Effects of antiretroviral therapy on glycemic and inflammatory indices in people living with HIV (PLWH)

Abstract

Background

This study explores the relationship between different ART therapy based on NRTIs, and inflammatory markers, along with fasting blood glucose levels in treatment-naïve people living with HIV (PLWH).

Methods

We retrospectively analyzed the variations in fasting blood glucose and inflammatory markers and their relationship with different ART regimens in 497 treatment-naïve PLWH at the ART clinic of Zhongnan Hospital of Wuhan University from June 2018 to March 2022.

Results

From baseline to 24 months, fasting blood glucose, systemic immune-inflammation index (SII), pan-immune-inflammation value (PIV) and lymphocyte-to-monocyte ratio (LMR) in PLWH receiving ART increased, while neutrophillymphocyte ratio (NLR) decreased (p < .05). In the NNRTIs group, fasting blood glucose, SII, PIV and LMR were higher than before (p < .05). In the INSTIs group, fasting blood glucose and LMR increased (p < .05), while NLR was lower (p < .05). Compared to the INSTIs, fasting blood glucose in the NNRTIs group was higher at 12 and 24 months (p < .05). At 24 months, both NLR and SII were higher in the NNRTIs group than in the INSTIs group (p < .05).

Conclusions

Despite the virus suppression, fasting blood glucose and certain inflammatory markers in PLWH can gradually increase. Compared to NNRTIs, the INSTIs regimen was associated with favorable alterations in the levels of glucose and inflammatory markers.

Keywords

HIV blood glucose inflammatory markers non-nucleoside reverse transcriptase inhibitors integrase strand transfer inhibitors antiretroviral therapy

Introduction

Currently, more than 37 million people are living with HIV-1, which has become a critical global public health issue.¹ Before the advent of ART in the late 1990s, HIV infection was likely to develop into AIDS, leading to frequent opportunistic infections and death. The extensive use of ART has largely transformed HIV infection into a chronic disease condition.² At present, the most commonly used regimens in China include the combination of nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) and/or integrase strand transfer inhibitors (INSTIs).³ But HIV infection and the usage of ART regimens are associated with metabolic and endocrine perturbations, and people living with HIV (PLWH) may be at risk of accelerating CVD and metabolic syndrome.^2,4,5 A modeling study also shows that 73% of PLWH would be aged 50 years and 78% of PLWH will have CVD by the year 2030.⁶

Systemic inflammation had been proven to increase the risk of CVD and could independently predict the occurrence of future cardiovascular events such as myocardial infarction.^7–10 Persistent inflammation may increase the incidence of subclinical atherosclerosis, myocardial infarction and stroke, and increase CVD-related mortality among PLWH.^11–13 In addition, inflammatory reactions expressed by abnormal blood indicators are commonly observed in PLWH.^14,15 Research has shown that total lymphocyte count, total white blood cell count and platelet count are suggested as surrogate markers of AIDS to reflect the prognosis of AIDS patients, especially in developing countries with limited financial resources.^16,17 Nevertheless, most of these markers have not been routinely adopted. Therefore, furthering our studies is essential to determine better inflammatory response markers in the HIV infection environment for intervention to reduce the incidence of chronic diseases such as CVD and metabolic syndrome in PLWH at an early stage.

Some new biomarkers of inflammation, such as NLR (neutrophil-to-lymphocyte ratio), PLR (platelet-to-lymphocyte ratio), SII (neutrophil count x platelet count/lymphocyte count), PIV (pan-immune inflammation value) and LMR (lymphocte-to-monocyte ratio), which can be measured in peripheral blood, has been proven by many studies to be related to the incidence of cardiovascular events.^18–22 Research data showed that NLR ≥2.15 was the independent predictor of coronary artery disease (CAD),²³ and NLR was markedly enhanced in patients with severe CAD. Furthermore, other researches had demonstrated that the NLR in the INSTI group was lower than in the NNRTIs group.²⁴ Higher SII (either as a continuous or categorical variable) had been demonstrated to be substantially linked to an increased risk of dying from CVD.²⁵ Some researches indicated a correlation between high PLR and CAD.²⁶ The PIV, a novel metric, was found to be more effective in predicting primary and secondary outcomes in STEMI patients than NLR, PLR and SII.²² To our knowledge, there has been no comprehensive study evaluating the correlation between PLWH and the aforementioned indicators. The aim of our study was to investigate the changes in these inflammatory markers and blood glucose levels in PLWH who have been receiving ART for 24 months, as well as the effect of different NRTIs-based antiretroviral drugs on these inflammatory markers and blood glucose. Appropriate lifestyle and drug interventions can be adopted in the early stage of the disease to reduce the inflammatory response, thus lowering the occurrence of adverse prognosis events.

