Development of type 2 diabetes and insulin resistance in people with HIV infection: Prevalence, incidence and associated factors

Göran Bratt; Johanna Brännström; Catharina Missalidis; Thomas Nyström

doi:10.1371/journal.pone.0254079

Peer Review History

Original SubmissionDecember 8, 2020
31 Mar 2021 Decision Letter - Graciela Andrei, Editor PONE-D-20-38599 Development of type 2 diabetes and insulin resistance in people with HIV infection: Prevalence, incidence and associated factors PLOS ONE Dear Dr. Nystrom, 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, take into account all the pertinent comments raised by both reviewers, who have several concerns regarding: Methodology and patients' cohorts Presentation of the results and conclusions drawn from the data Grammatical and typographical errors Please submit your revised manuscript by May 14 2021 11:59PM. 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The conclusions must be drawn appropriately based on the data presented. Reviewer #1: Partly Reviewer #2: Yes ******** 2. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: Yes Reviewer #2: Yes ****** 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: No 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: Bratt and colleagues investigate the incidence of T2D in PLHIV. Importantly, though morbidity and mortality have decreased significantly over the past few decades in this population, primarily due to improved treatment options, the prevalence of co-morbidities such as T2D is increasing and having a significant negative impact on long-term health. The authors suggest that the incidence of T2D in this cohort of PLHIV is higher than would be expected in the general population and associated risk factors are similar to those in the general population and not related to HIV infection or treatment. Introduction: 1. The inclusion of HLA B 5701 as part of the 4th paragraph seems random. There is not enough information provided as to its relevance and expanding on why this marker was chosen would provide clarity; perhaps as a paragraph of its own. This is especially relevant since HLA B 5701 is a focus of the results and discussion. Material and Methods: 1. Remove the additional words 'at baseline' in this title since the longitudinal aspect of the study is described as well. 2. Explain why reference 20 (Koppel et al.) follows the first sentence under the title 'Procedure and follow up.' 3. Provide evidence that a fasting HOMA-IR of ≥3.0 is diagnostic of insulin resistance in PLHIV. 4. In the last sentence of this section, it states that a BMI≥30 kg/m2 was used to define central adiposity. BMI is not a measure of central adiposity. 5. The term Total Clinic Population is used along with Total Study Population to describe the same group. Only one title should be presented. Results: 1. It would be my suggestion to remove the data presented in the results section on the Total Study Population since the focus of the article is on the Prospective Cohort. Inclusion of the data on the total group makes the results more confusing without adding to the findings. Stating that the initial Total Study Population presented with n=7 with T1D and n=58 with T2D is the only information that is needed. All other data presented should be only on the Prospective Cohort, pre and post follow-up. 2. It states in methods that there were n=570 in the Total Study Population and that the 505 individuals without a diagnosis of diabetes were prospectively followed. If that is the case, please clarify the central adiposity numbers presented in table 1. There is only an n=65 difference between the two groups in total numbers. 3. The relevance of table 4 isn't clear. There needs to be more development of the importance of HLA B 5701 in the introduction. Discussion: 1. The findings suggest that predictive factors underlying the development of T2D in PLHIV are similar to the general population and not related to the HIV infection itself. There needs to be a paragraph added to the discussion regarding this finding since there are a number of other studies suggesting that HIV-related factors do contribute to the increased prevalence of T2D in PLHIV. There are a number of spelling and grammatical errors that need to be fixed throughout the manuscript. Reviewer #2: Please see attached document with same review- easier readability. The manuscript by Bratt et al. demonstrates a nice prospective study to evaluate the incidence of type 2 diabetes (T2D) and insulin resistance among a cohort of 570 people living with HIV. While the topic is not novel, this study provides additive data to ongoing literature describing prevalence and incidence of T2D in people living with HIV in different countries. The following are suggested changes to add clarity and rigor to the manuscript. Major Changes: - The ‘total study population’ is described as a cohort of 570 patients including those with T2D and T1D at baseline and the ‘prospective study population’ as a cohort of 505 patients excluding those with T2D and T1D at baseline. o It is unclear to me