Caregivers of children with HIV in Botswana prefer monthly IV Broadly Neutralizing Antibodies (bNAbs) to daily oral ART

Maureen Sakoi-Mosetlhi; Gbolahan Ajibola; Roxanna Haghighat; Oganne Batlang; Kenneth Maswabi; Molly Pretorius-Holme; Kathleen M. Powis; Shahin Lockman; Joseph Makhema; Mathias Litcherfeld; Daniel R. Kuritzkes; Roger Shapiro

doi:10.1371/journal.pone.0299942

Peer Review History

Original SubmissionNovember 15, 2023
19 Dec 2023 Decision Letter - Jayanta Bhattacharya, Editor PONE-D-23-35663Caregivers of Children with HIV in Botswana Prefer Monthly IV Broadly Neutralizing Antibodies (bNAbs) to Daily Oral ARTPLOS ONE Dear Dr. SAKOI-MOSETLHI, 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 Feb 02 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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If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice. [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: Partly Reviewer #2: Partly ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: 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. 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: Yes ****** 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 ****** 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: This is a small study focussing on assessing acceptability of once a month bNAbs as against daily antiretroviral therapy among caregivers of 25 HIV infected children. These children were those who were put on ART very early in life and were virologically suppressed. They also had participated in some of the studies under taken by the investigators. bNAbs are likely to become an important area of work in management of HIV disease. Children depend on their parents, more often mothers or other caregivers to provide antiretroviral therapy everyday. Low adherence to ART is common among children. This study finds that monthly bNAb regimen was more acceptable to caregivers compared to daily ART regimen. The authors mention a limitation that it had more close ended questions. However, there are certain areas which require clarifications; 1. All the children and thus their caregivers included in the study had been participating one or the other study protocols, it reduces generalisability of findings additionally. 2. The responses could have been different if the caregivers were informed about the plasma viral loads on real time basis/ or at least before the post-assessment. 3. A significant proportion of children had to be shifted from bNAbs to antiretrovirals again, it is unclear whether the caregivers were informed of the reasons. It would have helped if their responses would have been recorded then as well. It helps in understanding whether care givers convenience or their concern about viral suppression influenced their post-assessment response. This is partly reflected in responses to a question “if infusions were better at suppressing the virus than ART”. Reviewer #2: In this study, Ajibola G et al have evaluated monthly infusion of dual bNAbs (VRCO1LS and 10-1074) as a treatment alternative to ART among children living with HIV-1, who are virally suppressed by ART (HIV RNA 68 <40 copies/mL) at least 24 weeks prior to enrolment in the Tatelo Study in Botswana. Primary caregivers of 25 children enrolled in the study answered closed-ended questionnaires prior to the first bNAb administration (pre-intervention) and after the completion of the final bNAb administration (post-intervention). 14 (56%) of the 25 enrolled children had viral rebound on dual bNAb, while 11 (44%) maintained viral suppression for 24 weeks. Acceptability data were available from 24 out of the 25 caregivers pre- and post-intervention. Pre-intervention, the most common reasons for preferring bNAbs over ART were the perception that bNAbs were better at suppressing the virus than ART (n=10) and the fact that infusions were dosed once monthly compared to daily ART (n=9). Post-intervention, no dominant reason for preferring bNAbs over ART emerged from caregivers. 2/25 preferred ART post-intervention (1 for a child who remained virally suppressed, 1 for a child with viral rebound on bNAbs). Intervention success was defined as maintenance of HIV RNA <400 copies/ml for 24 weeks while on dual bNAb-only treatment. The authors report that monthly bNAb infusions were highly acceptable among caregivers of children living with HIV in Botswana, with most caregivers preferring this form of treatment over daily ART if treatments were equally effective and suggest that caregiver acceptability is unlikely to be a barrier to bNAb uptake and eventual use of bnAbs to treat children living with HIV. The study findings are supportive towards the acceptability of caregivers of the bnAb based therapy in children living with HIV in Botswana. However there are few concerns, some of which have been partly addressed by the authors and should be detailed as limitations in the present study. 1. Being a close ended questionnaire based study, the extent of understanding of the care givers, about the implications of viral rebound in 14 children who were on dual bNAb, is not addressed. Intervention success was defined as maintenance of HIV RNA <400 copies/ml for 24 weeks while on dual bNAb-only treatment. The viremic status of children who had progressed to viral copies >40 from the time of recruitment would be clear only on further follow up beyond the course of this study. Whether these caregivers were counselled and informed of the above implications at the pre and post intervention stages prior to answering the questionnaire is not clear. 2. The education status and socioeconomic conditions of the caregivers, and the inclusion of subjects only within the study catchment area for close follow-up for at least 12 weeks, may be confounding factors that limit the observations and need to be addressed in detail as limitations of the study. 3. The sample size is vey small and the observations should be described as preliminary findings that need to be validated in a larger cohort. ****** 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. Attachments Attachment Submitted filename: PONE-D-23-35663. comments.docx https://doi.org/10.1371/journal.pone.0299942.r001
Revision 1
15 Feb 2024 Author Response POINT-BY-POINT RESPONSE TO REVIEWER COMMENTS Reviewer #1 1. All the children and thus their caregivers included in the study had been participating one or the other study protocols, it reduces the generalisability of findings additionally. Response: We appreciate the reviewer’s concerns and acknowledge that working with established cohorts from previous studies within a research setting could be a potential limitation as it provides less information on the real-life applicability of our intervention. However, as with all caregivers caring for children living with HIV, our participants face similar challenges with daily ART administration and have similar desires for simplified/alternative treatment approaches as we have emphasized in the manuscript (Line 33-39). In addition, any child receiving bNAbs in the foreseeable future will be a similar study setting, and studies such as Tatelo will be the only source of acceptability information to help determine the feasibility of this strategy. Therefore the findings of this study can be useful and applicable to other caregivers who find themselves caring for children living with HIV in Botswana and beyond. 2. The responses could have been different if the caregivers were informed about the plasma viral loads on real real-time basis/ or at least before the post-assessment. Response: We thank the reviewer for this comment and confirm that all caregivers were informed of their child’s plasma viral load (near real-time) at every scheduled visit per the study procedures. For those who experienced viral rebound during the bNAb only treatment phase, caregivers were contacted immediately and invited to the study clinic where they were notified of the occurrence of the rebound and the implication to their child’s inability to continue in the bNAb-only phase of the study. Upon this notification, study phase exit visits were conducted including administration of the post-intervention acceptability questionnaire. We have modified the data collection and definitions section of the manuscript to reflect these details in lines 99-102 which now reads “Primary caregivers answered closed-ended questionnaires prior to the first bNAb administration (pre-intervention) and after the completion of the final bNAb administration or at the time of viral rebound for those with HIV RNA >400 copies/mL while on bNAb only (post-intervention). 3. A significant proportion of children had to be shifted from bNAbs to antiretrovirals again, it is unclear whether the caregivers were informed of the reasons. It would have helped if their responses would have been recorded then as well. It helps in understanding whether caregivers convenience or their concern about viral suppression influenced their post-assessment response. This is partly reflected in responses to a question “if infusions were better at suppressing the virus than ART”. Response: All children who rebounded while on the intervention phase of the study (monthly dual bNAbs only) were switched back to ART and monthly dual bNAbs were permanently discontinued. Information on caregiver acceptability was collected and assessed at the end of the intervention phase for those with no viral rebound or at the time of viral rebound for those with HIV RNA >400 copies/mL while on dual bNAb only. As highlighted in 2 above, we have updated the study methods to further clarify that caregivers were informed of their child’s HIV plasma RNA levels at every study visit as well as the reason for the permanent discontinuation of bNAbs where appropriate. Reviewer #2 1. Being a close-ended questionnaire-based study, the extent of understanding of the caregivers, about the implications of viral rebound in 14 children who were on dual bNAb, is not addressed. Intervention success was defined as maintenance of HIV RNA <400 copies/ml for 24 weeks while on dual bNAb-only treatment. The viremic status of children who had progressed to viral copies >40 from the time of recruitment would be clear only on further follow-up beyond the course of this study. Whether these caregivers were counselled and informed of the above implications at the pre and post-intervention stages prior to answering the questionnaire is not clear. Response: Caregivers were made aware of the possibility of their children rebounding while on dual bNAb-only treatment, and its implications for permanent discontinuation of the bNAbs and re-introduction of daily ART. Caregivers of participants who rebounded were given this information as part of the informed consent process and at the time of viral rebound. All the participants who were taken off the intervention step due to detectable plasma HIV RNA were followed weekly until they attained viral suppression and for up to 24 weeks post bNAbs cessation. We have now reported on the time to re-suppression for all participants who were re-initiated on ART before completing the dual bNAb-only treatment phase due to HIV RNA >400 copies/mL. Lines 147 – 149 of the manuscripts now read “All participants who experienced a viral rebound in the intervention phase of the study were immediately re-initiated on ART and all re-suppressed to levels <40 copies/mL at a median of 4 weeks (range: 1 to 20 weeks)”. 2. The education status and socioeconomic conditions of the caregivers, and the inclusion of subjects only within the study catchment area for close follow-up for at least 12 weeks, may be confounding factors that limit the observations and need to be addressed in detail as limitations of the study. Response: We thank the reviewer for this comment and agree that this could potentially limit the generalizability of our findings. However, Table 1 of the manuscript describes the basic socio-demographics of study participants and shows that participants were enrolled from different geographical locations and socioeconomic backgrounds, reducing the possibility of bias. Because the cohort was created by screening nearly all HIV exposed children in the catchment areas, and these areas covered ~ 30% of all exposed children in Botswana during the initial accrual period, and almost 100% of the children who screened positive enrolled, the demographics of the Tatelo cohort are highly representative of children living with HIV in Botswana. 3. The sample size is very small and the observations should be described as preliminary findings that need to be validated in a larger cohort. Response: We agree with the reviewer on the need for the validation of our findings in other cohorts of early-treated infants globally and have included this in our conclusion. Lines 206 - 208 of our conclusion state the need for further research in a larger and more diverse population as encouraged by the reviewer. Attachments Attachment Submitted filename: FINALIZED POINT-By-POINT-CLEANED_rs (1).docx https://doi.org/10.1371/journal.pone.0299942.r002
20 Feb 2024 Decision Letter - Jayanta Bhattacharya, Editor Caregivers of Children with HIV in Botswana Prefer Monthly IV Broadly Neutralizing Antibodies (bNAbs) to Daily Oral ART PONE-D-23-35663R1 Dear Dr. SAKOI-MOSETLHI, 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 for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, 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, Jayanta Bhattacharya Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0299942.r003
Formally Accepted
16 Mar 2024 Acceptance Letter - Jayanta Bhattacharya, Editor PONE-D-23-35663R1 PLOS ONE Dear Dr. Sakoi-Mosetlhi, 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. Jayanta Bhattacharya Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0299942.r004

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