PONE-D-22-26706Effect of antiretrovirals on the regression of arterial stiffness, metabolic, vascular, and systemic inflammatory cytokines at one year of virologic controlPLOS ONE

Dear Dr. Andrade-Villanueva, 

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.

==============================

Dear Dr. Andrade,

Thank you for submit your manuscript to PLOS One. Both reviewers are experts in the area and I hope you and your group appreciate the constructive and positive comments to your work. Please make the suggested changes if you agreed. If you do not agreed please contact me to discussed with the group.

Best Regards,

Eliseo Eugenin

==============================

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Eliseo A Eugenin, Ph.D.

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PLOS ONE

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Reviewers' comments:

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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

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2. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

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3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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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: Effect of antiretrovirals on the regression of arterial stiffness, metabolic, vascular, and systemic inflammatory cytokines at one year of virologic control

Pedro Martínez-Ayala PlosOne

HIV creates an increase inflammation with vascular consequences and been only partially reversed by ART. Such inflammation is driven by HIV itself and also by leaky gut allowing microbial translocation of bacterial and fungus products.

Investigators assessed the effect of one-year treatment-naïve HIV individuals on arterial stiffness and inflammatory and vascular cytokines. tonometry, inflammatory, and vascular serum cytokines on treatment-naïve (n=20) and HIV uninfected (n=9) age matched control with metabolic profile, and Framingham score evaluation.

Study findings indicate that ART had a significant effect on reducing inflammatory and most vascular cytokines and arterial stiffness.

Comments:

As nearly half of participants receive and NNRT vs PI comparison of these 2 groups will be of interest as PI increased cholesterol and have a cumulative risk for CV events.

The difficulty of such studies with many markers only a few fit with the study hypothesis. Here the 2 inflammatory markers linked with non-AIDS events d-dimers and IL-6 were not different. Discussion on these 2 validated markers for CVV risks should be discussed in detail.

LPS, sCD14 and beta-d-glucan play an important role in HIV-related inflammation and are linked with CV risk by imaging. Measurement of these markers will add value to the manuscript

Isnard S, et al. Circulating β-d-Glucan as a Marker of Subclinical Coronary Plaque in Antiretroviral Therapy-Treated People With Human Immunodeficiency Virus. Open Forum Infect Dis. 2021 Mar 7;8(6):ofab109.

Isnard S, et al. Gut Leakage of Fungal-Related Products: Turning Up the Heat for HIV Infection. Front Immunol. 2021 Apr 12;12:656414.

In addition, the stress cytokine GDF-15 emerges as one of the best markers in CV disorders: ischemic conditions, atrial fibrillation and cardiac insufficiency and in 2022 in HIV. Assessment of one the best CV markers will be welcome for this study.

Royston L, . Growth differentiation factor-15 as a biomarker of atherosclerotic coronary plaque: Value in people living with and without HIV. Front Cardiovasc Med. 2022 Aug 26;9:964650.

Discussion is much too long and should not be structured, no subchapters are necessary. Investigators should focus only on novelty as many data are confirming previous findings.

Increased in Cholesterol and TG are considered to augment as return to health at one year as generally patients gain 2 kg initially taken for HIV. Therefore, early changes are not linked to inflammation or PI effects on lipids after one year of ART.

Limitations: absence of cellular markers of adaptative and innate immunity.

As cells were not assessed a small paragraph on the role of adaptive immunity cells, such as CD4 cells are acknowledged to participate to CVD pathogenesis (Emeson et al., 1996; Zhou et al., 2005). CD4 cells were found infiltrated in atherosclerotic plaques (Saigusa et al., 2020). Recent evidence indicates that T helper 1 (Th1) cells have pro-atherogenic roles, whereas regulatory T cells (Tregs) can play a dual role being both anti-atherogenic or pro-atherogenic (George et al., 2012; Maganto-Garcia et al., 2011).

Similarly in HIV, innate immunity: Elevated frequency of circulating non-classical monocytes (CD14dimCD16++) (Gu et al., 1998) and the intermediate CD14+CD16+ monocyte counts were associated to subclinical atherosclerosis (Hanna et al., 2017) and the expression of CX3CR1 on CD16+ monocytes predicted carotid artery thickness (Westhorpe et al., 2014)

Reviewer #2: This is important research. The study provides novel, prospective data in the field of HIV-associated CVD and warrants publication, even considering the relatively small number of participants. I do however think the manuscript could be improved before publication.

Major Comments:

My biggest concern is how the group of 20 HIV infected persons were recruited. The authors mention prior work with 51 individuals. Were these persons included from the prior cohort or are the participants all new? How were they selected if previously enrolled? Was everyone that was recruited followed up fully and included? Attrition? This needs to be discussed that possible bias may be evaluated. If they were chosen based on viral suppression alone, comparison with a virally unsuppressed group will be valuable and should be strongly considered.

A significant limitation is the fact that the study essentially only included males. This should be discussed as a significant limitation as sex-differences were not evaluated and females are already significantly under-represented in CV research.

