Subclinical coronary artery disease in Swiss HIV-positive and HIV-negative persons

Subclinical coronary artery disease in Swiss HIV-positive and HIV-negative persons Abstract Aims HIV-positive persons have increased cardiovascular event rates but data on the prevalence of subclinical atherosclerosis compared with HIV-negative persons are not uniform. We assessed subclinical atherosclerosis utilizing coronary artery calcium (CAC) scoring and coronary computed tomography angiography (CCTA) in 428 HIV-positive participants of the Swiss HIV Cohort Study and 276 HIV-negative controls concurrently referred for clinically indicated CCTA. Methods and results We assessed the association of HIV infection, cardiovascular risk profile, and HIV-related factors with subclinical atherosclerosis in univariable and multivariable analyses. HIV-positive participants (median duration of HIV infection, 15 years) were younger than HIV-negative participants (median age 52 vs. 56 years; P < 0.01) but had similar median 10-year Framingham risk scores (9.0% vs. 9.7%; P = 0.40). The prevalence of CAC score >0 (53% vs. 56.2%; P = 0.42) and median CAC scores (47 vs. 47; P = 0.80) were similar, as was the prevalence of any, non-calcified/mixed, and high-risk plaque. In multivariable adjusted analysis, HIV-positive participants had a lower prevalence of calcified plaque than HIV-negative participants [36.9% vs. 48.6%, P < 0.01; adjusted odds ratio (aOR) 0.57; 95% confidence interval (CI) 0.40–0.82; P < 0.01], lower coronary segment severity score (aOR 0.72; 95% CI 0.53–0.99; P = 0.04), and lower segment involvement score (aOR 0.71, 95% CI 0.52–0.97; P = 0.03). Advanced immunosuppression was associated with non-calcified/mixed plaque (aOR 1.97; 95% CI 1.09–3.56; P = 0.02). Conclusion HIV-positive persons in Switzerland had a similar degree of non-calcified/mixed plaque and high-risk plaque, and may have less calcified coronary plaque, and lower coronary atherosclerosis involvement and severity scores than HIV-negative persons with similar Framingham risk scores. View largeDownload slide View largeDownload slide Subclinical atherosclerosis , Accelerated atherosclerosis , Coronary artery disease , HIV infection , Coronary artery calcium score , Coronary CT angiography Introduction HIV-positive persons in Western countries now have an essentially normal life expectancy in the setting of effective antiretroviral therapy (ART). However, a major long-term concern in HIV includes accelerated atherosclerosis, as suggested by increased rates of coronary artery disease (CAD), stroke, and peripheral vascular disease, compared with HIV-negative persons.1–3 Accelerated atherosclerosis in HIV may be related to pro-coagulant and pro-inflammatory mechanisms in the setting of immunosuppression, adverse viral effects on endothelial and other cells, deleterious metabolic effects of certain ART agents including dyslipidaemia and insulin resistance, a high prevalence of smoking and other substance use, and genetic factors.4–6 Therefore, there has been considerable interest in early diagnosis of subclinical atherosclerosis in HIV-positive persons. Studies using carotid intima-media thickness (CIMT) measurement and coronary artery calcium (CAC) determination have not consistently shown an increased atherosclerosis prevalence in HIV-positive compared with HIV-negative persons, however.7–9 Coronary artery disease may in part be non-calcified in patients aged <50 years,10 and HIV-positive persons may experience cardiovascular events at a younger age than HIV-negative persons.2 Coronary computed tomography angiography (CCTA) can accurately and reproducibly detect non-calcified plaque when compared with intravascular ultrasound,11 and non-calcified plaque more accurately predicts cardiovascular events than CAC or CIMT.12 In recent large CCTA studies from the USA, an increased13 and a similar14 prevalence of non-calcified plaque was identified in HIV-positive compared with HIV-negative persons. These inconsistent results, the lower CAD rates in middle/southern Europe compared to North America,15,16 and recent reports suggesting similar cardiovascular event rates in HIV-positive and HIV-negative non-smokers in Switzerland17 and Denmark18 highlight the need for additional studies. The aims of our study were to compare the prevalence of subclinical atherosclerosis in HIV-positive and HIV-negative persons in Switzerland using CAC/CCTA, and to assess associations between cardiovascular risk factors, HIV infection, and subclinical CAD. Methods Study design and study participants Enrolment was from 10/2013 to 7/2016. We investigated the association of HIV-infection with subclinical CAD by CCTA and non-contrast CT scan for calculating the CAC score. Enrolment criteria included age ≥45 years, no documented CAD/stroke, GFR ≥60 mL/min, no allergy to iodinated contrast agent, and no history of atrial fibrillation or other irregular heartbeat. HIV-positive persons were participants of the metabolism and aging core project of the Swiss HIV Cohort Study (www.shcs.ch). HIV-negative participants were referred for clinically indicated CCTA/CAC during the enrolment period. We attempted to obtain comparable populations with regards to age, gender and Framingham risk score16 by periodic comparisons of their characteristics and adjusting the selection criteria for HIV-negative individuals. The study was approved by the local ethics committees. Participants provided written informed consent; they had access to imaging results via their HIV physician and were offered management of any abnormality detected. Data collection For HIV-positive participants, data were collected within the SHCS, a prospective cohort study that has continuously enrolled HIV-positive adults since 1988.19 Demographic, clinical, and laboratory data are collected every 6 months using a standardized protocol, including detailed information on cardiovascular events, hypertension, diabetes mellitus, smoking, alcohol and drug use, and medication. For HIV-negative participants, clinical information was obtained using a structured questionnaire that included indication for CCTA/CAC referral, verification of inclusion criteria, co-morbidities, medication, smoking, alcohol, and drug use. Data were verified by chart review. Vital signs, fasting total, LDL-, HDL-cholesterol, triglycerides, glucose, and creatinine were measured at the time of CCTA/CAC in all participants. Cardiac imaging Cardiac imaging was performed at University Hospitals Zurich and Geneva. Coronary computed tomography angiography with low radiation exposure was completed using a 64-slice Discovery 750 HD or 256-slice Revolution CT Scanner (both GE Healthcare, Waukesha, WI, USA) or a dual tube 64-slice Somatom Definition Flash CT scanner (Siemens Healthcare, Erlangen, Germany) with a prospectively electrocardiogram (ECG)-triggered cardiac acquisition protocol with tube voltage and current adapted to body mass index (BMI).20 Imaging was done at a temporal resolution of 83–175 ms with either a step-and-shoot scan mode (64-slice scanner) or a single-beat-acquisition mode (256-slice scanner and dual-tube). Slice thickness was 0.625 mm. A BMI-adapted contrast protocol (Visipaque 320, GE Healthcare) was applied. All patients received 2.5 mg of sublingual isosorbide dinitrate; metoprolol was injected intravenously as needed to attain a heart rate <65/min. A prospectively ECG-triggered, non-contrast cardiac computed tomography scan was performed to determine the CAC score. Imaging findings were assessed by two experienced readers of the Cardiac Imaging divisions at University Hospitals Zurich and Geneva. Definitions Coronary artery calcium was defined as CAC score >0 based on the Agatston method. Coronary arteries were subdivided into 16 segments,21 with the intermediate artery defined as segment 16, if present. Segments with a diameter of ≥1.5 mm at origin were included in the analysis. Atherosclerotic plaque was defined as a lesion ≥1 mm2 in orthogonal reconstructions within and/or adjacent to the vessel lumen, not belonging to surrounding tissue.22 Plaques were classified as calcified, non-calcified, or mixed. High-risk plaque was defined23 as plaque with positive remodelling (remodelling index ≥1.1) and/or low attenuation plaque (≤30 HU). The segment involvement score (SIS) was calculated using one point for each coronary segment with any plaque. The segment severity score (SSS) was calculated using the total of all segments scored according to lesion severity.24 Hypertension was defined as blood pressure ≥140/90 mmHg or use of antihypertensive medication. Dyslipidaemia was defined as total cholesterol ≥6.2 mmol/L, or HDL ≤1.0 mmol/L in men (≤1.2 mmol/L in women), or use of lipid-lowering drugs. Diabetes mellitus was diagnosed with confirmed plasma glucose >7.0 mmol/L (fasting) or >11.1 mmol/L (non-fasting) or receiving antidiabetic medication. Alcohol consumption was assessed by using the Alcohol Use Disorders identification Test-Consumption. Undetectable HIV-RNA was defined as <50 copies/mL. Coronary age was calculated based on CAC score, age, sex, and ethnicity.8 Statistical analysis Characteristics of HIV-positive and HIV-negative participants were compared using the χ2/Fisher’s exact test for categorical and the Wilcoxon rank-sum test for continuous variables. To evaluate the association between HIV-infection and subclinical atherosclerosis, we used five separate dichotomous outcomes: (i) CAC score >0, (ii) any CCTA-detected plaque, (iii) calcified plaque, (iv) non-calcified/mixed plaque, and (v) high-risk plaque. Uni- and multivariable logistic regression models were used to explore the association between HIV and each outcome separately. Co-variables included HIV infection, sex, age, smoking, hypertension, dyslipidaemia, diabetes, and study centre. Subgroup analyses were done for females and for age groups 45–54, 55–64, and 65–74 years. In the analyses limited to HIV-positive participants we added CD4 nadir <50 cells/µL, HIV-1 RNA max >100 000 copies/mL, and ART duration to the models. In a sensitivity analysis, we used propensity scores for bias reduction in the selection of an unmatched control group.25,26 The propensity of being HIV positive was calculated by logistic regression (see Supplementary material online, Table S5). The