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Evaluation of inflammatory biomarkers, carotid intima-media thickness and cardiovascular risk in HIV-1 treatment-naive patients

Abstract

INTRODUCTION

Mortality among HIV patients is 3-15 times higher than that among the general population. Currently, most deaths are due to non-infectious diseases. Chronic inflammation and adverse events due to antiretroviral therapy play crucial roles in increasing cardiovascular risk (CVR).

METHODS:

This cross-sectional study aimed to evaluate carotid intima-media thickness (CIMT) and inflammatory biomarkers (D-dimer, ADAMTS13, GDF-15, sICAM-1, MPO, myoglobin, NGAL, SAA, sVCAM-1, and p-selectin) among naïve patients.

RESULTS:

Sixty-seven participants were included: median age, 32 years; males, 82.1%; non-white, 61.1%; higher education level, 62.7%; and exposed to HIV through sexual relationship (men who have sex with men), 68.7%. The median viral load and LTCD4+ value were 42,033 copies/mL and 426 cells/mm³. The prevalence of arterial hypertension was 16.4%; those of diabetes mellitus and dyslipidemia were 3% and 70.1%, respectively. The CIMT was 494.08 (± 96.84mm). The mean vascular age was 33.2 ± 18.9 years, one year longer than the chronological age, without statistical significance.

CONCLUSIONS

The majority of participants had a low CVR (94%). After reclassification, considering the CIMT percentiles, 13 (19.4%) patients had medium/ high CVR, while 54 (80.6%) patients had low CVR. The difference between the proportions of CVR when considering the CIMT and its corresponding percentile was statistically relevant. Body mass index was the only predictor of higher CVR (p = 0.03). No biomarker was found to predict CVR. People living with HIV have a high prevalence of dyslipidemia before ARV therapy.

Keywords:
HIV; Cardiovascular risk; Biomarkers; Inflammation; Intima-media thickness

INTRODUCTION

Infection caused by human immunodeficiency virus (HIV) is the fifth-leading cause of death among adults worldwide11. The Joint United Nations Programme on HIV/AIDS (UNAIDS). Global AIDS Update 2016. Available in: http://www.unaids.org/sites/default/files/media_asset/global-AIDS-update-2016_en.pdf
http://www.unaids.org/sites/default/file...
. The policy of universalizing access to antiretroviral therapy (ART) has been determined to impact on patient survival, changing the profile of the epidemic characterized by the reduction of new cases and mortality11. The Joint United Nations Programme on HIV/AIDS (UNAIDS). Global AIDS Update 2016. Available in: http://www.unaids.org/sites/default/files/media_asset/global-AIDS-update-2016_en.pdf
http://www.unaids.org/sites/default/file...
. Despite this, mortality is still 3 to 15 times higher in the population living with HIV than the general population22. Palella Jr FJ, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med. 1998;338(13):853-60.

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7. Rodger AJ, Lodwick R, Schechter M, Deeks S, Amin J, Gilson R, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS. 2013;27(6):973-9.

8. Baker JV, Peng G, Rapkin J, Abrams DI, Silverberg MJ, MacArthur RD, et al. CD4+ count and risk of non-AIDS diseases following initial treatment for HIV infection. AIDS. 2008 ;22(7):841-8.

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13. Freiberg MS, Bebu I, Tracy R, So-Armah K, Okulicz J, Ganesan A, et al. D-dimer levels before HIV seroconversion remain elevated even after viral suppression and are associated with an increased risk of non-AIDS events. PLoS ONE. 2016;11(4):e0152588.

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15. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):2506-12.

16. Stein JH. Cardiovascular risk and dyslipidemia management in HIV-infected patients. Top Antivir Med . 2012;20(4):129-33.

17. Grinspoon SK. Cardiovascular disease in HIV: traditional and nontraditional risk factors. Top Antivir Med . 2014;22(4):676-9.

18. Stein JH, Currier JS, Hsue PY. Arterial disease in patients with human immunodeficiency virus infection: what has imaging taught us? JACC Cardiovascular imaging. 2014;7(5):515-25.

