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===Immune dysfunction and immune activation===
===Immune dysfunction and immune activation===
Several studies have indicated that immune dysfunction is associated with CVD risk among HIV-infected patients. CD4+ T-cell counts of <500/IL have been associated with an increase in cardiovascular events, independent of traditional CVD risk factors or ART, carrying an additive risk comparable with that of smoking or sub-optimally treated LDL cholesterol levels ( ). CD4+ T-cell counts of <200/IL were associated with an increased risk of AMI, which was comparable in magnitude to the risk imposed by traditional CVD risk factors ( ). Consistently, episodic CD4+ cell count-guided ART is associated with a substantial increase in risk for AMI compared with continuous ART, indicating an important role of viral load and immune dysfunction for the extent of CVD risk ( ). Moreover, several studies have shown a decrease in non-AIDS related events following the start of ART, and a notable increase in CVD events in patients with incomplete immune recovery following start of ART ( ). In addition, the risk of AMI was recently shown to be significantly increased in patients with a recent episode of immune dysfunction defined as CD4 count <200 or HIV-RNA count of >500 copies ( pmid=22112603). It can therefore be acknowledged that (residual) compromise of immune function is an important determinant of risk for CVD as well.
Several studies have indicated that immune dysfunction is associated with CVD risk among HIV-infected patients. CD4+ T-cell counts of <500/IL have been associated with an increase in cardiovascular events, independent of traditional CVD risk factors or ART, carrying an additive risk comparable with that of smoking or sub-optimally treated LDL cholesterol levels.<cite>50</cite> CD4+ T-cell counts of <200/IL were associated with an increased risk of AMI, which was comparable in magnitude to the risk imposed by traditional CVD risk factors.<cite>51</cite> Consistently, episodic CD4+ cell count-guided ART is associated with a substantial increase in risk for AMI compared with continuous ART, indicating an important role of viral load and immune dysfunction for the extent of CVD risk.<cite>52</cite> Moreover, several studies have shown a decrease in non-AIDS related events following the start of ART, and a notable increase in CVD events in patients with incomplete immune recovery following start of ART.<cite>53</cite><cite>54</cite> In addition, the risk of AMI was recently shown to be significantly increased in patients with a recent episode of immune dysfunction defined as CD4 count <200 or HIV-RNA count of >500 copies.<cite>55</cite> It can therefore be acknowledged that (residual) compromise of immune function is an important determinant of risk for CVD as well.
 


===Virologic Suppression and the Risk of CVD===
===Virologic Suppression and the Risk of CVD===
The associations discussed in the previous sections may implicate that suppression of HIV replication, and normalization of inflammation and immune function by (c)ART mitigates the associated CVD risk. However, even viral replication suppression with (c)ART does not fully normalize these processes, and even residual levels may result in adverse cardiovascular outcome. Concordantly, it was shown that carotid intima media thickness is increased in all HIV-infected subgroups compared with controls, including HIV-infected patients that maintain an undetectable HIV viral load without the use of (c)ART ( ). This finding was independent of prior ART exposure duration, viremia, or advanced immunodeficiency. Moreover, a recent large cohort study of HIV-infected patients compared with age and CVD-risk matched non-infected controls including more than 80.000 subjects indicated that, although mitigated by virologic suppression, the risk for CVD, and AMI in particular, remains present despite virologic suppression ( ).
The associations discussed in the previous sections may implicate that suppression of HIV replication, and normalization of inflammation and immune function by (c)ART mitigates the associated CVD risk. However, even viral replication suppression with (c)ART does not fully normalize these processes, and even residual levels may result in adverse cardiovascular outcome. Concordantly, it was shown that carotid intima media thickness is increased in all HIV-infected subgroups compared with controls, including HIV-infected patients that maintain an undetectable HIV viral load without the use of (c)ART.<cite>56</cite><cite>57</cite> This finding was independent of prior ART exposure duration, viremia, or advanced immunodeficiency. Moreover, a recent large cohort study of HIV-infected patients compared with age and CVD-risk matched non-infected controls including more than 80.000 subjects indicated that, although mitigated by virologic suppression, the risk for CVD, and AMI in particular, remains present despite virologic suppression.<cite>58</cite>


In summary, the available evidence indicates that CVD in HIV-infected population is indeed a complex multi-factorial process, which etiology goes beyond the role of traditional risk factors, and beyond the effects of antiretroviral medication. HIV-infection related factors, as well as persistent inflammation and immune dysfunction most probably constitute important additional factors resulting in premature atherosclerosis and accelerated ageing even when the viral replication is suppressed.
In summary, the available evidence indicates that CVD in HIV-infected population is indeed a complex multi-factorial process, which etiology goes beyond the role of traditional risk factors, and beyond the effects of antiretroviral medication. HIV-infection related factors, as well as persistent inflammation and immune dysfunction most probably constitute important additional factors resulting in premature atherosclerosis and accelerated ageing even when the viral replication is suppressed.