score was then included as adjustment term in the logistic regression models, used both as untransformed linear variable, and after stratification into quintiles. All statistical analyses were done using Stata/SE 14.2 (StataCorp, College Station, TX, USA). Results Study population A total of 704 study participants (median age 54 years, 83% men, 89% white, 428 HIV-positive, 276 HIV-negative) underwent both CAC determination and CCTA. Median effective radiation exposure was 1.8 mSv (IQR, 1.2–2.3). HIV-positive participants were asymptomatic. HIV-negative controls were asymptomatic (36.6%), had typical angina (8.3%), atypical chest pain (44.2%), or dyspnoea (10.9%). Baseline characteristics are shown in Table 1. HIV-positive participants were more likely to be men, they were younger, and had lower BMI. Median Framingham risk scores and percentages of patients in the low, intermediate and high-risk categories were similar among HIV-positive and HIV-negative participants. HIV-positive participants had a lower prevalence of hypertension, diabetes, and dyslipidaemia, but were more likely to smoke and use drugs. Among the HIV-positive participants, men who had sex with men were the predominant group, 21% had prior AIDS-defining events, and 87% were on suppressive ART. Table 1 Characteristics of HIV-positive and HIV-negative study participants at time of cardiac imaging Characteristic  All participants (n = 704)  HIV-positive participants (n = 428)  HIV-negative participants (n = 276)  P-value  Male sex, n (%)  586 (83.2)  367 (85.8)  219 (79.4)  0.03  Median age (years), IQR  54 (50–59)  52 (49–57)  56 (51–61)  <0.01  Ethnicity, n (%)           White  629 (89.3)  388 (90.7)  243 (88)  0.06   Black  47 (6.7)  29 (6.8)  16 (5.8)   Other/missing  28 (4)  11 (2.6)  17 (6.2)  Body mass index (kg/m2), median (IQR)  25.3 (23.2–28.4)  24.9 (22.8–27.7)  26.2 (23.7–29.4)  <0.01   <18.5  15 (2.1)  11 (2.6)  4 (1.5)  <0.01   ≥18.5, <25  314 (44.6)  211 (49.3)  103 (37.3)   ≥25, ≤30  268 (38.1)  161 (37.6)  107 (38.8)   ≥30  107 (15.2)  45 (10.5)  62 (22.5)  Hypertension, n (%)  299 (42.5)  144 (33.6)  155 (56.2)  <0.01  Diabetes mellitus, n (%)  48 (6.8)  24 (5.6)  24 (8.7)  0.13  Dyslipidaemia, n (%)  304 (43.2)  167 (39.0)  137 (49.6)  <0.01  Total cholesterol (mmol/L), median (IQR)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  0.61  HDL cholesterol (mmol/L), median (IQR)  1.3 (1.1–1.6)  1.3 (1.1–1.6)  1.4 (1.1–1.6)  0.05  LDL cholesterol (mmol/L), median (IQR)  3.1 (2.5–3.7)  3.0 (2.5–3.6)  3.2 (2.4–3.8)  0.33  Triglycerides (mmol/L), median (IQR)  1.3 (0.9–2.1)  1.4 (1.0–2.2)  1.3 (0.9–2.0)  0.01  Lipid-lowering medication use, n (%)  91 (12.9)  28 (6.5)  63 (22.8)  <0.01   Statin  88 (12.5)  27 (6.3)  60 (21.7)   Fibrate  4 (0.4)  1 (0.2)  3 (1.1)  Current smoking, n (%)  197 (28.0)  151 (35.3)  46 (16.7)  <0.01  Alcohol consumption, n (%)           None/mild  481 (68.3)  340 (79.4)  141 (51.2)  0.04   Moderate  120 (17.1)  72 (16.8)  48 (17.4)   Severe  8 (1.1)  7 (1.6)  1 (0.4)   Missing  95 (13.5)  9 (2.1)  86 (31.2)  Active illicit drug use, n (%)  14 (2.0)  14 (3.3)  0  <0.01  Framingham risk score (10-year risk), median (IQR)  9.4 (6.1–14.3)  9.0 (6.0–14.1)  9.7 (6.1–14.4)  0.40   <10%  368 (52.3)  229 (53.5)  139 (50.4)  0.68   10–20%  277 (39.4)  163 (38.1)  114 (41.3)   >20%  59 (8.4)  36 (8.4)  23 (8.3)  HIV acquisition mode, n (%)           MSM    255 (59.6)       IDU    43 (10.1)       Heterosexual    121 (28.3)       Other    9 (2.1)      Years HIV-infected, median (IQR)    15 (7–22)      Prior AIDS, n (%)    89 (20.8)      CD4 current (cells/µL), median (IQR)    598 (449–741)      CD4 nadir (cells/µL), median (IQR)    189 (91–281)      CD4 nadir <50 cells/µL, n (%)    68 (15.9)      HIV-1 RNA max. >100 000 copies/mL    267 (62.4)      On ART, n (%)    397 (92.8)      Undetectable HIV-1 RNA, n (%)    374 (87.4)      ART naïve, n (%)    6 (1.4)      ART interrupted, n (%)    25 (5.8)      Total years on ART, median (IQR)    10.1 (4.8–16.4)      Hepatitis C seropositivity, n (%)    66 (15.4)      Characteristic  All participants (n = 704)  HIV-positive participants (n = 428)  HIV-negative participants (n = 276)  P-value  Male sex, n (%)  586 (83.2)  367 (85.8)  219 (79.4)  0.03  Median age (years), IQR  54 (50–59)  52 (49–57)  56 (51–61)  <0.01  Ethnicity, n (%)           White  629 (89.3)  388 (90.7)  243 (88)  0.06   Black  47 (6.7)  29 (6.8)  16 (5.8)   Other/missing  28 (4)  11 (2.6)  17 (6.2)  Body mass index (kg/m2), median (IQR)  25.3 (23.2–28.4)  24.9 (22.8–27.7)  26.2 (23.7–29.4)  <0.01   <18.5  15 (2.1)  11 (2.6)  4 (1.5)  <0.01   ≥18.5, <25  314 (44.6)  211 (49.3)  103 (37.3)   ≥25, ≤30  268 (38.1)  161 (37.6)  107 (38.8)   ≥30  107 (15.2)  45 (10.5)  62 (22.5)  Hypertension, n (%)  299 (42.5)  144 (33.6)  155 (56.2)  <0.01  Diabetes mellitus, n (%)  48 (6.8)  24 (5.6)  24 (8.7)  0.13  Dyslipidaemia, n (%)  304 (43.2)  167 (39.0)  137 (49.6)  <0.01  Total cholesterol (mmol/L), median (IQR)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  0.61  HDL cholesterol (mmol/L), median (IQR)  1.3 (1.1–1.6)  1.3 (1.1–1.6)  1.4 (1.1–1.6)  0.05  LDL cholesterol (mmol/L), median (IQR)  3.1 (2.5–3.7)  3.0 (2.5–3.6)  3.2 (2.4–3.8)  0.33  Triglycerides (mmol/L), median (IQR)  1.3 (0.9–2.1)  1.4 (1.0–2.2)  1.3 (0.9–2.0)  0.01  Lipid-lowering medication use, n (%)  91 (12.9)  28 (6.5)  63 (22.8)  <0.01   Statin  88 (12.5)  27 (6.3)  60 (21.7)   Fibrate  4 (0.4)  1 (0.2)  3 (1.1)  Current smoking, n (%)  197 (28.0)  151 (35.3)  46 (16.7)  <0.01  Alcohol consumption, n (%)           None/mild  481 (68.3)  340 (79.4)  141 (51.2)  0.04   Moderate  120 (17.1)  72 (16.8)  48 (17.4)   Severe  8 (1.1)  7 (1.6)  1 (0.4)   Missing  95 (13.5)  9 (2.1)  86 (31.2)  Active illicit drug use, n (%)  14 (2.0)  14 (3.3)  0  <0.01  Framingham risk score (10-year risk), median (IQR)  9.4 (6.1–14.3)  9.0 (6.0–14.1)  9.7 (6.1–14.4)  0.40   <10%  368 (52.3)  229 (53.5)  139 (50.4)  0.68   10–20%  277 (39.4)  163 (38.1)  114 (41.3)   >20%  59 (8.4)  36 (8.4)  23 (8.3)  HIV acquisition mode, n (%)           MSM    255 (59.6)       IDU    43 (10.1)       Heterosexual    121 (28.3)       Other    9 (2.1)      Years HIV-infected, median (IQR)    15 (7–22)      Prior AIDS, n (%)    89 (20.8)      CD4 current (cells/µL), median (IQR)    598 (449–741)      CD4 nadir (cells/µL), median (IQR)    189 (91–281)      CD4 nadir <50 cells/µL, n (%)    68 (15.9)      HIV-1 RNA max. >100 000 copies/mL    267 (62.4)      On ART, n (%)    397 (92.8)      Undetectable HIV-1 RNA, n (%)    374 (87.4)      ART naïve, n (%)    6 (1.4)      ART interrupted, n (%)    25 (5.8)      Total years on ART, median (IQR)    10.1 (4.8–16.4)      Hepatitis C seropositivity, n (%)    66 (15.4)      ART, antiretroviral therapy; IDU, injection drug use; MSM, men who have sex with men. Table 1 Characteristics of HIV-positive and HIV-negative study participants at time of cardiac imaging Characteristic  All participants (n = 704)  HIV-positive participants (n = 428)  HIV-negative participants (n = 276)  P-value  Male sex, n (%)  586 (83.2)  367 (85.8)  219 (79.4)  0.03  Median age (years), IQR  54 (50–59)  52 (49–57)  56 (51–61)  <0.01  Ethnicity, n (%)           White  629 (89.3)  388 (90.7)  243 (88)  0.06   Black  47 (6.7)  29 (6.8)  16 (5.8)   Other/missing  28 (4)  11 (2.6)  17 (6.2)  Body mass index (kg/m2), median (IQR)  25.3 (23.2–28.4)  24.9 (22.8–27.7)  26.2 (23.7–29.4)  <0.01   <18.5  15 (2.1)  11 (2.6)  4 (1.5)  <0.01   ≥18.5, <25  314 (44.6)  211 (49.3)  103 (37.3)   ≥25, ≤30  268 (38.1)  161 (37.6)  107 (38.8)   ≥30  107 (15.2)  45 (10.5)  62 (22.5)  Hypertension, n (%)  299 (42.5)  144 (33.6)  155 (56.2)  <0.01  Diabetes mellitus, n (%)  48 (6.8)  24 (5.6)  24 (8.7)  0.13  Dyslipidaemia, n (%)  304 (43.2)  167 (39.0)  137 (49.6)  <0.01  Total cholesterol (mmol/L), median (IQR)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  0.61  HDL cholesterol (mmol/L), median (IQR)  1.3 (1.1–1.6)  1.3 (1.1–1.6)  1.4 (1.1–1.6)  0.05  LDL cholesterol (mmol/L), median (IQR)  3.1 (2.5–3.7)  3.0 (2.5–3.6)  3.2 (2.4–3.8)  0.33  Triglycerides (mmol/L), median (IQR)  1.3 (0.9–2.1)  1.4 (1.0–2.2)  1.3 (0.9–2.0)  0.01  Lipid-lowering medication use, n (%)  91 (12.9)  28 (6.5)  63 (22.8)  <0.01   Statin  88 (12.5)  27 (6.3)  60 (21.7)   Fibrate  4 (0.4)  1 (0.2)  3 (1.1)  Current smoking, n (%)  197 (28.0)  151 (35.3)  46 (16.7)  <0.01  Alcohol consumption, n (%)           None/mild  481 (68.3)  340 (79.4)  141 (51.2)  0.04   Moderate  120 (17.1)  72 (16.8)  48 (17.4)   Severe  8 (1.1)  7 (1.6)  1 (0.4)   Missing  95 (13.5)  9 (2.1)  86 (31.2)  Active illicit drug use, n (%)  14 (2.0)  14 (3.3)  0  <0.01  Framingham risk score (10-year risk), median (IQR)  9.4 (6.1–14.3)  9.0 (6.0–14.1)  9.7 (6.1–14.4)  0.40   <10%  368 (52.3)  229 (53.5)  139 (50.4)  0.68   10–20%  277 (39.4)  163 (38.1)  114 (41.3)   >20%  59 (8.4)  36 (8.4)  23 (8.3)  HIV acquisition mode, n (%)           MSM    255 (59.6)       IDU    43 (10.1)       Heterosexual    121 (28.3)       Other    9 (2.1)      Years HIV-infected, median (IQR)    15 (7–22)      Prior AIDS, n (%)    89 (20.8)      CD4 current (cells/µL), median (IQR)    598 (449–741)      CD4 nadir (cells/µL), median (IQR)    189 (91–281)      CD4 nadir <50 cells/µL, n (%)    68 (15.9)      HIV-1 RNA max. >100 000 copies/mL    267 (62.4)      On ART, n (%)    397 (92.8)      Undetectable HIV-1 RNA, n (%)    374 (87.4)      ART naïve, n (%)    6 (1.4)      ART interrupted, n (%)    25 (5.8)      Total years on ART, median (IQR)    10.1 (4.8–16.4)      Hepatitis C seropositivity, n (%)    66 (15.4)      Characteristic  All participants (n = 704)  HIV-positive participants (n = 428)  HIV-negative participants (n = 276)  P-value  Male sex, n (%)  586 (83.2)  367 (85.8)  219 (79.4)  0.03  Median age (years), IQR  54 (50–59)  52 (49–57)  56 (51–61)  <0.01  Ethnicity, n (%)           White  629 (89.3)  388 (90.7)  243 (88)  0.06   Black  47 (6.7)  29 (6.8)  16 (5.8)   Other/missing  28 (4)  11 (2.6)  17 (6.2)  Body mass index (kg/m2), median (IQR)  25.3 (23.2–28.4)  24.9 (22.8–27.7)  26.2 (23.7–29.4)  <0.01   <18.5  15 (2.1)  11 (2.6)  4 (1.5)  <0.01   ≥18.5, <25  314 (44.6)  211 (49.3)  103 (37.3)   ≥25, ≤30  268 (38.1)  161 (37.6)  107 (38.8)   ≥30  107 (15.2)  45 (10.5)  62 (22.5)  Hypertension, n (%)  299 (42.5)  144 (33.6)  155 (56.2)  <0.01  Diabetes mellitus, n (%)  48 (6.8)  24 (5.6)  24 (8.7)  0.13  Dyslipidaemia, n (%)  304 (43.2)  167 (39.0)  137 (49.6)  <0.01  Total cholesterol (mmol/L), median (IQR)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  0.61  HDL cholesterol (mmol/L), median (IQR)  1.3 (1.1–1.6)  1.3 (1.1–1.6)  1.4 (1.1–1.6)  0.05  LDL cholesterol (mmol/L), median (IQR)  3.1 (2.5–3.7)  3.0 (2.5–3.6)  3.2 (2.4–3.8)  0.33  Triglycerides (mmol/L), median (IQR)  1.3 (0.9–2.1)  1.4 (1.0–2.2)  1.3 (0.9–2.0)  0.01  Lipid-lowering medication use, n (%)  91 (12.9)  28 (6.5)  63 (22.8)  <0.01   Statin  88 (12.5)  27 (6.3)  60 (21.7)   Fibrate  4 (0.4)  1 (0.2)  3 (1.1)  Current smoking, n (%)  197 (28.0)  151 (35.3)  46 (16.7)  <0.01  Alcohol consumption, n (%)           None/mild  481 (68.3)  340 (79.4)  141 (51.2)  0.04   Moderate  120 (17.1)  72 (16.8)  48 (17.4)   Severe  8 (1.1)  7 (1.6)  1 (0.4)   Missing  95 (13.5)  9 (2.1)  86 (31.2)  Active illicit drug use, n (%)  14 (2.0)  14 (3.3)  0  <0.01  Framingham risk score (10-year risk), median (IQR)  9.4 (6.1–14.3)  9.0 (6.0–14.1)  9.7 (6.1–14.4)  0.40   <10%  368 (52.3)  229 (53.5)  139 (50.4)  0.68   10–20%  277 (39.4)  163 (38.1)  114 (41.3)   >20%  59 (8.4)  36 (8.4)  23 (8.3)  HIV acquisition mode, n (%)           MSM    255 (59.6)       IDU    43 (10.1)       Heterosexual    121 (28.3)       Other    9 (2.1)      Years HIV-infected, median (IQR)    15 (7–22)      Prior AIDS, n (%)    89 (20.8)      CD4 current (cells/µL), median (IQR)    598 (449–741)      CD4 nadir (cells/µL), median (IQR)    189 (91–281)      CD4 nadir <50 cells/µL, n (%)    68 (15.9)      HIV-1 RNA max. >100 000 copies/mL    267 (62.4)      On ART, n (%)    397 (92.8)      Undetectable HIV-1 RNA, n (%)    374 (87.4)      ART naïve, n (%)    6 (1.4)      ART interrupted, n (%)    25 (5.8)      Total years on ART, median (IQR)    10.1 (4.8–16.4)      Hepatitis C seropositivity, n (%)    66 (15.4)      ART, antiretroviral therapy; IDU, injection drug use; MSM, men who have sex with men. Prevalence of subclinical coronary artery disease The prevalence of CAC score >0, median CAC scores and percentages of patients in different CAC score categories were similar in HIV-positive and HIV-negative participants (Table 2). Figure 1 illustrates the similar age-specific CAC prevalence. Coronary computed tomography angiography showed a trend towards a lower prevalence of any coronary plaque in HIV-positive compared to HIV-negative participants, a lower prevalence of calcified plaque, and a similar prevalence of both non-calcified/mixed plaque, high-risk plaque, and coronary artery stenosis >50% and >70%. There were trends towards lower average SSS and SIS in HIV-positive participants. Table 2 Prevalence of subclinical CAD outcomes in HIV-positive and HIV-negative study participants   Total (n = 704)  HIV-positive  participants (n = 428)  HIV-negative participants (n = 276)  P-value  CAC determination   CAC score, median (IQR)  47 (14–193)  47 (14–183)  47 (12–218)  0.80   CAC score, n (%)            0  322 (45.7)  201 (47)  121 (43.8)  0.70    1–9  78 (11.1)  45 (10.5)  33 (12)    10–99  163 (23.2)  102 (23.8)  61 (22.1)    100–399  89 (12.6)  49 (11.5)  40 (14.5)    ≥400  52 (7.4)  31 (7.2)  21 (7.6)   Any CAC (CAC score >0), n (%)  382 (54.3)  227 (53)  155 (56.2)  0.42  Coronary CT angiography   Any plaque, n (%)  390 (55.4)  226 (52.8)  164 (59.4)  0.09   Calcified plaque, n (%)  292 (41.5)  158 (36.9)  134 (48.6)  <0.01   Non-calcified/mixed plaque, n (%)  257 (36.5)  158 (36.9)  99 (35.9)  0.78   High-risk plaque, n (%)  115 (16.3)  67 (17.4)  67 (15.7)  0.54   Coronary artery stenosis >50%, n (%)  98 (13.9)  55 (12.9)  43 (15.6)  0.31   Coronary artery stenosis >70%, n (%)  38 (5.4)  23 (5.4)  15 (5.4)  0.97   Segment severity score, mean (IQR)  2.0 (0–3)  1.8 (0–3)  2.3 (0–3)  0.06   Segment involvement score, mean (IQR)  1.7 (0–3)  1.6 (0–2)  1.9 (0–3)  0.08    Total (n = 704)  HIV-positive  participants (n = 428)  HIV-negative participants (n = 276)  P-value  CAC determination   CAC score, median (IQR)  47 (14–193)  47 (14–183)  47 (12–218)  0.80   CAC score, n (%)            0  322 (45.7)  201 (47)  121 (43.8)  0.70    1–9  78 (11.1)  45 (10.5)  33 (12)    10–99  163 (23.2)  102 (23.8)  61 (22.1)    100–399  89 (12.6)  49 (11.5)  40 (14.5)    ≥400  52 (7.4)  31 (7.2)  21 (7.6)   Any CAC (CAC score >0), n (%)  382 (54.3)  227 (53)  155 (56.2)  0.42  Coronary CT angiography   Any plaque, n (%)  390 (55.4)  226 (52.8)  164 (59.4)  0.09   Calcified plaque, n (%)  292 (41.5)  158 (36.9)  134 (48.6)  <0.01   Non-calcified/mixed plaque, n (%)  257 (36.5)  158 (36.9)  99 (35.9)  0.78   High-risk plaque, n (%)  115 (16.3)  67 (17.4)  67 (15.7)  0.54   Coronary artery stenosis >50%, n (%)  98 (13.9)  55 (12.9)  43 (15.6)  0.31   Coronary artery stenosis >70%, n (%)  38 (5.4)  23 (5.4)  15 (5.4)  0.97   Segment severity score, mean (IQR)  2.0 (0–3)  1.8 (0–3)  2.3 (0–3)  0.06   Segment involvement score, mean (IQR)  1.7 (0–3)  1.6 (0–2)  1.9 (0–3)  0.08  CAC, coronary artery calcium; IQR, interquartile range. Table 2 Prevalence of subclinical CAD outcomes in HIV-positive and HIV-negative study participants   Total (n = 704)  HIV-positive  participants (n = 428)  HIV-negative participants (n = 276)  P-value  CAC determination   CAC score, median (IQR)  47 (14–193)  47 (14–183)  47 (12–218)  0.80   CAC score, n (%)            0  322 (45.7)  201 (47)  121 (43.8)  0.70    1–9  78 (11.1)  45 (10.5)  33 (12)    10–99  163 (23.2)  102 (23.8)  61 (22.1)    100–399  89 (12.6)  49 (11.5)  40 (14.5)    ≥400  52 (7.4)  31 (7.2)  21 (7.6)   Any CAC (CAC score >0), n (%)  382 (54.3)  227 (53)  155 (56.2)  0.42  Coronary CT angiography   Any plaque, n (%)  390 (55.4)  226 (52.8)  164 (59.4)  0.09   Calcified plaque, n (%)  292 (41.5)  158 (36.9)  134 (48.6)  <0.01   Non-calcified/mixed plaque, n (%)  257 (36.5)  158 (36.9)  99 (35.9)  0.78   High-risk plaque, n (%)  115 (16.3)  67 (17.4)  67 (15.7)  0.54   Coronary artery stenosis >50%, n (%)  98 (13.9)  55 (12.9)  43 (15.6)  0.31   Coronary artery stenosis >70%, n (%)  38 (5.4)  23 (5.4)  15 (5.4)  0.97   Segment severity score, mean (IQR)  2.0 (0–3)  1.8 (0–3)  2.3 (0–3)  0.06   Segment involvement score, mean (IQR)  1.7 (0–3)  1.6 (0–2)  1.9 (0–3)  0.08    Total (n = 704)  HIV-positive  participants (n = 428)  HIV-negative participants (n = 276)  P-value  CAC determination   CAC score, median (IQR)  47 (14–193)  47 (14–183)  47 (12–218)  0.80   CAC score, n (%)            0  322 (45.7)  201 (47)  121 (43.8)  0.70    1–9  78 (11.1)  45 (10.5)  33 (12)    10–99  163 (23.2)  102 (23.8)  61 (22.1)    100–399  89 (12.6)  49 (11.5)  40 (14.5)    ≥400  52 (7.4)  31 (7.2)  21 (7.6)   Any CAC (CAC score >0), n (%)  382 (54.3)  227 (53)  155 (56.2)  0.42  Coronary CT angiography   Any plaque, n (%)  390 (55.4)  226 (52.8)  164 (59.4)  0.09   Calcified plaque, n (%)  292 (41.5)  158 (36.9)  134 (48.6)  <0.01   Non-calcified/mixed plaque, n (%)  257 (36.5)  158 (36.9)  99 (35.9)  0.78   High-risk plaque, n (%)  115 (16.3)  67 (17.4)  67 (15.7)  0.54   Coronary artery stenosis >50%, n (%)  98 (13.9)  55 (12.9)  43 (15.6)  0.31   Coronary artery stenosis >70%, n (%)  38 (5.4)  23 (5.4)  15 (5.4)  0.97   Segment severity score, mean (IQR)  2.0 (0–3)  1.8 (0–3)  2.3 (0–3)  0.06   Segment involvement score, mean (IQR)  1.7 (0–3)  1.6 (0–2)  1.9 (0–3)  0.08  CAC, coronary artery calcium; IQR, interquartile range. Figure 1 View largeDownload slide Prevalence of coronary artery calcification by age in HIV-positive and HIV-negative study participants. Coronary artery calcium scores are shown according to age for HIV-positive (red squares) and HIV-negative (green circles) participants. Filled squares/circles are participants with no coronary artery calcium; empty squares/circles are participants with coronary artery calcium scores of ≥100. Figure 1 View largeDownload slide Prevalence of coronary artery calcification by age in HIV-positive and HIV-negative study participants. Coronary artery calcium scores are shown according to age for HIV-positive (red squares) and HIV-negative (green circles) participants. Filled squares/circles are participants with no coronary artery calcium; empty squares/circles are participants with coronary artery calcium scores of ≥100. Associations between cardiovascular risk factors, HIV infection and subclinical coronary artery disease In univariable analysis, HIV showed trends towards lower SIS [odds ratio (OR) 0.78; 95% confidence interval (CI) 0.59–1.03; P = 0.08] and lower SSS (OR 0.77; 95% CI 0.59–1.02; P = 0.06) (Figure 2, Supplementary material online, Table S1). HIV infection was not associated with CAC score >0 (OR 0.88; 95% CI 0.65–1.20; P = 0.42). HIV infection was significantly associated with less calcified plaque (OR 0.62; 95% CI 0.46–0.84), with a trend towards less CCTA-detected plaque (OR 0.76; 95% CI 0.56–1.04; P = 0.09), but not with non-calcified/mixed plaque (OR 1.04; 95% CI 0.76–1.43; P = 0.78), or with high-risk plaque (OR 0.88; 95% CI 0.59–1.32, P = 0.54). Figure 2 View largeDownload slide Associations of subclinical coronary artery disease endpoints with HIV infection and cardiovascular risk factors among 704 participants. Figure 2 View largeDownload slide Associations of subclinical coronary artery disease endpoints with HIV infection and cardiovascular risk factors among 704 participants. In the final multivariable model (Figure 2, Supplementary material online, Table S1), HIV infection was associated with lower SIS [adjusted odds ratio (aOR) 0.72; 95% CI 0.53–0.99; P = 0.04] and lower SSS (aOR 0.71, 95% CI 0.52–0.97; P = 0.03). HIV was not associated with CAC >0 (aOR 0.79; 95% CI 0.55–1.14; P = 0.22). HIV was associated with less calcified plaque (aOR 0.57; 95% CI 0.40–0.82; P < 0.01), with a trend towards less CCTA-detected plaque (aOR 0.74; 95% CI 0.51–1.06; P = 0.10), but not with non-calcified/mixed plaque (aOR 1.01; 95% CI 0.70–1.46; P = 0.95), or high-risk plaque (aOR 0.94; 95% CI 0.59–1.49; P = 0.79). Subgroup analyses in women Results in women (n = 118) were consistent with the entire study population, but confidence intervals were wider (see Supplementary material online, Table S2). Subgroup analyses in different age groups Results were consistent with the entire study population (Figure 