Cardiovascular disease associated with human immunodeficiency virus: A review | Revista Portuguesa de Cardiologia (English edition)

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Adaptado de: European AIDS Clinical Society Guidelines Version 7.1 – Novembro 2014<a class="elsevierStyleCrossRef" href="#bib0340">68</a>. Traduzido pelos autores. Observações: A. Existe informação muito limitada em relação a agentes antidiabéticos orais no âmbito da prevenção de doença cardiovascular e não há informação em indivíduos VIH‐seropositivos." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Luísa Amado Costa, Ana G. Almeida" "autores" => array:2 [ 0 => array:2 [ "nombre" => "Luísa" "apellidos" => "Amado Costa" ] 1 => array:2 [ "nombre" => "Ana G." 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Almeida" "autores" => array:2 [ 0 => array:4 [ "nombre" => "Luísa" "apellidos" => "Amado Costa" "email" => array:1 [ 0 => "analuisamado@hotmail.com" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:2 [ "nombre" => "Ana G." "apellidos" => "Almeida" ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "University Clinic of Cardiology, Faculty of Medicine of Lisbon University, Hospital Santa Maria, CHLN, Lisbon, Portugal" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Patologia cardiovascular associada ao vírus da imunodeficiência humana" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1444 "Ancho" => 1953 "Tamanyo" => 261280 ] ] "descripcion" => array:1 [ "en" => "Assessment of cardiovascular risk in HIV-positive individuals. Adapted from European AIDS Clinical Society Guidelines Version 7.1 – November 2014.<a class="elsevierStyleCrossRef" href="#bib0840">68</a> a The Framingham equation can be used. This assessment and the associated considerations outlined in this figure should be repeated annually in all persons under care. b Of the modifiable risk factors outlined, drug treatment is reserved for certain subgroups where benefits are considered to outweigh potential harm. c Target levels are to be used as guidance and are not definitive – expressed as mmol/l with mg/dl in parentheses. d Evidence for benefit when used in persons without a history of CVD (including diabetics) is less compelling. Blood pressure should be reasonably controlled before aspirin use in such a setting." ] ] ] "textoCompleto" => "IntroductionHuman immunodeficiency virus (HIV) is a retrovirus with tropism for cells expressing CD4. In 2012 the number of HIV-positive individuals was estimated at 35.3 million.<a class="elsevierStyleCrossRef" href="#bib0505">1</a>The introduction of highly active antiretroviral therapy (HAART) has prolonged the survival of HIV-positive individuals, turning acquired immunodeficiency syndrome (AIDS) into a chronic disease.A retrospective analysis of causes of death in 13 cohort studies of HIV type 1 (HIV-1)-infected patients who initiated antiretroviral therapy (ART) in Europe and North America from 1996 through 2006 showed lower mortality from AIDS-related causes and higher mortality from causes associated with aging, such as non-AIDS malignancies and cardiovascular disease (CVD). The latter accounted for 7.9% of deaths, of which 40% were from myocardial infarction (MI)/ischemic heart disease (IHD), which suggests that the process of aging will become a dominant factor in HIV-1 mortality in the next decade.<a class="elsevierStyleCrossRef" href="#bib0510">2</a>The cardiovascular manifestations of HIV infection have changed following the introduction of HAART. Cardiovascular involvement in treatment-naive patients is still important in individuals who do not adhere to treatment or start treatment late, and in countries with limited access to ART. We therefore describe the cardiovascular consequences in treatment-naive HIV-positive individuals and the potential effect of treatment on their regression, as well as the implications of HAART.Cardiovascular manifestations of human immunodeficiency virus infectionCardiomyopathyFour types of cardiomyopathy are associated with HIV infection: myocarditis, hypokinetic cardiomyopathy (particularly in advanced stages of infection), dilated cardiomyopathy, and reduced left ventricular systolic function.<a class="elsevierStyleCrossRef" href="#bib0515">3</a>Pre-HAART studies reported high prevalences of myocarditis, in up to 52% of patients.<a class="elsevierStyleCrossRef" href="#bib0520">4</a> Acute myocarditis can lead to congestive heart failure (HF) and arrhythmias. Myositis is common in this population, and myoglobin is thus less specific as a marker of myocardial damage.<a class="elsevierStyleCrossRef" href="#bib0525">5</a> Clinical features, risk factors such as drugs or antivirals, and complementary exams have a role in diagnosis. The gold standard in the diagnosis of myocarditis is endomyocardial biopsy.<a class="elsevierStyleCrossRef" href="#bib0530">6</a>Dilated cardiomyopathy: With regard to dilated cardiomyopathy, the pre-HAART incidence was reported to range between 8%<a class="elsevierStyleCrossRef" href="#bib0535">7</a> and 35%.<a class="elsevierStyleCrossRef" href="#bib0540">8</a> In the HAART era, a reduction in the prevalence of cardiomyopathy has been reported in developed countries,<a class="elsevierStyleCrossRef" href="#bib0545">9</a> possibly due to reduced viral replication, lower incidence of myocarditis and prevention of opportunistic infections. In developing countries, with less access to ART, cardiomyopathy is a significant problem; a prospective study in Rwanda reported a 17.7% prevalence of dilated cardiomyopathy.<a class="elsevierStyleCrossRef" href="#bib0550">10</a>The pathogenesis of dilated cardiomyopathy is thought to be multifactorial, possibly linked to infection of the myocardium by HIV,<a class="elsevierStyleCrossRef" href="#bib0535">7</a> immunodepression,<a class="elsevierStyleCrossRefs" href="#bib0515">3,10</a> nutritional deficiencies,<a class="elsevierStyleCrossRef" href="#bib0550">10</a> diffuse-regressive alterations,<a class="elsevierStyleCrossRef" href="#bib0555">11</a> cardiac autoimmunity,<a class="elsevierStyleCrossRef" href="#bib0560">12</a> infectious endocarditis, coinfection with cardiotropic viruses,<a class="elsevierStyleCrossRef" href="#bib0535">7</a> the action of cytokines,<a class="elsevierStyleCrossRef" href="#bib0555">11</a> and the cardiotoxicity of certain drugs, including zidovudine.<a class="elsevierStyleCrossRef" href="#bib0565">13</a>Clinically, it is often asymptomatic or non-specific and the symptoms of HF may be masked by other conditions. Echocardiography is the method of choice to assess ventricular function.Cardiomyopathy is associated with increased mortality, with progressive left ventricular (LV) dysfunction leading to HF. The importance of ventricular dysfunction is demonstrated by the reduced survival of patients with cardiomyopathy who died of AIDS in the pre-HAART era compared to those with preserved cardiac function at a similar stage of infection (101 vs. 472 days).<a class="elsevierStyleCrossRef" href="#bib0570">14</a>Barbaro et al. studied the influence of development of encephalopathy on the clinical course of HIV-associated cardiomyopathy and observed that patients with encephalopathy were more likely to die from congestive HF.<a class="elsevierStyleCrossRef" href="#bib0575">15</a> The virus may persist in reservoir cells in the myocardium and cerebral cortex even after ART, and these cells may chronically release cytotoxic cytokines, contributing to progressive tissue damage in both systems. Antagonists of cytokines or inducible nitric oxide synthase (iNOS) or apoptosis inhibitors can reduce cell damage caused by chronic release of cytotoxic cytokines and by activation of iNOS by these reservoir cells.<a class="elsevierStyleCrossRef" href="#bib0575">15</a> However, further studies are needed to assess their therapeutic potential.In general, standard HF treatment regimens are recommended for HIV-positive individuals with dilated cardiomyopathy and HF.<a class="elsevierStyleCrossRef" href="#bib0525">5</a> Angiotensin-converting enzyme inhibitors may be poorly tolerated because of low systemic vascular resistance from diarrheal disease, infection or dehydration.<a class="elsevierStyleCrossRef" href="#bib0525">5</a> Digoxin may be added for the treatment of patients with persistent symptoms or atrial fibrillation with rapid ventricular response.<a class="elsevierStyleCrossRef" href="#bib0525">5</a> When the patient is euvolemic, a beta-blocker may be started because of its beneficial effects on circulating levels of cytokines.<a class="elsevierStyleCrossRef" href="#bib0580">16</a> There is little evidence that HAART is beneficial in this respect, although it may reduce the incidence of cardiac disease by preventing opportunistic infections.Diastolic dysfunctionHigh prevalences of left ventricular diastolic dysfunction (LVDD) have been reported in HIV-positive individuals (36%<a class="elsevierStyleCrossRef" href="#bib0590">18</a>–55.7%<a class="elsevierStyleCrossRef" href="#bib0515">3</a>),<a class="elsevierStyleCrossRefs" href="#bib0515">3,17–19</a> although some studies contradict this.<a class="elsevierStyleCrossRef" href="#bib0600">20</a>Subclinical cardiac abnormalities have been detected at early stages of HIV infection, independently of ART, suggesting that HIV itself may play a part in the genesis of diastolic dysfunction.<a class="elsevierStyleCrossRef" href="#bib0590">18</a> Traditional risk factors are strongly associated with impaired diastolic relaxation.<a class="elsevierStyleCrossRef" href="#bib0585">17</a>LVDD frequently appears in patients with few or no symptoms or in those whose symptoms are related to other conditions. Echocardiography provides a reliable non-invasive assessment of LV systolic and diastolic function and can detect subclinical myocardial involvement in HIV-positive individuals.<a class="elsevierStyleCrossRef" href="#bib0515">3</a> However, in the absence of symptoms, it may be premature to recommend routine screening echocardiograms.<a class="elsevierStyleCrossRef" href="#bib0595">19</a>It is unclear whether HIV-infected patients require any specific therapeutic interventions to manage or prevent cardiac dysfunction. Reduction of HIV-related inflammation with ART would appear to be a reasonable approach, although the benefit of treatment on cardiac function remains unproven.<a class="elsevierStyleCrossRef" href="#bib0595">19</a>Infectious endocarditisStudies in the pre-HAART era reported increased risk of infectious endocarditis (IE) in HIV-positive individuals, but in one study its incidence decreased from 20.5 to 6.6 per 1000 person-years between the pre- and post-HAART eras.<a class="elsevierStyleCrossRef" href="#bib0605">21</a>The risk factors most strongly associated with IE were intravenous drug use<a class="elsevierStyleCrossRefs" href="#bib0605">21,22</a> and severe immunodepression.<a class="elsevierStyleCrossRef" href="#bib0605">21</a> In some studies Staphylococcus aureus was the most common agent in HIV-positive individuals,<a class="elsevierStyleCrossRefs" href="#bib0605">21–23</a> most often involving the tricuspid valve.<a class="elsevierStyleCrossRef" href="#bib0615">23</a> In HIV-positive individuals with methicillin-resistant S. aureus (MRSA) bacteremia, community-associated MRSA was significantly associated with increased IE prevalence.<a class="elsevierStyleCrossRef" href="#bib0620">24</a>Patients may present fever, weight loss, and concomitant pneumonia and/or meningitis. Transthoracic echocardiography (TTE), complemented by transesophageal echocardiography, is essential to confirm the diagnosis and to guide treatment.Left heart involvement and severe immunodepression (CD4 <200/mm3) are associated with greater mortality.<a class="elsevierStyleCrossRefs" href="#bib0610">22,23</a> Gebo et al. reported higher recurrence and mortality rates within one year of IE infection and recommended more aggressive follow-up, especially in those over 40 years of age.<a class="elsevierStyleCrossRef" href="#bib0605">21</a>Antibiotic therapy is often effective, but surgery is indicated in selected patients.Pericardial effusionPericardial effusion (PE) is relatively common in this population. Cardiac tamponade is rare.<a class="elsevierStyleCrossRef" href="#bib0625">25</a> In the pre-HAART era, an annual incidence of 11% was reported in AIDS patients.<a class="elsevierStyleCrossRef" href="#bib0625">25</a> In the HAART era, an incidence of 0.25% has been reported in HIV-positive individuals.<a class="elsevierStyleCrossRef" href="#bib0630">26</a>Possible etiologies of PE in these patients include opportunistic infections,<a class="elsevierStyleCrossRef" href="#bib0635">27</a> malignancies such as Kaposi sarcoma (KS) and non-Hodgkin lymphoma (NHL),<a class="elsevierStyleCrossRef" href="#bib0625">25</a> tuberculosis, hypoalbuminemia,<a class="elsevierStyleCrossRef" href="#bib0625">25</a> idiopathic, and end-stage HIV capillary leak syndrome.<a class="elsevierStyleCrossRef" href="#bib0625">25</a>Previous studies of PE in this population reported that pericardial involvement was often an echocardiographic finding that was not clinically suspected, and that since most PEs were small<a class="elsevierStyleCrossRefs" href="#bib0540">8,25</a> and rarely progressive<a class="elsevierStyleCrossRef" href="#bib0625">25</a> an exhaustive search for a pericardial diagnosis is usually not indicated.