PONE-D-22-15455Effectiveness and safety of glecaprevir/pibrentasvir for Taiwanese patients with hepatitis C and compensated cirrhosis in a real-world settingPLOS ONE

Dear Dr. Chang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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COMMENTS FROM ACADEMIC EDITOR: The authors should pay more attention in making a more comprehensive review of the published articles, and avoid citing outdated and inadequate references. The content should be significantly reorganized before further consideration. (1) The authors should discuss and compare the current knowledges with regard to first-line pan-genotypic DAAs in Taiwan, including GLE/PIB and SOF/VEL (Liu CH, et al Liver Int 2020, Huang CF et al. Sci Rep 2021; Liu CH, et al Hepatol Int 2021; Cheng PN, et a;. Infect Dis Ther 2022).(2) Delete Reference No. 14 because cirrhosis is not a significant factor to predict SVR in the era of pan-GT DAAs, particularly for HCV GT1 and GT2. (If cirrhosis significantly impact SVR, why GLE/PIB to be shorten from 12 weeks to 8 weeks in compensated cirrhosis? As the authors stated in the study, all cirrhotic patients achieved SVR)(3) Delete Reference No. 18 because it was only a phase II study. Please use Phase III trial GLE/PIB pooled analysis to support your discussion. (Puoti M, et al. J Hepatol 2018;69:293-300)(4) Discussion: Strongly disagree with the illustration "Liver cirrhosis has long been considered a major factor in reducing the SVR rates of HCV treatment even in the era of DAA [14, 19]" Please delete the wordings in the Introduction and Discussion(5) In addition to Reference No., 23, 24. The authors should discuss three published articles (Klinker H, et al. Liver Int 2021;41:1518-22, Flamm SL, et al. Adv Ther 2020;37:2267-74, Zuckerman E, et al. Clin Gastroenterol Hepatol 2020;18:2544-53).(6) Delete Reference No. 27 because it was a poorly written article.  Replace it with two articles (Liu CH, et al Liver Int 2020, Huang CF et al. Sci Rep 2021).(7) Discussion: Strongly disagree with the wording "This could also explain the lower eGFR in the 12-week group because GLE/PIB was one of the first TFDA-approved DAAs for patients with severe renal impairment, especially for those with genotype 2 HCV". Since this study comprised all genotypes, simply attributing to GT2 as the presence of significant difference in eGFR was not correct. The authors should stated a statistical difference for HCV GT2 patients in Results receiving 8 or 12-week GLE/PIB. The original wording should be replaced with "the first TFDA-approved DAAs for HCV GT2 patients with severe renal impairment"(8) How about the potential drug-drug interactions (DDIs) in all these patients? Did these patients take "red contradictory co-medication" before or during GLE/PIB? Please also refer Taiwan DDI data (Liu CH, et al. Aliment Pharmacol Ther 2018) to show a higher risk of DDI compared to SOF-based DAAs, and to alert the healthcare providers to judiciously check DDI before and during GLE/PIB.==============================

Please submit your revised manuscript by Aug 11 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

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We look forward to receiving your revised manuscript.

Kind regards,

Chen-Hua Liu

Academic Editor

PLOS ONE

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"This work was supported by research grant CMRPG6J0173 from Chang Gung

Memorial Hospital."

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Reviewers' comments:

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Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

Reviewer #2: Yes

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: No

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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4. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: It is an important mission to eliminate HCV by 2030. Therefore, effectiveness and safety of antiviral therapy are a critical issue. This real-world study pointed that the 8-week GP therapy were effectiveness as the 12-week GP therpay in patients with compensated liver cirrhosis. However, the novelty of this observative and descriptive study is relative low. There are some weak points to overcome.