1, Supplementary material online, Table S3). Associations between HIV-related variables and subclinical coronary artery disease These associations were inconsistent (Figure 3, Supplementary material online, Table S4). Advanced immunosuppression (CD4 nadir <50 cells/µL) was associated with non-calcified/mixed plaque. Maximum HIV viral load >100 000 copies/mL was associated with CAC >0, any plaque, and calcified plaque. Duration of antiretroviral treatment was associated with CAC >0. Figure 3 View largeDownload slide Associations between the presence of subclinical coronary artery disease endpoints and HIV-related variables in 428 HIV-positive participants. Figure 3 View largeDownload slide Associations between the presence of subclinical coronary artery disease endpoints and HIV-related variables in 428 HIV-positive participants. Chronological and coronary age HIV-negative participants [median age 56; interquartile range (IQR) 51–61 years] were older than HIV-positive participants (median age 52; IQR 49–57 years; P < 0.01), and had a higher coronary age (median 58.8, IQR 54.3–68.4 years) than HIV-positive participants (median 56.6, IQR 51–65.9 years; P < 0.01). However, the difference between coronary age and chronological age was similar in HIV-negative (mean difference 5.2 years; median difference 0; IQR 0–10 years) and HIV-positive participants (mean difference 5.5 years; median difference 0; IQR 0–10.6 years; P = 0.73). Sensitivity analysis There was no evidence of effect modification for any outcome by the propensity score which discriminated reasonably well between HIV-positive and HIV-negative participants. By including additional variables to those already included in the multivariable models, the c-statistic increased from 0.70 to 0.77 (see Supplementary material online, Table S5). Discussion To our knowledge, this is the first large-scale assessment of subclinical CAD in HIV-positive and HIV-negative persons from Europe. As expected, age, male sex, and traditional cardiovascular risk factors were significantly associated with subclinical CAD. HIV infection, however, did not independently contribute to CAC score, any plaque on CCTA, or non-calcified/mixed or high-risk plaque. On the contrary, HIV was associated with less calcified plaque and lower coronary SSS and SIS compared with the HIV-negative participants. Our findings appear robust, because results were consistent across different age groups and in both men and women. In addition, we found no evidence of advanced coronary age in our HIV-positive patients, and we were thus unable to confirm a previous report.8 Take home figure View largeDownload slide Subclinical atherosclerosis was associated with traditional cardiovascular risk factors in our study using coronary CT angiography, but not with HIV infection. HIV was associated with a similar prevalence of high risk plaque, lower prevalence of calcified plaque and lower coronary segment severity and involvement scores. Take home figure View largeDownload slide Subclinical atherosclerosis was associated with traditional cardiovascular risk factors in our study using coronary CT angiography, but not with HIV infection. HIV was associated with a similar prevalence of high risk plaque, lower prevalence of calcified plaque and lower coronary segment severity and involvement scores. Our results differ from the results of a recent CCTA study conducted in the USA. Post et al.13 noted a higher prevalence of any plaque and of non-calcified plaque in HIV-positive compared with HIV-negative US men who have sex with men in the Multicenter AIDS Cohort Study (MACS; n = 759). In contrast, CCTA findings were similar in 1257 HIV-positive and HIV-negative African Americans with high levels of cocaine use from Baltimore reported by Lai et al.14 Explanations for these different results are speculative. Regular follow-up, high rates of successful treatment, modern ART regimens, and decreasing smoking rates in recent years in the Swiss HIV Cohort Study27 might indicate a study population in better health than the MACS patients,13 with presumably lower degrees of deleterious systemic inflammation.5 Well-controlled HIV infection might also explain the similar or even lower degrees of subclinical CAD that we noted in our HIV-positive compared with the HIV-negative participants who had similar Framingham risk scores. The median age of our HIV-positive and HIV-negative participants (52 vs. 56 years) was similar to MACS13 (53.2 vs. 55.8 years), and higher than in the study by Lai et al.14 (46 vs. 44 years). We found the associations of HIV with subclinical CAD also in multivariable analyses that were adjusted for age and other factors, because an increase of coronary calcification with age is well documented.10,28 Additional possible explanations for the differences between our results and those in MACS may include differences in demographics, cardiovascular risk profile, drug use patterns, geographic origin of the participants, and different ART exposure patterns. A conservative definition of plaque22 may have resulted in a lower overall subclinical atherosclerosis prevalence in our study and the report by Lai et al.,14 compared with MACS.13 The association of cardiovascular events with duration of ART or advanced immunosuppression in the setting of HIV remains debated.3,6 We did not identify any association of ART duration with either calcified or non-calcified plaque, similar to the findings in non-cocaine users by Lai et al.,14 and in contrast to MACS.13 Consistent with MACS,13 we found that low nadir CD4 count was associated with non-calcified plaque, potentially providing support for the now established recommendation for early initiation of ART. Our observation that CAC score and calcified plaque were associated with high pre-treatment levels of HIV viral load needs to be confirmed. Strengths of our study include this being the first large scale CAC/CCTA evaluation comparing HIV-positive and HIV-negative persons in Europe, and that HIV-positive participants were followed in a well-established study, the SHCS.19 Limitations include the cross-sectional nature and the absence of formal matching on cardiovascular risk factors of HIV-positive and HIV-negative participants in our study and in the two US studies.13,14 Thus, each of these studies’ results are an indicator of how study participants were selected. However, we periodically adjusted selection criteria for the controls, resulting in comparable Framingham risk scores in the HIV-positive and HIV-negative participants, and we used propensity scores for bias reduction in the selection of an unmatched control group, which consistently showed comparable results for each of the imaging outcomes. HIV-negative controls were extensively matched on CAD risk factors to the HIV-positive participants in two previous studies, which showed no difference in CIMT progression7 and a similar prevalence of non-calcified coronary plaque.29 Our study included relatively few women and participants >65 years and therefore should be cautiously interpreted in these populations. Finally, even though we compared asymptomatic HIV-positive individuals with symptomatic HIV-negative CCTA referral patients, the similar prevalence of >50% coronary stenosis (see Table 2) documents that the symptoms that prompted CCTA referral of the controls were mostly of non-coronary origin.30 HIV was not associated with more subclinical atherosclerosis in our study. Our findings appear to be consistent with recent reports that myocardial infarction rates were similar in HIV-positive and HIV-negative non-smokers in Denmark18 and in Switzerland.17 Taken together, these reports somewhat attenuate concerns about accelerated subclinical atherosclerosis in HIV-positive persons. Supplementary material Supplementary material is available at European Heart Journal online. Acknowledgements Swiss HIV Cohort Study data are collected by 5 Swiss University Hospitals, 2 Cantonal Hospitals, 15 affiliated hospitals, and 36 private physicians (listed in shcs.ch/180-health-care-providers). Members of the SHCS are listed in the Supplementary material online. Funding This study was supported by the Swiss National Science Foundation (SNF; 324730_144209/1) and the SHCS, which is funded by the SNF. Additional funds were obtained from ViiV and Gilead. The funders had no role in the study design, data collection, analysis or interpretation, or manuscript writing. Conflict of interest: P.E.T. institution has received unrestricted grants and advisory fees from ViiV and Gilead. B.L. has received grants from ViiV and Gilead and personal fees from Janssen, ViiV, and Gilead. A.C., R.W., R.N., and R.R.B. have received grants from ViiV and Gilead. T.D.L. has received travel grants from Gilead. A.M. and P.A.K. report no conflicts. H.K. has received travel grants from Gilead and MSD and her institution received consultancy fees from Gilead. References 1 Periard D, Cavassini M, Taffe P, Chevalley M, Senn L, Chapuis-Taillard C, de Valliere S, Hayoz D, Tarr PE; Swiss HIV Cohort Study. High prevalence of peripheral arterial disease in HIV-infected persons. Clin Infect Dis  2008; 46: 761– 767. Google Scholar CrossRef Search ADS PubMed  2 Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, Boccara F, Bingham A, Costagliola D; French Hospital Database on HIV-ANRS CO4. 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A long-term prognostic value of coronary CT angiography in suspected coronary artery disease. JACC Cardiovasc Imaging  2012; 5: 690– 701. Google Scholar CrossRef Search ADS PubMed  25 Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med  1997; 127: 757– 763. Google Scholar CrossRef Search ADS PubMed  26 D'Agostino RB. Propensity score methods for bias reduction in the comparison of a treatment to a non-randomized control group. Stat Med  1998; 17: 2265– 2281. Google Scholar CrossRef Search ADS PubMed  27 Huber M, Ledergerber B, Sauter R, Young J, Fehr J, Cusini A, Battegay M, Calmy A, Orasch C, Nicca D, Bernasconi E, Jaccard R, Held L, Weber R; Swiss HIV Cohort Study Group. Outcome of smoking cessation counselling of HIV-positive persons by HIV care physicians. HIV Med  2012; 13: 387– 397. Google Scholar CrossRef Search ADS PubMed  28 Hoff JA, Chomka EV, Krainik AJ, Daviglus M, Rich S, Kondos GT. Age and gender distributions of coronary artery calcium detected by electron beam tomography in 35, 246 adults. Am J Cardiol  2001; 87: 1335– 1339. Google Scholar CrossRef Search ADS PubMed  29 Duarte H, Matta JR, Muldoon N, Masur H, Hadigan C, Gharib AM. Non-calcified coronary plaque volume inversely related to CD4(+) T-cell count in HIV infection. Antivir Ther  2011; 17: 763– 767. Google Scholar CrossRef Search ADS PubMed  30 Goldstein JA, Chinnaiyan KM, Abidov A, Achenbach S, Berman DS, Hayes SW, Hoffmann U, Lesser JR, Mikati IA, O'Neil BJ, Shaw LJ, Shen MYH, Valeti US, Raff GL; CT-STAT Investigators. The CT-STAT (Coronary Computed Tomographic Angiography for Systematic Triage of Acute Chest Pain Patients to Treatment) trial. J Am Coll Cardiol  2011; 58: 1414– 1422. Google Scholar CrossRef Search ADS PubMed  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com. 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Abstract

