Cardiovascular Risk Assessment in Antiretroviral-Naïve HIV Patients

Abstract

Various studies have been conducted to evaluate the role of antiretroviral therapy in the onset of cardiovascular risk among HIV-1–infected patients, while fewer data are available regarding antiretroviral-naïve patients. Our objective was to evaluate the cardiovascular risk among naïve subjects examining traditional risk factors, immunovirologic parameters, assessing the Framingham risk score (FRS), and detecting the presence of subclinical carotid lesions by means of color Doppler ultrasonography. One hundred seventy-two antiretroviral-naïve patients underwent color Doppler ultrasonography. An intima-media thickness (IMT) greater than 0.9 mm and/or atherosclerotic plaques were considered pathologic findings. Demographic, immunovirologic data, and risk factors for cardiovascular disease were collected. The 10-year probability of acute coronary events was assessed by the FRS. The statistical analysis was performed using t test and χ², Fisher's test, and conditional multiple logistic. Thirty-six patients (20.9%) had lesions at ultrasonographic investigation. The presence of lesions was significantly related to male gender (p = 0.005), age (p = 0.003), sedentary life (p = 0.05), Centers for Disease Control and Prevention (CDC) group C or CD4⁺ less than 150 cells/mm³, and viral load (VL) > 100,000 copies per milliliter (p = 0.04). The presence of subclinical carotid lesions showed a highly significant direct association with the estimated FRS (p < 0.002). The presence of subclinical atheromasic lesion results was also high among antiretroviral-naïve patients. FRS is highly predictive of the lesions, but also an advanced stage of disease plays a significant role. Our data support the hypothesis that HIV infection per se is a risk factor for atherosclerosis. We recommend an ultrasonographic assessment both among patients with FRS 6% or more and among those in advanced stage of disease.

Introduction

A lthough the introduction of highly active antiretroviral therapy (HAART) has led to a sharp reduction in mortality, cardiovascular disease has progressively emerged as a significant cause of morbidity and mortality among HIV-1–positive patients treated with HAART. Studies conducted on mega-cohorts have been evaluated the role of antiretroviral therapies in the onset of cardiovascular risk.^1

–4 More recently, the role of treatment interruption^5,7 and low CD4⁺ cell count has been associated with a higher rate of acute myocardial infarction^5,6 or subclinical atherosclerosis,⁷ thus suggesting a direct role of immune deficiency and of HIV infection on cardiovascular risk, whereas few data are available regarding the cardiovascular risk among antiretroviral-naïve patients.

To better understand the direct role of HIV disease in the onset of cardiovascular risk, our objective was to evaluate naïve subjects examining traditional risk factors, immunovirologic parameters, assessing the 10-year probability of acute coronary events by the Framingham risk score (FRS),⁸ and detecting the presence of subclinical carotid lesions by means of color Doppler ultrasonography.

Methods

Patient selection

PREVALEAT (PREmature Vascular Lesions and Antiretroviral Therapy) is an ongoing study evaluating premature atherosclerotic lesions of the epi-aortic vessels in HIV-1–positive patients, which was started in 1998. In the context of this study, 172 consecutive antiretroviral-naïve patients were evaluated in the period 1998–2008 for familial history of cardiovascular disease, sedentary life (<1 hour per week of sport activity), cigarette smoking, alcohol abuse (>80 g/d), active drug addiction, values for fasting glycemia, cholesterolemia, and triglyceridemia, and blood pressure. Demographic and immunovirologic data were collected. The 10-year probability of acute coronary events (<5%, 5%–10% and >10%) was assessed in all patients by the FRS. Patients being treated with antihypertensive drugs or with a past history of cardiovascular disease were excluded from the study.