19. Klein DB, Leyden WA, Xu L, Chao CR, Horberg MA, Towner WJ, et al. Declining relative risk for myocardial infarction among HIV-positive compared with HIV-negative individuals with access to care. Clin Infect Dis . 2015;60(8):1278-80.

20. Freiberg MS, Chang CH, Kuller LH, Skanderson M, Lowy E, Kraemer KL, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173(8):614-22.
-2121. Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, et al. Increased risk of myocardial infarction in HIV-infected patients in France, relative to the general population. AIDS. 2010;24(8):1228-30.. This increase may be related to chronic immune-inflammatory activity and immunosenescence in HIV33. Deeks SG, Phillips AN. HIV infection antiretroviral treatment, aging and non-AIDS related morbidity. BMJ. 2009;338:a3172.,66. Powderly W. Growing old with HIV - dealing with co-morbidities. Journal of the International AIDS Society 2010;13(Suppl 4):O25.,99. Aberg JA. Aging, inflammation and HIV infection. Top Antivir Med. 2012;20(3):101-5., in addition to the classic risk factors. Inflammatory biomarkers are generally elevated in PLHIV1212. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008 ;5(10):e203.,2222. Bahrami H, Budoff M, Haberlen SA, Rezaeian P, Ketlogetswe K, Tracy R, et al. Inflammatory markers associated with subclinical coronary artery disease: The multicenter AIDS cohort study. J Am Heart Assoc. 2016;5(6)pii:e003371.

23. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease risk: a consensus satement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr. 2008 ;21(2):93-111.

24. Polak J. Carotid intima-media thickness; an early marker of cardiovascular disease. Ultrasound Q. 2009;25(2):55-61.

25. Tattersall MC, Gassett A, Korcarz CE, Gepner AD, Kaufman JD, Liu KJ, et al. Predictors of carotid thickness and plaque progression during a decade: the Multi-Ethnic Study of Atherosclerosis (MESA). Stroke. 2014;45(11):3257-62.

26. Engelen L, Ferreira I, Stehouwer CD, Boutouyrie P, Laurent S; Reference Values for Arterial Measurements Collaboration. Reference intervals for common carotid intima-media thickness measured with echotracking: relation with risk factors. Eur Heart J. 2013;34(30):2368-80.

27. Hulten E, Mitchell J, Scally J, Gibbs B, Villines TC. HIV positivity, protease inhibitor exposure and subclinical artheroscleroses: a systemic review and metanalysis of observation studies. Heart. 2009;95(22):1826-32.

28. Grunfeld C, Delaney JAC, Wanke C, Currier JS, Scherzer R, Biggs ML, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS. 2009;23(14):1841-9.

29. Tien PC, Benson C, Zolopa AR, Sidney S, Osmond D, Grunfeld C, et al. The study of fat redistribution and metabolic change in HIV infection (FRAM): methods, design, and sample characteristics. Am J Epidemiol. 2006;63(9):860-9.
-3030. Bosch RJ, Zhang X, Sandler NG. Study design issues in evaluating immune biomarkers. Curr Opin HIV AIDS. 2013;8(2):147-54.. These markers have been associated with an increased risk of cardiovascular disease (CVD), opportunistic conditions, and other causes of mortality77. Rodger AJ, Lodwick R, Schechter M, Deeks S, Amin J, Gilson R, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS. 2013;27(6):973-9.,1212. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008 ;5(10):e203.,1313. Freiberg MS, Bebu I, Tracy R, So-Armah K, Okulicz J, Ganesan A, et al. D-dimer levels before HIV seroconversion remain elevated even after viral suppression and are associated with an increased risk of non-AIDS events. PLoS ONE. 2016;11(4):e0152588.,2222. Bahrami H, Budoff M, Haberlen SA, Rezaeian P, Ketlogetswe K, Tracy R, et al. Inflammatory markers associated with subclinical coronary artery disease: The multicenter AIDS cohort study. J Am Heart Assoc. 2016;5(6)pii:e003371.,3131. Guimarães MMM, Greco DB, O Júnior AR, Penido MG, Machado LJC. Distribuição da gordura corporal e perfis lipídico e glicêmico de pacientes infectados pelo HIV. Arq Bras Endocrinol Metab. 2007;51(1):42-51.

