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Effective therapies are now available that can stop the progression of HIV infection and significantly delay the onset of AIDS. The "highly active antiretroviral therapy" (HAART) is a combination of potent antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors, that has a variety of serious side effects, including lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance as well as fat wasting in face and limbs. There is still an open debate that concerns the precise responsibility of HAART as well as metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. The similarities with multiple symmetric lipomatosis (MSL), in which mitochondria impairment plays a crucial role, lead to the hypothesis that drug-induced damages to mitochondrial DNA are able to alter mitochondria functionality to an extent that is similar to what occurs in MSL. In addition, several evidences indicate that HAART is also linked to a deregulated production of tumour necrosis factor-alpha, which uses mitochondria as intracellular targets. In this paper, we review data concerning the role of mitochondria in the pathogenesis of lipodystrophy, and advance a unifying hypothesis involving either direct or indirect effects of the drugs employed during HAART.
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PMID:Mitochondria in the pathogenesis of lipodystrophy induced by anti-HIV antiretroviral drugs: actors or bystanders? 1174 23

The long term use of antiretroviral therapy is associated with metabolic and morphological abnormalities named lipodystrophy. The understanding of its epidemiology is in progress. NRTIs and Pls are involved in the origin of these abnormalities. So, NRTIs inhibit mitochondrial gamma polymerase and induce body fat distribution disorders. PIs interfere with lipid metabolism, leading to hyperlipidaemia and insulin resistance symptomatology. The diagnosis is made by clinical (far wasting or accumulation, or mixed syndrome) and biological signs (hyperlipidaemia, hyperglycaemia, hyperlactacidaemia). Radiological exams can quantify morphological abnormalities. The management consists in drug substitution, diet and exercise, and corrective drugs. Plastic surgery can be useful.
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PMID:[Morphological and metabolic abnormalities related to antiretroviral therapy]. 1189 93

Protease inhibitors used as therapy for HIV-1 infection have been associated with metabolic side-effects such as peripheral fat wasting, central adiposity, hyperlipidaemia and insulin resistance. This metabolic disorder is known as the lipodystrophy syndrome. This syndrome can be recognized by the early appearance of an increase in serum triglyceride, cholesterol and plasma-free fatty acid levels. Here, we describe an HIV-1 positive patient with the lipodystrophy syndrome in whom a decline in serum triglycerides was seen along with a significant improvement in glucose uptake following treatment with bezafibrate for 3 months. This improvement may be a consequence of the Randle effect, i.e. increased availability of plasma-free fatty acids is negatively correlated to glucose uptake. We also noted a significant improvement in endothelial-dependent flow-mediated dilatation after treatment with bezafibrate. This effect could result from the increased glucose uptake observed and a decrease in insulin resistance secondary to the lowered triglyceride levels by bezafibrate. We conclude that bezafibrate may be of clinical utility in the lipodystrophy syndrome, through its beneficial effects on insulin resistance, glucose uptake and endothelial dysfunction.
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PMID:Bezafibrate-induced improvement in glucose uptake and endothelial function in protease inhibitor-associated insulin resistance. 1247 19

Highly active antiretroviral therapy, which includes a combination of protease inhibitors, is highly successful in controlling human immunodeficiency virus (HIV) infection and reducing the morbidity and mortality of autoimmune deficiency syndrome (AIDS). However, the benefits of HIV protease inhibitors are compromised by numerous undesirable side effects. These include peripheral fat wasting and excessive central fat deposition (lipodystrophy), overt hyperlipidemia, and insulin resistance. The mechanism associated with protease inhibitor-induced metabolic abnormalities is multifactorial. One major effect of the protease inhibitor is its suppression of the breakdown of the nuclear form of sterol regulatory element binding proteins (nSREBP) in the liver and adipose tissues. Hepatic accumulation of nSREBP results in increased fatty acid and cholesterol biosynthesis, whereas nSREBP accumulation in adipose tissue causes lipodystrophy, reduces leptin expression, and promotes insulin resistance. The HIV protease inhibitors also suppress proteasome-mediated breakdown of nascent apolipoprotein (apo) B, thus resulting in the overproduction and secretion of triglyceride-rich lipoproteins. Finally, protease inhibitor also suppresses the inhibition of the glucose transporter GLUT-4 activity in adipose and muscle. This latter effect also contributes directly to insulin resistance and diabetes. These adverse effects need to be alleviated for long-term use of protease inhibitor therapy in treatment of HIV infection.
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PMID:Effects of HIV protease inhibitor therapy on lipid metabolism. 1254 52

Fat redistribution (lipodystrophy) and metabolic anomalies are reported increasingly in HIV-infected patients being treated with protease inhibitors. The incidence of these side effects ranges from 5% to 75% in such patients, who often complain of spontaneous fat wasting in the face, arms, or legs, with or without central obesity. Hyperlipidemia and insulin resistance are almost always associated with lipodystrophy. We review the metabolic complications of antiretroviral therapies and discuss possible therapeutic interventions.
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PMID:Metabolic effects of protease inhibitor therapy. 1273 15

