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

. 2021 Jun 30;16(6):e0254079. doi: 10.1371/journal.pone.0254079

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

Göran Bratt ^1,², Johanna Brännström ^2,³, Catharina Missalidis ^2,⁴, Thomas Nyström ^1,^5,^*

Editor: Graciela Andrei⁶

PMCID: PMC8244855 PMID: 34191847

Abstract

Background

Diabetes and insulin resistance is an emerging issue in people with HIV. HIV-related mortality and morbidities have decreased markedly over the last few decades, while co-morbidities including type 2 diabetes (T2D) have increased.

Setting

This study investigated the incidence of T2D and insulin resistance in a cohort of HIV-patients on effective treatment.

Methods

Prevalence and baseline predictors of T2D were assessed in a cohort of 570 HIV-positive patients 50 years or older. Patients without diabetes (n = 505) were followed prospectively over a median period of 7.25 year (2012–2020) until T2D development, death or end of the study. T2D was defined as repeated fasting glucose values ≥7.0 mmol/L. Insulin resistance was defined as HOMA-IR ≥3.0. Predictors of T2D development (HIV-related parameters, lipids, hypertension, central obesity, inflammation, smoking and use of statins) were assessed using logistic regression analysis.

Results

30% (153/505) had insulin resistance. During follow up (3485 patient-years) 9% (43/505) developed T2D and 7% (36/505) insulin resistance. Thus, at follow up the prevalence of either T2D or insulin resistance was 46% (232/505). T2D incidence was 1.2/100 patient-years. In multivariate analysis, after adjustment for age, T2D development was associated with baseline insulin resistance, hypertriglyceridemia, central obesity and statin treatment, but no HIV-related factors.

Conclusion

The incidence of T2D in this cohort of patients with well controlled HIV-infection was high. The predictive factors associated with the development of T2D were not unique for HIV positive patients. The findings underline the importance of lifestyle changes in avoidance of T2D in people with HIV.

Introduction

Mortality and morbidity among people living with human immunodeficiency virus type 1 (PLHIV) have decreased the last two decades [1]. This is mainly due to a continual increase in uptake of highly efficient and long-term safe combined antiretroviral treatment (cART). Thus, co-morbidities will have a greater impact on the long-term health and survival of HIV-patients.

In the ongoing American prospective HIV Outpatient Study (HOPS) the death rate fell from 12.1 to 1.6 deaths per 100 person-years between 1994 and 2017 [2] whereas the proportion of non-AIDS causes of death (cardiovascular, hepatic, pulmonary and non-AIDS associated malignancies) increased [3]. However, the role and impact of life-long cART on the development and progress of significant comorbidities is as yet unclear.

In Sweden over 95% of all diagnosed HIV-patients are on cART and more than 95% of these are virally suppressed [4]. A recently published Swedish cohort study of 4066 PLHIV followed for 15 years found a non-AIDS-associated mortality rate of successfully treated patients to be 2.4 times greater than that of 8072 HIV-negative controls matched for age, gender and region of birth [5].

Many studies have indicated that PLHIV on cART have an over risk for myocardial infarction, cerebrovascular events and type 2 diabetes (T2D) [6–11]. Some investigators have found T2D to be 3–4 times more common among PLHIV on cART as compared to the general population, the prevalence being reported as up to 20% in the 51–60 years age group [12]. T2D among PLHIV is associated with an increased risk for cardiovascular events (e.g. RR 3.0, in the DAD study), cardiac diastolic dysfunction, liver fibrosis (even without hepatitis C co-infection), chronic kidney disease and peripheral neuropathy [13–17]. Moreover, in the general population, insulin resistance, as measured by the homeostasis model assessment for insulin resistance (HOMA-IR) index, has been reported to be an independent risk factor for CVD events and all-cause mortality in subjects with arterial disease even without manifest T2D [18].

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.

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.

Baseline predictors of T2D such as metabolic and lifestyle related parameters (lipids, hypertension, central obesity, insulin resistance and smoking), inflammation and statin use as well as HIV-related parameters, HLA B 5701 positivity and cART-composition, were documented.

Material and methods

Ethics

The study was approved by the Karolinska Institutet Ethics Committee (Regionala Etikprövningsnämden, Karolinska Institutet), Stockholm Sweden (2015 2^th of September), and written informed consent from the study subjects was obtained.

Patients

In early 2012 all HIV-patients older than 50 years received written and verbal information about the study and those who gave informed consent verbally were included. Out of 573 patients 570 agreed to participate.

At baseline the 570 eligible patients were analysed cross-sectionally. Of these, one percent (7/570) had T1D and 10% (58/570) had T2D, Fig 1. 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.