32. Graham SM, Rajwans N, Tapia KA, Jaoko W, Estambale BB, McClelland RS, et al. A prospective study of endothelial activation biomarkers, including plasma angiopoietin-1 and angiopoietin-2, in Kenyan women initiating antiretroviral therapy. BMC Infect Dis. 2013;13:263-68.

33. Papasavvas E, Azzoni L, Pistilli M, Hancok A, Reynolds G, Gallo C, et al. Increased soluble vascular cell adhesion molecule-1 plasma levels and soluble intercellular adhesion molecule-1 during antiretroviral therapy interruption and retention of elevated soluble vascular cellular adhesion molecule-1 levels following resumption of antiretroviral therapy. AIDS. 2008 ;22(10):1153-61.

34. Borges AH, O’Connor JL, Phillips AN, Baker JV, Vjecha MJ, Losso MH, et al. Factors Associated with D-Dimer Levels in HIV-Infected Individuals. PLoS One. 2014;9(3):e90978.
-3535. Vos AG, Idris NS, Barth RE, Klipstein-Grobusch K, Grobbee DE. Pro-inflammatory markers in relation to cardiovascular disease in HIV infection. A systematic review. PLoS One . 2016;11(1):e0147484.. Persistent immune activation and inflammation associated with classical factors play an important role in the etiology of CVDs1717. Grinspoon SK. Cardiovascular disease in HIV: traditional and nontraditional risk factors. Top Antivir Med . 2014;22(4):676-9.. The identification of subclinical coronary artery disease, assessed by measuring the carotid intima-media thickness (CIMT), considered as a substitutive marker, may represent an early diagnostic strategy in this population1818. Stein JH, Currier JS, Hsue PY. Arterial disease in patients with human immunodeficiency virus infection: what has imaging taught us? JACC Cardiovascular imaging. 2014;7(5):515-25.,2323. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease risk: a consensus satement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr. 2008 ;21(2):93-111.

24. Polak J. Carotid intima-media thickness; an early marker of cardiovascular disease. Ultrasound Q. 2009;25(2):55-61.

25. Tattersall MC, Gassett A, Korcarz CE, Gepner AD, Kaufman JD, Liu KJ, et al. Predictors of carotid thickness and plaque progression during a decade: the Multi-Ethnic Study of Atherosclerosis (MESA). Stroke. 2014;45(11):3257-62.
-2626. Engelen L, Ferreira I, Stehouwer CD, Boutouyrie P, Laurent S; Reference Values for Arterial Measurements Collaboration. Reference intervals for common carotid intima-media thickness measured with echotracking: relation with risk factors. Eur Heart J. 2013;34(30):2368-80.. The CIMT of PLHIV is thicker than that in the uninfected population2525. Tattersall MC, Gassett A, Korcarz CE, Gepner AD, Kaufman JD, Liu KJ, et al. Predictors of carotid thickness and plaque progression during a decade: the Multi-Ethnic Study of Atherosclerosis (MESA). Stroke. 2014;45(11):3257-62.,2727. Hulten E, Mitchell J, Scally J, Gibbs B, Villines TC. HIV positivity, protease inhibitor exposure and subclinical artheroscleroses: a systemic review and metanalysis of observation studies. Heart. 2009;95(22):1826-32.

28. Grunfeld C, Delaney JAC, Wanke C, Currier JS, Scherzer R, Biggs ML, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS. 2009;23(14):1841-9.
-2929. Tien PC, Benson C, Zolopa AR, Sidney S, Osmond D, Grunfeld C, et al. The study of fat redistribution and metabolic change in HIV infection (FRAM): methods, design, and sample characteristics. Am J Epidemiol. 2006;63(9):860-9.. In this context, the present study evaluated the profiles of the inflammatory biomarkers related to CVDs and the intima-media thickness as predictors of CVD risk in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) patients before antiretroviral therapy.

METHODS

This observational, cross-sectional study was performed among PLWHIV before starting ART, between 2014 and 2015 in a specialized service.

