Postepy Hig Med Dosw. (online), 2011; 65: 770-783
Original Article
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Subclinical carotid atherosclerosis and cardiovascular risk factors in HIV-infected patients
Subkliniczne zmiany miażdżycowe tętnic szyjnych i czynniki ryzyka sercowo-naczyniowego u pacjentów zakażonych HIV
Wiesława Kwiatkowska1  ABDEF, Brygida Knysz2  ABDEF, Justyna Drelichowska-Durawa1  BDEF, Marcin Czarnecki2  AB, Jacek Gąsiorowski2  B, Ewa Biłyk3  C, Maciej Karczewski3  C, Wojciech Witkiewicz1  A
1Department of Angiology Regional Specialist Hospital in Wroclaw, Research and Development Center, Poland
2Department of Infectious Diseases, Liver Diseases and Acquired Immune Deficiencies Wroclaw Medical University, Poland
3Manteion – Statistical Laboratory. Wrovasc Project – Regional Specialist Hospital in Wroclaw, Research and Development Center, Poland
Corresponding author
Dr med. Wieslawa Kwiatkowska, Department of Angiology, Regional Specialist Hospital, Research and Development Center, 51-124 Wroclaw, ul. Kamienskiego 73a; e-mail: kwiatkowska_w@interia.pl

Authors' Contribution:
A - Study Design, B - Data Collection, C - Statistical Analysis, D - Data Interpretation, E - Manuscript Preparation, F - Literature Search, G - Funds Collection

Source of support
This publication is part of the project "Wrovasc - Integrated Cardiovascular Center", co-financed by the European Regional Development Fund, within the Innovative Economy Operational Program, 2007-2013

Received:  2011.09.06
Accepted:  2011.11.14
Published:  2011.11.25

Streszczenie
Wstęp: U osób zakażonych HIV, zwłaszca leczonych antyretrowirusowo, obserwuje się zwiększone ry­zyko i występowanie chorób sercowo-naczyniowych.
Cele pracy: Celem pracy jest ocena zaawansowania subklinicznych zmian miażdżycowych w tętnicach szyj­nych wyrażonych wartością cIMT (carotid intima-media thickness) i liczbą blaszek miażdżyco­wych oraz analiza zależności cIMT od czynników ryzyka chorób sercowo-naczyniowych w ko­horcie osób zakażonych HIV.
Materiał/Metody: Do analizy włączono 72 osób zakażonych HIV, w średnim wieku 39,4 lata i 27 osób zdrowych, niezakażonych HIV, odpowiednio dobranych pod względem płci i wieku. Zgromadzone dane obejmowały: ocenę stanu zakażenia, leczenie antyretrowirusowe, przebycie incydentów serco­wo-naczyniowych, ocenę tradycyjnych i nietradycyjnych czynników ryzyka chorób sercowo-na­czyniowych, pomiar cIMT i liczba blaszek miażdżycowych w tętnicach szyjnych.
Wyniki/Wnioski: Osoby zakażone HIV wykazują istotnie większe zaawansowanie subklinicznych zmian miażdży­cowych w tętnicach szyjnych (cIMT i liczba blaszek). Profil ryzyka sercowo-naczyniowego osób zakażonych HIV znamiennie różni się od osób niezakażonych - stężenia wszystkich frakcji cho­lesterolu są niższe, a triglicerydów wyższe, odsetek palaczy wiekszy, BMI niższe, a WHR wyż­sze. Poza wiekiem, stężeniem cholesterolu całkowitego i LDL oraz intensywnością dotychcza­sowego palenia, silny wpływ na cIMT mają cholesterol nie-HDL, nadciśnienie tętnicze i czas leczenia ARV. Związek między cIMT i aktualnym HIV RNA może wskazywać na wpływ aktu­alnego stanu zakażenia na dynamizm cIMT w tej subpopulacji.
Słowa kluczowe: zakażenie HIV • ryzyko sercowo-naczyniowe • miażdżyca • tętnice szyjne • cholesterol • cholesterol nie-HDL • triglicerydy • nadciśnienie tętnicze


