Longitudinal Changes in Utility Scores and Health-Related Quality of Life During Interferon-Free Direct-Acting Antiviral Therapy for Chronic Hepatitis C in Japan: Implications for Cost–Utility Analysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this study, Dr. Hirao et al. conducted a multicenter longitudinal study of adults with chronic HCV treated with interferon‑free DAAs in Japan, to evaluate health‑related quality of life (HRQoL) by using longitudinal changes using EQ‑5D‑5L, SF‑8, and CLDQ. Adults with chronic HCV completed patient-reported outcomes (PROs) at baseline (pre-treatment), 12, 24, and 36 weeks (or 48 weeks, where available) during routine visits or via mail/telephone. Complete‑case panels were defined per instrument (SF‑8 n=112, CLDQ n=131, EQ‑5D‑5L n=128). They found that SF‑8 improved by 36 weeks: General Health 50.42→52.47, Vitality 50.73→52.55, Mental Health 51.02→53.05. CLDQ improved in Worry 5.21→5.82 and Total 5.21→5.47. EQ‑5D‑5L utilities remained high and stable (0.913→0.920), consistent with ceiling effects at high baseline health. External real‑world data indicated better on‑treatment HRQoL with ribavirin‑free regimens. 

The study is of interest, well-written, and presented. I have a single comment to improve the clinical impact. As chronic hepatitis C is not rarely associated with extraintestinal manifestations as well as autoimmune phenomena, the authors should recall and discuss the impact of such conditions on HRQoL. In particular, autoimmune extrahepatic disorders may be present, particularly in HCV patients exhibiting serum non-organ-specific autoantibody positivity. Among them, HCV patients developing liver-kidney microsome antibodies (LKM1) have a higher risk of associated autoimmune thyroid disorders, as previously demonstrated (DOI: 10.1016/S1542-3565(05)00018-2), and a genetic background may explain the different prevalence of these disorders among different geographical areas, as previously demonstrated (DOI: 10.1007/s10620-006-9495-4).

 

Author Response

Comment 1

In this study, Dr. Hirao et al. conducted a multicenter longitudinal study of adults with chronic HCV treated with interferon‑free DAAs in Japan, to evaluate health‑related quality of life (HRQoL) by using longitudinal changes using EQ‑5D‑5L, SF‑8, and CLDQ. Adults with chronic HCV completed patient-reported outcomes (PROs) at baseline (pre-treatment), 12, 24, and 36 weeks (or 48 weeks, where available) during routine visits or via mail/telephone. Complete‑case panels were defined per instrument (SF‑8 n=112, CLDQ n=131, EQ‑5D‑5L n=128). They found that SF‑8 improved by 36 weeks: General Health 50.42→52.47, Vitality 50.73→52.55, Mental Health 51.02→53.05. CLDQ improved in Worry 5.21→5.82 and Total 5.21→5.47. EQ‑5D‑5L utilities remained high and stable (0.913→0.920), consistent with ceiling effects at high baseline health. External real‑world data indicated better on‑treatment HRQoL with ribavirin‑free regimens. 

The study is of interest, well-written, and presented. I have a single comment to improve the clinical impact. As chronic hepatitis C is not rarely associated with extraintestinal manifestations as well as autoimmune phenomena, the authors should recall and discuss the impact of such conditions on HRQoL. In particular, autoimmune extrahepatic disorders may be present, particularly in HCV patients exhibiting serum non-organ-specific autoantibody positivity. Among them, HCV patients developing liver-kidney microsome antibodies (LKM1) have a higher risk of associated autoimmune thyroid disorders, as previously demonstrated (DOI: 10.1016/S1542-3565(05)00018-2), and a genetic background may explain the different prevalence of these disorders among different geographical areas, as previously demonstrated (DOI: 10.1007/s10620-006-9495-4).

