HIV Infection and Primary Prevention of Cardiovascular Disease: Lights and Shadows in the HAART Era

    HIV Infection and Primary Prevention of Cardiovascular Disease: Lights and Shadows in the HAART Era Flavia Ballocca, Sebastiano Gili, Fabrizio D’Ascenzo, Walter Grosso Marra, Margherita Cannillo, Andrea Calcagno, Stefano Bonora, Andreas Flammer, John Coppola, Claudio Moretti, Fiorenzo Gaita PII: DOI: Reference:

S0033-0620(16)30017-2 doi: 10.1016/j.pcad.2016.02.008 YPCAD 721

To appear in:

Progress in Cardiovascular Diseases

Please cite this article as: Ballocca Flavia, Gili Sebastiano, D’Ascenzo Fabrizio, Marra Walter Grosso, Cannillo Margherita, Calcagno Andrea, Bonora Stefano, Flammer Andreas, Coppola John, Moretti Claudio, Gaita Fiorenzo, HIV Infection and Primary Prevention of Cardiovascular Disease: Lights and Shadows in the HAART Era, Progress in Cardiovascular Diseases (2016), doi: 10.1016/j.pcad.2016.02.008

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HIV Infection and Primary Prevention of Cardiovascular Disease: Lights and Shadows in the

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HAART Era Flavia Ballocca*, Sebastiano Gili*, Fabrizio D’Ascenzo, Walter Grosso Marra, Margherita Cannillo, Andrea Calcagno, Stefano Bonora, Andreas Flammer, John Coppola, Claudio Moretti, Fiorenzo Gaita

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FB, SG, FDA, WGM, MC, CM, FG: Division of Cardiology, Department of Medical Sciences, Città della Salute e della Scienza, Turin, Italy

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AC, SB: Division of Infectious Disease, Amedeo di Savoia Hospital, Turin, Italy

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AF: University Heart Center, University Hospital Zurich, Switzerland JC: Division of Cardiology, Department of Medicine, New York University School of Medicine, New York, New York.

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*both authors contributed equally to the manuscript and have to be considered first co-authors Running Title: cardiovascular primary prevention in HIV Key Words:HIV;human immunodeficiency virus;cardiovascular disease;primary

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prevention;HAART

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Conflicts of Interest: None Corresponding author: Fabrizio D’Ascenzo

Division of Cardiology, Department of Medical Sciences Città Della Salute e Della Scienza, Turin, Italy Email; [email protected] Website: www.cardiogroup.org ABSTRACT

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With the progressive increase in life-expectancy of human immunodeficiency virus (HIV)-positive patients in the “highly active antiretroviral therapy” (HAART) era, co-morbidities, particularly

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cardiovascular (CV) diseases (CVD) are emerging as an important concern. The pathophysiology of CVD in this population is complex, due to the interaction of classical CV risk factors, viral infection and the effects of antiretroviral therapy (ARV). The role of ARV drugs in HIV is double edged. While these drugs reduce systemic inflammation, an important factor in CV development, they may at the

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same time be proatherogenic by inducing dyslipidemia, body fat redistribution and insulin resistance. In these patients primary prevention is challenging, considering the lower median age at which acute coronary syndromes occur. Furthermore prevention is still limited by the lack of robust evidence-

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based, HIV-specific recommendations. Therefore we performed a comprehensive evaluation of the literature to analyze current knowledge on CVD prevalence in HIV-infected patients, traditional and

prevention of CVD in this HIV population.

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Abbreviations:

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HIV-specific risk factors and risk stratification, and to summarize the recommendations for primary

ARV = Antiretroviral

ASCVD = Atherosclerotic cardiovascular disease

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CHD = Coronary heart disease

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CRP = C-reactive protein CV =Cardiovascular

CVD =Cardiovascular disease CYP = Cytochrome D :A:D = Data Collection on Adverse Effects of Anti-HIV Drugs FRS = Framingham Risk Score GLUT = Glucose transporter HAART = Highly active antiretroviral therapy HDL-C = High-density lipoprotein cholesterol

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hs-CRP = Highly-sensitive C-reactive protein

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HTN = Hypertension IL = Interleukin LDL-C = Low-density lipoprotein cholesterol