Summary
Background: HIV infected patients, especially those treated with antiretroviral (ARV) drugs, show an incre­ased risk and incidence of cardiovascular disease.
Objectives:
The aim of this study was to evaluate the progression of subclinical atherosclerosis in the caro­tid arteries, expressed as the value of carotid intima-media thickness (cIMT) and the amount of atherosclerotic plaques, and to analyze the correlation between cIMT and risk factors for cardio­vascular diseases in a cohort of HIV infected patients.
Methods:
The analysis included 72 HIV infected patients, mean age 39.4 years, and 27 healthy HIV negati­ve individuals, matched for age and sex. The data collected included evaluation of the infection, ARV treatment, past cardiovascular events, assessment of traditional and nontraditional risk fac­tors for cardiovascular diseases, cIMT measurements and amount of atherosclerotic plaques in the carotid arteries.
Results:
HIV infected patients show more advanced subclinical atherosclerosis in the carotid arteries (cIMT and plaques incidence). The cardiovascular risk profile of the HIV infected patients is si­gnificantly different from HIV negative people. Among the HIV positive group lower body mass index (BMI) and higher waist/hip ratio (WHR) are observed. The concentration of all choleste­rol fractions is lower, whereas the concentration of triglycerides is higher. Cigarette smoking is more common among HIV-infected individuals. A strong statistical correlation between cIMT and age, hypertension, non-high-density lipoprotein (non-HDL) cholesterol and ARV time were found. Total and LDL cholesterol, and lifetime smoking exposure also affect the cIMT. The re­lationship between cIMT and current HIV RNA may indicate the impact of the current infection status on the cIMT dynamics in this subpopulation.
Key words: HIV infection • cardiovascular risk • atherosclerosis • carotid arteries • cholesterol • non-HDL cholesterol • triglycerides • hypertension




Introduction
Due to the continuous development of antiretroviral therapy in recent years and the significantly prolonged survival time of HIV infected patients, in addition to many other diseases coexisting with HIV infection, there have been numerous reports on increased risk of cardiovascular disease (CVD) in this subpopulation. In order to organize the knowledge on the subject, international medical circles involved in the care of HIV infected patients publish the results of their cli­nical observations, retrospective and prospective studies, including large prospective research programs, which re­veal that this group of patients exhibits an increased risk of CVD incidence and that the progression of atheroscle­rosis is faster than in uninfected people [20,39,40,64,73].
Considering the research results, there are no single CVD risk factors in the HIV infected subpopulation. Currently, we can rather discuss etiopathogenic areas gathering the risk factors and determining faster development of athe­rosclerosis. The first of these risk areas is the incidence of well-known typical and non-typical risk factors in HIV in­fected patients, the existence and development of which, resulting from prolonged survival time, can be observed as in the general population. A statistically higher inciden­ce of some classical risk factors such as male gender and smoking, or of nonspecific factors - lifestyle, low physical activity and poor diet - is characteristic of the HIV infec­ted subpopulation [13,19,20,38,57]. Another area may be a proatherogenic effect of the combined antiretroviral the­rapy (cART), which is currently thought to directly activa­te the endothelium functioning, as well as a well-known phenomenon of metabolic disorders, such as dyslipide­mia or insulin resistance, that promote the development of atherosclerosis [4,5,14,17,29,45,50,51,52,54,55,65,68,80]. The last and, as it currently seems, the most impor­tant role in pathogenesis in augmented atherosclerosis is played by chronic HIV infection, which, featuring a wide range of interactions with the host system, proinflamma­tory action of adhesion molecules, cytokines and infected lymphocytes, monocytes and mainly macrophages infil­trating the vessel wall, is a damaging factor for the vascu­lar endothelium [6,11,28,36,47,56,61,63,67,70,78,79,82].
Atherosclerosis in HIV infected patients is evaluated using non-invasive research techniques, such as intima-media thickness measurement in the carotid and/or femoral ar­teries, brachial artery flow-mediated dilatation test or the coronary artery calcium score [12,49]. The most popular tool to assess the severity and dynamics of atherosclero­sis is ultrasound carotid intima-media thickness measure­ment (cIMT). cIMT as an important predictive factor fa­vorably correlates with the risk of myocardial infarction and stroke, even after excluding the impact of other CVD risk factors. Finally, it is taken as a soft endpoint in clini­cal trials [8,13,17,35,37,44,49].
Aim of the study
The aim of this study was to evaluate the progression of subc­linical atherosclerosis in the carotid arteries, expressed as the cIMT value and the number of atherosclerotic plaques, and to analyze the correlation between cIMT and CVD risk fac­tors in a cohort of HIV infected patients treated and not tre­ated with antiretroviral therapy. Moreover, the impact of HIV infection, infection duration, basic parameters of virological and immunological status over the course of infection and im­pact of the overall antiretroviral treatment duration on the de­velopment of the subclinical atherosclerosis were evaluated.
Material and methods
The study lasted from March 2008 to May 2009 and in­cluded 72 HIV infected patients treated at the Clinic of Acquired Immune Disorders.
The study group comprised 48 men and 24 women, mean age 39.4±8.9 years, including 68 ART-treated and 4 non­-ART-treated patients. The inclusion criteria were a dia­gnosed HIV infection and the patient's informed consent to participate in the study. The following exclusion criteria were adopted: currently diagnosed acute medical condition, currently diagnosed AIDS, serum creatinine concentration higher than 2 mg%, more than 5-fold increase in transami­nase levels. HIV infected patients entered the study with a known clinical, immunological and virological status of the HIV infection as well as HBV and/or HCV co-infections.
The control group comprised 27 healthy individuals (18 men and 9 women, average age 39.3 years ±10.9), inhabi­tants of the same region as the study cohort, respectively matched for age and sex, in good general condition, witho­ut history of cardiovascular events, not meeting the labo­ratory exclusion criteria adopted in the project.
This paper presents the preliminary cross-sectional re­sults of the study on atherosclerosis in 72 HIV infected pa­tients. The study was conducted with the approval of the Bioethics Committee.
The characteristics of the immunological and virological status of the study group are presented in Table 1.
Table 1. Characteristics of the study group

