose…”.
• Line 169–174: Include a clearer explanation of dosing regimens (α-2a vs α-2b LD/HD).

We have modified and completed all these sentences

• Line 175–182: Define RBV at first mention; ensure consistent units (e.g., 15 mg/kg/day).

Now, we first mentioned Ribavirin (RBV) in line 142, and then also in legend of new figure S1 and in abbreviations. Units of RBV used were confirmed at the standard dose of 15mg/kg/tid

• Line 184–196: Laboratory description is complete, but consider summarizing to avoid excessive detail.

We shortened the description

• Line 197–211: Statistical methods are appropriate; however, ensure consistent p-value formatting and software citation styles.

Now, we formatted the correct citation

COMMENTS TO ANSWER - Results

• Line 213–232: Table 1 is informative, but text repeats many table values; consider reducing redundancy.

We have completely revised the text corresponding to the table 1, shortening it considerably.

• Line 219–221: “showing a different epidemiologic and clinical pattern” is vague—specify key differences.

Now, we modified all the paragraph related to table 1 description and we hope it seem clearer

• Line 233–238: “the hacient” appears to be a typo; likely meant “the ancient wave”.

Thanks, we corrected the typo

• Line 244–255: Figure 1 caption is clear but age ranges in text and figure should match.

We have clarified the range of years considered in the figure 1 and therefore the text has now been set in a manner consistent with the figure.

• Line 257–268: Table 2 description is clear; however, avoid repeating numerical values already in the table.

We revised the text corresponding to the table 2, shortening it.

• Line 272–284: Viral load comparisons need clearer explanation of the clinical relevance.

Thanks, now we added this relevant explanation.

• Line 287–303: Figure 3 panel descriptions are detailed but could be streamlined.

We modified the figure 3, eliminating 1 column relating to the overall data and leaving only those relating to the 2 genotype groups 1-4 and 2-3.

• Line 309–329:The presentation of outcomes (deaths, HCC) is good but complex; consider reorganizing with subsections.

We have reconstructed the text of this paragraph and it now appears easier to read  

• Line 323–327: Ensure consistency in units (“person-years”).

Now we report in the text and figure 4 “cumulative HCC incidence rate per 100 person-years (100 p-y)”

• Line 329–330: Clarify timepoints for HCC risk calculations.

We complete the figure 4 with  the corresponding data on the number of cases at risk in each of the time-points from 0 to 10 years.

COMMENTS TO ANSWER - Discussion

• Line 336–343: Introductory paragraph repeats parts of the Introduction; consider shortening.

We modified and shortening the text

• Line 350–365: The comparison between the two waves is valuable but lengthy—consider concisely summarizing.

We now have made a more concise version

• Line 369–374: Improve grammar and fix word breaks (“prob abilistic”).

We reported this problem also to the Cancers editorial team, asking them to verify that no major biases of this type emerge by editorial system in the final draft.

• Line 376–381: Avoid speculative statements unless supported by references.

Ok thanks, we have made

• Line 385–400: Discussion on untreated cases needs clearer connection to clinical implications.

Now we have made these clarifications in the text

• Line 401–420: The interpretation of genotype-specific response should be clarified; some claims appear overly general.

Now we have made these clarifications in the text

• Line 431–437: Present HCC incidence more concisely.

We have reduced the sentences in the text

• Line 438–453: Recommendations for elimination strategies should be more structured.

We have included the recommendations in the discussion

COMMENTS TO ANSWER - Conclusions

• Line 455–462: Conclusion is clear but contains small grammar issues (“cancelled” → “does not cancel”).

We corrected the grammar of the text

• Consider adding a sentence on public health implications.

We added a sentence in conclusions

We really hope that you will now find our paper improved and clearer. We wanted to thank you once again for your help and expertise in improving our paper.

Best regards. Liliana Chemello and Luisa Cavalletto

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have addressed my comments.

This manuscript can be considered for publication.