Vascular diseases, primarily arterial, have been described in HIV/AIDS, but today an emphasis on atherosclerotic disease is worthwhile. A number of clinical studies have documented an increased risk of adverse cardiovascular events in patients with HIV/AIDS who receive HAART. Although there is some variation among these different studies, the consensus is that HIV/AIDS patients have higher risk for atherosclerotic cardiovascular disease and MI than uninfected controls.30,129,130,131,132,133,134,135
The Data Collection on Adverse Events of Anti-HIV-1 Drugs (D:A:D) study generated a risk equation for cardiovascular disease in HIV/AIDS while incorporating traditional risk factors (age, sex, family history of atherosclerotic disease, systolic blood pressure, smoking status, total cholesterol:high-density lipoprotein [HDL] ratio) with duration of PI therapy, given their association with atherosclerotic cardiovascular disease.129,130 The D:A:D study offered improved estimates for the risk of developing cardiovascular disease compared to the Framingham risk score, and identified duration of HAART as a positive association factor.129,130,136
Lipodystrophy and the Metabolic Syndrome in HIV/AIDS
Lipodystrophy is an ill-defined syndrome comprising central fat accumulation and peripheral lipoatrophy in association with dyslipidemia and insulin resistance. A variety of antiretroviral agents may be implicated in the development of this syndrome in HIV/AIDS.42 Patients with HIV/AIDS lipodystrophy exhibit both the metabolic and anthroprometric abnormalities that are associated with increased risk of cardiovascular diseases, and lipodystrophy in HIV/AIDS patients closely resembles that of their non-HIV/AIDS counterparts.137 It includes hypertriglyceridemia, hypercholesterolemia (particularly raised total and low-density lipoprotein [LDL] cholesterol), insulin resistance, type II diabetes mellitus, lactic academia, and hepatic dysfunction.137, 138
The prevalence of these abnormalities may be dependent on the type and duration of HAART, but lipodystrophy can be seen in up to 35% of HIV/AIDS patients after 12 months of PI or NRTI therapies, particularly with older drugs.139 Use of less lipotoxic HAART regimens and earlier initiation of therapy may be beneficial in reducing the risk of metabolic syndrome and cardiovascular disease in HIV/AIDS patients.
Fat wasting, as a characteristic side effect in early-generation PI-related lipodystrophy, extends from the face, buttocks, and extremities. It coexists with abnormal fat accumulation in the torso and neck.41,111,140,141,142,143 These characteristic and disabling phenotypic changes lead to plasma lipid derangements with increased triglycerides, total cholesterol, and LDL-cholesterol and decreased HDL-cholesterol levels.
The pathogenesis of HIV/AIDS lipodystrophy is not known, but may include lipid and adipocyte regulatory protein dysfunction through PI binding or NRTI-induced mitochondrial toxicity.137,138,144 The syndrome does not appear to be a direct effect of HIV/AIDS itself, as lipodystrophy appears to occur exclusively in patients receiving antiretroviral therapy.145 Similarly, although the dyslipidemia noted in these patients may merely be a consequence of insulin resistance and lipodystrophy, PI therapy in non-HIV/AIDS patients results in abnormal cholesterol, triglyceride, apolipoprotein B, and lipoprotein levels and rapidly induces insulin resistance.146 Some PIs (ritonavir, indinavir, and amprenavir) can also lead secondarily to an upregulation of CD-36-dependent cholesteryl ester within vascular macrophages that promote atherosclerotic plaque formation.111,142,147
It should be noted that data suggest NRTI therapy also contributes to increased cardiovascular risk.111,142,148,149,150 The HIV/AIDS Outpatient Study (HOPS) cohort helped define how HIV-specific factors contribute to the risk of atherosclerosis. Their investigation yielded the “attributable risk” for different factors on overall risk. A CD4+ count of < 500 cells/mm3 had an attributable risk of 25.6% that was comparable to tobacco use (26.7%) and less than the attributable risks of age (49.2%) and hypertension (34.4%). The attributable risk of a CD4+ count of < 500 cells/mm3 was higher than the attributable risk associated with an elevated LDL (21.5%), low HDL (21.5%), male gender (20.9%), and diabetes (2.4%).151
As mentioned previously, HIV/AIDS patients should be assessed for traditional risk factors for premature cardiovascular disease that are prevalent in HIV/AIDS patients irrespective of therapy. Thus, family history and sedentary lifestyle that could be associated with the development of the metabolic syndrome in HIV/AIDS should be noted. Hypertension, diabetes, and tobacco use are more common in HIV/AIDS patients in comparison to non-HIV/AIDS patients, and because HIV-1 infection often leads to early decreases in HDL-cholesterol and elevations in triglycerides,111,142,152,153,154,155 preexisting lipid abnormalities will be an additional risk for cardiovascular disease.