The study protocol included obtaining the informed patient consent, interview with questions about traditional and se­lected non-traditional CVD risk factors, pharmacotherapy including cART, and symptoms of CVD: cerebrovascular and cardiac events, and intermittent claudication. A stan­dard physical examination with anthropometric measure­ments of height, waist and hip circumference was perfor­med to calculate the body mass index (BMI) and waist/hip ratio (WHR). Blood pressure measurement was performed in accordance with generally accepted standards. The pa­tients were examined from the angiological point of view. Lower limb ischemia was evaluated on the basis of claudi­cation in the interview and angiological examination and the ankle-brachial index (ABI) using a continuous wave Doppler detector, assuming the value <0.9 as incorrect.
Hypertension was diagnosed if the patient had a history of diagnosed and pharmacologically treated hypertension or based on two pressure measurement results equal to or above 140/90 (at least first degree according to WHO).
Metabolic syndrome (MS) was recognized based on the NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) criteria revised in 2004 and the assessment of waist circumference, typical for American standards, and the IDF (International Diabetes Federation) 2005 definition, with the waist circumference assessment typical for Europe [74,76].
Ischemic heart disease was recognized on the basis of the medical history, and a resting electrocardiogram (ECG) was performed in all patients. Exercise ECG had been planned in the case of a medical history suggesting angina, but so far there have been no indications for the exercise test in any of our patients. In all patients, a duplex ultrasound of carotid and vertebral arteries was performed, their patency assessed and ultrasound images recorded for further pro­cessing in order to evaluate subclinical atherosclerosis by means of computer-measured cIMT. Carotid artery stenosis was recognized according to the NASCET (North American Symptomatic Carotid Endarterectomy Trial) and Bluth cri­teria. Carotid ultrasound was performed using a high-reso­lution ultrasound GE LOGIQ 7 GE with broadband line­ar probe 6-12 MHz and 5x magnification. Four series of images were collected for each patient: left common caro­tid artery (LCA), right common carotid artery (RCA), left bulb (LB) and right bulb (RB). The images were recorded in three projections for each series - anterior, lateral and posterior. Far wall images of the distal common carotid ar­teries and bulbs were recorded parallel to the probe surface at the smallest artery diameter and then saved on the hard drive and on DVDs. cIMT was measured using a specially designed computer program. For each projection of a given series, manual cIMT measurement within a 1 cm long sec­tion was performed and 10 measurement points were esta­blished (30 measurement points per series, 120 points per patient). Atherosclerotic plaque was assessed using a crite­rion treating the plaque as focal IMT growth >1.5 mm. The measurement results were transferred to a database analy­zing a number of statistical features for the measurements of each projection and series. The main parameter for each patient was the average IMT value obtained for all the se­ries, defined as cIMT. Ultrasound examinations and cIMT measurements were performed by the same angiologist, a doctor with eighteen years of experience in vascular ultra­sound and cIMT measurements [41,42,43]. Intra- and in­terobserver reproducibility tests of the cIMT measurement in the common carotid arteries and bulbs were carried out using the Bland and Altman plot and the intraclass corre­lation coefficient (ICC). The assumptions of the Bland and Altman plot were met, and the correlation coefficients for the intra- and interobserver reproducibility tests were 0.99.
Laboratory tests
The serum HIV RNA level was determined using the Roche Amplicor 1.0 standard assay (detection threshold 40 copies/mL), and CD4 T cells were counted by means of FACScan flow cytometry (Becton-Dickinson).
After 14 hours of fasting, blood samples were collected for other laboratory tests carried out by standard methods: complete blood count, transaminase level, creatinine, glu­cose, total cholesterol, HDL cholesterol, triglycerides, lipo­proteins (a), homocysteine, fibrinogen, D-dimers, wrCRP (wide range C-reactive protein - latex-enhanced immuno­turbidimetry) levels. LDL cholesterol was calculated ac­cording to the Friedewald equation, and non-HDL chole­sterol by subtracting HDL from TC (total cholesterol). The presence of anti-HIV, anti-HBc and anti-HCV antibodies was determined in the control group using the enzyme im­munoassay (EIA) method with microparticles.
Statistical analysis
Quantitative variables were presented as an arithmetic mean, geometric mean or median, depending on normali­ty of distribution. For each estimator, 95% confidence in­tervals were calculated. Qualitative variables are presen­ted as the number of patients in each group. Differences in quantitative features between the study and control gro­ups were analyzed by Student's t-test, the Welch test or the Mann-Whitney test, respectively. To achieve normality, the logarithmic transform was applied to the variable elements. Differences in the qualitative features were analyzed using the c2 test or Fisher's exact test (for small groups). The cor­relation between continuous variables was described using Pearson's or Spearman's correlation coefficient (depending on the normality of data). The effect of clinical features on the cIMT value in the studied group was assessed using uni­variate or multivariate regression. The multivariate analy­sis employed the stepwise method, which removed all sta­tistically insignificant features from the model.
The analysis was made using R and MedCalc statistical packages. All results with a significance level p<0.05 were considered significant.
Due to the small number of ARV non-treated patients in the cohort, the differences between ARV treated and non­-treated patients were not analyzed in this study. The effect of drug class on subclinical atherosclerosis was not consi­dered either, as individual therapy might have changed se­veral times before the beginning of this study.
Results
Tables 2 and 3 show the statistical analysis of quantitati­ve variables in the studied cohort and the control group.
Table 2. Quantitative characteristics of the experimental and control groups - arithmetic and geometric mean, and confidence interval - Student's t-test