why the authors compare these 2 cohorts when the primary outcome is incidence of T2D. I recommend the authors either better justify why they are including those with baseline diabetes (both T1D and T2D) in the analyses or exclude the ‘total study population’ in the analyses. Minor Changes: - Methods section: Please include the inclusion/exclusion criteria o Justify why you only include those >50 years old. - Procedure and follow up section: Please be explicit in how many ‘repeated’ measures of fasting glucose, cholesterol, BP measurements, etc were needed or done before diagnosing participants with T2D, hyperlipidemia, HTN, etc. - Page 7, ‘Description of the population data at baseline’ section: Paragraph that starts with “more than 95% of the patients were on cART…. The second sentence uses the word “respectively”- but it is unclear which groups you are ‘respectively’ referring to. Please clarify. - ‘Prevalence of T1D, T2D and insulin resistance at baseline and follow up’ section: 2nd sentence needs clarification- what follow up are you referring to when describing the 10% of T2D diagnosed- the 58 patients with T2D were those with T2D at baseline, correct? - Same section: sentence that begins: “During the follow up 69% (40/58) of the patients diagnosed with T2D…” – the numbers you report do not add up to 100%. I believe the “21%” should be 31%- please check the math. - Same section: Last sentence of this section that begins with “Death occurs in 8%...”- needs grammatical attention. - Discussion section: Need more detail on the association of T2D and HLA B5701- compare with other literature. - Generally: I advise the authors work with a writing coach or copyeditor to improve the flow and readability of the text. There are minor grammatical edits that should be addressed throughout the paper. ****** 6. 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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. Attachments Attachment Submitted filename: PLOSONE_Review_DM prevalence in HIV_2021.docx https://doi.org/10.1371/journal.pone.0254079.r001
Revision 1
24 Apr 2021 Author Response Responses to the reviewers’ specific comments: Reviewer # 1: Response: We thank this reviewer for constructive comments on the manuscript. Re: Introduction 1. “The inclusion of HLA B 5701 as part of the 4th paragraph seems random. There is not enough information provided as to its relevance and expanding on why this marker was chosen would provide clarity, perhaps as a paragraph of its own. This is especially relevant since HLA B 5701 is a focus of the results and discussion” Response: Thanks for this important comment. We have added more information about, and why, HLA B 5701 was included in the study. To our knowledge this has not been previously examined. We have now inserted following text in the revised manuscript (Introduction): “The HLA B 5701 allele was recently suggested to protect against type 1 diabetes (T1D) in the large international Type 1 Diabetes Genetics Consortium (T1DGC) study [19]. This allele is also the only genetic marker routinely screened for in HIV-care in order to avoid abacavir hypersensitivity [20] . In addition to indicating abacavir hypersensitivity the HLA B 5701 allele is also associated with restriction of HIV-replication in long-term non-progressors [21]. Whether HLA B 5701 expression also has an impact on T2D development has, to the best of our knowledge, not been investigated.” Re: Material and Methods 1.”Remove the additional words 'at baseline' in this title since the longitudinal aspect of the study is described as well” Response: The words 'at baseline' has been removed and the title is now “Material and Methods” 2.”Explain why the ref 20 (Koppel K et al) as part of the 4th paragraph seems random”. Response: Reference 20 (Koppel et al.) has been moved to a different place in the text (Procedure and follow up): “Since the introduction of protease-inhibitor based cART (PI-cART) in 1996 there has been a special interest in metabolic and hemostatic parameters in our clinic [20] and a yearly evaluation of all patients includes the fasting testing…” 3. “Provide evidence that a fasting HOMA-IR >=3.0 is diagnostic of insulin resistance in PLHIV”. Response: This point is well taken. We have included more text motivating this cut off level and inserted two more references (24, 25) to justify cut off value of 3 and above. Also, our own results and clinical experience from cross-sectional HOMA examinations in 455 50+, HIV+ patients were contributed to this value. Following text has been inserted in the revised manuscript (Procedure and follow up): “For the definition of insulin resistance in non-diabetic patients HOMA-IR ≥3.0 was used (24). This value was close to the median of 2.7 (interquartile range: 1,8-4,1) among non-diabetic HIV-patients 50 years or older in our clinic in 2020 (n=455), and similar to the cut-off value defining insulin resistance in the BRAMS study [25]” 4. “In the last sentence of this section, it states that a BMI≥30 kg/m2 was used to define central adiposity. BMI is not a measure of central adiposity”. Response: We thank for this comment. BMI≥30 kg/m2 has been omitted as a measure of central adiposity (Procedure and follow up): “Central obesity was defined by waist circumference ≥94 cm and ≥80 cm for men and women, respectively”. 