Inclusion criteria for the study were: 1. Having a verified HIV-1 infection being treated at Venhälsan, South Hospital, Stockholm. 2. Born before the 1^st of January 1963. 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.

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 [22] and a yearly evaluation of all patients includes the fasting testing of total cholesterol, HDL- and LDL cholesterol, triglycerides, fasting insulin and glucose, and high sensitivity C-reactive Protein (hsCRP). Also, HIV-RNA, CD4, blood pressure, length, weight, BMI, waist and hip circumference and routine hematological, renal and liver tests are documented. All patient data were available for this study and collected from patients´ medical records and assembled in an anonymized database including all results from the yearly evaluation at baseline. Also, date of HIV-diagnosis, HLA B 5701 status, date of cART start, time with known HIV-infection (months), the lowest (nadir) CD4, time (months) with CD4 < 200 x10⁶/L (as defined by the period from the first CD4 value < 200 x10⁶/L up to the first CD4 value > 200 x10⁶/L), the lowest (nadir) CD4/CD8 ratio, the initial HIV-RNA, the highest HIV-RNA, length of any cART interruption longer than 1 month, smoking history, history of treatment with the d-drugs Stavudine (d4t) and Didanosine (DDI) (months), actual CD4 and HIV-RNA and all on-going medication, both cART and medications for co-morbidity, were obtained.

Insulin resistance was defined using the homeostasis model assessment for insulin resistance (HOMA-IR) ((fasting insulin (mIU/l) x fasting glucose (mmol/l))/22.5) in all non-diabetic patients. Although a fasting HOMA-IR provides a valid surrogate marker to assess peripheral insulin sensitivity in epidemiological studies in subjects without diabetes there is no consensus in the literature to define the optimal cut-off value [23, 24].

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]. 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.

Non-HDL cholesterol was calculated as the difference between total cholesterol and HDL cholesterol. Hypertension was defined by repeated BP ≥140/90 mmHg on at least two different occasions or on-going antihypertensive treatment. Central obesity was defined by waist circumference ≥94 cm and ≥80 cm for men and women, respectively.

Outcomes

The patients in the cohort were followed up from baseline until the last yearly control, loss to follow up or death. All files were re-reviewed regarding the most recent testing for T2D and insulin resistance the 1^st of May 2020. The primary outcome was a diagnosis of T2D. Also, development of insulin resistance was one outcome of interest.

Statistical analysis

Descriptive statistics were used to provide an overview of all HIV and metabolic variables. Patient data are presented as median with 95% confidence interval for continuous variables and numbers and percentages for categorical variables. Fishers exact test was used to compare proportions. The significance level was set at p <0.05. T2D in the cohort was analysed using univariate logistic regression to obtain odds ratio (OR) for the association between the dependent variable and the independent variables. In the full multivariate logistic regression, all factors with p-values below 0.2 in the univariate analysis were entered and controlled for age. The patients were followed up until moving to another city, death or the last yearly test before 1^st of May 2020. The last value was carried forward and used in the analysis. The statistic program SPSS, version 25 (IBM Svenska AB, 16492 Stockholm), was used for the analysis.

Results

Description of the prospectively followed cohort

The cohort consisted of 87% (n = 440) males and 13% (n = 65) females. Of the males 89% (n = 391) were Caucasians, 5% (n = 23) of Latin origin, 3% (n = 14) of African descent, 1% (n = 5) from the Middle East and 2% (n = 7) from Asia. Of the females 55% (n = 36) were Caucasians, 8% (n = 5) of Latin origin, 34% (n = 22) of African descent and 3% (n = 2) from Asia.

The majority (98%) were infected through sexual contact: 393 were men who have sex with men (MSM), 35 were heterosexually infected men, 11 were infected through iv drug use. Of the females 62 were sexually infected and 4 through iv drug use.

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).

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%)

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The CD4 count had increased from less than 200 x10⁶/L to 600 x10⁶/L, Table 1.

The majority had a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimen, one third were on protease inhibitors (PIs) and approximately 20% on an integrase inhibitor. The only integrase inhibitor used at baseline was Raltegravir, Table 1.

Insulin resistance occurred in 30% (153/505), Table 1. Hyperlipidemia and hypertension were common. Treatment with an ACE inhibitor occurred in 17% and with an Angiotensin II antagonist in 8%, Table 1.

Development of T2D and insulin resistance at follow up

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, 7% (36/505) (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 prevalence of either T2D or insulin resistance was 46% (232 (153+79)/505) at follow up, Fig 2.