Table 3. Quantitative characteristics of the experimental and control groups - median and confidence interval - Mann-Whitney test

Among the laboratory parameters relevant to the CVD risk assessment (Tables 2, 3), statistically significant changes in the lipid profile can be observed: in the study cohort, the level of all cholesterol fractions was significantly re­duced and triglyceride concentration was higher, while in the hemostatic system, a significantly lower platelet count and fibrinogen concentration was recorded. No differen­ces were found in the average concentration of lipoprote­in (a) between the two groups. Other tests revealed lower hematocrit in the infected group; this difference is at the border of statistical significance. Fasting glucose, CRP and the homocysteine level did not differ significantly between the two groups. Table 4 shows the prevalence of classical risk factors in the study and control group.
Among the major risk factors, tobacco smoking is the most representative and covers 2/3 of the cohort. Such parame­ters as current and past smoking, considered as categori­cal variables, differentiate the two groups to a statistical­ly significant degree.
Another risk factor is hyperlipoproteinemia, understood as hypercholesterolemia, hypertriglyceridemia or mixed di­sorders. The proportion of these changes is similar in both groups (Table 4), but there are significant qualitative dif­ferences (Table 5). In the study group, dominant disorders involve dyslipidemia or hypertriglyceridemia, and in the control group, the dyslipidemia and hypercholesterolemia incidence is the same. No isolated triglyceride-related di­sorders were observed in the control group.
Table 4. Risk factors and metabolic profile in the test and control group, χ2 test or Fisher's exact test

Table 5. Type of lipid disorders in the cohort and control group - χ2 test or Fisher's exact test

The percentage of diagnosed hypertension was similar in the cohort and in the control group (Table 4). Diabetes was found in two patients from the cohort and one person from the control group. A family history of CVD, asses­sed according to current guidelines, was positive in 29% of the infected patients and 14.8% of the control group. The differences are not statistically significant. The ge­neral assessment of body posture revealed a significan­tly higher waist-hip ratio (WHR) and a significantly lo­wer body mass index (BMI) in the cohort participants compared with the control group. WHR is markedly af­fected not by waist circumference, which is similar in both groups, but by hip circumference, and this is significan­tly lower among HIV infected people. Adopting two dif­ferent definitions of the metabolic syndrome (MS) gene­rated the same percentage of infected patients suffering from it, despite the fact that using different criteria resul­ted in obtaining two groups of the same size but of diffe­rent composition. The MS incidence is higher than in the control group; the difference is on the border of statisti­cal significance (Table 4).
Based on the physical examination, medical history and available medical records, cardiovascular disease was dia­gnosed in three of the cohort participants (4.2%). These three patients are exposed to multiple risk factors, inclu­ding family history and hyperlipoproteinemia. Peripheral occlusive arterial disease with symptomatic lower limb ischemia (claudication) and reduced ABI value concomi­tant with coexistent asymptomatic high-grade stenosis of the carotid artery was found in one patient. Ischemic heart disease and a previous stroke were discovered in one pa­tient and ischemic heart disease alone in one patient. Thus, ischemic heart disease in the form of documented stable angina pectoris occurred in 2.8% of the respondents, ische­mic stroke in 1.4% and peripheral occlusive arterial dise­ase (POAD) in 1.4% of the study cohort. Asymptomatic high-grade carotid artery stenosis (80%) was identified in one infected patient, and in another one, stenosis was slight (< 50%). One healthy man from the control group showed features of slight carotid artery stenosis.
Table 6 presents the results of IMT measurements: mean, standard deviation, median, minimum and maximum IMT for the location (LCA, LB, RCA, RB) and cIMT in both groups - the cohort and the control group.
Table 6. Comparison of IMT in the study group (n=72) and the control group (n=27) in different locations