Therapy for Lipodystrophy and Related Conditions in HIV/AIDS
Dietary therapy for dyslipidemia in HIV/AIDS remains contentious and has not been fully evaluated, although healthy diets rich in fruit, vegetables, and fish oils (possibly through supplementation) are encouraged. Drug therapy may also be necessary, particularly if antiretroviral treatment cannot be changed or interrupted. Bile acid sequestrants, although attractive from the point of view of drug interactions, may have adverse effects on serum triglyceride levels or impair absorption of antiretrovirals.
Most HMG-CoA reductase inhibitors (statins) are metabolized in the liver through the cytochrome P450 system. Simvastatin, lovastatin, and atorvastatin use the CYP 3A4 enzyme, and fluvastatin’s metabolism is through the CYP 2C9 enzyme. Pravastatin is unique in that its breakdown takes place in absence of this enzyme system. Given that PI and NNRTI metabolism is also CYP 3A4 dependent, co-prescription of some statins may be associated with increased risk of myopathy and rhabdomyolysis through competitive inhibition and significantly increased plasma statin levels.
For this reason, pravastatin and fluvastatin are attractive as agents of choice in patients receiving HAART. However, these statins are relatively weak and may not achieve target cholesterol levels. At present, it is recommended that hypercholesterolemia in HIV/AIDS patients treated with PIs is initially treated with pravastatin 20 mg/d with careful monitoring of virologic parameters and serum creatine kinase levels. Low-dose atorvastatin (10 mg/d) may be used with care and is generally well tolerated, but simvastatin and lovastatin are not recommended. Rosuvastatin is highly effective and is metabolized through the CYP 2C19 system. As such, it may be attractive for patients who do not respond to other statins (Table 102–4).156
TABLE 102–4.Drug Treatments for Lipid Abnormalities in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome ||Download (.pdf) TABLE 102–4. Drug Treatments for Lipid Abnormalities in Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome
|Lipid Abnormality ||First Choice ||Second Choice ||Comments |
|Isolated high LDL, non-HDL cholesterol ||Statin ||Fibrate ||Start with pravastatin* or atorvastatin* (available as generics). Use low statin dosages and titrate upward; patients have increased risk of myopathy. |
|Isolated high TG ||Fibrate ||Statin, N-3 (omega-3) fatty acids ||Start with gemfibrozil or fenofibrate. Combined statin and fibrate may increase myopathy risk. |
|High HDL and TG (TG level 200-500 mg/dL [2.3-5.6 mmol/L]) ||Statin ||Fibrate ||Start with pravastatin or atorvastatin* (available as generics). Use fluvastatin,* rosuvastatin,* pitavastatin,* gemfibrozil, or fenofibrate as alternatives. Combined statin and fibrate may increase myopathy risk. |
|High HDL and TG (TG level > 500 mg/dL [> 5.6 mmol/L]) ||Fibrate ||N-3 (omega-3) fatty acids, niacin, statin ||Start with gemfibrozil or fenofibrate. Niacin is associated with insulin resistance. May need to add statin if cholesterol is not controlled adequately. |
HIV/AIDS patients may develop severe hypertriglyceridemia, and traditional secondary causes such as high alcohol consumption, hypothyroidism, renal disease, and diabetes mellitus should be excluded. A low-fat diet together with reductions in alcohol and refined carbohydrate intake should be advised. When this nondrug therapy fails to correct hypertriglyceridemia, gemfibrozil (600 mg twice daily) or fenofibrate (200 mg once daily) may be used in isolation, although combination of fibrates, gemfibrozil in particular, and statins are not recommended.42 Other potential major cardiovascular drug interactions with specific HIV/AIDS therapies are noted in Table 102–5.