<a class="elsevierStyleCrossRef" href="#bib0625">25</a> Large symptomatic pericardial effusions do occur, however, and may need aggressive evaluation and therapy.<a class="elsevierStyleCrossRef" href="#bib0625">25</a> Dyspnea, exercise intolerance or edema should prompt investigation by TTE.<a class="elsevierStyleCrossRef" href="#bib0630">26</a>PE may be a marker of end-stage HIV infection,<a class="elsevierStyleCrossRef" href="#bib0625">25</a> but it is rarely the cause of death,<a class="elsevierStyleCrossRef" href="#bib0635">27</a> although it has been associated with shorter survival.<a class="elsevierStyleCrossRefs" href="#bib0540">8,25</a>Pulmonary hypertensionHIV-related pulmonary arterial hypertension (PAH) has similar clinical, laboratory, imaging and pathological manifestations to those of idiopathic PAH.<a class="elsevierStyleCrossRef" href="#bib0640">28</a>An incidence of 0.5% in HIV-positive individuals was reported in the pre-HAART era,<a class="elsevierStyleCrossRef" href="#bib0645">29</a> while a prospective study in the HAART era reported a prevalence of 0.46%.<a class="elsevierStyleCrossRef" href="#bib0650">30</a> PAH may develop at any stage of HIV infection and all risk groups may be affected.<a class="elsevierStyleCrossRef" href="#bib0655">31</a>The mean age of HIV-positive individuals diagnosed with PAH as reported in a systematic review<a class="elsevierStyleCrossRef" href="#bib0640">28</a> was 35±9.6 years and 59% were male; the main risk factors for contracting HIV infection were injection drug use (49%) and male-to-male sexual activity (21%), and mean CD4 count at the time of diagnosis of PAH was 352±304 cells/μl. AIDS had been diagnosed in 53%, hepatitis B in 12%, and hepatitis C in 14%. The mean time from diagnosis of HIV infection to diagnosis of PAH was 4.3±4.0 years.The underlying vasculopathy is severe angioproliferative disease. Pulmonary veno-occlusive disease is relatively rare<a class="elsevierStyleCrossRefs" href="#bib0645">29,31,32</a>; pulmonary vascular dysfunction probably results from risk factors such as viral infections, autoimmunity, drugs or toxins, possibly triggering an underlying genetic susceptibility.<a class="elsevierStyleCrossRef" href="#bib0660">32</a> Inflammation appears to play a more active role in the pathogenesis of HIV-related PAH than in idiopathic PAH.<a class="elsevierStyleCrossRef" href="#bib0660">32</a>Diagnosis requires confirmation of pulmonary hypertension and of HIV infection and exclusion of other causes of pulmonary hypertension.<a class="elsevierStyleCrossRef" href="#bib0665">33</a> It should be suspected in cases of unexplained dyspnea.<a class="elsevierStyleCrossRefs" href="#bib0650">30,31</a> Symptoms at the time of diagnosis as reported by Janda et al. included dyspnea (93%), pedal edema (18%), syncope (13%), fatigue (11%), cough (8%) and chest pain (6%).<a class="elsevierStyleCrossRef" href="#bib0640">28</a> Echocardiography should be performed in patients with unexplained dyspnea to investigate possible HIV-related cardiovascular complications.<a class="elsevierStyleCrossRef" href="#bib0670">34</a> Right heart catheterization is the gold standard to diagnose PAH and to assess hemodynamic status and response to treatment.<a class="elsevierStyleCrossRef" href="#bib0675">35</a>Development of PAH is associated with worse prognosis, particularly in NYHA functional class III–IV, with 28% survival at three years.<a class="elsevierStyleCrossRef" href="#bib0680">36</a> Patients with HIV-related PAH frequently die from conditions associated with PAH.<a class="elsevierStyleCrossRefs" href="#bib0640">28,35,36</a> The most common complication is right-sided HF.<a class="elsevierStyleCrossRef" href="#bib0640">28</a>Since there is no curative treatment, the aim is to improve patients’ functional class. Conventional treatment is directed at controlling its consequences and is similar to that for all forms of pulmonary hypertension.<a class="elsevierStyleCrossRef" href="#bib0665">33</a> In cases of decompensated right heart failure, fluid restriction and diuretics should be used with caution to avoid excessive reduction of intravascular volume. Inotropic agents are used when necessary and home oxygen therapy can be prescribed in patients with chronic hypoxemia.<a class="elsevierStyleCrossRef" href="#bib0665">33</a> Anticoagulation is not routinely recommended because of an increased risk of bleeding, treatment compliance issues, and drug interactions,<a class="elsevierStyleCrossRef" href="#bib0670">34</a> and these individuals should not receive calcium channel blockers (CCBs).<a class="elsevierStyleCrossRef" href="#bib0670">34</a>There have been few studies on PAH treatment in this population and there is a need for controlled randomized trials with large population samples. Administration of sildenafil is the subject of debate, since it interacts with protease inhibitors (PIs); according to Galie et al., if sildenafil is used, the dose should be adjusted if ritonavir and saquinovir are co-administered.<a class="elsevierStyleCrossRef" href="#bib0670">34</a>There are conflicting data on the efficacy of HAART in the treatment of PAH.<a class="elsevierStyleCrossRefs" href="#bib0685">37–39</a>HIV infection is generally considered an exclusion criterion for lung transplantation, although in some centers a specific program has been implemented.<a class="elsevierStyleCrossRef" href="#bib0670">34</a>Autonomic dysfunctionCardiovascular autonomic tone has been shown to be involved in advanced HIV disease. Spectral analysis of heart rate variability showed severe global autonomic dysfunction in AIDS patients without clinical or echocardiographic evidence of cardiac disease, and this has been suggested as a possible mechanism of arrhythmogenesis.<a class="elsevierStyleCrossRef" href="#bib0700">40</a> HIV-positive individuals under ART for more than 44 months present increased resting heart rate and reduced short-term heart rate variability, indicative of parasympathetic dysfunction.<a class="elsevierStyleCrossRef" href="#bib0705">41</a> However, a recent prospective study suggests that ART may not contribute to short-term alterations in autonomic function in healthy individuals early in the course of the disease.<a class="elsevierStyleCrossRef" href="#bib0710">42</a>Cardiac malignanciesThe introduction of HAART has led to significant reductions in the incidence of KS and NHL,<a class="elsevierStyleCrossRef" href="#bib0715">43</a> both of which can affect the heart.In the pre-HAART era, individuals with AIDS were at increased risk of KS.<a class="elsevierStyleCrossRef" href="#bib0720">44</a> Cardiac involvement usually occurs as a part of disseminated KS.<a class="elsevierStyleCrossRef" href="#bib0635">27</a> Clinical cardiac findings are obscure and pericardiocentesis not only has no diagnostic role but is also a high-risk procedure in this group of patients.<a class="elsevierStyleCrossRef" href="#bib0635">27</a> When there is a high index of suspicion of PE due to KS, a pericardial window should be performed for providing decompression and establishing the pathologic diagnosis.<a class="elsevierStyleCrossRef" href="#bib0635">27</a>An increased incidence of NHL in AIDS patients was also reported in the pre-HAART era.<a class="elsevierStyleCrossRef" href="#bib0720">44</a> Cardiac involvement, usually derived from B cells, is typically high grade and is often disseminated early in patients with AIDS.<a class="elsevierStyleCrossRefs" href="#bib0635">27,45</a> It is usually clinically silent, but may present with HF, arrhythmias and/or PE,<a class="elsevierStyleCrossRefs" href="#bib0730">46,47</a> and cardiac tamponade.<a class="elsevierStyleCrossRef" href="#bib0725">45</a> Echocardiography may reveal an intracardiac mass or nodular lesions within the three layers of the heart wall, but in infiltrative forms of cardiac NHL, it may underestimate the extent of myocardial involvement.<a class="elsevierStyleCrossRef" href="#bib0725">45</a> Magnetic resonance imaging is useful for assessing the characteristics and potential complications of the malignancy.<a class="elsevierStyleCrossRef" href="#bib0735">47</a>In HIV patients, the occurrence of NHL does not correlate closely with an advanced stage of immunosuppression.<a class="elsevierStyleCrossRef" href="#bib0725">45</a> Although prognosis is poor, systemic chemotherapy may prolong survival.<a class="elsevierStyleCrossRef" href="#bib0725">45</a>VasculopathiesVirtually all types of vasculitides of small, medium and large vessels have been observed in this population.<a class="elsevierStyleCrossRef" href="#bib0740">48</a> They may result from abnormalities induced by HIV and/or other agents. Various inflammatory vascular diseases may develop, including polyarteritis nodosa-like vasculitis,<a class="elsevierStyleCrossRef" href="#bib0740">48</a> Henoch-Schönlein purpura, drug-induced hypersensitivity vasculitis, Kawasaki-like syndromes<a class="elsevierStyleCrossRef" href="#bib0745">49</a> and Takayasu arteritis.<a class="elsevierStyleCrossRef" href="#bib0750">50</a>HIV-related aneurysms have been identified as a distinct entity, characterized by their predilection for young patients, multiplicity, atypical location and distinct histological features. Most patients were asymptomatic and 68% presented advanced HIV disease.<a class="elsevierStyleCrossRef" href="#bib0755">51</a> The pathogenesis of these aneurysms remains unclear.<a class="elsevierStyleCrossRef" href="#bib0755">51</a>A type of occlusive arterial disease apparently unique to HIV-positive individuals has been reported. It is more common in young patients, generally those with advanced disease and significant immunodepression.<a class="elsevierStyleCrossRef" href="#bib0760">52</a> They frequently present with advanced tissue necrosis that precludes limb salvage.<a class="elsevierStyleCrossRef" href="#bib0760">52</a>Human immunodeficiency virus and coronary diseaseElectrocardiographic evidence of asymptomatic IHD has been reported in 10.9% of HIV-infected adults without known IHD, irrespective of type and duration of ART.<a class="elsevierStyleCrossRef" href="#bib0765">53</a>Alterations in lipid metabolism have been described in HIV-positive individuals.<a class="elsevierStyleCrossRefs" href="#bib0770">54,55</a>The role of HIV as a risk factor for accelerated atherosclerosis is controversial.<a class="elsevierStyleCrossRefs" href="#bib0780">56–59</a> The virus has effects on the endothelium and platelets (<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>).<a class="elsevierStyleCrossRef" href="#bib0800">60</a> Endothelial dysfunction occurs early in the process of atherogenesis and contributes to the formation, progression and complications of atherosclerotic plaques.<a class="elsevierStyleCrossRef" href="#bib0800">60</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>Atherosclerotic alterations of the arterial wall lead to increased arterial stiffness, which has been reported in untreated HIV-positive individuals in some studies<a class="elsevierStyleCrossRefs" href="#bib0790">58,61</a> but not in others.<a class="elsevierStyleCrossRef" href="#bib0810">62</a>Chronic HIV infection leads to immune activation and chronic inflammation, only partially corrected by HAART.<a class="elsevierStyleCrossRef" href="#bib0800">60</a> Immunodepression can have adverse effects on the vasculature.<a class="elsevierStyleCrossRef" href="#bib0795">59</a>Corrected QT interval prolongationAn increased prevalence of corrected QT interval (QTc) prolongation in HIV-positive individuals has been reported.<a class="elsevierStyleCrossRefs" href="#bib0815">63–66</a> This may be associated with drugs used to treat other conditions, electrolyte disturbances, longer duration of HIV infection,<a class="elsevierStyleCrossRefs" href="#bib0820">64,65</a> cardiomyopathy, autonomic dysfunction or myocardial ischemia.<a class="elsevierStyleCrossRef" href="#bib0820">64</a> Shavadia et al. reported a significantly increased risk for QTc prolongation in HIV-positive individuals under ART compared to untreated individuals,<a class="elsevierStyleCrossRef" href="#bib0815">63</a> but other studies found no significant association.<a class="elsevierStyleCrossRefs" href="#bib0825">65,66</a> According to Reinsch et al., factors such as gender, diabetes and hypertension may also be involved in the development of QTc prolongation.<a class="elsevierStyleCrossRef" href="#bib0830">66</a>The use of noncardiac QTc-prolonging drugs has been associated with increased risk for sudden cardiac death in the general population.<a class="elsevierStyleCrossRef" href="#bib0835">67</a> It is important to monitor QTc interval in patients under ART, particular when ART is combined with drugs that can prolong QTc.Effects of human immunodeficiency virus infection on the cardiovascular system in the highly active antiretroviral therapy eraHighly active antiretroviral therapyThe initial combination regimens recommended by the European AIDS Clinical Society (EACS)<a class="elsevierStyleCrossRef" href="#bib0840">68</a> are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>.