5. “The term Total Clinic Population is used along with Total Study Population to describe the same group. Only one title should be presented”. Response: Many thanks for this comment. In the revised manuscript the term Total Clinic Population has been omitted Re: Results: 1. “It would be my suggestion to remove the data presented in the results section on the Total Study Population since the focus of the article is on the Prospective Cohort. Inclusion of the data on the total group makes the results more confusing without adding to the findings. Stating that the initial Total Study Population presented with n=7 with T1D and n=58 with T2D is the only information that is needed. All other data presented should be only on the Prospective Cohort, pre and post follow-up.” Response: Again, many thanks for helping us in a more straightforward way show our data. We have, in the revised manuscript, removed the data on Total Study Population from Table 1 and now only include the data for the Prospectively Followed Cohort. The paragraph has been changed to read (Patients [Material and Methods]): “At baseline the 570 eligible patients were analysed cross-sectionally. Of these, one percent (7/570) had T1D and 10% (58/570) had T2D. Of the T2D patients 69% (40/58) were treated with glucose lowering medication: 14 individuals were on insulin only, 20 on metformin only and 6 on insulin in combination with metformin; 31% (18/58) were treated with diet and physical activation only. The remaining 505 patients without diabetes (referred to as “the cohort”) were prospectively followed with yearly routine testing in the clinic for the development of the outcomes of interest, i.e. T2D and insulin resistance”. Table 1. Descriptive population data of the patients without diabetes (n=505) at baseline Patients N (M; F, n (%)) 505 (M 440 (88%); F 65 (12%)) Age (median (range); years 57 (49-83) HLA B 5701 pos (n; (%)) 21/500 (4%) Time with known HIV-infection (months; median (range)) 204 (6-374) AIDS diagnosis (n; (%)) 94 (19%) Initial, pre-ART, HIV-RNA (median (range); copies/ml) 42100 (19-10000000) CD4 nadir (x106/L; median; (range)) 193 (0-870) CD4 nadir <200 x106/L (n; (%)) 266 (53%) Time without cART (median (range); months) 54 (0-372) Treatment interruption of at least one month: prevalence (%); time (median (range); months) 26%; 16.0 (1-105) Ever on D4t (Stavudine) (n; (%)) 179 (35%) Ever on DDI (Didanosine) (n; (%)) 179 (35%) On cART (n; (%)) 491 (97%) cART including a NNRTI (n; (%)) 306 (61%) cART including a Protease inhibitor (n; (%)) 162 (32%) cART including an Integrase inhibitor (n; (%)) 100 (20%) cART including Emtricitabine (n; (%)) 260 (51%) cART including Lamivudine (n; (%)) 193 (38%) cART including Abacavir (n; (%)) 176 (35%) cART including Tenofovir (n; (%)) 268 (53%) cART including Zidovudine (n; (%)) 5 (1%) CD4 count (median; (range)) 600 (30–1620) HIV-RNA <100 copies/ml at baseline (n; (%)) 489 (97%) Hypertension (n; (%)) 205 (41%) Hyperlipidemia (n; (%)) 202 (40%) Central obesity 114 (23%) Insulin resistance (n; (%)) 153 (30%) On statin treatment (n; (%)) 115 (23%) 2. “It states in methods that there were n=570 in the Total Study Population and that the 505 individuals without a diagnosis of diabetes were prospectively followed. If that is the case, please clarify the central adiposity numbers presented in table 1. There is only an n=65 difference between the two groups in total numbers”. Response: Table 1 now only contains data on the Prospectively followed cohort. The incorrect figures for central obesity have been corrected (Table 1 above) 3. “The relevance of table 4 isn't clear. There needs to be more development of the importance of HLA B 5701 in the introduction”. Response: Table 4 has been removed. In the introduction we have included further motivation of why we included HLA B5701 in the study: See response #1 We have also inserted new text (which replace Table 4) in the revised manuscript for the association between HLA B5701 at baseline and at follow up (Characteristics of the HLA B5701 positive patients [Results]: “At baseline, regarding all patients (n=570), T2D was more common among HLA B 5701 positive as compared to HLA B5701 negative patients (22% (6/27) vs 10% (52/531); p=0.05). Expressing HLA B5701 and having been HIV-positive longer in months than the median (HIV-months >209 months) were significantly related to the presence of T2D in univariate analysis. In multivariate analysis, controlled for age, only being HLA B 5701 positive showed a trend (p=0.055) for association with T2D, Table 2. However, during follow up there was no difference in new T2D diagnoses between HLA B 5701 positive and negative patients (14% (3/21) vs 8% (39/479); ns). None of the patients with T1D were HLA B 5701 positive (0/7).” Re: Discussion: 1. “The findings suggest