TABLE 102–5.Major Potential Cardiovascular Drug Interactions of Specific Human Immunodeficiency Virus Therapies ||Download (.pdf) TABLE 102–5. Major Potential Cardiovascular Drug Interactions of Specific Human Immunodeficiency Virus Therapies
|Drug Class ||Examples ||Possible Cardiovascular Drug Interactions ||Potential Risk |
|Protease inhibitors || |
| || |
↑ Plasma concentration of antiarrhythmic drug Enhanced pro-arrhythmic effect
Enhanced/reduced anticoagulant effect
↑ Risk of torsades de pointes
↑ Plasma concentration of CCA.
↑ Enhanced antihypertensive effect
↑ Risk of myopathy/rhabdomyolysis (avoid simvastatin/lovastatin)
Possible ↑ plasma concentration of PDVI (avoid use with ritonavir)
↑ Plasma concentration of bosentan (use with care with Ritonavir)
|Nucleoside reverse transcriptase inhibitors || |
|Few major cardiovascular drug interactions reported, but clinical data limited || |
|Non-nucleoside reverse transcriptase inhibitors || |
| || |
↑ Plasma concentration/proarrhythmic effect
May enhance/reduce anticoagulant effect
Delavirdine ↑ plasma concentration of CCA, toxicity
↓/↑ Plasma concentration of statins
↓ or ↑ plasma concentration of PDVI
|Fusion inhibitors ||Enfuviritide ||No major cardiovascular drug interaction reported but clinical data limited || |
The treatment of glucose intolerance and diabetes also requires care, but if healthy diet and exercise are insufficient, drug treatment may again be necessary. Metformin reduces visceral adiposity and insulin resistance and remains the drug of choice in overweight individuals, but may infrequently cause lactic acidosis, particularly in the setting of renal dysfunction. Short-acting sulfonylureas may also be used in patients with normal renal function. Thiazolidinediones should be avoided in patients with liver disease, and although rosiglitazone, which is not metabolized through the P450 system, has been studied in HIV/AIDS patients, bringing about improvements in insulin sensitivity, at present it remains unlicensed for HIV/AIDS patients. In some cases insulin may be the safest drug therapy available.41,157
Tesamorelin is a growth–hormone-releasing agent that is associated with a 15% to 18% reduction in visceral fat in HIV/AIDS lipodystrophy, which may be useful for some patients.158,159,160 Alternatives to HAART compound medication may also be helpful in the management of some aspects of lipodystrophy, but should be carried out only after careful assessment of the potential risk to the patient’s long-term management.
Clinical Evidence for Atherosclerotic Disease in HIV/AIDS
Overall, controversy persists regarding the effect of HIV/AIDS on the development of atherosclerotic diseases. The D:A:D study of 23,437 patients demonstrated a risk of MI that was related to the duration of HAART treatment. This finding was refined to focus on PI therapy and the absence of such risk in patients treated with combinations that contained non-nucleosides (NNRTI).130,133,161 HIV/AIDS disease markers such as CD4+ count and viral load were not predictive of cardiovascular risk compared to correlates with traditional risk factors (age, gender, diabetes mellitus, smoking, hypertension, dyslipidemia).130,155 However, it must be noted that the D:A:D study period examined the effects of the therapy that was available at the time, some of which was more toxic than current HAART.
