From Discovery to Cure—Where Are We Now? Mortality Trends in Chronic Hepatitis C: An Analysis of CDC WONDER Database (1999–2023)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors analyzed the CDC WONDER multiple cause of death to analyze the trends of HCV-related deaths in the USA to assess the benefit of DAAs against hepatitis C in its reduction. They found as expected a reduction after 2014, with some populations (Native American, non-Hispanic Black individuals where mortality remains high. The information is important, but some concerns should be addressed before publication.

 

1. One of the main aspects limiting access to DAAs for HCV is the high cost of this treatment, making this cure not affordable unless adequate health insurance. Although addressed with more details in the Introduction (third paragraph: not only the price, but the cascade from detection to cure), a mention as conclusion in the Abstract would be appreciated.
2. Another important stratifying factor not included in this study is HIV-coinfection, that would be interesting to include in this study. See for example DOI: 10.1016/j.jhep.2020.08.008.
3. The corresponding author is not signaled.
4. The references are not cited in the text.
5. Please revise the author´s name. What is the meaning of MBBS and IFNU in the names?
6. A list of abbreviation is missing at the end of the manuscript.
7. Introduction, first paragraph. What is the support to state that HCV infection in USA has historically been concentrated among persons born during 1945-1965?
8. Materials and Methods. Please include the reference to the page web of CDC WONDER and the date of accession in references.
9. Figure 2. Hawaii is not shown.
10. Point 3.7. In addition, New Mexico is not the state with the highest mortality: Oklahoma was no mentioned in the list, with a mortality rate near 8 per 100,000.
11. There is no need to stratify the Discussion in points. Moreover, an overall discussion would be appreciated. Again, no reference is cited.
12. References to other studies like this one, describing the reduction in the incidence of mortality since the introduction of DAAs.

Author Response

 

One of the main aspects limiting access to DAAs for HCV is the high cost of this treatment, making this cure not affordable unless adequate health insurance. Although addressed with more details in the Introduction (third paragraph: not only the price, but the cascade from detection to cure), a mention as conclusion in the Abstract would be appreciated.

We thank the reviewer for this important comment. We have revised the Abstract conclusion and the main Discussion/Conclusion to emphasize that, despite the mortality decline observed in the DAA era, barriers to cure remain important. We now specifically note that unequal access to treatment may be related not only to the cost of DAAs, but also to broader gaps across the HCV care cascade, including diagnosis, linkage to care, insurance coverage, and treatment affordability.” 
Added to  Introduction last two sentences 

2.    Another important stratifying factor not included in this study is HIV-coinfection, that would be interesting to include in this study. See for example DOI: 10.1016/j.jhep.2020.08.008.

Although HIV coinfection is a clinically relevant stratifying factor, our analysis was designed to focus on overall HCV-related mortality trends at the national level. We also did not specifically assess HBV coinfection, which may similarly contribute to worse outcomes. We have added this point as a limitation and note that future studies should explore the impact of HIV and HBV coinfection on HCV-related mortality.

3.The corresponding author is not signaled.
The corresponding author has now been clearly identified in the revised manuscript, with the appropriate symbol and contact details provided on the title page in accordance with the journal’s formatting requirements.”

 

4.The references are not cited in the text.
We thank the reviewer for this observation. We have carefully revised the manuscript to ensure that all references are appropriately cited in the text at relevant locations, including the Introduction, Materials and Methods, Discussion, and Conclusion.
5.Please revise the author´s name. What is the meaning of MBBS and IFNU in the names?

The author name has been revised for clarity in the updated manuscript. In this case, ‘FNU’ refers to ‘First Name Unknown,’ which is sometimes used in official records when a given name is not available in the standard format. We have corrected and standardized the author information to avoid confusion and to comply with the journal’s formatting requirements. We have also clarified that ‘MBBS’ stands for Bachelor of Medicine, Bachelor of Surgery

6.A list of abbreviation is missing at the end of the manuscript.

