Viral load suppression and HIV-1 drug resistance mutations in persons with HIV on TLD/TAFED in Zambia

Emmanuel L. Luwaya; Lackson Mwape; Kaole Bwalya; Chileleko Siakabanze; Benson M. Hamooya; Sepiso K. Masenga

doi:10.1371/journal.pone.0308869

Peer Review History

Original SubmissionMarch 27, 2024
7 Jun 2024 Decision Letter - Anne Kapaata, Editor PONE-D-24-12439Viral load suppression and HIV-1 drug resistance mutations in persons with HIV on TLD/TAFED in Zambia: A cross-sectional studyPLOS ONE Dear Dr. Luwaya, 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 Jul 22 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. 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Additional Editor Comments: Viral load suppression and HIV-1 drug resistance mutations in persons with HIV on TLD/TAFED in Zambia: A cross-sectional study Review comments In the background 1. Its mentioned that “In 2021, 75% of people with HIV knew their status, 85% were receiving treatment, and 68% had viral suppression according to a review by Frescura” The precentages seem low, is this the current situation in Zambia as of 2023 when the study was carried out? 2. Provide more literature on levels of HIVDR in the DTG era apart from Malawi…what is the situation in other countries especially Zambia? Are there no other studies that have reported resistance to DTG in zambia? When was DTG adopted in Zambia? Under methods 1. Correct the dates of carrying out the study is it between 5th, June 2023 and 10th, August 2023 or between May 2023 and August 2023 “ 2. For sample size calculation, what guided a viral load suppression of 50%? Is the national rate? 3. What guided the virally suppressed categories of 20 -1000 copies/ml, less 20 copies/ml and Target Not Detected (TND). Under results 1. What drugs made up the NNRTI +NRTI regimen? 2. Were all the 384 participants non suppressed? 3. How were the OR for viral suprresssion after swutching to DTG calculated?- it appears that these were calculated as if all participants were non-suppressed before switching, therefore giving the impression that PI-based regimen were 85% less likely to suppress after switching, something which is not consistent with the body of literature in this area. See the numbers of the different regimens in table one and two. 4. Table is redundant since number of those with HIVDR mutation is just 4 and its distribution is described in the section before the table [Note: HTML markup is below. Please do not edit.] 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 ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes ****** 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. 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(Please upload your review as an attachment if it exceeds 20,000 characters) Reviewer #1: The manuscript is interesting and worth publishing. tTe author brought out the science clearly it is clear that introduction of integrate inhibitors reduces virology failure . a good recommendation for the public health of Zambia ****** 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 ******** [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: For Maria to review.pdf https://doi.org/10.1371/journal.pone.0308869.r001
Revision 1
22 Jul 2024 Author Response Mulungushi University, P.O Box 60009, Livingstone. 22nd July 2024. The Reviewers, PLOS ONE Journal. Dear PLOS ONE reviewers, RE: RESPONSE TO REVIEWER COMMENTS Thank you so much for reviewing our manuscript and providing invaluable reviews. We appreciate your review comments which we believe have improved our manuscript's readability and credibility. We have taken time to correct our manuscript and provided a manuscript copy with track changes to reflect our work on the manuscript. Below are our responses to the review comments. When submitting your revision, we need you to address these additional requirements. 1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf Response from authors: Thank you. We have referred to the comments and have since adjusted the naming of the manuscript and supporting documents to PLOS ONE’s style requirements. 2. We note that your Data Availability Statement is currently as follows: All relevant data are within the manuscript and its supporting information files. Please confirm at this time whether or not your submission contains all raw data required to replicate the results of your study. Authors must share the “minimal data set” for their submission. PLOS defines the minimal data set to consist of the data required to replicate all study findings reported in the article, as well as related metadata and methods (https://journals.plos.org/plosone/s/data-availability#loc-minimal-data-set-definition). Response from authors: Thank you, we have since attached the raw data to this submission. 3. When completing the data availability statement of the submission form, you indicated that you will make your data available on acceptance. We strongly recommend all authors decide on a data sharing plan before acceptance, as the process can be lengthy and hold up publication timelines. Please note that, though access restrictions are acceptable now, your entire data will need to be made freely accessible if your manuscript is accepted for publication. This policy applies to all data except where public deposition would breach compliance with the protocol approved by your research ethics board. If you are unable to adhere to our open data policy, please kindly revise your statement to explain your reasoning and we will seek the editor's input on an exemption. Please be assured that, once you have provided your new statement, the assessment of your exemption will not hold up the peer review process. Response from authors: Thank you, we have since attached the raw data to this submission. 4. Please amend either the title on the online submission form (via Edit Submission) or the title in the manuscript so that they are identical. Response from authors: Thank you very much. The title on the online submission has been edited to make identical to the title in the manuscript. 5. Your ethics statement should only appear in the Methods section of your manuscript. If your ethics statement is written in any section besides the Methods, please move it to the Methods section and delete it from any other section. Please ensure that your ethics statement is included in your manuscript, as the ethics statement entered into the online submission form will not be published alongside your manuscript. Response from authors: Thank you, we have since deleted the ethics statement in other parts of the manuscript and only retained it in the methods section. 6. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information. Response from authors: Thank you, we have since made the captions as per recommendation. 7. 