<elsevierMultimedia ident="tbl0005"></elsevierMultimedia>The 2014 Recommendations of the International Antiviral Society–USA Panel propose that ART should be initiated in all individuals who are willing and ready to start treatment after confirmed diagnosis of HIV infection.<a class="elsevierStyleCrossRef" href="#bib0845">69</a> ART is recommended for the treatment of HIV infection and the prevention of transmission of HIV regardless of CD4 cell count (strength of recommendation AIa-BIII).<a class="elsevierStyleCrossRef" href="#bib0845">69</a> These measures will subject HIV-positive individuals to earlier exposure to HAART and its adverse effects. The recommendations of the 2014 EACS guidelines for initiation of ART in HIV-positive persons without prior ART exposure are graded taking into account both the degree of progression of HIV disease and the presence of, or high risk for developing, various types of (comorbid) conditions.<a class="elsevierStyleCrossRef" href="#bib0840">68</a> ART is always recommended in any HIV-positive person with a current CD4 count <350 cells/μl.<a class="elsevierStyleCrossRef" href="#bib0840">68</a> For persons with CD4 counts above this level, the decision to start ART should be considered on an individual basis.<a class="elsevierStyleCrossRef" href="#bib0840">68</a>Effects of highly active antiretroviral therapyVarious cardiovascular risk factors can be induced or strengthened by HAART. Traditional risk factors have been significantly associated with increased risk for MI in HIV-positive individuals.<a class="elsevierStyleCrossRefs" href="#bib0850">70,71</a>The incidence of diabetes in HIV-positive men under HAART has been reported as over four times higher than in HIV-negative individuals.<a class="elsevierStyleCrossRef" href="#bib0860">72</a> Traditional risk factors (age, male gender, obesity, low HDL cholesterol and high total cholesterol) play an important role in the increased risk of diabetes in this population,<a class="elsevierStyleCrossRefs" href="#bib0865">73–75</a> while lipodystrophy<a class="elsevierStyleCrossRefs" href="#bib0865">73,76</a> and immunodepression<a class="elsevierStyleCrossRef" href="#bib0880">76</a> have also been associated with increased incidence of diabetes in HIV-positive individuals. The impact of coinfection with hepatitis C virus is the subject of debate.<a class="elsevierStyleCrossRefs" href="#bib0870">74–76</a> ART is not unanimously recognized as a risk factor for diabetes, but several studies have reported increased prevalence of diabetes with certain antiretrovirals<a class="elsevierStyleCrossRefs" href="#bib0865">73,74,77</a> and with longer exposure to ART.<a class="elsevierStyleCrossRefs" href="#bib0865">73,78</a> The drugs most often associated with diabetes are PIs<a class="elsevierStyleCrossRefs" href="#bib0870">74,77</a> and some nucleoside reverse-transcriptase inhibitors (NRTIs).<a class="elsevierStyleCrossRefs" href="#bib0865">73,74,77</a>Certain PIs have been associated with a dyslipidemic profile.<a class="elsevierStyleCrossRefs" href="#bib0775">55,79,80</a> Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) generally result in a more favorable lipid profile than PIs.<a class="elsevierStyleCrossRef" href="#bib0900">80</a> However, studies have shown a significant risk of dyslipidemia induced by efavirenz.<a class="elsevierStyleCrossRefs" href="#bib0770">54,81</a> Of the NRTIs, tenofovir appears to be associated with less unfavorable lipid profiles.<a class="elsevierStyleCrossRefs" href="#bib0910">82,83</a> It has been suggested that integrase strand transfer inhibitor-based regimens may be a good option for patients with pre-existing dyslipidemia.<a class="elsevierStyleCrossRef" href="#bib0845">69</a>HIV-related lipodystrophy, mainly considered an adverse effect of HAART, has a reported mean prevalence of 42% in HIV-positive individuals treated with PI-containing HAART.<a class="elsevierStyleCrossRef" href="#bib0920">84</a> The term ‘lipodystrophy syndrome’ is used by some authors to include morphological and metabolic phenomena, but it is not clear that they result from the same mechanism. Not all patients present all the characteristics of the syndrome; dyslipidemia has been reported in 70% and diabetes in 8–10% of these patients.<a class="elsevierStyleCrossRef" href="#bib0925">85</a>HypertensionSome studies suggest that the prevalence of hypertension is increased in HIV-positive individuals under ART,<a class="elsevierStyleCrossRefs" href="#bib0930">86,87</a> but this is not confirmed by others.<a class="elsevierStyleCrossRef" href="#bib0940">88</a>The role of HIV and ART in the pathogenesis of hypertension is not clear. Possible mechanisms are presented in <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>. A prospective study in HIV-infected patients starting HAART found an increase in blood pressure (BP) after 48 weeks.<a class="elsevierStyleCrossRef" href="#bib0930">86</a> In HIV-positive individuals starting their first HAART regimen, treatment with lopinavir/ritonavir was associated with increased BP,<a class="elsevierStyleCrossRef" href="#bib0945">89</a> while patients taking atazanavir, efavirenz, nelfinavir or indinavir were less likely to develop high BP.<a class="elsevierStyleCrossRef" href="#bib0945">89</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Highly active antiretroviral therapy and cardiovascular diseaseMendes et al. detected abnormalities in myocardial deformation through assessment of strain and strain rate in a population of relatively healthy HIV-infected patients without established CVD or risk factors.<a class="elsevierStyleCrossRef" href="#bib0600">20</a>It has been demonstrated that HIV infection and HAART are independent risk factors for early carotid atherosclerosis,<a class="elsevierStyleCrossRef" href="#bib0780">56</a> but Kaplan et al. reported that ART was not consistently associated with atherosclerosis<a class="elsevierStyleCrossRef" href="#bib0795">59</a> and there is conflicting evidence on the effects of ART on arterial stiffness.<a class="elsevierStyleCrossRefs" href="#bib0805">61,62</a>HIV-positive patients, especially those under ART, are at increased risk of CVD, particularly MI and coronary disease, compared to HIV-negative individuals.<a class="elsevierStyleCrossRefs" href="#bib0785">57,70,90,91</a> Several studies have shown a higher frequency of vascular events in HIV-infected adults under ART compared to untreated individuals,<a class="elsevierStyleCrossRefs" href="#bib0950">90,92,93</a> although other studies disagree.<a class="elsevierStyleCrossRef" href="#bib0970">94</a> It has been suggested that immune reconstitution may be partly responsible for the increased risk of IHD.<a class="elsevierStyleCrossRef" href="#bib0950">90</a>Nevertheless, the benefits of ART continue to outweigh the increased cardiovascular risk associated with this treatment, and concerns about coronary risk should not prevent HIV-positive individuals from receiving ART.Several studies have shown an increased frequency of MI with longer exposure to certain antiretrovirals.<a class="elsevierStyleCrossRefs" href="#bib0850">70,71,95</a> However, Obel et al. did not observe any increase up to eight years after treatment initiation.<a class="elsevierStyleCrossRef" href="#bib0950">90</a> In a shorter study, ART was independently associated with a 26% increase in the rate of MI per year of exposure in the first 4–6 years of treatment.<a class="elsevierStyleCrossRef" href="#bib0850">70</a> Another study showed higher relative risk of MI for every year of exposure to PIs, but no significant association was seen with NNRTIs.<a class="elsevierStyleCrossRef" href="#bib0855">71</a> Treatment with indinavir, lopinavir/ritonavir, didanosine and abacavir was associated with an increased risk of MI,<a class="elsevierStyleCrossRef" href="#bib0975">95</a> but other authors found no association between exposure to abacavir and increased risk of MI.<a class="elsevierStyleCrossRef" href="#bib0980">96</a> Consideration should be given to avoiding use of abacavir, ritonavir/lopinavir, and ritonavir/fosamprenavir in persons at high risk for CVD because these regimens have been associated with increased risk of cardiovascular events in some studies.<a class="elsevierStyleCrossRef" href="#bib0845">69</a>Assessment of cardiovascular riskCardiovascular risk should be assessed and monitored in order to identify those at high risk and to implement preventive measures (<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>HIV-positive individuals have various risk factors for CVD, both traditional factors and those related to their HIV status, including the infection itself, duration of infection, viral load, therapy, and altered immune response.The Framingham risk score may underestimate risk in this population.<a class="elsevierStyleCrossRef" href="#bib0790">58</a> Two other risk scores have recently been developed: a risk equation developed from a population of HIV-infected patients, incorporating routinely collected cardiovascular risk parameters and exposure to antiretrovirals<a class="elsevierStyleCrossRef" href="#bib0985">97</a>; and a model to predict the short-term risk of new-onset diabetes in HIV-positive populations during follow-up.<a class="elsevierStyleCrossRef" href="#bib0880">76</a>RecommendationsBehavioral and therapeutic interventions to reduce cardiovascular risk are recommended in HIV-positive individuals under ART. They should be advised regarding diet, weight loss, smoking cessation and exercise. An independent association has been reported between high salt consumption and increased arterial stiffness.<a class="elsevierStyleCrossRef" href="#bib0990">98</a>Lima et al. analyzed the effect of a prevention program (non-pharmacological and, when appropriate, pharmacological therapy) on cardiovascular risk in HIV-positive patients.<a class="elsevierStyleCrossRef" href="#bib0995">99</a> After a six-month follow-up, significant changes were seen in triglycerides and total and LDL cholesterol and a significant reduction in the number of individuals at high cardiovascular risk.<a class="elsevierStyleCrossRef" href="#bib0995">99</a>The EACS has published recommendations on the treatment of dyslipidemia, diabetes and hypertension in HIV-positive individuals.<a class="elsevierStyleCrossRef" href="#bib0840">68</a>If lifestyle modification and change of ART are not effective, lipid-lowering medication should be considered.<a class="elsevierStyleCrossRef" href="#bib0840">68</a> Of the drugs used to lower LDL cholesterol, statins are the first-line treatment, and should be prescribed in patients with established vascular disease and in those with type 2 diabetes or at high risk of CVD, irrespective of lipid levels.<a class="elsevierStyleCrossRef" href="#bib0840">68</a> However, interactions between statins and antiretrovirals are common; PIs can interact with statin metabolism via cytochrome CYP3A4, increasing overall exposure to statins. Simvastatin is contraindicated with concurrent PI use.<a class="elsevierStyleCrossRef" href="#bib0770">54</a> In a small pilot study, rosuvastatin for 24 weeks was effective against hyperlipidemia in patients taking PIs, with a favorable tolerability profile.<a class="elsevierStyleCrossRef" href="#bib1000">100</a>The goals and characteristics of treatment of type 2 diabetes recommended by the EACS<a class="elsevierStyleCrossRef" href="#bib0840">68</a> are shown in <a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>.<elsevierMultimedia ident="fig0020"></elsevierMultimedia>The aim of treatment for hypertension is to achieve BP <140/90 mmHg. The EACS recommendations for drug treatment of hypertension<a class="elsevierStyleCrossRef" href="#bib0840">68</a> are presented in <a class="elsevierStyleCrossRef" href="#fig0025">Figure 5</a>. CCBs should be used with caution, since they may interact with PIs. Comorbidities should be borne in mind when selecting drug therapy.