The SMART study evaluated cut-offs for HAART termination and initiation as they reflected on HIV/AIDS-related deaths and cardiovascular diseases.162 Participants received either continuous HAART or intermittent HAART treatment based on regularly assessed CD4+ counts (initiation: CD4+ < 250 cells/mm3; discontinuation CD4+ > 350 cells/mm3). Interim analysis led to premature study termination because of a clear increase in adverse outcomes, including cardiovascular diseases in the intermittent treatment HAART cohort.163
A contemporary meta-analysis164 points to an overall increased risk of 2.68 for acute MI in patients exposed to PI treatment. The reported incidence of acute MI was 9.42% with an in-hospital death rate of 8% attributable to both cardiovascular events and cardiogenic shock. CAD, however, was relatively infrequent (3%) in a large observational survey of South African HIV/AIDS patients, more than half of whom were taking HAART.29 This indirectly contradicts previous evidence and is in keeping with an earlier meta-analysis that suggested that HIV-1 infection and PI exposure are not strong independent risk factors for subclinical atherosclerosis.165
Although controversy persists, it should be remembered that the benefits of consistent, early HAART are “highly favorable” over risks of HAART-associated cardiovascular complications.131,142 A Veterans Affairs system study demonstrated that the overall death rate among HIV/AIDS patients dropped significantly after HAART initiation, most likely through reduction in viral loads and improvement in CD4+ counts.131,166,167
Coronary Artery Disease and Myocardial Ischemia in HIV/AIDS
It remains likely that some HIV/AIDS patients are at risk of acute MI and coronary heart disease (CHD). Compared with national registries of non-HIV/AIDS patients, CHD in HIV/AIDS patients occurs mostly in men and at a younger age, suggesting that the age-adjusted incidence may be significantly higher.164,168,169 The incidence of CHD appears to be up to three times that of a general male population and results in up to 40% higher rates of acute MI, hospitalization, and in-hospital deaths for acute coronary syndromes (ACS) compared with non-HIV/AIDS patients.134,170,171,172,173 With the improvement in survival with HIV/AIDS, the therapy for cardiovascular diseases should be similar to that in the non-HIV/AIDS population.
The full mechanism underlying ACS in HIV patients remains unclear. Acute MI appears to be a common presentation of CHD, and a high ratio of acute MI to stable angina exists in HIV/AIDS populations.168 Because these ACS may involve low-volume, lipid-rich plaques, the metabolic syndrome of HIV/AIDS lipodystrophy may promote development of vulnerable lesions or influence acute plaque rupture. However, in a study of South African HIV/AIDS patients presenting with acute MI, coronary intravascular ultrasound typically revealed fresh thrombus in the absence of underlying atherosclerotic disease and HAART did not appear to be a specific risk factor.29 It remains difficult, therefore, to establish an absolute link between PI exposure and CHD, and further long-term studies are required.164
HIV-1 infection itself and HAART may contribute to a pro-thrombotic state, which increases proportionally with viral load and reduced CD4+ count, or be further implicated in the atherosclerotic process through direct effects on cholesterol processing and intimal monocyte activation. ACS are, however, not clearly related to HIV replication because HIV RNA may be undetectable in up to one-third of patients at the time of presentation.168 Rapid changes in the immune state (immune reconstitution inflammatory syndrome [IRIS]) may emerge as a factor in future studies, but therapeutic improvements in immunological, metabolic, and cardiovascular risk profiles through time may counterbalance these factors and paradoxically result in an overall reduced cardiovascular risk.174,175
As a definitive diagnostic test, coronary angiography can be carried out safely in HIV/AIDS patients and frequently reveals patterns of coronary disease similar to that in young non-HIV/AIDS patients, including proximal vessel involvement and single artery disease.168 Treatment with percutaneous coronary intervention, fibrinolysis, and coronary artery bypass are all described with reasonable survival rates, although nonfatal reinfarction and restenosis after percutaneous coronary intervention is unexpectedly high.176 Care is required over choice of antiplatelet agents for use in ACS to avoid potential interactions with HAART.177 However, it seems reasonable that the clinical situation should determine the use of invasive and noninvasive coronary investigations and treatments, rather than the HIV status of patients.178
Myocardial Infarction (MI) and a Side Effect of Therapy in HIV/AIDS
Abacavir ((1S, 4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol sulfate; ABC) is associated with MI in HIV/AIDS.179,180,181 The relationship was emphasized in a World Health Organization report on adverse drug events that was published in 2005.182 Clinical side effects of ABC include hypersensitivity in 5% to 8% of patients that is associated with HLA-B*5701, and suggests genetic screening to prevent the reaction in susceptible patients.183,184,185,186,187 Other reports showed ABC was associated with increased risk of MI in HIV/AIDS.188