Early antiretroviral therapy for HIV-infected patients admitted to an intensive care unit (EARTH-ICU): A randomized clinical trial

Márcio M. Boniatti; José Augusto S. Pellegrini; Leonardo S. Marques; Josiane F. John; Luiz G. Marin; Lina R. D. M. Maito; Thiago C. Lisboa; Lucas P. Damiani; Diego R. Falci

doi:10.1371/journal.pone.0239452

Peer Review History

Original SubmissionMarch 9, 2020
29 May 2020 Decision Letter - Felipe Dal Pizzol, Editor PONE-D-20-06158 Early antiretroviral therapy for HIV-infected patients admitted to an intensive care unit (EARTH-ICU): a randomized clinical trial PLOS ONE Dear Dr. Boniatti, 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. The reasons why of early termination should be adequately explained and discussed Please submit your revised manuscript by Jul 13 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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We will update your Data Availability statement on your behalf to reflect the information you provide. [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 Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: No ****** 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 ****** 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 well-written study describing the results of a clinical trial to compare outcomes in ICU patients with differing onsets of ART initiation. The study addresses the data from a meta-analysis (Andrade, 2017) on the topic that indicated benefit for initiation of ART in the ICU. The study protocol is well described but recruitment to reach the calculated sample size of 172 patients per group was prematurely ended due to low enrollment with only 115 patients randomized. The failure to enroll the requisite number of patients compromises the trial design and this should be clearly stated in the abstract and throughout the manuscript. The authors need to further explain their rationale for early termination of the trial. Minor comments: Page 4, line 4 – the meaning of “inability to use the gastrointestinal tract” should be clarified. Page 8 - the meaning of “…patients admitted for AIDS-defining illnesses and with poor immunoblot status…” Reviewer #2: Overall, the methods and analyses seem to be performed well. I had a few comments with the aim of improving the description or methods. 1. (p.5) The language here suggests the trial was stopped early because of futility, but on p.6 the says the trip was stopped early due to slow recruitment. I suggest clearing this up and making sure these statements correspond with each other. Also, if there was some sort of planned interim analysis, please describe the criteria that were a priori chosen to stop for futility. 2. (p.6) Your variable selection appears to be a combination of bivariate screening and stepwise variable selection. With the sample sizes you have, stepwise variable selection procedures usually do not do a good job of finding the most appropriate model (e.g., https://doi.org/10.1002/sim.3943). Stepwise procedures and any p-value based selection have quite a bit of evidence suggesting that they are poor at selecting the appropriate variables. For a decent summary, see the link above. Bivariate screening is really just a form of stepwise selection. Sun et al. (http://dx.doi.org/10.1016/0895-4356(96)00025-X) found that bivariate screening can miss a variable that may be a confounder even when a p-value is as high as what you have. Generally, it's better to select based on more robust criteria, especially measures which assess the fit of the model or, better yet, a shrinkage-based estimator such as lasso or lars. I don't know where in SPSS this can be fit, but in R the glmnet package can do it. 3. (p.6) Although I know this is used quite a bit, I don't understand the term "independent predictors" in a multivariable model since the effect is dependent on the other predictors in the model. I recommend something along the lines of "after controlling for other factors". Also, I don't think it's "after multivariate analysis" makes sense since you are pulling the information from the model. Maybe "in the multivariate analysis". 4. It felt like survival analysis might have been a useful analysis in this trial. I'm curious if this was considered. I'm not sure the results would change, but it would seem the timing of the outcomes could have an impact. 5. Although the tables are pretty standard, I feel as though they need more descriptive titles. For instance, table 2 should say what the numbers are and what tests are used for the p-values. Probably some info on the sample as well. Table 3 should mention the statistical analyses used. ****** 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. https://doi.org/10.1371/journal.pone.0239452.r001
Revision 1