<elsevierMultimedia ident="fig0025"></elsevierMultimedia>Conflicts of interestThe authors have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:10 [ 0 => array:3 [ "identificador" => "xres538928" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec558597" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres538929" "titulo" => "Resumo" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec558598" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Cardiovascular manifestations of human immunodeficiency virus infection" "secciones" => array:10 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Cardiomyopathy" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Diastolic dysfunction" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Infectious endocarditis" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Pericardial effusion" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Pulmonary hypertension" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Autonomic dysfunction" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Cardiac malignancies" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Vasculopathies" ] 8 => array:2 [ "identificador" => "sec0055" "titulo" => "Human immunodeficiency virus and coronary disease" ] 9 => array:2 [ "identificador" => "sec0060" "titulo" => "Corrected QT interval prolongation" ] ] ] 6 => array:3 [ "identificador" => "sec0065" "titulo" => "Effects of human immunodeficiency virus infection on the cardiovascular system in the highly active antiretroviral therapy era" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0070" "titulo" => "Highly active antiretroviral therapy" ] 1 => array:2 [ "identificador" => "sec0075" "titulo" => "Effects of highly active antiretroviral therapy" ] 2 => array:2 [ "identificador" => "sec0080" "titulo" => "Hypertension" ] ] ] 7 => array:3 [ "identificador" => "sec0085" "titulo" => "Highly active antiretroviral therapy and cardiovascular disease" "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0090" "titulo" => "Assessment of cardiovascular risk" ] 1 => array:2 [ "identificador" => "sec0095" "titulo" => "Recommendations" ] ] ] 8 => array:2 [ "identificador" => "sec0100" "titulo" => "Conflicts of interest" ] 9 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2014-06-11" "fechaAceptado" => "2015-03-08" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec558597" "palabras" => array:6 [ 0 => "Cardiovascular disease" 1 => "Antiretroviral therapy" 2 => "Pulmonary hypertension" 3 => "Lipodystrophy" 4 => "Vasculopathy" 5 => "Human immunodeficiency virus" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec558598" "palabras" => array:6 [ 0 => "Doença cardiovascular" 1 => "Terapêutica antirretroviral" 2 => "Hipertensão Pulmonar" 3 => "Lipodistrofia" 4 => "Vasculopatia" 5 => "Vírus da imunodeficiência humana" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "The cardiovascular manifestations of human immunodeficiency virus (HIV) infection have changed significantly following the introduction of highly active antiretroviral therapy (HAART) regimens. On one hand, HAART has altered the course of HIV disease, with longer survival of HIV-infected patients, and cardiovascular complications of HIV infection such as myocarditis have been reduced. On the other hand, HAART is associated with an increase in the prevalence of both peripheral and coronary arterial disease. As longevity increases in HIV-infected individuals, long-term effects, such as cardiovascular disease, are emerging as leading health issues in this population. In the present review article, we discuss HIV-associated cardiovascular disease, focusing on epidemiology, etiopathogenesis, diagnosis, prognosis, management and therapy. Cardiovascular involvement in treatment-naive patients is still important in situations such as non-adherence to treatment, late initiation of treatment, and/or limited access to HAART in developing countries. We therefore describe the cardiovascular consequences in treatment-naive patients and the potential effect of antiretroviral treatment on their regression, as well as the metabolic and cardiovascular implications of HAART regimens in HIV-infected individuals." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "As manifestações cardiovasculares da infeção pelo vírus da imunodeficiência humana (VIH) modificaram-se significativamente com a introdução dos regimes de terapêutica antirretroviral de elevada potência (HAART). Por um lado, a HAART modificou o curso da doença VIH, com o prolongamento da sobrevivência dos doentes VIH-infetados. Complicações cardiovasculares da infeção VIH, como a miocardite, foram reduzidas. Por outro lado, a HAART tem sido associada ao aumento da prevalência de doenças arteriais periféricas e coronárias. Com o aumento da longevidade dos indivíduos VIH-infetados, efeitos a longo prazo, como a doença cardiovascular, estão a emergir como questões de saúde proeminentes nesta população. No presente artigo de revisão, discutiremos a patologia cardiovascular associada ao VIH, focando-nos na epidemiologia, etiopatogénese, diagnóstico, prognóstico, abordagem e terapêutica. A importância do envolvimento cardiovascular em doentes não tratados pelas novas terapêuticas é ainda uma realidade em situações como o não cumprimento da terapêutica, o início tardio da terapêutica ou o acesso limitado à HAART nos países em desenvolvimento. Assim, descreveremos as consequências cardiovasculares nos doentes não tratados e o potencial efeito da terapêutica antirretroviral na sua regressão, e as consequências metabólicas e implicações cardiovasculares dos regimes HAART nas pessoas infetadas pelo VIH." ] ] "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "Please cite this article as: Amado Costa L, Almeida AG. Patologia cardiovascular associada ao vírus da imunodeficiência humana. Rev Port Cardiol. 2015;34:479–491." ] ] "nomenclatura" => array:1 [ 0 => array:2 [ "identificador" => "nom0005" "listaDefinicion" => array:1 [ 0 => array:2 [ "titulo" => "List of abbreviations" "definicion" => array:26 [ 0 => array:2 [ "termino" => "AIDS" "descripcion" => "acquired immunodeficiency syndrome" ] 1 => array:2 [ "termino" => "ART" "descripcion" => "antiretroviral therapy" ] 2 => array:2 [ "termino" => "BP" "descripcion" => "blood pressure" ] 3 => array:2 [ "termino" => "CCB" "descripcion" => "calcium channel blocker" ] 4 => array:2 [ "termino" => "CVD" "descripcion" => "cardiovascular disease" ] 5 => array:2 [ "termino" => "EACS" "descripcion" => "European AIDS Clinical Society" ] 6 => array:2 [ "termino" => "HAART" "descripcion" => "highly active antiretroviral therapy" ] 7 => array:2 [ "termino" => "HIV" "descripcion" => "human immunodeficiency virus" ] 8 => array:2 [ "termino" => "HF" "descripcion" => "heart failure" ] 9 => array:2 [ "termino" => "HTN nephropathy" "descripcion" => "hypertensive nephropathy" ] 10 => array:2 [ "termino" => "IE" "descripcion" => "infectious endocarditis" ] 11 => array:2 [ "termino" => "IHD" "descripcion" => "ischemic heart disease" ] 12 => array:2 [ "termino" => "iNOS" "descripcion" => "inducible nitric oxide synthase" ] 13 => array:2 [ "termino" => "KS" "descripcion" => "Kaposi sarcoma" ] 14 => array:2 [ "termino" => "LV" "descripcion" => "left ventricular" ] 15 => array:2 [ "termino" => "LVDD" "descripcion" => "left ventricular diastolic dysfunction" ] 16 => array:2 [ "termino" => "MI" "descripcion" => "myocardial infarction" ] 17 => array:2 [ "termino" => "MRSA" "descripcion" => "methicillin-resistant Staphylococcus aureus" ] 18 => array:2 [ "termino" => "NHL" "descripcion" => "non-Hodgkin lymphoma" ] 19 => array:2 [ "termino" => "NNRTI" "descripcion" => "non-nucleoside reverse-transcriptase inhibitor" ] 20 => array:2 [ "termino" => "NRTI" "descripcion" => "nucleoside reverse-transcriptase inhibitor" ] 21 => array:2 [ "termino" => "PAH" "descripcion" => "pulmonary arterial hypertension" ] 22 => array:2 [ "termino" => "PE" "descripcion" => "pericardial effusion" ] 23 => array:2 [ "termino" => "PI" "descripcion" => "protease inhibitor" ] 24 => array:2 [ "termino" => "QTc" "descripcion" => "corrected QT" ] 25 => array:2 [ "termino" => "TTE" "descripcion" => "transthoracic echocardiography" ] ] ] ] ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 914 "Ancho" => 1507 "Tamanyo" => 214678 ] ] "descripcion" => array:1 [ "en" => "Schematic representation of the possible interactions between human immunodeficiency virus and the endothelium and platelets. Adapted from Gresele et al.<a class="elsevierStyleCrossRef" href="#bib0800">60</a> FMD: flow-mediated dilation; LIGHT: TNFSF14 (tumor necrosis factor superfamily member 14); NAP-2: neutrophil activating peptide 2; RANTES: regulated on activation normal T cell expressed and presumably secreted; sCD40L: soluble CD40 ligand; sP selectin: soluble P-selectin." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 838 "Ancho" => 1402 "Tamanyo" => 114752 ] ] "descripcion" => array:1 [ "en" => "Factors associated with hypertension, human immunodeficiency virus and cardiovascular disease. ART: antiretroviral therapy; CKD: chronic kidney disease; CVD: cardiovascular disease; HIV: human immunodeficiency virus; HTN: hypertension." ] ] 2 => array:7 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1444 "Ancho" => 1953 "Tamanyo" => 261280 ] ] "descripcion" => array:1 [ "en" => "Assessment of cardiovascular risk in HIV-positive individuals. Adapted from European AIDS Clinical Society Guidelines Version 7.1 – November 2014.<a class="elsevierStyleCrossRef" href="#bib0840">68</a> a The Framingham equation can be used. This assessment and the associated considerations outlined in this figure should be repeated annually in all persons under care. b Of the modifiable risk factors outlined, drug treatment is reserved for certain subgroups where benefits are considered to outweigh potential harm. c Target levels are to be used as guidance and are not definitive – expressed as mmol/l with mg/dl in parentheses. d Evidence for benefit when used in persons without a history of CVD (including diabetics) is less compelling. Blood pressure should be reasonably controlled before aspirin use in such a setting." ] ] 3 => array:7 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1120 "Ancho" => 1763 "Tamanyo" => 212303 ] ] "descripcion" => array:1 [ "en" => "Management of type 2 diabetes in HIV-positive individuals. Adapted from European AIDS Clinical Society Guidelines Version 7.1 – November 2014.<a class="elsevierStyleCrossRef" href="#bib0840">68</a> a Very limited data for any oral antidiabetic agents in terms of CVD prevention, and no data in HIV-positive persons." ] ] 4 => array:7 [ "identificador" => "fig0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1048 "Ancho" => 1511 "Tamanyo" => 187319 ] ] "descripcion" => array:1 [ "en" => "Choosing drugs for HIV-infected persons newly diagnosed with hypertension. Adapted from European AIDS Clinical Society Guidelines Version 7.1 – November 2014.<a class="elsevierStyleCrossRef" href="#bib0840">68</a> ACEi: angiotensin-converting enzyme inhibitor (e.g. perindopril, lisinopril or ramipril); ARB: low-cost angiotensin receptor blocker (e.g. losartan, candesartan); CCB: calcium-channel blocker (e.g. amlodipine). Thiazide-type diuretic includes e.g. indapamide or chlorthalidone but excludes thiazides (e.g. hydrochlorothiazide, bendroflumethiazide, etc.)" ] ] 5 => array:7 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "tabla" => array:2 [ "leyenda" => "A drug from column A should be combined with the drugs listed in column B./r: ritonavir used as booster; 3TC: lamivudine; ABC: abacavir; ATV: atazanavir; COBI: cobicistat; DRV: darunavir; DTG: dolutegravir; EFV: efavirenz; EVG: elvitegravir; FTC: emtricitabine; INSTI: integrase strand transfer inhibitor; NNRTI: non-nucleoside reverse transcriptase inhibitors; NRTI: nucleoside reverse transcriptase inhibitors; PI: protease inhibitors; RAL: raltegravir; RPV: rilpivirine; TDF: tenofovir.Adapted from the European AIDS Clinical Society Guidelines<a class="elsevierStyleCrossRef" href="#bib0840">68</a>." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">A \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">B \t\t\t\t\t\t\n \t\t\t\t</th><th class="td" title="table-head " align="left" valign="top" scope="col" style="border-bottom: 2px solid black">Remarks \t\t\t\t\t\t\n \t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">NNRTI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">NRTI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="" valign="top"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">EFVRPV \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ABC/3TC or TDF/FTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ABC/3TC co-formulatedTDF/FTC co-formulatedEFV/TDF/FTC co-formulatedRPV/TDF/FTC co-formulated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">PI/r</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">ATV/rDRV/r \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ABC/3TC or TDF/FTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ATV/r: 300/100 mg qdDRV/r: 800/100 mg qd \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top">INSTI</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">EVG+COBI \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TDF/FTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">TDF/FTC/EVG/COBIco-formulated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">DTG \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ABC/3TC or TDF/FTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">DTG 50 mg qdTDF/FTC co-formulatedABC/3TC/DTG co-formulated \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="table-entry " colspan="3" align="left" valign="top"></td></tr><tr title="table-row"><td class="td" title="table-entry " align="left" valign="top">RAL \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">ABC/3TC or TDF/FTC \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="table-entry " align="left" valign="top">RAL: 400 mg bd \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab866177.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Initial combination regimens recommended by the European AIDS Clinical Society." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:100 [ 0 => array:3 [ "identificador" => "bib0505" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "UNAIDS. 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Cardiovascular disease associated with human immunodeficiency virus: A review

Patologia cardiovascular associada ao vírus da imunodeficiência humana

Luísa Amado Costa

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analuisamado@hotmail.com

Corresponding author.