Response: We sincerely thank the reviewer for this insightful and clinically important suggestion. We agree that chronic hepatitis C virus infection may be associated not only with liver-related morbidity but also with extrahepatic manifestations and autoimmune phenomena that can influence health-related quality of life. In response, we have expanded the Discussion to acknowledge that extrahepatic manifestations may impair physical and mental health-related quality of life and contribute to the overall economic burden of chronic hepatitis C. We also added discussion of autoimmune thyroid disorders in hepatitis C virus-infected patients with liver-kidney microsomal antibody type 1 positivity and noted that geographic variation in this autoantibody profile may partly reflect host genetic background. In addition, we clarified in the limitations that extrahepatic autoimmune comorbidities, thyroid disease, and autoantibody status were not systematically assessed in our cohort. The reviewer-suggested references and an additional meta-analysis on extrahepatic manifestations, quality of life, and economic burden have been added.

Location in revised manuscript: Discussion, Limitations, and References.

Reviewer 2 Report

Comments and Suggestions for Authors

I thank the authors for their efforts in revising the manuscript. The study presents an interesting approach and methodology; however, several aspects remain unclear. Before the review process can proceed further, certain sections require clarification and revision. Please consider the following comments and provide appropriate responses:

1. Abbreviations should not be used in the title. In addition, the abstract contains abbreviations that are not introduced in their full form. Please correct this throughout the manuscript.
2. The abstract is currently unclear, as it presents numerical values without sufficient context for the reader. Please revise the entire abstract to improve clarity and coherence.
3. Lines 56–59: please provide a clearer explanation of the data presented in relation to reference 3.
4. Line 74: the use of parentheses is inappropriate and duplicated. Please correct.
5. The introduction is generally unclear. It should be restructured and clarified to establish a stronger connection with the objectives and design of the study.
6. The Materials and Methods section is difficult to follow, primarily due to abbreviations that are not properly introduced (e.g., CLDQ). Please revise accordingly.
7. In the Materials and Methods section, it is not clear which parameters and indicators were assessed, and which of them were accessible to the patients. Please clarify which parameters were self-reported by patients and which objective data were collected via email or telephone.
8. The study is described as multicentric, yet lines 109–111 list only two institutional approvals. Please clearly specify where the study was conducted and provide the ethics approval number for each participating institution.
9. Results: tables and figures are not referenced or explained in the main text. This section should be restructured and expanded accordingly.
10. It would be useful to include the questionnaire to improve clarity and support the discussion. The supplementary material currently contains only a list of assessed parameters, but not the actual questionnaire. Please revise.

Author Response

Comment 1

Abbreviations should not be used in the title. In addition, the abstract contains abbreviations that are not introduced in their full form. Please correct this throughout the manuscript.

Response: Thank you for this helpful comment. We revised the title to remove abbreviations and improve readability. Specifically, we replaced abbreviated terms such as HRQoL and DAA with their full forms in the title. We also carefully reviewed the abstract, main text, tables, and figure legends to ensure that abbreviations are introduced in full at first appearance and used consistently thereafter.

Location in revised manuscript: Title, Abstract, and throughout the revised manuscript.

Comment 2

The abstract is currently unclear, as it presents numerical values without sufficient context for the reader. Please revise the entire abstract to improve clarity and coherence..

Response: We appreciate this important suggestion. We rewrote the abstract to provide clearer context for the numerical values, including the names of the instruments, the relevant domains, and the time points being compared. We also clarified the interpretation of the results, including the distinction between improvements observed in disease-specific and symptom-proximal domains and the relative stability of generic utility scores.

Location in revised manuscript: Abstract.

Comment 3

Lines 56-59: please provide a clearer explanation of the data presented in relation to reference 3.

Response: Thank you for pointing this out. We revised the relevant part of the Introduction to explain more clearly what was shown in Reference 3 and how those data support the rationale for the present study. The revised text now provides a clearer transition from previous evidence to the remaining need for longitudinal evaluation of utility scores and health-related quality of life in Japanese patients receiving interferon-free direct-acting antiviral therapy.

Location in revised manuscript: Introduction.

Comment 4

Line 74: the use of parentheses is inappropriate and duplicated. Please correct.

Response: Thank you for pointing this out. As part of the restructuring of the Introduction, we removed the sentence that contained the inappropriate and duplicated parenthetical expression. The revised Introduction no longer includes the parenthetical regimen comparison and instead presents the study rationale in a clearer form focused on longitudinal changes in utility scores and health-related quality of life in the overall cohort.

Location in revised manuscript: Introduction.