Methods

Study environment and population

Census sampling was used, and we collected electronic medical records for a retrospective study from 497 eligible treatment-naïve PLWH who were in the ART clinic of Zhongnan Hospital of Wuhan University, from June 2018 to March 2022, which provides HIV/AIDS interventions including free diagnosis, treatment and monitoring. They were followed up for minimum of 2 years at the ART Clinic and consistently adhered to the designated treatment plan.

Inclusion criteria and exclusion criteria

Inclusion criteria were as follows: (1) All patients were older than 18 years old, and were treatment-naïve PLWH; (2) PLWH having at least three follow-up measurements of Hematological indicators and fasting blood glucose; (3) Receiving first-line ART regimens consisted of 2 NRTIs in combination with 1 NNRTI, or 2 NRTIs in combination with 1 INSTI; (4) PLWH who constantly and regularly maintained the assigned treatment regimen at least during the study period.

Exclusion criteria were as follows: (1) PLWH with diabetes, coronary heart disease, hypertension and other underlying diseases; (2) Patients with severe liver, kidney, heart, brain and other dysfunctions; (3) The presence of viral hepatitis, active syphilis, tuberculosis, autoimmune diseases and other active infectious diseases; (4) Women who were known to be pregnant, lactating, or intending to become pregnant during the study; (5) Those did not regularly conduct follow-up testing in ART clinics after starting ART therapy; (6) Receiving protease inhibitors (PIs) or other ART treatment regimens; and (7) Those who had poor compliance and unable to cooperate with treatment and intervention.

Data collection

The collected data included patient demographics (age, gender, BMI, smoking and drinking history), absolute T lymphocyte count, absolute auxiliary/induced T lymphocyte count, HIV viral load duration of ART use and types of ART regimens. Besides, the fasting blood glucose and hematological indicators (including white blood cells, red blood cells, platelets, neutrophils, etc) were collected at baseline, 12 and 24 months of follow-up. The data came from the medical records and laboratory test results registered in the hospital management system. We performed a review of patient databases, validated the type of treatment patients received and formed NRTI-based treatment groups for NNRTIs and INSTIs.

Statistical analysis

SPSS (SPSS26.0) software was used for data management and statistical analysis. The variables of normal distribution were expressed as the mean ± standard deviation and compared to t test. Variables with skewed distribution are represented by median and quartile intervals, and compared by rank sum test. The categorical data are expressed as absolute frequencies and percentages, using χ² test. In addition, Wilcoxon signed rank sum test was used to compare the changes in blood glucose and inflammatory markers in 0, 12, 24 months in PLWH using ART and with different ART treatments. The mean changes of indicators from the baseline to 24 months with ART drugs and different ART treatment groups were calculated, and the difference between the NNRTIs group and the INSTIs group were compared by Rank sum test. Double-tailed p < .05 was considered statistically significant.

Results

General characteristics of the study participants

There were 497 patients included in this study. According to the ART medication plan, there were 350 patients in the NNRTIs group and 147 patients in the INSTIs group. The median age of the PLWH was 31 years old. The time point of the baseline data is month 0, which is following an HIV diagnosis in the Table 1. Among them, the proportion of men was higher than women (94.0% vs 6.0%, p < .05), and there were no significant differences between the two groups in other indicators (Table 1).

Table 1.