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MI = Myocardial infarction

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NRTI = Nucleoside reverse transcriptase inhibitor

PAH = Pulmonary arterial hypertension

sCD = Soluble CD T2D = Type 2 diabetes

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TGs = Triglycerides

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PIs = Protease inhibitors

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NNRTI = non- Nucleoside reverse transcriptase inhibitor

TMA = Trimethylamine

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INTRODUCTION

The introduction of highly active antiretroviral therapy (ARV;HAART) has dramatically altered the natural history of human immunodeficiency virus (HIV) infection. Infection with the HIV virus was once a devastating condition resulting in the development of acquired immunodeficiency syndrome. With the introduction of HAART, infection with HIV has morphed into a chronic condition with a life expectancy comparable to the general population [1] . As a result of HAART treatment, patients are living longer and morbidities not historically related to HIV infection but associated with aging have gained more and more relevance in the HIV population. Cardiovascular (CV) disease (CVD) nowadays is recognized as a significant health issue encountered in HIV patients: Sackoff, in a review of New York City death certificates, found in HIV patients aged 55 years or older that CVD was the greatest cause of mortality [2] . HIV-positive

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patients are exposed to a higher risk of CVD [3] and are usually affected at a younger age when compared to the general population. With the progressive increase in life expectancy of the HIV

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population [4] , CVD risk assessment and prevention are becoming a critical element in the management of HIV infected patients. Currently 30 million people worldwide and about 2.2 million people in North America and Western and Central Europe are estimated to live with HIV infection. This presents a real challenge from a public health perspective [5] .

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From a clinical standpoint, almost every form of CVD has been reported in the HIV population, with coronary heart disease (CHD) representing the main clinical manifestation of CVD [6] , [7] , [8] .

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An increased prevalence of high-risk atherosclerotic plaques with features consistent with a destabilization has been described. The higher rates of acute coronary syndromes, particularly of ST-

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segment elevation myocardial infarction (MI), lead to high intra-hospital and one-year mortality [9] , [10] .

Despite the growing incidence of CVD in the HIV population, only limited data, mainly derived

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from non-HIV populations or small sample sized studies, allow an evidence-based approach to CVD prevention in the HIV infected patient. This would be an area calling for the development of focused research and prevention guidelines [11] , [12] . The present review attempts to summarize our understanding and current knowledge

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pertaining to primary prevention of CVD in HIV-positive patients and to highlight the substantial gaps in evidence-based recommendations in treatment.

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WHY ARE HIV PATIENTS EXPOSED TO AN INCREASED RISK OF CVD? A comprehensive understanding of CVD prevention in HIV patients needs to be viewed through the mechanisms involved in the development of CVD in this population. Pathogenesis of CVD in HIV-positive patients, even if not fully understood, is the result of the complex interplay of infection-related factors, HAART-related factors and traditional risk factors [13] (Figure 1). Role of HIV infection The existence of a relationship between HIV infection and development of CVD is suggested by the inverse correlation reported between the risk of MI and the nadir count of CD4+, as well as the increased risk of MI reported for RNA viral counts > 50 copies/ml [14] , [15] , [16] .

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HIV infection leads to an activation of the innate immune system and, despite medical therapy, this will lead to an activation of macrophages and monocytes [17] . This may suggest one mechanism

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since monocytes and macrophages play a significant role in atherogenesis. Soluble CD14 (sCD14), and, to a minor extent, soluble CD163 (sCD163), both known markers of monocyte/macrophage activation, have been identified as reliable predictors of increased atherosclerotic disease [18] ; sCD14, has been associated with an increased risk of death in HIV-positive patients [19] with a

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history of CVD in a cross-sectional study including 540 patients [20] .

Deregulation of CD8+ T-cells has also been shown to relate to adverse CVD events in HIV-positive

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patients. It has been shown in patients with higher expression of CD8(+)CD38(+)HLA-DR(+) phenotypes, higher values of carotid intimal media thickness and arterial stiffness [21] , [22] .

