A randomized pilot trial to evaluate the benefit of the concomitant use of atorvastatin and Raltegravir on immunological markers in protease-inhibitor-treated subjects living with HIV

Eugènia Negredo; Montse Jiménez; Jordi Puig; Cora Loste; Núria Pérez-Álvarez; Victor Urrea; Patricia Echeverría; Anna Bonjoch; Bonaventura Clotet; Julià Blanco

doi:10.1371/journal.pone.0238575

Peer Review History

Original SubmissionJanuary 29, 2020
13 Mar 2020 Decision Letter - Alan Winston, Editor PONE-D-20-01200 Limited Benefit of the Concomitant Use of Atorvastatin and Raltegravir on Immunological Markers in Treated Subjects living with HIV. PLOS ONE Dear Dr Negredo, 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. We would appreciate receiving your revised manuscript by Apr 27 2020 11:59PM. When you are 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. If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. 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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: Partly ******** 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: No ****** 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: Negredo et al present a pilot trial to assess the concomitant use of atorvastatin and raltegravir on immunological markers in treated subjects living with HIV switching from PI. The idea to combine two potentially effective strategies options is original and merit consideration for publication, regardless negative results in reducing inflammation and immune activation. Some issues should be considered to improve understanding of methods and overall discussion. 1. Title should mention that PLWH were PI-experienced. 2. Inclusion criteria should specify if all the patients were Raltegravir and statine naïve. 3. Table 1 should mention the cardiovascular risk profile of the patients and the proportion of the individuals offered statine regardless of dyslipidemia or low CVR. 4. It should be mention why a LDL cut off of 160 mg was chosen for stratification and be consistent through the paper when using mg of mmol units . 5. Line 284-294 is in fact part of the background and can be summarized in this section. 6. Background should mention the relevance of using IL6 as the primary end point of the study 7. It is not clear why mentioning data regarding BMD 8. Limitation should mention not using hsCRP and the possible low dose of statine which has been used (it was mentioned the fear of statines’ toxicities) 9. Line 256 which discuss the choice of using a mix linear iodel should be anticipated in statistical methods 10. Figured have low resolution and are difficult to be read. All together the paper is well written and contributes to the research in the field of inflammaging in HIV Reviewer #2: The authors evaluated the impact of switching from a Protease Inhibitor based regimen to raltegravir and addition of atorvastatin on metabolic disorders, inflammation and immune activation in people living with HIV. There was no power calculation done as this was a pilot study. That in itself is not a problem as long as the authors are aware that they can only describe their results without attempting formal comparisons between groups. However the authors have tried to demonstrate differences between the two arms despite the study not being powered to do so. Table 1: Change ‘drug users’ to either drug use or injecting drug use Line 199: sentence relating to CD4 count should be revised for clarity Line 201 Authors stated: Eight participants early discontinued the study protocol This should be revised to ‘eight participants discontinued the study protocol early Line 203: bad adherence should be changed to poor adherence Line 224 & Table 2, line 527 authors should avoid comments like ‘no SIGNIFICANT differences were observed between groups or time points’. The study was not powered to detect differences between groups. The presentation of the results should be purely descriptive without need of any formal statistical tests to assess differences between groups Lines 231/232: No significant changes in absolute counts or percentages of CD4 and CD8 T cells, either intragroup or intergroup were observed at any time point. The authors should remove the word significant. I would not read too much meaning into the significant difference reported in lines 239, 254 and 259. Line 266: The sample size is too small to examine for any meaningful interaction. OK, the authors pointed this out, so no need to even report this in the paper. Lines 275 to 277: This should be reported as differences in lipid parameters rather than whether significant or not. Sample is too small to detect any significant change in BMD. The discussion of the findings should be presented bearing in mind that lack of a difference does not mean a difference does not truly exist but the study was not powered to detect any difference. Any significant differences observed with some measured parameters could have just been due to chance. I suggest the discussion is moderated accordingly. ****** 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. 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Revision 1
27 Jul 2020 Author Response Reviewer #1: Negredo et al present a pilot trial to assess the concomitant use of atorvastatin and raltegravir on immunological markers in treated subjects living with HIV switching from PI. The idea to combine two potentially effective strategies options is original and merit consideration for publication, regardless negative results in reducing inflammation and immune activation. We thank the reviewer for his/her comments. Some issues should be considered to improve understanding of methods and overall discussion. 1. Title should mention that PLWH were PI-experienced. Authors have included this information in the title. 2. Inclusion criteria should specify if all the patients were Raltegravir and statine naïve. The following exclusion criterium was already included in Methods: “.... and therapy with statins within the last 6 months”. Following the reviewer’s comment, authors have added raltegravir as a exclusion criteria: “.... and therapy with statins and raltegravir within the last 6 months” (Methods section). 3. Table 1 should mention the cardiovascular risk profile of the patients and the proportion of the individuals offered statine regardless of dyslipidemia or low CVR. Table 1 already includes information about lipid profile. In addition, the proportion of individuals with baseline LDL-cholesterol >160mg/dL, according to the study group, has been included in Table 1, following the reviewer suggestion. Only 2 (9%) patients from the Control group and 1 (5%) patient from the Raltegravir group presented LDL>160 at baseline, that was always <170 during the follow up. Unfortunately, no data about proportion of patients with hypertension are available. 