Evidence-Based Decisions in Human Immunodeficiency Virus Infection and Cardiac Disease

Fig. 6.1

As the frequency of the use of antiretroviral therapy, including PIs, increased in HIV–infected patients, their mortality during this same time period decreased [107]

6.2 Pericarditis

The most frequent clinical manifestation of cardiovascular disease in patients with AIDS is pericardial disease. Pericardial effusion is the most frequent type of effusion associated with HIV in about one third of cases [16]. Echocardiographic studies have identified a pericardial effusion in approximately 20% of these patients [53, 97].
Incidence of pericardial effusion in HIV patients before the introduction of treatment with HAART was found to be 11% per year in one study [47]. The incidence after introducing HAART is unknown [88].
The picture of clinical pericarditis is similar to that of pericarditis from etiologies other than HIV. Some patients are symptomatic with fever, pleuritic chest pain. However, most patients present with an asymptomatic increase in the cardiac silhouette on chest X-ray.
Patients with pericardial effusion have shorter 6 month survival rate than AIDS patients without pericardial effusion (36% vs. 93%) [88]. Overall, the development of pericardial effusion in a patient with AIDS is a bad prognostic sign, even if asymptomatic [14, 46].

6.3 Coronary Artery Disease

6.3.1 Clinical Features of CAD in HIV Patients

Typical HIV patient with coronary artery disease is a male, smoker, with very low HDL cholesterol, and significantly younger than non-HIV patients with coronary artery disease. The main studies addressing these features are summarized in Table 6.1 [88].

Table 6.1

Clinical features of coronary disease in HIV patients [35]
Study
Patients (n)
Age (years)
Current smoking (%)
CD4 count (cells/mm3)
PI use (%)
MI on presentation (n) (%)
Single-vessel disease (n) (%)
David et al. [53]
16
43*
81
234 (74–731)*
69
8/16 (50)
NA
Matetzky et al. [88]
24
47 ± 9
58
318 ± 210
71
24 (100)
5/21 (24)
Escaut et al. [46]
17
46 ± 6
71
272 ± 185
65
11/17 (65)
9/17 (53)
Mehta et al. [82]
129a
42 ± 10
NA
313 ± 209
NA
82/106 (77)
26/76 (35)
Ambrose et al. [14]
51
48 ± 9
55
426 ± 290
59
34/51 (67)
21/45 (47)
Varriale et al. [54]
29
46 ± 10
55
>500 in 18/29
66
29 (100)
NA
Hsue et al. [108]
68
50 ± 8
68
341 (3–4360)*
49
37/68 (54)
20/56 (36)
NA not reported
*Median value; all other values are means
aPatients drawn from 25 previous reports
HIV-infected patients with acute coronary syndromes differ in several ways from other ACS patients. Apart from being more than a decade younger than controls, the HIV patients were more likely to be male and current smokers and have low HDL cholesterol. Although they have less extensive coronary disease, they have a significantly higher rate of restenosis after PCI than other ACS patients.
The most common presentation of CAD among patients with HIV disease is myocardial infarction (MI), and 67% of HIV patients presented with acute MI. It is interesting that majority of cases are males; only 9% were females.
In a small French study, patients treated with PIs had almost a threefold increase in the risk of MI compared with untreated HIV-infected patients, suggesting that rapidly forming drug-induced plaques are unstable and prone to rupture [75].
A retrospective analysis of two large cohorts of patients with HIV infection over the course of an 8-year period showed that MI rates in patients receiving PI therapy were 5 times greater than MI rates in those not on such therapy [59]. This relative increase risk was explained partly by dyslipidemia [110].
Regarding cholesterol profile in HIV patients with acute coronary syndrome, mean HDL cholesterol level was very low, reported between 28 and 35 mg/dL which is significantly lower than those of HIV patients without coronary artery disease and lower than non-HIV control patients with coronary artery disease. In one study, mean LDL was much higher in these HIV patients in comparison with those without coronary artery disease.
In one report, HIV patients diagnosed with acute coronary syndrome, on an average are 11 years younger than control non-HIV patients with acute coronary syndrome.
The HIV patients have frequent single coronary artery disease, low TIMI score (blood flow in the coronary artery which is determined by angiogram). Coronary angiogram and revascularization has the same indications as in non-HIV patient with coronary artery disease. Coronary angioplasty and stent placement have very good immediate results. Interestingly, HIV-infected patients who had undergone coronary percutaneous intervention had a significantly higher rate of restenosis compared with their HIV-negative counterparts, after both balloon angioplasty and bare metal stent placement; data are not available for the drug eluting stent [88]. For example, in one study, restenosis has developed in 15 of 29 HIV patients compared with 3 of 21 non-HIV patients. It means that the rate of restenosis in HIV patients is 52% vs. 14% in non-HIV patients (p = 0.006) [54].
Regarding coronary artery revascularization by coronary bypass surgery, no long-term follow-up data are available [88]. Median age for bypass surgery HIV patients was 44 years [54].