Abstract Aims HIV-positive persons have increased cardiovascular event rates but data on the prevalence of subclinical atherosclerosis compared with HIV-negative persons are not uniform. We assessed subclinical atherosclerosis utilizing coronary artery calcium (CAC) scoring and coronary computed tomography angiography (CCTA) in 428 HIV-positive participants of the Swiss HIV Cohort Study and 276 HIV-negative controls concurrently referred for clinically indicated CCTA. Methods and results We assessed the association of HIV infection, cardiovascular risk profile, and HIV-related factors with subclinical atherosclerosis in univariable and multivariable analyses. HIV-positive participants (median duration of HIV infection, 15 years) were younger than HIV-negative participants (median age 52 vs. 56 years; P < 0.01) but had similar median 10-year Framingham risk scores (9.0% vs. 9.7%; P = 0.40). The prevalence of CAC score >0 (53% vs. 56.2%; P = 0.42) and median CAC scores (47 vs. 47; P = 0.80) were similar, as was the prevalence of any, non-calcified/mixed, and high-risk plaque. In multivariable adjusted analysis, HIV-positive participants had a lower prevalence of calcified plaque than HIV-negative participants [36.9% vs. 48.6%, P < 0.01; adjusted odds ratio (aOR) 0.57; 95% confidence interval (CI) 0.40–0.82; P < 0.01], lower coronary segment severity score (aOR 0.72; 95% CI 0.53–0.99; P = 0.04), and lower segment involvement score (aOR 0.71, 95% CI 0.52–0.97; P = 0.03). Advanced immunosuppression was associated with non-calcified/mixed plaque (aOR 1.97; 95% CI 1.09–3.56; P = 0.02). Conclusion HIV-positive persons in Switzerland had a similar degree of non-calcified/mixed plaque and high-risk plaque, and may have less calcified coronary plaque, and lower coronary atherosclerosis involvement and severity scores than HIV-negative persons with similar Framingham risk scores. View largeDownload slide View largeDownload slide Subclinical atherosclerosis , Accelerated atherosclerosis , Coronary artery disease , HIV infection , Coronary artery calcium score , Coronary CT angiography Introduction HIV-positive persons in Western countries now have an essentially normal life expectancy in the setting of effective antiretroviral therapy (ART). However, a major long-term concern in HIV includes accelerated atherosclerosis, as suggested by increased rates of coronary artery disease (CAD), stroke, and peripheral vascular disease, compared with HIV-negative persons.1–3 Accelerated atherosclerosis in HIV may be related to pro-coagulant and pro-inflammatory mechanisms in the setting of immunosuppression, adverse viral effects on endothelial and other cells, deleterious metabolic effects of certain ART agents including dyslipidaemia and insulin resistance, a high prevalence of smoking and other substance use, and genetic factors.4–6 Therefore, there has been considerable interest in early diagnosis of subclinical atherosclerosis in HIV-positive persons. Studies using carotid intima-media thickness (CIMT) measurement and coronary artery calcium (CAC) determination have not consistently shown an increased atherosclerosis prevalence in HIV-positive compared with HIV-negative persons, however.7–9 Coronary artery disease may in part be non-calcified in patients aged <50 years,10 and HIV-positive persons may experience cardiovascular events at a younger age than HIV-negative persons.2 Coronary computed tomography angiography (CCTA) can accurately and reproducibly detect non-calcified plaque when compared with intravascular ultrasound,11 and non-calcified plaque more accurately predicts cardiovascular events than CAC or CIMT.12 In recent large CCTA studies from the USA, an increased13 and a similar14 prevalence of non-calcified plaque was identified in HIV-positive compared with HIV-negative persons. These inconsistent results, the lower CAD rates in middle/southern Europe compared to North America,15,16 and recent reports suggesting similar cardiovascular event rates in HIV-positive and HIV-negative non-smokers in Switzerland17 and Denmark18 highlight the need for additional studies. The aims of our study were to compare the prevalence of subclinical atherosclerosis in HIV-positive and HIV-negative persons in Switzerland using CAC/CCTA, and to assess associations between cardiovascular risk factors, HIV infection, and subclinical CAD. Methods Study design and study participants Enrolment was from 10/2013 to 7/2016. We investigated the association of HIV-infection with subclinical CAD by CCTA and non-contrast CT scan for calculating the CAC score. Enrolment criteria included age ≥45 years, no documented CAD/stroke, GFR ≥60 mL/min, no allergy to iodinated contrast agent, and no history of atrial fibrillation or other irregular heartbeat. HIV-positive persons were participants of the metabolism and aging core project of the Swiss HIV Cohort Study (www.shcs.ch). HIV-negative participants were referred for clinically indicated CCTA/CAC during the enrolment period. We attempted to obtain comparable populations with regards to age, gender and Framingham risk score16 by periodic comparisons of their characteristics and adjusting the selection criteria for HIV-negative individuals. The study was approved by the local ethics committees. Participants provided written informed consent; they had access to imaging results via their HIV physician and were offered management of any abnormality detected. Data collection For HIV-positive participants, data were collected within the SHCS, a prospective cohort study that has continuously enrolled HIV-positive adults since 1988.19 Demographic, clinical, and laboratory data are collected every 6 months using a standardized protocol, including detailed information on cardiovascular events, hypertension, diabetes mellitus, smoking, alcohol and drug use, and medication. For HIV-negative participants, clinical information was obtained using a structured questionnaire that included indication for CCTA/CAC referral, verification of inclusion criteria, co-morbidities, medication, smoking, alcohol, and drug use. Data were verified by chart review. Vital signs, fasting total, LDL-, HDL-cholesterol, triglycerides, glucose, and creatinine were measured at the time of CCTA/CAC in all participants. Cardiac imaging Cardiac imaging was performed at University Hospitals Zurich and Geneva. Coronary computed tomography angiography with low radiation exposure was completed using a 64-slice Discovery 750 HD or 256-slice Revolution CT Scanner (both GE Healthcare, Waukesha, WI, USA) or a dual tube 64-slice Somatom Definition Flash CT scanner (Siemens Healthcare, Erlangen, Germany) with a prospectively electrocardiogram (ECG)-triggered cardiac acquisition protocol with tube voltage and current adapted to body mass index (BMI).20 Imaging was done at a temporal resolution of 83–175 ms with either a step-and-shoot scan mode (64-slice scanner) or a single-beat-acquisition mode (256-slice scanner and dual-tube). Slice thickness was 0.625 mm. A BMI-adapted contrast protocol (Visipaque 320, GE Healthcare) was applied. All patients received 2.5 mg of sublingual isosorbide dinitrate; metoprolol was injected intravenously as needed to attain a heart rate <65/min. A prospectively ECG-triggered, non-contrast cardiac computed tomography scan was performed to determine the CAC score. Imaging findings were assessed by two experienced readers of the Cardiac Imaging divisions at University Hospitals Zurich and Geneva. Definitions Coronary artery calcium was defined as CAC score >0 based on the Agatston method. Coronary arteries were subdivided into 16 segments,21 with the intermediate artery defined as segment 16, if present. Segments with a diameter of ≥1.5 mm at origin were included in the analysis. Atherosclerotic plaque was defined as a lesion ≥1 mm2 in orthogonal reconstructions within and/or adjacent to the vessel lumen, not belonging to surrounding tissue.22 Plaques were classified as calcified, non-calcified, or mixed. High-risk plaque was defined23 as plaque with positive remodelling (remodelling index ≥1.1) and/or low attenuation plaque (≤30 HU). The segment involvement score (SIS) was calculated using one point for each coronary segment with any plaque. The segment severity score (SSS) was calculated using the total of all segments scored according to lesion severity.24 Hypertension was defined as blood pressure ≥140/90 mmHg or use of antihypertensive medication. Dyslipidaemia was defined as total cholesterol ≥6.2 mmol/L, or HDL ≤1.0 mmol/L in men (≤1.2 mmol/L in women), or use of lipid-lowering drugs. Diabetes mellitus was diagnosed with confirmed plasma glucose >7.0 mmol/L (fasting) or >11.1 mmol/L (non-fasting) or receiving antidiabetic medication. Alcohol consumption was assessed by using the Alcohol Use Disorders identification Test-Consumption. Undetectable HIV-RNA was defined as <50 copies/mL. Coronary age was calculated based on CAC score, age, sex, and ethnicity.8 Statistical analysis Characteristics of HIV-positive and HIV-negative participants were compared using the χ2/Fisher’s exact test for categorical and the Wilcoxon rank-sum test for continuous variables. To evaluate the association between HIV-infection and subclinical atherosclerosis, we used five separate dichotomous outcomes: (i) CAC score >0, (ii) any CCTA-detected plaque, (iii) calcified plaque, (iv) non-calcified/mixed