In the group of HIV infected patients, the values of cIMT and IMT for each location (RB, LB, LCA and RCA) were significantly higher, as was the percentage of people in whom atherosclerotic plaques were found (Table 7).
Table 7. Characteristics of atherosclerotic lesions in the carotid arteries in the HIV infected group and the control group

Analysis of the effect of CVD risk factors and duration of HIV infection and ARV treatment time on the cIMT va­lue (Table 8) carried out using univariate regression indi­cates the relationship between cIMT and the age of HIV infected patients, hypertension, total cholesterol concen­tration, LDL cholesterol, non-HDL cholesterol and dura­tion of the ARV treatment. The final model obtained after multivariate regression analysis employing the stepwi­se method shows that the cIMT value strongly correlates with age, hypertension, non-HDL cholesterol concentra­tion and duration of ARV treatment.
Table 8. Univariate and multivariate regression - cIMT and risk factors in the study group

Analysis of regression between cIMT and smoking as a categorical variable shows no correlation of smoking and cIMT (Table 8). However, the correlation between a quanti­tative parameter ("pack-years") and cIMT indicates a close positive relationship of cIMT values and lifetime smoking exposure, and cIMT is significantly higher in HIV-positive smokers compared with non-infected smokers (Table 9). There is no difference in cIMT between smokers and non­-smokers in the cohort. At present, these validations are not strong enough due to the low number of smokers in the control group and non-smokers in the cohort.
Table 9. Lifetime smoking (pack-years) - statistical analysis of the effect of smoking on cIMT among cohort smokers and control smokers

Correlation analysis (Table 10) of the infection and immu­nological status quantitative parameters indicates a weak correlation between cIMT and the current HIV RNA va­lue (p=0.012).
Table 10. cIMT and selected virological and immunological quantitative characteristics of the cohort - Spearman correlation

After dividing the cohort according to the assumed crite­rion of treatment duration, a significant difference in the advancement of subclinical carotid atherosclerosis was re­vealed. Patients treated with ARV therapy for over 5 years have a higher value of cIMT.
MSM mode infected patients show a significantly higher cIMT value compared with a subgroup of those infected by intravenous drug use. No present correlation between cIMT and co-infection with HBV, HCV or AIDS history was observed (Table 11).
Table 11. Analysis of cIMT dependence on selected clinical features of the study cohort

