US Pharm. 2010;35(2):HS2-HS7.
In the mid-1990s, case reports of young patients with HIV who were experiencing myocardial infarction (MI) sparked interest in the connection between HIV and cardiovascular (CV) disease (CVD).1,2 Highly active antiretroviral therapy (HAART) has greatly reduced AIDS-related morbidity and mortality; however, its widespread use has been associated with a marked rise in the frequency of insulin resistance—a metabolic syndrome that increases CV risk—in patients with HIV.3
Recent cohort and database studies suggest that CV events substantially contribute to mortality in HIV patients receiving successful HAART.4 CV events are the underlying cause in more than 10% of deaths in patients with HIV, and CVD consistently ranks in the top four or five leading causes of mortality in this population (usually after AIDS-related events, end-stage liver disease, and malignancy).5,6 Typically, an HIV patient receiving antiretroviral therapy (ART) has a lipid profile that includes a low high-density lipoprotein (HDL) level, an elevated low-density lipoprotein (LDL) level, and elevated triglycerides (TG)—a combination that places the patient at high risk for future CVD. Metabolic disturbances associated with HIV infection and ART use are likely to have important consequences for CV health.
Etiology and Clinical Manifestations
Patients with HIV may have a multitude of CV manifestations, such as pericarditis, cardiomyopathy, coronary artery disease, valvular disease, and myocarditis. Pericarditis is the most frequent clinical manifestation; most patients with pericardial effusions are asymptomatic and require no treatment. The virus persists in reservoir cells in the cerebral cortex and in macrophages that may present between myocardial cells even after effective ART.7,8 Several hypotheses have arisen regarding the pathophysiology of atherosclerotic coronary artery disease in HIV-infected patients receiving HAART. Many of the metabolic disturbances found in HIV patients may be attributable to HAART. TABLE 1 lists the potential mechanisms by which HIV infection and ART can impact the body.8
Metabolic side effects associated with protease inhibitor (PI) therapy may promote atherosclerosis. Such side effects include hypercholesterolemia (in 30%-95% of HIV patients), hypertriglyceridemia (50%-90%), lipodystrophy syndrome (20%-83%), insulin resistance (25%-62%), diabetes mellitus (5%-10%), and hypertension (20%-74%).9-12 The differentiation of adipocytes may be impaired by PI therapy, causing dyslipidemia and insulin resistance, while lipodystrophy syndrome could be related to the mitochondrial toxicity of nucleoside reverse-transcriptase inhibitors (NRTIs).10,13,14 Prior to the introduction of HAART, the frequency and severity of both hypercholesterolemia and hypertriglyceridemia were inversely related to the decrease in CD4+ lymphocyte count.15 Since the advent of PIs, hypertriglyceridemia has been associated more frequently with the use of ritonavir compared with nelfinavir and indinavir.16,17 Mild-to-moderate hypercholesterolemia is more common among patients receiving nelfinavir and ritonavir compared with indinavir.16,17 Saquinavir did not increase serum lipid levels, or raised them only slightly.14
PIs have been suspected of inducing CV damage based on their propensity to cause dyslipidemia. An analysis of data from a prospective study of 23,437 HIV patients conducted by the Data Collection of Adverse Events of Anti-HIV Drugs (DAD) Study Group found that 345 patients had MIs during the study period. The incidence of MI increased from 1.53 per 1,000 person-years in patients not exposed to PIs to 6.01 per 1,000 patient-years in those exposed to PIs for more than 6 years.18 NRTIs also were shown to affect CV health in another DAD study. The risk of MI was found to be higher in patients with recent use of abacavir or didanosine versus those who had never received the therapy.19
Research has found that patients with HIV are at greater risk for CVD. One study found that 17% of men and 12% of women with HIV had a high predicted 10-year risk of developing coronary heart disease (CHD) in excess of 25%.20 These subjects had modifiable CHD risk factors such as smoking (in up to 40%), and more than 40% of men and 60% of women met criteria for being overweight, with a basal metabolic rate (BMR) of 25 or more. HAART therapy may be responsible for this increase in CV risk. Another recent study compared 259 men (47%) on a non-NRTI (NNRTI) regimen and 297 men (53%) on a PI-based regimen.21 Increases in total cholesterol, systolic blood pressure, and BMR were greater in the PI-based group than in the NNRTI group. Predicted CHD rate ratios were 1.40 (95% CI 1.13-1.75) and 1.17 (0.95-1.47) for PI-based and NNRTI-based HAART, respectively.