plaque, and (v) high-risk plaque. Uni- and multivariable logistic regression models were used to explore the association between HIV and each outcome separately. Co-variables included HIV infection, sex, age, smoking, hypertension, dyslipidaemia, diabetes, and study centre. Subgroup analyses were done for females and for age groups 45–54, 55–64, and 65–74 years. In the analyses limited to HIV-positive participants we added CD4 nadir <50 cells/µL, HIV-1 RNA max >100 000 copies/mL, and ART duration to the models. In a sensitivity analysis, we used propensity scores for bias reduction in the selection of an unmatched control group.25,26 The propensity of being HIV positive was calculated by logistic regression (see Supplementary material online, Table S5). The score was then included as adjustment term in the logistic regression models, used both as untransformed linear variable, and after stratification into quintiles. All statistical analyses were done using Stata/SE 14.2 (StataCorp, College Station, TX, USA). Results Study population A total of 704 study participants (median age 54 years, 83% men, 89% white, 428 HIV-positive, 276 HIV-negative) underwent both CAC determination and CCTA. Median effective radiation exposure was 1.8 mSv (IQR, 1.2–2.3). HIV-positive participants were asymptomatic. HIV-negative controls were asymptomatic (36.6%), had typical angina (8.3%), atypical chest pain (44.2%), or dyspnoea (10.9%). Baseline characteristics are shown in Table 1. HIV-positive participants were more likely to be men, they were younger, and had lower BMI. Median Framingham risk scores and percentages of patients in the low, intermediate and high-risk categories were similar among HIV-positive and HIV-negative participants. HIV-positive participants had a lower prevalence of hypertension, diabetes, and dyslipidaemia, but were more likely to smoke and use drugs. Among the HIV-positive participants, men who had sex with men were the predominant group, 21% had prior AIDS-defining events, and 87% were on suppressive ART. Table 1 Characteristics of HIV-positive and HIV-negative study participants at time of cardiac imaging Characteristic  All participants (n = 704)  HIV-positive participants (n = 428)  HIV-negative participants (n = 276)  P-value  Male sex, n (%)  586 (83.2)  367 (85.8)  219 (79.4)  0.03  Median age (years), IQR  54 (50–59)  52 (49–57)  56 (51–61)  <0.01  Ethnicity, n (%)           White  629 (89.3)  388 (90.7)  243 (88)  0.06   Black  47 (6.7)  29 (6.8)  16 (5.8)   Other/missing  28 (4)  11 (2.6)  17 (6.2)  Body mass index (kg/m2), median (IQR)  25.3 (23.2–28.4)  24.9 (22.8–27.7)  26.2 (23.7–29.4)  <0.01   <18.5  15 (2.1)  11 (2.6)  4 (1.5)  <0.01   ≥18.5, <25  314 (44.6)  211 (49.3)  103 (37.3)   ≥25, ≤30  268 (38.1)  161 (37.6)  107 (38.8)   ≥30  107 (15.2)  45 (10.5)  62 (22.5)  Hypertension, n (%)  299 (42.5)  144 (33.6)  155 (56.2)  <0.01  Diabetes mellitus, n (%)  48 (6.8)  24 (5.6)  24 (8.7)  0.13  Dyslipidaemia, n (%)  304 (43.2)  167 (39.0)  137 (49.6)  <0.01  Total cholesterol (mmol/L), median (IQR)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  0.61  HDL cholesterol (mmol/L), median (IQR)  1.3 (1.1–1.6)  1.3 (1.1–1.6)  1.4 (1.1–1.6)  0.05  LDL cholesterol (mmol/L), median (IQR)  3.1 (2.5–3.7)  3.0 (2.5–3.6)  3.2 (2.4–3.8)  0.33  Triglycerides (mmol/L), median (IQR)  1.3 (0.9–2.1)  1.4 (1.0–2.2)  1.3 (0.9–2.0)  0.01  Lipid-lowering medication use, n (%)  91 (12.9)  28 (6.5)  63 (22.8)  <0.01   Statin  88 (12.5)  27 (6.3)  60 (21.7)   Fibrate  4 (0.4)  1 (0.2)  3 (1.1)  Current smoking, n (%)  197 (28.0)  151 (35.3)  46 (16.7)  <0.01  Alcohol consumption, n (%)           None/mild  481 (68.3)  340 (79.4)  141 (51.2)  0.04   Moderate  120 (17.1)  72 (16.8)  48 (17.4)   Severe  8 (1.1)  7 (1.6)  1 (0.4)   Missing  95 (13.5)  9 (2.1)  86 (31.2)  Active illicit drug use, n (%)  14 (2.0)  14 (3.3)  0  <0.01  Framingham risk score (10-year risk), median (IQR)  9.4 (6.1–14.3)  9.0 (6.0–14.1)  9.7 (6.1–14.4)  0.40   <10%  368 (52.3)  229 (53.5)  139 (50.4)  0.68   10–20%  277 (39.4)  163 (38.1)  114 (41.3)   >20%  59 (8.4)  36 (8.4)  23 (8.3)  HIV acquisition mode, n (%)           MSM    255 (59.6)       IDU    43 (10.1)       Heterosexual    121 (28.3)       Other    9 (2.1)      Years HIV-infected, median (IQR)    15 (7–22)      Prior AIDS, n (%)    89 (20.8)      CD4 current (cells/µL), median (IQR)    598 (449–741)      CD4 nadir (cells/µL), median (IQR)    189 (91–281)      CD4 nadir <50 cells/µL, n (%)    68 (15.9)      HIV-1 RNA max. >100 000 copies/mL    267 (62.4)      On ART, n (%)    397 (92.8)      Undetectable HIV-1 RNA, n (%)    374 (87.4)      ART naïve, n (%)    6 (1.4)      ART interrupted, n (%)    25 (5.8)      Total years on ART, median (IQR)    10.1 (4.8–16.4)      Hepatitis C seropositivity, n (%)    66 (15.4)      Characteristic  All participants (n = 704)  HIV-positive participants (n = 428)  HIV-negative participants (n = 276)  P-value  Male sex, n (%)  586 (83.2)  367 (85.8)  219 (79.4)  0.03  Median age (years), IQR  54 (50–59)  52 (49–57)  56 (51–61)  <0.01  Ethnicity, n (%)           White  629 (89.3)  388 (90.7)  243 (88)  0.06   Black  47 (6.7)  29 (6.8)  16 (5.8)   Other/missing  28 (4)  11 (2.6)  17 (6.2)  Body mass index (kg/m2), median (IQR)  25.3 (23.2–28.4)  24.9 (22.8–27.7)  26.2 (23.7–29.4)  <0.01   <18.5  15 (2.1)  11 (2.6)  4 (1.5)  <0.01   ≥18.5, <25  314 (44.6)  211 (49.3)  103 (37.3)   ≥25, ≤30  268 (38.1)  161 (37.6)  107 (38.8)   ≥30  107 (15.2)  45 (10.5)  62 (22.5)  Hypertension, n (%)  299 (42.5)  144 (33.6)  155 (56.2)  <0.01  Diabetes mellitus, n (%)  48 (6.8)  24 (5.6)  24 (8.7)  0.13  Dyslipidaemia, n (%)  304 (43.2)  167 (39.0)  137 (49.6)  <0.01  Total cholesterol (mmol/L), median (IQR)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  0.61  HDL cholesterol (mmol/L), median (IQR)  1.3 (1.1–1.6)  1.3 (1.1–1.6)  1.4 (1.1–1.6)  0.05  LDL cholesterol (mmol/L), median (IQR)  3.1 (2.5–3.7)  3.0 (2.5–3.6)  3.2 (2.4–3.8)  0.33  Triglycerides (mmol/L), median (IQR)  1.3 (0.9–2.1)  1.4 (1.0–2.2)  1.3 (0.9–2.0)  0.01  Lipid-lowering medication use, n (%)  91 (12.9)  28 (6.5)  63 (22.8)  <0.01   Statin  88 (12.5)  27 (6.3)  60 (21.7)   Fibrate  4 (0.4)  1 (0.2)  3 (1.1)  Current smoking, n (%)  197 (28.0)  151 (35.3)  46 (16.7)  <0.01  Alcohol consumption, n (%)           None/mild  481 (68.3)  340 (79.4)  141 (51.2)  0.04   Moderate  120 (17.1)  72 (16.8)  48 (17.4)   Severe  8 (1.1)  7 (1.6)  1 (0.4)   Missing  95 (13.5)  9 (2.1)  86 (31.2)  Active illicit drug use, n (%)  14 (2.0)  14 (3.3)  0  <0.01  Framingham risk score (10-year risk), median (IQR)  9.4 (6.1–14.3)  9.0 (6.0–14.1)  9.7 (6.1–14.4)  0.40   <10%  368 (52.3)  229 (53.5)  139 (50.4)  0.68   10–20%  277 (39.4)  163 (38.1)  114 (41.3)   >20%  59 (8.4)  36 (8.4)  23 (8.3)  HIV acquisition mode, n (%)           MSM    255 (59.6)       IDU    43 (10.1)       Heterosexual    121 (28.3)       Other    9 (2.1)      Years HIV-infected, median (IQR)    15 (7–22)      Prior AIDS, n (%)    89 (20.8)      CD4 current (cells/µL), median (IQR)    598 (449–741)      CD4 nadir (cells/µL), median (IQR)    189 (91–281)      CD4 nadir <50 cells/µL, n (%)    68 (15.9)      HIV-1 RNA max. >100 000 copies/mL    267 (62.4)      On ART, n (%)    397 (92.8)      Undetectable HIV-1 RNA, n (%)    374 (87.4)      ART naïve, n (%)    6 (1.4)      ART interrupted, n (%)    25 (5.8)      Total years on ART, median (IQR)    10.1 (4.8–16.4)      Hepatitis C seropositivity, n (%)    66 (15.4)      ART, antiretroviral therapy; IDU, injection drug use; MSM, men who have sex with men. Table 1 Characteristics of HIV-positive and HIV-negative study participants at time of cardiac imaging Characteristic  All participants (n = 704)  HIV-positive participants (n = 428)  HIV-negative participants (n = 276)  P-value  Male sex, n (%)  586 (83.2)  367 (85.8)  219 (79.4)  0.03  Median age (years), IQR  54 (50–59)  52 (49–57)  56 (51–61)  <0.01  Ethnicity, n (%)           White  629 (89.3)  388 (90.7)  243 (88)  0.06   Black  47 (6.7)  29 (6.8)  16 (5.8)   Other/missing  28 (4)  11 (2.6)  17 (6.2)  Body mass index (kg/m2), median (IQR)  25.3 (23.2–28.4)  24.9 (22.8–27.7)  26.2 (23.7–29.4)  <0.01   <18.5  15 (2.1)  11 (2.6)  4 (1.5)  <0.01   ≥18.5, <25  314 (44.6)  211 (49.3)  103 (37.3)   ≥25, ≤30  268 (38.1)  161 (37.6)  107 (38.8)   ≥30  107 (15.2)  45 (10.5)  62 (22.5)  Hypertension, n (%)  299 (42.5)  144 (33.6)  155 (56.2)  <0.01  Diabetes mellitus, n (%)  48 (6.8)  24 (5.6)  24 (8.7)  0.13  Dyslipidaemia, n (%)  304 (43.2)  167 (39.0)  137 (49.6)  <0.01  Total cholesterol (mmol/L), median (IQR)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  0.61  HDL cholesterol (mmol/L), median (IQR)  1.3 (1.1–1.6)  1.3 (1.1–1.6)  1.4 (1.1–1.6)  0.05  LDL cholesterol (mmol/L), median (IQR)  3.1 (2.5–3.7)  3.0 (2.5–3.6)  3.2 (2.4–3.8)  0.33  Triglycerides (mmol/L), median (IQR)  1.3 (0.9–2.1)  1.4 (1.0–2.2)  1.3 (0.9–2.0)  0.01  Lipid-lowering medication use, n (%)  91 (12.9)  28 (6.5)  63 (22.8)  <0.01   Statin  88 (12.5)  27 (6.3)  60 (21.7)   Fibrate  4 (0.4)  1 (0.2)  3 (1.1)  Current smoking, n (%)  197 (28.0)  151 (35.3)  46 (16.7)  <0.01  Alcohol consumption, n (%)           None/mild  481 (68.3)  340 (79.4)  141 (51.2)  0.04   Moderate  120 (17.1)  72 (16.8)  48 (17.4)   Severe  8 (1.1)  7 (1.6)  1 (0.4)   Missing  95 (13.5)  9 (2.1)  86 (31.2)  Active illicit drug use, n (%)  14 (2.0)  14 (3.3)  0  <0.01  Framingham risk score (10-year risk), median (IQR)  9.4 (6.1–14.3)  9.0 (6.0–14.1)  9.7 (6.1–14.4)  0.40   <10%  368 (52.3)  229 (53.5)  139 (50.4)  0.68   10–20%  277 (39.4)  163 (38.1)  114 (41.3)   >20%  59 (8.4)  36 (8.4)  23 (8.3)  HIV acquisition mode, n (%)           MSM    255 (59.6)       IDU    43 (10.1)       Heterosexual    121 (28.3)       Other    9 (2.1)      Years HIV-infected, median (IQR)    15 (7–22)      Prior AIDS, n (%)    89 (20.8)      CD4 current (cells/µL), median (IQR)    598 (449–741)      CD4 nadir (cells/µL), median (IQR)    189 (91–281)      CD4 nadir <50 cells/µL, n (%)    68 (15.9)      HIV-1 RNA max. >100 000 copies/mL    267 (62.4)      On ART, n (%)    397 (92.8)      Undetectable HIV-1 RNA, n (%)    374 (87.4)      ART naïve, n (%)    6 (1.4)      ART interrupted, n (%)    25 (5.8)      Total years on ART, median (IQR)    10.1 (4.8–16.4)      Hepatitis C