==Prevention of CVD in HIV-infected patients==
==Prevention of CVD in HIV-infected patients==
As a corollary of the aforementioned interplay of CVD risk factors and HIV-infection/–therapy, it may be appreciated that prevention of CVD in HIV-positive patients should be emphasized, especially in the light of the contemporary life expectancy of this patient population. In general, cardiovascular therapy guidelines aimed at prevention of CVD in HIV-patients follow those for the general population, although some HIV-related factors must be taken into consideration ( ).  
As a corollary of the aforementioned interplay of CVD risk factors and HIV-infection/–therapy, it may be appreciated that prevention of CVD in HIV-positive patients should be emphasized, especially in the light of the contemporary life expectancy of this patient population. In general, cardiovascular therapy guidelines aimed at prevention of CVD in HIV-patients follow those for the general population, although some HIV-related factors must be taken into consideration.<cite>59</cite>
Special emphasis should focus upon the identification and treatment of dyslypidemia, which is frequently present in HIV-infected patients, and which is known to occur in reponse to the start of (c)ART therapy, with a particular association with PIs ( ) and first generation NRTIs ( ). Therefore, assessment of lipid status, especially triglycerides, should be performed prior to the start of cART therapy, at 3-6 months after initiation of therapy, and at least yearly in the absence of abnormalities. A special point of care lies within lipid-lowering therapy in concomitance with cART treatment, because of the possibility of interaction between statins and for example PIs and NNRTIs ( ). The primary mode of interaction is seen through the cytochrome P450 (CYP) pathway. PIs mainly inhibit CYP, and could therefore lead to toxicity of statins as these drugs are most frequently metabolized through particular CYP pathways. NNRTIs are associated with CYP induction, leading to impairment of statin efficacy. Statins not or only mildly associated with CYP interactions include rosuvastatine and pravastatin, and may therefore be considered in HIV-infected patients on cART. More novel statins, such as pitavastatin, without CYP interaction have not yet been evaluated in this setting. Ezetemibe, which is not metabolized through the CYP pathway, may be considered in addition to statin therapy or as stand-alone therapy when statin therapy leads to unendured side effects. Nonetheless, statin therapy should be tailored to the specific situation and side effects or inefficacy of agents may necessitate statin or cART agent switch along the way. Especially when cART leads to a subsequent severe dyslipidemia, switching to another cART combination may be considered ( pmid=23369416). However, no clinical trials have been performed on this subject, and therefore the best approach remains patient-tailored. Moreover, in the light of the complex interplay between all CVD risk factors discussed in the previous paragraphs, it is important to note that the actual role of statin therapy in primary prevention in HIV-infected patients has not been established to date. Nonetheless, the evidence to date indicates a very important role of dyslipidemia in the CVD-risk associated with HIV-infection and –therapy, and optimal medical therapy should be pursued.
 
In addition, smoking cessation should be actively pursued in patients with HIV, because of its high prevalence and associated increase in CVD risk in this patient population, as well as the significant benefit of smoking cessation ( pmid=21251183). The recent smoking cessation guidelines consequently indentified the HIV-infected population as and important target population for smoking cessation therapy, both interms of counseling as well as medical therapeutic strategies ( pmid=18617085).
Special emphasis should focus upon the identification and treatment of dyslypidemia, which is frequently present in HIV-infected patients, and which is known to occur in reponse to the start of (c)ART therapy, with a particular association with PIs<cite>60</cite> and first generation NRTIs.<cite>61</cite> Therefore, assessment of lipid status, especially triglycerides, should be performed prior to the start of cART therapy, at 3-6 months after initiation of therapy, and at least yearly in the absence of abnormalities. A special point of care lies within lipid-lowering therapy in concomitance with cART treatment, because of the possibility of interaction between statins and for example PIs and NNRTIs.<cite>62</cite> The primary mode of interaction is seen through the cytochrome P450 (CYP) pathway. PIs mainly inhibit CYP, and could therefore lead to toxicity of statins as these drugs are most frequently metabolized through particular CYP pathways. NNRTIs are associated with CYP induction, leading to impairment of statin efficacy. Statins not or only mildly associated with CYP interactions include rosuvastatine and pravastatin, and may therefore be considered in HIV-infected patients on cART. More novel statins, such as pitavastatin, without CYP interaction have not yet been evaluated in this setting. Ezetemibe, which is not metabolized through the CYP pathway, may be considered in addition to statin therapy or as stand-alone therapy when statin therapy leads to unendured side effects. Nonetheless, statin therapy should be tailored to the specific situation and side effects or inefficacy of agents may necessitate statin or cART agent switch along the way. Especially when cART leads to a subsequent severe dyslipidemia, switching to another cART combination may be considered.<cite>63</cite> However, no clinical trials have been performed on this subject, and therefore the best approach remains patient-tailored. Moreover, in the light of the complex interplay between all CVD risk factors discussed in the previous paragraphs, it is important to note that the actual role of statin therapy in primary prevention in HIV-infected patients has not been established to date. Nonetheless, the evidence to date indicates a very important role of dyslipidemia in the CVD-risk associated with HIV-infection and –therapy, and optimal medical therapy should be pursued.
In the presence of hypertension, renin angiotensin system blockers are considered first choice owing to their global protective effects on kidney function, glucose metabolism, and the vasculature in general ( pmid=23369416).
 