Ethical considerations

The study protocol was approved by the Research Ethics Committee of the Federal University of Minas Gerais (no. 12649713.4.0000.5149).

The inclusion criteria were: age between 18 and 60 years, and both genders with a diagnosis of HIV infection without the prior use of ART. The exclusion criteria were: lack of completion of the protocol for the collection of clinical or laboratory data, pregnancy, or history of chronic non-controlled diseases.

The following information was collected: sociodemographic (age, gender, race, education, and marital status), lifestyle (smoking, alcoholism, and alcohol abuse through the CAGE questionnaire)3636. Willians N. The CAGE questionnaire. Occup Med. 2014;64(6):473-4., systolic and diastolic blood pressure, anthropometric data (weight and height), and biochemical parameters as fibrinogen, 25-hydroxyvitamin D, lipidogram, blood glucose, polymerase chain reaction (PCR) results, in addition to viral load (HIV-PCR), and LTCD4+ lymphocyte count.

The levels of biomarkers related to CVDs were measured using the Human Cardiovascular Disease (Merck Millipore) kit according to the manufacturer’s recommendations3737. MILLIPLEX MAP. Human Cardiovascular Disease (CVD) Magnetic Bead Panel 2 - Cardiovascular Disease Multiplex Assay, HCVD2MAG-67K. Darmstadt: Available in:http://www.merckmillipore.com/BR/pt/product/MILLIPLEX-MAP
http://www.merckmillipore.com/BR/pt/prod...
. Ultrasonography of the carotid arteries was also performed by a single trained examiner, within 10 days after initiation of the treatment. The measurement of CIMT followed the current technical principles2626. Engelen L, Ferreira I, Stehouwer CD, Boutouyrie P, Laurent S; Reference Values for Arterial Measurements Collaboration. Reference intervals for common carotid intima-media thickness measured with echotracking: relation with risk factors. Eur Heart J. 2013;34(30):2368-80.,3737. MILLIPLEX MAP. Human Cardiovascular Disease (CVD) Magnetic Bead Panel 2 - Cardiovascular Disease Multiplex Assay, HCVD2MAG-67K. Darmstadt: Available in:http://www.merckmillipore.com/BR/pt/product/MILLIPLEX-MAP
http://www.merckmillipore.com/BR/pt/prod...

38. Stein JH, Fraizer MC, Aeschlimann SE, Nelson-Worel J, McBride PE, Douglas PS. Vascular age: Integrating carotid intima-media thickness measurements with global coronary risk assessment. Clin Cardiol. 2004;27(7):388-92.
-3939. Howard G, Sharrett AR, Heiss G, Evans GW, Chambless LE, Riley WA, et al. Carotid artery intimal-medial thickness distribution in general populations as evaluated by B-mode ultrasound. Stroke. 1993;24(9):1297-304.. The values of intima-media thickness ​​were expressed in terms of vascular age, based on the vascular age calculator (VAC)3838. Stein JH, Fraizer MC, Aeschlimann SE, Nelson-Worel J, McBride PE, Douglas PS. Vascular age: Integrating carotid intima-media thickness measurements with global coronary risk assessment. Clin Cardiol. 2004;27(7):388-92..

In the descriptive analysis, qualitative variables were summarized as absolute and relative frequencies and quantitative variables were summarized as means and standard deviations or medians and interquartile ranges. The assumption of normality for the probability distribution of the variables was verified using the Shapiro-Wilk test. Comparisons between two quantitative variables were performed using the Kruskal-Wallis test for non-normally distributed variables and analysis of variance for normally distributed variables. The tests were used to compare serum levels of the biomarkers (ADAMTS13, D-dimer, GDF-15, myoglobin, sICAM-1, MPO, p-selectin, lipocalin-2/NGAL, sVCAM-1, and SAA) among the categories of viral load and Framingham risk score. Biomarkers and viral load correlations were analyzed using Spearman’s rank correlation test. Receiver operating characteristic (ROC) curve analysis was used to investigate cardiovascular risk prediction and verify the association of biomarkers with cardiovascular risk and viral load. The log-binomial model was used to evaluate whether biomarkers were predictors of cardiovascular risk. The univariate model of each marker was adjusted with the risk variable (yes or no); markers that had p-values ≤ 0.20 were considered as candidates for the multivariate model. A multivariate model was fitted with all candidates and step-by-step the markers with higher p-values were withdrawn until all significant markers remained at the 0.05 level. The quality of fit of the model was assessed by the deviance and quality measures of the model, i.e., Akaike information criterion, corrected version of the Akaike information criterion, Bayesian information criterion, and consistent Akaike information criterion. The multivariate linear regression model was used to investigate the correlation between the study variables and the thickness of the intima media. It was initiated by univariate adjustment of the simple linear regression model of each group of variables. Within each group, the candidate variables (with p ≤0.20) were selected, adjusting the multivariate models for each group individually with their respective candidate variables and step-by-step, with the variables with the highest p-values being removed until they were all significant at the 0.05 level. The quality of fit was verified by residual analysis (normality, homoscedasticity, and independence). In all applied tests, significance levels of 5% were used.