seropositivity, n (%)    66 (15.4)      Characteristic  All participants (n = 704)  HIV-positive participants (n = 428)  HIV-negative participants (n = 276)  P-value  Male sex, n (%)  586 (83.2)  367 (85.8)  219 (79.4)  0.03  Median age (years), IQR  54 (50–59)  52 (49–57)  56 (51–61)  <0.01  Ethnicity, n (%)           White  629 (89.3)  388 (90.7)  243 (88)  0.06   Black  47 (6.7)  29 (6.8)  16 (5.8)   Other/missing  28 (4)  11 (2.6)  17 (6.2)  Body mass index (kg/m2), median (IQR)  25.3 (23.2–28.4)  24.9 (22.8–27.7)  26.2 (23.7–29.4)  <0.01   <18.5  15 (2.1)  11 (2.6)  4 (1.5)  <0.01   ≥18.5, <25  314 (44.6)  211 (49.3)  103 (37.3)   ≥25, ≤30  268 (38.1)  161 (37.6)  107 (38.8)   ≥30  107 (15.2)  45 (10.5)  62 (22.5)  Hypertension, n (%)  299 (42.5)  144 (33.6)  155 (56.2)  <0.01  Diabetes mellitus, n (%)  48 (6.8)  24 (5.6)  24 (8.7)  0.13  Dyslipidaemia, n (%)  304 (43.2)  167 (39.0)  137 (49.6)  <0.01  Total cholesterol (mmol/L), median (IQR)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  5.2 (4.6–5.8)  0.61  HDL cholesterol (mmol/L), median (IQR)  1.3 (1.1–1.6)  1.3 (1.1–1.6)  1.4 (1.1–1.6)  0.05  LDL cholesterol (mmol/L), median (IQR)  3.1 (2.5–3.7)  3.0 (2.5–3.6)  3.2 (2.4–3.8)  0.33  Triglycerides (mmol/L), median (IQR)  1.3 (0.9–2.1)  1.4 (1.0–2.2)  1.3 (0.9–2.0)  0.01  Lipid-lowering medication use, n (%)  91 (12.9)  28 (6.5)  63 (22.8)  <0.01   Statin  88 (12.5)  27 (6.3)  60 (21.7)   Fibrate  4 (0.4)  1 (0.2)  3 (1.1)  Current smoking, n (%)  197 (28.0)  151 (35.3)  46 (16.7)  <0.01  Alcohol consumption, n (%)           None/mild  481 (68.3)  340 (79.4)  141 (51.2)  0.04   Moderate  120 (17.1)  72 (16.8)  48 (17.4)   Severe  8 (1.1)  7 (1.6)  1 (0.4)   Missing  95 (13.5)  9 (2.1)  86 (31.2)  Active illicit drug use, n (%)  14 (2.0)  14 (3.3)  0  <0.01  Framingham risk score (10-year risk), median (IQR)  9.4 (6.1–14.3)  9.0 (6.0–14.1)  9.7 (6.1–14.4)  0.40   <10%  368 (52.3)  229 (53.5)  139 (50.4)  0.68   10–20%  277 (39.4)  163 (38.1)  114 (41.3)   >20%  59 (8.4)  36 (8.4)  23 (8.3)  HIV acquisition mode, n (%)           MSM    255 (59.6)       IDU    43 (10.1)       Heterosexual    121 (28.3)       Other    9 (2.1)      Years HIV-infected, median (IQR)    15 (7–22)      Prior AIDS, n (%)    89 (20.8)      CD4 current (cells/µL), median (IQR)    598 (449–741)      CD4 nadir (cells/µL), median (IQR)    189 (91–281)      CD4 nadir <50 cells/µL, n (%)    68 (15.9)      HIV-1 RNA max. >100 000 copies/mL    267 (62.4)      On ART, n (%)    397 (92.8)      Undetectable HIV-1 RNA, n (%)    374 (87.4)      ART naïve, n (%)    6 (1.4)      ART interrupted, n (%)    25 (5.8)      Total years on ART, median (IQR)    10.1 (4.8–16.4)      Hepatitis C seropositivity, n (%)    66 (15.4)      ART, antiretroviral therapy; IDU, injection drug use; MSM, men who have sex with men. Prevalence of subclinical coronary artery disease The prevalence of CAC score >0, median CAC scores and percentages of patients in different CAC score categories were similar in HIV-positive and HIV-negative participants (Table 2). Figure 1 illustrates the similar age-specific CAC prevalence. Coronary computed tomography angiography showed a trend towards a lower prevalence of any coronary plaque in HIV-positive compared to HIV-negative participants, a lower prevalence of calcified plaque, and a similar prevalence of both non-calcified/mixed plaque, high-risk plaque, and coronary artery stenosis >50% and >70%. There were trends towards lower average SSS and SIS in HIV-positive participants. Table 2 Prevalence of subclinical CAD outcomes in HIV-positive and HIV-negative study participants   Total (n = 704)  HIV-positive  participants (n = 428)  HIV-negative participants (n = 276)  P-value  CAC determination   CAC score, median (IQR)  47 (14–193)  47 (14–183)  47 (12–218)  0.80   CAC score, n (%)            0  322 (45.7)  201 (47)  121 (43.8)  0.70    1–9  78 (11.1)  45 (10.5)  33 (12)    10–99  163 (23.2)  102 (23.8)  61 (22.1)    100–399  89 (12.6)  49 (11.5)  40 (14.5)    ≥400  52 (7.4)  31 (7.2)  21 (7.6)   Any CAC (CAC score >0), n (%)  382 (54.3)  227 (53)  155 (56.2)  0.42  Coronary CT angiography   Any plaque, n (%)  390 (55.4)  226 (52.8)  164 (59.4)  0.09   Calcified plaque, n (%)  292 (41.5)  158 (36.9)  134 (48.6)  <0.01   Non-calcified/mixed plaque, n (%)  257 (36.5)  158 (36.9)  99 (35.9)  0.78   High-risk plaque, n (%)  115 (16.3)  67 (17.4)  67 (15.7)  0.54   Coronary artery stenosis >50%, n (%)  98 (13.9)  55 (12.9)  43 (15.6)  0.31   Coronary artery stenosis >70%, n (%)  38 (5.4)  23 (5.4)  15 (5.4)  0.97   Segment severity score, mean (IQR)  2.0 (0–3)  1.8 (0–3)  2.3 (0–3)  0.06   Segment involvement score, mean (IQR)  1.7 (0–3)  1.6 (0–2)  1.9 (0–3)  0.08    Total (n = 704)  HIV-positive  participants (n = 428)  HIV-negative participants (n = 276)  P-value  CAC determination   CAC score, median (IQR)  47 (14–193)  47 (14–183)  47 (12–218)  0.80   CAC score, n (%)            0  322 (45.7)  201 (47)  121 (43.8)  0.70    1–9  78 (11.1)  45 (10.5)  33 (12)    10–99  163 (23.2)  102 (23.8)  61 (22.1)    100–399  89 (12.6)  49 (11.5)  40 (14.5)    ≥400  52 (7.4)  31 (7.2)  21 (7.6)   Any CAC (CAC score >0), n (%)  382 (54.3)  227 (53)  155 (56.2)  0.42  Coronary CT angiography   Any plaque, n (%)  390 (55.4)  226 (52.8)  164 (59.4)  0.09   Calcified plaque, n (%)  292 (41.5)  158 (36.9)  134 (48.6)  <0.01   Non-calcified/mixed plaque, n (%)  257 (36.5)  158 (36.9)  99 (35.9)  0.78   High-risk plaque, n (%)  115 (16.3)  67 (17.4)  67 (15.7)  0.54   Coronary artery stenosis >50%, n (%)  98 (13.9)  55 (12.9)  43 (15.6)  0.31   Coronary artery stenosis >70%, n (%)  38 (5.4)  23 (5.4)  15 (5.4)  0.97   Segment severity score, mean (IQR)  2.0 (0–3)  1.8 (0–3)  2.3 (0–3)  0.06   Segment involvement score, mean (IQR)  1.7 (0–3)  1.6 (0–2)  1.9 (0–3)  0.08  CAC, coronary artery calcium; IQR, interquartile range. Table 2 Prevalence of subclinical CAD outcomes in HIV-positive and HIV-negative study participants   Total (n = 704)  HIV-positive  participants (n = 428)  HIV-negative participants (n = 276)  P-value  CAC determination   CAC score, median (IQR)  47 (14–193)  47 (14–183)  47 (12–218)  0.80   CAC score, n (%)            0  322 (45.7)  201 (47)  121 (43.8)  0.70    1–9  78 (11.1)  45 (10.5)  33 (12)    10–99  163 (23.2)  102 (23.8)  61 (22.1)    100–399  89 (12.6)  49 (11.5)  40 (14.5)    ≥400  52 (7.4)  31 (7.2)  21 (7.6)   Any CAC (CAC score >0), n (%)  382 (54.3)  227 (53)  155 (56.2)  0.42  Coronary CT angiography   Any plaque, n (%)  390 (55.4)  226 (52.8)  164 (59.4)  0.09   Calcified plaque, n (%)  292 (41.5)  158 (36.9)  134 (48.6)  <0.01   Non-calcified/mixed plaque, n (%)  257 (36.5)  158 (36.9)  99 (35.9)  0.78   High-risk plaque, n (%)  115 (16.3)  67 (17.4)  67 (15.7)  0.54   Coronary artery stenosis >50%, n (%)  98 (13.9)  55 (12.9)  43 (15.6)  0.31   Coronary artery stenosis >70%, n (%)  38 (5.4)  23 (5.4)  15 (5.4)  0.97   Segment severity score, mean (IQR)  2.0 (0–3)  1.8 (0–3)  2.3 (0–3)  0.06   Segment involvement score, mean (IQR)  1.7 (0–3)  1.6 (0–2)  1.9 (0–3)  0.08    Total (n = 704)  HIV-positive  participants (n = 428)  HIV-negative participants (n = 276)  P-value  CAC determination   CAC score, median (IQR)  47 (14–193)  47 (14–183)  47 (12–218)  0.80   CAC score, n (%)            0  322 (45.7)  201 (47)  121 (43.8)  0.70    1–9  78 (11.1)  45 (10.5)  33 (12)    10–99  163 (23.2)  102 (23.8)  61 (22.1)    100–399  89 (12.6)  49 (11.5)  40 (14.5)    ≥400  52 (7.4)  31 (7.2)  21 (7.6)   Any CAC (CAC score >0), n (%)  382 (54.3)  227 (53)  155 (56.2)  0.42  Coronary CT angiography   Any plaque, n (%)  390 (55.4)  226 (52.8)  164 (59.4)  0.09   Calcified plaque, n (%)  292 (41.5)  158 (36.9)  134 (48.6)  <0.01   Non-calcified/mixed plaque, n (%)  257 (36.5)  158 (36.9)  99 (35.9)  0.78   High-risk plaque, n (%)  115 (16.3)  67 (17.4)  67 (15.7)  0.54   Coronary artery stenosis >50%, n (%)  98 (13.9)  55 (12.9)  43 (15.6)  0.31   Coronary artery stenosis >70%, n (%)  38 (5.4)  23 (5.4)  15 (5.4)  0.97   Segment severity score, mean (IQR)  2.0 (0–3)  1.8 (0–3)  2.3 (0–3)  0.06   Segment involvement score, mean (IQR)  1.7 (0–3)  1.6 (0–2)  1.9 (0–3)  0.08  CAC, coronary artery calcium; IQR, interquartile range. Figure 1 View largeDownload slide Prevalence of coronary artery calcification by age in HIV-positive and HIV-negative study participants. Coronary artery calcium scores are shown according to age for HIV-positive (red squares) and HIV-negative (green circles) participants. Filled squares/circles are participants with no coronary artery calcium; empty squares/circles are participants with coronary artery calcium scores of ≥100. Figure 1 View largeDownload slide Prevalence of coronary artery calcification by age in HIV-positive and HIV-negative study participants. Coronary artery calcium scores are shown according to age for HIV-positive (red squares) and HIV-negative (green circles) participants. Filled squares/circles are participants with no coronary artery calcium; empty squares/circles are participants with coronary artery calcium scores of ≥100. Associations between cardiovascular risk factors, HIV infection and subclinical coronary artery disease In univariable analysis, HIV showed trends towards lower SIS [odds ratio (OR) 0.78; 95% confidence interval (CI) 0.59–1.03; P = 0.08] and lower SSS (OR 0.77; 95% CI 0.59–1.02; P = 0.06) (Figure 2, Supplementary material online, Table S1). HIV infection was not associated with CAC score >0 (OR 0.88; 95% CI 0.65–1.20; P = 0.42). HIV infection was significantly associated with less calcified plaque (OR 0.62; 95% CI 0.46–0.84), with a trend towards less CCTA-detected plaque (OR 0.76; 95% CI 0.56–1.04; P = 0.09), but not with non-calcified/mixed plaque (OR 1.04; 95% CI 0.76–1.43; P = 0.78), or with high-risk plaque (OR 0.88; 95% CI 0.59–1.32, P = 0.54). Figure 2 View largeDownload slide Associations of subclinical coronary artery disease endpoints with HIV infection and cardiovascular risk factors among 704 participants. Figure 2 View largeDownload slide Associations of subclinical coronary artery disease endpoints with HIV infection and cardiovascular risk factors among 704 participants. In the final multivariable model (Figure 2, Supplementary material online, Table S1), HIV infection was associated with lower SIS [adjusted