AAMR, age-adjusted mortality rate; AI/AN, American Indian/Alaska Native; APC, annual percent change; CDC, Centers for Disease Control and Prevention; CI, confidence interval; DAA, direct-acting antiviral; HCC, hepatocellular carcinoma; HCV, hepatitis C virus; ICD-10, International Classification of Diseases, Tenth Revision; IRB, institutional review board; NCHS, National Center for Health Statistics; RR, rate ratio; US, United States; WHO, World Health Organization.

7.Introduction, first paragraph. What is the support to state that HCV infection in USA has historically been concentrated among persons born during 1945-1965?
 We have revised the Introduction and added supporting references for this statement. Prior CDC guidance reported that persons born during 1945-1965 accounted for a substantial proportion of chronic HCV infections among U.S. adults and had a markedly higher prevalence of infection than adults born in other years, which formed the basis for earlier birth-cohort screening recommendations.  Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the Identification of Chronic Hepatitis C Virus Infection Among Persons Born During 1945–1965. MMWR Recomm Rep. 2012;61(RR-4):1-32.

 

8.Materials and Methods. Please include the reference to the page web of CDC WONDER and the date of accession in references.

 We have now added the CDC WONDER Multiple Cause of Death database webpage to the References section and included the date of access in the revised manuscript.  https://wonder.cdc.gov/mcd.html

10. Point 3.7. In addition, New Mexico is not the state with the highest mortality: Oklahoma was no mentioned in the list, with a mortality rate near 8 per 100,000.
Corrected as per data 

11. There is no need to stratify the Discussion in points. Moreover, an overall discussion would be appreciated. Again, no reference is cited.
Modified 
10.  References to other studies like this one, describing the reduction in the incidence of mortality since the introduction of DAAs. 
References are diven

 

 

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This article provides a recent overview of the national burden of hepatitis C in the US based on the CDC WONDER Database between 1999 and 2023, including the periods before and after the availability of DAAs.  It also highlights geographical and ethnic disparities, as well as disparities between urban and rural areas.

Strengths

Well-written article, the methodologies of data collection are described with sufficient detail. The data are available for reuse

The data are original and their source is clearly defined

The paper provides an overview of the challenges of HCV care based on clearly outlined disparities between different states (income level, geographic isolation, ethnicity, lack of health insurance).

The interest lies in its longitudinal nature from 1999 to 2023.

It particularly highlights the role of the periods before and after DAA.

No recent articles using this methodology on the status of HCV-related mortality in the US are available in the littérature

Talking points

A multiple-cause approach, including deaths for which HCV was listed as the underlying cause or contributing cause, improves sensitivity in capturing HCV-associated mortality but not specificity. It is therefore important to discuss the multiple associated causes of cirrhosis and complications of cirrhosis in HCV patients (e.g., alcohol, MASH, viral co-infections, etc.). Would it be possible to identify them?

Important point to be clarified with figures « Younger age groups had substantially lower mortality rates but showed modest increases in recent years ».

It would be interesting to also analyzes the COVID and post-COVID period in this longitudinal study

It would be relevant in the discussion to:

1)Compare the situation in the US with Global, European and Asian experiences already published on the same topic and to queries from US databases focused on HCC linked to HCV. Ex PMID: 41430134, PMID: 41055396, PMID: 40613625, PMID: 40360141, PMID: 39072924, PMID: 41691615, PMID: 40214295

2)Describe in more detail the solutions envisaged to overcome the difficulties encounted in the treatment of hepatitis C in the US and discuss the solutions already implemented in the US and other countries.

Minor comments

Would it be possible to include the year 2024 (1999-2024) in the analysis? Articles already published on the subject in other countries or dealing with a more specific consequence of HCV, such as HCC, only go up to 2022-2023.