that predictive factors underlying the development of T2D in PLHIV are similar to the general population and not related to the HIV infection itself. There needs to be a paragraph added to the discussion regarding this finding since there are a number of other studies suggesting that HIV-related factors do contribute to the increased prevalence of T2D in PLHIV.” Response: Thanks for this point. We have added, in the revised manuscript, a paragraph and two more references from 2018 (Nausseau JR and Echecopai-Sabogal J) regarding HIV-related factors that contribute to the increased prevalence of T2D in PLHIV found in other studies (Discussion): “A systematic review and meta-analysis in 2008 found an association between PIs and the metabolic syndrome but not T2D [40]. However, the metabolic syndrome or combinations of its components might develop into T2D as our results indicate. In a more recent metanalysis from 2018 the major risk factors, apart from aging, for diabetes and prediabetes were found to be family history of diabetes, Black or Hispanic origin, overweight/obesity, central obesity, lipodystrophy/lipoatrophy, dyslipidemia, metabolic syndrome, increased baseline fasting glycemia, and certain cART regimens [34]. Integrase inhibitors, mainly Dolutegravir, have been anectodically associated to T2D, possibly due to weight gain, which we could not confirm. We failed to find any influence on T2D of different cART regimes or of treatment interruption. The only integrase inhibitor used in our clinic in 2012 was Raltegravir. The manuscript has thoroughly been revised regarding spelling and grammatical errors by a native English speaker. Reviewer #2: We would like to thank this reviewer for valuable critics which has strengthen the manuscript. Re: Major Changes: - The ‘total study population’ is described as a cohort of 570 patients including those with T2D and T1D at baseline and the ‘prospective study population’ as a cohort of 505 patients excluding those with T2D and T1D at baseline. o It is unclear to me why the authors compare these 2 cohorts when the primary outcome is incidence of T2D. I recommend the authors either better justify why they are including those with baseline diabetes (both T1D and T2D) in the analyses or exclude the ‘total study population’ in the analyses. Response: This point is well taken (which also was raised by reviewer #1 issue #5). We thank for the advice to rearrange our cohort. We have, in the revised manuscript, removed the data on Total Study Population from Table 1 and now only include the data for the Prospectively Followed Cohort. The paragraph has been changed to read (Patients [Material and Methods]): “At baseline the 570 eligible patients were analysed cross-sectionally. Of these, one percent (7/570) had T1D and 10% (58/570) had T2D. Of the T2D patients 69% (40/58) were treated with glucose lowering medication: 14 individuals were on insulin only, 20 on metformin only and 6 on insulin in combination with metformin; 31% (18/58) were treated with diet and physical activation only. The remaining 505 patients without diabetes (referred to as “the cohort”) were prospectively followed with yearly routine testing in the clinic for the development of the outcomes of interest, i.e. T2D and insulin resistance”. Table 1. Descriptive population data of the patients without diabetes (n=505) at baseline Patients N (M; F, n (%)) 505 (M 440 (88%); F 65 (12%)) Age (median (range); years 57 (49-83) HLA B 5701 pos (n; (%)) 21/500 (4%) Time with known HIV-infection (months; median (range)) 204 (6-374) AIDS diagnosis (n; (%)) 94 (19%) Initial, pre-ART, HIV-RNA (median (range); copies/ml) 42100 (19-10000000) CD4 nadir (x106/L; median; (range)) 193 (0-870) CD4 nadir <200 x106/L (n; (%)) 266 (53%) Time without cART (median (range); months) 54 (0-372) Treatment interruption of at least one month: prevalence (%); time (median (range); months) 26%; 16.0 (1-105) Ever on D4t (Stavudine) (n; (%)) 179 (35%) Ever on DDI (Didanosine) (n; (%)) 179 (35%) On cART (n; (%)) 491 (97%) cART including a NNRTI (n; (%)) 306 (61%) cART including a Protease inhibitor (n; (%)) 162 (32%) cART including an Integrase inhibitor (n; (%)) 100 (20%) cART including Emtricitabine (n; (%)) 260 (51%) cART including Lamivudine (n; (%)) 193 (38%) cART including Abacavir (n; (%)) 176 (35%) cART including Tenofovir (n; (%)) 268 (53%) cART including Zidovudine (n; (%)) 5 (1%) CD4 count (median; (range)) 600 (30–1620) HIV-RNA <100 copies/ml at baseline (n; (%)) 489 (97%) Hypertension (n; (%)) 205 (41%) Hyperlipidemia (n; (%)) 202 (40%) Central obesity 114 (23%) Insulin resistance (n; (%)) 153 (30%) On statin treatment (n; (%)) 115 (23%) Re: Minor Changes Re: Methods section: Please include the inclusion/exclusion criteria Response: We have now included inclusion and exclusion criteria in the revised manuscript (Patients [Material and Methods]:“Inclusion criteria for the study were: 1. Having a verified HIV-1 infection being treated at Venhälsan, South Hospital, Stockholm. 2. Born 2012 or earlier. 