Přehledový článek | article The power and wisdom of prevention. Cardiovascular risk, new challenge, and approach to PLWH

In recent years, quality of life is one of the important points of discussion among specialists working with people living with HIV (PLWH). With the introduction of highly effective antiretroviral therapy (1996), the expectation of life has dramati- cally increased and atherosclerotic diseases have become an important cause of morbidity and mortality in people infected with human immunodeﬁ ciency virus (HIV). Cardiovascular diseases are the third leading cause of mortality in HIV patients behind non-AIDS-related malignancies and non-AIDS-related infection. One of the many aspects in the treatment of PLWH concerns the prevention of cardiovascular diseases. The absolute risk of developing major cardiovascular disease events (CVD), for example, sudden cardiac death, cardiac arrest, and stroke in HIV-infected patients receiving antiretroviral therapy is still low. Ho-wever, this risk is increased compared to the risk of uninfected people. This fact is substantially due to a higher prevalence of traditional cardiovascular risk factors that are mostly dependent on the host. Different types of antiretroviral treatment impact differently on metabolic effects and CVD. Prevention of cardiovascular disease in HIV-infected patients is an important goal for a better quality of life. Traditional risk factors should be detected and treated vigorously when possible, to avoid the development of major adverse cardiovascular events (MACE).


Introduction
The reduction in mortality in PLWH has transformed HIV into a long-term chronic illness for many patients, characterised by an aging HIV-infected population who are increasingly affected by age-related non-communicable diseases (NCDs).
Background combination antiretroviral therapy (ART) has signifi cantly increased survival among HIV-positive adults, have dramatically reduced mortality and improved the quality of life of HIV-infected patients. Although the survival rate of the HIV-infected patient is generally lower than that of the non-HIV population. 1 Survival rates are estimated to overlap with the general population when the patient has been on antiretroviral therapy for more than 5 years with immunologic recovery. Cardiovascular diseases are the third leading cause of mortality in HIV patients behind non-AIDS related malignancies (11.8%) and non-AIDS related infection (8.2%). 2,3 For this reason, cardiovascular diseases and preventive medicine have become a focus in PLWH. 4 Initially the introduction of protease inhibitors (PIs) was associated with hyperlipidemia and consequently even a higher risk of major cardiovascular events. 5,6 However, the risk of CVD, including acute myocardial infarction, 7 sudden cardiac death, 8 stroke, 9,10 heart failure 11 and peripheral arterial disease, 12 remains signifi cantly higher than in the general population, and cannot be explained by PIs alone. 13 Some studies show a higher prevalence of cardiovascular risk factors, such as hypertension, cigarette smoking, 14 metabolic syndrom, 15 diabetes, 16 dyslipidemia, 17 and depression 18 in HIV-infected individuals compared with uninfected individuals. However, other studies have found no signifi cant differences between the two populations. These discrepancies may be related to methodological aspects or the low prevalence of cardiovascular risk factors in HIV-infected patients included in the studies. In recent years, the scientifi c community has debated the specifi c weight of each of the factors involved in this increased risk, seeking to reduce the effect of antiretroviral therapy on HIV infection and on host-dependent factors.
The distribution of HIV is very different depending on the geographic area. The economic and social situation also plays an important role. In Europe, the situation is different from the reality in sub-Saharan Africa, Latin America or Asia. In the last decade, the number of infections has remained stable in Europe, while in Asia, Latin America and Eastern Europe the percentage of infections has increased.
Access to ART and the quality of health services differ according to geographical areas. Different dietary, urban, and social habits will play an important role in the development of cardiovascular diseases. Our understanding of this question is more developed for Europe 19 and the USA, thanks to the majority of research. A summary of the most important studies is shown in Table 1.

Classic cardiovascular risk factors related to HIV patients
Specifi c mechanisms that contribute to increased CVD include smoking, diabetes, dyslipidemia, hypertension and biological sex. 20 As mentioned above, there are some regions in which exposure to any of these factors may be higher.
In PLWH, lifestyle habits, such as the consumption of toxic substances such as tobacco, alcohol, cocaine, and a sedentary lifestyle, as well as the high frequency with which patients develop dyslipidemia and insulin resistance, play a recognized role in the development of cardiovascular disease in HIV-infected persons. All these factors and its higher intensity have a recognized role in the development of cardiovascular disease in PLWH.
Smoking rates among HIV-infected adults worldwide are generally higher than in the general population. 21 Drug addicts to parenteral lattes acquire hepatitis C and/or B in almost 80-90%. It is well known that infections in general, and for example hepatitis C, are associated with an increased risk of cardiovascular disease. In the case of hepatitis B, this association has not been proven.
Although controversial, CMV infection has been associated with an increased risk of CVD in the general population and with coronary atherosclerosis in cardiac transplant recipients. It is possible that CMV-associated immune responses play a key role in the development of atherosclerosis in persons living with HIV.