19 Aug 2020 Author Response Please provide additional details regarding participant consent. In the ethics statement in the Methods and online submission information, please ensure that you have specified whether consent was written or verbal/oral. If consent was verbal/oral, please specify: 1) whether the ethics committee approved the verbal/oral consent procedure, 2) why written consent could not be obtained, and 3) how verbal/oral consent was recorded. If your study included minors, please state whether you obtained consent from parents or guardians in these cases. The informed consent was written. We made this clearer in the manuscript. We note that you have indicated that data from this study are available upon request. PLOS only allows data to be available upon request if there are legal or ethical restrictions on sharing data publicly. For information on unacceptable data access restrictions, please see http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. In your revised cover letter, please address the following prompts: a) If there are ethical or legal restrictions on sharing a de-identified data set, please explain them in detail (e.g., data contain potentially identifying or sensitive patient information) and who has imposed them (e.g., an ethics committee). Please also provide contact information for a data access committee, ethics committee, or other institutional body to which data requests may be sent. b) If there are no restrictions, please upload the minimal anonymized data set necessary to replicate your study findings as either Supporting Information files or to a stable, public repository and provide us with the relevant URLs, DOIs, or accession numbers. Please see http://www.bmj.com/content/340/bmj.c181.long for guidelines on how to de-identify and prepare clinical data for publication. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. We will update your Data Availability statement on your behalf to reflect the information you provide. We made the manuscript data available through file upload (as Supporting Information file). Reviewer #1: This is a well-written study describing the results of a clinical trial to compare outcomes in ICU patients with differing onsets of ART initiation. The study addresses the data from a meta-analysis (Andrade, 2017) on the topic that indicated benefit for initiation of ART in the ICU. The study protocol is well described but recruitment to reach the calculated sample size of 172 patients per group was prematurely ended due to low enrollment with only 115 patients randomized. The failure to enroll the requisite number of patients compromises the trial design and this should be clearly stated in the abstract and throughout the manuscript. The authors need to further explain their rationale for early termination of the trial. We appreciate the reviewer's comments. We made it clearer in the abstract and in the manuscript that the premature interruption of the trial may have compromised the results. Minor comments: Page 4, line 4 – the meaning of “inability to use the gastrointestinal tract” should be clarified. We replaced "inability to use the gastrointestinal tract" by impossibility to use the enteral route Page 8 - the meaning of “…patients admitted for AIDS-defining illnesses and with poor immunoblot status…” We replaced "…patients admitted for AIDS-defining illnesses and with poor immunoblot status…" by "patients admitted for AIDS-defining illnesses and with low CD4+ cell count" Reviewer #2: Overall, the methods and analyses seem to be performed well. I had a few comments with the aim of improving the description or methods. 1. (p.5) The language here suggests the trial was stopped early because of futility, but on p.6 the says the trip was stopped early due to slow recruitment. I suggest clearing this up and making sure these statements correspond with each other. Also, if there was some sort of planned interim analysis, please describe the criteria that were a priori chosen to stop for futility. We made it clearer that the trial interruption was due to a progressively slower recruitment rate. We did not perform interim analysis. 2. (p.6) Your variable selection appears to be a combination of bivariate screening and stepwise variable selection. With the sample sizes you have, stepwise variable selection procedures usually do not do a good job of finding the most appropriate model (e.g., https://doi.org/10.1002/sim.3943). Stepwise procedures and any p-value based selection have quite a bit of evidence suggesting that they are poor at selecting the appropriate variables. For a decent summary, see the link above. Bivariate screening is really just a form of stepwise selection. Sun et al. (http://dx.doi.org/10.1016/0895-4356(96)00025-X) found that bivariate screening can miss a variable that may be a confounder even when a p-value is as high as what you have. Generally, it's better to select based on more robust criteria, especially measures which assess the fit of the model or, better yet, a shrinkage-based estimator such as lasso or lars. I don't know where in SPSS this can be fit, but in R the glmnet package can do it. The selection of variables for the initial model was based on a combination of biological plausibility and bivariate screening. The regression model was then constructed through stepwise forward. We agree with the reviewer that stepwise forward selection may not be the most appropriate. We applied LASSO as requested by the reviewer. The R script is below: library(glmnet) library(ggplot2) # Modelo LASSO Hospital Mortality data_EARTHICU <- read.csv("~/Downloads/data_EARTHICU.csv", sep=";") data_EARTHICU xfactors <- model.matrix(data_EARTHICU$Hospital_mortality ~ data_EARTHICU$age + data_EARTHICU$control_treatment_group + data_EARTHICU$origin_ward + data_EARTHICU$AIDSrelated + data_EARTHICU$tuberculosis + data_EARTHICU$pneumocystosis + data_EARTHICU$cryptococosis + data_EARTHICU$saps3 + data_EARTHICU$cd4adm + data_EARTHICU$sepsis + data_EARTHICU$shock + data_EARTHICU$dialysis + data_EARTHICU$MV_adm + data_EARTHICU$ards)[, -1] glmmod <- glmnet(xfactors, y=as.factor(data_EARTHICU$Hospital_mortality), alpha=1, family="binomial") plot(glmmod, xvar="lambda") coef(glmmod)[, 14] # Modelo LASSO 6-month mortality data_EARTHICU6 <- read.csv("~/Downloads/data_EARTHICU6.csv", sep=";") xfactors6 <- model.matrix(data_EARTHICU6$Mortality_6_month ~ data_EARTHICU6$age + data_EARTHICU6$control_treatment_group + data_EARTHICU6$origin_ward + data_EARTHICU6$AIDSrelated + data_EARTHICU6$tuberculosis + data_EARTHICU6$pneumocystosis + data_EARTHICU6$cryptococosis + data_EARTHICU6$saps3 + data_EARTHICU6$cd4adm + data_EARTHICU6$sepsis + data_EARTHICU6$shock + data_EARTHICU6$dialysis + data_EARTHICU6$MV_adm + data_EARTHICU6$ards)[, -1] glmmod6 <- glmnet(xfactors6, y=as.factor(data_EARTHICU6$Mortality_6_month), alpha=1, family="binomial") plot(glmmod6, xvar="lambda") coef(glmmod6)[, 14] The coefficients for hospital mortality suggest the original model presented is OK, with only dyalisis and shock. LASSO regression coefficients are shown below: > coef(glmmod)[, 14] (Intercept) data_EARTHICU$age -0.475622602 0.006561752 data_EARTHICU$control_treatment_group data_EARTHICU$origin_ward 0.000000000 0.000000000 data_EARTHICU$AIDSrelated data_EARTHICU$tuberculosis 0.000000000 0.081332622 data_EARTHICU$pneumocystosis data_EARTHICU$cryptococosis 0.000000000 0.241028316 data_EARTHICU$saps3 data_EARTHICU$cd4adm 0.000000000 -0.002027852 data_EARTHICU$sepsis data_EARTHICU$shock 0.190074265 0.884827694 data_EARTHICU$dialysis data_EARTHICU$MV_adm 0.664720062 0.000000000 data_EARTHICU$ards 0.000000000 The LASSO coefficients for 6 mo mortality suggest that cryptococcosis should also remain in the final model with dyalisis, shock and tuberculosis. LASSO Coefficients are shown below: > coef(glmmod6)[, 14] (Intercept) data_EARTHICU6$age -0.15380567 0.00000000 data_EARTHICU6$control_treatment_group data_EARTHICU6$origin_ward 0.06275091 0.00000000 data_EARTHICU6$AIDSrelated data_EARTHICU6$tuberculosis 0.00000000 0.71715198 data_EARTHICU6$pneumocystosis data_EARTHICU6$cryptococosis 0.00000000 0.64094844 data_EARTHICU6$saps3 data_EARTHICU6$cd4adm 0.00000000 0.00000000 data_EARTHICU6$sepsis data_EARTHICU6$shock 0.00000000 0.69197132 data_EARTHICU6$dialysis data_EARTHICU6$MV_adm 0.98541680 0.00000000 data_EARTHICU6$ards 0.00000000 In the original logistic regression model presented, cryptococcosis bivariate OR was uncomputable and was removed from the final model due to numerical instability as this variable had an infinite estimated coefficient. This analysis will be available in supplementary material. 3. (p.6) Although I know this is used quite a bit, I don't understand the term "independent predictors" in a multivariable model since the effect is dependent on the other predictors in the model. I recommend something along the lines of "after controlling for other factors". Also, I don't think it's "after multivariate analysis" makes sense since you are pulling the information from the model. Maybe "in the multivariate analysis". We agreed with the reviewer and made the changes as suggested. 4. It felt like survival analysis might have been a useful analysis in this trial. I'm curious if this was considered. I'm not sure the results would change, but it would seem the timing of the outcomes could have an impact. We added the survival analysis as Supplemental File. exp(coef) exp(-coef) lower .95 upper .95 arv$control_treatment_group 0.8591 1.1641 0.5250 1.406 5. Although the tables are pretty standard, I feel as though they need more descriptive titles. For instance, table 2 should say what the numbers are and what tests are used for the p-values. Probably some info on the sample as well. Table 3 should mention the statistical analyses used. We added the information in the tables as suggested by the reviewer. Attachments Attachment Submitted filename: Response to reviewers.docx https://doi.org/10.1371/journal.pone.0239452.r002
8 Sep 2020 Decision Letter - Felipe Dal Pizzol, Editor Early antiretroviral therapy for HIV-infected patients admitted to an intensive care unit (EARTH-ICU): a randomized clinical trial PONE-D-20-06158R1 Dear Dr. Boniatti, 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, Felipe Dal Pizzol 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 #1: All comments have been addressed Reviewer #2: All comments have been addressed ******** 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: (No Response) ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: (No Response) 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 #1: (No Response) Reviewer #2: (No Response) ****** 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: (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 #1: (No Response) Reviewer #2: (No Response) ****** 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 #2: No https://doi.org/10.1371/journal.pone.0239452.r003
Formally Accepted
10 Sep 2020 Acceptance Letter - Felipe Dal Pizzol, Editor PONE-D-20-06158R1 Early antiretroviral therapy for HIV-infected patients admitted to an intensive care unit (EARTH-ICU): a randomized clinical trial Dear Dr. Boniatti: 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 Dr. Felipe Dal Pizzol Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0239452.r004

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