Prevalence and variables associated with an abnormal ankle-brachial index among patients with human immunodeficiency virus/acquired immunodeficiency syndrome

Abstract

Objectives

The longer survival of patients with human immunodeficiency virus/acquired immunodeficiency syndrome and the introduction of the highly active antiretroviral therapy have increased the number of chronic conditions; among these, cardiovascular diseases. The aim of this study is to determine patient, disease, and factors associated with peripheral arterial disease in a population of patients with human immunodeficiency virus/acquired immunodeficiency syndrome.

Methods

A prospective nested case–control study of a cohort of patients with human immunodeficiency virus/acquired immunodeficiency syndrome was conducted in a tertiary medical center in Mexico City. A sample size of 206 patients was calculated. Medical history, relevant laboratory data, peripheral arterial exam, and screening ankle-brachial index tests were obtained.

Results

The prevalence of abnormal ankle-brachial indexes was 20% (42 patients). Patient’s mean age was 44 years ±13. The majority (98.5%) were actively receiving highly active antiretroviral therapy; active smoking was reported in 55 (27%), arterial hypertension and type 2 diabetes mellitus were found in 24 (12%) and 22 (11%) patients. Median time from the human immunodeficiency virus diagnosis was eight years (Interquartile range ±11); the mean CD4 count was 481, with a mean viral load of 13,557 copies (SD ± 69025.27) and 1889.18 (SD ± 9052.77) for patients with normal and abnormal ankle-brachial index and a median of 40 (IQ ± 2). Viral load (p = 0.04) and number of years with human immunodeficiency virus/acquired immunodeficiency syndrome (p = 0.04) were significantly associated with abnormal ankle-brachial indexes.

Conclusions

Abnormal ankle-brachial index seems to be more frequent in Mexican patients with human immunodeficiency virus/acquired immunodeficiency syndrome when compared with the general population at the same age. The most important factors associated with arterial disease were the viral load and the number of years with human immunodeficiency virus/acquired immunodeficiency syndrome.

Trial Registration: ClinicalTrials.gov NCT02264509.

Keywords

Prevalence ankle-brachial index peripheral arterial disease human immunodeficiency virus acquired immunodeficiency syndrome

Introduction

Human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) is considered as one of the most important epidemics of the last century.¹ Estimates were that by the end of 2005, there were approximately 38.6 million infected HIV people and 4.1 million new infections from HIV occurred during that year.² With the introduction of highly active antiretroviral therapy (HAART) in the mid-1990s, the mortality rates have decreased significantly, achieving levels of the general population in western countries.³ Since it was recognized clinically in 1981, this infectious entity has shifted from a fatal syndrome to a chronic disease.⁴ This phenomenon is the result of the longer survival of HIV patients, and the increasing number of chronic conditions; among these, cardiovascular diseases (CVDs).⁵ In this respect, there are literature reports including two large observational studies that demonstrated that compared to the general population at the same age, HIV-infected patients have higher rate of coronary artery disease (CAD),^6–8 furthermore cardiovascular deaths accounted 6.5% of total deaths in a large observational cohort of HIV infected patients from Europe and North America.^9–11

Not only the presence of traditional cardiovascular risk factors but also the known side effects and metabolic disorders associated to HAART such as dyslipidemia, insulin resistance, and lipodystrophy have contributed to an increase incidence of CVD in this patient population.¹² Although a substudy of the INSIGHT – Strategic Timing of Antiretroviral Treatment trial demonstrated no significant association among the use of antiretroviral therapy with alterations in arterial elasticity.¹³ Over the last two decades, studies have suggested an association of CVD in HIV/AIDS secondary to the accelerated atherogenesis stimulated by infected macrophages/monocytes in addition to the alterations in leukocyte adherence and the inflammation of the arterial wall.^14–17 Specifically, peripheral arterial disease (PAD) manifests in bimodal pattern in HIV patients in a similar way to individuals that suffered from vasculitis in whom aneurysms and occlusive disease can be found.^15,16 Typically, this cohort of PAD patients is younger, and with less of the traditional risk factors than patients affected with PAD in the general population.^15–17 In HIV/AIDS patients, usually intraluminal occlusive lesions present with long segments and in distal locations with limited outflow, similarly to fibro-obliterative diseases which cannot typically be treated by standard endovascular or surgical management.¹⁷ Nair et al.¹⁸ proposed that the pattern of aneurismal disease is secondary to leukocytoclastic vasculitis of the vasa vasorum similar to patients with Takayasu’s arteritis or Behcet’s disease.