, Ana G. Almeida

University Clinic of Cardiology, Faculty of Medicine of Lisbon University, Hospital Santa Maria, CHLN, Lisbon, Portugal

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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Assessment of cardiovascular risk in HIV-positive individuals&#46; Adapted from European AIDS Clinical Society Guidelines Version 7&#46;1 &#8211; November 2014&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a></p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span> The Framingham equation can be used&#46; This assessment and the associated considerations outlined in this figure should be repeated annually in all persons under care&#46;</p> <p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">b</span> Of the modifiable risk factors outlined&#44; drug treatment is reserved for certain subgroups where benefits are considered to outweigh potential harm&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">c</span> Target levels are to be used as guidance and are not definitive &#8211; expressed as mmol&#47;l with mg&#47;dl in parentheses&#46;</p> <p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">d</span> Evidence for benefit when used in persons without a history of CVD &#40;including diabetics&#41; is less compelling&#46; Blood pressure should be reasonably controlled before aspirin use in such a setting&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0130" class="elsevierStylePara elsevierViewall">Human immunodeficiency virus &#40;HIV&#41; is a retrovirus with tropism for cells expressing CD4&#46; In 2012 the number of HIV-positive individuals was estimated at 35&#46;3 million&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">1</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">The introduction of highly active antiretroviral therapy &#40;HAART&#41; has prolonged the survival of HIV-positive individuals&#44; turning acquired immunodeficiency syndrome &#40;AIDS&#41; into a chronic disease&#46;</p><p id="par0140" class="elsevierStylePara elsevierViewall">A retrospective analysis of causes of death in 13 cohort studies of HIV type 1 &#40;HIV-1&#41;-infected patients who initiated antiretroviral therapy &#40;ART&#41; in Europe and North America from 1996 through 2006 showed lower mortality from AIDS-related causes and higher mortality from causes associated with aging&#44; such as non-AIDS malignancies and cardiovascular disease &#40;CVD&#41;&#46; The latter accounted for 7&#46;9&#37; of deaths&#44; of which 40&#37; were from myocardial infarction &#40;MI&#41;&#47;ischemic heart disease &#40;IHD&#41;&#44; which suggests that the process of aging will become a dominant factor in HIV-1 mortality in the next decade&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">2</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The cardiovascular manifestations of HIV infection have changed following the introduction of HAART&#46; Cardiovascular involvement in treatment-naive patients is still important in individuals who do not adhere to treatment or start treatment late&#44; and in countries with limited access to ART&#46; We therefore describe the cardiovascular consequences in treatment-naive HIV-positive individuals and the potential effect of treatment on their regression&#44; as well as the implications of HAART&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Cardiovascular manifestations of human immunodeficiency virus infection</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Cardiomyopathy</span><p id="par0150" class="elsevierStylePara elsevierViewall">Four types of cardiomyopathy are associated with HIV infection&#58; myocarditis&#44; hypokinetic cardiomyopathy &#40;particularly in advanced stages of infection&#41;&#44; dilated cardiomyopathy&#44; and reduced left ventricular systolic function&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">3</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">Pre-HAART studies reported high prevalences of myocarditis&#44; in up to 52&#37; of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0520"><span class="elsevierStyleSup">4</span></a> Acute myocarditis can lead to congestive heart failure &#40;HF&#41; and arrhythmias&#46; Myositis is common in this population&#44; and myoglobin is thus less specific as a marker of myocardial damage&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">5</span></a> Clinical features&#44; risk factors such as drugs or antivirals&#44; and complementary exams have a role in diagnosis&#46; The gold standard in the diagnosis of myocarditis is endomyocardial biopsy&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">6</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Dilated cardiomyopathy&#58;</span> With regard to dilated cardiomyopathy&#44; the pre-HAART incidence was reported to range between 8&#37;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">7</span></a> and 35&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">8</span></a> In the HAART era&#44; a reduction in the prevalence of cardiomyopathy has been reported in developed countries&#44;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">9</span></a> possibly due to reduced viral replication&#44; lower incidence of myocarditis and prevention of opportunistic infections&#46; In developing countries&#44; with less access to ART&#44; cardiomyopathy is a significant problem&#59; a prospective study in Rwanda reported a 17&#46;7&#37; prevalence of dilated cardiomyopathy&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">10</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">The pathogenesis of dilated cardiomyopathy is thought to be multifactorial&#44; possibly linked to infection of the myocardium by HIV&#44;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">7</span></a> immunodepression&#44;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">3&#44;10</span></a> nutritional deficiencies&#44;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">10</span></a> diffuse-regressive alterations&#44;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">11</span></a> cardiac autoimmunity&#44;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">12</span></a> infectious endocarditis&#44; coinfection with cardiotropic viruses&#44;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">7</span></a> the action of cytokines&#44;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">11</span></a> and the cardiotoxicity of certain drugs&#44; including zidovudine&#46;<a class="elsevierStyleCrossRef" href="#bib0565"><span class="elsevierStyleSup">13</span></a></p><p id="par0170" class="elsevierStylePara elsevierViewall">Clinically&#44; it is often asymptomatic or non-specific and the symptoms of HF may be masked by other conditions&#46; Echocardiography is the method of choice to assess ventricular function&#46;</p><p id="par0175" class="elsevierStylePara elsevierViewall">Cardiomyopathy is associated with increased mortality&#44; with progressive left ventricular &#40;LV&#41; dysfunction leading to HF&#46; The importance of ventricular dysfunction is demonstrated by the reduced survival of patients with cardiomyopathy who died of AIDS in the pre-HAART era compared to those with preserved cardiac function at a similar stage of infection &#40;101 vs&#46; 472 days&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">14</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Barbaro et al&#46; studied the influence of development of encephalopathy on the clinical course of HIV-associated cardiomyopathy and observed that patients with encephalopathy were more likely to die from congestive HF&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">15</span></a> The virus may persist in reservoir cells in the myocardium and cerebral cortex even after ART&#44; and these cells may chronically release cytotoxic cytokines&#44; contributing to progressive tissue damage in both systems&#46; Antagonists of cytokines or inducible nitric oxide synthase &#40;iNOS&#41; or apoptosis inhibitors can reduce cell damage caused by chronic release of cytotoxic cytokines and by activation of iNOS by these reservoir cells&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">15</span></a> However&#44; further studies are needed to assess their therapeutic potential&#46;</p><p id="par0185" class="elsevierStylePara elsevierViewall">In general&#44; standard HF treatment regimens are recommended for HIV-positive individuals with dilated cardiomyopathy and HF&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">5</span></a> Angiotensin-converting enzyme inhibitors may be poorly tolerated because of low systemic vascular resistance from diarrheal disease&#44; infection or dehydration&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">5</span></a> Digoxin may be added for the treatment of patients with persistent symptoms or atrial fibrillation with rapid ventricular response&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">5</span></a> When the patient is euvolemic&#44; a beta-blocker may be started because of its beneficial effects on circulating levels of cytokines&#46;<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">16</span></a> There is little evidence that HAART is beneficial in this respect&#44; although it may reduce the incidence of cardiac disease by preventing opportunistic infections&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Diastolic dysfunction</span><p id="par0190" class="elsevierStylePara elsevierViewall">High prevalences of left ventricular diastolic dysfunction &#40;LVDD&#41; have been reported in HIV-positive individuals &#40;36&#37;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">18</span></a>&#8211;55&#46;7&#37;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">3</span></a>&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0515"><span class="elsevierStyleSup">3&#44;17&#8211;19</span></a> although some studies contradict this&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">20</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">Subclinical cardiac abnormalities have been detected at early stages of HIV infection&#44; independently of ART&#44; suggesting that HIV itself may play a part in the genesis of diastolic dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">18</span></a> Traditional risk factors are strongly associated with impaired diastolic relaxation&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">17</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">LVDD frequently appears in patients with few or no symptoms or in those whose symptoms are related to other conditions&#46; Echocardiography provides a reliable non-invasive assessment of LV systolic and diastolic function and can detect subclinical myocardial involvement in HIV-positive individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">3</span></a> However&#44; in the absence of symptoms&#44; it may be premature to recommend routine screening echocardiograms&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">19</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">It is unclear whether HIV-infected patients require any specific therapeutic interventions to manage or prevent cardiac dysfunction&#46; Reduction of HIV-related inflammation with ART would appear to be a reasonable approach&#44; although the benefit of treatment on cardiac function remains unproven&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">19</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Infectious endocarditis</span><p id="par0210" class="elsevierStylePara elsevierViewall">Studies in the pre-HAART era reported increased risk of infectious endocarditis &#40;IE&#41; in HIV-positive individuals&#44; but in one study its incidence decreased from 20&#46;5 to 6&#46;6 per 1000 person-years between the pre- and post-HAART eras&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">21</span></a></p><p id="par0215" class="elsevierStylePara elsevierViewall">The risk factors most strongly associated with IE were intravenous drug use<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">21&#44;22</span></a> and severe immunodepression&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">21</span></a> In some studies <span class="elsevierStyleItalic">Staphylococcus aureus</span> was the most common agent in HIV-positive individuals&#44;<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">21&#8211;23</span></a> most often involving the tricuspid valve&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">23</span></a> In HIV-positive individuals with methicillin-resistant <span class="elsevierStyleItalic">S&#46; aureus</span> &#40;MRSA&#41; bacteremia&#44; community-associated MRSA was significantly associated with increased IE prevalence&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">24</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">Patients may present fever&#44; weight loss&#44; and concomitant pneumonia and&#47;or meningitis&#46; Transthoracic echocardiography &#40;TTE&#41;&#44; complemented by transesophageal echocardiography&#44; is essential to confirm the diagnosis and to guide treatment&#46;</p><p id="par0225" class="elsevierStylePara elsevierViewall">Left heart involvement and severe immunodepression &#40;CD4 &#60;200&#47;mm<span class="elsevierStyleSup">3</span>&#41; are associated with greater mortality&#46;<a class="elsevierStyleCrossRefs" href="#bib0610"><span class="elsevierStyleSup">22&#44;23</span></a> Gebo et al&#46; reported higher recurrence and mortality rates within one year of IE infection and recommended more aggressive follow-up&#44; especially in those over 40 years of age&#46;<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">21</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Antibiotic therapy is often effective&#44; but surgery is indicated in selected patients&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Pericardial effusion</span><p id="par0235" class="elsevierStylePara elsevierViewall">Pericardial effusion &#40;PE&#41; is relatively common in this population&#46; Cardiac tamponade is rare&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">25</span></a> In the pre-HAART era&#44; an annual incidence of 11&#37; was reported in AIDS patients&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">25</span></a> In the HAART era&#44; an incidence of 0&#46;25&#37; has been reported in HIV-positive individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">26</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">Possible etiologies of PE in these patients include opportunistic infections&#44;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">27</span></a> malignancies such as Kaposi sarcoma &#40;KS&#41; and non-Hodgkin lymphoma &#40;NHL&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">25</span></a> tuberculosis&#44; hypoalbuminemia&#44;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">25</span></a> idiopathic&#44; and end-stage HIV capillary leak syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">25</span></a></p><p id="par0245" class="elsevierStylePara elsevierViewall">Previous studies of PE in this population reported that pericardial involvement was often an echocardiographic finding that was not clinically suspected&#44; and that since most PEs were small<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">8&#44;25</span></a> and rarely progressive<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">25</span></a> an exhaustive search for a pericardial diagnosis is usually not indicated&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">25</span></a> Large symptomatic pericardial effusions do occur&#44; however&#44; and may need aggressive evaluation and therapy&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">25</span></a> Dyspnea&#44; exercise intolerance or edema should prompt investigation by TTE&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">26</span></a></p><p id="par0250" class="elsevierStylePara elsevierViewall">PE may be a marker of end-stage HIV infection&#44;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">25</span></a> but it is rarely the cause of death&#44;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">27</span></a> although it has been associated with shorter survival&#46;<a class="elsevierStyleCrossRefs" href="#bib0540"><span class="elsevierStyleSup">8&#44;25</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Pulmonary hypertension</span><p id="par0255" class="elsevierStylePara elsevierViewall">HIV-related pulmonary arterial hypertension &#40;PAH&#41; has similar clinical&#44; laboratory&#44; imaging and pathological manifestations to those of idiopathic PAH&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">28</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">An incidence of 0&#46;5&#37; in HIV-positive individuals was reported in the pre-HAART era&#44;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">29</span></a> while