PONE-D-23-22283High Viral Suppression Rates among PLHIV on Dolutegravir who had an Initial Episode of Viral Non-Suppression in Uganda September 2020–July 2021.PLOS ONE

Dear Dr. Namayanja,

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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Academic Editor

PLOS ONE

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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: Partly

Reviewer #2: Yes

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

Reviewer #1: No

Reviewer #2: I Don't Know

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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: No

Reviewer #2: No

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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: The contribution of the paper is unclear. DBRs were introduced because they are effective. More is needed in terms of the factors associated with viral suppression. The analysis focuses on geography, type of facility, duration DBRs. It is not clear what lessons can be taken away and which may be used to inform programmes.

Reviewer #2: Namayanja et al. studied individuals treated for HIV with dolutegravir-based regimens who experienced an episode of viral non-suppression, then received intensive adherence counseling for 3 months, then were retested for viral load. The authors found that 80% of individuals had a suppressed viral load at followup, suggesting that their prior non-suppression was due to lower medication adherence rather than viral resistance. Overall, this is a well described study that makes important use of a large amount of data in the Uganda Central Public Health Laboratory. I have several questions that would help readers understand and interpret this information.

Please include information about the the followup interval for each individual, i.e. the amount of time between the initial episode of viral non-suppression and the first followup visit. Was the duration of that interval associated with suppression (in either direction)?

Why do the authors think that the reported adherence decreased, but viral suppression increased, at the first followup?

Please provide more detail about the formula used for sample size calculation, for a broad audience.

Please check line 160 – is this text intended to be in the manuscript?

Line 282 indicates that repeat viral load testing took place if the patient reported >95% medication adherence. This would seem to strongly bias results towards finding viral suppression. If this is accurate, I would include this earlier in the manuscript as a condition of the specific population under investigation (ie, those with good medication adherence).

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Reviewer #1: No

Reviewer #2: No

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PONE-D-23-22283R1High Viral Suppression Rates among PLHIV on Dolutegravir who had an Initial Episode of Viral Non-Suppression in Uganda September 2020–July 2021.PLOS ONE

Dear Dr. Namayanja,

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.

Some comments from the reviewers have been addressed. Kindly address the outstanding comments from a reviewer, which has been reiterated. These are critical to the study methodology and findings.

Please submit your revised manuscript by Apr 26 2024 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 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: 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,

Chika Kingsley Onwuamah, Ph.D.

Academic Editor

PLOS ONE

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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: (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: (No Response)

Reviewer #2: Partly

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

Reviewer #1: (No Response)

Reviewer #2: I Don't Know

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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: (No Response)

Reviewer #2: No

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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: (No Response)

Reviewer #2: Yes

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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: (No Response)

Reviewer #2: While the authors have addressed some of my prior comments, others have not yet been addressed and the text was not updated to include important information. It would also be helpful if the authors can explain what changes have been made to the tables.

Please include information about the the followup interval for each individual on a per-individual basis, i.e. the amount of time between the initial episode of viral non-suppression and the first followup visit. Was the duration of that interval associated with suppression (in either direction)? The authors replied that the visits were meant to be one month apart, but did not indicate specific information about the interval or evaluate whether the interval was associated with suppression. For example, if someone didn’t come back until 6 weeks later, were they more likely to be non-suppressed? Please also address this question in the manuscript itself, not just the response here.

Why do the authors think that the reported adherence decreased, but viral suppression increased, at the first followup? The authors replied that the paper shows “when ART adherence improves, the PLHIV get virally suppressed” – while I agree with this, the analysis also shows that viral suppression can happen before adherence improves..

At repeat VL testing, 80.8% (421/521) achieved viral suppression

Overall, at initial VL testing, … 94.1% (480/510) had good self-reported adherence despite VNS

Among 493 PLHIV who had a documented adherence assessment at repeat testing, 91.9% (453/493) had good self-reported adherence

What would explain that? Please also address this question in the manuscript itself, not just the response here

The section on line 160 (now line 176) does not seem appropriate for the main text of a manuscript, based on the way it is phrased and the way it describes individual investigators and explains why they are not co-authors. I haven’t seen something like this in the main text of a manuscript before. I recommend removing it and putting this information in acknowledgements, funding, etc. The specific text is pasted below, including the word “Response:” which seems to me like a response to a review question, and not something that should be in the manuscript.

Response: “CDC Uganda with support from the associate director of science, strategic information branch chief, CDC Uganda staff and Ministry of health among others developed a broad protocol that provides for review and use of retrospective routinely collected de-identified data. This protocol received approval from the CDC Science and integrity branch and exemption from the Makerere School of Public Health to develop and write abstracts manuscripts from various data sources used in the country e.g., dashboards, databases, Registers. In our manuscript we utilized de-identified data from the Central Public Health laboratory (CPHL) database or Lab Information management system (LIMS). The CPHL conducts viral load testing on all samples national wide. This broad protocol had the senior leadership from the various institutions that CDC works with e.g., MOH – where Dr. Joshua Musinguzi is the Program Manager of the AIDS control program and CDC Uganda Strategic Information branch chief – Jenny Ward. Joshua and Jenny only served as the co-authors on the CDC broad protocol for programmatic data utilization. However, for this manuscript they were not specifically engaged in the work and therefore, we did not include them in as co-authors.

Line 282 indicates that repeat viral load testing took place if the patient reported >95% medication adherence. This would seem to strongly bias results towards finding viral suppression. Please include this earlier in the manuscript as a condition of the specific population under investigation (ie, those with good medication adherence), and include this as an overall limitation to the study.

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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.

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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: Yes: Akudo Ikpeazu MD, MPH, DrPH

Reviewer #2: No

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[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.

High Viral Suppression Rates among PLHIV on Dolutegravir who had an Initial Episode of Viral Non-Suppression in Uganda September 2020–July 2021.

PONE-D-23-22283R2

Dear Dr. Namayanja,

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,

Chika Kingsley Onwuamah, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

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 #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 #2: (No Response)

**********

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

Reviewer #2: (No Response)

**********

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 #2: (No Response)

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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 #2: (No Response)

**********

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 #2: (No Response)

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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 #2: No

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