It has been speculated that intermittent therapy may reduce CV risk; however, the Strategies for Management of Antiretroviral Therapy trial did not find this to be the case. Patients were randomly assigned to continuous HIV therapy if the CD4+ count was ≥350/mm3 or to episodic treatment, in which therapy was deferred until the CD4+ count was ≤250/mm3 and then stopped when the CD4+ count was ≥350/mm3. The hazard ratio for CVD in the episodic treatment group was 1.5.22
The side effects of HAART are thought to play a role in the increase of CV risk from the therapy.23,24 PIs have been linked to hepatotoxicity. NNRTIs are known to cause skin rash and hepatotoxicity, and NRTIs have been associated with hepatotoxicity, lactic acidosis, lipodystrophy, and skin rash.
Prevention and Clinical Approach
The reduction of risk factors should be a vital aspect of managing patients with HIV. There are certain medications within the aforementioned drug classes that have been shown to cause fewer of the specified side effects. An analysis of the DAD study concluded that ritonavir caused the most lipid abnormalities and saquinavir had the least effect on lipids.20 In addition, the Simplification Lopinavir Atazanavir Trial concluded that, compared with lopinavir, atazanavir reduced total cholesterol and TG levels without increasing the risk of virologic failure.25
Tenofovir was found to have a more favorable lipid profile than stavudine when each was combined with lamivudine and efavirenz. There was a statistically significant difference between tenofovir and stavudine in terms of reductions in TG, total cholesterol, and LDL. In addition, tenofovir was associated with a lower rate of lipodystrophy (3%, vs. 19% for stavudine).26
Intervention studies on reducing CV risk in HIV patients (involving aspirin, lipid-lowering drugs, smoking cessation, and physical activity) are needed. Aspirin should be prescribed as a primary preventive measure. Aspirin use reduces the absolute risk of MI by 0.4% per year among high-risk subjects (baseline rate of 1.5% per year).27,28 In the high-risk group, treatment for 5 years is required for the prevention of 1 MI in 44 subjects. Particular caution should be exercised in patients with untreated or unstable hypertension, owing to the increased risk of hemorrhagic stroke, and in the overall population owing to the risk of major gastrointestinal bleeding. In the low-risk population (rate of <0.6% per year) the reduction in absolute risk of MI is proportional to the risk of gastrointestinal bleeding.27,28
A patient’s serum lipids, especially TG, should be evaluated prior to commencement of HAART, then every 3 to 6 months thereafter. Owing to the lack of clinical data on the treatment of HAART-induced cholesterol and TG elevations, National Cholesterol Education Program III guidelines should be applied to patients with HIV (TABLE 2), as suggested in the preliminary guidelines for the management of dyslipidemia in HIV patients developed by the Adult AIDS Clinical Trial Group Cardiovascular Disease Focus Group.29,30
Guidelines developed by the HIV Medical Association of the Infectious Diseases Society of America suggest that HIV patients undergo screening for dyslipidemia.31 In the presence of dyslipidemia, the patient should also be screened for secondary causes, such as hypothyroidism, obstructive liver disease, excessive alcohol use, diabetes mellitus, chronic renal failure, hypogonadism, and drug-induced elevated LDL level (anabolic steroids, progestins, corticosteroids). Patients with dyslipidemia may be candidates for treatment with hydroxymethyl glutaryl coenzyme A reductase inhibitors or fibrates, depending on the patient’s lipid profile and needs. If statin therapy is required, the clinician must be aware of potential interactions with PIs through the CYP450 3A4 pathway. Rosuvastatin and pravastatin may be chosen for their avoidance of this pathway, as well as atorvastatin for its lesser interaction compared with simvastatin.31
