**2. HIV lipodystrophy syndrome**

According to UNAIDS and World Health Organization (WHO) (2009) there was a large increase in the prevalence of HIV carriers in the world, reaching 33.4 million in 2008, value explained by the maintenance of annual incidence and the increase of the survival (Lihn et al. 2003; Mallewa et al., 2008). However, was noted a illness pattern change of these patients which ever left to be affected by a clinical feature characteristic of opportunistic diseases to develop HIV lipodystrophy syndrome (HIVLS) (Kramer et al., 2009; Ministry of Health of Brazil, 2008; Samaras et al., 2009; Stankov & Behrens, 2010).

Body composition abnormalities have been reported in 40-50% of HIV-positive outpatients. This proportion is higher in patients receiving antiretroviral therapy. The rate of lipodystrophy can be high depending on the characteristics of the cohort (sex, age and possibly race), the type and duration of antiretroviral therapy (Grinspoon & Carr, 2005).

Dyslipidemia in Patients with Lipodystrophy in the Use of Antiretroviral Therapy 429

2007; Chen et al., 2002; Garg, 2000; Sattler, 2008, Yu et al., 2005). The changes in the concentrations of plasma lipids are more observed in patients receiving protease inhibitors

Prospective studies investigating body composition in patients starting HAART for the first time have showed increases in fat during the initial months of treatment, followed by a progressive declining in the following three years. In one study, the decline was estimated at 14% per year in white men who received treatment regimens containing zidovudine/lamivudine or stavudine/lamivudine plus protease inhibitor or non-nucleoside reverse transcriptase inhibitor. In contrast, trunk fat increases initially and then remains stable for two or three years, resulting in relative central adiposity. These changes are clinically evident in 20 to 35% of patients after about 12 to 24 months of combination

The type, duration and current use or not of antiretroviral therapy are strongly associated with the lipoatrophy severity. Therapy based on two nucleoside analogue reverse transcriptase inhibitors and one protease inhibitor has strong association with severe

Now, the mechanism by which the protease inhibitor causes lipodystrophy remains unknown. Several protease inhibitors prevent preadipocytes differentiation and mild to moderate apoptosis in subcutaneous adipose tissue. Adipose tissue of patients with lipodystrophy has reduced expression of mRNA of several key factors involved in adipogenesis, including Sterol regulatory element binding protein (SREBP1c) and Peroxisome proliferator-activated receptor gamma (PPARγ). *In vitro* studies have shown that protease inhibitors can inhibit lipogenesis and adipocyte differentiation, stimulate lipolysis and prevent nuclear localization of SREBP-1c (Garg, 2000; Grinspoon & Carr, 2005). The nucleoside analog more strongly associated with lipoatrophy is stavudine, particularly when used in combination with didanosine. Lipoatrophy associated with nucleoside analogue may be due in part by mitochondrial injury caused by inhibition of the mitochondrial DNA polymerase γ within adipocyte and mitochondrial DNA depletion, although the extent and specificity of this effect remains unknown. The nucleoside analogue can inhibit adipogenesis and adipocyte differentiation, promote lipolysis and exert synergistic toxic effect with protease inhibitors *in vitro* and *in vivo* (Grinspoon & Carr, 2005). In nine studies assessing risk factors for lipoatrophy, were statistically significant more common duration and exposure to thymidine analogues, most commonly stavudine (d4T) (6/9), age (5/9), markers of disease severity (CD4/HIV RNA) (5/9), duration of therapy (3/9) and Caucasian (3/9). A prospective nonrandomized study in 40 HIV-positive patients starting antiretroviral therapy for the first time resulted after an average of 96 weeks, using multivariate analysis, that treatment with d4T is an independent factor for lipoatrophy

In eight studies assessing lipohypertrophy, the most significant risk factors were duration of therapy (3/8), a marker of disease severity (3/8), age (3/8) and protease inhibitor use (4/8). An additional study evaluating 2258 HIV-positive patients evaluated change in adipose tissue for both gender. Logistic regression showed that men have a significantly lower adjusted risk than women have (OR: 0.47, CI 95%: from 0.38 to 0.58) and a significantly lower risk of lipohypertrophy and mixed redistribution, while the risk of lipoatrophy was similar between genders. Therefore, a rigorous multivariate analysis controlling for numerous variables reveals multiple risk factors, suggesting that the pathogenic mechanism

(PI) (Yu et al., 2005).

antiretroviral therapy (Grinspoon & Carr, 2005).

lipoatrophy (Mallon et al., 2003).

(Lichtenstein, 2005).

The HIVLS presents three distinct forms according to distribution pattern: lipoatrophy, with fat loss in limbs, face and buttocks; lipohypertrophy, with localized increase of abdominal, breast and dorsocervical subcutaneous cellular tissue, besides visceral deposit and lipoma formation; and the mixed form with signs of both syndromes earlier (Sattler, 2008; Mello et al., 2008) (Figure 1).

Legend: A) facial lipoatrophy with facial furrows accentuated, bony prominence, and loss of Bichat's fat (malar fat). B) Lipoatrophy of the lower limbs with prominent veins. C) Visceral lipohypertrophy, with increased waist circumference and little subcutaneous tissue. D) Dorsocervical lipohypertrophy. Photos of the collection of Dr. Rosana Libonati.

Fig. 1. Morphological changes in HIV patients with lipodystrophy syndrome, Pará, Brazil.