6.3.2 Cardiovascular Risk Factors in HIV Patients

Many studies have demonstrated high rates of cardiovascular risk factors in patients with HIV infection. Some of these, such as dyslipidemia, diabetes mellitus, hypertention, chronic inflammation, altered immune system function, and metabolic syndrome, may be related to HIV infection or to HIV therapies. Others, such as high smoking rates, are independent of HIV infection. More than half of HIV patients are smokers at the time of the coronary event. Dyslipidemia and alterations in serum lipid values have been reported in HIV-infected patients.
Lower CD4 count in untreated HIV patients are associated with lower total cholesterol, lower HDL, and higher TG [43].
The proportion of patients receiving Protease Inhibitors (PIs) ranged from 49 to 71%.
In one study, a 10-year coronary heart disease risk of >20% was twice as common among patients receiving combination antiviral therapy (ART) as in a matched control group without HIV infection, 11.9% vs. 5.3%, respectively [54].
In one report of HIV-infected patients, total cholesterol exceeded 240 mg/dL in 27% of those receiving a PI, 23% of those receiving an NNRTI, 44% of those receiving a PI and an NNRTI, and 10% of those receiving only an NRTI, compared with 8% of patients not receiving ART [70]. Triglyceride levels above 200 mg/dL were present in 40% of PI-treated patients, 32% of those treated with NNRTIs, 54% of those receiving both PIs and NNRTIs, 23% of NRTI-treated patients, and 15% of the untreated.
Insulin resistance and hyperglycemia appear to be more common in persons with HIV infection than in uninfected individuals. Patients receiving ART may have even higher rates of insulin resistance and diabetes, and certain ARV medications, such as Indinavir, may confer greater risk than others [81, 111].
Hypertension occurs in up to one third of patients with HIV infection [37, 57]. NNRTIs or PIs have been linked to hypertension in some studies but not in others [13, 17, 57]. The hypertension associated with HIV appears to be linked to insulin resistance and the metabolic syndrome [37].

6.3.3 Pathogenesis of Atherosclerosis in HIV Patients

HIV disease is in itself atherogenic which is associated with accelerated T-cell proliferation, heightened T-cell activation, and high levels of inflammatory markers [45, 48]. T lymphocytes play a key role in parthenogenesis [44, 56, 112]. CD4 cell activation promotes atherosclerosis through proinflammatory cytokines such as tumor necrosis factor and interleukins [36]. Chronic low-grade inflammation accelerates atherosclerosis [71]. C-reactive protein levels are higher in HIV patients than in control subjects [55]. Some data indicate that C-reactive protein is an active participant in the process of atherosclerosis [84, 113].
Monocyte chemoattractant protein-1 is a potent activator of macrophages and monocytes, stimulating them to migrate to the subendothelial space where they begin phagocytosis of modified lipoproteins to become lipid-laden foam cells, an early step in atherogenesis. Among HIV patients with subclinical atherosclerosis by carotid and femoral ultrasound, monocyte chemoattractant protein-1 plasma levels were higher compared with HIV patients without atherosclerosis [1].
Coagulation abnormalities are another factor that would predispose HIV patients to thrombotic events [99]. Protein S deficiency is the most common, reported in 73% of HIV-infected men in 1 study [103]. Serum levels of Von Willebrand factor are higher in untreated HIV patients than in control subjects, reflecting endothelial activation, but tend to decrease toward normal with HAART. Platelet activation also increases in HIV patients [5]. Smoking cigarettes activates platelets and increases coagulability, and smoking rates are very high in HIV patients [88].
So, endothelial dysfunction, inflammation associated with platelets activation and hypercoagulation can explain the increased atherogenesis and thrombosis of the arterial wall in HIV positive patients.
On the other hand, PIs induce deleterious metabolic effects such as dyslipidemia and insulin resistance which has been shown to induce atherosclerosis in HIV patients [12].