Clinical features between all people living with HIV (PLWH), NNRTIs and INSTIs group.

Variables	Total population (n = 497)	NNRTIs (n = 350)	INSTIs (n = 147)	P a
Age (years)	31 (25, 44)	31 (25, 46)	32 (27, 39)	0.598
Sex
Men	467 (94.0%)	323 (69.2%)	144 (30.8%)	0.015
Women	30 (6.0%)	27 (90.0%)	3 (10.0%)
Height (m)	1.73 (1.70,1.77)	1.73 (1.70,1.77)	1.73 (1.69,1.78)	0.752
Weight (kg)	64 (58,72)	65 (60,73)	64 (56,71)	0.372
BMI (kg/m²)	21.60 (19.59,23.33)	21.58 (19.59,24.14)	21.60 (19.55,22.65)	0.247
History of smoking	68 (13.6%)	45 (66.2%)	23 (33.8%)	0.279
History of drinking	64 (12.9%)	43 (67.2%)	21 (32.8%)	0.218
Absolute count of auxiliary/inducible T lymphocytes (uL)	255.64 ± 163.17	266.31 ± 153.21	232.00 ± 187.29	0.520
Absolute T lymphocyte count (uL)	1200.35 ± 599.56	1295.25 ± 618.78	990.21 ± 513.85	0.115
HIV Viral load (cps/ml)	33100 (8733,59225)	29350 (10977,41075)	38450 (6182,111000)	0.425
The fasting blood glucose (mmol/L)	5.10 (4.76,5.55)	5.11 (4.80,5.56)	5.06 (4.71,5.52)	0.375
NLR	1.57 (1.13,2.38)	1.50 (1.10,2.32)	1.74 (1.26,2.49)	0.062
PLR	125.00 (92.36,163.13)	124.08 (92.55,157.58)	129.25 (91.97,170.30)	0.278
SII	333.95 (212.71,526.69)	317.01 (207.46,512.97)	355.09 (225.58,540.33)	0.186
PIV	133.58 (80.15,239.23)	131.11 (75.13,232.91)	151.29 (87.57,260.30)	0.115
LMR	4.11 (3.09,5.16)	4.19 (3.12,5.30)	4.00 (2.94,5.03)	0.084
Monocytes counts	0.42 (0.33,0.51)	0.42 (0.33,0.50)	0.43 (0.34,0.53)	0.113
HCT	43.50 (40.55,45.60)	43.30 (40.60,45.50)	43.80 (40.10,45.70)	0.374
RDW	12.90 (12.30,13.60)	12.80 (12.30,13.50)	13.10 (12.30,14.20)	0.082
MPV	9.90 (9.38,10.50)	9.90 (9.40,10.50)	10.00 (9.30,10.50)	0.687

Data are median (25th to 75th percentile) or mean ± standard.

^aP for trend was calculated using rank sum test for variables of skewed distribution,t test for variables variables of normal distribution and chi square test for categorical variables, p < .05 was considered as statistically significant.

Comparison of fasting blood glucose and inflammatory markers between baseline, 12 and 24 months

In PLWH receiving ART, fasting blood glucose and LMR were higher than baseline at 12 months, and at 24 months, in addition to fasting blood glucose and LMR, SII and PIV were also higher than baseline, while NLR was lower than baseline at 12 and 24 months (p < .05). In the NNRTIs group, fasting blood glucose, SII, PIV and LMR increased compared to the baseline at 12 and 24 months (p < .05). In the INSTIs group, NLR and PLR decreased and LMR increased compared to the baseline at 12 months, furthermore, fasting blood glucose and LMR were higher than baseline and NLR was lower than baseline at 24 months (p < .05). (Tables 2 and 3).

Table 2.

Comparisons of fasting blood glucose and inflammatory markers at baseline and 12 months.