Doppler studies

The patients underwent color Doppler ultrasonography. They were subjected to ultrasonography of the epi-aortic vessels using a last-generation power color Doppler with 7.5 MHz probes. Ultrasonography was performed by two physicians specifically trained on carotid vessels, with at least 15 years experience with the ultrasound color Doppler technique and approximately 10,000 documented epi-aortic examinations (F.P. and A.L.). They were blinded to the patient's treatment history and status and unaware of the diagnosis of the other colleague. Moreover, during the study, periodic meetings were held using filmed reports aimed at the comparison and standardization of the technique. The patients were placed in a supine position after at least 10 minutes of acclimatization in a comfortable room. They were informed that the investigation was noninvasive. The common carotid, the bifurcation, and at least the first 2 cm of the internal and external carotid vessels were examined in the short and long axis using high magnification; this assisted in correctly distinguishing the real lumen from plaques markedly hypoechoic with the color or power Doppler. The morphologic investigation of the plaque was performed using both ultrasonography and the ultrasound power color Doppler in order to better characterize the profile of the plaque and the intima-media thickness (IMT).^9

–12

An IMT greater than 0.9 mm was considered a pathologic finding. An artery was classified as being affected by plaque if there was an IMT greater than 1.2 mm.

Statistics

The association between pathologic findings and possibly related variables was evaluated by means of t test and χ² or Fisher's test, as appropriate. To account simultaneously for the effects of several potential confounding factors, we used conditional multiple logistic regression to obtain odds ratios (OR) and their corresponding 95% confidence interval (CI).

The Ethics Committee of the hospital approved the study and the patients provided informed written consent.

Results

Of the 172 patients evaluated, 36 (20.9%) showed subclinical atheromasic lesions at ultrasonographic investigation. In Table 1, the characteristics of the patients and the general statistical analysis are summarized. Evaluating the crude risk in subclinical atherosclerosis related to risk factors, as shown in Table 2, the presence of lesions was significantly related to male gender (p = 0.01), increasing age (χ² for trend 7.9, p = 0.005), Centers for Disease Control and Protection (CDC) group C or CD4⁺ less than 150 cells/mm³, and log viral load (VL) 25 (p = 0.025), high low-density lipoprotein (LDL) cholesterol (p = 0.01), and high blood pressure (p = 0.01); whereas family history of CV disease (p = 0.09) and sedentary life (p = 0.06) were not significant. Body mass index (BMI), alcohol abuse, and cigarette smoking were also investigated as potential related factors, but no association emerged with pathologic IMT.

Table 1.

General Characteristics and Immunological Status of Patients Enrolled in the Study

Variables	Lesions at echo color doppler		Normal at echo color doppler		p
Variables	No = 36	%	No = 136	%	p
Gender
Male	34	25.7	98	74.2	0.005
Female	2	5.0	38	95.0
Age
<33	4	8.3	44	91.6
34–37	10	22.7	34	77.2
38–43	10	20.8	38	79.1	0.003
≥44	12	37.5	20	62.5
Risk factor for HIV infection
IVDA	18	29.0	44	70.9
Homosexual	2	60.2	30	93.7
Heterosexual	12	18.7	52	81.2	0.06
Unknown	4	28.5	10	71.4
Time from diagnosis of HIV infection (years)
New diagnosis	6	11.3	47	88.6
2–9 ys	12	23.5	39	76.4
≥10 ys	14	25.4	41	74.5	0.14
CD4⁺ count (cells/mm³)
<200	14	24.1	44	75.8
200–500	16	19.5	66	80.4
>500	6	18.7	26	81.2	0.53
Log HIV RNA
<5	22	20.5	85	79.4	0.75
≥5	14	22.5	48	77.4
CDC group C or VL CD4 <150 and VL >100,000 (copies/mL)
Yes	14	31.8	26	68.2	0.04
No	22	17.2	110	82.8
Stage of disease
A + B	26	19.1	110	80.8	0.19
C	10	29.4	24	70.5
BMI
<20	6	27.2	16	72.7
20–25	20	20.41	78	79.5	0.55
>25	10	19.2	42	80.8
Family history of CVD
Yes	20	27.0	54	72.9	0.09
No	16	16.33	82	83.62
Cigarette smoking
Yes	24	21.4	88	78.5	0.82
No	12	20.0	48	80.0
Sedentary life
Yes	32	24.2	100	75.7
No	4	10.0	36	90.0	0.052
Total cholesterol
<200	30	20.2	118	75.0
≥200	6	25.0	18	79.7	0.60
LDL-C
<130	10	40.0	15	60.0
≥130	26	17.7	121	82.3	0.01
HDL-C/TC
<0.35	27	20.7	103	79.2
≥0.35	9	21.4	33	78.6	0.93
Triglyceridemia <150
<150	32	20.7	122	79.2
≥150	4	22.2	14	77.7	0.89
Blood pressure
SBP <130 and DBP < 85	16	14.8	92	85.2
SBP ≥130 or DBP ≥85	20	31.2	44	68.8	0.01
Hyperglycemia
Yes	34	20.7	130	79.2
No	2	25.0	6	75.0	0.77
Framingham risk score
<5.00	12	14.0	74	86.0
5.00–9.99	8	17.8	37	82.2
≥10.00	16	39.0	25	61.0	0.002