a prospective study in the HAART era reported a prevalence of 0&#46;46&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">30</span></a> PAH may develop at any stage of HIV infection and all risk groups may be affected&#46;<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">31</span></a></p><p id="par0265" class="elsevierStylePara elsevierViewall">The mean age of HIV-positive individuals diagnosed with PAH as reported in a systematic review<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">28</span></a> was 35&#177;9&#46;6 years and 59&#37; were male&#59; the main risk factors for contracting HIV infection were injection drug use &#40;49&#37;&#41; and male-to-male sexual activity &#40;21&#37;&#41;&#44; and mean CD4 count at the time of diagnosis of PAH was 352&#177;304 cells&#47;&#956;l&#46; AIDS had been diagnosed in 53&#37;&#44; hepatitis B in 12&#37;&#44; and hepatitis C in 14&#37;&#46; The mean time from diagnosis of HIV infection to diagnosis of PAH was 4&#46;3&#177;4&#46;0 years&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">The underlying vasculopathy is severe angioproliferative disease&#46; Pulmonary veno-occlusive disease is relatively rare<a class="elsevierStyleCrossRefs" href="#bib0645"><span class="elsevierStyleSup">29&#44;31&#44;32</span></a>&#59; pulmonary vascular dysfunction probably results from risk factors such as viral infections&#44; autoimmunity&#44; drugs or toxins&#44; possibly triggering an underlying genetic susceptibility&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">32</span></a> Inflammation appears to play a more active role in the pathogenesis of HIV-related PAH than in idiopathic PAH&#46;<a class="elsevierStyleCrossRef" href="#bib0660"><span class="elsevierStyleSup">32</span></a></p><p id="par0275" class="elsevierStylePara elsevierViewall">Diagnosis requires confirmation of pulmonary hypertension and of HIV infection and exclusion of other causes of pulmonary hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">33</span></a> It should be suspected in cases of unexplained dyspnea&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">30&#44;31</span></a> Symptoms at the time of diagnosis as reported by Janda et al&#46; included dyspnea &#40;93&#37;&#41;&#44; pedal edema &#40;18&#37;&#41;&#44; syncope &#40;13&#37;&#41;&#44; fatigue &#40;11&#37;&#41;&#44; cough &#40;8&#37;&#41; and chest pain &#40;6&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">28</span></a> Echocardiography should be performed in patients with unexplained dyspnea to investigate possible HIV-related cardiovascular complications&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">34</span></a> Right heart catheterization is the gold standard to diagnose PAH and to assess hemodynamic status and response to treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">35</span></a></p><p id="par0280" class="elsevierStylePara elsevierViewall">Development of PAH is associated with worse prognosis&#44; particularly in NYHA functional class III&#8211;IV&#44; with 28&#37; survival at three years&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">36</span></a> Patients with HIV-related PAH frequently die from conditions associated with PAH&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">28&#44;35&#44;36</span></a> The most common complication is right-sided HF&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">28</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">Since there is no curative treatment&#44; the aim is to improve patients&#8217; functional class&#46; Conventional treatment is directed at controlling its consequences and is similar to that for all forms of pulmonary hypertension&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">33</span></a> In cases of decompensated right heart failure&#44; fluid restriction and diuretics should be used with caution to avoid excessive reduction of intravascular volume&#46; Inotropic agents are used when necessary and home oxygen therapy can be prescribed in patients with chronic hypoxemia&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">33</span></a> Anticoagulation is not routinely recommended because of an increased risk of bleeding&#44; treatment compliance issues&#44; and drug interactions&#44;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">34</span></a> and these individuals should not receive calcium channel blockers &#40;CCBs&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">34</span></a></p><p id="par0290" class="elsevierStylePara elsevierViewall">There have been few studies on PAH treatment in this population and there is a need for controlled randomized trials with large population samples&#46; Administration of sildenafil is the subject of debate&#44; since it interacts with protease inhibitors &#40;PIs&#41;&#59; according to Galie et al&#46;&#44; if sildenafil is used&#44; the dose should be adjusted if ritonavir and saquinovir are co-administered&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">34</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">There are conflicting data on the efficacy of HAART in the treatment of PAH&#46;<a class="elsevierStyleCrossRefs" href="#bib0685"><span class="elsevierStyleSup">37&#8211;39</span></a></p><p id="par6490" class="elsevierStylePara elsevierViewall">HIV infection is generally considered an exclusion criterion for lung transplantation&#44; although in some centers a specific program has been implemented&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">34</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Autonomic dysfunction</span><p id="par0300" class="elsevierStylePara elsevierViewall">Cardiovascular autonomic tone has been shown to be involved in advanced HIV disease&#46; Spectral analysis of heart rate variability showed severe global autonomic dysfunction in AIDS patients without clinical or echocardiographic evidence of cardiac disease&#44; and this has been suggested as a possible mechanism of arrhythmogenesis&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">40</span></a> HIV-positive individuals under ART for more than 44 months present increased resting heart rate and reduced short-term heart rate variability&#44; indicative of parasympathetic dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0705"><span class="elsevierStyleSup">41</span></a> However&#44; a recent prospective study suggests that ART may not contribute to short-term alterations in autonomic function in healthy individuals early in the course of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">42</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Cardiac malignancies</span><p id="par0305" class="elsevierStylePara elsevierViewall">The introduction of HAART has led to significant reductions in the incidence of KS and NHL&#44;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">43</span></a> both of which can affect the heart&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">In the pre-HAART era&#44; individuals with AIDS were at increased risk of KS&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">44</span></a> Cardiac involvement usually occurs as a part of disseminated KS&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">27</span></a> Clinical cardiac findings are obscure and pericardiocentesis not only has no diagnostic role but is also a high-risk procedure in this group of patients&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">27</span></a> When there is a high index of suspicion of PE due to KS&#44; a pericardial window should be performed for providing decompression and establishing the pathologic diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">27</span></a></p><p id="par0315" class="elsevierStylePara elsevierViewall">An increased incidence of NHL in AIDS patients was also reported in the pre-HAART era&#46;<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">44</span></a> Cardiac involvement&#44; usually derived from B cells&#44; is typically high grade and is often disseminated early in patients with AIDS&#46;<a class="elsevierStyleCrossRefs" href="#bib0635"><span class="elsevierStyleSup">27&#44;45</span></a> It is usually clinically silent&#44; but may present with HF&#44; arrhythmias and&#47;or PE&#44;<a class="elsevierStyleCrossRefs" href="#bib0730"><span class="elsevierStyleSup">46&#44;47</span></a> and cardiac tamponade&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">45</span></a> Echocardiography may reveal an intracardiac mass or nodular lesions within the three layers of the heart wall&#44; but in infiltrative forms of cardiac NHL&#44; it may underestimate the extent of myocardial involvement&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">45</span></a> Magnetic resonance imaging is useful for assessing the characteristics and potential complications of the malignancy&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">47</span></a></p><p id="par0320" class="elsevierStylePara elsevierViewall">In HIV patients&#44; the occurrence of NHL does not correlate closely with an advanced stage of immunosuppression&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">45</span></a> Although prognosis is poor&#44; systemic chemotherapy may prolong survival&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">45</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Vasculopathies</span><p id="par0325" class="elsevierStylePara elsevierViewall">Virtually all types of vasculitides of small&#44; medium and large vessels have been observed in this population&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">48</span></a> They may result from abnormalities induced by HIV and&#47;or other agents&#46; Various inflammatory vascular diseases may develop&#44; including polyarteritis nodosa-like vasculitis&#44;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">48</span></a> Henoch-Sch&#246;nlein purpura&#44; drug-induced hypersensitivity vasculitis&#44; Kawasaki-like syndromes<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">49</span></a> and Takayasu arteritis&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">50</span></a></p><p id="par0330" class="elsevierStylePara elsevierViewall">HIV-related aneurysms have been identified as a distinct entity&#44; characterized by their predilection for young patients&#44; multiplicity&#44; atypical location and distinct histological features&#46; Most patients were asymptomatic and 68&#37; presented advanced HIV disease&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">51</span></a> The pathogenesis of these aneurysms remains unclear&#46;<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">51</span></a></p><p id="par0335" class="elsevierStylePara elsevierViewall">A type of occlusive arterial disease apparently unique to HIV-positive individuals has been reported&#46; It is more common in young patients&#44; generally those with advanced disease and significant immunodepression&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">52</span></a> They frequently present with advanced tissue necrosis that precludes limb salvage&#46;<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">52</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Human immunodeficiency virus and coronary disease</span><p id="par0340" class="elsevierStylePara elsevierViewall">Electrocardiographic evidence of asymptomatic IHD has been reported in 10&#46;9&#37; of HIV-infected adults without known IHD&#44; irrespective of type and duration of ART&#46;<a class="elsevierStyleCrossRef" href="#bib0765"><span class="elsevierStyleSup">53</span></a></p><p id="par0345" class="elsevierStylePara elsevierViewall">Alterations in lipid metabolism have been described in HIV-positive individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0770"><span class="elsevierStyleSup">54&#44;55</span></a></p><p id="par0350" class="elsevierStylePara elsevierViewall">The role of HIV as a risk factor for accelerated atherosclerosis is controversial&#46;<a class="elsevierStyleCrossRefs" href="#bib0780"><span class="elsevierStyleSup">56&#8211;59</span></a> The virus has effects on the endothelium and platelets &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Figure 1</a>&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">60</span></a> Endothelial dysfunction occurs early in the process of atherogenesis and contributes to the formation&#44; progression and complications of atherosclerotic plaques&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">60</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0355" class="elsevierStylePara elsevierViewall">Atherosclerotic alterations of the arterial wall lead to increased arterial stiffness&#44; which has been reported in untreated HIV-positive individuals in some studies<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">58&#44;61</span></a> but not in others&#46;<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">62</span></a></p><p id="par0360" class="elsevierStylePara elsevierViewall">Chronic HIV infection leads to immune activation and chronic inflammation&#44; only partially corrected by HAART&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">60</span></a> Immunodepression can have adverse effects on the vasculature&#46;<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">59</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Corrected QT interval prolongation</span><p id="par0365" class="elsevierStylePara elsevierViewall">An increased prevalence of corrected QT interval &#40;QTc&#41; prolongation in HIV-positive individuals has been reported&#46;<a class="elsevierStyleCrossRefs" href="#bib0815"><span class="elsevierStyleSup">63&#8211;66</span></a> This may be associated with drugs used to treat other conditions&#44; electrolyte disturbances&#44; longer duration of HIV infection&#44;<a class="elsevierStyleCrossRefs" href="#bib0820"><span class="elsevierStyleSup">64&#44;65</span></a> cardiomyopathy&#44; autonomic dysfunction or myocardial ischemia&#46;<a class="elsevierStyleCrossRef" href="#bib0820"><span class="elsevierStyleSup">64</span></a> Shavadia et al&#46; reported a significantly increased risk for QTc prolongation in HIV-positive individuals under ART compared to untreated individuals&#44;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">63</span></a> but other studies found no significant association&#46;<a class="elsevierStyleCrossRefs" href="#bib0825"><span class="elsevierStyleSup">65&#44;66</span></a> According to Reinsch et al&#46;&#44; factors such as gender&#44; diabetes and hypertension may also be involved in the development of QTc prolongation&#46;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">66</span></a></p><p id="par0370" class="elsevierStylePara elsevierViewall">The use of noncardiac QTc-prolonging drugs has been associated with increased risk for sudden cardiac death in the general population&#46;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">67</span></a> It is important to monitor QTc interval in patients under ART&#44; particular when ART is combined with drugs that can prolong QTc&#46;</p></span></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Effects of human immunodeficiency virus infection on the cardiovascular system in the highly active antiretroviral therapy era</span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Highly active antiretroviral therapy</span><p id="par0375" class="elsevierStylePara elsevierViewall">The initial combination regimens recommended by the European AIDS Clinical Society &#40;EACS&#41;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a> are presented in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0380" class="elsevierStylePara elsevierViewall">The 2014 Recommendations of the International Antiviral Society&#8211;USA Panel propose that ART should be initiated in all individuals who are willing and ready to start treatment after confirmed diagnosis of HIV infection&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">69</span></a> ART is recommended for the treatment of HIV infection and the prevention of transmission of HIV regardless of CD4 cell count &#40;strength of recommendation AIa-BIII&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">69</span></a> These measures will subject HIV-positive individuals to earlier exposure to HAART and its adverse effects&#46; The recommendations of the 2014 EACS guidelines for initiation of ART in HIV-positive persons without prior ART exposure are graded taking into account both the degree of progression of HIV disease and the presence of&#44; or high risk for developing&#44; various types of &#40;comorbid&#41; conditions&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a> ART is always recommended in any HIV-positive person with a current CD4 count &#60;350 cells&#47;&#956;l&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a> For persons with CD4 counts above this level&#44; the