The aim of this study is to determine the prevalence of clinical and subclinical lower extremity PAD among patients with HIV/AIDS at the National Institute of Medical Sciences and Nutrition “Salvador Zubirán” (INMCNSZ). In addition, to examine if variables related to patients (demographics, comorbidities, and lifestyle), disease (time of diagnosis, number of CD4, viral load, clinical categories), and treatment (antiretroviral therapy, duration, and number of previous HAART) are associated to the development of PAD.

Methods

Study design

Case–control study nested in a cohort of patients with HIV/AIDS followed at our institution. The sample was calculated with 206 patients by Simple Random Sampling in order to achieve 80% power with 99% of confident intervals. To estimate our sample, we utilized the global estimates of prevalence and risk factors of PAD worldwide¹⁹ using the software Epi Info™ from the Centers for Disease Control and Prevention (CDC),²⁰ and confirmed with the program Power Analysis and Sample Size system version 13.0 (UT, USA). The protocol was approved by our Institutional Review Board and registered in ClinicalTrials.gov with the number NCT02264509; the inclusion criteria considered all adults with serologic diagnosis of HIV infection and treated in our institution. Prior to the interview process and physical examination, consent for procedure was obtained; all patients were seen and carefully examined in our vascular clinic, and all risk factors were documented. Complete physical examination including pulse exam in upper and lower extremities (brachial, radial, ulnar, femoral, popliteal, posterior tibial, and dorsalis pedis arteries) was performed, intentional search for femoral bruits in addition to ankle brachial indexes (ABIs) were determined in our non-invasive vascular laboratory. To determine ABIs, we used an ultrasound Doppler, 8 mHz transducer and cuffs for arterial pressure 20% larger than the arm’s circumference. The technique for ABIs determination was according to the one described by Grenon et al.²¹ Abnormal ABIs was defined as a value of <0.9 and/or >1.4.

Study setting

Academic and research medical center which is a tertiary referral facility serving a catchment area of 22 million people.

Statistical analysis

Descriptive statistics was conducted, demographics and clinical data were summarized using percentages, mean (standard deviation (SD)), median (Interquartile (IQ) range). For nonparametric statistics, we utilized Mann–Whitney U test to determine differences between the population with normal and abnormal ABIs; linear regression for continuous variables and Student’s t-test for independent means. Associations were analyzed with ANOVA; all tests were performed using the statistical program STATA 14.0.

Results

Characteristics of patients

A total of 206 patients from the HIV/AIDS clinic at the INCMNSZ were included in this study, all of them had confirmed diagnosis of HIV, 168 were male (82%), mean age was 44 years (SD ± 13, range 19–84). The prevalence of abnormal ABIs was 20% (42 patients); 133 individuals (65%) had family history of arterial hypertension, type 2 diabetes mellitus (DM), or CAD. A total of 109 patients (53%) had known comorbidities: arterial hypertension in 24 (12%), diagnosed in a range from less than a year up to 20 years (<1 to 20 y), with a median of 2.5 years (IQ ± 5); 22 had history of type 2 DM (11%) (diagnosed <1 to 20 y), with a median of eight years (IQ ± 12); history of CAD in five cases (2%). None of them had known diagnosis of PAD; however, there were 19 subjects with chronic venous insufficiency (9%). Three individuals (2%) had history of transient ischemic attack, four (1%) suffered from acute myocardial infarction. Patients with previous surgeries accounted 103 (50%); the most common procedure was appendectomy in 14 (7%). Neither arterial hypertension (p = 0.256) nor type 2 DM (p = 0.159) affected the distribution of the studied groups (see Table 1).

Table 1.

Patient’s demographics, comorbidities and previous surgeries in HIV/AIDS with patients with normal and abnormal ABIs.

Characteristics	Normal ABI (n = 164) No. (%)	Abnormal ABI (n = 42) No. (%)	p
Age, years	43.1 SD ± 12.2	47.5 SD± 14.2	.071
Gender			.436
Female	32 (20)	6 (14)
Male	132 (80)	36 (81)
Family history (DM, HTN, CAD)	107 (65)	26 (61)	.686
Comorbidities	87 (53)	22 (52)	.938
Arterial hypertension	17 (10)	7 (16)	.256
Diabetes mellitus	15 (9)	7 (16)	.159
CVI	15 (9)	4 (9)	.940
CAD	7 (4)	2 (5)	.983
Cerebrovascular disease	3 (2)	0 (0)	.377
Previous surgeries	77 (47)	26 (62)	.084

CVI: chronic venous insufficiency; HTN: arterial hypertension; CAD: coronary artery disease; ABI: ankle-brachial index; DM: diabetes mellitus.