4. It should be mention why a LDL cut off of 160 mg was chosen for stratification and be consistent through the paper when using mg of mmol units. LDL cut off of 160 mg was chosen for stratification since LDL cholesterol 130-159 mg/dL is considered borderline high and >160 mg/dL is considered high for people without cardiovascular risk factors. This information has been added to the Methods section. All units have been changed to mg/dL in Table 1. 5. Line 284-294 is in fact part of the background and can be summarized in this section. This entire paragraph has been moved at the end of the Introduction to justify the purpose of the current study. 6. Background should mention the relevance of using IL6 as the primary end point of the study A brief sentence highlighting the key role of IL-6 has been included in the Introduction section with a reference to justify it. 7. It is not clear why mentioning data regarding BMD. Following the suggestion of both reviewers, sentences describing changes in BMD have been removed from methods and result sections since no additional data were provided. 8. Limitation should mention not using hsCRP and the possible low dose of statine which has been used (it was mentioned the fear of statines’ toxicities). We have reinforced this limitation by including the reason why we used low doses of atorvastatin (to avoid toxicities) in the paragraph describing the limitations of the study. 9. Line 256 which discuss the choice of using a mix linear iodel should be anticipated in statistical methods A brief description of methods has been included in the Methods section, as follow: “Longitudinal comparisons were performed by linear mixed effects models.” 10. Figured have low resolution and are difficult to be read. The resolution of figures has been improved. All together the paper is well written and contributes to the research in the field of inflammaging in HIV Reviewer #2: The authors evaluated the impact of switching from a Protease Inhibitor based regimen to raltegravir and addition of atorvastatin on metabolic disorders, inflammation and immune activation in people living with HIV. There was no power calculation done as this was a pilot study. That in itself is not a problem as long as the authors are aware that they can only describe their results without attempting formal comparisons between groups. However the authors have tried to demonstrate differences between the two arms despite the study not being powered to do so. Table 1: Change ‘drug users’ to either drug use or injecting drug use. This term has been changed. Thanks. Line 199: sentence relating to CD4 count should be revised for clarity. In text, the overall mean CD4 T cells count and nadir values of all participants has been described while in Table 1, we described the mean values in each study group. Sentence has been modified for clarity. Line 201 Authors stated: Eight participants early discontinued the study protocol. This should be revised to ‘eight participants discontinued the study protocol early. Authors have changed the sentences following the reviewer’s comment. Line 203: bad adherence should be changed to poor adherence. Authors have changed the sentences following the reviewer’s comment. Line 224 & Table 2, line 527 authors should avoid comments like ‘no SIGNIFICANT differences were observed between groups or time points’. The study was not powered to detect differences between groups. The presentation of the results should be purely descriptive without need of any formal statistical tests to assess differences between groups Lines 231/232: No significant changes in absolute counts or percentages of CD4 and CD8 T cells, either intragroup or intergroup were observed at any time point. The authors should remove the word significant. I would not read too much meaning into the significant difference reported in lines 239, 254 and 259. Following the reviewer comment, the word significant has been removed when describing difference between groups throughout the manuscript. Line 266: The sample size is too small to examine for any meaningful interaction. OK, the authors pointed this out, so no need to even report this in the paper. The sentence describing the analysis of interaction has been removed. Lines 275 to 277: This should be reported as differences in lipid parameters rather than whether significant or not. Following the reviewer comment, the word significant has been removed when describing difference between groups throughout the manuscript. Sample is too small to detect any significant change in BMD. Following the suggestion of both reviewers, the sentences describing changes in BMD have been removed from methods (Objectives) and result sections. The discussion of the findings should be presented bearing in mind that lack of a difference does not mean a difference does not truly exist but the study was not powered to detect any difference. Any significant differences observed with some measured parameters could have just been due to chance. I suggest the discussion is moderated accordingly. Discussion has been modified by removing any reference to significant changes between groups, and highlighting the minimal longitudinal changes observed (as mention in the conclusions). Attachments Attachment Submitted filename: Reviewers RALATOR.docx https://doi.org/10.1371/journal.pone.0238575.r002
20 Aug 2020 Decision Letter - Alan Winston, Editor A Randomized Pilot Trial to Evaluate the Benefit of the Concomitant Use of Atorvastatin and Raltegravir on Immunological Markers in Protease-Inhibitor-Treated Subjects living with HIV PONE-D-20-01200R1 Dear Dr. Negredo, 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, Alan Winston Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0238575.r003
Formally Accepted
4 Sep 2020 Acceptance Letter - Alan Winston, Editor PONE-D-20-01200R1 A Randomized Pilot Trial to Evaluate the Benefit of the Concomitant Use of Atorvastatin and Raltegravir on Immunological Markers in Protease-Inhibitor-Treated Subjects living with HIV. Dear Dr. Negredo: 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 Prof. Alan Winston Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0238575.r004

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