RESULTS

In this study, out of 105 patients who were screened, 5 did not meet the inclusion criteria, and 9 did not undergo laboratory data collection. Among the 91 patients included in the study, 67 (73.6%) underwent carotid ultrasonography and measurement of biomarkers.

The median age of the participants was 32 (26-41) years, the majority being men who have sex with other men (MSM). Regarding comorbidities, the prevalences of hypertension, diabetes, and dyslipidemia were 16.4%, 3% and 70.1%, respectively. The median viral load was 42,033 (16,189-101,069) copies/mL and the median LTCD4+ lymphocyte count was 426 (262-561) cell/mm³. The median time between diagnosis of HIV infection and initiation of antiretroviral therapy was 4.6 months, ranging from 1 to 301.7 months, as shown in Table 1.

TABLE 1:
Clinical and laboratory characteristics of treatment-naïve people living with HIV, assessed in a reference center, Belo Horizonte, State of Minas Gerais, March 2014 - September 2015.

The mean CIMT was 494.08 (± 96.84mm). The mean vascular age was 33.2 ± 18.9 years, one year longer than the chronological age (32 years), but with no statistical significance. The majority of participants had a low cardiovascular risk (94%) as measured by the Framingham score (Table 2). According to the consensus, individuals with CIMT values greater than or equal to the 75th percentile are considered as high risk and indicate an increased CVD risk2323. Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, et al. Use of carotid ultrasound to identify subclinical vascular disease risk: a consensus satement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr. 2008 ;21(2):93-111.. Thus, after the reclassification, considering the CIMT percentiles, 13 (19.4%) patients had medium/high cardiovascular risk, and 54 (80.6%) patients had low cardiovascular risk. Considering the CIMT measure for the estimation of cardiovascular risk was statistically significant (p = 0.02).

TABLE 2:
Carotid ultrasonography findings and Framingham score of people living with HIV before antiretroviral therapy treatment in a reference center, Belo Horizonte, State of Minas Gerais, March 2014 - September 2015.

ROC curve analysis showed that body mass index was the only predictor of higher cardiovascular risk (p = 0.03) (Table 3). D-dimer and p-selectin presented predictive tendencies (p = 0.06 and 0.06, respectively). D-dimer showed a significant correlation with viral load level, (r = -0.389, p <0.01). P-selectin was uncorrelated to the intima-media thickness, and without statistical significance, i.e. β = -5.57 (95% confidence interval: -12.31-1.18), p = 0.10. There was an association between measured thickness and cardiovascular risk and age.

Variable AUC 95% CI of AUC p-value BMI 0.69 0.52; 0.86 0.03 VL 0.64 0.49; 0.80 0.11 sVCAM-1 0.51 0.35; 0.67 0.89 ADAMTS13 0.55 0.37; 0.73 0.60 D-Dimer 0.33 0.18; 0.48 0.06 GDF15 0.44 0.28; 0.61 0.53 sICAM 0.37 0.22; 0.52 0.16 MPO 0.64 0.48; 0.80 0.11 P-Selectin 0.33 0.17; 0.49 0.06 Lipocalin-2NGAL 0.50 0.31; 0.70 0.99 SAA 0.53 0.35; 0.71 0.74 Myoglobin 0.53 0.35; 0.72 0.71 BMI: body mass index; VL: viral load; 95% CI: confidence interval 95%; AUC: area under the curve; CI: confidence interval; sVCAM-1: vascular adhesion molecule1; ADAMTS13: Disintegrin and Metalloproteinase with Thrombospondin motifs; GDF15: growth differentiation factor 15; sICAM: soluble molecule of intercellular adhesion; MPO: myeloperoxidase; 2NGAL: vascular growth factors angiopoietin; SAA: serum amyloid A.