Social history and lifestyle

From the total of patients interviewed, 107 patients exercised regularly (52%), the median time of exercise was 210 min per week (IQ ± 240), ranging from 30 to 1680 min, walking was the most common physical activity (33.5%). With respect to substance use, active smoking was reported in 27% (55 patients) with a pack-year history ≥2, while five patients recognized illicit drug use (2%) (Table 2).

Table 2.

Social history and lifestyle in HIV/AIDS patients with normal and abnormal ABIs.

Social History and lifestyle	Normal ABI (n = 164) No. (%)	Abnormal ABI (n = 42) No. (%)	p
Regular exercise	87 (53)	20 (48)	.530
Active smoking	45 (27)	10 (24)	.635
Smoking history (former smokers)	33 (20)	13 (31)	.133
Illicit drug use	5 (3)	1 (2)	.818

ABI: ankle-brachial index.

CDC HIV/AIDS classification system and HAART

According to the US CDC HIV/AIDS classification system,²² the distribution of the clinical categories was as follows: in the A1 1.6% of the patients, A2 9%, A3 3%, B1 10.7%, B2 8.2%, B3 3.3%, C1 31.1%, C2 23.8%, and C3 9.8% of the total (Figure 1). A total of 98.5% of patients received at least one HAART regimen. For those with less of one regimen of HAART, the median of years was 5 (IQ ± 8), with a maximum of 27 years. The median of the number of HAART regimens was 2 (IQ ± 2), with maximum of 14. With respect to the antiretroviral medications used for the management of our patients, 77% received nucleoside analog reverse transcriptase inhibitors, 55% non-nucleoside reverse transcriptase inhibitors, 24% of the patients with one protease inhibitors, 8% with one integrase inhibitor drug and none of them with fusion inhibitors or coreceptor CCR5 antagonist. Lipodystrophy occurred in 12 patients (6%).

Figure 1.

Centers for Disease Control and Prevention (CDC) HIV/AIDS classification system for the patients included in this study.

Time since HIV/AIDS diagnosis (years) and laboratory values

From the 206 patients included in this study, the median of years since HIV/AIDS diagnosis was eight years (IQ ± 11), there were two patients with this disease diagnosed in less than a year period, while the longest period of time since the diagnosis was 27 years. Peripheral blood samples were requested, CD4 levels, viral load, and lipid profile were assessed. The mean in the number of CD4 was 481 (SD ± 253), with a mean viral load of 13,557 copies (SD± 69025.27) and 1889.18 (SD ± 9052.77) for patients with normal and abnormal ABIs, respectively, and a median of 40, IQ ± 2 (p = 0.04). With respect to the levels of high-density lipoprotein (HDL), the median was 41 mg/dL (IQ ± 14, 13–80), the median of low-density lipoprotein was 102 mg/dL (IQ ± 44, 10–315) while triglycerides with 144 mg/dL (IQ ± 87, 48–1683) (Table 3).

Table 3.

Time since HIV/AIDS diagnosis (years) and laboratory data.

HIV/AIDS patients	Normal ABI (n = 164) (SD)	Abnormal ABI (n = 42)	p
Time since HIV/AIDS diagnosis (median years)	8.36 IQ ± 6.6	10.62 IQ ± 6.1	.048*
CD4 count (mean)	470.86 SD ± 239.11	522.77 SD ± 300.90	.323
Viral load number of copies (mean)	13557.18 SD ± 69025.27	1889.18 SD ± 9052.77	.044*
Lipid profile
HDL (median) mg/dL	42.86 IQ ± 11.52	42.30 IQ ± 13.40	.813
LDL (median) mg/dL	107.35 IQ ± 38.57	95.13 IQ ± 36.84	.073
TG (median) mg/dL	168.82 IQ ± 100.42	233.45 IQ ± 43.50	.152

IQ: interquartile; SD: standard deviation; HDL: high-density lipoprotein; LDL: low-density lipoprotein; TG: triglycerides.*Statiscally significant.