6.3.4 Endothelial Dysfunction and HIV Infection

HIV can damage endothelium through several mechanisms. Tat protein is a small cationic polypeptide released from infected cells, interacts with different types of receptors present on the surface of endothelial cells, activating signal transduction pathways and triggers the expression of adhesion molecules, vascular endothelial growth factor, and platelet activation factor [94].
Moreover, the death of CD4 T lymphocytes caused by HIV increased the amount of shed membrane particles which induce endothelial dysfunction by reduction in nitric oxide and prostacyclin-induced vasodilatation [6, 74].

6.3.5 Endothelial Dysfunction and HIV Medications

The use of PIs in HIV patients is associated with endothelial dysfunction as assessed by brachial artery flow-mediated vasodilatation. This is mediated, probably, by the atherogenic dyslipidemia induced by PIs [104].

6.3.6 Surrogate Measurement of Atherosclerosis in HIV Patients

6.3.6.1 Carotid Intima-Media Thickness (IMT)

In one study, mean carotid IMT was thicker in HIV patients than in control subjects (p < 0.001) [17]. Predictors of thicker IMT in HIV patients included: older age, higher LDL cholesterol, cigarette pack-years, and hypertension. Also, there was a rapid progression of carotid IMT in HIV patients after 1 year, but not in control subjects (p = 0.002). The rapid progression of carotid IMT in HIV patients and their thicker baseline values strongly suggests very high rates of coronary and cerebrovascular events.
In this study, carotid IMT correlated with classic risk factors and with low nadir CD4 count [55].

6.4 Metabolic Abnormalities Associated with Antiretroviral Therapy

There are many studies suggesting that chronic HIV therapy is associated with the development of metabolic disturbances, which may have a negative effect on cardiovascular risk.
Hypertension associated with HIV appears to be linked to insulin resistance and metabolic syndrome [37].
Higher rate of MI in young HIV-infected patients receiving PIs have focused interest on the association between HIV infection coronary artery disease and antiretroviral medications. The main studies addressing this issue are summarized in Table 6.2 [88]. Taken together, these studies suggest that the rate of MI is higher in HIV patients taking PIs and this risk increases by lengthening the duration of treatment.