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HIV-positive patients on HAART therapy have high levels of systemic inflammatory response, which has been related to CVD mortality in the general population. HIV-positive patients typically have higher levels of several inflammatory cytokines (i.e., highly sensitive C-reactive protein (CRP;hs-

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CRP), and interleukin 6 (IL6)) as compared to the general population: HAART, while able to reduce these markers to lower levels as compared to HAART-naïve HIV-positive patients, is still inadequate to reach values comparable to HIV-negative patients [23] . The clinical significance of this inflammatory imbalance is confirmed by the association of increased levels of inflammatory cytokines,

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especially CRP, hsCRP, IL-6 and D-dimer (the latter reflecting also coagulation activation), with fatal and non-fatal CVD events [24] and all-cause mortality [25] .

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An area of recent interest is the association between serum levels of the microbiota-derived metabolites of phosphatidylcholine, more specifically trimethylamine (TMA), with plaque burden seen at coronary computed tomography in HIV-positive patients [26] . Analysis of these markers, which can be significantly altered in HIV-positive patients, offers a promising, relatively novel research area. It has already been shown in HIV-negative patients that higher levels of microbiota-derived metabolites, such asTMA-N-oxide are significantly related to the development of major adverse CVD events [27] . Role of antiretroviral therapy The drugs used to treat HIV infection have been associated with the development of CVD. It is felt this association is via two main mechanisms: alterations of lipid metabolism and change in particle size and, more controversial, direct detrimental effects of specific drugs. HAART is associated with increased values of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and triglycerides (TGs) and reduced values of high-density lipoprotein cholesterol (HDL-C). Untreated HIV infection

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tends to increase serum TGs and reduce levels of HDL-C, LDL-C and total cholesterol. Protease inhibitors (PIs) have been shown to lead to the development of pro-atherogenic lipid profiles.

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More controversial is the alleged association between some specific ARV drugs and the increased risk of CVD events. Studies reporting these associations are mainly registry-based or meta-analyses of observational studies and randomized clinical trials, with subsequent limitations concerning the power to account for possible bias. After the first report by the Data Collection on

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Adverse Effects of Anti-HIV Drugs (D:A:D) study group that abacavir, a nucleoside reverse transcriptase inhibitor (NRTI), may increase the risk of MI in HIV-positive patients [28] , [29] , several

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conflicting studies followed: two meta-analyses, one of which conducted by the Food and Drug Administration, did not report an increased risk associated with the use of this drug [30] , [31] ; a

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second meta-analysis from the Swiss HIV cohort showed evidence of an increased risk of CVD events associated with abacavir use. This study suggested a possible cumulative effect, which is maximized after exposure to the drug for a period of 36 months [32] , [33] . It should, however, be

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noted that abacavir is mainly used as a second or third-line drug in clinical practice, often used in patients with renal impairment or metabolic syndrome, implying that these patients present a more advanced stage of HIV infection[28].

The first-generation PIs Lopinavir and, to a lesser extent, Indinavir, have been suspected to

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increase CVD risk: by change in LDL particle size and insulin resistance. This association has been more consistent, despite being based on observational data and a meta-analysis including only one

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randomized clinical trial[32], [34] , [35] , [36] . Role of traditional risk factors Traditional risk factors for CVD contribute to the development of CVD in both HIV-positive patients as well as HIV-negative patients. The pathogenesis of CVD is often accelerated by the effects of HAART and HIV infection. Patients with HIV infection exhibit higher rates of conventional CVD risk factors [37] , [38] , [39] . A high prevalence of hypertension (HTN) and type 2 diabetes (T2D;see below) has been reported, with possible contribution of ARV therapy in their etiology. Smoking has been reported to be more prevalent in HIV populations and smoking has been demonstrated to increase the risk of CVD events to a higher extent as compared to T2D and HTN in HIV-positive patients[7], [40] . Dyslipidemia is a side effect of HAART and is to date one of the more debated topics pertaining CVD prevention and HIV, particularly concerning treatment with certain statins [41] .

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Hypertension With effective therapy HIV-positive patients are living longer and the incidence of HTN

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increases with aging [42] , [43] . It is unclear if the infection or the therapy also play a role in the increase of HTN in this population. The elastic component and vasomotor activity are altered by endothelial inflammatory processes, leading to imbalance between vasodilator and vasoconstrictor molecules [44] . The significant impairment in endothelial function is worse in patients with higher viral

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loads and intravenous drug use [45] . HAART therapy as well can contribute to the insurgence of interactions with anti-HTN drugs [46] , [47] , [48] .

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HTN, deregulating the renin-angiotensin system, provoking metabolic alterations and causing

The effective treatment of HTN in this population is thus very important to prevent CVD morbidity and

therapy in HIV-infected patients [49] .

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Diabetes

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mortality. Nevertheless only limited data are available on the standard care and efficacy of HTN

Metabolic complications in HIV-positive patients are frequent, ranging from lipodystrophy and dyslipidemia to insulin resistance and T2D [50] . Rates of disorders in glucose metabolism have been reported to range between 2 and 14% in HIV infected patients.

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The D:A:D study reported an incidence of T2D of 4.2 per 1000 per year [51] , [52] . The factors involved in the development of glucose-intolerance and T2D - age, obesity, low HDL-C and high total

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cholesterol values – also play a role in HIV-positive patients, but the pathophysiology may be more complex in this population [53] , [54] , including lipodystrophy and immunosuppression [55] . Some of the older ARV medications, such as first generation PIs and thymidine-containing analogues reverse transcriptase inhibitors were associated with drug-induced T2D. The mechanism is possibly mitochondrial toxicity and glucose transporter GLUT-4 blocking [56] , [57] . The newer ARV drugs do not seem to lead to the development of glucose disorders [58] , [59] . The systemic immune response may be another factor associated with an increased risk of T2D, through an imbalance in hs-CRP and tumor necrosis factors 1 and 2 levels [60] . Models for predicting the risk of T2D in the general population - based on age, sex, weight, glucose, blood pressure, HDL-C, TGs, parental T2D and receipt of medications - have been developed [61] , but their accuracy in HIV patients is still under investigation [62] , [63] .

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Cigarette smoking Although there has been a decrease in the prevalence of smoking in the general population,

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rates of cigarette smoking are high among HIV-positive patients, ranging between 40% and 70% of the examined population [64] . Social conditions, psychiatric comorbidities, polysubstance abuse as well as physical and mental distress have been suggested as possible reasons for this high prevalence. Smoking is associated with the development of pulmonary and CVD, with a 2 fold

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increased risk of MI in smoking patients with HIV infection [65] , [66] .

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Dyslipidemia

Dyslipidemia in HIV-positive patients in the HAART era is often made worse as a result of the

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complex interactions of antiretroviral drugs with lipid metabolism (Figure 2). All classes of antiretroviral drugs have been associated with some form of alteration of lipid

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metabolism, with non-NRTIs (NNRTIs) and, to a far greater extent, PIs are more decisively associated with the development of pro-atherogenic lipid profiles [67] . NRTIs have also been associated with alterations of lipid metabolism, but with more heterogeneous and drug-specific patterns: stavudine, zidovudine, abacavir and didanosine have been associated with increases in all lipid values (mainly total cholesterol and LDL-C, but also HDL-C and TGs), while tenofovir has been

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associated with scarce increases in lipid values, resulting in lower levels of total cholesterol, LDL-c, triglycerides and non-HDL -C, but also a decrease in HDL-C [68] , [69] .

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NNRTIs have been associated with increasing levels of total cholesterol and TGs with stable to reduced levels of HDL-c, implying a pro-atherogenic increase in non-HDL-cl[67]. These effects are similar and usually of lesser extent than those encountered with PIs. Some data suggests that NNRTIs, particularly efavirenz, may increase lipid levels to a higher extent than second generation PIs [70] . PIs are the class of drugs most often associated with alteration of lipid metabolism (increases of total cholesterol, LDL-C, TGs). In particular, the first generation PIs (Ritonavir, Saquinavir, Indinavir, Nelfinavir, Lopinavir) severely elevated lipid values, in particular TGs. These effects are partly attenuated with second generation PIs [71] . Increases in HDL-C have been reported for Ritonavirboosted regimens[69]. Patients on a PI containing regimen have been shown to have marked endothelial dysfunction, a powerful surrogate for atherosclerosis [72] . The abnormal endothelial

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function has been attributed to the altered lipid profiles, however endothelial dysfunction does not improve by switching PI therapy to atazanavir, a PI not known to negatively alter lipid profiles [73] .

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This suggests that a potentially direct toxic mechanism may be responsible for the effect of PI on the vasculature rather than the altered lipid profile.

Mechanisms by which PIs may induce these alterations of lipid metabolism are not fully understood, but are thought to involve hepatic synthesis of TGs, alterations of retinoic acid and LDL-C binding

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proteins and alterations in insulin sensitivity mediated by GLUT-4 [74] , [75] , [76] .

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HIV-positive patients are reported to develop lipodystrophy, a redistribution of body fat with peripheral loss (lipatrophy, especially face and limbs) and central accumulation, in any where from 11-83% of series reported. This can lead to visceral adipose tissue increase and accumulation in the liver, heart,

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muscles and intrathoracic region [77] . A recent systematic review failed to find a strong association between specific HAART regimens and lipodystrophy. The only consistent relationship described was between PIs and visceral abdominal lipohypertrophy[77]. Similar to the metabolic syndrome,

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lipodystrophy is also often associated with insulin resistance, T2D and alteration of lipid values[55]. Despite the worsened metabolic profile, it has been observed that this condition can sometimes reflect a “return-to-health” phenomenon by which patients positively restore their body mass due to the control of infection with antiretroviral therapy [78] . Since there is a lack of robust data connecting

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lipodystrophy to worsened CV outcome in HIV-positive patients, the approach to this condition may require a comprehensive metabolic assessment with a case-by-case evaluation.

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Pulmonary Arterial Hypertension (PAH) The association between pulmonary arterial HTN (PAH) - a disease characterized by elevated pulmonary arterial pressures and pulmonary vascular resistance - and HIV was described for the first time in 1987 by Kim and Factor and supported by other investigators [79] , [80] . The prevalence in HIV-infected patients is low (around 0.5%), but it is 25 times higher than in general population (0.02%) [81] . The pathophysiological mechanism is unknown, and multiple hypotheses have been suggested: altered endothelial function caused by chronic inflammation [82] , co-infections with other viruses (human herpes virus type 8 , hepatitis B and C ) [83] , pulmonary embolism due to intravenous drug use, protein S deficiency and a genetic predisposition [84] . The diagnosis of PAH is often difficult since symptoms are non-specific (dyspnea, oedema, nonproductive cough, fatigue, chest pain and syncope). Since symptoms and physical findings may not

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be helpful, the diagnosis is often suggested by chest X-ray, ECG or echocardiography and confirmed by right heart catheterization [85] .

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PAH therapy in HIV-infected patients is not well established: apart from HAART, the use of other drugs such as sildenafil and bosentan require close monitoring due to multiple interactions. Anticoagulation may increase the risk of bleeding and drug interactions; the effects of prostacyclin

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and prostacyclin analogues are still debated [86] , [87] , [88] . RISK STRATIFICATION

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Considering the increased prevalence of CVD events in HIV-infected patients, risk stratification is important to help tailor primary prevention, diagnostic exams and therapy on the single

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patient according to his risk. Several risk models both for the general population and specifically for HIV-positive patients have been proposed [89] . American and European guidelines use different models for assessing CVD risk, but uncertainty still remains on the best one to use in clinical practice.

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Framingham Risk Scoring (FRS) is one of the most used models; it was developed from data of Framingham Heart Study to estimate the 10-year CVD risk basing on age, sex, smoking addiction, total and HDL-C levels and systolic blood pressure in the general population [90] , [91] , [92] . Similar data are computed in the Pooled Cohort Equations for atherosclerotic CVD (ASCVD), with the

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addiction of diabetes and race [93] .

European Systematic Coronary Risk Evaluation score is another model used to predict the 10-year

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risk of a first fatal atherosclerotic event (eg, MI, stroke, aortic aneurysm) and calibrated versions exist to adjust for different death rates in European countries [94] . All of these models are non-specific for the HIV population, therefore the influence of ARV therapy and HIV infection itself is not considered. In order to identify with higher accuracy HIV-positive patients at high risk of CVD, specific models have been developed. The most widely known is the D:A:D equation, which includes classical CVD risk factors and HIV-specific variables, in particular related to HIV-therapy [95] . However, the follow-up in the D:A:D Study is still relatively short and only small data exists comparing classical risk scores and D:A:D risk equation, which still needs a larger patient follow up for validation [96] . PRIMARY PREVENTION FOR CVD IN HIV

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CV primary prevention in HIV-positive patients is limited by the lack of population-specific data. The difference in the pathogenesis of CVD in the HIV-positive patient requires a more tailored

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approach. The paucity of large-scale population-specific studies assessing CV risk prevention interventions and the many unanswered questions pertaining to the development of CVD in HIVpositive patients are the main limitations to the formulation of evidence-based recommendations with proven effectiveness. Despite the many studies highlighting the different pathogenesis of CVD in HIV-

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positive patients, no specific interventions to treat these mechanisms are available. In the subsequent paragraphs we will review and discuss the current approach to primary prevention

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of CVD in HIV-positive patients.

