Treatment-related changes in serum lipids and inflammation: clinical relevance remains unclear. Analyses from the Women's Interagency HIV study
Parrinello, Christina M.a; Landay, Alan L.b; Hodis, Howard N.c; Gange, Stephen J.d; Norris, Philip J.e; Young, Maryf; Anastos, Kathryna,g; Tien, Phyllis C.h,i; Xue, Xiaonana; Lazar, Jasonj; Benning, Loried; Tracy, Russell P.k; Kaplan, Robert C.a
aDepartment of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, New York
bDepartment of Immunology/Microbiology, Rush University Medical Center, Chicago, Illinois
cAtherosclerosis Research Unit, University of Southern California, Los Angeles, California
dDepartment of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
eBlood Systems Research Institute, University of California, San Francisco, Departments of Laboratory Medicine and Medicine, San Francisco, California
fDepartment of Medicine, Georgetown University Medical Center, Washington, District of Columbia
gDepartment of Medicine, Albert Einstein College of Medicine, Bronx, New York
hDepartment of Medicine, University of California, San Francisco
iSan Francisco Veterans Affairs Medical Center, San Francisco, California
jDepartment of Medicine, State University of New York, Downstate Medical Center, Brooklyn, New York
kDepartments of Pathology and Biochemistry, University of Vermont College of Medicine, Burlington, Vermont, USA.
Correspondence to Robert C. Kaplan, PhD, 1300 Morris Park Avenue, Belfer 1306C, Bronx, NY 10461, USA. Tel: +1 718 430 4076; e-mail: email@example.com
Received 4 December, 2012
Accepted 5 February, 2013
Among 127 HIV-infected women, the magnitude of high-density lipoprotein cholesterol (HDLc) increases after HAART initiation predicted the magnitude of concurrent decreases in inflammation biomarkers. After HAART initiation, changes in low-density lipoprotein cholesterol (LDLc) and inflammation were unrelated. In the same population, predicted risk of coronary heart disease, based upon levels of standard clinical risk factors, was similar before and after HAART. Thus, it remains unknown whether short-term treatment-related changes in standard risk factors may appreciably change risk of cardiovascular disease (CVD).
A recent article in AIDS by Piconi et al. reported that among HIV-infected individuals, prothrombotic and inflammation factors were lower and metabolic factors (i.e. serum cholesterol and lipoproteins) were higher in persons on antiretroviral therapy (ART) than untreated persons. The authors concluded that HIV replication and inflammatory/thrombotic factors may be an important pathway to atherosclerosis in untreated HIV-infected individuals, whereas changes in metabolic factors may be important atherosclerosis risk factors in those using ART. Although an important contribution, the Piconi study lacked data on women, was limited by a cross-sectional study design and made no conclusions about changes after ART initiation in widely used clinical measures of future cardiovascular disease (CVD) risk.
We confirmed and extended the key conclusions of Piconi et al. using longitudinal data from the Women's Interagency HIV Study (WIHS). Using data from a WIHS substudy of 127 HIV-infected women who initiated HAART while enrolled in the WIHS , we measured levels of lipids and inflammation factors at three semi-annual visits prior to first use of HAART and again at three semi-annual visits after first use of HAART. These data were used to examine the association between changes in serum lipids and concurrent changes in levels of inflammation-related biomarkers. Levels of high-density lipoprotein cholesterol (HDLc) increased after initiation of HAART (from 48 to 54 mg/dl), whereas low-density lipoprotein cholesterol (LDLc) increased only among the 67 women who initiated protease inhibitor-based HAART regimens (in PI-HAART users, 92–109 mg/dl, and in nonprotease inhibitor-based HAART users, 101–103 mg/dl). Regardless of the type of HAART regimen used, the magnitude of increase in HDLc was correlated with the magnitude of decrease in soluble CD14 (sCD14), tumor necrosis factor alpha (TNF-α), soluble interleukin 2 receptors (sIL-2R), interleukin 6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) (Fig. 1). Change in LDLc level was not associated with changes in inflammation biomarker levels, suggesting a largely inflammation-independent mechanism for increased LDLc with PI-HAART.