Table 6.2

Studies comparing coronary event rates in HIV patients with vs. without PIs [35]
Study
Patients (n)
Age (years)
Follow-up
Events
Results
Bozette et al. [30]
36,766
NA
40 months
1,207 admissions for CVD
No increase in CVD admissions with PIs or with increase in duration of PI treatment
Coplan et al. [78]
10,986
37 (mean)
1 year
29 MIs
Risk of MI not increased in PI- vs. non-PI-treated patients; OR, 1.69; 95% CI, 0.54–7.48
Holmberg et al. [16]
5,672
42.6 (mean)
3.1 years
21 MIs
Risk of MI increased in PI- vs. non-PI-treated patients; OR, 7.1; 95% CI, 1.6–44.3
DAD Study Group [47]
23,468
39 (median)
1.6 years on PIs
126 MIs
Risk of MI increased with increased exposure to PI combination therapy (p < 0.001)
Mary-Krause et al. [97]
34,976
37.7 (mean)
33 months
60 MIs
Risk of MI increased in PI- vs. non-PI-treated patients; OR, 2.56; 95% CI, 1.03–6.34
Klein et al. [33]
4,159
42.6 (mean)
3.6 years
72 CHD events, including 47 MIs
Event rates in PI- vs. non-PI-treated patients similar but increased in HIV patients vs. controls
Barbaro et al. [32]
1551
35.5 (median)
36 months
25 coronary events, including 13 MIs
Risk of MI increased in PI- vs. non-PI-treated patients; RR, 11.5; 95% CI, 2.7–48.5
CVD cardiovascular disease; OR odds ratio; CHD coronary heart disease
In HIV-infected patients, clinical studies of the effects of PIs on lipid levels have shown that PIs increased total cholesterol by 66%, LDL cholesterol by 37%, and triglycerides by 80% at 48 weeks [61]. PIs appear to have drug-specific effects on lipid and glucose metabolism. Some PIs, such as Atazanavir, do not appear to perturb lipid or glucose levels. However, in studies of HIV-uninfected subjects, Ritonavir increased triglycerides and lowered HDL cholesterol slightly, with no increase in LDL cholesterol, whereas Indinavir did not affect lipoproteins but caused insulin resistance [81, 91, 95]. Lopinavir/Ritonavir increased triglycerides without affecting LDL or HDL cholesterol or insulin resistance [67]. Amprenavir had no effect on lipoproteins [95].
Long-term consequences of these metabolic abnormalities result in an increase in coronary events and stroke [88].
In HIV-infected patients, Lipodystrophy can be a possible side effect of Antiretroviral Therapy which is characterized by peripheral fat wasting with fat accumulation in the neck, dorsocervical region, abdomen, and trunk. Its development and severity is strongly associated with the type and duration of therapy.
Lipodystrophy was seen in 20–35% patients after 1–2 years of HAART. Lipodystrophy in HIV patients is associated with metabolic abnormalities such as insulin resistance, impaired glucose tolerance, elevated triglyceride, low HDL, and hypertention.
The most likely regimen to induce severe lipodystrophy is the combination of PI + 2 NRTIs (particularly stavudine+didanosine) [88].

6.5 Treatment of Coronary Risk Factors in HIV Patients

There are no definitive studies at present showing that treatment of traditional coronary risk factors improves outcomes in patients with HIV infection.
The Adult AIDS Clinical Trials group recommends that dyslipidemia be managed according to the guidelines of the National Cholesterol Education Program Adult Treatment Panel III [26]. Certain considerations should guide the selection of lipid-lowering agents in HIV-infected individuals who are taking PIs. Both PIs and Statins (with the exception of Pravastatin) are metabolized by the cytochrome P450 system. In non-HIV-infected individuals, the combination of Ritonavir/Saquinavir has been shown to increase the area under the curve (AUC) by 30-fold for Simvastatin and by 79% for Atorvastatin, whereas the AUC decreased by 50% for Pravastatin [29]. Simvastatin and lovastatin are contraindicated in patients taking PIs, whereas atorvastatin should be used cautiously, and, if used, should be initiated at low dosage [26]. Pravastatin is safe, but has lower potency with respect to LDL cholesterol lowering. The cholesterol absorption inhibitor Ezetimibe has not been studied in HIV-infected patients, but represents an attractive approach to LDL cholesterol lowering because of its lack of drug–drug interactions. A newer PI, Atazanavir, does not appear to be associated with lipid abnormalities [96]. Thus, switching patients with hyperlipidemia who are on other PIs to Atazanavir represents an alternate approach to lipid management.
Many HIV-infected patients also have elevated triglyceride levels. Fibrates (bezafibrate, fenofibrate, and gemfibrozil) appear to reduce triglycerides effectively in HIV-infected patients receiving ART [7, 40]. Fibrates should be used cautiously in combination with statins because of the increased risk of myopathy. Fibrates are conjugated by glucuronidation with renal elimination. Ritonavir and Nelfinavir are inducers of glucuronidation and could decrease the effect of the Fibrates [27].
Niacin is an alternate option for triglyceride reduction, but may be a poor choice for many HIV patients because of its propensity to worsen blood glucose levels [88].
Hypertriglyceridemia is often accompanied by the other components of the metabolic syndrome: low HDL cholesterol, increased remnant lipoproteins, small LDL particle size, abdominal obesity, hypertension, insulin resistance and glucose intolerance, a proinflammatory state, and a prothrombotic state [41].
There have been a limited number of studies investigating cigarette smoking in HIV-infected patients. The prevalence of cigarette smoking in HIV patients has been reported to be as high as 70–80% in some areas, and HIV-infected persons appear less likely to have contemplated tobacco cessation compared with other smokers [80].
The primary treatment target for the metabolic syndrome is obesity, and the recommended measures include diet and exercise [42]. Even modest reductions in body weight may improve dyslipidemia, hypertension, and glucose intolerance, as well as levels of inflam matory and thrombotic markers [42]. Also smoking cessation should be a major focus of attention in the clinical care of HIV-infected smokers.