decision to start ART should be considered on an individual basis&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Effects of highly active antiretroviral therapy</span><p id="par0385" class="elsevierStylePara elsevierViewall">Various cardiovascular risk factors can be induced or strengthened by HAART&#46; Traditional risk factors have been significantly associated with increased risk for MI in HIV-positive individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0850"><span class="elsevierStyleSup">70&#44;71</span></a></p><p id="par0390" class="elsevierStylePara elsevierViewall">The incidence of diabetes in HIV-positive men under HAART has been reported as over four times higher than in HIV-negative individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">72</span></a> Traditional risk factors &#40;age&#44; male gender&#44; obesity&#44; low HDL cholesterol and high total cholesterol&#41; play an important role in the increased risk of diabetes in this population&#44;<a class="elsevierStyleCrossRefs" href="#bib0865"><span class="elsevierStyleSup">73&#8211;75</span></a> while lipodystrophy<a class="elsevierStyleCrossRefs" href="#bib0865"><span class="elsevierStyleSup">73&#44;76</span></a> and immunodepression<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">76</span></a> have also been associated with increased incidence of diabetes in HIV-positive individuals&#46; The impact of coinfection with hepatitis C virus is the subject of debate&#46;<a class="elsevierStyleCrossRefs" href="#bib0870"><span class="elsevierStyleSup">74&#8211;76</span></a> ART is not unanimously recognized as a risk factor for diabetes&#44; but several studies have reported increased prevalence of diabetes with certain antiretrovirals<a class="elsevierStyleCrossRefs" href="#bib0865"><span class="elsevierStyleSup">73&#44;74&#44;77</span></a> and with longer exposure to ART&#46;<a class="elsevierStyleCrossRefs" href="#bib0865"><span class="elsevierStyleSup">73&#44;78</span></a> The drugs most often associated with diabetes are PIs<a class="elsevierStyleCrossRefs" href="#bib0870"><span class="elsevierStyleSup">74&#44;77</span></a> and some nucleoside reverse-transcriptase inhibitors &#40;NRTIs&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0865"><span class="elsevierStyleSup">73&#44;74&#44;77</span></a></p><p id="par0395" class="elsevierStylePara elsevierViewall">Certain PIs have been associated with a dyslipidemic profile&#46;<a class="elsevierStyleCrossRefs" href="#bib0775"><span class="elsevierStyleSup">55&#44;79&#44;80</span></a> Non-nucleoside reverse-transcriptase inhibitors &#40;NNRTIs&#41; generally result in a more favorable lipid profile than PIs&#46;<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">80</span></a> However&#44; studies have shown a significant risk of dyslipidemia induced by efavirenz&#46;<a class="elsevierStyleCrossRefs" href="#bib0770"><span class="elsevierStyleSup">54&#44;81</span></a> Of the NRTIs&#44; tenofovir appears to be associated with less unfavorable lipid profiles&#46;<a class="elsevierStyleCrossRefs" href="#bib0910"><span class="elsevierStyleSup">82&#44;83</span></a> It has been suggested that integrase strand transfer inhibitor-based regimens may be a good option for patients with pre-existing dyslipidemia&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">69</span></a></p><p id="par0400" class="elsevierStylePara elsevierViewall">HIV-related lipodystrophy&#44; mainly considered an adverse effect of HAART&#44; has a reported mean prevalence of 42&#37; in HIV-positive individuals treated with PI-containing HAART&#46;<a class="elsevierStyleCrossRef" href="#bib0920"><span class="elsevierStyleSup">84</span></a> The term &#8216;lipodystrophy syndrome&#8217; is used by some authors to include morphological and metabolic phenomena&#44; but it is not clear that they result from the same mechanism&#46; Not all patients present all the characteristics of the syndrome&#59; dyslipidemia has been reported in 70&#37; and diabetes in 8&#8211;10&#37; of these patients&#46;<a class="elsevierStyleCrossRef" href="#bib0925"><span class="elsevierStyleSup">85</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Hypertension</span><p id="par0405" class="elsevierStylePara elsevierViewall">Some studies suggest that the prevalence of hypertension is increased in HIV-positive individuals under ART&#44;<a class="elsevierStyleCrossRefs" href="#bib0930"><span class="elsevierStyleSup">86&#44;87</span></a> but this is not confirmed by others&#46;<a class="elsevierStyleCrossRef" href="#bib0940"><span class="elsevierStyleSup">88</span></a></p><p id="par0410" class="elsevierStylePara elsevierViewall">The role of HIV and ART in the pathogenesis of hypertension is not clear&#46; Possible mechanisms are presented in <a class="elsevierStyleCrossRef" href="#fig0010">Figure 2</a>&#46; A prospective study in HIV-infected patients starting HAART found an increase in blood pressure &#40;BP&#41; after 48 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0930"><span class="elsevierStyleSup">86</span></a> In HIV-positive individuals starting their first HAART regimen&#44; treatment with lopinavir&#47;ritonavir was associated with increased BP&#44;<a class="elsevierStyleCrossRef" href="#bib0945"><span class="elsevierStyleSup">89</span></a> while patients taking atazanavir&#44; efavirenz&#44; nelfinavir or indinavir were less likely to develop high BP&#46;<a class="elsevierStyleCrossRef" href="#bib0945"><span class="elsevierStyleSup">89</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Highly active antiretroviral therapy and cardiovascular disease</span><p id="par0415" class="elsevierStylePara elsevierViewall">Mendes et al&#46; detected abnormalities in myocardial deformation through assessment of strain and strain rate in a population of relatively healthy HIV-infected patients without established CVD or risk factors&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">20</span></a></p><p id="par0420" class="elsevierStylePara elsevierViewall">It has been demonstrated that HIV infection and HAART are independent risk factors for early carotid atherosclerosis&#44;<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">56</span></a> but Kaplan et al&#46; reported that ART was not consistently associated with atherosclerosis<a class="elsevierStyleCrossRef" href="#bib0795"><span class="elsevierStyleSup">59</span></a> and there is conflicting evidence on the effects of ART on arterial stiffness&#46;<a class="elsevierStyleCrossRefs" href="#bib0805"><span class="elsevierStyleSup">61&#44;62</span></a></p><p id="par0425" class="elsevierStylePara elsevierViewall">HIV-positive patients&#44; especially those under ART&#44; are at increased risk of CVD&#44; particularly MI and coronary disease&#44; compared to HIV-negative individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0785"><span class="elsevierStyleSup">57&#44;70&#44;90&#44;91</span></a> Several studies have shown a higher frequency of vascular events in HIV-infected adults under ART compared to untreated individuals&#44;<a class="elsevierStyleCrossRefs" href="#bib0950"><span class="elsevierStyleSup">90&#44;92&#44;93</span></a> although other studies disagree&#46;<a class="elsevierStyleCrossRef" href="#bib0970"><span class="elsevierStyleSup">94</span></a> It has been suggested that immune reconstitution may be partly responsible for the increased risk of IHD&#46;<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">90</span></a></p><p id="par0430" class="elsevierStylePara elsevierViewall">Nevertheless&#44; the benefits of ART continue to outweigh the increased cardiovascular risk associated with this treatment&#44; and concerns about coronary risk should not prevent HIV-positive individuals from receiving ART&#46;</p><p id="par0435" class="elsevierStylePara elsevierViewall">Several studies have shown an increased frequency of MI with longer exposure to certain antiretrovirals&#46;<a class="elsevierStyleCrossRefs" href="#bib0850"><span class="elsevierStyleSup">70&#44;71&#44;95</span></a> However&#44; Obel et al&#46; did not observe any increase up to eight years after treatment initiation&#46;<a class="elsevierStyleCrossRef" href="#bib0950"><span class="elsevierStyleSup">90</span></a> In a shorter study&#44; ART was independently associated with a 26&#37; increase in the rate of MI per year of exposure in the first 4&#8211;6 years of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">70</span></a> Another study showed higher relative risk of MI for every year of exposure to PIs&#44; but no significant association was seen with NNRTIs&#46;<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">71</span></a> Treatment with indinavir&#44; lopinavir&#47;ritonavir&#44; didanosine and abacavir was associated with an increased risk of MI&#44;<a class="elsevierStyleCrossRef" href="#bib0975"><span class="elsevierStyleSup">95</span></a> but other authors found no association between exposure to abacavir and increased risk of MI&#46;<a class="elsevierStyleCrossRef" href="#bib0980"><span class="elsevierStyleSup">96</span></a> Consideration should be given to avoiding use of abacavir&#44; ritonavir&#47;lopinavir&#44; and ritonavir&#47;fosamprenavir in persons at high risk for CVD because these regimens have been associated with increased risk of cardiovascular events in some studies&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">69</span></a></p><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Assessment of cardiovascular risk</span><p id="par0440" class="elsevierStylePara elsevierViewall">Cardiovascular risk should be assessed and monitored in order to identify those at high risk and to implement preventive measures &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Figure 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia><p id="par0445" class="elsevierStylePara elsevierViewall">HIV-positive individuals have various risk factors for CVD&#44; both traditional factors and those related to their HIV status&#44; including the infection itself&#44; duration of infection&#44; viral load&#44; therapy&#44; and altered immune response&#46;</p><p id="par0450" class="elsevierStylePara elsevierViewall">The Framingham risk score may underestimate risk in this population&#46;<a class="elsevierStyleCrossRef" href="#bib0790"><span class="elsevierStyleSup">58</span></a> Two other risk scores have recently been developed&#58; a risk equation developed from a population of HIV-infected patients&#44; incorporating routinely collected cardiovascular risk parameters and exposure to antiretrovirals<a class="elsevierStyleCrossRef" href="#bib0985"><span class="elsevierStyleSup">97</span></a>&#59; and a model to predict the short-term risk of new-onset diabetes in HIV-positive populations during follow-up&#46;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">76</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Recommendations</span><p id="par0455" class="elsevierStylePara elsevierViewall">Behavioral and therapeutic interventions to reduce cardiovascular risk are recommended in HIV-positive individuals under ART&#46; They should be advised regarding diet&#44; weight loss&#44; smoking cessation and exercise&#46; An independent association has been reported between high salt consumption and increased arterial stiffness&#46;<a class="elsevierStyleCrossRef" href="#bib0990"><span class="elsevierStyleSup">98</span></a></p><p id="par0460" class="elsevierStylePara elsevierViewall">Lima et al&#46; analyzed the effect of a prevention program &#40;non-pharmacological and&#44; when appropriate&#44; pharmacological therapy&#41; on cardiovascular risk in HIV-positive patients&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">99</span></a> After a six-month follow-up&#44; significant changes were seen in triglycerides and total and LDL cholesterol and a significant reduction in the number of individuals at high cardiovascular risk&#46;<a class="elsevierStyleCrossRef" href="#bib0995"><span class="elsevierStyleSup">99</span></a></p><p id="par0465" class="elsevierStylePara elsevierViewall">The EACS has published recommendations on the treatment of dyslipidemia&#44; diabetes and hypertension in HIV-positive individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a></p><p id="par0470" class="elsevierStylePara elsevierViewall">If lifestyle modification and change of ART are not effective&#44; lipid-lowering medication should be considered&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a> Of the drugs used to lower LDL cholesterol&#44; statins are the first-line treatment&#44; and should be prescribed in patients with established vascular disease and in those with type 2 diabetes or at high risk of CVD&#44; irrespective of lipid levels&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a> However&#44; interactions between statins and antiretrovirals are common&#59; PIs can interact with statin metabolism via cytochrome CYP3A4&#44; increasing overall exposure to statins&#46; Simvastatin is contraindicated with concurrent PI use&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">54</span></a> In a small pilot study&#44; rosuvastatin for 24 weeks was effective against hyperlipidemia in patients taking PIs&#44; with a favorable tolerability profile&#46;<a class="elsevierStyleCrossRef" href="#bib1000"><span class="elsevierStyleSup">100</span></a></p><p id="par0475" class="elsevierStylePara elsevierViewall">The goals and characteristics of treatment of type 2 diabetes recommended by the EACS<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a> are shown in <a class="elsevierStyleCrossRef" href="#fig0020">Figure 4</a>&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0480" class="elsevierStylePara elsevierViewall">The aim of treatment for hypertension is to achieve BP &#60;140&#47;90 mmHg&#46; The EACS recommendations for drug treatment of hypertension<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a> are presented in <a class="elsevierStyleCrossRef" href="#fig0025">Figure 5</a>&#46; CCBs should be used with caution&#44; since they may interact with PIs&#46; Comorbidities should be borne in mind when selecting drug therapy&#46;</p><elsevierMultimedia ident="fig0025"></elsevierMultimedia></span></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conflicts of interest</span><p id="par0485" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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          "identificador" => "xres538928"
          "titulo" => "Abstract"
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              "identificador" => "abst0005"
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          "identificador" => "xpalclavsec558597"
          "titulo" => "Keywords"
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          "titulo" => "Palavras-chave"
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          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Cardiovascular manifestations of human immunodeficiency virus infection"
          "secciones" => array:10 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Cardiomyopathy"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Diastolic dysfunction"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Infectious endocarditis"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Pericardial effusion"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Pulmonary hypertension"
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            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Autonomic dysfunction"
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            6 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Cardiac malignancies"
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            7 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Vasculopathies"
            ]
            8 => array:2 [
              "identificador" => "sec0055"
              "titulo" => "Human immunodeficiency virus and coronary disease"
            ]
            9 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Corrected QT interval prolongation"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0065"
          "titulo" => "Effects of human immunodeficiency virus infection on the cardiovascular system in the highly active antiretroviral therapy era"
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            0 => array:2 [
              "identificador" => "sec0070"
              "titulo" => "Highly active antiretroviral therapy"
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              "identificador" => "sec0075"
              "titulo" => "Effects of highly active antiretroviral therapy"
            ]
            2 => array:2 [
              "identificador" => "sec0080"
              "titulo" => "Hypertension"
            ]
          ]
        ]
        7 => array:3 [
          "identificador" => "sec0085"
