**3. Pathophysiology of dyslipidemia secondary to antiretroviral therapy**

Since the implementation of antiretroviral therapy (HAART), in the 90s of last century, the treatment of AIDS has increased the mean life expectancy of HIV-infected population. Until then seen as a death sentence in a matter of short time, the disease have been faced like chronic, and with more optimism. However, despite a decrease in morbidity and mortality, HAART led to a problem that has become a major challenge that patients with AIDS must control: dyslipidemia (Cahn et al., 2010).

The dyslipidemia associated with HAART has been characteristic of elevated total cholesterol (TC), low-density lipoprotein (LDL-C) and triglycerides (TG), in addition to decreased high-density lipoprotein (HDL-C), which results in increased predisposition to the development of hypertension, insulin resistance, diabetes mellitus and cardiovascular complications. There are evidences that cardiovascular manifestations proportions in HIVinfected patients on HAART are higher than in general population (Almeida et al., 2009). This does not mean that the occurrence of dyslipidemia has emerged only with the implementation of antiretroviral drugs to treat AIDS. Before the existence of HAART had been reported lipid profile changes with high levels of triglycerides and low rate of VLDL-C and HDL-C (Sprinz et al., 2010; Grunfeld et al., 1992).

Several studies investigate ways of relating to HAART the effects of dyslipidemia like type of drug used by the patient and how the treatment regimen it has been implemented, but is still lacking a precise explanation for the lipid profile origin. Protease inhibitors (PI) are associated with dyslipidemia and insulin resistance for a considerable time, specifically ritonavir, and a variety of hypotheses (albeit not conclusive) it is presented to explain this association (Noor, 2007; Dubé et al., 2003).

One proposed mechanism to emergence of dyslipidemia is the lipoprotein lipase inhibition by PI, responsible for LDL-C increased, due to difficulty in capturing chylomicrons, resulting in lower hepatic clearance of triglycerides (Sprinz et al., 2010, as cited in Carr & Mooser, 2001). Another hypothesis is that PI has the ability to inhibit steps in lipid metabolism by binding to cellular retinoic acid binding protein type 1 (CRABP-1) and

for fat redistribution seems to be the result of complex interactions between host, disease

As for the diagnosis of HIVLS, there is not one standard pattern used to subjective body changes mentioned by the patients, anthropometric measurements and metabolic changes demonstrated in fasting laboratory tests (Diehl et al., 2008). Other tests that assist in conducting the HIVLS patients are: bone densitometry, for the investigation of osteopenia/osteoporosis; Dual-emission X-ray absorptiometry (DEXA), which allows an analysis of body composition, especially fat in the limbs, Computed Tomography, to observe presence of visceral fat deposits, and upper abdominal ultrasound for hepatic

Therefore, the main consequences of HIVLS are increased cardiovascular risk and consequent development of hypertension, diabetes mellitus, atheromatous disease, stroke, myocardial infarction (Kramer et al., 2009). Psychological disorders as well as, like stress and low self-esteem by stigmatizing body changes (Santos et al., 2005; Seidl & Machado, 2008), which not cease to be risk factor for these events already mentioned by activation of sympathetic and glucocorticoids systems, and neuropeptide Y production potentiating the

**3. Pathophysiology of dyslipidemia secondary to antiretroviral therapy** 

Since the implementation of antiretroviral therapy (HAART), in the 90s of last century, the treatment of AIDS has increased the mean life expectancy of HIV-infected population. Until then seen as a death sentence in a matter of short time, the disease have been faced like chronic, and with more optimism. However, despite a decrease in morbidity and mortality, HAART led to a problem that has become a major challenge that patients with AIDS must

The dyslipidemia associated with HAART has been characteristic of elevated total cholesterol (TC), low-density lipoprotein (LDL-C) and triglycerides (TG), in addition to decreased high-density lipoprotein (HDL-C), which results in increased predisposition to the development of hypertension, insulin resistance, diabetes mellitus and cardiovascular complications. There are evidences that cardiovascular manifestations proportions in HIVinfected patients on HAART are higher than in general population (Almeida et al., 2009). This does not mean that the occurrence of dyslipidemia has emerged only with the implementation of antiretroviral drugs to treat AIDS. Before the existence of HAART had been reported lipid profile changes with high levels of triglycerides and low rate of VLDL-C