Owing to their potentially high toxicity (rhabdomyolysis, hepatitis) and interaction with PIs, the combination of statin and fibrate is not recommended as first-line therapy. In patients at high risk for CHD and uncontrolled combined dyslipidemia, this combination, if necessary, should be used with caution: Start at a low dose and titrate upward, with regular monitoring for signs of myopathy and creatine kinase plasma levels.31
New drugs, such as peroxisome proliferator-activated receptors (PPARs), control several key enzymes that catalyze the oxidation of fatty acids and could be a promising therapy for HIV-induced dyslipidemia and insulin resistance.32,33 Agonists PPAR-alpha and PPAR-gamma can improve dyslipidemia in metabolic syndromes by reducing TG levels and increase HDL levels by regulating the expression of genes involved in lipoprotein metabolism.13,32-34 The metabolic syndrome characterized by central obesity, hypertension, dyslipidemia, and hypercoagulability needs to be targeted for a new drug therapy in patients with HIV.35
The prevalence of cigarette smoking among HIV patients is higher than in the general population.36-39 In a cohort study involving 2,526 patients with HIV, tobacco use was the second most predominant risk factor for coronary heart disease (prevalence 18.8%), after hyperlipidemia (21.5%), and was twice as common as in an HIV-negative control group (9.5%).36 Smoking-associated pulmonary diseases such as chronic bronchitis, obstructive lung disease, and bronchiectasis have been found to be increased in the HIV-infected population.40 A recent study of causes of death in HIV-infected patients in San Francisco (5,234 deaths from 1994-1998) concluded that lung cancer was the most common cause of death from non–AIDS-defining malignancies (11%), followed by Hodgkin’s disease (5%), hepatocellular cancer (4%), and anal cancer (3%).40 Smoking cessation should be a priority when educating HIV-infected patients to reduce their overall CV risk, along with other global risk-reduction approaches, such as dyslipidemia, diabetes mellitus, inactivity, and overweight.
Exercise is known to improve strength and CV function while reducing CVD in the general population.41 Changes in body composition mediate improvements in insulin sensitivity and blood pressure and may improve endothelial vasodilator function.42 Various clinical interventions (including exercise and diet, switching ART agents, use of lipid-lowering and insulin-sensitizing agents, recombinant human growth hormone therapy, and plastic surgery) are being investigated for the treatment of morphologic changes (lipodystrophy syndrome).43,44
Hyperhomocysteinemia is associated with an increased risk of heart and vascular diseases.45 Children with HIV who are receiving PI therapy have higher homocysteine concentrations and lower folate values when compared to adult patients receiving other forms of ART.46 Folic acid supplements should be prescribed in case of hyperhomocysteinemia.47,48
Chronic exposure to ART may contribute to endothelial dysfunction, hypertension, and insulin resistance. In addition, multifactorial causes of atherosclerosis and thrombosis that are involved in AIDS patients might be accelerated with HAART, including PIs. Although HAART increases the risk of metabolic complications, this does not outweigh the survival benefits. It is vital to stratify CVD risk in patients with HIV. Clinicians may use existing general risk-stratification algorithms, such as the Framingham risk score, to measure HIV patients’ risk for heart disease. Assessment of cardiac risk factors should be considered when designing an initial ART regimen for patients with increased CV risks. The ART regimen should be scrutinized to determine whether drug modification may be helpful. Research has yet to determine whether the elevated risk of heart disease is attributed more to the disease, to ART, or to an interaction between the two.
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