3. Had given verbal consent to participate. Exclusion criteria were: Having been diagnosed with T1D or T2D prior to the start of the study and refusing to participate” Justify why you only include those >50 years old. Response: We have now in the revised manuscript explained the reason for only including >50 years old patients (Introduction): “The aim of this study was to investigate the incidence of T2D and insulin resistance in a group of well controlled PLHIV over 50 years of age and over a long-term period. The decision to only include this age group was based on our clinic´s focus on co-morbidity in an aging HIV-population.” Re: Procedure and follow up section: Please be explicit in how many ‘repeated measurements of fasting glucose, cholesterol, BP etc were needed or done before diagnosing participants with T2D, hyperlipidemia, HTN, etc. Response: This point is well taken. We have in the revised manuscript now clarified how many ‘repeat measurements of fasting glucose, cholesterol and BP measurements that were carried out before diagnosing participants with T2D, hyperlipidemia and hypertension (Procedure and follow up): ”T2D was defined as repeated fasting glucose values ≥7.0 mmol/l [26]. Hyperlipidaemia was defined as repeated values of either total cholesterol ≥5.0 mmol/l, LDL cholesterol ≥3.0 mmol/l or on-going lipid lowering therapy. Pathological fasting glucose and lipid values were verified at least once. Hypertension was defined by repeated BP ≥140/90 mmHg on at least two different occasions or on-going antihypertensive treatment”. - Page 7, ‘Description of the population data at baseline’ section: Paragraph that starts with “more than 95% of the patients were on cART…. The second sentence uses the word “respectively”- but it is unclear which groups you are ‘respectively’ referring to. Please clarify. Response: Thanks for this comment. The word “respectively”- has been excluded and the sentence rewritten (Description of the prospectively followed cohort): “More than 95% of the patients were on cART and over 95% had HIV-RNA <100 copies/ml. A previous history of advanced immune deficiency and AIDS had occurred in 50% and 20%, respectively, Table 1. Furthermore, 29% had had a treatment interruption of at least one month. The median time of treatment interruption was 14.5 months (range: 1-105 months). The CD4 count had increased from less than 200 x106/L to 600 x106/L, Table 1”. - The prevalence of T1D, T2D and insulin resistance at baseline and follow up’ section: 2nd sentence needs clarification- what follow up are you referring to when describing the 10% of T2D diagnosed- the 58 patients with T2D were those with T2D at baseline, correct? ‘ Response: Thanks for this comment. It is correct that the 58 patients with T2D are those with T2D at baseline. However, this has now been clarified that this 570 was analysed cross-sectional due to HLA B5701 and excluded in the prospectively followed cohort. Following text has been inserted to further clarify this (Patients [Materials and Methods]):“At baseline the 570 eligible patients were analysed cross-sectionally. Of these, one percent (7/570) had T1D and 10% (58/570) had T2D. Of the T2D patients 69% (40/58) were treated with glucose lowering medication: 14 individuals were on insulin only, 20 on metformin only and 6 on insulin in combination with metformin; 31% (18/58) were treated with diet and physical activation only. The remaining 505 patients without diabetes (referred to as “the cohort”) were prospectively followed with yearly routine testing in the clinic for the development of the outcomes of interest, i.e. T2D and insulin resistance.” - Same section: sentence that begins: “During the follow up 69% (40/58) of the patients diagnosed with T2D…” – the numbers you report do not add up to 100%. I believe the “21%” should be 31%- please check the math. Response: We have checked the figures and “21%” should be “31%”. This has now been corrected: “Of the T2D patients 69% (40/58) were treated with glucose lowering medication: 14 individuals were on insulin only, 20 on metformin only and 6 on insulin in combination with metformin; 31% (18/58) were treated with diet and physical activation only”. - Same section: Last sentence of this section that begins with “Death occurs in 8%...”- needs grammatical attention. Response: The sentence has been grammatically corrected to:” Death occurred in 8% (42/505) (mortality rate 1.2/100 patient-years)”. Re: Discussion section Need more detail on the association of T2D and HLA B5701- compare with other literature. Response: This point is well taken. We now discuss the association of T2D and HLA B5701 in more depth. We have, however, failed to find any references on B 5701 in relation to T2D. So, there seems to be no studies of the relation between HLA B5701 and T2D in HIV. Following text has been inserted in the revised manuscript (Discussion):“The trend suggesting a possible association of T2D with HLA B5701 at baseline was surprising and difficult to explain as HLA B5701 has been found to be protective for T1D [19]. One explanation might be a survival bias since time with HIV-infection was also associated to T2D in univariate regression analyse at baseline and HLA B5701 is associated with restriction of HIV-replication in long-term non-progressors [21]. The HLA B5701 link needs further studying.” The manuscript also been revised regarding spelling and grammatical errors by an English speaker. Attachments Attachment Submitted filename: Responses to the reviewers.docx https://doi.org/10.1371/journal.pone.0254079.r002
