PONE-D-22-13596

The prevalence of hyperglycemia and its impact on mortality among people living with HIV in Georgia

PLOS ONE

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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

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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?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: No

Reviewer #2: Yes

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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

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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: Increasing prevalence of noncommunicable diseases among people living with HIV is of growing concern globally. The authors aim to characterize the presence of hyperglycemia and its associated risk of mortality among a large cohort of HIV positive individuals in Georgia. Overall, these results fill an important knowledge gap in the current literature and should be published. However, authors should address or take into consideration the comments below:

1) In the introduction, the authors clearly establish an association between specific classes of ART regimens - including PIs, NRTIs, and some NNRTIs - and ART duration with type 2 diabetes. Do the authors have any data on regimen type and/or duration? If so, given this established increased risk of hyperglycemia among people living with HIV with longer exposure to ART and on certain regimens, authors should present median ART duration and ART regimen class in Table 1. If it is found that ART duration and/or class has a statistically significant relationship with hyperglycemia, authors should adjust for these variables in the multivariate analyses.

2) Authors state a major limitation of the paper is the potential underestimation of hyperglycemia because all glucose measurements with unknown fasting information were considered postprandial. In order to give the reader a sense of how much this may have impacted your results, authors should report what % of glucose measurements had unknown fasting information.

3) Per journal requirement, ethics statement needs to be included in the methods section of the manuscript.

4) Per journal requirement, authors need to make all raw data available or provide an explanation to data restrictions.

Reviewer #2: Overall: This is an interesting paper about the prevalence of hyperglycaemia and its impact on people living with HIV. It well-written paper, however, there are some problems with definition of hyperglycemia that need addressing. It highlights the importance of screening for dysglycaemia in individual living with HIV at the entry into care and as a part continually assessment.

Revision

1. Major changes

Line 90-92: Authors should justify why impaired fasting glucose levels were used to define hyperglycaemia. According to the guidelines, the postprandial glucose level > 7.8 mmol/L was based on an oral glucose tolerance test (OGTT) which is not highlighted in this paper.

The use of single point random glucose level may cause a misclassification of some patients as hyperglycaemic. A single high glucose level is less definitive (compared to OGTT or HbA1c) to classify dysglycemia. Consider highlighting this as a limitation of the study.

The authors should clarify if the glucose level considered for analysis was at the entry into HIV care as recommended by National guidelines or at any point during follow-up (or before ART initiation). Because both HIV and ART are implicated in development of hyperglycaemia/diabetes.

2. Minor changes

Abstract

Line 37: Please change 242 to Two hundred and forty-two

Line 38: Also, change 301 to Three hundred one

Introduction

Line 56: Change Type to type 2 diabetes

Line 59: Please change Efavirenz to efavirenz.

Line 59: Write PI, NRTI, and NNRT in full and abbreviate thereafter.

Method

Line 81: What is the percentage of patients that were excluded from the analysis due to loss of follow-up?

Line 93: rewrite ifit as if it

Authors should add the under method that the approval was obtained from the Ethics Committee of the Infectious Disease, AIDS, & Clinical Immunology Research Center.

Results

Line 120-121 (table 1):

• Please update the percentages for the population (total cohort) with hyperglycaemia to 8.3% and adjust accordingly throughout the manuscript including the abstract.

• Age category (30-39)- change 5.3 to 5.4%

• Age category (65+) – change to 25.8 %

Discussion

Line 178-179: The authors should explain the possible reason why they found a lower prevalence of hyperglycaemia compared to other published studies.

Line 190: Consider rephrasing ‘our study cannot be clearly explained’ statement.

Line 192-193: ‘The higher prevalence of hyperlycemia in people with advanced HIV should be interpreted considering previous findings indicating an association between low CD4 count and non-AIDS event’. It sounds there missing phrase? Consider rephrasing it.

Under discussion, authors should add the mechanism linking HIV to hyperglycaemia

Other factors such as obesity/ high BMI, and lifestyle that may contribute to hyperglycaemia/impaired fasting glucose were not assessed in this study. Should be highlighted as a limitation.

General comment:

Authors should leave the space between the last word and reference consistent throughout the manuscript.

Modify the font type for references

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Reviewer #1: Yes: Emma M. Kileel

Reviewer #2: No

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The prevalence of hyperglycemia and its impact on mortality among people living with HIV in Georgia

PONE-D-22-13596R1

Dear Dr. Borkowska,

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.

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Cristian Apetrei, MD, PhD

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: (No Response)

Reviewer #2: All comments have been addressed

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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

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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

**********

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: Thank you to the authors for taking the time to address the previous comments. The authors clarified that glucose measurements used in analyses were measured prior to ART initiation, which was a primary question/concern. Overall, the results of this analysis are clear and have important implications re screening for hyperglycemia at the point of entry into HIV care. The content of this paper is sound, however there are few remaining formatting edits that would help with the readability of the manuscript.

Overall comments:

How hyperglycemia was defined in this study, lines 94 - 103, remains slightly unclear. Consider restructuring by starting with a clear statement that that hyperglycemic status was based off of glucose measures at the time of entry into HIV care (i.e., prior to ART initiation), according to fasting status and the ADA criteria referenced. The authors could then follow with how they defined postprandial glucose measurements, and finally, end with the sentence on lines 95-97, regarding the referment of patients with hyperglycemia to relevant specialists.

The authors abbreviate people living with HIV to PLWH in the introduction section of the manuscript, therefore any future mentions of 'people living with HIV' can be replaced with PLWH.

Minor comments:

Line 59: Change areon to are on

Line 68: Change 'The longer ART exposure is linked...' to 'Longer ART exposure is linked'

Line 87: Change studyincluded to study included

Line 87: Consider changing "The study included adults (age >=18 years) living with HIV diagnosed in 2012-2018 and followed through to 2020" to "The study included adults (age >= 18 years) diagnosed with HIV between 2012-2018 and followed through to 2020."

Line 93: Change allconfirmed to all confirmed

Line 107: Change includingall to including all

Line 109: For consistency, consider changing 'AIDS-related deaths' to just 'AIDS-related' or, changing 'non-AIDS' to 'non-AIDS-related deaths'

Line 136: Authors state "AIDS was documented in 1189 (40.8%) patients", consider changing (if accurate) to "History of AIDS was documented in 1189 (40.8%) patients."

Line 137: Authors state "Every single patient has begun ART." Consider changing to "Every single patient initiated ART".

Line 143: Suggest changing "fasting glucose" to "fasting status" and further suggest changing 'cases' to 'patients'

Line 144: Authors state: "Two hundred and forty-two (8.3%) patients had hyperglycemia, increasing prevalence by age", consider changing to "Overall, 242 (8.3%) patients had hyperglycemia at entry into HIV care, with an increasing prevalence by age"

Reviewer #2: Thank you for taking time to addressing the comments. I am looking forward seeing your paper published.

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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: Yes: Emma Kileel

Reviewer #2: No

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