DISCUSSION

The majority of participants were male and MSM with a mean age of 32 years. Being a young population, there were low prevalences of arterial hypertension and diabetes mellitus. However, the prevalence of smoking was higher than that reported in Brazilian national surveys4040. Instituto Brasileiro de Geografia e Estatistica (IBGE). Pesquisa Nacional de Saúde 2013: Percepção do estado de saúde, estilos de vida e doenças crônicas. Rio de Janeiro: IBGE; 2014. 181p. Disponível em: http://biblioteca.ibge.gov.br/visualizacao/livros/liv91110.pdf
http://biblioteca.ibge.gov.br/visualizac...

41. Granjeiro A, Escuder MM, Cassanote AJF, Souza RA, Kalichman AO, Veloso VG, et al. The HIV-Brazil Cohort Study: Design, Methods and Participant Characteristics. PLoS One . 2014;9(5):e95673.

42. Chor D, Ribeiro ALP, Sá CM, Duncan BB, Andrade LP, Araújo AN, et al. Prevalence, awareness, treatment and influence of socioeconomic variables on control of high blood pressure: results of the ELSA-Brasil Study. PLoS One . 2015;10(6):e0127382.
-4343. Santos IS, Alencar AP, Rundek T, Goulart AC, Barreto SM, Pereira AC, et al. Low impact of traditional risk factors on carotid intima-media thickness. The ELSA-Brasil Cohort. Arterioscler Thromb Vasc Biol. 2015;35(9):2054-59. In addition, we found a high (70%) prevalence of dyslipidemia, mainly with high density lipoprotein cholesterol reduction, despite the young population and prior ART4444. Siegel MO, Borkowska AG, Dubrovsky L, Roth M, Welti R, Roberts AD, et al. HIV infection induces structural and functional changes in high density lipoproteins. Atherosclerosis. 2015;243(1):19-29., which can be explained, among other factors by the alteration in the maturation of this lipoprotein caused by the direct action of HIV4545. Rose H, Hoy J, Woolley I, Tchoua U, Bukrinsky M, Dart A, et al. HIV infection and high density lipoprotein metabolism. Atherosclerosis . 2008 ;199(1):79-86.,4646. Ministério da Saúde (MS). Departamento de Vigilância em Saúde. Departamento de DST, AIDS e Hepatites Virais. Clinical protocol and therapeutic guidelines for management of HIV infection in adults. Brasília: MS; 2015. Disponível em: http://www.aids.gov.br/sites/default/files/anexos/publicacao/2013/55308/protocolofinal_31_7_2015_pdf_31327.pdf
http://www.aids.gov.br/sites/default/fil...
. All efforts should be made to promote health and disease prevention in this population, aiming to reduce the classical factors of chronic-degenerative diseases, mainly smoking cessation. Regarding the immunological statuses of the patients, the majority had LTCD4+ counts above 400 cells/mm³, considered adequate and higher than those reported in another study in Brazil4646. Ministério da Saúde (MS). Departamento de Vigilância em Saúde. Departamento de DST, AIDS e Hepatites Virais. Clinical protocol and therapeutic guidelines for management of HIV infection in adults. Brasília: MS; 2015. Disponível em: http://www.aids.gov.br/sites/default/files/anexos/publicacao/2013/55308/protocolofinal_31_7_2015_pdf_31327.pdf
http://www.aids.gov.br/sites/default/fil...
,4747. Valentini MB, Toledo ML, Fonseca MO, Thiersch LM, Toledo ISB, Machado FC, et al. Evaluation of late presentation for HIV treatment in a reference center in Belo Horizonte, Southeastern Brazil, from 2008 to 2010. Braz J Infect Dis. 2015;19(3):253-62. There was no association between biomarkers and cardiovascular risk.