Comment 5

The introduction is generally unclear. It should be restructured and clarified to establish a stronger connection with the objectives and design of the study.

Response: We agree with the reviewer and have substantially restructured the Introduction. The revised Introduction now first explains the importance of health-related quality of life assessment in chronic hepatitis C, then describes the relevance of interferon-free direct-acting antiviral therapy and instrument responsiveness, and finally states the objective of the present multicenter longitudinal study. We also removed the over-specific regimen-level comparative hypothesis to improve consistency between the Introduction, Methods, Results, and Discussion.

Location in revised manuscript: Introduction.

Comment 6

The Materials and Methods section is difficult to follow, primarily due to abbreviations that are not properly introduced (e.g., CLDQ). Please revise accordingly.

Response: Thank you for this helpful comment. We reorganized the Materials and Methods section into clearer subsections and defined all abbreviations at first use, including the EuroQol 5-Dimension 5-Level questionnaire, the 8-Item Short-Form Health Survey, and the Chronic Liver Disease Questionnaire. We also clarified the purpose and scoring interpretation of each patient-reported outcome instrument.

Location in revised manuscript: Materials and Methods.

Comment 7

In the Materials and Methods section, it is not clear which parameters and indicators were assessed, and which of them were accessible to the patients. Please clarify which parameters were self-reported by patients and which objective data were collected via email or telephone.

Response: We appreciate this important comment. We revised the Materials and Methods section to distinguish explicitly between patient-reported outcomes and objective clinical/treatment-related variables. In the revised manuscript, we state that the EuroQol 5-Dimension 5-Level questionnaire, the 8-Item Short-Form Health Survey, and the Chronic Liver Disease Questionnaire were completed by patients as patient-reported outcome measures at the scheduled assessment points. In contrast, baseline clinical characteristics and treatment-related variables were obtained from medical records and were not self-reported by patients. We also clarified the follow-up procedure, indicating that patient-reported outcome data were collected during routine clinic visits or remotely according to the study protocol, and that telephone or mail-based procedures were used only to collect standardized questionnaire responses or confirm follow-up information.

Location in revised manuscript: Materials and Methods.

Comment 8

The study is described as multicentric, yet lines 109-111 list only two institutional approvals. Please clearly specify where the study was conducted and provide the ethics approval number for each participating institution.

Response: Thank you for this important comment. We revised the manuscript to clarify the multicenter nature of the study, including the participating institutions and the applicable ethical review framework. The manuscript now specifies the available ethics approval information, including the approval numbers for Daito Bunka University (K-14-010) and Kagawa University (Heisei 26-141).

Location in revised manuscript: Materials and Methods and Institutional Review Board Statement.

Comment 9

Results: tables and figures are not referenced or explained in the main text. This section should be restructured and expanded accordingly.

Response: We agree and have revised the Results section accordingly. The Results section has been reorganized into clearer subsections, including participant flow and analytic samples, baseline characteristics, longitudinal changes in each patient-reported outcome instrument, and contextual/exploratory findings. All tables and figures are now cited in the main text in the appropriate order, and the narrative explanation of the major findings presented in each table and figure has been expanded.

Location in revised manuscript: Results section and Tables/Figures.

Comment 10

It would be useful to include the questionnaire to improve clarity and support the discussion. The supplementary material currently contains only a list of assessed parameters, but not the actual questionnaire. Please revise.

Response: Thank you for this helpful suggestion. We agree that additional information on the questionnaire improves transparency and supports interpretation of the patient-reported outcome data. We have therefore added a questionnaire overview as Supplementary File S2, including the patient information sheet, assessment schedule, baseline demographic and clinical questions, treatment-related follow-up items, and an overview of the standardized patient-reported outcome instruments used at each assessment point. Because the standardized instruments used in this study, including the EuroQol 5-Dimension 5-Level questionnaire, the 8-Item Short-Form Health Survey, and the Chronic Liver Disease Questionnaire, are subject to copyright or licensing restrictions, we did not reproduce their full item wording verbatim in the supplementary material. We also revised the Materials and Methods section and Supplementary Materials statement accordingly.

Location in revised manuscript: Materials and Methods, Supplementary Materials statement, and Supplementary File S2.