18 May 2021 Decision Letter - Graciela Andrei, Editor PONE-D-20-38599R1 Development of type 2 diabetes and insulin resistance in people with HIV infection: Prevalence, incidence and associated factors PLOS ONE Dear Dr. Nystrom, 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. ============================== There are a few remaining grammatical errors. Reviewer #1 has also a few additional minor concerns. ============================== Please submit your revised manuscript by Jul 02 2021 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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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. [Note: HTML markup is below. Please do not edit.] 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 ******** 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 ****** 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: Minor Concerns: 1. There are remaining grammatical errors, including missing periods, in the revised manuscript (outlined below). Also, review manuscript carefully with regards to using a comma or decimal point to separate numbers and be consistent throughout manuscript; in particular, tables 2 & 3 and throughout discussion. Introduction: First sentence – Mortality and morbidity among people living with human immunodeficiency virus type 1 (PLHIV) has decreased over the last two decades. Introduction: 4th Paragraph – Many studies have indicated that PLHIV on cART have an over risk for myocardial infarction, cerebrovascular events and type 2 diabetes (T2D) [6-11]. Materials and methods: Patients – Exclusion criteria were: having been diagnosed with T1D or T2D prior to the start of the study and refusing to participate. Funding Statement: The study has received economical support from Physicians against AIDS research fund (Läkare mot AIDS forskningsfond). Data availability: Participants in this study have not consented for their data to be used by other researchers. Legends to figure: Figure 2. Proportions of T1D, T2D and insulin resistance at follow up. All PLHIV who developed T2D and insulin resistance in the prospectively followed cohort are included in this diagram. 2. Materials and methods: Patients: Inclusion criteria number 2 needs to be corrected - 2. Born 2012 or earlier. 3. Results: Development of T2D and insulin resistance at follow up – Second sentence reads “Another 7% (36/505) (M: n=19; F: n=17) developed insulin resistance (incidence of 1.0/100 patient-years).” However, table 1 indicates that 153/505 of the prospectively followed cohort already had insulin resistance at baseline. This would indicate that 36 of the remaining 352 individuals developed insulin resistance. Please clarify here and in discussion. 4. Consider adding sample sizes, n=570 and n=505, to your figure legends. Reviewer #2: All concerns have been adequately addressed by the authors. I believe this manuscript is much stronger and acceptable for publication in this journal. ****** 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 [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. 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Revision 2
26 May 2021 Author Response Responses to the reviewers’ specific comments: Reviewer # 1: Re: Minor concerns The remaining grammatical errors including missing periods have been corrected. The use of comms and decimal point has been made consistent throughout the manuscript and in Tables II and III. Re: Introduction First sentence: “Mortality and morbidity among people living with human immunodeficiency virus type 1 infection has decreased over the last two decades” has been changed to “Mortality and morbidity among people living with human immunodeficiency virus type 1 infection have decreased over the last two decades” Re: Material and Methods Patients: Inclusion criteria number 2 needs to be corrected Response: Inclusion criteria number 2 has been clarified to: “Born before the 1st of January 2013” Re: Results: 1 Development of T2D and insulin resistance at follow up – Second sentence reads “Another 7% (35/505) (M:n=19; F:n=17) developed insulin resistance (incidence of 1.1/100 patient-years)”. However, table 1 indicates that 135/505 of the prospectively followed cohort already had insulin resistance at baseline. This would indicate that 36 of the remaining 352 individuals developed insulin resistance. Please clarify here and in discussion. Response: We have made new calculations and rewritten the sentence to: “During a median follow-up time of 7.25 years (3485 patient-years) 9% (43/505) (M: n=43; F: n=0) developed T2D (incidence of 1.2/100 patient-years). Another 36 patients (M: n=19; F: n=17) developed insulin resistance (incidence of 1.0/100 patient-years). Thus, at follow up, 79 patients (M: n=62; F: n=17) had developed either T2D or insulin resistance (incidence of 2.3/100 patient-years). In total, the occurrence of either T2D or insulin resistance was 46% (232 (153+79)/505) at follow up, Figure 2”. We also added the sentence: ”Insulin resistance occurred in 30% (153/505), Table 1” in the first part of the Results: Description of the Prospectively Followed Cohort for further clarification. The Table 1 and Tables 2-3 have been slightly reorganized for clarification and improved symmetry as shown: Table 1. Descriptive population data of the patients without diabetes (n=505) at baseline. Patients Total number (M; F, n (%)) 505 (M 440 (88%); F 65 (12%)) Median age in years (range) 57 (49-83) HLA B 5701 pos n; (%) 21/500 (4%) Median time with known HIV-infection in months (range) 204 (6-374) AIDS diagnosis n; (%) 94 (19%) Median initial, pre-ART, HIV-RNA in copies/ml (range) 42100 (19-10000000) Median CD4 nadir x106/L median (range) 193 (0-870) CD4 nadir <200 x106/L n; (%) 266 (53%) Median time in months without cART (range) 54 (0-372) Treatment interruption of at least one month: prevalence in %; median time in months (range) 26%; 16.0 (1-105) Ever on D4t (Stavudine) n; (%) 179 (35%) Ever on DDI (Didanosine) n; (%) 179 (35%) On cART n; (%) 491 (97%) cART including a NNRTI n; (%) 306 (61%) cART including a Protease inhibitor n; (%) 162 (32%) cART including an Integrase inhibitor n; (%) 100 (20%) cART including Emtricitabine n; (%) 260 (51%) cART including Lamivudine n; (%) 193 (38%) cART including Abacavir n; (%) 176 (35%) cART including Tenofovir n; (%) 268 (53%) cART including Zidovudine n; (%) 5 (1%) Median CD4 count x106/L (range) 600 (30–1620) HIV-RNA <100 copies/ml at baseline n; (%) 489 (97%) Hypertension n; (%) 205 (41%) Hyperlipidemia n; (%) 202 (40%) Central obesity n; (%) 114 (23%) Insulin resistance n; (%) 153 (30%) On statin treatment n; (%) 115 (23%) Table 2. Uni and multivariate analysis regarding T2D in all patients including patients with diabetes (n=570) at baseline. The multivariate analysis was controlled for age. All parameters with p<0.20 in the univariate analysis were entered in the multivariate equation. OR and 95% confidence interval. Univariate OR (95% CI) P-value Multivariate OR (95% CI) P-value HLA B 5701 positive 2.6 (1.0-6.8) 0.046 2.6 (1.0-7.1) 0.055 HIV-months >the median (209 months) 1.9 (1.1-3.3) 0.03 ns Ever an AIDS diagnosis 1.7 (1.0-3.1) 0.11 ns First HIV-RNA >300000 copies/ml 1.4 (0.8-2.5) 0.21 CD4 nadir <200 x 106/L 1.7 (1.0-3.0) 0.065 ns CD4<200 x 106/L for >12 months 1.7 (1.0-3.1) 0.061 ns Ever on D4t (Stavudine) 1.4 (0.8-2.4) 0.25 Ever on DDI (Didanosine) 1.7 (1.0-2.9) 0.057 ns Ever been a smoker 1.4 (0.8-2.4) 0.29 Table 3. HIV-parameters, treatment, metabolic and inflammatory factors at baseline in relation to T2D development during follow up (n=505). Uni and multivariate analysis at baseline. The multivariate analysis was controlled for age. All parameters with p<0.20 in the univariate analysis were entered in the multivariate equation. Odds Ratio (OR) and 95% confidence interval. Univariate OR (95% CI) P-value Multivariate OR (95% CI) P-value HLA B 5701 positive 1.6 (0.5-5.5) 0.46 HIV-months >the median (209 months) 0.8 (0.4-1.5) 0.52 Ever an AIDS diagnosis 0.8 (0.3-1.8) 0.59 First HIV-RNA >300000 copies/ml 0.8 (0.4-1.6) 0.59 CD4 nadir <200 x 106/L 1.4 (0.7-2.7) 0.31 CD4<200 x 106/L for >12 months 0.9 (0.4-1.9) 0.76 Ever on D4t (Stavudine) 0.9 (0.5-1.7) 0.88 Ever on DDI (Didanosine) 1.2 (0.6-2.3) 0.60 On an NNRTI 0.9 (0.5-1.6) 0.68 On a protease inhibitor 1.2 (0.6-2.2) 0.68 On an integrase inhibitor 0.6 (0.2-1.4) 0.22 On abacavir 1.5 (0.8-2.7) 0.25 On tenofovir 0.8 (0.4-1.4) 0.38 Hypertension 1.9 (1.0-3.6) 0.051 ns Triglycerides >2.6 mmol/L 3.6 (1.8-7.2) <0.001 2.4 (1.1-5.7) 0.036 Non-HDL cholesterol >3.8 mmol/L 1.5 (0.8-2.9) 0.20 ns Central obesity 2.6 (1.3-5.2) 0.005 2.8 (1.2-5.7) 0.015 Insulin resistance 3.4 (1.8-6.5) <0.0001 2.4 (1.1-5.1) 0.018 Hs CRP >3.0 mg/L 1.6 (0.8-3.2) 0.20 ns On statin treatment 2.6 (1.4-4.9) 0.004 2.6 (1.2-5.5) 0.015 Actual smoker 0.9 (0.5-1.8) 0.81 Re: Consider adding sample sizes, n=570 and n=505 to your figure legends Response: the figure legends have been changed to: “ Figure 1. Proportions of T1D, T2D and insulin resistance in the cross-sectional analysis at baseline (n=570). Figure 2. Proportions of T1D, T2D and insulin resistance in the prospectively followed cohort at follow up (n=505). Furthermore, the figure 2 has been corrected accordingly Figure 1. Proportions of type 1 diabetes (T1D), type 2 diabetes (T2D) and insulin resistance in the cross-sectional analysis (n=570) at baseline Figure 2. Proportions of type 2 diabetes (T2D) and insulin resistance in the prospectively followed cohort (n=505) at follow up. Attachments Attachment Submitted filename: Response to the reviewers_R2.docx https://doi.org/10.1371/journal.pone.0254079.r004