After risk stratification based on classic risk factors and infectious risk factors, a strategy to reduce

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CVD risk in the HIV-positive patient should be started. Guidelines on cardiovascular risk reduction in this subgroup of patients generally follow those for the general population [97] , [98] . The foundation of risk reduction should address lifestyle changes (e.g., smoking cessation, increased physical

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activity, diet, weight loss, use of lipid-lowering and anti-HTN drugs). Medical therapy in the setting of primary prevention plays a relevant role, even if it significantly resents of the many pharmacological interactions reported between ARV and CV drugs (Table 1). The health benefits of smoking cessation in the general population are well documented, with a

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progressive risk reduction along with the smoking-free time [99] . A similar trend in HIV-positive patients has been documented with data extrapolated from the D:A:D study and smoking cessation

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efforts should be a priority in the management of HIV Patients [100] . Effective treatment of HTN in HIV-positive patients is very important to prevent CVD morbidity and mortality, but data are still lacking about the compliance and the extent of HTN control. Many therapeutic options exist for the management of HTN, but additional considerations should be given to potential drug interactions between anti-HTN agents and ARV drugs [101] . Renin angiotensin system blockers (angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) may be a valuable choice, because of their beneficial effects on the vasculature, glucose metabolism and kidney function [102] . Beta-blockers and diuretics are a valid alternative, while calcium channel blockers are metabolized by cytochrome (CYP) 3A4, leading to potential interactions with NNRTIs and PIs. Since there exists a high risk of metabolic complications in HIV infected patients treated with HAART, a metabolic assessment should be performed at least annually [103] , including a lipid profile and

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hemoglobin A1C levels. Hopefully a model to predict the risk of developing T2D over time will become available. The therapeutic strategies are similar to the general population.

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Considering the increased risk of CHD among HIV-infected patients, the use of antiplatelet drugs may be an option; nevertheless little is known about the use of aspirin for primary prevention in HIV infected patients. Owing to the absence of HIV-specific guidelines, indications follow the guidelines for the general population [104] , [105] . The prescription of aspirin in primary prevention should be

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given if the level of CVD risk (based on one of the several risk models, eg, FRS or ASCVD) is high and in the absence of contraindications. Despite this recommendation, some studies have shown that

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aspirin is under-prescribed in HIV-positive patients. This is felt to be due to the high level of comorbidities, raising the risk of bleeding, and for the possible drug-drug interactions that may

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decrease antiplatelet activity [106] , [107] , [108] . Lipid lowering therapy

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Since there is a high prevalence of dyslipidemia occurring in HIV-positive patients, treatment of dyslipidemia seems to be crucial (Figure 2). Life-style interventions, as in the general population, are recommended, with a healthy diet and physical exercise. Switching medications in the HAART regimens has been proposed for patients developing dyslipidemia on therapy. This approach is based on the substitution of PIs with Atazanavir, a PI with limited effects on lipid metabolism [109] .

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However, this approach has a limited role and it is not feasible in all patients, since suppression of viral load and maintaining CD4 counts is of paramount importance.

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Statins are frequently prescribed in HIV-positive patients, but issues of safety, due to the pharmacokinetics interactions between statins and HAART, are of concern. Furthermore, the effectiveness of statin therapy in HIV-positive patients is not well established[41]. Studies analyzing statin therapy in the HIV population are mainly observational or small-sized trials with surrogate end-points [110] . The prescription of statins in HIV-positive patients is based on recommendations drawn from general population. Reference lipid values have not been defined in the HIV population, with no definite levels for initiation of lipid lowering therapies and no target values for such therapies. The Infectious Disease Society of America and the Adult AIDS Clinical Trials Group indeed propose the application of the same reference values defined in the Adult Treatment Panel III , with individual refinement based on FRS The European Society of Cardiology’s guidelines acknowledged that there exists a need for tailored reference values, but fell short to provide any recommendations due to the lack of validated data [111] , [112] .

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Safety concerns regarding statin prescription are based on the interaction of HAART and some statins with CYP system, mainly the 3A4 isoform, which can result in significant alterations of

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plasmatic levels of statins. These increased levels, potentially, can lead to increasing rates of adverse effects. PIs as a class, and particularly ritonavir, are potent inhibitors of CYP3A4, and their coadministration with statins metabolized by this pathway, especially simvastatin and lovastatin, can lead to dangerous plasma accumulation of the drug. Atorvastatin is metabolized via CYP3A4 but is

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less affected by these interactions [113] , as well as rosuvastatin, and the plasma concentrations may be partially effected. These drugs can be administered with PIs providing careful dose-adjustments and a strict monitoring of side effects. Some statins are not metabolized via CYP system and have a

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safer profile in this population [114] . NNRTIs may induce CYP3A4, leading to reductions of plasma concentrations of the statins metabolized via this system and potentially requiring dose increases of

been finally reported for NRTIs.

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statins to reach desired target lipid values[114]. No significant pharmacokinetic interactions have

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The actual clinical relevance of the pharmacokinetic interactions between HAART and statins is not clearly defined. A systematic review of 18 clinical trials failed to show significantly increased risks of statin-related adverse events [115] .

Data supporting the effectiveness of statins in HIV-positive patients are and mainly based on small

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sample sized trials and observational studies. A recent meta-analysis confirmed that statins, when appropriately prescribed and dose-adjusted for drug-drug interactions, effectively reduce lipid values in HIV-positive patients with low rates of adverse events, even when administered with NNRTIs and

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PIs [116] . Introduction of statin therapy has been also shown to be more effective in control of elevated lipids than changing from PIs to NNRTIs [117] . Effectiveness of statins on hard clinical CVD end-points has not been tested in HIV-positive patients. A retrospective, observational cohort study suggested a possible benefit of statins in HIV-positive patients with increased CVD risk, but prospective corroboration of this finding is lacking [118] . Indirect evidence suggests a potential beneficial role of statins in HIV-positive patients. A number of small clinical trials have demonstrated the ability of this therapy to positively slow subclinical parameters of CVD. Indirect markers of atherosclerosis and immune activation (sCD14 and Lysosomal phospholipase A2), endothelial function, mean carotid intima media thickness, atherosclerotic burden at coronary computerized tomography and N-terminal-proBrain Natriuretic Peptide[115],[116] have been shown to benefit from statin therapy [119] , [120] .

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The REPRIEVE clinical trial (clinicaltrials.gov: NCT02344290), a large multicenter statin trial in HIVpositive patients, has started in March 2015 randomizing HIV-positive patients to pitavastatin 4 mg, a

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statin not metabolized via CYP3A4, or placebo. The primary end-point will be a composed of major CVD events after a 6 years follow up. This study will permit eventually to more comprehensively appreciate the risk/benefit ratio of statin therapy in HIV-positive patients.

Ezetimibe can be administered to HIV-positive patients safely. This drug does not present significant

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pharmacokinetic interactions with HAART and has proven to be safe and effective in this population

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as a single agent or in combination with statins [121] , [122] . CONCLUSIONS

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HIV-positive patients are at increased risk of adverse CVD and incidence of these events is increasing due to the aging of this population in the HAART era. Pathophysiological pathways leading to CVD in this population are complex, different from general population and not fully understood.

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Interactions of infection, ARV therapy and individual factors are likely to play an important role in this respect.

Primary prevention of CVD in HIV-positive patients is challenging and is becoming a critical publichealth issue, but is to date limited by the lack of robust evidence-based, HIV-specific,

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recommendations. A comprehensive evaluation of traditional risk factors, as well as HIV-specific parameters (CD4 counts and viral load) and drug interactions, is mandatory to obtain a meaningful risk profile of these patients. Due to the lack of evidence-based interventions to reduce CVD risk in

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HIV-positive patients, we are forced to rely on guidelines from the general population. Since many of the models to predict CVD risk and to guide therapy are based on age, they will often underestimate the risk in the HIV infected patient. Treatment requires an understanding of the risk of interactions between HAART and CV drugs. Figure 1. Complex interplay of different mechanisms implied in the pathogenesis of CVD in HIVpositive patients. Figure 2. Controversial issues pertaining etiology, management and treatment of dyslipidemia in HIVpositive patients.