6.6 Myocardial Disease

There are three major forms of myocardial disease in patients with AIDS:

  • Focal myocarditis
  • Echocardiographic evidence of left ventricular dysfunction
  • Clinical cardiomyopathy
Clinical dilated cardiomyopathy is seen in approximately 1–3% of patients with AIDS for an annual rate of 1–2% [2, 68, 69, 93, 98].
By multivariate analysis, low socio-economic status, long duration of HIV infection, low CD4 count, HIV viral load, and low plasma level of selenium were factors significantly associated with dilated cardiomyopathy.
It is not clear if HIV-associated disease is due to direct myocardial infection, an autoimmune process induced by HIV or other cardiotropic viruses or coexisting opportunistic infection [51].
In autopsy studies, in the pre-HAART era, myocarditis was identified in more than half of 71 patients evaluated and biventricular dilatation was present in 10% of cases [3].
Histological studies showed evidence of myocyte hypertrophy and myocarditis [24].
Before the use of HAART, congestive heart failure due to HIV-induced left ventricular dysfunction was diagnosed in 2% of all HIV patients, most commonly with lowest CD4 count. Global left ventricular dysfunction was detected by echocardiogram in 15% of randomly selected HIV patients, in one study [50].
Since the introduction of HAART regimens, there has been a marked reduction in the incidence of myocarditis and opportunistic infections, which has led to a nearly 30% reduction in HIV-associated cardiomyopathy [90].
Zidovudine (ZDV) has been demonstrated to cause mitochondrial myopathy in skeletal muscles, and may cause similar dysfunction in myocardial muscle [25]. Studies performed on transgenic mice suggest that ZDV is associated with diffuse destruction of cardiac mitochondrial ultrastructures and inhibition of cardiac mitochondrial DNA replication [70]. A study of six patients with cardiac dysfunction reported clinical association between cardiac disease and therapy with ZDV and dideoxyinosine (didanosine) [49]. Three patients improved after ZDV was discontinued. However, another study evaluated left ventricular dysfunction by echocardiography in 60 HIV-infected patients with left ventricular dysfunction who were receiving ZDV and in 38 HIV-infected patients not on ZDV. It found that patients receiving ZDV did not have worse left ventricular function or more frequent evidence of diastolic dysfunction than did patients who were not on ZDV [10]. These findings are consistent with those of a previous study by the same investigators showing that ZDV does not affect left ventricular function during short-term use [11].

6.7 Pulmonary Hypertension

Pulmonary hypertension, with and without cor pulmonale and right heart failure, have been described in patients with AIDS. The incidence of HIV-related pulmonary hypertension before the use of HAART has been 0.5% [52, 76, 83, 85, 100, 102].
The etiology of this problem is not well understood. The pathogenesis is unknown, but could relate to infection with human herpesvirus 8 (HHV-8) [22].
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