odds ratio (aOR) 0.72; 95% CI 0.53–0.99; P = 0.04] and lower SSS (aOR 0.71, 95% CI 0.52–0.97; P = 0.03). HIV was not associated with CAC >0 (aOR 0.79; 95% CI 0.55–1.14; P = 0.22). HIV was associated with less calcified plaque (aOR 0.57; 95% CI 0.40–0.82; P < 0.01), with a trend towards less CCTA-detected plaque (aOR 0.74; 95% CI 0.51–1.06; P = 0.10), but not with non-calcified/mixed plaque (aOR 1.01; 95% CI 0.70–1.46; P = 0.95), or high-risk plaque (aOR 0.94; 95% CI 0.59–1.49; P = 0.79). Subgroup analyses in women Results in women (n = 118) were consistent with the entire study population, but confidence intervals were wider (see Supplementary material online, Table S2). Subgroup analyses in different age groups Results were consistent with the entire study population (Figure 1, Supplementary material online, Table S3). Associations between HIV-related variables and subclinical coronary artery disease These associations were inconsistent (Figure 3, Supplementary material online, Table S4). Advanced immunosuppression (CD4 nadir <50 cells/µL) was associated with non-calcified/mixed plaque. Maximum HIV viral load >100 000 copies/mL was associated with CAC >0, any plaque, and calcified plaque. Duration of antiretroviral treatment was associated with CAC >0. Figure 3 View largeDownload slide Associations between the presence of subclinical coronary artery disease endpoints and HIV-related variables in 428 HIV-positive participants. Figure 3 View largeDownload slide Associations between the presence of subclinical coronary artery disease endpoints and HIV-related variables in 428 HIV-positive participants. Chronological and coronary age HIV-negative participants [median age 56; interquartile range (IQR) 51–61 years] were older than HIV-positive participants (median age 52; IQR 49–57 years; P < 0.01), and had a higher coronary age (median 58.8, IQR 54.3–68.4 years) than HIV-positive participants (median 56.6, IQR 51–65.9 years; P < 0.01). However, the difference between coronary age and chronological age was similar in HIV-negative (mean difference 5.2 years; median difference 0; IQR 0–10 years) and HIV-positive participants (mean difference 5.5 years; median difference 0; IQR 0–10.6 years; P = 0.73). Sensitivity analysis There was no evidence of effect modification for any outcome by the propensity score which discriminated reasonably well between HIV-positive and HIV-negative participants. By including additional variables to those already included in the multivariable models, the c-statistic increased from 0.70 to 0.77 (see Supplementary material online, Table S5). Discussion To our knowledge, this is the first large-scale assessment of subclinical CAD in HIV-positive and HIV-negative persons from Europe. As expected, age, male sex, and traditional cardiovascular risk factors were significantly associated with subclinical CAD. HIV infection, however, did not independently contribute to CAC score, any plaque on CCTA, or non-calcified/mixed or high-risk plaque. On the contrary, HIV was associated with less calcified plaque and lower coronary SSS and SIS compared with the HIV-negative participants. Our findings appear robust, because results were consistent across different age groups and in both men and women. In addition, we found no evidence of advanced coronary age in our HIV-positive patients, and we were thus unable to confirm a previous report.8 Take home figure View largeDownload slide Subclinical atherosclerosis was associated with traditional cardiovascular risk factors in our study using coronary CT angiography, but not with HIV infection. HIV was associated with a similar prevalence of high risk plaque, lower prevalence of calcified plaque and lower coronary segment severity and involvement scores. Take home figure View largeDownload slide Subclinical atherosclerosis was associated with traditional cardiovascular risk factors in our study using coronary CT angiography, but not with HIV infection. HIV was associated with a similar prevalence of high risk plaque, lower prevalence of calcified plaque and lower coronary segment severity and involvement scores. Our results differ from the results of a recent CCTA study conducted in the USA. Post et al.13 noted a higher prevalence of any plaque and of non-calcified plaque in HIV-positive compared with HIV-negative US men who have sex with men in the Multicenter AIDS Cohort Study (MACS; n = 759). In contrast, CCTA findings were similar in 1257 HIV-positive and HIV-negative African Americans with high levels of cocaine use from Baltimore reported by Lai et al.14 Explanations for these different results are speculative. Regular follow-up, high rates of successful treatment, modern ART regimens, and decreasing smoking rates in recent years in the Swiss HIV Cohort Study27 might indicate a study population in better health than the MACS patients,13 with presumably lower degrees of deleterious systemic inflammation.5 Well-controlled HIV infection might also explain the similar or even lower degrees of subclinical CAD that we noted in our HIV-positive compared with the HIV-negative participants who had similar Framingham risk scores. The median age of our HIV-positive and HIV-negative participants (52 vs. 56 years) was similar to MACS13 (53.2 vs. 55.8 years), and higher than in the study by Lai et al.14 (46 vs. 44 years). We found the associations of HIV with subclinical CAD also in multivariable analyses that were adjusted for age and other factors, because an increase of coronary calcification with age is well documented.10,28 Additional possible explanations for the differences between our results and those in MACS may include differences in demographics, cardiovascular risk profile, drug use patterns, geographic origin of the participants, and different ART exposure patterns. A conservative definition of plaque22 may have resulted in a lower overall subclinical atherosclerosis prevalence in our study and the report by Lai et al.,14 compared with MACS.13 The association of cardiovascular events with duration of ART or advanced immunosuppression in the setting of HIV remains debated.3,6 We did not identify any association of ART duration with either calcified or non-calcified plaque, similar to the findings in non-cocaine users by Lai et al.,14 and in contrast to MACS.13 Consistent with MACS,13 we found that low nadir CD4 count was associated with non-calcified plaque, potentially providing support for the now established recommendation for early initiation of ART. Our observation that CAC score and calcified plaque were associated with high pre-treatment levels of HIV viral load needs to be confirmed. Strengths of our study include this being the first large scale CAC/CCTA evaluation comparing HIV-positive and HIV-negative persons in Europe, and that HIV-positive participants were followed in a well-established study, the SHCS.19 Limitations include the cross-sectional nature and the absence of formal matching on cardiovascular risk factors of HIV-positive and HIV-negative participants in our study and in the two US studies.13,14 Thus, each of these studies’ results are an indicator of how study participants were selected. However, we periodically adjusted selection criteria for the controls, resulting in comparable Framingham risk scores in the HIV-positive and HIV-negative participants, and we used propensity scores for bias reduction in the selection of an unmatched control group, which consistently showed comparable results for each of the imaging outcomes. HIV-negative controls were extensively matched on CAD risk factors to the HIV-positive participants in two previous studies, which showed no difference in CIMT progression7 and a similar prevalence of non-calcified coronary plaque.29 Our study included relatively few women and participants >65 years and therefore should be cautiously interpreted in these populations. Finally, even though we compared asymptomatic HIV-positive individuals with symptomatic HIV-negative CCTA referral patients, the similar prevalence of >50% coronary stenosis (see Table 2) documents that the symptoms that prompted CCTA referral of the controls were mostly of non-coronary origin.30 HIV was not associated with more subclinical atherosclerosis in our study. Our findings appear to be consistent with recent reports that myocardial infarction rates were similar in HIV-positive and HIV-negative non-smokers in Denmark18 and in Switzerland.17 Taken together, these reports somewhat attenuate concerns about accelerated subclinical atherosclerosis in HIV-positive persons. Supplementary material Supplementary material is available at European Heart Journal online. Acknowledgements Swiss HIV Cohort Study data are collected by 5 Swiss University Hospitals, 2 Cantonal Hospitals, 15 affiliated hospitals, and 36 private physicians (listed in shcs.ch/180-health-care-providers). Members of the SHCS are listed in the Supplementary material online. Funding This study was supported by the Swiss National Science Foundation (SNF; 324730_144209/1) and the SHCS, which is funded by the SNF. Additional funds were obtained from ViiV and Gilead. The funders had no role in the study design, data collection, analysis or interpretation, or manuscript writing. Conflict of interest: P.E.T. institution has received unrestricted grants and advisory fees from ViiV and Gilead. B.L. has received grants from ViiV and Gilead and personal fees from Janssen, ViiV, and Gilead. A.C., R.W., R.N., and R.R.B. have received grants from ViiV and Gilead. T.D.L. has received travel grants from Gilead. A.M. and P.A.K. report no conflicts. H.K. has received travel grants from Gilead and MSD and her institution received consultancy fees from Gilead. References 1 Periard D, Cavassini M, Taffe P, Chevalley M, Senn L, Chapuis-Taillard C, de Valliere S, Hayoz D, Tarr PE; Swiss HIV Cohort Study. High prevalence of peripheral arterial disease in HIV-infected persons. Clin Infect Dis  2008; 46: 761– 767. Google Scholar CrossRef Search ADS PubMed  2 Lang S, Mary-Krause M, Cotte L, Gilquin J, Partisani M, Simon A, Boccara F, Bingham A, Costagliola D; French Hospital Database on HIV-ANRS CO4. 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European Heart JournalOxford University Press

Published: Mar 24, 2018

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