Death occurred in 8% (42/505) (mortality rate 1.2/100 patient-years).

Predictors of T2D at follow up

At follow up high triglycerides, central obesity, statin treatment and insulin resistance at baseline were associated to T2D development in univariate and multivariate analysis, controlled for age. Neither HIV-related factors nor HLA B5701 status or a history of Didanosine or Stavudine usage had any significant influence on T2D development, Table 2.

Table 2. 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

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Characteristics of the HLA B5701 positive patients

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 3. 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).

Table 3. 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

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Discussion

In this study multiple factors were analysed in PLHIV 50 years or older. T2D and insulin resistance were documented at baseline and during a 7.25 year follow up in a cohort without diabetes. The main findings were that both the prevalence and the incidence of T2D were considerable. At baseline, T2D was about twice as common as in the general Swedish population where the prevalence of T2D requiring treatment was 4.4% in 2013 [27]. During follow up 9% developed T2D, the incidence being 1.2/100 patient years, 3 times higher than in the general Swedish population. We found T2D to develop more often in males than in females, while the development of insulin resistance was equally common.

Well known T2D risk factors, such as insulin resistance, central obesity and hypertriglyceridemia as well as receiving statin treatment but no specific HIV or cART related factors remained predictive of developing T2D after multivariate analysis. Our results parallel those of a similar Italian study where obesity and hypertriglyceridemia were associated with T2D development [28]. In a London study of a similar, but more ethnically diverse group than ours, hypertension and liver steatosis as well as weight gain and longer time with known HIV-infection were found to be predictors of T2D [29].

Comparing prevalence and incidence of T2D in patients with HIV-infection among different international studies is complicated by varying age spans, time of HIV-infection and cART composition. The fairest comparison might be to a Canadian study, similar to ours, which found a T2D incidence of 1.6/100 patient-years, 1.4 times higher than in the general population [30]. In our study the occurrence of T2D at follow up (approximately 18% if the 9% of the baseline population is added to the 9% of the prospectively followed cohort) was higher than in the North American AIDS Cohort Study (MACS) (14%) [31], a recent French study of well-treated patients with an age of 60 or older (14.2%) [32] and a cross-sectional study from the London area (15.1%). In the latter study the prevalence increased from 6.8% over 10 years and contributed to a prevalence of 2.4 times higher than in the general population [29]. On the other hand, our incidence was lower than in both a Spanish cohort study, followed for 2 years after starting cART (2.8/100 patient years) [33], and the MACS cohort (4.7/100 patient years). However, in the MACS study many patients were on first generation protease inhibitors, known to be diabetogenic [31].

Furthermore, our incidence was slightly lower than in a metanalysis which included 44 studies (1.37/100 patient years) [34]. In a Swiss cohort study with over 8000 patients including 2683 patients, 50 years or older, the T2D incidence was age dependent: 0.47/100 person-years in age group 50–64 years which increased to 0.86/100 person-years in those over 64 years [35].

In the current cohort study increased serum lipid levels were common. Lipid-lowering therapy with statins is considered to prevent CVD and decrease all-cause mortality [36, 37]. Statins have also been implicated in having a dose dependent diabetogenic effect [38]. In contrast to the Italian study, we could document an association between statin therapy and T2D development [28]. The diverging results might be explained by differences in prescribing practice and other unknown factors. At our clinic statins are mainly recommended in PLHIV with high cardiovascular risk which could explain the association. In contrast to the Italian study, we failed to find any association between T2D development and historical exposure to Stavudine or Didanosine [28].

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.

With today’s well tolerated and safe antiviral drugs, it is uncertain how much, if any, HIV will impair life expectancy in a non-smoking patient with a healthy lifestyle starting cART early after seroconversion. However, the increased T2D risk as well as other factors such as higher levels of inflammatory markers, might impact all-cause mortality [39].

One strength of the current study is the high number of factors that was followed. Another strength is the long term follow up period. However, there are limitations. We have not systematically studied HbA1c levels, since this is not recommended in HIV-infection [11]. Although oral glucose challenge test (OGTT) would give more information about impaired glucose tolerance we consider increased HOMA-index to be an acceptable, simple and patient-friendly surrogate marker for insulin resistance. A HOMA-IR of 3.0 was chosen, -partly from other large studies [23–25], but also due to our own experience. Our finding that patients with insulin resistance have a more than doubled risk to develop T2D strengthens the relevance of HOMA-IR defined insulin resistance. Other weaknesses of the study include the relatively few females and the relatively ethnically homogeneous study group. We also lacked data about weekly physical activity and liver steatosis which would have added valuable information.

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.