Please refer to the most recent data on WHO recommendations (updated in 2022): https://iris.who.int/server/api/core/bitstreams/9c5821b1-2b09-4566-a030-7ad95e1ab682/content

Author Response

. Reviewer comment: A multiple-cause approach improves sensitivity but not specificity. It is important to discuss other associated causes of cirrhosis and complications in HCV patients, such as alcohol, MASH, and viral coinfections. Would it be possible to identify them?
Response: We thank the reviewer for this important comment. We agree that coexisting liver disease etiologies may contribute to mortality in patients with HCV. However, the CDC WONDER multiple cause-of-death database does not provide sufficient clinical detail to reliably determine the relative contribution of alcohol, MASH, viral coinfections, or other competing causes at the individual level. Because our study was designed as a national mortality trend analysis of HCV-associated deaths, we did not perform further etiologic decomposition. We have instead acknowledged this as a limitation in the Discussion.
 2. Reviewer comment: “Younger age groups had substantially lower mortality rates but showed modest increases in recent years” should be clarified with figures.
Response: We appreciate this suggestion. However, the absolute mortality burden in younger age groups remained much lower than in older adults, and we aimed to keep the figures focused on the main findings of the study. We therefore did not add additional figures, but we can clarify this statement in the text to better reflect the modest nature of these increases.
 3. Reviewer comment: It would be interesting to also analyze the COVID and post-COVID period in this longitudinal study.
Response: We agree this is an important area. However, a dedicated COVID and post-COVID analysis would represent a separate research question beyond the primary scope of this manuscript, which was to describe long-term mortality trends from 1999 to 2023 with emphasis on the pre-DAA and post-DAA eras. We have instead noted in the Discussion that the pandemic period may have influenced mortality trends.
 4. Reviewer comment: It would be relevant to compare the US situation with global, European, and Asian experiences and with studies focused on HCC linked to HCV.
Response: We thank the reviewer for this suggestion. While such comparisons are valuable, we chose to keep the Discussion focused on the US national mortality trends identified using a single consistent data source and methodology. Detailed international comparison is challenging because of major differences in datasets, definitions, and outcomes across studies. We therefore did not expand the Discussion extensively in this direction.
 5. Reviewer comment: Please describe in more detail the solutions to overcome the difficulties encountered in HCV treatment in the US and discuss solutions implemented in the US and other countries.
Response: We appreciate this comment. However, our manuscript was intended primarily as an epidemiologic mortality analysis rather than a policy or implementation review. For this reason, we kept the discussion of solutions concise and focused on key implications supported by our findings, including improving access to screening, linkage to care, and treatment in underserved populations.
 6. Reviewer comment: Would it be possible to include the year 2024 in the analysis?
Response: We thank the reviewer for this suggestion. Our analysis was finalized using the 1999–2023 CDC WONDER dataset, which provided a complete and consistent 25-year study period. Inclusion of 2024 would require repeating the full extraction and trend analysis process. We believe that the current study period already provides a robust contemporary assessment of HCV-related mortality trends.
 7. Reviewer comment: Please refer to the most recent WHO recommendations updated in 2022.
Response: We thank the reviewer for this helpful suggestion. We agree and will update the manuscript to include the most recent WHO recommendations where appropriate.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

  Although ansewred in the Reply, some concerns were not addressed in the manuscript. I wrote again these concerns:

1. Another important stratifying factor not included in this study is HIV-coinfection, that would be interesting to include in this study. See for example DOI: 10.1016/j.jhep.2020.08.008.

Reply (not shown in manuscript)
Although HIV coinfection is a clinically relevant stratifying factor, our analysis was designed to focus on overall HCV-related mortality trends at the national level. We also did not specifically assess HBV coinfection, which may similarly contribute to worse outcomes. We have added this point as a limitation and note that future studies should explore the impact of HIV and HBV coinfection on HCV-related mortality.

2.Please revise the author´s name. What is the meaning of MBBS and IFNU in the names?