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. Response from authors: Thank you, we have reviewed our reference list as recommended. We have not cited any retracted article. Review Comments to the Author Reviewer 1 1. It’s mentioned that “In 2021, 75% of people with HIV knew their status, 85% were receiving treatment, and 68% had viral suppression according to a review by Frescura” The percentages seem low, is this the current situation in Zambia as of 2023 when the study was carried out? Response from authors: Thank you very much. We have made the revisions and included the correct percentages from the Zambia Population-based HIV and AIDS Impact Assessment (ZAMPHIA) survey conducted between May-December 2021. This is the latest country-wide data showing that Zambia has improved. Among adults (15 years and older) in Zambia living with HIV, 88.7 percent were aware of their status, 98.0 percent of those who knew their status were on ART, and 96.3 percent of those on ART achieved viral load suppression.. 2. Provide more literature on levels of HIVDR in the DTG era apart from Malawi…what is the situation in other countries especially Zambia? Are there no other studies that have reported resistance to DTG in Zambia? When was DTG adopted in Zambia? Response from authors: Thank you so much. We have revised and included the period of adoption of DTG. We’ve also included literature from other countries on DTG. However, according to our knowledge, there are no studies that have reported DTG resistance in Zambia. Reviewer 2 1. Correct the dates of carrying out the study is it between 5th, June 2023 and 10th, August 2023 or between May 2023 and August 2023 “ Response from author: Thank you for the comment. We have corrected the dates of carrying out of the study, which is between 5th June, 2023 and 10th August, 2023 2. For sample size calculation, what guided a viral load suppression of 50%? Is the national rate? Response from authors: Thank you so much for the comment. The 50% was used to help obtain the maximal sample size from our study population since national rate was not well documented 3. What guided the virally suppressed categories of 20 -1000 copies/ml, less 20 copies/ml and Target Not Detected (TND). Response from authors: Thank you very much. The categories were guided by the result output of the viral load instrument that was used. The machine gives result such Target not detected (TND) and less than 20 copies/ml. So the categorization was only for descriptive purposes that provides more data around those that were virally suppressed. However, since the outcome variable “viral load suppression” was categorized as a binary variable, where viral suppression categories included “virally suppressed <1000 copies/ml” and “unsuppressed viral load >1000 copies/ml”, we have now used these categories in the manuscript for consistency. Under results 1. What drugs made up the NNRTI +NRTI regimen? Response from author: Thank you so much. The NNRTI + NRTI combination was made up of Tenofovir + Efavirenz + Lamivudine/Emtricitabine. We have since revised and included this description in our results. 2. Were all the 384 participants non-suppressed? Response from authors: Thank you so much. Not all participants were non-suppressed. Only 116 participants were non-suppressed before switching to DTG and only 35 were non-suppressed after switching to DTG 3. How were the OR for viral suppression after switching to DTG calculated?- it appears that these were calculated as if all participants were non-suppressed before switching, therefore giving the impression that PI-based regimen were 85% less likely to suppress after switching, something which is not consistent with the body of literature in this area. See the numbers of the different regimens in table one and two. Response from authors: The OR for the Regimen before switching to DTG-based regimen was calculated for all participants regardless of viral suppression status before switching to DTG. This is because some participants who were virally suppressed before switching became unsuppressed after at last 6 months on DTG suggesting an interplay of other factors contributing to viral suppression. Therefore, to account for changes occurring even in those who were suppressed during the period on DTG, we included them in the analysis. We have recalculated the OR only for those who were unsuppressed (as shown below), and the multivariable results are not very different in terms of statistical significance. However, neither of the specific regimen were associated with viral suppression in the multivariable model either because the sample size was not highly powered for subgroup analysis or because of confounding factors that have been included in the multivariable regression model. PI based regimen were not significantly associated with viral suppression even on univariable analysis with this change. Variables Univariate OR (95%CI) P value AOR (95%CI) P value Regimen before switch/initiation (ref: NNRTI+NRTI) PI-based (TDF/3TC/LPV-r) 0.405 (0.130,1.262) 0.119 0.777 (0.193, 3.135) 0.723 INSTI-based (AZT/3TC/DTG) 0.135 (0.029,0.627) 0.011 0.350 (0.050, 2.476) 0.293 Note: other variables in the model are not shown here 4. Table is redundant since number of those with HIVDR mutation is just 4 and its distribution is described in the section before the table Response from authors: Thank you very much for the review. We have revised and removed the table. We want to thank the reviewers again for taking time to review and make suggestions that has improved our manuscript. We now hope it is acceptable for publication. Yours, Emmanuel Luwaya On behalf of the authors Attachments Attachment Submitted filename: Response to Reviewers.docx https://doi.org/10.1371/journal.pone.0308869.r002
1 Aug 2024 Decision Letter - Anne Kapaata, Editor Viral load suppression and HIV-1 drug resistance mutations in persons with HIV on TLD/TAFED in Zambia PONE-D-24-12439R1 Dear Dr. Luwaya, 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. An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org. If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. Kind regards, Anne Kapaata Academic Editor PLOS ONE Additional Editor Comments (optional): The comments have been addressed and the manuscript is ready for publication however all sequences generated as part of this study should be deposited into Genbank. Reviewers' comments: https://doi.org/10.1371/journal.pone.0308869.r003
Formally Accepted
29 Aug 2024 Acceptance Letter - Anne Kapaata, Editor PONE-D-24-12439R1 PLOS ONE Dear Dr. Luwaya, I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team. At this stage, our production department will prepare your paper for publication. This includes ensuring the following: * All references, tables, and figures are properly cited * All relevant supporting information is included in the manuscript submission, * There are no issues that prevent the paper from being properly typeset If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps. Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org. If we can help with anything else, please email us at customercare@plos.org. Thank you for submitting your work to PLOS ONE and supporting open access. Kind regards, PLOS ONE Editorial Office Staff on behalf of Dr. Anne Kapaata Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0308869.r004

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