Reviewer 3 Report

Comments and Suggestions for Authors

Dear Authors,

Comments to the Authors: The manuscript presents interesting, clinically relevant real-world data on HRQoL in patients treated with DAA. As a clinician working with similar populations, I find the observation of increased "Worry" particularly noteworthy. In my experience, this often correlates with the shock of a recent diagnosis or treatment initiation, rather than with the treatment itself—a "recent diagnosis effect" that differs from the long-term effects of known infections.

I have a few suggestions to improve the clarity and consistency of the reporting before it is finalized:

1. Clarification of Attrition: There is a noticeable difference between the enrolled N=344 and the analyzed N=112–131. While this is common in real-world studies, it is crucial to show that the analyzed group is representative. Please add a brief comparison (e.g., in a Supplementary Table) of the baseline characteristics of "completers" vs. "dropouts". If they are similar, stating this will significantly strengthen your manuscript.

2. Alignment of Aims: The Introduction mentions comparing regimens (LDV/SOF vs. SOF/RBV), but the Discussion correctly notes that the sample size was too limited for this. I recommend removing this specific comparative hypothesis from the Introduction. Focusing the paper on its strong point—the longitudinal trajectory of the entire cohort—will make the narrative much more coherent.

3. Discussion Point: Consider adding a sentence in the Discussion about the potential confounding factor of the "recent diagnosis" or "treatment initiation anxiety," which might explain the baseline scores and subsequent improvement in the "Worry" domain.

Author Response

Comment 1

Clarification of Attrition: There is a noticeable difference between the enrolled N=344 and the analyzed N=112-131. While this is common in real-world studies, it is crucial to show that the analyzed group is representative. Please add a brief comparison (e.g., in a Supplementary Table) of the baseline characteristics of 'completers' vs. 'dropouts'. If they are similar, stating this will significantly strengthen your manuscript.

Response: Thank you for this important suggestion. We agree that attrition should be addressed more explicitly. In response, we added Supplementary Table S1, which compares baseline characteristics and baseline HRQoL scores between participants included in the CLDQ complete-case analysis and non-completers. Because the CLDQ panel had the largest complete-case sample among the HRQoL instruments, we used CLDQ complete-case status as the primary basis for the attrition comparison. Sex, age group, occupation, SF-8 physical and mental component summary scores, EQ-5D-5L utility values, and CLDQ scores were generally comparable between completers and non-completers, with no statistically significant differences observed. We also added a brief description of Supplementary Table S1 in the Results section and noted in the Discussion that attrition and instrument-specific missingness remain potential sources of bias in this real-world longitudinal study.

Location in revised manuscript: Results, Discussion/Limitations, and Supplementary Table S1.

Comment 2

Alignment of Aims: The Introduction mentions comparing regimens (LDV/SOF vs. SOF/RBV), but the Discussion correctly notes that the sample size was too limited for this. I recommend removing this specific comparative hypothesis from the Introduction. Focusing the paper on its strong point-the longitudinal trajectory of the entire cohort-will make the narrative much more coherent.

Response: We appreciate this helpful suggestion and agree with the reviewer. We removed the specific regimen-level comparative hypothesis from the Introduction and clarified that the primary aim of this study was to describe longitudinal changes in utility scores and health-related quality of life in the overall multicenter cohort. We also added a sentence explaining that the complete-case samples were limited for formal subgroup comparisons.

Location in revised manuscript: Introduction.

Comment 3

Discussion Point: Consider adding a sentence in the Discussion about the potential confounding factor of the 'recent diagnosis' or 'treatment initiation anxiety,' which might explain the baseline scores and subsequent improvement in the 'Worry' domain.

Response: Thank you for this clinically meaningful suggestion. We expanded the Discussion to acknowledge that the improvement observed in the Worry domain may partly reflect anxiety associated with treatment initiation, recent diagnosis, or renewed awareness of chronic hepatitis C infection at baseline, rather than a treatment-specific effect alone. Because the timing of diagnosis and the psychological context surrounding treatment initiation were not systematically assessed in our dataset, we present this interpretation as exploratory and have also noted it as a limitation and an important topic for future research.

Location in revised manuscript: Discussion and Limitations.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Accept in present form