Among the same patient population, we also investigated the net effect of changes in lipid profile and other vascular risk factors after ART initiation on predicted risk of clinical CVD events. Hence, we calculated predicted coronary heart disease risk in HIV-infected women at visits shortly before initiating HAART, and again 18 months after beginning HAART. The Framingham risk score for estimating the 10-year risk of total coronary heart disease (including angina and fatal and nonfatal acute coronary events)  was calculated on the basis of age, total cholesterol (TC), HDLc, DBP and SBP, diabetes and current smoking status. We grouped women into low (10-year risk <15%), moderate (15–25%) or high risk (≥25%) categories, while placing all diabetic patients into the high-risk category [4,5]. We then determined the proportion of women who were reclassified after HAART initiation. Among all HIV-infected women prior to treatment, 84% had low predicted risk of coronary heart disease, 1% had moderate risk and 15% had high risk. After HAART initiation, 97% remained in the same risk category, 1% moved into a lower risk category and 2% moved into a higher risk category.
In summary, consistent with the findings from Piconi et al., our data demonstrate the reciprocal relationship of inflammation and lipid perturbation in HIV-infected patients, while also suggesting that LDLc and inflammation are biologically discrete pathways that may alter atherosclerosis risk. We [2,6] and Piconi et al., among others, have demonstrated that in HIV-infected patients, inflammation and lipid levels are associated with common carotid artery intima–media thickness, a measure of subclinical atherosclerosis. However, it can be difficult to translate findings from this subclinical atherosclerosis measure into clinically meaningful information on risk of CVD. At least among middle-aged HIV-infected women, we find little evidence that the net balance of short-term metabolic alterations related to HAART initiation would appreciably change future risk of CVD as measured by standard clinical risk factors. Therefore, as research into novel CVD biomarkers and long-term treated HIV natural history continues to mature, it will become increasingly important to evaluate the clinical relevance of changes in intermediate biomarkers.
Data in this manuscript were collected by the WIHS Collaborative Study Group with centres (Principal Investigators) at New York City/Bronx Consortium (Kathryn Anastos); Brooklyn, New York (Howard Minkoff); Washington, District of Columbia Metropolitan Consortium (Mary Young); The Connie Wofsy Study Consortium of Northern California (Ruth Greenblatt); Los Angeles County/Southern California Consortium (Alexandra Levine); Chicago Consortium (Mardge Cohen); Data Coordinating Center (Stephen Gange). The WIHS is funded by the National Institute of Allergy and Infectious Diseases (UO1-AI-35004, UO1-AI-31834, UO1-AI-34994, UO1-AI-34989, UO1-AI-34993 and UO1-AI-42590) and by the Eunice Kennedy Shriver National Institute of Child Health and Human Development (UO1-HD-32632). The study is cofunded by the National Cancer Institute, the National Institute on Drug Abuse, and the National Institute on Deafness and Other Communication Disorders. Funding is also provided by the National Center for Research Resources (UCSF-CTSI Grant Number UL1 RR024131). Additional cofunding is provided by the National Heart, Lung and Blood Institute (1R01HL095140, 1R01HL083760 to R.C.K.). Partial funding for laboratory and work as well as assistance with general study coordination was provided by the University of Washington's CVD and Metabolic Complications of HIV/AIDS Data Coordinating Center (5R01HL095126).
The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
Conflicts of interest
The authors have no conflicts of interest to disclose.
1. Piconi S, Parisotto S, Rizzardini G, Passerini S, Meraviglia P, Schiavini M, et al. Atherosclerosis is associated with multiple pathogenic mechanisms in HIV-infected antiretroviral-naive or -treated individuals. AIDS. 2013; 27:381–389.
2. Kaplan RC, Landay AL, Hodis HN, Gange SJ, Norris PJ, Young M, et al. Potential cardiovascular disease risk markers among HIV-infected women initiating antiretroviral treatment. J Acquir Immune Defic Syndr. 2012; 60:359–368.
3. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998; 97:1837–1847.
4. National Cholesterol Education Program; National Heart, Lung, and Blood Institute; National Institutes of Health. 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) Final Report. Circulation. 2002; 106:3143–3420.
[NIH Publication No. 02-5215. September 2002.]
5. Kaplan RC, Kingsley LA, Sharrett AR, Li X, Lazar J, Tien PC, et al. Ten-year predicted coronary heart disease risk in HIV-infected men and women. Clin Infect Dis. 2007; 45:1074–1081.
6. Parrinello CM, Landay AL, Hodis HN, Gange SJ, Norris PJ, Young M, et al. Association of subclinical atherosclerosis with lipid levels amongst antiretroviral-treated and untreated HIV-infected women in the Women's Interagency HIV study. Atherosclerosis. 2012; 225:408–411.
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