In addition, smoking cessation should be actively pursued in patients with HIV, because of its high prevalence and associated increase in CVD risk in this patient population, as well as the significant benefit of smoking cessation.<cite>64</cite> The recent smoking cessation guidelines consequently indentified the HIV-infected population as and important target population for smoking cessation therapy, both interms of counseling as well as medical therapeutic strategies.<cite>65</cite>


Antiplatelet regimens have not extensively been investigated in HIV-infected populations and it is therefore currently advocated to adhere to general antiplatelet guidelines. In particular aspirin treatment should be initiated as in the general population in the presence of high CVD risk when contraindications are absent ( pmid=22809746). For more aggressive antiplatelet agents, including clopidogrel, prasugrel and ticagrelor, recent investigations have implicated interactions between cART and these potent platelet inhibitors. Ritonavir, a PI-subclass ART, in particular was found to impair prasugrel activity in in vitro experiments ( pmid=21550074). Furthermore, ticagrelor is metabolized by CYP and is contraindicated in patients on PI therapy, in particular in those patients using ritonavir (both ritonavir and ticagrelor are associated with the CYP 3A4/5 pathway) ( pmid=21177984). Although the stent-thrombosis rates in HIV-infected patients after percutaneous coronary intervention and coronary stent implantation have not been found to be substantially higher compared with the general population, it should be borne in mind that evidence on the effectiveness of antiplatelet therapy in terms of platelet activity is very limited, and residual platelet activity levels may well play a role in a particular patient.  
In the presence of hypertension, renin angiotensin system blockers are considered first choice owing to their global protective effects on kidney function, glucose metabolism, and the vasculature in general.<cite>66</cite>
 
Antiplatelet regimens have not extensively been investigated in HIV-infected populations and it is therefore currently advocated to adhere to general antiplatelet guidelines. In particular aspirin treatment should be initiated as in the general population in the presence of high CVD risk when contraindications are absent ( ). For more aggressive antiplatelet agents, including clopidogrel, prasugrel and ticagrelor, recent investigations have implicated interactions between cART and these potent platelet inhibitors. Ritonavir, a PI-subclass ART, in particular was found to impair prasugrel activity in in vitro experiments ( ). Furthermore, ticagrelor is metabolized by CYP and is contraindicated in patients on PI therapy, in particular in those patients using ritonavir (both ritonavir and ticagrelor are associated with the CYP 3A4/5 pathway) ( ). Although the stent-thrombosis rates in HIV-infected patients after percutaneous coronary intervention and coronary stent implantation have not been found to be substantially higher compared with the general population, it should be borne in mind that evidence on the effectiveness of antiplatelet therapy in terms of platelet activity is very limited, and residual platelet activity levels may well play a role in a particular patient.  


==Clinical presentation and revascularization==
==Clinical presentation and revascularization==
Clinical presentation of advanced CVD in HIV-infected patients involves an equivalently wide spectrum as in the general non-infected population ( pmid=1731952). Nonetheless, as may be appreciated from the previous sections, clinical presentation is predominated by the occurrence of acute coronary syndrome (ACS) ( pmid=12888138, 12739013). Acute coronary syndrome typically occurs in males, at a relatively young age (<50 years of age), in particular in those patients with a prolonged known HIV-infection (>8 years), who remain on (c)ART. The most frequent presentation occurs with an ST-segment elevation myocardial infarction. Nevertheless, presentation with non-ST-segment elevation myocardial infarction and unstable angina occur frequently as well  pmid=1731952, 12739013, 14691419, 12588205). Contrariwise, stable CVD is less frequent. The extent of coronary artery disease in general does not differ between HIV-infected and non-infected populations (12739013).
Clinical presentation of advanced CVD in HIV-infected patients involves an equivalently wide spectrum as in the general non-infected population ( ). Nonetheless, as may be appreciated from the previous sections, clinical presentation is predominated by the occurrence of acute coronary syndrome (ACS) ( ). Acute coronary syndrome typically occurs in males, at a relatively young age (<50 years of age), in particular in those patients with a prolonged known HIV-infection (>8 years), who remain on (c)ART. The most frequent presentation occurs with an ST-segment elevation myocardial infarction. Nevertheless, presentation with non-ST-segment elevation myocardial infarction and unstable angina occur frequently as well  ( ). Contrariwise, stable CVD is less frequent. The extent of coronary artery disease in general does not differ between HIV-infected and non-infected populations ( ).
Clinical outcome after revascularization (predominantly for ACS) is similar for HIV-infected and non-infected populations, regardless of whether revascularization is performed percutaneously or surgically ( pmid=16537777, 18288976). HIV-infected patients, however, do remain at increased risk for recurrent ACS during follow-up ( pmid=20965887), which is importantly associated with persistently elevated lipid spectra.
Clinical outcome after revascularization (predominantly for ACS) is similar for HIV-infected and non-infected populations, regardless of whether revascularization is performed percutaneously or surgically ( ). HIV-infected patients, however, do remain at increased risk for recurrent ACS during follow-up ( ), which is importantly associated with persistently elevated lipid spectra.


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</biblio>
</biblio>
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