To our knowledge, this is the largest study comparing IL-6, sCD14, and D-dimer by BMI and HIV status in a cohort including HIV+ and uninfected participants. A recent investigation compared 35 HIV+ with 30 matched, uninfected, obese participants, and found that IL-6 did not significantly differ according to HIV status. They also found sCD14 was increased in obese/HIV+ when compared with obese/uninfected participants, the opposite of the association seen in our study. The characteristics of this smaller cohort differed from those in our cohort in terms of age and gender distributions, and D-dimer levels were not measured.30
Multiple prior studies investigated the association between these biomarkers and obesity in HIV+ participants without comparison with an uninfected population. IL-6 did not have a consistent association with adipose tissue mass in HIV+ participants in 1 investigation,49 whereas in other reports, IL-6 was associated with increases in BMI, particularly for HIV+ men.31,50 sCD14 was found to increase with weight gain in virologically suppressed, predominately normal weight HIV+ participants between 0 and 48 weeks after antiretroviral initiation across 9 countries.29 In the Strategies for Management of Antiretroviral Therapy (SMART) Study, investigators did not detect an association between obesity and D-dimer in HIV+ participants,32 similar to our findings. Likewise, D-dimer was not associated with obesity in a cohort of uninfected participants.33 These studies, which did not compare HIV+ with uninfected participants in the same cohort, have limited ability to comment on the differential impact of obesity on these biomarkers in those living with HIV versus without HIV infection.
There are limitations to this analysis. This is an observational, cross-sectional study, preventing us from examining trends over time in inflammatory parameters. It would be useful to examine trends in relation to the duration of virologic suppression or in the setting of weight change or aging. BMI is used as a measure of adiposity rather than a measurement of waist circumference or visceral adipose tissue, known to be more strongly correlated with cardiovascular outcomes. The population is overwhelmingly male and older, limiting generalizability to women and younger HIV+ people. The individual biomarkers measured may not capture the full complexity of the immune processes they represent, although all 3 are well studied in both HIV+ and uninfected cohorts. Data on diet and physical activity, which can confound associations of obesity with inflammatory biomarkers, were not included in this analysis. As with any observational study, there is the possibility of unmeasured confounding from drug use, multiple comorbidities, or other factors.
Despite uncertainty surrounding the impact of rising BMI in this population, the difference in median IL-6 levels between obese/HIV+ and nonobese/uninfected participants our analysis is similar to or greater than differences associated with increased mortality risk in other prospective studies.53,54 As obesity prevalence among people living with HIV rises,17 further investigation into the long-term implications of this weight gain is needed. Future prospective studies should assess whether intentional weight loss or similar interventions affect inflammatory processes similarly in HIV-infected and uninfected people.68–70
1. Mokdad AH, Marks JS, Stroup DF, et al. Actual causes of death in the United States, 2000. JAMA. 2004;291:1238–1245.
2. Flegal KM, Graubard BI, Williamson DF, et al. Cause-specific excess deaths associated with underweight, overweight, and obesity
. JAMA. 2007;298:2028–2037.
3. Flegal KM, Kit BK, Orpana H, et al. Association of all-cause mortality with overweight and obesity
using standard body mass index categories: a systematic review and meta-analysis. JAMA. 2013;309:71–82.
4. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of Obesity
in the United States, 2009–2010. in: National Center for Health Statistics Data Brief No. 82. Hyattsville, MD: National Center for Health Statistics; 2012.
5. Wang Y, Beydoun MA. The obesity
epidemic in the United States–gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev. 2007;29:6–28.
6. Centers for Disease Control and Prevention (CDC). Vital signs: state-specific obesity
prevalence among adults—United States, 2009. MMWR Morb Mortal Wkly Rep. 2010;59:951–955.
7. Robert SA, Reither EN. A multilevel analysis of race, community disadvantage, and body mass index among adults in the US. Soc Sci Med. 2004;59:2421–2434.
8. Zhang Q, Wang Y. Trends in the association between obesity
and socioeconomic status in U.S. adults: 1971 to 2000. Obes Res. 2004;12:1622–1632.