In addition to fat distribution alterations, metabolic changes are expressed as a mixed dyslipidemia with hypertriglyceridemia, total hypercholesterolemia, low density lipoprotein (LDL-C) elevation, reduction of high density lipoprotein (HDL-C), besides the induction of insulin resistance culminating in establishment of type II diabetes (Furtado et.,

The HIVLS presents three distinct forms according to distribution pattern: lipoatrophy, with fat loss in limbs, face and buttocks; lipohypertrophy, with localized increase of abdominal, breast and dorsocervical subcutaneous cellular tissue, besides visceral deposit and lipoma formation; and the mixed form with signs of both syndromes earlier (Sattler, 2008; Mello et

Legend: A) facial lipoatrophy with facial furrows accentuated, bony prominence, and loss of Bichat's fat (malar fat). B) Lipoatrophy of the lower limbs with prominent veins. C) Visceral lipohypertrophy, with increased waist circumference and little subcutaneous tissue. D) Dorsocervical lipohypertrophy. Photos

Fig. 1. Morphological changes in HIV patients with lipodystrophy syndrome, Pará, Brazil. In addition to fat distribution alterations, metabolic changes are expressed as a mixed dyslipidemia with hypertriglyceridemia, total hypercholesterolemia, low density lipoprotein (LDL-C) elevation, reduction of high density lipoprotein (HDL-C), besides the induction of insulin resistance culminating in establishment of type II diabetes (Furtado et.,

al., 2008) (Figure 1).

of the collection of Dr. Rosana Libonati.

2007; Chen et al., 2002; Garg, 2000; Sattler, 2008, Yu et al., 2005). The changes in the concentrations of plasma lipids are more observed in patients receiving protease inhibitors (PI) (Yu et al., 2005).

Prospective studies investigating body composition in patients starting HAART for the first time have showed increases in fat during the initial months of treatment, followed by a progressive declining in the following three years. In one study, the decline was estimated at 14% per year in white men who received treatment regimens containing zidovudine/lamivudine or stavudine/lamivudine plus protease inhibitor or non-nucleoside reverse transcriptase inhibitor. In contrast, trunk fat increases initially and then remains stable for two or three years, resulting in relative central adiposity. These changes are clinically evident in 20 to 35% of patients after about 12 to 24 months of combination antiretroviral therapy (Grinspoon & Carr, 2005).

The type, duration and current use or not of antiretroviral therapy are strongly associated with the lipoatrophy severity. Therapy based on two nucleoside analogue reverse transcriptase inhibitors and one protease inhibitor has strong association with severe lipoatrophy (Mallon et al., 2003).

Now, the mechanism by which the protease inhibitor causes lipodystrophy remains unknown. Several protease inhibitors prevent preadipocytes differentiation and mild to moderate apoptosis in subcutaneous adipose tissue. Adipose tissue of patients with lipodystrophy has reduced expression of mRNA of several key factors involved in adipogenesis, including Sterol regulatory element binding protein (SREBP1c) and Peroxisome proliferator-activated receptor gamma (PPARγ). *In vitro* studies have shown that protease inhibitors can inhibit lipogenesis and adipocyte differentiation, stimulate lipolysis and prevent nuclear localization of SREBP-1c (Garg, 2000; Grinspoon & Carr, 2005). The nucleoside analog more strongly associated with lipoatrophy is stavudine, particularly when used in combination with didanosine. Lipoatrophy associated with nucleoside analogue may be due in part by mitochondrial injury caused by inhibition of the mitochondrial DNA polymerase γ within adipocyte and mitochondrial DNA depletion, although the extent and specificity of this effect remains unknown. The nucleoside analogue can inhibit adipogenesis and adipocyte differentiation, promote lipolysis and exert synergistic toxic effect with protease inhibitors *in vitro* and *in vivo* (Grinspoon & Carr, 2005).

In nine studies assessing risk factors for lipoatrophy, were statistically significant more common duration and exposure to thymidine analogues, most commonly stavudine (d4T) (6/9), age (5/9), markers of disease severity (CD4/HIV RNA) (5/9), duration of therapy (3/9) and Caucasian (3/9). A prospective nonrandomized study in 40 HIV-positive patients starting antiretroviral therapy for the first time resulted after an average of 96 weeks, using multivariate analysis, that treatment with d4T is an independent factor for lipoatrophy (Lichtenstein, 2005).

In eight studies assessing lipohypertrophy, the most significant risk factors were duration of therapy (3/8), a marker of disease severity (3/8), age (3/8) and protease inhibitor use (4/8). An additional study evaluating 2258 HIV-positive patients evaluated change in adipose tissue for both gender. Logistic regression showed that men have a significantly lower adjusted risk than women have (OR: 0.47, CI 95%: from 0.38 to 0.58) and a significantly lower risk of lipohypertrophy and mixed redistribution, while the risk of lipoatrophy was similar between genders. Therefore, a rigorous multivariate analysis controlling for numerous variables reveals multiple risk factors, suggesting that the pathogenic mechanism

Dyslipidemia in Patients with Lipodystrophy in the Use of Antiretroviral Therapy 431

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

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

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

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

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

Hyperlipidemia is a major risk factor for developing of atherosclerosis. Epidemiological studies in adults show a direct association between high levels of total cholesterol and LDL and the incidence of mortality and morbidity in coronary artery disease (CAD) and is LDL-C a predictor of CAD risk at any age, besides low HDL and *diabetes mellitus* (Giddings, 1999).

apolipoprotein B and SREBP-1c in liver (Riddle et al., 2001; Liang et al., 2001).

triglycerides and HDL-C (Sprinz et al., 2010, as cited in Carr et al., 1998).

in HIV infection is related to a multifactorial framework (Sprinz et al., 2010).

**4. Treatment of dyslipidemia secondary to antiretroviral therapy** 

of drug interactions with HAART (Sprinz et al., 2010).

identified (Shahmanesh et al., 2001).

for fat redistribution seems to be the result of complex interactions between host, disease and drugs factors (Lichtenstein, 2005).

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 steatosis assessment (Mallon et al., 2003).

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