Variables	Total population		NNRTIs		INSTIs
Variables	12 months	P a	12 months	P a	12 months	P a
The fasting blood glucose (mmol/L)	5.31 (5.01,5.67)	<0.001	5.35 (5.04,5.72)	<0.001	5.23 (4.92,5.57)	0.058
NLR	1.51 (1.18,2.15)	<0.001	1.52 (1.18,2.16)	0.147	1.47 (1.16,2.14)	0.002
PLR	120.33 (97.64,156.94)	0.06	121.10 (98.56,156.81)	0.751	117.67 (94.12,158.33)	0.005
SII	346.35 (261.15,489.11)	0.158	355.12 (261.45,495.23)	0.020	325.80 (254.44,481.12)	0.333
PIV	140.45 (98.84,213.70)	0.26	137.24 (99.51,211.00)	0.042	143.50 (94.14,224.95)	0.358
LMR	4.66 (3.74,5.73)	<0.001	4.67 (3.75,5.73)	<0.001	4.53 (3.69,5.73)	<0.001

Data are median (25th to 75th percentile).

^aP for trend was calculated using Wilcoxon signed rank sum test to compare the differences in blood glucose and inflammation indexes between baseline and 12 months, and p < .05 was considered statistically significant.

Table 3.

Comparisons of fasting blood glucose and inflammatory markers at baseline and 24 months.

Variables	Total population		NNRTIs		INSTIs
Variables	24 months	P a	24 months	P a	24 months	P a
The fasting blood glucose (mmol/L)	5.48 (5.17, 5.83)	<0.001	5.55 (5.23, 5.91)	<0.001	5.38 (5.06, 5.70)	<0.001
NLR	1.53 (1.18, 2.05)	0.014	1.61 (1.22, 2.10)	0.713	1.43 (1.10, 1.88)	<0.001
PLR	121.56 (98.77, 151.13)	0.385	122.93 (99.37, 153.86)	0.822	116.42 (96.70, 145.23)	0.055
SII	363.25 (265.95, 488.75)	0.023	379.52 (270.74, 512.05)	<0.001	335.15 (252.10, 441.38)	0.130
PIV	146.37 (97.04, 233.03)	0.029	149.49 (97.68, 248.45)	<0.001	138.24 (92.02, 208.11)	0.095
LMR	4.65 (3.71, 5.74)	<0.001	4.62 (3.68, 5.72)	<0.001	4.79 (3.80, 5.82)	<0.001

Data are median (25th to 75th percentile).

^aP for trend was calculated using Wilcoxon signed rank sum test to compare the differences in blood glucose and inflammation indexes between baseline and 24 months, and p < .05 was considered statistically significant.

Changes of fasting blood glucose and inflammatory markers at baseline, 12 and 24 months

The changes in fasting blood glucose and inflammatory markers at baseline, 12 months and 24 months in all PLWH on ART, NNRTIs and INSTIs groups were shown in Figures 1 and 2. In PLWH in ART, blood glucose, SII, PIV and LMR showed an increasing trend, while NLR and PLR showed a decreasing trend. Among them, LMR decreased in 24 months compared with 12 months, and PLR and NLR increased compared with 12 months. In the NNRTIs group, fasting blood glucose, NLR, SII, PIV and LMR showed an upward trend, and PLR showed a downward trend. Among them, compared with 12 months, LMR showed a downward trend and PLR showed an upward trend in 24 months. In the INSTIs group, fasting blood glucose and LMR showed an upward trend, while NLR, PLR, SII and PIV all showed a downward trend.

Figure 1.

Changes of fasting blood glucose and inflammatory markers over time. A, Changes of fasting blood glucose in all three groups. B, Changes of NLR in all three groups. C, Changes of PLR in all three groups. D, Changes of SII in all three groups. E, Changes of PIV in all three groups. F, Changes of LMR in all three groups. * means p < .05.

Figure 2.

Average alterations from baseline to 24 months in each group. A, mean changes of fasting blood glucose, LMR and NLR. B, mean changes of PLR, SII and PIV. * means p < .05, *** means p < .001.