Further analyses of the study cohort showed a signifi­cantly higher cIMT value in infected patients with dia­gnosed hyperlipoproteinemia compared to the subgroup with a normal lipid profile. No significant effect of MS on the cIMT value was proven.
Discussion
The paper on the cohort of HIV infected patients evalu­ating the cardiovascular risk and subclinical atheroscle­rosis brought about a number of interesting observations. Atherogenic lipoprotein concentration is lower than in he­althy subjects, duration and intensity of smoking (lifetime smoking) are similar among the infected and healthy pe­ople, blood rheological properties appear to be more favo­rable than in the control group, but still the severity of sub­clinical atherosclerosis in the carotid arteries expressed as the cIMT value and the amount of atherosclerotic plaqu­es is significantly higher among infected patients compa­red to the age and sex adjusted control group. The statisti­cal analysis reveals a more complex relationship between cIMT and CVD risk factors and certain characteristics of the infection and ARV treatment.
In the study group of HIV-positive patients, the rate of cardiovascular events is higher for men and lower for wo­men (0%) compared to the general population. In the ge­neral English population, this percentage for men aged 16 to 64 is 2% and for women 0.9% [27]. In the Spanish po­pulation, it is 4.3% [3].
The frequency of symptomatic POAD, confirmed by ABI, is similar (1.3%) to the non-infected population of this age [3] and twice as low as in the other described HIV infec­ted cohorts [23,60].
It is difficult to discuss the impact of HIV infection on the incidence of CVD in our cohort in a clear way given the sample size and the number of people with episodes (one of the CVD events happened before HIV infection was do­cumented), and also taking into account the exposure to multiple risk factors, including such potent factors as age, gender and positive family history.
The results of numerous studies, and mostly of the SMART study [64], which confirmed a higher rate of cardiovascu­lar diseases among patients who interrupted cART com­pared to those treated in a continuous manner, indicate the impact of HIV infection on changes in the cardiovascular system. There are reports suggesting that cART may be an additional risk factor for the development of cardiovascu­lar disease [20,29,50].
The prevailing classic risk factor in our cohort is smoking, followed by lipid disorders and hypertension. The preva­lence of risk factors in the adult Polish population is diffe­rent. The strongest risk factors are lipid disorders and then hypertension followed by smoking.
Comparison of this young cohort with the results of epi­demiological studies in Poland is not easy, as all major studies were conducted among the elderly population. An analysis of incidence and intensity of risk factors was per­formed for a separate group aged 18-59 in the NATPOL PLUS study, and this will often be referred to in the discus­sion. Comparison of individual risk factors with the Polish epidemiological data shows an overrepresentation of smo­kers in the cohort, 63.8% of patients, while the percentage of smokers in the adult (18-59) Polish population is abo­ut 38%, which is the same as in the matched age and sex control group (37%) in this study [83]. This traditional risk factor is emphasized in many papers on HIV infected pa­tients. Usually, the percentage of smokers is similar to that shown in our study, while in the Warsaw HIV cohort, it is very high at 90% [9,18,30,34,35,37,51,61,70]. Quantitative evaluation by means of lifetime smoking suggests a rela­tionship between cIMT and smoking intensity over time: the more intense and longer the smoking period, the fur­ther the progress of subclinical atherosclerosis, which was also reported by Hsue [30]. Two surprising facts are lack of difference in cIMT between smoking and non-smoking HIV infected patients, and a significant cIMT difference between infected and non-infected smokers. The probable explanation for both cases, apart from the small number of infected non-smokers and non-infected smokers, may be the complex character of the infection, ARV treatment and the accompanying metabolic disorders that reduce the differences among infected patients and exacerbate the dif­ferences between infected and non-infected participants.
The second most important risk factors in our cohort are lipid disorders, which occur in a similar proportion in the cohort and the control group (53% vs. 51%) and are co­nvergent with NATPOL PLUS epidemiological data for the Polish adult population (50%) [83]. However, the Polish population is dominated by hypercholesterolemia (appro­ximately 55-60%) [62,77,83]. Comparison of lipid disor­ders in these two groups demonstrated substantial quali­tative differences. In the study group, significantly lower total cholesterol and LDL and HDL cholesterol levels were observed, and hypercholesterolemia was three times less frequent than in the control group (8.3% vs. 25.9%). Dyslipidemia or isolated hypertriglyceridemia prevail in the infected group, and the average triglyceride level in the cohort is statistically higher than in the control group and compared with Polish epidemiological studies, where the average concentration of triglycerides in a comparable age group is lower [83]. The total percentage of infected pa­tients with a high triglyceride level is 43%. Similar data can be found in many papers on lipid disorders in HIV in­fected people. Usually, the induction of these disorders is linked to antiretroviral treatment, as the disorders may be affected by all classes of drugs: protease inhibitors (PIs), nucleoside (NRTIs) and non-nucleoside reverse transcrip­tase inhibitors (NNRTIs) [14,20,24,25,26,58,65].
The cause of low total cholesterol and both its fractions in HIV infected patients is not clear; possible explanations include the young age of the cohort, low BMI, improper diet and lifestyle, and coexisting hepatitis B and C, as well as cigarette smoking (effect on HDL). The mean total cho­lesterol concentration in infected patients is significantly lower than in the control group and lower than in Polish population studies for this age group [83]. Although the literature on this emphasizes the existence of such a con­figuration in the past, before the cART era, there are still similar results in some works on infected patients publi­shed within the last decade [13,24,25,26,47].