          "titulo" => "Highly active antiretroviral therapy and cardiovascular disease"
          "secciones" => array:2 [
            0 => array:2 [
              "identificador" => "sec0090"
              "titulo" => "Assessment of cardiovascular risk"
            ]
            1 => array:2 [
              "identificador" => "sec0095"
              "titulo" => "Recommendations"
            ]
          ]
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          "titulo" => "Conflicts of interest"
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          "titulo" => "References"
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    "fechaRecibido" => "2014-06-11"
    "fechaAceptado" => "2015-03-08"
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec558597"
          "palabras" => array:6 [
            0 => "Cardiovascular disease"
            1 => "Antiretroviral therapy"
            2 => "Pulmonary hypertension"
            3 => "Lipodystrophy"
            4 => "Vasculopathy"
            5 => "Human immunodeficiency virus"
          ]
        ]
      ]
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        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec558598"
          "palabras" => array:6 [
            0 => "Doen&#231;a cardiovascular"
            1 => "Terap&#234;utica antirretroviral"
            2 => "Hipertens&#227;o Pulmonar"
            3 => "Lipodistrofia"
            4 => "Vasculopatia"
            5 => "V&#237;rus da imunodefici&#234;ncia humana"
          ]
        ]
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">The cardiovascular manifestations of human immunodeficiency virus &#40;HIV&#41; infection have changed significantly following the introduction of highly active antiretroviral therapy &#40;HAART&#41; regimens&#46; On one hand&#44; HAART has altered the course of HIV disease&#44; with longer survival of HIV-infected patients&#44; and cardiovascular complications of HIV infection such as myocarditis have been reduced&#46; On the other hand&#44; HAART is associated with an increase in the prevalence of both peripheral and coronary arterial disease&#46; As longevity increases in HIV-infected individuals&#44; long-term effects&#44; such as cardiovascular disease&#44; are emerging as leading health issues in this population&#46; In the present review article&#44; we discuss HIV-associated cardiovascular disease&#44; focusing on epidemiology&#44; etiopathogenesis&#44; diagnosis&#44; prognosis&#44; management and therapy&#46; Cardiovascular involvement in treatment-naive patients is still important in situations such as non-adherence to treatment&#44; late initiation of treatment&#44; and&#47;or limited access to HAART in developing countries&#46; We therefore describe the cardiovascular consequences in treatment-naive patients and the potential effect of antiretroviral treatment on their regression&#44; as well as the metabolic and cardiovascular implications of HAART regimens in HIV-infected individuals&#46;</p></span>"
      ]
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">As manifesta&#231;&#245;es cardiovasculares da infe&#231;&#227;o pelo v&#237;rus da imunodefici&#234;ncia humana &#40;VIH&#41; modificaram-se significativamente com a introdu&#231;&#227;o dos regimes de terap&#234;utica antirretroviral de elevada pot&#234;ncia &#40;HAART&#41;&#46; Por um lado&#44; a HAART modificou o curso da doen&#231;a VIH&#44; com o prolongamento da sobreviv&#234;ncia dos doentes VIH-infetados&#46; Complica&#231;&#245;es cardiovasculares da infe&#231;&#227;o VIH&#44; como a miocardite&#44; foram reduzidas&#46; Por outro lado&#44; a HAART tem sido associada ao aumento da preval&#234;ncia de doen&#231;as arteriais perif&#233;ricas e coron&#225;rias&#46; Com o aumento da longevidade dos indiv&#237;duos VIH-infetados&#44; efeitos a longo prazo&#44; como a doen&#231;a cardiovascular&#44; est&#227;o a emergir como quest&#245;es de sa&#250;de proeminentes nesta popula&#231;&#227;o&#46; No presente artigo de revis&#227;o&#44; discutiremos a patologia cardiovascular associada ao VIH&#44; focando-nos na epidemiologia&#44; etiopatog&#233;nese&#44; diagn&#243;stico&#44; progn&#243;stico&#44; abordagem e terap&#234;utica&#46; A import&#226;ncia do envolvimento cardiovascular em doentes n&#227;o tratados pelas novas terap&#234;uticas &#233; ainda uma realidade em situa&#231;&#245;es como o n&#227;o cumprimento da terap&#234;utica&#44; o in&#237;cio tardio da terap&#234;utica ou o acesso limitado &#224; HAART nos pa&#237;ses em desenvolvimento&#46; Assim&#44; descreveremos as consequ&#234;ncias cardiovasculares nos doentes n&#227;o tratados e o potencial efeito da terap&#234;utica antirretroviral na sua regress&#227;o&#44; e as consequ&#234;ncias metab&#243;licas e implica&#231;&#245;es cardiovasculares dos regimes HAART nas pessoas infetadas pelo VIH&#46;</p></span>"
      ]
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    "NotaPie" => array:1 [
      0 => array:2 [
        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Amado Costa L&#44; Almeida AG&#46; Patologia cardiovascular associada ao v&#237;rus da imunodefici&#234;ncia humana&#46; Rev Port Cardiol&#46; 2015&#59;34&#58;479&#8211;491&#46;</p>"
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        "identificador" => "nom0005"
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          0 => array:2 [
            "titulo" => "<span class="elsevierStyleSectionTitle" id="sect0025">List of abbreviations</span>"
            "definicion" => array:26 [
              0 => array:2 [
                "termino" => "AIDS"
                "descripcion" => "<p id="par0005" class="elsevierStylePara elsevierViewall">acquired immunodeficiency syndrome</p>"
              ]
              1 => array:2 [
                "termino" => "ART"
                "descripcion" => "<p id="par0010" class="elsevierStylePara elsevierViewall">antiretroviral therapy</p>"
              ]
              2 => array:2 [
                "termino" => "BP"
                "descripcion" => "<p id="par0015" class="elsevierStylePara elsevierViewall">blood pressure</p>"
              ]
              3 => array:2 [
                "termino" => "CCB"
                "descripcion" => "<p id="par0020" class="elsevierStylePara elsevierViewall">calcium channel blocker</p>"
              ]
              4 => array:2 [
                "termino" => "CVD"
                "descripcion" => "<p id="par0025" class="elsevierStylePara elsevierViewall">cardiovascular disease</p>"
              ]
              5 => array:2 [
                "termino" => "EACS"
                "descripcion" => "<p id="par0030" class="elsevierStylePara elsevierViewall">European AIDS Clinical Society</p>"
              ]
              6 => array:2 [
                "termino" => "HAART"
                "descripcion" => "<p id="par0035" class="elsevierStylePara elsevierViewall">highly active antiretroviral therapy</p>"
              ]
              7 => array:2 [
                "termino" => "HIV"
                "descripcion" => "<p id="par0040" class="elsevierStylePara elsevierViewall">human immunodeficiency virus</p>"
              ]
              8 => array:2 [
                "termino" => "HF"
                "descripcion" => "<p id="par0045" class="elsevierStylePara elsevierViewall">heart failure</p>"
              ]
              9 => array:2 [
                "termino" => "HTN nephropathy"
                "descripcion" => "<p id="par0050" class="elsevierStylePara elsevierViewall">hypertensive nephropathy</p>"
              ]
              10 => array:2 [
                "termino" => "IE"
                "descripcion" => "<p id="par0055" class="elsevierStylePara elsevierViewall">infectious endocarditis</p>"
              ]
              11 => array:2 [
                "termino" => "IHD"
                "descripcion" => "<p id="par0060" class="elsevierStylePara elsevierViewall">ischemic heart disease</p>"
              ]
              12 => array:2 [
                "termino" => "iNOS"
                "descripcion" => "<p id="par0065" class="elsevierStylePara elsevierViewall">inducible nitric oxide synthase</p>"
              ]
              13 => array:2 [
                "termino" => "KS"
                "descripcion" => "<p id="par0070" class="elsevierStylePara elsevierViewall">Kaposi sarcoma</p>"
              ]
              14 => array:2 [
                "termino" => "LV"
                "descripcion" => "<p id="par0075" class="elsevierStylePara elsevierViewall">left ventricular</p>"
              ]
              15 => array:2 [
                "termino" => "LVDD"
                "descripcion" => "<p id="par0080" class="elsevierStylePara elsevierViewall">left ventricular diastolic dysfunction</p>"
              ]
              16 => array:2 [
                "termino" => "MI"
                "descripcion" => "<p id="par0085" class="elsevierStylePara elsevierViewall">myocardial infarction</p>"
              ]
              17 => array:2 [
                "termino" => "MRSA"
                "descripcion" => "<p id="par0090" class="elsevierStylePara elsevierViewall">methicillin-resistant <span class="elsevierStyleItalic">Staphylococcus aureus</span></p>"
              ]
              18 => array:2 [
                "termino" => "NHL"
                "descripcion" => "<p id="par0095" class="elsevierStylePara elsevierViewall">non-Hodgkin lymphoma</p>"
              ]
              19 => array:2 [
                "termino" => "NNRTI"
                "descripcion" => "<p id="par0100" class="elsevierStylePara elsevierViewall">non-nucleoside reverse-transcriptase inhibitor</p>"
              ]
              20 => array:2 [
                "termino" => "NRTI"
                "descripcion" => "<p id="par0105" class="elsevierStylePara elsevierViewall">nucleoside reverse-transcriptase inhibitor</p>"
              ]
              21 => array:2 [
                "termino" => "PAH"
                "descripcion" => "<p id="par0110" class="elsevierStylePara elsevierViewall">pulmonary arterial hypertension</p>"
              ]
              22 => array:2 [
                "termino" => "PE"
                "descripcion" => "<p id="par0115" class="elsevierStylePara elsevierViewall">pericardial effusion</p>"
              ]
              23 => array:2 [
                "termino" => "PI"
                "descripcion" => "<p id="par0120" class="elsevierStylePara elsevierViewall">protease inhibitor</p>"
              ]
              24 => array:2 [
                "termino" => "QTc"
                "descripcion" => "<p id="par0490" class="elsevierStylePara elsevierViewall">corrected QT</p>"
              ]
              25 => array:2 [
                "termino" => "TTE"
                "descripcion" => "<p id="par0125" class="elsevierStylePara elsevierViewall">transthoracic echocardiography</p>"
              ]
            ]
          ]
        ]
      ]
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the possible interactions between human immunodeficiency virus and the endothelium and platelets&#46; Adapted from Gresele et al&#46;<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">60</span></a></p> <p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">FMD&#58; flow-mediated dilation&#59; LIGHT&#58; TNFSF14 &#40;tumor necrosis factor superfamily member 14&#41;&#59; NAP-2&#58; neutrophil activating peptide 2&#59; RANTES&#58; regulated on activation normal T cell expressed and presumably secreted&#59; sCD40L&#58; soluble CD40 ligand&#59; sP selectin&#58; soluble P-selectin&#46;</p>"
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Factors associated with hypertension&#44; human immunodeficiency virus and cardiovascular disease&#46;</p> <p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">ART&#58; antiretroviral therapy&#59; CKD&#58; chronic kidney disease&#59; CVD&#58; cardiovascular disease&#59; HIV&#58; human immunodeficiency virus&#59; HTN&#58; hypertension&#46;</p>"
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Assessment of cardiovascular risk in HIV-positive individuals&#46; Adapted from European AIDS Clinical Society Guidelines Version 7&#46;1 &#8211; November 2014&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a></p> <p id="spar0040" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">a</span> The Framingham equation can be used&#46; This assessment and the associated considerations outlined in this figure should be repeated annually in all persons under care&#46;</p> <p id="spar0045" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">b</span> Of the modifiable risk factors outlined&#44; drug treatment is reserved for certain subgroups where benefits are considered to outweigh potential harm&#46;</p> <p id="spar0050" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">c</span> Target levels are to be used as guidance and are not definitive &#8211; expressed as mmol&#47;l with mg&#47;dl in parentheses&#46;</p> <p id="spar0055" class="elsevierStyleSimplePara elsevierViewall"><span class="elsevierStyleSup">d</span> Evidence for benefit when used in persons without a history of CVD &#40;including diabetics&#41; is less compelling&#46; Blood pressure should be reasonably controlled before aspirin use in such a setting&#46;</p>"
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          "en" => "<p id="spar0075" class="elsevierStyleSimplePara elsevierViewall">Choosing drugs for HIV-infected persons newly diagnosed with hypertension&#46; Adapted from European AIDS Clinical Society Guidelines Version 7&#46;1 &#8211; November 2014&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">68</span></a></p> <p id="spar0080" class="elsevierStyleSimplePara elsevierViewall">ACEi&#58; angiotensin-converting enzyme inhibitor &#40;e&#46;g&#46; perindopril&#44; lisinopril or ramipril&#41;&#59; ARB&#58; low-cost angiotensin receptor blocker &#40;e&#46;g&#46; losartan&#44; candesartan&#41;&#59; CCB&#58; calcium-channel blocker &#40;e&#46;g&#46; amlodipine&#41;&#46; Thiazide-type diuretic includes e&#46;g&#46; indapamide or chlorthalidone but excludes thiazides &#40;e&#46;g&#46; hydrochlorothiazide&#44; bendroflumethiazide&#44; etc&#46;&#41;</p>"
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      "titulo" => "References"
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Article information

ISSN: 21742049
Original language: English

DOI:10.1016/j.repce.2015.06.008

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Year/Month	Html	Pdf	Total

2024 November	6	2	8
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2024 August	59	24	83
2024 July	36	31	67
2024 June	43	21	64
2024 May	37	17	54
2024 April	37	29	66
2024 March	41	21	62
2024 February	33	30	63
2024 January	30	20	50
2023 December	30	28	58
2023 November	56	25	81
2023 October	46	26	72
2023 September	28	21	49
2023 August	31	18	49
2023 July	57	14	71
2023 June	34	12	46
2023 May	52	28	80
2023 April	49	6	55
2023 March	71	27	98
2023 February	84	15	99
2023 January	35	20	55
2022 December	76	32	108
2022 November	79	24	103
2022 October	43	11	54
2022 September	36	37	73
2022 August	18	32	50
2022 July	60	30	90
2022 June	35	23	58
2022 May	31	33	64
2022 April	44	26	70
2022 March	31	35	66
2022 February	38	26	64
2022 January	48	23	71
2021 December	40	31	71
2021 November	36	35	71
2021 October	37	36	73
2021 September	41	32	73
2021 August	71	27	98
2021 July	71	27	98
2021 June	27	28	55
2021 May	43	35	78
2021 April	40	34	74
2021 March	70	13	83
2021 February	52	14	66
2021 January	30	10	40
2020 December	58	17	75
2020 November	64	10	74
2020 October	64	15	79
2020 September	82	9	91
2020 August	23	6	29
2020 July	57	8	65
2020 June	78	18	96
2020 May	86	6	92
2020 April	74	17	91
2020 March	88	12	100
2020 February	196	24	220
2020 January	77	7	84
2019 December	72	8	80
2019 November	62	16	78
2019 October	52	8	60
2019 September	92	10	102
2019 August	33	3	36
2019 July	64	14	78
2019 June	47	22	69
2019 May	56	11	67
2019 April	42	10	52
2019 March	54	16	70
2019 February	67	10	77
2019 January	66	9	75
2018 December	58	13	71
2018 November	225	17	242
2018 October	806	21	827
2018 September	189	20	209
2018 August	380	17	397
2018 July	59	12	71
2018 June	53	9	62
2018 May	53	17	70
2018 April	55	8	63
2018 March	91	12	103
2018 February	39	6	45
2018 January	48	9	57
2017 December	76	9	85
2017 November	79	17	96
2017 October	55	18	73
2017 September	56	17	73
2017 August	54	24	78
2017 July	49	18	67
2017 June	59	26	85
2017 May	72	22	94
2017 April	51	16	67
2017 March	90	16	106
2017 February	113	16	129
2017 January	72	9	81
2016 December	75	29	104
2016 November	66	21	87
2016 October	71	16	87
2016 September	76	14	90
2016 August	44	4	48
2016 July	57	14	71
2016 June	33	15	48
2016 May	40	3	43
2016 April	58	1	59
2016 March	100	52	152
2016 February	84	50	134
2016 January	88	27	115
2015 December	84	21	105
2015 November	79	39	118
2015 October	79	38	117
2015 September	145	66	211
2015 August	236	115	351

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