Effects of different drug regimens on fasting blood glucose and inflammatory markers

At 12 months, fasting blood glucose was lower in the INSTIs group than that in the NNRTIs group (p < .05). At 24 months, fasting blood glucose, NLR and SII were lower in the INSTIs group compared with the NNRTIs group (p < .05). (Table 4, Figure 2).

Table 4.

Comparison of fasting blood glucose and inflammatory markers between NNRTIs and INSTIs groups.

Variables	12 months			24 months
Variables	NNRTIs	INSTIs	P a	NNRTIs	INSTIs	P a
The fasting blood glucose (mmol/L)	5.35 (5.04, 5.72)	5.23 (4.92, 5.57)	0.036	5.55 (5.23, 5.91)	5.38 (5.06, 5.70)	0.001
NLR	1.52 (1.18, 2.16)	1.47 (1.16, 2.14)	0.303	1.61 (1.22, 2.10)	1.43 (1.10, 1.88)	0.003
PLR	121.10 (98.56, 156.81)	117.67 (94.12, 158.33)	0.341	122.93 (99.37, 153.86)	116.42 (96.70, 145.23)	0.107
SII	355.12 (261.45, 495.23)	325.80 (254.44, 481.12)	0.329	379.52 (270.74, 512.05)	335.15 (252.10, 441.38)	0.008
PIV	137.24 (99.51, 211.00)	143.50 (94.14, 224.95)	0.952	149.49 (97.68, 248.45)	138.24 (92.02, 208.11)	0.075
LMR	4.67 (3.75, 5.73)	4.53 (3.69, 5.73)	0.459	4.62 (3.68, 5.72)	4.79 (3.80, 5.82)	0.294

Data are median (25th to 75th percentile).

^aP for trend was calculated using rank sum test for continuous variables, p < .05 was considered as statistically significant.

Discussion

Although persistent associations between inflammatory markers and CVD in PLWH have been demonstrated, few biomarkers are utilized clinically.^27–29 The indicators we studied are relatively simple to obtain in a clinical setting. In our study, we discovered that despite ART, fasting blood glucose and certain inflammatory markers in PLWH still gradually elevated, suggesting that the inflammatory response might remain relatively active in PLWH. Additionally, compared to the NNRTIs group, the NLR, SII and fasting blood glucose in INSTIs group were lower, and in INSTIs group, the NLR, PLR, SII and PIV showed a downward trend, while making LMR display an upward trend, which would have a beneficial impact on the inflammatory response.

We found that the fasting blood glucose of PLWH who used ART during the follow-up would increase, and the fasting blood glucose level of the INSTIs group was lower than that in the NNRTIs group, which suggested that the metabolic dysfunction of the NNRTIs group might be more severe. In the MACS cohort, which evaluated the risk of diabetes events in prediabetic subjects from 1999 to 2019, the investigators found that PLWH had a 40% higher risk of developing diabetes than non-infected individuals, even if they were younger and with a lower BMI, and history of AIDS was linked to incident diabetes.³⁰ Tadesse et al investigated the prevalence of glucose metabolic disorders (GMDs) in PLWH receiving combination antiretroviral therapy (cART) based on efavirenz and atazanavir/ritonavir, and found a higher prevalence of GMDs in adults receiving efavirenz compared to atazanavir/ritonavir.³¹ Compared to the non-INSTIs group in the WIHS study, patients who used INSTIs saw a higher rise in HbA1c and a lower incidence of insulin resistance. However, studies also showed INSTIs may cause insulin resistance,³² weight gain,^33–36 an increased risk of developing diabetes mellitus, and even diabetic ketoacidosis (DKA). Regarding how INSTIs and NNRTIs affect blood sugar, there is some debate. It is unclear if INSTIs are the recommended course of treatment for patients with a history of diabetes because the PLWH in our study were all NRTIs-based treatments and there was a small sample size included in our study. The different effects on PLWH’s blood sugar between INSTIs and NNRTIs require further prospective clinical trials.