9. Zhang Q, Wang Y. Socioeconomic inequality of obesity
in the United States: do gender, age, and ethnicity matter? Soc Sci Med. 2004;58:1171–1180.
10. Prejean J, Song R, Hernandez A, et al. Estimated HIV
incidence in the United States, 2006–2009. PLoS One. 2011;6:e17502.
11. Hall HI, Song R, Rhodes P, et al. Estimation of HIV
incidence in the United States. JAMA. 2008;300:520–529.
12. Tate T, Willig AL, Willig JH, et al. HIV
infection and obesity
: where did all the wasting go? Antivir Ther. 2012;17:1281–1289.
13. Crum-Cianflone N, Roediger MP, Eberly L, et al. Increasing rates of obesity
-infected persons during the HIV
epidemic. PLoS One. 2010;5:e10106.
14. Amorosa V, Synnestvedt M, Gross R, et al. A tale of 2 epidemics: the intersection between obesity
infection in Philadelphia. J Acquir Immune Defic Syndr. 2005;39:557–561.
15. Koethe JR, Jenkins CA, Shepherd BE, et al. An optimal body mass index range associated with improved immune reconstitution among HIV
-infected adults initiating antiretroviral therapy. Clin Infect Dis. 2011;53:952–960.
16. Taylor BS, Liang Y, Garduno LS, et al. High risk of obesity
and weight gain for HIV
-infected uninsured minorities. J Acquir Immune Defic Syndr. 2014;65:e33–40.
17. Koethe JR, Jenkins CA, Lau B, et al. Rising obesity
prevalence and weight gain among adults starting antiretroviral therapy in the United States and Canada. AIDS Res Hum Retroviruses. 2016;32:50–58.
18. McGee DL, Diverse Populations Collaboration. Body mass index and mortality: a meta-analysis based on person-level data from twenty-six observational studies. Ann Epidemiol. 2005;15:87–97.
19. Arnlov J, Ingelsson E, Sundstrom J, et al. Impact of body mass index and the metabolic syndrome on the risk of cardiovascular disease and death in middle-aged men. Circulation. 2010;121:230–236.
20. Lavie CJ, McAuley PA, Church TS, et al. Obesity
and cardiovascular diseases: implications regarding fitness, fatness, and severity in the obesity
paradox. J Am Coll Cardiol. 2014;63:1345–1354.
21. Freiberg MS, Chang CC, Kuller LH, et al. HIV
infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173:614–622.
22. Paisible AL, Chang CC, So-Armah KA, et al. HIV
infection, cardiovascular disease risk factor profile, and risk for acute myocardial infarction. J Acquir Immune Defic Syndr. 2015;68:209–216.
23. Panagiotakos DB, Pitsavos C, Yannakoulia M, et al. The implication of obesity
and central fat on markers of chronic inflammation
: the ATTICA study. Atherosclerosis. 2005;183:308–315.
24. Hotamisligil GS. Inflammation
and metabolic disorders. Nature. 2006;444:860–867.
25. Amirayan-Chevillard N, Tissot-Dupont H, Capo C, et al. Impact of Highly Active Anti-Retroviral Therapy (HAART) on cytokine production and monocyte subsets in HIV
-infected patients. Clin Exp Immunol. 2000;120:107–112.
26. Neuhaus J, Jacobs DR Jr, Baker JV, et al. Markers of inflammation
, and renal function are elevated in adults with HIV
infection. J Infect Dis. 2010;201:1788–1795.
27. Armah KA, McGinnis K, Baker J, et al. HIV
status, burden of comorbid disease, and biomarkers of inflammation
, altered coagulation
, and monocyte activation
. Clin Infect Dis. 2012;55:126–136.
28. Triant VA, Meigs JB, Grinspoon SK. Association of C-reactive protein and HIV
infection with acute myocardial infarction. J Acquir Immune Defic Syndr. 2009;51:268–273.
29. Mave V, Erlandson KM, Gupte N, et al. Inflammation
and change in body weight with antiretroviral therapy initiation in a multinational cohort of HIV
-infected adults. J Infect Dis. 2016;214:65–72.