Physical exam and noninvasive vascular laboratory evaluation

Nineteen patients (9%) endorsed lower extremity rest pain and 20 (10%) claudication, with a mean walking distance of 136 m before the pain started (SD ± 87.92 m), the minimum distance was 30 m and maximum was 250 m. When we studied these patients in our vascular clinic, we concluded that the etiology of claudication was neurogenic. Fourteen patients had angina pectoris (7%), 15 dypsnea (7%), only 1 patient had previous history of lower extremity ulcers related to venous insufficiency. With respect to the vascular exam, pulses in all four extremities were palpated and found in all upper extremities. In the lower extremities, pulses in the right leg were palpated in 96% of patients and absent in 4%; on the left leg, 98% were present and in 2% absent. Systolic blood pressure was measured at the level of the brachial artery with a median of 110 mmHg (IQ ± 20, 80–180). In the right lower extremity at the level of the dorsalis pedis artery with a median of 129 mmHg (IQ ± 22, 90–220) and the posterior tibial artery was 130 mmHg (IQ ± 30, 90–220), while in the left lower extremity, the dorsalis pedis artery with a median of 130 mmHg (IQ ± 22, 70–220) and posterior tibial of 130 mmHg (IQ ± 30, 70–220).

The determination of ABI in the right leg at the level of the dorsalis pedis (ABIDP) artery showed a median of =1.18 (IQ ± 0.19, 0.83–1.82), in the posterior tibial (ABIPT) = 1.2 (IQ ± 0.24, 0.85–1.91). In the left leg, ABIs at the level of the dorsalis pedis artery, the median (ABIDP) was = 1.2 (IQ ± 0.2, 0.77–1.82), and in the posterior tibial artery (ABIPT) = 1.22 (IQ ± 0.24, 0.86–1.82) (Table 4). According to the standardized international measurement, the median of ABI was 1.27 (IQ ± 0.19, 0.77–1.9). Forty-two patients had abnormal ABIs (20%), three of them with ABI ≤0.9 (1.5%), and 39 with ABI ≥1.4 noncompressible vessels (19%) (Table 5). Patients with abnormal ABIs are currently followed and managed in our vascular clinic with modification of traditional risk factors. We did not find statistical differences among patients with abnormal ABIs with several variables when compared with patients with normal ABIs. In patients with complaints of claudication, there was no association with abnormal ABIs, the same for smoking history. From the group with abnormal ABIs, 20 patients exercised regularly (48%), with an OR = 0.79. The association between the current use HAART and the past use of this therapy and different drugs regimens showed no statistical difference, but when performing an analysis through ANOVA, we observed the influence of the use of protease inhibitors (p = 0.006). Lastly, when we compared the level of lipids in blood, the results were not statistically significant.

Table 4.

Clinical manifestations in HIV/AIDS patients with normal and abnormal ABIs.

	Normal ABI (n = 164) No. (%)	Abnormal ABI (n = 42) No. (%)	p
Baseline clinical symptoms
Lower extremity rest pain (non-arterial etiology)	16 (10)	3 (7)	.431
Claudication (non-arterial etiology)	16 (10)	4 (9)	.614
No symptoms in lower extremities	132 (80)	35 (83)	NS
Chest pain	11 (7)	3 (7)	.920
Dyspnea	14 (8)	1 (3)	.171
Baseline clinical signs
Lower extremity ulcer (venous origin)	1 (1)	0 (0)	.612
Lipodystrophy	10 (6)	2 (5)	.779

NS: not significant.

Table 5.

Lower extremity vascular exam.

Vascular exam	Normal ABI (n = 164) No. (%)	Abnormal ABI (n = 42) No. (%)	p
Palpable pulses +	162 (99)	36 (86)	<.001
ABI < 0.9		3 (7)
ABI > 1.4		39 (93)

Discussion

A significant progress in the management of HIV/AIDS and their complications had led to an increased survival and a dramatic shift in how physicians approach this disease.^23–24 Its clinical spectrum changed from opportunistic AIDS-related disease toward long-term age-related complications, including cardiometabolic alterations. It is reported that HIV patients are at higher calculated risk for CVD compared with the general population of the same age.^25–27 With this growing burden of HIV-related heart, lung, and blood diseases, the National Heart, Lung and Blood Institute and the American Heart Association in the United States of America recognized that they must support research that addresses how the chronic phase of HIV affects the cardiovascular system.^24,28,29