Tools and based CVD prediction models
The increased CVD morbidity and mortality among HIV--infected patients warrants routine implementation of inexpensive and noninvasive risk assessment tools such as CVD risk estimation calculators. However, the predictability of existing CVD risk calculators derived and generally validated in HIV-uninfected patient populations have been variable, with many studies suggesting they may estimate CVD risk in HIV-infected patients inaccurately.

USA
The United States have historically used the Framingham Risk Score (FRS), which was developed from the Framingham Heart Study, to predict individuals' 10-year risk of developing CHD.
In 2013, the Atherosclerotic CVD (ASCVD) risk score derived from the Pooled Cohort Equation was developed by the American College of Cardiology and American Heart Association and has begun replacing the FRS. 22 The ASCVD risk score includes the variables in the FRS plus diabetes mellitus diagnosis or treatment.

Europe
There have been some widely used CVD prediction models that were derived in Europe as well. The United Kingdom utilizes the QRISK2 score to predict the 10-year risk of CVD defi ned in this case as CHD, stroke, and transient ischemic attack. 23 The Systematic Coronary Risk Evaluation (SCORE) is a risk estimator of 10-year fatal CVD derived from 12 European cohort studies mainly from general population settings. 24 Another tool was the Prospective Cardiovascu-

Mechanisms related to HIV infection
The mechanisms involved in the proinfl ammatory effects in PLWH are directly related to the presence of human immunodefi ciency virus. 20 The depletion of T lymphocytes increases intestinal permeability, altering lipid metabolism and favoring bacterial translocation. 32 CD4 depletion is associated with increased cardiovascular risk and a higher incidence of acute myocardial infarction, heart failure, peripheral artery disease, and ischemic stroke. This phenomenon is well studied and several studies have shown that infl ammatory biomarkers are elevated. 33 Many of these markers are known to be associated with atherogenesis and consequently with major cardiovascular events. Lipodystrophy may also be a contributing factor to increased cardiovascular risk due to metabolic changes. Lipodystrophy, which is an abnormal distribution of body fat, occurs as a result of HIV infection and, in fact, with some antiretroviral drugs. This fat change can be in the form of lipoacoumulo, with an increase in fat in the abdomen, breasts and/or buffalo hump, which remembers the metabolic syndrome in the HIV-infected patient to show the same metabolic changes. It can also manifest as lipoatrophy, with loss of fat from the extremities and face. It is not uncommon for patients to have mixed lipodystrophy. Lipodystrophy is associated with dyslipidemia and insulin resistance. 34

Atherosclerosis
Atherosclerosis is considered a chronic infl ammatory process. HIV infection is known to cause endothelial dysfunction. HIV infects smooth muscle cells in in vitro and in vivo studies and promotes the secretion of infl ammatory cytokines.
The differences between atherosclerosis in patients without HIV and PLWH are morphological. Imaging studies confi rm these differences. Techniques such as ultrasound and computed tomographic angiography show a higher prevalence of hypogenic plaques and a higher incidence of CV events. [35][36][37] Using angiographic computed tomography, noncalcifi ed plaques are more com-lar Münster (PROCAM) score that was derived from a German cohort of industrial employees to predict the risk of CVD. 25 Nonetheless, the various risk prediction models also share some similarities with signifi cant overlap of predictive variables and derivation from high-income European countries or American cohorts.
None of the CVD risk estimation tools described above were derived from HIV-infected populations, and therefore they may not adequately predict the risk of developing CVD in HIV-infected patients  26 An interesting study compares cardiovascular risk prediction scores in HIV-infected patients: the Framingham, Atherosclerotic Cardiovascular Disease risk score (ASCVD), Systematic Coronary Risk Evaluation for the Netherlands (SCORE-NL), and Data Collection on Adverse Events of Anti-HIV Drugs (D:A:D) risk prediction models and concluded that when using FHS-CVD and FHS-CHD, a higher overall CVD risk was attributed to the HIV-infected patients than when using the D:A:D, ASCVD, and SCORE-NL models. 27 An other interesting study was derived from people living with HIV engaged in care at JPS Health Network (JPS), a large, urban safety-net health system in North Texas. They estimated the predicted 5-year risk of CVD using and validating the original or updated D:A:D model for HIV populations fi nding that the HIV D:A:D model may be useful for decisions about CVD intervention for high--risk patients. 28 Recently in a study conducted in Germany, Framingham Risk Score (FRS), the Systematic Coronary Risk Evaluation (SCORE) and the Atherosclerotic Cardiovascular Disease (ASCVD) risk score in PLWH were compared with the general population to quantify score-specifi c differences in risk prediction. Associations between risk scores and future CVD were observed in both cohorts, but the score performances were less reliable in PLWH than in the general population. 29 Depending on the population to be studied and until a new CVD risk assessment tool has been derived and validated in the HIV population, we are left to apply and choose between FRS, or the newer ASCVD risk score to HIV-infected patients 30 or the D:A:D cardiovascular disease risk score that has recently been updated to facilitate use in everyday clinical practice ( Table 2). 31