The proportion of hypertensive patients was similar in the cohort and control group; the results are comparable to the total adult population in Poland, where it is estimated at 29% to 74%, but in the age group 18-59 the figure is 19.1% [72,83]. And thus, in both our groups, the incidence of hypertension was higher than in the epidemiological stu­dies of Poles of the same age. The occurrence of hyper­tension among HIV infected people, especially those rece­iving cART and with diagnosed lipodystrophy syndrome, has been described by other authors [18,24,31,68]. The prevalence of hypertension in individual cohorts varies - from a few percent up to 34% in the slightly older Italian cohort [21]. The D.A.D study (Data Collection on Adverse Events of Anti-HIV Drugs) indicates the impact of tradi­tional CVD risk factors on blood pressure and lack of cor­relation between pressure and particular classes of antire­troviral drugs, with the exception of NNRTIs, which are correlated with a low risk of developing hypertension [75].
Diabetes occurs in the two groups at a similar frequency as in the adult Polish population aged 18-59 [83]. The mean fasting glucose shows no differences and is similar in both groups. In other cohorts, the incidence of diabetes seems to be higher. The percentage of diabetics among infected patients is 6-7.3%, depending on the authors [18,30,51].
A general assessment of body posture revealed significan­tly higher WHR and significantly lower BMI in the cohort participants compared with the control group. Obesity is al­most twice less frequent than in the control group. A lower BMI in HIV-positive people was also observed by other au­thors [9,44]. In the adult population of Poles aged 18-59, in as many as 47.3%, the BMI was equal to or greater than 25, which is reflected in our control group. Considering only ab­normal WHR as an expression of central obesity, abdominal obesity concerns 43.1% of our study cohort. In Poland, this percentage in the same age group is slightly higher at 45.4% (NATPOL PLUS). The predictive importance of WHR for CVD risk assessment in HIV infected people has not been established yet. Special attention should be paid when as­sessing central obesity using this index, especially in ARV treated patients, because its value may be higher due to the loss of fat around the hips and buttocks in the course of HIV-associated adipose redistribution syndrome (HARS) [46]. In the studies of Johnsen et al., both the waist and hip cir­cumference affected WHR; however, the effect was stronger for the reduced hip circumference [37]. This situation was also confirmed in our cohort, in which high WHR is signi­ficantly affected by low hip circumference, and waist cir­cumference is irrelevant and does not differentiate the two groups. This paper does not deal with the symptoms of li­podystrophy (which occurs in various forms in the majori­ty of the cohort). This will be the subject of further studies.
Metabolic syndrome is significantly more frequently dia­gnosed in the cohort, using both ATP III and IDF criteria, and this is consistent with previous reports. The percen­tage of patients with MS was also similar to that found in other studies [7,21,35,54,81]. We were somewhat surpri­sed by the identical percentage of people with MS diagno­sed according to various criteria, taking into account low BMI in the cohort and no effect of waist circumference on the WHR. Usually, the percentage is higher after adop­tion of more flexible NCEP ATP III criteria. The relatively high percentage of MS according to IDF criteria was pro­bably due to using a waist circumference consistent with European standards and strong representation of factors other than waist circumference. MS as a categorical va­riable shows no association with cIMT, which had already been reported [37]. This observation is in contrast to other works showing the effect of MS on the cIMT value [2].
Observation of the basic hemostatic parameters is also interesting. Configuration changes may indicate chronic consumption of platelets and fibrinogen in an ongoing inflammatory process. Fibrinogen is an acute phase pro­tein involved in the clotting process in response to infec­tion. It is one of the major plasma proteins affecting the viscometric properties of blood. It may seem that its le­vel in HIV infected patients should be higher than in he­althy people, but the literature on this topic contains con­trary reports. Some authors confirm higher concentrations of fibrinogen in a HIV infected cohort [26,30]. Low fibri­nogen concentrations in HIV-positive individuals were also reported in other papers [1,26]. Fibrinogen concen­tration may differ depending on the type of antiretroviral drugs, as high concentrations were observed while using PI, and low concentrations were observed for drugs from the NNRTI group [48]. At the moment, we do not know what the reason for reduced fibrinogen levels in the cohort is and how important its observation is. Is this a symp­tom of deep pathology in the chain of inflammatory pro­cesses or a symptom of liver dysfunction? Possible causes may include malnutrition (as indicated by a significantly lower BMI) or the coexistence of other infections - hepa­titis B or C - which may lead to the weakening of fibri­nogen synthesis. D-dimers are higher in the cohort, but this difference is not significant compared to the control group. Results for the basic hemostatic parameters plus significantly lower hematocrit in the infected group may indirectly indicate that blood rheological properties sho­uld be more favorable than in the healthy group. The si­gnificantly lower mean platelet count in the infected gro­up is easily explained by coinfections with HBV and HCV as well as thrombocytopenia, which often accompany the infection and the main pathogenic mechanisms of which are already known [69].
There is no difference in the homocysteine concentration between the infected and control groups. Elevated concen­trations were observed by other authors, especially in HIV infected patients treated with cART [10]. An effect of ho­mocysteine on cIMT progression in HIV positive people has also been reported [13].
CRP is an acute phase protein and a known marker of in­flammation. Its elevated concentration is a risk factor for cardiovascular diseases. Despite the observations of other authors claiming increased concentration of CRP in HIV infected patients [30,59], our study showed no differences in CRP concentration between the infected and non-infec­ted group. The mean CRP level is even slightly lower in the cohort. Noursadeghi M et al. believe that the higher CRP concentration in the HIV subpopulations may be as­sociated with an inflammatory response in the course of HIV infection per se [59]. In our study cohort, approxi­mately 40% of patients suffer from coexisting HCV infec­tion, which may lead to lowering CRP levels, as indicated by the observations of other authors [66].