There were isolated delta (change over time) correlations mentioned , however, I miss a dedicated correlation analysis. Relevant correlations (or lack thereof) needs to be reported. Viral load, CD4 count, smoking, inflammatory markers, vascular markers and aortic stiffness?

Varying ways of referring to HIV infected persons and the HIV cohorts are used in manuscript. Decide on terminology and use this consistently.

NB: Mean CD4 count in table 1 is different to what is written in the abstract and the manuscript text.

The discussion section is too long and reads as quite meandering. Every section should have a clear message and build on the message of the article. The final message of the article should be clear, and I think the authors should work on the conclusion (both in the abstract and the manuscript) to clearly summarise what they think their findings mean.

Comments:

Introduction:

line 58-59: Unreferenced, inaccurate statement. CVD is not the leading cause of death in HIV. Rather say one of the leading causes of CVD.

line 65 onward: Needs rewrite to clarify. There are sweeping statements without references and should be avoided. Smoking (as the authors mention later) has been associated with HIV in certain studies. This sentence reads as contradictory.

line 68: reference please

line 69 onward: Tonometry-based cfPWV is frequently employed in clinical research, but is not considered to be the definitive method of PWV measurement as it is implied in the text. The statement in the manuscript should be corrected to only read: 'cfPWV is considered the gold standard of aortic stiffness measurement.' Consensus has not been reached as to the definitive method to measure cfPWV and various techniques are well described.

read

Rajzer, Marek W; Wojciechowska, Wiktoria; Klocek, Marek; Palka, Ilona; Brzozowska-Kiszka, Małgorzata; Kawecka-Jaszcz, Kalina (2008). Comparison of aortic pulse wave velocity measured by three techniques: Complior, SphygmoCor and Arteriograph. Journal of Hypertension, 26(10), 2001–2007. doi:10.1097/hjh.0b013e32830a4a25

line 77: Sparse work is available from low- and middle income countries, however, recent data have shown similar findings in sub-Saharan Africa. This may serve to strengthen your rationale for the research:

read

Robbertse PS, Doubell AF, Innes S, et al. Pulse wave velocity demonstrates increased aortic stiffness in newly diagnosed, antiretroviral naïve HIV infected adults: A case-control study. Medicine. 2022; 101:e29721.

line 113, 148 and other locations: Define all abbreviations with first use.

line 150: p-value of <0.05

line 153-155: This does not seem correct. Paired samples t-test with 80% power to detect a 0.6m/s difference and the quoted SD with alpha=0.05, calculates to 29 pairs on SPSS. This is more than double the number quoted in the text.

Results:

Were any of the patients of vasoactive mediation? I think this is a worthwhile to mention, even if no-one was on these medicines.

I find the BMI findings the inverse of what I would expect when compared to the controls. Any ideas why this may be the case in your study?

Not all abbreviations used in the tables are found in the legends. Please double check. Tables should be able to be able to be freestanding from the article and still be easy to interpret.

line 186: p=0.055 is not significant according to your study’s predefined level of significance. Rather state a trend toward significance for accuracy.

line 205: Again, consistent use of wording to refer to the study groups. Post-ART should rather be ART-group or ART-experienced group.

line 208: ‘In the beginning’. Do the authors mean at baseline?

Dedicated correlation analysis is an omission in my opinion as discussed earlier.

Discussion:

I would restructure the first paragraph to emphasise your own novel, longitudinal findings first. The mention of lack of longitudinal studies belong in the introduction. Rather state own strengths, than others weaknesses in this critical paragraph.

line 254: ‘slightly or did not decrease’. Reword this to communicate your findings clearly. Median hs-CRP essentially halved after ART. I would say something like ‘The hs-CRP showed a strong trend towards decrease, however, this did not reach statistical significance. hs-CRP, despite ART, remained significantly higher in ART-experienced persons when compared to the control group.’

line 265-270: This is all true. However, I think the reader would benefit from better packaging of these facts using our current theoretical framework of the factors that underpin cfPWV (especially in light of your young cohort, with likely negligible amounts of atherosclerotic disease). Pressure amplification by peripheral arterial tone. Vasomotor arterial tone is modulated by endothelial function, sympathetic tone, and the RAAS system. The manuscript would benefit from the incorporation of key concepts from the following articles (In general and in the setting of HIV). Use your excellent data to examine some of these concepts and what you think actually drive the increased (and decreased on ART) PWV mechanistically. Your study is explorative and should make the best use of your data.

read:

1. Cavalcante JL, Lima JAC, Redheuil A, et al. Aortic Stiffness. J Am Coll Cardiol. 2011;57:1511–22.

2. Robbertse PS, Doubell AF, Innes S, et al. Pulse wave velocity demonstrates increased aortic stiffness in newly diagnosed, antiretroviral naïve HIV infected adults: A case-control study. Medicine. 2022; 101:e29721.

line 319: reference

line 320: contrasting what? Use clear language.

line 367-368: I would be careful with these strong statements. Your findings do not quite support this and I suggest rewording this statement. I would focus on what you could show: that was that ART had an overall positive effect (decreased vascular pathology markers, decreased markers of inflammation, and decreased cfPWV). The observation that aortic stiffness decreased with ART is important, as this means (as you stated) that a reversible component of aortic stiffness remains and there is likely a window before this becomes irreversible (collagen deposition, degradation of elastin etc). When this window is, remains unknown.