Endothelial dysfunction and novel biomarkers
Endothelial dysfunction is prevalent among HIV-infected patients despite successful administration of antiretroviral drugs. It is important to recognize that these are surrogate markers of subclinical disease that do not necessarily translate into observed CVD events. 39 Endothelial function could be measured with noninvasive methods like blood-based biomarkers, such as endothelial leukocyte adhesion molecule-1 (E-selectin), soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), von Willebrand factor (vWF), TNF-, interleukin 6 (IL-6) and soluble thrombomodulin (sTM). 40 In addition to mortality, higher circulating infl ammatory markers are associated with contemporaneous insulin resistance or the future risk of diabetes in PLWH.

Factors associated with antiretroviral therapy
The adverse effects of ART in CVD must be balanced against the benefi cial effects of the therapy. Older ART regimens (e.g. abacavir, lopinavir, and ritonavir) had adverse effects on glucose metabolism, lipids, and mitochondrial toxicity. Weight gain after initiation of ART and viral suppression partly refl ects the effects of viral suppression. 41 HIV patients undergoing cART exhibit a partial reversal of immune activation and infl ammation. Additionally, cART reduces opportunistic infections and cardiovascular risk factors, which is likely a result of some reduction in infl ammation, although residual markers of infl ammation and coagulation remain elevated in ART--treated HIV-infected patients.
There are currently 6 major groups of antiretroviral drugs. The scientifi c community has made many efforts to try to catalogue the cardiovascular risk of antiretroviral drugs. The impact of each on cardiovascular disease is diffi cult to assess for the following limitations: a) It is necessary to combine two or three drugs to achieve viral suppression. b) Continuous treatment reduces the risk, but some drugs alone increase this risk. c) The increased risk due to ART would be mediated by abnormalities of lipid metabolism, other metabolic alterations are still poorly understood, such as coagulation alterations. d) The increase in cardiovascular risk increases gradually with years of treatment. e) The change from antiretroviral medication to less toxic ones makes it diffi cult to assess the real risk. f) The follow-up is relatively short. g) And ad least ART history is unclear, and most do not have uninfected HIV controls. Historically with the administration of ART and the emergence of protease inhibitors (PIs), cases of early atherosclerosis and myocardial infarction began to emerge in HIV-infected patients. The temporal relationship between these facts suggested some causality. The possible cardiovascular effect of these early PIs (nelfi navir or ritonavir in high doses) was mainly because they caused signifi cant metabolic and fatty changes. Since then, new drugs and even new therapeutic targets have emerged. Current antiretroviral therapy generally requires a combination of three or two active drugs 42 for sustained control of HIV replication and avoid resistance.
Until now the largest prospective cohort study that compiles data on adverse effects of anti-HIV drugs (the DAD study with more than 23.000 consecutive patients), the incidence of myocardial infarction is low (3.5 cases per 1.000 person-years), and conventional cardiovascular risk factors show a higher relative contribution to the development of myocardial infarction than PI exposure. In this study, the relative risk attributable to PIs (16% increase in risk of drug exposure per year) was halved after adjustment for increases in total cholesterol and decreases in HDL cholesterol, suggesting that a substantial portion of the risk attributable to PIs cannot be explained solely by lipid changes. The DAD cohort evaluated the contribution of each NRTI to the risk of myocardial infarction and the results were surprising. Contrary to expectations, patients taking thymidine analog inhibitors were not associated with increased cardiovascular risk, despite their contribution to dyslipidemia, insulin resistance, and lipoatrophy. Surprisingly, exposure to abacavir or didanosine in the past 6 months was associated with a 90% and 50% increased risk of myocardial infarction, respectively, after adjustment for several cardiovascular factors. Interestingly, the excess risk as described by the authors quickly disappears after treatment. The relative risk associated with these patients was higher in those with high cardiovascular risk. 43 Also in the SMART study (Strategies for Management of Antiretroviral Therapy), 44 the episodic use of ART was compared with continuous ART. During 16 months of follow up, the episodic use of ART was associated with an increased risk of death and opportunistic infections including an increase in CV events. Infl ammatory and coagulation biomarkers in SMART, namely IL-6 and D-dimer, were strongly related to all-cause mortality, suggesting that this was the mechanism whereby intermittent ART increased the risk. 45 In the SMART study, the use of abacavir (but not didanosine) is associated with excess risk of myocardial infarction and other cardiovascular events. The increased risk is not due to lipid changes, according to both studies. Researchers found higher levels of infl ammatory markers in patients taking abacavir than in those who did not, suggesting a potential fi re mechanism. Another alternative for pathogenesis speculates that abacavir may interfere with the pro-infl ammatory signaling molecules tri-adenosine (ATP) and diphosphate (ADP) present in vascular endothelial cells. 46 No defi nitive conclusions can be drawn from the currently available data. The fact that abacavir is associated with an excess risk of myocardial infarction according to the DAD cohort does not necessarily imply that abacavir plays a causal role.
A different group of ART, NNRTI, shows a superior cardiovascular profi le compared with the PI family in clinical trials. The results are not limited exclusively to a higher increase in HDL cholesterol, but also to a de-crease in procoagulant markers and to a lower oxidative stress.
Other recent studies with integrase inhibitors suggest that dyslipidemia was less common in patients treated with the INSTI regime. Dyslipidemia was less common with INSTI than with PI/b. Compared with dolutegravir, dyslipidemia was more common with elvitegravir/cobicistat and raltegravir, but less common with rilpivirine. 47 Other studies show that the risk of CVD in PLWH on INSTI-based regimens were associated with a 43% decreased risk of CVD. Authors agree that validation of these fi ndings in cohorts with longer follow-up is needed (Table 3). 48 Aging patients with HIV, like the general population, tend to have polypharmacy, which increases drug interactions and consequent adverse reactions.

Insulin resistance and ART
It is generally accepted that there is a correlation between innate immune system activation and insulin resistance, which contributes to glucose metabolism dysregulation and dyslipidemia. However, untreated HIV patients display an enhanced infl ammatory state, which is characterized by high levels of proinfl amma-tory cytokines, like tumor necrosis factor-alpha (TNF-), and interleukins (IL-6 and IL-1), and is associated with a procoagulant state. Under these conditions, the insulin resistance is probably severe and could occur in the liver, muscle, and adipose tissue. In fact, severe insulin resistance in the adipose tissue (as observed in HIV untreated patients), may prevent adipose mass gain as described in mice. 49 Protease inhibitors (PI) or nucleoside analog reverse transcriptase inhibitors (NRTI) have been shown to induce insulin resistance, dyslipidemia, and lipodystrophy, and consequently, increase cardiovascular risk. 50 Insulin resistance can be caused by specifi c in vitro drugs, including indinavir and other fi rst-generation IPs. Clinical trials that initiate treatment with different long-term PIs (such as lopinavir/ritonavir, saquinavir/ritonavir, or tipranavir/ritonavir), moreover, do not show signifi cant changes in insulin sensitivity when the ART regimen does not include NRTIs. Thymidine analogous (NRTIs) such as stavudine and zidovudine, have been associated with increased insulin resistance in healthy volunteers; similarly, didanosine or thymidine analogs have been described in large cohort studies of HIV-infected patients to confer an increased risk of diabetes mellitus (Table 4). No association found between rate of MI and cumulative or recent zidovudine, stavudine, or lamivudine use

Conclusion
The absolute risk of cardiovascular disease in HIV-infected patients on antiretroviral therapy is low. However, this risk of cardiovascular disease in HIV-infected patients is higher compared with uninfected individuals. This is due, at least in large part, to the higher prevalence of classic cardiovascular risk factors. In addition, HIV infection may contribute to this risk through immunological activation, infl ammation, and immunodefi ciency. Also, although compared with HIV infections, the type of antiretroviral therapy may contribute to increased cardiovascular risk, primarily through metabolic changes, body-level changes, and other factors that are currently unclear. From a purely cardiovascular perspective, the benefi ts of antiretroviral therapy outweigh the potential risks. A big fi eld in PLWH is the prevention of major adverse cardiovascular events. Since HIV is becoming a chronic disease, it is necessary to think about the prevention of cardiovascular disease. Starting from the basics such as education of good alimentary habits, physical activity, reducing alcohol, and treating drug consumption. In outpatients, it's necessary to control blood pressure values, the lipid profi le, and have EKG recordings. Stress testing, echocardiography, cardiac magnetic resonance, and radionuclide imaging are also effective methods to identify patients who have a less coronary reserve.
Currently, there are programs that allow warning of drug interactions. The treating physician should prevent possible adverse interactions by looking for alternatives in therapy.
As can be seen, a complex and complete approach is required in the HIV patient. PLWH are not the same patients of 30 years ago when the main goal was practically to avoid opportunistic infections in patients already diagnosed late. As the morbidity and mortality from CVD in the HIV population increases, preventive and therapeutic efforts to provide these patients with the best care must increase as well. This all begins with an accurate CVD risk assessment.