Our study in the cohort of HIV infected patients compa­red with an appropriately matched group of healthy sub­jects showed, similarly to other studies, significantly greater severity of subclinical atherosclerosis in the carotid arte­ries, assessed by cIMT measurements and the amount of atherosclerotic plaques [22,30,49,61,70]. The cIMT is hi­gher in HIV infected subjects in all locations, both within the common carotid arteries and in the bulbs. The inciden­ce of atherosclerotic plaques in our cohort is significantly higher than in the control group. These results are similar to those obtained by other researchers [31,35].
Multivariate regression analysis revealed that cIMT is strongly affected by age, hypertension, non-HDL chole­sterol and ARV treatment time. Non-HDL cholesterol re­presents the most atherogenic cholesterol fractions (LDL and remnants). Although the concentration of non-HDL cholesterol in the study group is significantly lower than in the control group (as for other cholesterol fractions), this parameter seems to be a strong non-traditional risk factor for subclinical atherosclerosis among HIV infected pa­tients. Badiou et al. showed a relationship of cIMT with non-HDL cholesterol in HIV individuals, using the univa­riate regression analysis [2]. A non-HDL cholesterol effect on cIMT progression has also been reported [14]. Both the cited works and our study indicate the need to use this pa­rameter in assessing cardiovascular risk and as a secon­dary therapeutic target in connection with LDL choleste­rol, as recommended by NCEP ATP III. Our observation is also practical: many HIV infected patients treated with ARV suffer from hypertriglyceridemia with triglyceride concentration exceeding 400 mg%, making it impossible to calculate LDL cholesterol. Given our strong observa­tions, we believe that the assessment of lipid disorders in HIV infected patients should include the non-HDL cho­lesterol parameter, which is easy to calculate in a doctor's office. Total cholesterol and LDL cholesterol treated as in­dividual risk factors also affect cIMT, despite a lower ave­rage level among HIV infected patients. The effect of these cholesterol fractions on cIMT progression was reported by others [14,31]. The relationship between cIMT and hyper­tension is most often evaluated based on quantitative data - the value of systolic or diastolic blood pressure. The use of a categorical variable allowed us to exclude the impact of incidental blood pressure fluctuations and demonstrate the connection of subclinical atherosclerosis development with long-term hypertension.
Present studies on the interrelation of cIMT and virological and immunological parameters show a weak positive cor­relation between cIMT and the current HIV RNA concen­tration. At this stage, we treat this result as an interesting tendency, which will be given more attention in further stu­dies. The literature on this subject contains reports on te­sting the impact of HIV RNA on endothelial function using flow-mediated vasodilatation (FMD) in ARV non-treated patients [61]; yet no correlation was found between HIV RNA and cIMT. It is believed that cIMT growth is a long­-term process, but dynamic changes within cIMT are now widely discussed. Our observation, if confirmed in further studies, may indicate dynamic changes of IMT in this rela­tively young subpopulation - the possibility of progression but also regression, which is suggested in the Coll study, where both phenomena were reported [9]. This possibili­ty was confirmed in autopsy studies of people in the gene­ral population, who died at different ages, which showed that in young people the carotid arteries were dominated by foam cell infiltrates, considered to be a reversible athe­rosclerotic formation [15]. The dynamic nature of the chan­ges is also confirmed by the results of drug-based studies that demonstrated the regression of subclinical atherosc­lerosis expressed by IMT [53,71]. With this in mind, it can be assumed (and treated as a hypothesis) that the adverse period of HIV infection, confirmed by high viral load or a low number of CD4 T-cells, may result in an increased cIMT value. No effect of the number of CD4 T-cells on the cIMT value was found. Our observations are in line with studies that show the relationship of subclinical atherosc­lerosis with HIV infection per se [47,61,78]. Even in pa­tients treated successfully with antiretroviral therapy, chro­nic immune activation continues, although at a low level [32]. It is known that persistent stimulation of the immu­ne system, characteristic of HIV infection, accelerates the development of atherosclerosis. An atherogenic effect is observed both in the course of the immune deficit, as well as immune system stimulation related to antiretroviral tre­atment [28,31,32].
A history of AIDS, co-existing HBV and/or HCV infection did not significantly differentiate the cIMT value. Time of ARV treatment longer than 5 years is associated with gre­ater severity of subclinical atherosclerosis in our cohort.
Conclusions
The cohort of HIV infected patients shows significant pro­gression of subclinical atherosclerosis in the carotid arteries expressed by cIMT and incidence of atherosclerotic plaqu­es. The atherosclerosis is strongly influenced by a complex set of risk factors such as age, non-HDL cholesterol, hyper­tension and duration of antiretroviral treatment. The cIMT is also affected by total and LDL cholesterol. Lifetime smo­king exposure exerts a significant effect on cIMT. Based on the observation of a relationship between cIMT and current HIV RNA, we can claim an impact of the current infection status on the cIMT dynamics in this young subpopulation. Time of treatment longer than 5 years, as well as diagno­sed hyperlipoproteinemia, are associated with significantly greater severity of subclinical atherosclerosis. The cardio­vascular risk profile of HIV infected patients is significan­tly different from healthy people: the concentration of all cholesterol fractions and BMI are lower, whereas the con­centration of triglycerides, percentage of smokers and WHR are higher. Higher WHR is dependent on hip circumference.
Metabolic syndrome occurs slightly more often in infected patients, but we did not demonstrate its effect on subclini­cal atherosclerosis. Important changes in basic hemosta­tic parameters were observed, and their causes and signi­ficance will be investigated in further studies.
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The authors have no potential conflicts of interest to declare.