11 Jun 2021 Decision Letter - Graciela Andrei, Editor PONE-D-20-38599R2 Development of type 2 diabetes and insulin resistance in people with HIV infection: Prevalence, incidence and associated factors PLOS ONE Dear Dr. Nystrom, 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 revise your abstract, materials & methods, and results taking into account all the reviewer's comments. ============================== Please submit your revised manuscript by Jul 26 2021 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. 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. Please include the following items when submitting your revised manuscript: 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: http://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, Graciela Andrei Academic Editor PLOS ONE Journal Requirements: 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. [Note: HTML markup is below. Please do not edit.] 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) ******** 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 ****** 3. Has the statistical analysis been performed appropriately and rigorously? Reviewer #1: 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 ****** 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 ****** 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: Minor Concerns: Re: Material and Methods Inclusion criteria number 2 has been clarified to “Born before the 1st of January 2013.” However, this suggests that children as young as 8 years old could participate in the study. Please revise accordingly. Re: Results: The concerns regarding the incidence of insulin resistance at baseline in the prospective cohort were addressed but further clarity is needed. I would suggest the following changes addition to the second sentence of the paragraph “Another 36 patients, 10% (36/352) (M:n=19; F: n=17) developed insulin resistance (incidence of 1.0/100 patient-years). In addition, the last sentence reads “In total, the occurrence of either T2D or insulin resistance was 46% (232 (153+79)/505) at follow up, Figure 2. I would suggest using ‘prevalence’ in place of ‘occurrence.’ Re: Abstract Please make the correction above to the abstract as well since the old data for insulin resistance is still reflected. Results: During follow up (3485 patient-years) 9% (43/505) developed T2D and 7% (34/505) insulin resistance. ****** 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 [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.0254079.r005
Revision 3
14 Jun 2021 Author Response Responses to the minor comments: Reviewer #1: Minor Concerns: Re: Material and Methods Inclusion criteria number 2 has been clarified to “Born before the 1st of January 2013.” However, this suggests that children as young as 8 years old could participate in the study. Please revise accordingly. This is a typo, corrected to born before the 1st of January 1963 in the revised manuscript Re: Results: The concerns regarding the incidence of insulin resistance at baseline in the prospective cohort were addressed but further clarity is needed. I would suggest the following changes addition to the second sentence of the paragraph “Another 36 patients, 10% (36/352) (M:n=19; F: n=17) developed insulin resistance (incidence of 1.0/100 patient-years). In addition, the last sentence reads “In total, the occurrence of either T2D or insulin resistance was 46% (232 (153+79)/505) at follow up, Figure 2. I would suggest using ‘prevalence’ in place of ‘occurrence.’ We appreciate this comment and have now change the text accordingly in the revised manuscript. The development of insulin resistance during follow up was 7% (36 out of 505) Re: Abstract Please make the correction above to the abstract as well since the old data for insulin resistance is still reflected. Thanks for notice this, the abstract is now changed. Results: During follow up (3485 patient-years) 9% (43/505) developed T2D and 7% (34/505) insulin resistance. This is now corrected in the Abstract (Results). “During follow up (3485 patient-years) 9% (43/505) developed T2D and 7% (36/505) insulin resistance” Attachments Attachment Submitted filename: Response to the reviewers_R3.docx https://doi.org/10.1371/journal.pone.0254079.r006
21 Jun 2021 Decision Letter - Graciela Andrei, Editor Development of type 2 diabetes and insulin resistance in people with HIV infection: Prevalence, incidence and associated factors PONE-D-20-38599R3 Dear Dr. Nystrom, 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, Graciela Andrei Academic Editor PLOS ONE Additional Editor Comments (optional): Reviewers' comments: https://doi.org/10.1371/journal.pone.0254079.r007
Formally Accepted
22 Jun 2021 Acceptance Letter - Graciela Andrei, Editor PONE-D-20-38599R3 Development of type 2 diabetes and insulin resistance in people with HIV infection: Prevalence, incidence and associated factors Dear Dr. Nyström: 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. Graciela Andrei Academic Editor PLOS ONE https://doi.org/10.1371/journal.pone.0254079.r008

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