HIV infection can produce activation of inflammatory and coagulation pathways with elevated levels of plasma inflammatory and coagulation markers, both of which contribute to the occurrence of serious non-AIDS events,^37,38 even in virologically suppressed patients it can lead to increased all-cause mortality.^11,39 Raffetti et al conducted an Italian multicentre cohort study from 2000 to 2012 and found that NLR and PLR could reflect the severity of underlying systemic inflammatory processes and coagulation disturbances that lead to increased mortality in PLWH.⁴⁰ Masyuko et al studied the correlation between inflammatory markers, HIV status and traditional CVD risk factors. They found that virally suppressed PLWH still had higher levels of systemic inflammatory biomarkers, and this was not associated with traditional CVD risk factors.⁴¹ Elzarki et al had done a single time point, cross-sectional, observational study to determine the effect of INSTIs compared with NNRTIs regimens on CVD risk. They found that NLR was lower in the INSTIs group, and the mean fasting glucose level was also lower in the INSTIs than in the NNRTIs, therefore they speculated that the INSTIs regimen might provide a better CVD risk profile compared to the NNRTIs-based ART regimen.²⁴ These studies are similar to our findings. Different from the above studies, our study not only included the follow-up observation of blood glucose, NLR and PLR, but we also had less noticed inflammatory markers, including SII, PIV and LMR. We found that SII and PIV in all PLWH treated with ART and NNRTIs group were still elevated in 2 years, while in the INSTIs group, both of them were decreased and the SII was lower than that in the NNRTIs group (p < .05), which further support and complement the above researches.

Our study also has several limitations. Firstly, our study was designed as a preliminary study and the results should be interpreted in this context. Therefore, these differences observed in our study might be due to chance and need to be replicated in larger studies. Secondly, our study was not a prospective randomized controlled trial. Although the compliance of included PLWH was good, the results might still be influenced by many confounding factors. In the future, further large-sample prospective randomized controlled trials are needed. Here, it was important to note that our subgroups were based on NRTIs, because PLWH do not respond well to HIV monotherapy. Therefore, our findings might be affected by NRTIs. Thirdly, due to the retrospective nature of the design, any data not recorded in the medical records would have been overlooked. Our study focused only on comparisons of inflammatory markers and fasting blood glucose in each group, but does not addresses risk factors. We lacked data on relevant cardiovascular examination results and CVD endpoints events (such as myocardial infarction) to test whether these inflammatory markers were associated with cardiovascular events or could be used to predict these events.

Conclusion

Our study indicated that despite the combination of ART, the inflammatory response in PLWH was still active and the fasting blood glucose level gradually increased. Compared with PLWH using NNRTIs, the use of INSTIs may slow down the inflammatory response and slow the rise of fasting blood glucose. However, the impact of ART drugs on the prognosis of PLWH and whether INSTIs have better curative effect on patients require follow-up research. We recommend long-term monitoring of fasting blood glucose and inflammatory markers in PLWH for early prevention, intervention and management of related chronic diseases.

Supplemental Material

Supplemental Material - Effects of antiretroviral therapy on glycemic and inflammatory indices in people living with HIV (PLWH)

Supplemental Material for Effects of antiretroviral therapy on glycemic and inflammatory indices in people living with HIV (PLWH) by Fei Li, Shengnan Liu, Rewaan Baheti, Tielong Chen, Bing Zhang, Siyin Wang, Aihong Peng and Jing Wan in International Journal of STD & AIDS.

Footnotes

Acknowledgements

We would like to gratefully acknowledge the support from Zhongnan Hospital of Wuhan University, study participants who participated in this work.

Author contributions

Fei Li, Shengnan Liu and Jing Wan participated in the design of the study. Fei Li, Shengnan Liu and Rewaan Baheti collected and analyzed the data. Fei Li, Shengnan Liu, Rewaan Baheti, Bing Zhang, Siyin Wang and Aihong Peng conceived of the study, and participated in its design and coordination and helped to draft the manuscript. All the authors gave consent to the journal in which the article was submitted, and agree to be accountable for all aspects of the work.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Ethical statement

ORCID iD

Fei Li

Data availability statement

The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.*

Supplemental Material

Supplemental material for this article is available online.

Appendix

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