Available data suggest that antiretroviral drugs may be associated with insulin resistance and dyslipidemia, but those are not the only factors likely involved in the increased CVD risk seen in HIV patients. Traditional risk factors, such as increased rates of smoking, may be higher in these patients: HIV by itself may affect traditional risk factors, including lipid profiles; and/or there may be increased underlying inflammation and endothelium dysfunction.⁴ The presence of an accelerated process of atherosclerosis in this population is secondary to multiple factors, including the higher prevalence of conventional risk factors, emerging risk factors (chronic inflammation, immune activation, and senescence related to HIV infection itself), and the role of HAART for each individual to reduce the risk for CVD is warranted. The current understanding is that PAD is the result of several processes that damage the arterial wall to the level of the intimal layer, leading to stenosis and obstruction of the vessel due to atheroma plaques, causing diminished blood flow in the extremities and organs.¹⁹ The prevalence of PAD worldwide is estimated between 3% and 10%, this figure might depend on several factors such as ethnicity, smoking history with an increased relative risk of 3.7, and the presence of type 2 DM with 40–50% increased risk. Asymptomatic PAD which is prevalent among 40-year-old individuals in a 3% rising up to a 6% at the age of 60; meanwhile symptomatic PAD in a 2.5% of patients at the age of 50 years and 14.5% in individuals older than 70 years.^19,30

The literature regarding the prevalence of PAD and its association with HIV/AIDS remains controversial with conflicting reports in the literature. Some reports indicate a high prevalence in this population,^31–34 while other studies low.³⁵ An article from Poland that included 111 young-to-middle age HIV positive subjects and 40 non-infected patients was published in 2014;³¹ in this study, ABI measurements were performed and cardiovascular risk factors were analyzed. Subgroups were created according to ABI values: low (PAD) borderline, normal, high, and altered ABI. The authors concluded that in young HIV positive patients, symptomatic PAD prevalence is comparable to the observed in the overall population and an altered ABI showed a strong correlation with low HDL-C levels and metabolic syndrome. To our knowledge, our study represents the analysis of one of the largest cohorts of HIV/AIDS patients, and we found a PAD, the prevalence of 20% defined in measurement of ABIs as recommended by the international guidelines TASC-II.³⁰ Considering that PAD is not only ABI ≤ 0.9, but ABI ≥ 1.4, because the spectrum of this disease is obstruction at the arterial lumen and calcification in the arteries along their trajectory and manifested with ABIs ≥ 1.4, or noncompressible, which translates in lack of compliance of blood vessels. We used the ABIs measurement which is a validated, simple and inexpensive test to identify lower extremity PAD, unfortunately in our country there is no national registry of the prevalence of PAD and HIV/AIDS to compare our results, and this is one of the limitations of research work. In this study, we found that common associated risk factors with arterial disease such as diabetes, hypertension, and smoking history did not impact on the presence of abnormal ABIs; with respect to the gender, we observed a greater prevalence in males, although this was not statistically significant. Age is clearly a risk factor for PAD in the general population, however, in our sample was not due to the accelerated aging process secondary to HIV infection; as a result, age was not statistically significant, but it might result clinically important because in patients younger than 60 years, arterial calcifications would need to be searched intentionally and monitored closely. The comparison in the viral load in both groups was statistically significant; interestingly, we observed that four patients in the normal ABI cohort had elevated number of copies (>200,000 copies); these patients had initiated HAART within two years. This finding might be associated to the biology and the natural history of the disease; it seems that individuals with recent HIV diagnosis and relatively short time on HAART do not manifest damage in the arteries.

Conclusion

In this study, we found that the prevalence of abnormal ABI tests in patients with HIV/AIDS at the infections disease clinic of the INMCNSZ was 20%; this figure seems to be higher than reported when comparing with the general population with cardiovascular risk factors at the same age. The most important variables associated with an abnormal test were the viral load and the number of years with HIV. In addition, and based on the statistical analysis, we can conclude that the damage suffered in the arteries of our patients was not associated with comorbidities as diabetes and hypertension. Possibly, the HIV infection in our patients led to an inflammatory process at the level of the endothelium which damaged the arterial wall and resulted in abnormal ABIs. A precise understanding of the pathophysiology and the clinical impact of the atherosclerotic aging process in this patient population deserves further investigation.

Footnotes

Acknowledgments

This article was presented at the Society for Vascular Surgery annual meeting held in Chicago, IL, USA, June 2015.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

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