30. Koethe JR, Grome H, Jenkins CA, et al. The metabolic and cardiovascular consequences of obesity
in persons with HIV
on long-term antiretroviral therapy. AIDS. 2016;30:83–91.
31. Borges AH, O'Connor JL, Phillips AN, et al. Factors associated with plasma IL-6 levels during HIV
infection. J Infect Dis. 2015;212:585–595.
32. Borges AH, O'Connor JL, Phillips AN, et al. Factors associated with D-dimer levels in HIV
-infected individuals. PLoS One. 2014;9:e90978.
33. Orenes-Pinero E, Pineda J, Roldan V, et al. Effects of body mass index on the lipid profile and biomarkers of inflammation
and a fibrinolytic and prothrombotic state. J Atheroscler Thromb. 2015;22:610–617.
34. Justice AC, Dombrowski E, Conigliaro J, et al. Veterans Aging Cohort Study (VACS
): overview and description. Med Care. 2006;44(8 suppl 2):S13–S24.
35. Ives DG, Fitzpatrick AL, Bild DE, et al. Surveillance and ascertainment of cardiovascular events. The cardiovascular health study. Ann Epidemiol. 1995;5:278–285.
36. Every NR, Fihn SD, Sales AE, et al. Quality enhancement research initiative in ischemic heart disease: a quality initiative from the department of veterans affairs. QUERI IHD executive Committee. Med Care. 2000;38(6 suppl 1):I49–I59.
37. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation, and Treatment of high blood pressure. Hypertension. 2003;42:1206–1252.
38. Armah KA, Chang CC, Baker JV, et al. Prehypertension, hypertension, and the risk of acute myocardial infarction in HIV
-infected and -uninfected veterans. Clin Infect Dis. 2014;58:121–129.
39. Butt AA, McGinnis K, Rodriguez-Barradas MC, et al. HIV
infection and the risk of diabetes mellitus. AIDS. 2009;23:1227–1234.
40. McGinnis KA, Brandt CA, Skanderson M, et al. Validating smoking data from the Veteran's Affairs Health Factors dataset, an electronic data source. Nicotine Tob Res. 2011;13:1233–1239.
41. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA. 2001;285:2486–2497.
42. Bush K, Kivlahan DR, McDonell MB, et al. The AUDIT alcohol consumption questions (AUDIT-C): an effective brief screening test for problem drinking. Ambulatory Care Quality Improvement Project (ACQUIP). Alcohol Use Disorders Identification Test. Arch Intern Med. 1998;158:1789–1795.
43. Butt AA, Xiaoqiang W, Budoff M, et al. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis. 2009;49:225–232.
44. Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV
/HCV coinfection. Hepatology. 2006;43:1317–1325.
45. Loko MA, Castera L, Dabis F, et al. Validation and comparison of simple noninvasive indexes for predicting liver fibrosis in HIV
-HCV-coinfected patients: ANRS CO3 Aquitaine cohort. Am J Gastroenterol. 2008;103:1973–1980.
46. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis. 2002;39(2 suppl 1):S1–S266.
47. Park LS, Tate JP, Rodriguez-Barradas MC, et al. Cancer incidence in HIV
-infected versus uninfected veterans: comparison of cancer Registry and ICD-9 code diagnoses. J AIDS Clin Res. 2014;5:1000318.
48. Armah KA, Quinn EK, Cheng DM, et al. Human immunodeficiency virus, hepatitis C, and inflammatory biomarkers in individuals with alcohol problems: a cross-sectional study. BMC Infect Dis. 2013;13:399.
49. Koethe JR, Dee K, Bian A, et al. Circulating interleukin-6, soluble CD14, and other inflammation
biomarker levels differ between obese and nonobese HIV
-infected adults on antiretroviral therapy. AIDS Res Hum Retroviruses. 2013;29:1019–1025.
50. Conley LJ, Bush TJ, Rupert AW, et al. Obesity
is associated with greater inflammation
and monocyte activation
-infected adults receiving antiretroviral therapy. AIDS. 2015;29:2201–2207.