In summary, risk factors for T2D in PLHIV are similar to the general population. Our findings underline the importance of focusing PLHIV with central obesity, hypertriglyceridemia, insulin resistance and statin use on lifestyle interventions which can prevent or postpone manifest T2D and could be used as strong motivators in well treated HIV-infection. Recently the European guidelines for cardiovascular prevention were updated with focus on: No tobacco, low intake of saturated fat and high intake of full grain products, vegetables, fruit, fish and regular physical activity and to aim at attaining normal body measurements and blood pressure [41]. Continuous studies of metabolic parameters in well treated PLHIV are important.

Supporting information

S1 Dataset

(XLSX)

Click here for additional data file.^{(315.1KB, xlsx)}

Acknowledgments

We thank all the patients who participated in this project and the personal at Venhälsan, Södersjukhuset.

Data Availability

All relevant data are within the paper and its S1 Dataset.

Funding Statement

Physicians against AIDS research fund (Läkare mot AIDS forskningsfond).

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PLoS One. doi: 10.1371/journal.pone.0254079.r001

Decision Letter 0

Graciela Andrei

31 Mar 2021

PONE-D-20-38599

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

PLOS ONE

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Reviewer #2: Yes

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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.

**********

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Reviewer #1: No

Reviewer #2: No

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Attachment

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PLoS One. 2021 Jun 30;16(6):e0254079. doi: 10.1371/journal.pone.0254079.r002

Author response to Decision Letter 0

24 Apr 2021

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:

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”.

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.”

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.

Attachment

Submitted filename: Responses to the reviewers.docx

Click here for additional data file.^{(47.1KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0254079.r003

Decision Letter 1

Graciela Andrei

18 May 2021

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,

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

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. 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'.
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An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

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.

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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: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

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?

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

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.

**********

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Reviewer #1: No

Reviewer #2: No

PLoS One. 2021 Jun 30;16(6):e0254079. doi: 10.1371/journal.pone.0254079.r004

Author response to Decision Letter 1

26 May 2021

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.

Attachment

Submitted filename: Response to the reviewers_R2.docx

Click here for additional data file.^{(49.8KB, docx)}

PLoS One. doi: 10.1371/journal.pone.0254079.r005

Decision Letter 2

Graciela Andrei

11 Jun 2021

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,

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

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'.

We look forward to receiving your revised manuscript.

Kind regards,

Graciela Andrei

Academic Editor

PLOS ONE

Journal Requirements:

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

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?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

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.

**********

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Reviewer #1: No

PLoS One. 2021 Jun 30;16(6):e0254079. doi: 10.1371/journal.pone.0254079.r006

Author response to Decision Letter 2

14 Jun 2021

Responses to the minor comments:

Reviewer #1: Minor Concerns:

Re: Material and Methods

This is a typo, corrected to born before the 1st of January 1963 in the revised manuscript

Re: Results:

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”

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PLoS One. doi: 10.1371/journal.pone.0254079.r007

Decision Letter 3

Graciela Andrei

21 Jun 2021

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,

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Reviewers' comments:

PLoS One. doi: 10.1371/journal.pone.0254079.r008

Acceptance letter

Graciela Andrei

22 Jun 2021

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.

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Associated Data

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S1 Dataset

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Data Availability Statement

All relevant data are within the paper and its S1 Dataset.

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PERMALINK

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

Roles

Abstract

Background

Setting

Methods

Results

Conclusion

Introduction

Material and methods

Ethics

Patients

Fig 1. Proportions of T1D, T2D and insulin resistance in the cross-sectional analysis at baseline (n = 570).

Procedure and follow up

Outcomes

Statistical analysis

Results

Description of the prospectively followed cohort

Table 1. Descriptive population data of the patients without diabetes (n = 505) at baseline.

Development of T2D and insulin resistance at follow up

Fig 2. Proportions of T1D, T2D and insulin resistance in the prospectively followed cohort at follow up (n = 505).

Predictors of T2D at follow up

Table 2. HIV-parameters, treatment, metabolic and inflammatory factors at baseline in relation to T2D development during follow up (n = 505).

Characteristics of the HLA B5701 positive patients

Table 3. Uni and multivariate analysis regarding T2D in all patients including patients with diabetes (n = 570) at baseline.

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Decision Letter 0

Graciela Andrei

Roles

Author response to Decision Letter 0

Decision Letter 1

Graciela Andrei

Roles

Author response to Decision Letter 1

Decision Letter 2

Graciela Andrei

Roles

Author response to Decision Letter 2

Decision Letter 3

Graciela Andrei

Roles

Acceptance letter

Graciela Andrei

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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