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Table 1. Potential pharmacological interactions and specific recommendations for the prescription of anti-hypertensive (A), anti-diabetic (B) anti-thrombotic (C), pulmonary hypertension (D) and lipid

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lowering (E) drugs in patients treated with HAART.

Table 1. Potential pharmacological interactions and specific recommendations for the prescription of anti-

drugs in patients treated with HAART.

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hypertensive (A), anti-diabetic (B) anti-thrombotic (C), pulmonary hypertension (D) and lipid lowering (E)

Anti-hypertensive drugs

Angiotensin-converting enzyme

No significant interactions

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A

(ARBs) Calcium channel blockers (CCBs): amlodipine, diltiazem

Diuretics

Potential interactions with all PIs and NNRTIs

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and verapamil

Potential interactions with PIs, NNRTIs, abacavir, zidovudine, maraviroc

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Angiotensin II receptor blockers

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inhibitors (ACEIs)

Most of them have no significant interactions. Only indapamide has

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potential interactions with emtricitabine, lamivudine, and tenofovir

Alpha blockers: Doxazosin

Potential interactions with all PIs and NNRTIs

Beta blockers

Potential interactions with atazanavir, darunavir, lopinavir, ritonavir and tipranavir. atenolol is the one with less interactions

B

Antidiabetics

Insulin

No interactions

Metformin

Almost no interactions

Sulphonylureas and Intestinal α-

Potential interactions with PIs, NNRTIs, and elvitegravir; no interactions

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with NRTIs and integrase inhibitors

C

Anti-coagulant, Anti-platelet and Fibrinolytic

Acenocumarol and Warfarin

Potential interactions with PIs, NNRTIs, and elvitegravir-cobicistat; no

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glucosidase inhibitors

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interactions with NRTIs and integrase inhibitors No significant interactions

Clopidogrel

Potential interactions with PIs, NNRTIs, and elvitegravir-cobicistat; no

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Heparin

MA

interactions with NRTIs and integrase inhibitors Prasugrel

No significant interactions

Ticagrelor

Avoid association with PIs and elvitegravir-cobicistat; potential interactions

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with NNRTIs

Dabigatran

Potential interactions with PIs, NNRTIs, and elvitegravir-cobicistat; no interactions with NRTIs and integrase inhibitors Avoid association with PIs and elvitegravir; potential interactions with

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Rivaroxaban

D

AC

NNRTIs

Drugs for Pulmonary Arterial Hypertension

Bosentan, Isosorbide dinitrate,

Potential interactions with PIs, NNRTIs and elvitegravir-cobicistat; no

Macitentan, Tadalafil

interactions with NRTIs and integrase inhibitors

Sildenafil

Avoid association with PIs and elvitegravir-cobicistat; potential interactions with NNRTIs

Sodium nitroprusside

No interactions

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Lipid lowering drugs

Simvastatin

Contraindicated in association with PIs and elvitegravir-cobicistat (risk of

RI PT

E

plasma accumulation due to interferences with the CYP3A4-mediated metabolism); NNRTIs may reduce plasma concentrations Contraindicated in association with PIs and eviltegravir-cobicistat (risk of

SC

Lovastatin

plasma accumulation due to interferences with the CYP3A4-mediated

Atorvastatin

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metabolism); NNRTIs may reduce plasma concentrations Potential interactions with PIs, co-administration allowed with careful

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monitoring Rosuvastatin

Potential interactions with PIs, co-administration allowed wiht careful

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monitoring, no relevant safety concerns from clinical studies Pravastatin

No significant interactions reported, no relevant safety concerns from clinical studies

Fluvastatin

CE

Ezetimibe

No significant interactions reported, large ongoing randomized clinical trial No signifcant interactions reported, may be co-administered with statins

AC

Pitavastatin

No significant interactions reported, few clinical data available

CE AC

Figure 1

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MA

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SC

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References

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Figure 2

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