IVDA, intravenous drug abuser; CDC, Centers for Disease Control and Prevention; VL, viral load; BMI, body mass index; CVD, cardiovascular disease; LDL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; TC, total cholesterol; SBP, systolic blood pressure; DBP, diastolic blood pressure.

Table 2.

Crude and Adjusted Odds Ratios for Subclinical Atherosclerosis Related to Selected Factors

Variable	Crude			Adjusted
Variable	OR	95% CI	p	OR	95% CI	p
Age (< 33)
34–37	3.2	0.9–11.2	0.06	4.0	1.1–14.5	0.03
38–43	2.9	0.8–10.0	0.09	2.7	0.8–9.4	0.13
≥44	6.6	1.3–23.0	0.003	5.0	1.4–18.4	0.02
χ² for trend	7.9	—	0.005	5.8	—	0.04
Gender (M)
F	0.2	0.1–0.7	0.01	0.2	0.1–0.7	0.02
CDC stage (A-B)
C	1.8	0.8–4.1	0.19	1.5	0.6–3.7	0.39
CDC group C or CD4 <150 and logVL ≥5 (No)
Yes	2.5	1.1–5.4	0.025	2.3	1.0–5.2	0.05
Family history of CVD (no)
Yes	1.9	0.9–4.0	0.09	2.6	1.2–6.0	0.02
Sedentary life (no)
Yes	2.9	1.0–8.7	0.06	2.4	0.7–7.4	0.14
Total cholesterol (<200)
≥200	1.2	0.4–3.1	0.77	1.0	0.4–2.9	0.97
LDL cholesterol (<130)
≥130	3.1	1.3–7.7	0.01	0.9	0.4–1.9	0.71
HDL-C/TC (≥0.35)
<0.35	0.9	0.4–2.0	0.80	0.6	0.2–1.6	0.30
Triglycerides (<150)
≥150	1.1	0.5–2.3	0.81	0.9	0.4–2.0	0.76
Blood pressure (SBP <130 and DBP <85)
SBP ≥130 or DBP ≥85	2.6	1.2–5.5	0.01	2.1	0.9–4.7	0.07
FRS (<5.00)
5.00–9.99	2.0	0.8–5.1	0.13	2.1	0.8–5.2	0.13
≥10.00	5.9	2.1–16.3	0.0006	5.3	1.9–15.0	0.002

CDC, Centers for Disease Control and Prevention; CVD, cardiovascular disease; VL, viral load; LDL, low-density lipoprotein; HDL-C, high-density lipoprotein cholesterol; TC, total cholesterol; SBP, systolic blood pressure; DBP, diastolic blood pressure; FRS, Framingham risk score.

When the risk for subclinical atherosclerosis is adjusted for age, gender, and familial history of cardiovascular disease (Table 2), the role of gender (p = 0.02), and family history (p = 0.02) is confirmed, while the role of advanced disease (CDC group C or CD4⁺ < 150 cells/mm³ and log VL ≥ 5) was of borderline significance (p = 0.05). However, the estimated FRS showed the higher significant direct association with the presence of subclinical carotid lesions in both the models, respectively (p < 0.0006 and p < 0.003).