There was an association between the measured thickness, the cardiovascular risk, and the age. Age showed a positive correlation with the intima-media thickness; older patients had thicker intima-media. This result corroborates findings from the literature on risk factors of mean CIMT2525. Tattersall MC, Gassett A, Korcarz CE, Gepner AD, Kaufman JD, Liu KJ, et al. Predictors of carotid thickness and plaque progression during a decade: the Multi-Ethnic Study of Atherosclerosis (MESA). Stroke. 2014;45(11):3257-62..

The sample size may have been insufficient to show the relationship between biomarker changes and other classic cardiovascular risk factors, such as age, tabagism and immunological status, as evidenced in the literature77. Rodger AJ, Lodwick R, Schechter M, Deeks S, Amin J, Gilson R, et al. Mortality in well controlled HIV in the continuous antiretroviral therapy arms of the SMART and ESPRIT trials compared with the general population. AIDS. 2013;27(6):973-9.,1212. Kuller LH, Tracy R, Belloso W, De Wit S, Drummond F, Lane HC, et al. Inflammatory and coagulation biomarkers and mortality in patients with HIV infection. PLoS Med. 2008 ;5(10):e203.,3232. Graham SM, Rajwans N, Tapia KA, Jaoko W, Estambale BB, McClelland RS, et al. A prospective study of endothelial activation biomarkers, including plasma angiopoietin-1 and angiopoietin-2, in Kenyan women initiating antiretroviral therapy. BMC Infect Dis. 2013;13:263-68..

In this cross-sectional study, associated factors and effects were evaluated simultaneously. Therefore, this study only allows the establishment of associations between events, and it is not possible to define causality. No sedentary lifestyle was evaluated in this population, and no association could be made between physical activity and cardiovascular risk in the described population. Another limitation of the study is the absence of a control group of healthy participants in order to compare serum levels of studied biomarkers, due to the absence of reference values ​​in the literature.

In this study, we noted a high (70.4%) prevalence of dyslipidemia in relation (60.3%) to the general Brazilian population. This level of change was found prior to the individual’s exposure to ART and tended to increase significantly with the initiation of therapy, since most ART negatively modify the user’s long-term lipid profile, gradually increasing cardiovascular risk over time.

There was no association between cardiovascular biomarkers and carotid atherosclerosis, similar to other studies that did not find such an association4848. Lacerda HR, Falcão MC, de Albuquerque VM, Zírpoli JC, .Miranda-Filho DB, de Albuquerque MF, et al. Association of inflammatory cytokines and endothelial adhesion molecules with immunological, virological, and cardiometabolic disease in HIV-infected individuals. J Interferon Cytokine Res. 2014;34(5):385-93.. We identified early changes in the intima-media thickness and the increase in the vascular age calculated in the majority of participants, similar to other studies4949. Godoi ET, Brandt CT, Lacerda HR, Godoi JT, Oliveira DC, Costa GF, et al. Intima-media thickness in the carotid and femoral arteries for detection of arteriosclerosis in human immunodeficiency virus-positive individuals. Arq Bras Cardiol. 2017;108(1):3-11.. This result points to the role of HIV itself in the pathogenesis of atherosclerotic disease since the population studied was young, most of them were without classical risk factors, and were all without previous ART exposure. Prospective studies are needed to confirm this tendency. The intima-media thickness was directly associated with the age of the participants, a finding that corroborates those of the current literature, and shows that age is a risk factor for the increase in intima media thickness. The intima-media thickness seems to be a good marker for subclinical arteriosclerosis in the HIV population, as it is already in the general population. We suggest that prospective studies evaluate the effectiveness of inclusion of this variable in the care protocols for PLWHIV.

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  • Financial support: Fundação de Amparo à Pesquisa do Estado de Minas Gerais: Edital Universal 2014.

Publication Dates

  • Publication in this collection
    May-Jun 2018

History

  • Received
    07 Dec 2017
  • Accepted
    18 May 2018
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