Prevention and Treatment
As in the general population, cardiovascular risk stratification in HIV-infected patients needs to be evaluated before and during HAART. The “traditional” cardiovascular risk factors are present in the HIV- infected population: smoking, dyslipidemia, diabetes mellitus, hypertension, premature familial cardiovascular disease, and poor physical fitness.
Reducing risk factors should become a routine aspect in the care of HIV-infected patients, who now live longer because of the steep decline in morbidity and mortality as a result of HAART. Large prospective and matched control studies in HIV-infected patients in primary cardiovascular prevention are needed so as to identify specific risk factors and stratify the cardiovascular risk. Intervention studies on reducing the cardiovascular risk in HIV-infected patients, as in the general population, are needed (smoking cessation, physical activity, lipid- lowering drugs, aspirin). The first step is to evaluate the relative risk or the absolute risk of a cardiovascular event in each patient by using the Framingham risk score (www.CHD-taskforce.com) and/or the recommendations of the International Society of Atherosclerosis (www.athero.org). The objective is to identify, in primary prevention, patients who require risk reduction by prescribing aspirin, lipid-lowering, or antihypertensive medication to decrease mortality and morbidity as proven in the general population.
Primary Prevention
Aspirin
According to the North American and European task force, aspirin should be prescribed in primary prevention using Lauer’s algorithm (Fig. 8) [63] driven by the Framingham risk score, which is similar [64, 65]. Special caution should be recommended in patients with untreated or unstable hypertension because of the increased risk of hemorrhagic stroke and in the overall population because of the risk of major gastrointestinal bleeding.
For the low-risk population (recommended | Simvastatin | 3A4 | High toxicity with PI 32-fold increased AUC with RITO-SAQ | Not recommended |
| Fluvastatin | 2C9 | Not tested | Recommended at 40 mg daily |
| Pravastatin | No P450 interactions | 0.5-fold decreased AUC with RITO-SAQ | Recommended at 20-40 mg daily |
| Rosuvastatin | No | No interaction kwon but not tested | Recommended at 5-10 mg daily |
| Fibrates Bezafibrate | No P450 interactions | Not tested | Recommended at 400 mg daily |
| Fenofibrate | No P450 interactions | Not tested | Recommended at 200 mg daily |
| Gemfibrozil | No P450 interactions; interaction with simvastatin, cerivastatin rosuvastatin but not atorvastatin | Not tested | Recommended at 900-1,200 mg daily |
| Ezetimibe | No | Not Tested | Recommended at 10 mg alone or with a statin |
| AUC, area under the curve; RITO, ritonavir; SAQ, saquinavir; PI, protease inhibitor |
Table 3 Recommendations for the choice of drug therapy in dyslipidemia for HIV-infected patients undergoing HAART according to Dube et al. [29]
| Lipid abnormalities | First choice | Second choice |
| Isolated high LDL cholesterol | Statin | Fibrate |
| Combined hyperlipidemia | Fibrate or statin | If starting fibrate, add statin |
| Isolated hypertriglyceridemia | Fibrate | Statin |
should be avoided in patients receiving drugs that might interact with CYP-450.
Bezafibrate, gemfibrozil, and fenofibrate have been tested in HIV-infected patients with isolated or combined hypertriglyceridemia and proved safe and well tolerated, whereas the efficacy seemed to be reduced in this population [71]. Fibrates have no proven interaction with the cytochrome P-450 pathway and protease inhibitors. The use of a standard dose of rosuvas- tatin (5-10 mg daily) or pravastatin (20-40 mg daily) or fluvastatin (40 mg daily) seems to be the safest choice because of the lack of interaction with cytochrome P-450 in predominant hypercholesterolemia. A reduced dose of atorvastatin (10 mg daily) can be used also with monitoring of CK values because of a potential interaction with cytochrome P-450. Fibrates should be prescribed in the presence of an elevated triglyceride level (>5 g/L) with a normal or near-normal LDL cholesterol level after diet and exercise recommendations have failed.
The association of statin and fibrate should not be recommended as a first-line treatment because of their potentially high toxicity (rhabdomyolysis, hepatitis) and interaction with protease inhibitors. If necessary, in high-risk patient for CAD and uncontrolled combined dyslipidemia, this association should be used with caution: start at a low dose and titrate upward with regular control of signs of myopathy and CK plasma levels.
New lipid lowering therapies like niacin acid [72] and ezetemibe [73] may have indications in important hypertriglyceridemia and resistant dyslipidemia or hypersensitivity to statin, respectively. Table 3 indicates how lipid-lowering therapy should be prescribed, according to Dube et al. [29].The risk-benefit ratio in treating HIV-infected patients with dyslipidemia is unknown. Male patients aged over 45 years and female patients over 55 years with hypertension and/or diabetes and/or familial premature CAD are candidates for lipid-lowering therapy. Switching from one protease inhibitor, ritonavir or indinavir to nevirapine or efavirenz to nevirapine or to atazanavir [74-77], could have beneficial effects on the reversal of dyslipidemia.
In consideration of an unlimited duration of treatment with antiretroviral drugs, it became of great importance the management or the prevention of side effects. The management of the various aspects of the tolerability of HAART, such as abnormal lipid metabolism, is one of the main topics of the studies in the field of HIV infection in industrialized Countries. The use of atazanavir, in contrast to other protease inhibitors, determines low increase of total cholesterol, LDL cholesterol and triglycerides, also in experienced patients. For a more detailed discussion of strategy will switch leads to a final algorithm.
The advent of atazanavir with a low risk of inducing dyslipidemia should be evaluated in patients with a high-risk cardiovascular profile or dyslipidemia. Switching stavu- dine to tenofovir demonstrated a decrease in triglyceride and total cholesterol [78]. Whether protease inhibitor therapy should be discontinued after an acute coronary syndrome and treatment switched to a nonnucleoside reverse transcriptase inhibitor (efavirenz, nevirapine) or to other nucleoside or nucleotide analogs (abacavir, teno- fovir) with a better “atherogenic profile” needs further investigation.
Smoking Cessation
The prevalence of cigarette smoking among HIV-infected patients is higher compared to the general population [79]. Louie et al. [80] reported that smoking-associated pulmonary diseases such as obstructive lung disease, chronic bronchitis, and bronchiectasis were increased in the HIV-infected population. 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%). Smoking cessation should be a priority for HIV-infected patients and physicians, integrated into a global risk reduction approach (dyslipidemia, diabetes mellitus, overweight, inactivity) to prevent future coronary events [81].
Exercise Training and Healthy Diet
Exercise has been shown to improve strength, cardiovascular function, psychological status, and reduce cardiovascular disease in the general population [82].
Exercise training also reduces total and abdominal fat. These changes in body composition mediate improvements in insulin sensitivity and blood pressure and may improve endothelial vasodilator function [83]. Encouraging lifestyle changes should be done as soon as possible, as HIV infection becomes a chronic disease. Various clinical interventions, including diet and exercise [84-86], switching antiretroviral agents, use of lipid-lowering and insulin-sensitizing agents, recombinant human growth hormone therapy, and plastic surgery, are under investigation in the treatment of morphologic changes (lipodystrophy syndrome). Nutrition deficiencies (selenium, vitamin B12, carnitine, growth and thyroid hormones) should be sought because they are easily treatable and because of their great impact on ventricular function [87, 88]. Hyperhomocysteinemia is associated with an increased risk of heart and vascular diseases [89]. Vilaseca et al. [90] demonstrated that HIV-infected children undergoing protease inhibitor treatment have higher homocysteine concentrations and lower folate values compared with patients on other antiretroviral therapies, as in adults [91, 92]. In case of hyperhomocysteinemia, folic acid supplements should be prescribed.
Diabetes Mellitus
New-onset diabetes mellitus affects an increasing number of HIV-infected patients (5-10%) [93-95]. Impaired glucose tolerance and early insulin resistance are more frequent (10-25%) in HIV-infected patients mostly treated with HAART including protease inhibitors [95]. The risk factors that promote the onset of diabetes and insulin resistance are: use of certain drugs (protease inhibitors and NRTIs), ageing of the population HIV, visceral adiposity and the appearance of lipoatrophy [96].
Indinavir, lopinavir / ritonavir and ritonavir do sed, can induce, sometime s rapidly, insulin resistance [97]. Amprenavir, atazanavir, and saquinavir would seem to have a minor impact on the safety of insulin [98].
An Italian study has shown that atazanavir helps improve glucose tolerance even in pre-treated patients. From stress as all patients included in the study came from a system containing protease inhibitors and that the metabolic profile has improved after 24 weeks of therapy by the modification [99].
Insulin resistance is often accompanied by hyperinsulinemia and may predispose patients to atherosclerosis. Henry et al. [100] demonstrated that impaired fasting glucose (fasting plasma glucose 6.1-6.9 mmol/L) in seronegative patients was associated with the level of systolic blood pressure and could help predict cardiovascular mortality. Metformin increases the sensitivity of peripheral tissues to insulin and should be recommended for the treatment of type 2 diabetes mellitus in HIV-infected patients with documented insulin-resistance syndrome [93]. No cases of lactic acidosis have been reported in serial trials [101, 102], but warranted a regular followup.
New oral antidiabetic drugs such as thia- zolidinediones (pioglitazone, rosiglitazone)
could be promising therapy for lipodystrophy, metabolic syndrome, and insulin resistance in HIV-infected patients, however contradictory results have been reported [103, 104]. Thiazolidinediones reduce
insulin resistance not only in type 2 diabetes but also in non-diabetic conditions associated with insulin resistance such as obesity.
Systemic Hypertension
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