The use of anti-retroviral protease inhibitors in combination with nucleoside analog or non nucleoside reverse transcriptase inhibitors (HAART) has led to dramatic decreases in the mortality seen with HIV infected patients. In concert with these treatment regimens, especially with the inclusion of the anti-retroviral protease inhibitors (PI), a complex series of metabolic complications occurred. These included alterations of fat and carbohydrate metabolism. In some patients, one could observe either lipoatrophy (fat wasting) as well as lipohypertrophy (fat deposition) or both. The problem is that the lack of a case definition of the altered fat metabolism confuses diagnoses. In vitro, interference with fat cell differentiation has been demonstrated by PI. Further, in vitro studies demonstrate that indinavir, a PI currently used in HIV treatment, can interact with the insulin responsive glucose transporter (GLUT4). The activity of the GLUT4 is inhibited by indinavir and eventual insulin resistance has been shown (i.e. in vivo and in vitro). Also, controversy exists regarding insulin signaling in fat cells. Finally, the relationships between hyperlipidemia and/or lipolysis and altered carbohydrate metabolism (i.e. mild glucose intolerance, insulin resistance) suggest an association with cardiovascular risk in protease treated patients (Metabolic Syndrome X). In short, while multiple problems exist, no one mechanism can account for the changes observed.
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PMID:Anti-retroviral protease inhibitors--'a two edged sword?'. 1274 88

Effective therapies are available that can stop or slow down the progression of HIV infection. Highly active antiretroviral therapy (HAART) is a combination of antiretroviral drugs such as viral protease inhibitors or nucleoside-analogue reverse-transcriptase inhibitors. Among the side effects due to these drugs, lipodystrophy is a pathology characterized by fat wasting in face and limbs, accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia (hypertriglyceridemia and hypercholesterolemia), insulin resistance, and lactic acidemia. The main clinical features include peripheral fat loss (presumed lipoatrophy in the face, limbs, and buttocks) and central fat accumulation (within the abdomen, breasts, and over the dorsocervical spine, so-called "buffalo hump"). Histopathological features disclose a peculiar type of involutional lipodystrophy. Skin biopsies generally show thinning of the subcutaneous fat, associated with fibrosis, lipogranuloma and sometimes vessel proliferation. There is still an open debate concerning the precise responsibility of HAART as well as the metabolic pathways and mechanisms that are involved in the onset of lipodystrophy. There is no proven therapy for any component of lipodystrophy syndrome.
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PMID:[Antiretroviral treatments-related lipodystrophy syndrome: clinico-pathological findings]. 1632 57

The survival of patients with HIV infection who have access to highly active antiretroviral therapy has dramatically increased. In HIV-infected persons, cardiovascular disease can be associated with HIV infection, opportunistic infections or neoplasias, use of antiretroviral drugs or treatment of opportunistic complications, mode of HIV acquisition (such as intravenous drug use), or with the classic non-HIV-related cardiovascular risk factors (such as smoking or age). Diseases of the heart associated with HIV infection or its opportunistic complications include pericarditis and myocarditis. Pericarditis may lead to pericardial effusion rarely causing tamponade. Cardiomyopathy is often clinically silent with asymptomatic left ventricular systolic dysfunction. Endocarditis is mainly the consequence of intravenous drug abuse, possibly leading to life-threatening valvular insufficiency with the need for cardiac surgery. A further serious condition associated with HIV infection is pulmonary hypertension potentially leading to right heart failure. The cardiovascular complications of HIV infection such as cardiomyopathy and pericarditis have been reduced by highly active antiretroviral therapy, but premature coronary atherosclerosis is now a growing problem because antiretroviral drugs can lead to serious metabolic disturbances resembling those in the metabolic syndrome. Lipodystrophy, a clinical syndrome of peripheral fat wasting, central adiposity, dyslipidemia, and insulin resistance, is most prevalent among patients treated with protease inhibitors. These patients should thus be screened for hyperlipidemia, hyperglycemia, and hypertension, and they may be candidates for lipid-lowering therapies. When initiating lipid-lowering therapy, interactions between statins and HIV protease inhibitors affecting cytochrome P450 function must be considered. Restenosis rate after percutaneous coronary intervention may be unexpectedly high.
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PMID:Cardiovascular disease in HIV infection. 1678 Dec 13

Several drugs are currently used that can significantly prolong the course of the infection with the human immunodeficiency virus (HIV), the cause of the acquired immunodeficiency syndrome (AIDS). Among these drugs, the nucleosidic inhibitors of viral reverse transcriptase can alter mitochondrial (mt) function by inhibiting the mitochondrial DNA polymerase gamma (the enzyme responsible for the replication of mtDNA). Decreased mtDNA content provokes a diminished synthesis of respiratory chain enzymes, leading to alterations in mt function. These are in turn responsible for a variety of side effects frequently observed in HIV+ patients, that range from hyperlactatemia and lactic acidosis to lipodystrophy, a pathology characterized by accumulation of visceral fat, breast adiposity, cervical fat-pads, hyperlipidemia, insulin resistance and fat wasting in face and limbs. In this paper, data concerning the effects of different compounds on mitochondria, their role in the pathogenesis of lipodystrophy, and problems related to studies on the mt toxicity of antiviral drugs are reviewed and thoroughly discussed.
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PMID:Anti-HIV drugs and the mitochondria. 1678 42

A unique and unexpected syndrome consisting of metabolic abnormalities (hyperlipidaemia and insulin resistance) and body fat redistribution (central adiposity and peripheral fat wasting) has been reported with increasing frequency in HIV-1 infected patients, most of whom are receiving highly active antiretroviral therapies including HIV-1 protease inhibitors. This article reviews the clinical and laboratory characteristics, the pathogenesis, and the management of this syndrome.
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PMID:Metabolic abnormalities and body fat redistribution in HIV-1 infected patients: the lipodystrophy syndrome. 1703 54


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