PONE-D-21-04696

Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected Children After Test and Treat Strategies Launched in South Gondar Public Hospitals, Northwest, Ethiopia, 2021; A Multicentre Historical Follow-up Study

PLOS ONE

Dear Dr. Ermias Sisay Chanie,

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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We look forward to receiving your revised manuscript.

Kind regards,

Qigui Yu, M.D./Ph.D

Academic Editor

PLOS ONE

Additional Editor Comments:

Suggest to get help from someone with full professional proficiency in English to revise the manuscript.

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Reviewers' comments:

Reviewer's Responses to Questions

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: Yes

Reviewer #2: No

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

Reviewer #1: Yes

Reviewer #2: No

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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: No

Reviewer #2: No

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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: In this study, the authors performed institution-based retrospective follow-up study conducted from March 1, 2014, to January 12, 2021 on survival and predictors of mortality among 227 TB and HIV co-infected children in Ethiopia. They found that this population of children had a high mortality rate of 17% and that cotrimoxazole preventive therapy (CPT) non-users, ART treatment failure, and CD4 count below threshold were significant predictors of mortality. The study was well done, but the writing needs substantial improvement. There are no other major concerns. The following are some minor concerns and questions.

1) Please provide explanation to the test and treat strategies and ART service

2) Does duration on ART mean that the following time of the patients during the study.

3) How many patients in Stage III & IV were in Stage IV? Would Stage IV be a predictor of mortality?

4) In Table 3 CPT, the Yes and No groups were mislabeled.

5) The Figure legends for Kaplan-Meier survival curves of CD4 counts are mixed-up. The legends for CPT user and non-user were the same.

6) What were the major causes of death?

Reviewer #2: the manuscript "Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected

Children After Test and Treat Strategies Launched in South Gondar Public Hospitals, Northwest,

Ethiopia, 2021; A Multicentre Historical Follow-up Study" by Chanie et al touched a very important heath issue among the HIV/TB co-infected people. However, the studies are not very organized so its enthusiasm is reduced.

Major concerns:

1. language: The whole paper is very hard to understand, current wiring is very sloppy.

2. Statistical analysis is lacking for the Tables 1 and 2. Although the statistical power (p value) was shown for the Table 3, it lacks a description of how the authors did the statistical analysis.

3. As the authors concluded "In this study, mortality among TB and HIV co-infected children was found to be very high. Treatment failure and CD4 count below the threshold were the independent predictors of mortality.

Hence, it is better a special emphasis on monitoring and managing regularly of these contributing

factors. Besides, strengthen the WHO recommendation of cotrimoxazole preventive therapy for all

patients living with HIV is crucial." it is not novel at all, e.g. people have known the importance of CD4 count.

suggest the authors making Bar graphs for Table 1 and Table 2 to show more detailed data in clearer manner.

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6. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PONE-D-21-04696R1

Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected Children After Test and Treat Strategies Launched in Northwest, Ethiopia, 2021; A Multicentre Historical Follow-up Study

PLOS ONE

Dear Ermias Sisay Chanie,

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 October 1, 2021. 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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: http://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,

Qigui Yu, M.D./Ph.D

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: (No Response)

Reviewer #3: (No Response)

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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 #3: Partly

**********

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

Reviewer #1: Yes

Reviewer #3: 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 #3: Yes

**********

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: No

Reviewer #3: 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: The major issue had been poor English writing, which was improved in this revised version. However, there are still many grammar mistakes and the overall flow of the sentences need to be fixed. There are also some misstatements and typos, some of which are listed below.

The statement in the Abstract “However, there is no prior evidence in Ethiopia.” is not accurate as the authors themselves cited a reference to show the opposite (ref #18, Survival and predictors of mortality among children co-infected with tuberculosis and human immunodeficiency virus at University of Gondar Comprehensive Specialized Hospital, Northwest Ethiopia. A retrospective follow-up study. PLoS ONE [Internet]. 2018 May 22”). It appears that this current study and the above-mentioned 2018 study both recruited patients from the same Gondar Comprehensive Specialized Hospital. Were there any patients included in both studies? Some discussion on the similarities and differences between both studies would be helpful.

As the risk of mortality is associated with CPT therapy non-users, the concluding should emphasize CPT use along with ART therapy.

Some of the references need to be updated. For example, World Health Organization. Global tuberculosis report 2020 is available (ref #4); The data shown in the sentences “In 2015 worldwide, 1.6 million people…” should be replaced with more recent data.

Should the overall mortality rate be 3.7 per 100 person-years instead of 3.7 per person-years.

Should Debre Tabor compressive specialized hospital be Debre Tabor Comprehensive Specialized Hospital?

In “by taking sex as a predictor variable (on the male as the exposed group

denoted by q1 (0.38) and female group denoted by q0 (0.53)”, where the numbers come from?

The sentence “The patients provided informed written consent to have data/samples from their medical records used in research.” needs re-wording as the patients were too young to provide such consent.

In “half of 117 (51.54% and 122(53.74%) male and age between 6.10 years respectively.”, the order was wrong: 122 is for male and 117 for the age group.

In “118 (51.98%), 99 (43.61%), 103 (45.37%), and 218 (77.03%)…), what 218 is for?

Reviewer #3: The authors studied lifetime survival and predictors of mortality in children with TB and HIV coinfection. Overall mortality rate was 3.7, which as associated with treatment failure, especially CD4 count below the threshold. The manuscript has improved adequately, but there are minor concerns that should be made clear for the conclusion in relation to treatment failure.

1. Antiretroviral drug (ARV) combination in the patient cohorts and groups, especially those with treatment failure, since 18.94% co-infected children showed treatment failure;

2. Did the ART cessation happen in the co-infected patients, which likely contribute to treatment failure, such as CD4 decline to the levels of threshold and emergence of opportunistic infection. These are important to make statistical analysis and conclusion;

3. The ARV combination and treatment duration in cohort with treatment failure should be considered in the group classification in the statistical analysis, at least discussed.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

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 #3: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachments

Attachment

Submitted filename: PONE-D-21-04696R1.docx

PONE-D-21-04696R2

Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected Children After Test and Treat Strategies Launched in Northwest, Ethiopia, 2021; A Multicentre Historical Follow-up Study

PLOS ONE

Dear Dr. Chanie,

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 poor English writing, particularly in your discussion section.

Please submit your revised manuscript by November 16, 2021. 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 you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

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: http://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,

Qigui Yu, M.D./Ph.D

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.

Additional Editor Comments (if provided):

Suggest to seek professional English editing services to improve the flow and writing of your manuscript.

Reviewers' comments:

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Estimation of Lifetime Survival and Predictors of Mortality Among TB with HIV Co-infected Children After Test and Treat Strategies Launched in Northwest, Ethiopia, 2021; A Multicentre Historical Follow-up Study

PONE-D-21-04696R3

Dear Dr. Ermias Sisay Chanie

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,

Qigui Yu, M.D./Ph.D

Academic Editor

PLOS ONE

Reviewers' comments: