Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial

Lynda Stranix-Chibanda; Camlin Tierney; Dorothy Sebikari; Jim Aizire; Sufia Dadabhai; Admire Zanga; Cynthia Mukwasi-Kahari; Tichaona Vhembo; Avy Violari; Gerard Theron; Dhayandre Moodley; Kathleen George; Bo Fan; Markus J. Sommer; Renee Browning; Lynne M. Mofenson; John Shepherd; Bryan Nelson; Mary Glenn Fowler; George K. Siberry; for the PROMISE P1084s study team

doi:10.1371/journal.pone.0246272

Peer Review History

Original SubmissionMay 25, 2020
3 Nov 2020 Decision Letter - Nancy Beam, Editor PONE-D-20-15228 Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial PLOS ONE Dear Dr. Stranix-Chibanda, 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 update the Results and analyses as suggested by the reviewers. Please submit your revised manuscript by Dec 10 2020 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. 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In addition to naming the author group, please list the individual authors and affiliations within this group in the acknowledgments section of your manuscript. Please also indicate clearly a lead author for this group along with a contact email address. 5.Thank you for stating the following in the Financial Disclosure section: [Overall support for the International Maternal Pediatric Adolescent AIDS Clinical Trials Network (IMPAACT) was provided by the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH) under Award Numbers UM1AI068632 (IMPAACT LOC), UM1AI068616 (IMPAACT SDMC) and UM1AI106716 (IMPAACT LC), with co-funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the National Institute of Mental Health (NIMH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Antiretrovirals were provided free of charge for the PROMISE P1084s study by AbbVie, Gilead Sciences, and GlaxoSmithKline. Funding to purchase bone density scanners was provided for the PROMISE P1084s study by Gilead Sciences. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.]. 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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 well conducted study nested within the PROMISE randomised controlled trial conducted in four African countries. Selection, confounding bias and bias due to drop-out seems to be small. Also, the dilution of the effect due to people initially allocated to control and subsequently initiating TDF appears to be a conservative bias (might be worth mentioning in the Discussion). However, I have a number of points that need to be addressed, especially regarding the statistical analysis. Main Points 1. Line 109. The authors state that the main objective was to evaluate the possible impact of TDF exposure on BMD when used in combination with extended breastfeeding beyond the first year. In practice, 50% of the women in the study interrupted breastfeeding by week 61 and there were on average 17 weeks in which there was no extended breastfeeding before week 74. I believe that objectives need to be reworded accordingly or acknowledged that the data collected were shortfall for addressing the main aim. 2. Unclear why the earlier time-points (week 6 and week 26) have been ignored completely. It could be important to show whether the difference in BMD percentage change could be detected earlier on as it would re-inforce the hypothesis that breastfeeding was an issue. The most likely explanation for the findings seems to be the cumulative exposure/exacerbation of the effect of TDF in co-presence of boosted PIs instead. 3. Lines 156- 158. Were technicians evaluating the scans blind to treatment allocation? How can authors exclude that oucomes were not affected by technicians knowing who had received TDF? 4. Were percentage changes distributed approximately normal? It is unusual to use t-test and linear regression for a percentage ranging between -15% to +15%. Because confounding does not seem to be a major issue, how would the results look when using non-parametric tests? Why not using absolute change after controlling for baseline level? 5. Confounding, mediation, interaction. There is a lot of confusion on these issues. I think that it is agreeable that AP randomization, country, age, baseline weight, parity at PROMISE entry and plasma HIV-1RNA level are potential confounders. There is some evidence that AP randomization and baseline weight are effect modifiers for the primary endpoint while age and baseline weight for the secondary endpoint (Table 2). Therefore, these should be removed as confounders from the two analyses, respectively. Regarding the values measured at week 74, none of these should be included as confounders or as stratification factors in the subgroup analyses: breastfeeding status and current receipt of TDF are time-dependent confounders, so a standard regression analysis is unable to control for the possible introduced bias. Current weight, time and use of contraceptive are even potential mediators in the causa pathway between TDF and BMD change so should not be controlled for and cannot be evaluated as possible effect modifiers. On top of this, there should be consistency between text (Methods lines 176-178 vs. Discussion, lines 286-287) and the footnote of Figure 1 and what shown in Table 2 regarding the various adjustments. 6. If authors are really worried about drop-outs they should perform a per-protocol analysis controlling for cross-over dilution and possible informative censoring. 7. What is a change in BMD that can be considered as clinically relevant? In line 320 this is set to be as 5-7%. The actual estimate from the analysis in in the range of 2-3%, the long-term clinical implication of which are said to be unknown (lines 289-291). If this is the case than the study only shows a statistical difference which has unclear clinical implications and contradicts the conclusions. 8. Because INSTI have replaced PI/r even in resource limited settings, will TDF have a similar impact on BMD in the future? Other points 1. Line 139. A P is missing (P1084 sub-study) 2. Lines 180-181. Most statisticians are moving away for the concept of a threshold for significance such as the arbitrary 0.05 cut-off. Best to speak more generally about compatibility of the data with the null hypothesis. 3. Lines 321-322. Despite the lack of evidence for an interaction (the study was not powered to detect these), percent BMD change in Malawi appeared to be much smaller than that seen in other countries for the primary endpoint (Table 2). 4. Table 2. Typically this is shown as a forest plot, instead of a Table, although this mainly pertains to style 5. Figure 2. Unusual to show box-plots (medians, IQR) when the assumption is that the distribution of a percentage change is approximately normal so that means and SD are shown and means compared (see main point 4 above). Reviewer #2: This paper evaluated the impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in the IMPAACT P1084s sub-study of the PROMISE randomized trial. In general, pregnancy itself may lead to bone loss but if followed by lactation, it will have protective effect on bone density while the duration of lactation and parity may modulate its effect. In this study, having being exposed to TDF-ART during 74-week postpartum breastfeeding led to significant declines (-2.5 to 3 percent lower) than having being exposed to nevirapine alone. Specific comments 1. Although randomization and number of participants may have overcome bias, no data on diet or physical activity, calcium and vitamin D status or supplements are given. 2. More importantly than knowing the percent decrease in bone mineral density would have been which the clinical impact was: changes from normal to osteopaenia or from osteopaenia to osteoporosis, and incident bone fractures. ****** 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: Yes:** Esteban Martinez [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. https://doi.org/10.1371/journal.pone.0246272.r001
Revision 1
9 Dec 2020 Author Response Reviewer #1— General comment This is a well conducted study nested within the PROMISE randomised controlled trial conducted in four African countries. Selection, confounding bias and bias due to drop-out seems to be small. Also, the dilution of the effect due to people initially allocated to control and subsequently initiating TDF appears to be a conservative bias (might be worth mentioning in the Discussion). However, I have a number of points that need to be addressed, especially regarding the statistical analysis. General Response: Thank you. We have taken note of the points raised. Main Points M1.1. Line 109. The authors state that the main objective was to evaluate the possible impact of TDF exposure on BMD when used in combination with extended breastfeeding beyond the first year. In practice, 50% of the women in the study interrupted breastfeeding by week 61 and there were on average 17 weeks in which there was no extended breastfeeding before week 74. I believe that objectives need to be reworded accordingly or acknowledged that the data collected were shortfall for addressing the main aim. M1.1. Response: Thank you for this valid comment. To clarify the main aim, the study was not designed to compare BMD changes between study arms during the period of breastfeeding. We assumed breastfeeding cessation would take place 12-15 months postpartum and timed the week 74 DXA scan to occur after BMD restitution was expected to have taken place and before most women enter a subsequent pregnancy-breastfeeding cycle. If a greater BMD decline in women on TDF-ART was documented at that time, the study team considered that could be potentially detrimental to the mother’s future bone health. The last paragraph of the Introduction has been reworded in lines 99-118 in the version with tracked changes. M1.2. Unclear why the earlier time-points (week 6 and week 26) have been ignored completely. It could be important to show whether the difference in BMD percentage change could be detected earlier on as it would reinforce the hypothesis that breastfeeding was an issue. The most likely explanation for the findings seems to be the cumulative exposure/exacerbation of the effect of TDF in co-presence of boosted PIs instead. M1.2 Response: This comment relates to the unclear phrasing of the study aim alluded to earlier in comment M1.1. BMD was not assessed at postpartum weeks 6 and 26. The revised aim in the Introduction clarifies that the findings reflect the effect of exposure to TDF-ART on BMD change between baseline and postpartum week 74 in a population of women with HIV who breastfed. M1.3. Lines 156-158. Were technicians evaluating the scans blind to treatment allocation? How can authors exclude that outcomes were not affected by technicians knowing who had received TDF? M1.3 Response: Yes—DXA operators conducting the scans and the central DXA reading unit were blinded to treatment allocation. This important point has been added to line 164-165 in the revised manuscript with changes highlighted. M1.4. Were percentage changes distributed approximately normal? It is unusual to use t-test and linear regression for a percentage ranging between -15% to +15%. Because confounding does not seem to be a major issue, how would the results look when using non-parametric tests? Why not using absolute change after controlling for baseline level? M1.4 Response: We thank the reviewer for this comment relating to the statistical analysis plan adopted by the protocol team. The t-test is relatively robust to non-normality (e.g., see Lumley, et al. Annu. Rev. Public Health, 23:151–169, 2002). The sample size of 339 (334) participants is large enough to allow the statistical effects of averaging to come into play to perform an approximate t-test with non-normal distributions. Visual inspection of the data indicates symmetric and approximate normal distribution. Additionally, percent change in BMD has commonly been used as the outcome measure in these younger patients where standardized outcome data are lacking. Many experts regard a change or difference in BMD of 3-5% (or 0.5 SD) as significant in whom standardized outcome data are lacking. Results are similar when using a non-parametric Wilcoxon rank sum test (p<.001) M1.5. Confounding, mediation, interaction. There is a lot of confusion on these issues. I think that it is agreeable that AP randomization, country, age, baseline weight, parity at PROMISE entry and plasma HIV-1RNA level are potential confounders. There is some evidence that AP randomization and baseline weight are effect modifiers for the primary endpoint while age and baseline weight for the secondary endpoint (Table 2). Therefore, these should be removed as confounders from the two analyses, respectively. Regarding the values measured at week 74, none of these should be included as confounders or as stratification factors in the subgroup analyses: breastfeeding status and current receipt of TDF are time-dependent confounders, so a standard regression analysis is unable to control for the possible introduced bias. Current weight, time and use of contraceptive are even potential mediators in the causal pathway between TDF and BMD change so should not be controlled for and cannot be evaluated as possible effect modifiers. On top of this, there should be consistency between text (Methods lines 176-178 vs. Discussion, lines 286-287) and the footnote of Figure 1 and what shown in Table 2 regarding the various adjustments. M1.5 Response: The study team has taken your comments into consideration and removed post-randomization covariates from Table 2 and Figure 2. We removed also the main effects baseline adjusted analysis from Figure 2. Please see the new Tables and Figures submitted. The inconsistent text between Methods and Discussion has been reconciled by removing the factors listed in the Discussion, reflected in the first two highlighted paragraphs in the manuscript. M1.6. If authors are really worried about drop-outs they should perform a per-protocol analysis controlling for cross-over dilution and possible informative censoring. M1.6 Response: Subgroup results for lumbar spine BMD among participants who remained on their assigned regimen, and who ceased breastfeeding from Table 2 were moved to the Results section line 318-323 in the highlighted manuscript. Also, we thank this reviewer for pointing out that the dilution of the effect due to people initially allocated to control and subsequently initiating TDF appears to be a conservative bias and have added this point to the Discussion lines 330-331 in the highlighted manuscript. M1.7. What is a change in BMD that can be considered as clinically relevant? In line 320 this is set to be as 5-7%. The actual estimate from the analysis in in the range of 2-3%, the long-term clinical implication of which are said to be unknown (lines 289-291). If this is the case than the study only shows a statistical difference which has unclear clinical implications and contradicts the conclusions. M1.7 Response: The reviewer is correct; we do not think that the difference had an immediate clinical implication and the long-term effect remains unknown. The conclusion has been reworded to make that clear in lines 341-349 in the highlighted manuscript. M1.8. Because INSTI have replaced PI/r even in resource limited settings, will TDF have a similar impact on BMD in the future? M1.8 Response: That remains to be seen. Our findings can’t be used to speculate the effect on BMD when TDF is combined with other ARV agents. This has been clarified in the revised Limitations section of the Discussion in lines 389-396. Other points O1.1. Line 139. A P is missing (P1084 sub-study). O1.1 Response: Corrected. Thank you for pointing out this typographical error which is rectified in the highlighted manuscript. O1.2. Lines 180-181. Most statisticians are moving away for the concept of a threshold for significance such as the arbitrary 0.05 cut-off. Best to speak more generally about compatibility of the data with the null hypothesis. O1.2 Response: Since our analysis pre-specified a 0.05 significance level, we have left this statement in the manuscript. However, we reviewed and revised statements in the text about significance in the Results and Discussion sections and, for example, the Conclusion was revised by deleting the word significantly; ‘significantly greater’. O1.3. Lines 321-322. Despite the lack of evidence for an interaction (the study was not powered to detect these), percent BMD change in Malawi appeared to be much smaller than that seen in other countries for the primary endpoint (Table 2). O1.3 Response: We note this comment and inserted this observation in Results section lines 310-312 in the highlighted manuscript. O1.4. Table 2. Typically this is shown as a forest plot, instead of a Table, although this mainly pertains to style O1.4 Response Thank you for that suggestion which we have accepted. Table 2 has been replaced with forest plots (Figure 3A and 3B). 01.5. Figure 2. Unusual to show box-plots (medians, IQR) when the assumption is that the distribution of a percentage change is approximately normal so that means and SD are shown and means compared (see main point 4 above). O1.5 Response Thank you for your comment. We presented the boxplots for descriptive purposes. To provide more information on the distribution (see Comment M1.4) we have substituted the box plots with violin plots. These violin plots present density, quartiles, median, mean with 95% CI whiskers, and individual data points (please see revised Figure 2). Reviewer #2— General Comment This paper evaluated the impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in the IMPAACT P1084s sub-study of the PROMISE randomized trial. In general, pregnancy itself may lead to bone loss but if followed by lactation, it will have protective effect on bone density while the duration of lactation and parity may modulate its effect. In this study, having being exposed to TDF-ART during 74-week postpartum breastfeeding led to significant declines (-2.5 to 3 percent lower) than having being exposed to nevirapine alone. General response: No response needed to this summary from the reviewer. Specific comments 2.1. Although randomization and number of participants may have overcome bias, no data on diet or physical activity, calcium and vitamin D status or supplements are given. 2.2 Response: Calcium status is added to the baseline characteristics in Table 1. Data on diet, physical activity and Vitamin D status are not available at this time. The protocol did not specify supplements to be given, inserted to the Methods section line 151 in the highlighted manuscript. 2.2. More importantly than knowing the percent decrease in bone mineral density would have been which the clinical impact was: changes from normal to osteopaenia or from osteopaenia to osteoporosis, and incident bone fractures. 2.2 Response: The reviewer is correct; ultimately it is the clinical implications of bone loss that are important. To respond to this comment, incident fractures through exit from the PROMISE main study are summarized for each study arm in the Results section in lines 273-275 in the highlighted manuscript. Standardized outcome data on this population of young women who breastfeed are lacking, hence the clinical relevance of meeting traditional thresholds for osteopaenia or osteoporosis is unclear. The period of follow-up in this study was relatively short to document the full effect of TDF-ART on maternal bone health, especially the implications on bone loss following menopause. However, our data contribute towards understanding its role and remain a valuable addition to knowledge. The Conclusion has been revised to state what research questions remain unanswered in lines 400-407. Attachments Attachment Submitted filename: Response to Reviewers_PONE-D-20-15228 (R1).docx https://doi.org/10.1371/journal.pone.0246272.r002
18 Jan 2021 Decision Letter - Esteban Martinez, Editor Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial PONE-D-20-15228R1 Dear Dr. Stranix-Chibanda, 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, Esteban Martinez Guest Editor PLOS ONE Additional Editor Comments (optional): I declare that I participated as a reviewer for the initial evaluation of this manuscript. Authors have adequately addressed reviewers' comments and have provided satisfactory responses to queries. The manuscript has been definitely improved and is worth to publish now. Reviewers' comments: https://doi.org/10.1371/journal.pone.0246272.r003
Formally Accepted
22 Jan 2021 Acceptance Letter - Esteban Martinez, Editor PONE-D-20-15228R1 Impact of postpartum tenofovir-based antiretroviral therapy on bone mineral density in breastfeeding women with HIV enrolled in a randomized clinical trial Dear Dr. Stranix-Chibanda: I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department. 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 plosone@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 Professor Esteban Martinez Guest Editor PLOS ONE https://doi.org/10.1371/journal.pone.0246272.r004

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