[major problems]

1. The patients treated with the 8-week GP had higher platelet count, albumin level, Hb and eGFR values; lower proportion of prior HCC. It seemed that the patients receiving 8-week GP had less severe liver fibrosis/cirrhosis.

a). Please explain the reason(s)

b). List Child-Pugh score (Table 1)

c). Provide additional information (such as liver stiffness measurement or Fibrotest)

2. The clinical data is not normal distribution. Please use median (Q1-Q3; Table 1).

3. Please list the total and subgroup numbers of patients with FIB-4 >6 and FIB-4 between 3.25 and 6; please list detail numbers and percentage of the parameters for patients with a FIB-4 3.5-6.

4. The difference of each AE between the 8- and 12-week GP therapy should be compared with P-value. (Table 3)

5. Any predictors of each/total AE? The predictors of clinical significant AE (such as ALT > 5 xULN) and direct hyperbilirubinemia (> 1.5 xUNL) should be investigated. (additional information is necessary)

[minor problems]

1. It should be effectiveness "and safety" of GP for a treatment in patients with HCV and compensated cirrhosis. (line 12 & 14, page 4)

2. What dose superscript "6" mean? (line 3, page 5)

3. Please give references to support "...this AE (pruritis) can increase with longer treatment duration (line 7, page

12)."

4. Indirect hyperbilirubinemia is less clinically significant. Please list total bilirubin > 1.5 x or 3 x ULN AND direct hyperbilirubinemia. (Table 3)

5. Footnotes of Table 1 and 3 were missed.

6. The dataset in the Supporting Information was Chinese records.

Reviewer #2: This study aimed to compare the treatment efficacy and safety between 8-week and 12-week GLE/PIB therapy for patients with compensated HCV-related liver cirrhosis. The authors showed that both 8-week and 12-week GLE/PIB therapy provide excellent antiviral efficacy and safety profiles. Although it is interesting and has clinical implications, several concerns need to be clarified.

1. In this study, 7 patients had HBV and HCV dual infections. Were they treated with antiviral therapy for HBV? How many patients developed HBV reactivation during GIE/PIB therapy for HCV infection?

2. Moreover, 5 patients had a history of HCC. Were they active or non-active during GLE/PIB therapy? Did they undergo therapy for HCC during DAA therapy?

3. How many patients had clinically significant portal hypertension (CSPH)? Were the rates of CSPH different between these two groups of patients?

4. Were the rates of biochemical response or ALT normalization different between these two groups of patients?

5. In this study, patients in the 12-week treatment group had a lower baseline eGFR than those in the 8-week treatment group. Were the dynamic changes of eGFR during and after DAA therapy different between these two groups of patients?

6. It is suggested to provide a table to compare the laboratory data (such as albumin, bilirubin, ALT, platelet count, FIB-4, eGFR, etc.) at the time of end of follow-up (SVR12) between 8-week and 12-week treatment groups.

7. In Table 1, it is suggested to provide the exact p value instead of p< 0.05.

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Reviewer #1: No

Reviewer #2: No

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PONE-D-22-15455R1Comparison of 8- versus 12-weeks of glecaprevir/pibrentasvir for Taiwanese patients with hepatitis C and compensated cirrhosis in a real-world settingPLOS ONE

Dear Dr. Chang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Sep 01 2022 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Chen-Hua Liu

Academic Editor

PLOS ONE

Journal Requirements:

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

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2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Most responses were appropriate. However, some minor problems should be modified because of newly added figure 3.

1. Please add description about dynamic changes of eGFR in the Result section. The values of eGFR at different time points cannot be identified in the figure, and these values should be mentioned in the Result section.

2. Is any difference of the dynamic changes of eGFR values or percentages (baseline-EOT; baseline-12 weeks after EOT) between 8-week and 12-week group?

Reviewer #2: (No Response)

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: Yes: Chien-Wei Su

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Comparison of 8- versus 12-weeks of glecaprevir/pibrentasvir for Taiwanese patients with hepatitis C and compensated cirrhosis in a real-world setting

PONE-D-22-15455R2

Dear Dr. Chang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Chen-Hua Liu

Academic Editor

PLOS ONE