Several studies investigate ways of relating to HAART the effects of dyslipidemia like type of drug used by the patient and how the treatment regimen it has been implemented, but is still lacking a precise explanation for the lipid profile origin. Protease inhibitors (PI) are associated with dyslipidemia and insulin resistance for a considerable time, specifically ritonavir, and a variety of hypotheses (albeit not conclusive) it is presented to explain this

One proposed mechanism to emergence of dyslipidemia is the lipoprotein lipase inhibition by PI, responsible for LDL-C increased, due to difficulty in capturing chylomicrons, resulting in lower hepatic clearance of triglycerides (Sprinz et al., 2010, as cited in Carr & Mooser, 2001). Another hypothesis is that PI has the ability to inhibit steps in lipid metabolism by binding to cellular retinoic acid binding protein type 1 (CRABP-1) and

and drugs factors (Lichtenstein, 2005).

steatosis assessment (Mallon et al., 2003).

control: dyslipidemia (Cahn et al., 2010).

and HDL-C (Sprinz et al., 2010; Grunfeld et al., 1992).

association (Noor, 2007; Dubé et al., 2003).

metabolic changes (Licht et al., 2010; Rasmusson et al., 2010).

related protein receptor LDR-c, resulting in hyperlipidemia by higher release of lipids in the circulation. More specifically, the PI on CRABP-1 receptor leads to a reduction of 9-cis retinoic acid and dimerization with the receptor activated by peroxisome proliferatoractivated receptor gamma (PPAR-γ), which is involved both in apoptosis of adipocytes and in differentiation between these two. (Sprinz et al., 2010; Carr et al., 1998). A third theory, restricted to ritonavir, antiretroviral therapy suggests it increases the activity of sterol regulatory element binding protein 1 (SREBP-1c), increasing lipogenesis, the rate of VLDL-C and apolipoprotein B liver. Thus, the increase in triglycerides caused by ritonavir that could be related to elevation in hepatic lipoprotein, inhibiting degradation mediated by apolipoprotein B and SREBP-1c in liver (Riddle et al., 2001; Liang et al., 2001).

As regard the insulin resistance promoted by PI, this class of antiretroviral drugs has been related to inhibition of GLUT-4 in the transmembrane transport of glucose, leading to reduced glucose uptake mediated by insulin in peripheral tissue (skeletal muscle and adipocytes), which can lead the modification of lipid levels (Noor, 2007). The fact that some patients had a clinical and laboratory profile more or less flowered depending on the effects that PI has on the lipids metabolism may be related to genetics, suggesting that certain people are more prone to PI effects through manifestation of certain genes so far not identified (Shahmanesh et al., 2001).

With regard to nucleoside reverse transcriptase inhibitors (NRTIs), it is speculated that can lead to reduced synthesis of mitochondrial DNA, leading to decreased oxidative phosphorylation, resulting in subcutaneous adipocyte apoptosis, dyslipidemia, and increased insulin resistance (Maagaard & Kvale, 2009). The reverse transcriptase inhibitor non-nucleoside (NNRTI), particularly Efavirenz, are also related to the onset of metabolic disorders, including dyslipidemia – but they have lower participation. When compared to patients receiving Nevirapine, patients who make use of Efavirenz have higher levels of triglycerides and HDL-C (Sprinz et al., 2010, as cited in Carr et al., 1998).

The type of antiretroviral used in HAART case amends significantly the lipid profile of patient it might be replaced. However, make use of a change in medication or combination of drugs (a strategy that appears more practical than prescription of lipid, at least at first glance) does not always result in improving lipid metabolism, considering the dyslipidemia in HIV infection is related to a multifactorial framework (Sprinz et al., 2010).

Although there are doubts considering the mechanisms linked to development of dyslipidemia in patients receiving HAART, and about assumptions not fully understood, this is still the most effective treatment in patients with AIDS and should not be proscribed for patients. To minimize risks that dyslipidemia implies to health, we recommend the same precautions, both dietary and behavioral (avoiding a sedentary lifestyle) and drug (statins/fibrates) for the general population. The use of fibrates is primarily indicated for reduction of hypertriglyceridemia, while statins are used to reverse the hypercholesterolemia. However, must be careful in prescribing of statins, since there is risk of drug interactions with HAART (Sprinz et al., 2010).