51. Kuller LH, Tracy R, Belloso W, et al. Inflammatory and coagulation
biomarkers and mortality in patients with HIV
infection. PLoS Med. 2008;5:e203.
52. Duprez DA, Neuhaus J, Kuller LH, et al. Inflammation
and cardiovascular disease in HIV
-infected individuals. PLoS One. 2012;7:e44454.
53. Nordell AD, McKenna M, Borges AH, et al. Severity of cardiovascular disease outcomes among patients with HIV
is related to markers of inflammation
. J Am Heart Assoc. 2014;3:e000844.
54. McDonald B, Moyo S, Gabaitiri L, et al. Persistently elevated serum interleukin-6 predicts mortality among adults receiving combination antiretroviral therapy in Botswana: results from a clinical trial. AIDS Res Hum Retroviruses. 2013;29:993–999.
55. Deeks SG, Tracy R, Douek DC. Systemic effects of inflammation
on health during chronic HIV
infection. Immunity. 2013;39:633–645.
56. Tanaka T, Kishimoto T. The biology and medical implications of interleukin-6. Cancer Immunol Res. 2014;2:288–294.
57. Skurk T, Alberti-Huber C, Herder C, et al. Relationship between adipocyte size and adipokine expression and secretion. J Clin Endocrinol Metab. 2007;92:1023–1033.
58. Jernas M, Palming J, Sjoholm K, et al. Separation of human adipocytes by size: hypertrophic fat cells display distinct gene expression. FASEB J. 2006;20:1540–1542.
59. Cassol E, Malfeld S, Mahasha P, et al. Persistent microbial translocation and immune activation in HIV
-1-infected South Africans receiving combination antiretroviral therapy. J Infect Dis. 2010;202:723–733.
60. Lien E, Aukrust P, Sundan A, et al. Elevated levels of serum-soluble CD14 in human immunodeficiency virus type 1 (HIV
-1) infection: correlation to disease progression and clinical events. Blood. 1998;92:2084–2092.
61. Wallet MA, Rodriguez CA, Yin L, et al. Microbial translocation induces persistent macrophage activation unrelated to HIV
-1 levels or T-cell activation following therapy. AIDS. 2010;24:1281–1290.
62. du Plessis J, Korf H, van Pelt J, et al. Pro-inflammatory cytokines but not endotoxin-related parameters associate with disease severity in patients with NAFLD. PLoS One. 2016;11:e0166048.
63. Quon BS, Ngan DA, Wilcox PG, et al. Plasma sCD14 as a biomarker to predict pulmonary exacerbations in cystic fibrosis. PLoS One. 2014;9:e89341.
64. Bas S, Gauthier BR, Spenato U, et al. CD14 is an acute-phase protein. J Immunol. 2004;172:4470–4479.
65. Koethe JR, Jenkins CA, Lau B, et al. Body mass index and early CD4 T-cell recovery among adults initiating antiretroviral therapy in North America, 1998–2010. HIV
66. Koethe JR, Jenkins CA, Lau B, et al. Higher time-updated body mass index: association with improved CD4+ cell recovery on HIV
treatment. J Acquir Immune Defic Syndr. 2016;73:197–204.
67. Achhra AC, Mocroft A, Reiss P, et al. Short-term weight gain after antiretroviral therapy initiation and subsequent risk of cardiovascular disease and diabetes: the D:A:D study. HIV
68. Fitch K, Abbara S, Lee H, et al. Effects of lifestyle modification and metformin on atherosclerotic indices among HIV
-infected patients with the metabolic syndrome. AIDS. 2012;26:587–597.
69. Lindegaard B, Hansen T, Hvid T, et al. The effect of strength and endurance training on insulin sensitivity and fat distribution in human immunodeficiency virus-infected patients with lipodystrophy. J Clin Endocrinol Metab. 2008;93:3860–3869.
70. Troseid M, Ditlevsen S, Hvid T, et al. Reduced trunk fat and triglycerides after strength training are associated with reduced LPS levels in HIV
-infected individuals. J Acquir Immune Defic Syndr. 2014;66:e52–e54.