Reply (nor shown in the manuscript)

The author name has been revised for clarity in the updated manuscript. In this case, ‘FNU’ refers to ‘First Name Unknown,’ which is sometimes used in official records when a given name is not available in the standard format. We have corrected and standardized the author information to avoid confusion and to comply with the journal’s formatting requirements. We have also clarified that ‘MBBS’ stands for Bachelor of Medicine, Bachelor of Surgery

3.A list of abbreviation is missing at the end of the manuscript.

Still missing in the manuscript

4.Materials and Methods. Please include the reference to the page web of CDC WONDER and the date of accession in references. The date of accession is not provided nor in the text and nor in the references (where it should be provided)

5. References to other studies like this one, describing the reduction in the incidence of mortality since the introduction of DAAs.
References are diven

The authors responded that references were providede but not discussed in text..

Author Response

1. Another important stratifying factor not included in this study is HIV-coinfection, that would be interesting to include in this study. See for example DOI: 10.1016/j.jhep.2020.08.008.
Highlighted in the inclusion and exclusion criteria as follows
Reply highlighted in the inclusion and exclusion criteria 
Although HIV coinfection is a clinically relevant stratifying factor, our analysis was designed to focus on overall HCV-related mortality trends at the national level. We also did not specifically assess HBV coinfection, which may similarly contribute to worse outcomes. We have added this point as a limitation and note that future studies should explore the impact of HIV and HBV coinfection on HCV-related mortality.
2.Please revise the author´s name. What is the meaning of MBBS and IFNU in the names?
Reply highlighted at the start of the manuscript 
MBBS is corrected to MD , similarly FNU removed in the authors at the start
3.A list of abbreviation is missing at the end of the manuscript.
Provide at the end
4.Materials and Methods. Please include the reference to the page web of CDC WONDER and the date of accession in references. The date of accession is not provided nor in the text and nor in the references (where it should be provided)
Provided and is highlighted in methods section

5. References to other studies like this one, describing the reduction in the incidence of mortality since the introduction of DAAs.
References are diven
The authors responded that references were providede but not discussed in text..
Response: provide the first part of the discussion reference 15
 Lee YA, Friedman SL. Liver-related mortality in the United States: hepatitis C declines, NAFLD and alcohol rise. Transl Gastroenterol Hepatol. 2019;4:24.

 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

After carefully reviewing the article and the responses provided by the authors, whom I thank, I consider the new version of the article and the answers given to be satisfactory. I have no further comments.

Author Response

1. Another important stratifying factor not included in this study is HIV-coinfection, that would be interesting to include in this study. See for example DOI: 10.1016/j.jhep.2020.08.008.
Highlighted in the inclusion and exclusion criteria as follows
Reply highlighted in the inclusion and exclusion criteria 
Although HIV coinfection is a clinically relevant stratifying factor, our analysis was designed to focus on overall HCV-related mortality trends at the national level. We also did not specifically assess HBV coinfection, which may similarly contribute to worse outcomes. We have added this point as a limitation and note that future studies should explore the impact of HIV and HBV coinfection on HCV-related mortality.
2.Please revise the author´s name. What is the meaning of MBBS and IFNU in the names?
Reply highlighted at the start of the manuscript 
MBBS is corrected to MD , similarly FNU removed in the authors at the start
3.A list of abbreviation is missing at the end of the manuscript.
Provide at the end
4.Materials and Methods. Please include the reference to the page web of CDC WONDER and the date of accession in references. The date of accession is not provided nor in the text and nor in the references (where it should be provided)
Provided and is highlighted in methods section

5. References to other studies like this one, describing the reduction in the incidence of mortality since the introduction of DAAs.
References are diven
The authors responded that references were providede but not discussed in text..
Response: provide the first part of the discussion reference 15
 Lee YA, Friedman SL. Liver-related mortality in the United States: hepatitis C declines, NAFLD and alcohol rise. Transl Gastroenterol Hepatol. 2019;4:24.

 

Author Response File: Author Response.pdf