Discussion

Measurement of carotid IMT with color Doppler ultrasonography is a noninvasive, sensitive, and highly reproducible technique for identifying and quantifying atherosclerotic even in a very premature stage. It is a well-validated research tool, widely used in clinical practice. The American Heart Association (AHA) and the Third Adult Treatment Panel of the National Cholesterol Education Program (NCEP ATP III) have endorsed the use of carotid IMT in cardiovascular risk assessment.¹³ In preventive medicine IMT measurement may be important mainly in subjects defined at intermediate cardiovascular risk or rather subjects classified at 10-year risk of cardiovascular disease between 6% and 20%.¹⁴ Moreover pathologic IMT has consistently been related to future cardiovascular events.^15,16

Several studies had recently investigated the presence of preclinical atherosclerotic lesions using the ultrasonographic technique, Some of them^17

–20 have documented a significant difference in carotid IMT and/or plaque prevalence in HIV-positive patients versus HIV-negative subjects, others did not confirm the difference.^21
–23 Even regarding the association between carotid lesions and use of protease inhibitors (PIs) the data are inconsistent. The results of the cited studies are summarized in Table 3.

Table 3.

Studies Evaluating the Difference in Carotid IMT and/or Plaque Prevalence in HIV-Positive Patients vs. HIV-Negative Subjects and the Association Between Carotid Lesions and Use of PIs

Author	Journal/year	Difference in carotid preclinical atherosclerosis in HIV+ vs. HIV−	Association with use of PIs
van Vonderen	J Aquire Immune Defic Syndrome, 2009	Yes	No
Sankatsing	Atherosclerosis, 2009	Yes	Yes
Oliviero	Atherosclerosis 2009	Yes	Not evaluated
Grunfeld	16th CROI, 2009	Yes	Not evaluated
Lekakis	Clin Sci, 2008	No	No
Currier	AIDS, 2005	No	No
Currier	AIDS, 2007	No	Yes

IMT, intima-media thickness; PIs, protease inhibitors.

The results of our study evidence that the presence of subclinical atheromasic lesion is a frequent occurrence among patients naive to antiretrovirals (20.9%). A possible limitation of our present observation could be the absence of age-matched HIV-negative controls. However, this high prevalence is in line with other previous observations^24,25 in which we also observed²⁵ in an age-matched control group of 104 HIV-negative subjects, only 6.7% of subclinical carotid lesions. The hypothesis that there is an additional effect of HIV infection beyond that on traditional cardiovascular risk factors is corroborated by the significant association between preclinical atherosclerotic lesions and CDC group C or VL CD4 less than 150 and VL greater than 100,000 copies per milliliter. On the other hand, many clues recently emerged that HIV per se can impact cardiovascular risk via endothelial dysfunction,²⁶ endothelial activation, and inflammation.^27,28

Nevertheless, also some classic risk factors seem to play a significant role in cardiovascular risk of HIV-1 patients naïve to HAART, such as male gender, age, and sedentary lifestyle. It is noteworthy that in spite of the significant role played by the advanced stage of disease, FRS is highly predictive of the presence of preclinical carotid atherosclerotic lesions. We used the FRS that has been so far validated in the general population and provided the most pessimistic estimated cardiovascular risk in HIV-positive people.²⁹

Our data support the hypothesis that HIV infection per se is a risk factor for atherosclerosis. Moreover, echo-color Doppler seems a reliable tool also in these patients to detect preclinical atherosclerotic changes and FRS proved to be highly predictive of the presence of lesions. Consequently, in light of our findings, we recommend an ultrasonographic assessment among patients in advanced stage of disease and, in line with other studies suggesting the use of imaging techniques in patients with FRS 6%–20%, among those with FRS 6% or more.^13,14,30

Footnotes

Author Disclosure Statement

No competing financial interests exist.

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