Furthermore, if cfPWV is used a surrogate of CV risk, you demonstrated increased risk compared to HIV uninfected persons at baseline. As cfPWV decreased at one year on ART (in a small group of virally supressed individuals), I would see this as a relative decrease in CV risk. Yet another reason to give ART. The residual risk despite ART is still of concern, and as you mentioned stratification may be an issue, as people on ART have higher CVD compared to those without HIV.

Limitations:

The sample is small and explorative and should be stated in no uncertain terms. Selection of the cohort needs to be more detailed, as there is a perceived risk of inclusion bias.

Typo’s, spelling, and language: Various errors present. I would suggest involving a proof-reader before re-submission.

line 30. PWHIV

line 36. young, treatment-naïve. Not treatment-naïve young.

line 60: envelop

line 211: inflammation. rather biomarkers of inflammation

Minor comments for your discretion:

Title: I miss the word HIV, even though antiretrovirals imply this. I do not agree with the word "regression". Consider rewriting the title to refer to a decrease in aortic stiffness.

line 61: We generally refer to hs-CRP as high-sensitivity CRP, not highly sensitive CRP

line 62: remove increased

line 64: non-related should be unrelated

---

I look forward to the amended version of the manuscript and the inevitable publication of this important research.

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Reviewer #1: Yes: Jean-Pierre Routy

Reviewer #2: No

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PONE-D-22-26706R1Effect of antiretroviral therapy on decreasing of arterial stiffness,  metabolic profile, vascular and systemic inflammatory cytokines in treatment-naïve HIV: A one-year prospective study.PLOS ONE

Dear Dr. Andrade,

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.

==============================

ACADEMIC EDITOR: see comments below

==============================

Please submit your revised manuscript by 1 week. 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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• A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Eliseo A Eugenin, Ph.D.

Academic Editor

PLOS ONE

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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.

Additional Editor Comments (if provided):

Dear Dr. Andrade

Thank you for submit your manuscript to PLOSone. Please add the excellent comments of reviewer 2 and send the manuscript back

Eliseo

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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: (No Response)

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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: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

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: Yes

Reviewer #2: Yes

**********

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: Yes

Reviewer #2: Yes

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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: issues have been addressed including statistics and discussion conclusion.

Prospective data with relatively advanced patients add to current knowledge

Reviewer #2: Thank you for the author's responses to my comments. I am mostly satisfied with the responses and the amendments to the manuscript. The new title is excellent.

I discuss a few comments that still need to be adequately addressed below:

Original comment 1: Recruitment

Thank you for clarifying. Selection bias is be a factor that needs consideration by the reader and merits careful explanation. If the original cohort had 51 participants, the completion rate is 39%. (higher attrition than most HIV research, granted that PLWH are known to have high attrition). The quoted 20% dropout rate is therefore confusing, as the numbers do not add up. Please state how many were lost, withdrew, died, or had incomplete records. I would state this high attrition rate as a limitation of the study - it's higher than to be expected and likely influenced your results.

Original comment 3: Correlation analysis

I see the merit in the argument and agree that a future, larger sample size would be more appropriate for this. Please state explicitly in the methodology that a correlation analysis was not undertaken due to the small sample size in this explorative work.

New comments:

1. Limitations section: "Despite that we aimed to isolate the effect of HIV on arterial stiffness by choosing PLH without any other comorbidities and comparing them with healthy controls, there may be a series of genetic, lifestyle..."

Please improve the language here: My suggestion: "Despite our aim to isolate the effect HIV on arterial stiffness by choosing PLH without any other comorbidities and comparing them with healthy controls, there may be ..."

2. There are new, untracked additions to the manuscript. All changes should be stated or better yet, clearly tracked/highlighted for the editor.

Of note: "The literature vastly describes that ART does not completely suppress viral load, particularly in the viral reservoirs".

This is not in the academic style of writing. Rephrase. I suggest: "It is well described that ART does not completely suppress viral load..."

3. Define all abbreviations with first use: hs-CRP is never defined. hsCRP vs hs-CRP are both used in the manuscript.

4. I still feel the article could receive additional language manicuring. An academic proof reader should be considered.

I look forward to your work in print.

Regards,

**********

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Reviewer #1: Yes: Jean-Pierre Routy

Reviewer #2: No

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Effect of antiretroviral therapy on decreasing arterial stiffness,  metabolic profile, vascular and systemic inflammatory cytokines in treatment-naïve HIV: A one-year prospective study.

PONE-D-22-26706R2

Dear Dr. Andrade,

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.

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Kind regards,

Eliseo A Eugenin, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Dear Dr. Andrade

Thank you for submitting your manuscript to PLOSone and include the changes requested

Eliseo Eugenin

Reviewers' comments: