Lipodystrophy syndrome

In 1995 the FDA approved saquinavir, the first protease inhibitor, for use in combination with other nucleoside analogue medications. In 1999 a soft gel capsule formulation of saquinavir with considerably improved absorption characteristics was developed. Ritonavir and indinavir have been approved for use alone or in combination with nucleoside analogue medications in people with advanced HIV disease. Nelfinavir is the first protease inhibitor labeled for use in children. Amprenavir is the newest of the protease inhibitors. Amprenavir can be taken with or without food, but it should not be taken with a high-fat meal because the fat content may decrease the absorption of the drug. The most disturbing adverse reactions to protease inhibitors consist of the lipodystrophy syndrome with severe hyperlipidemia and unpredictable fat redistributions over the body... 

I Unlabeled Uses Treatment of HIV lipodystrophy syndrome, metabolic complications of AIDS, polycysfic ovary syndrome, prediabefes, weighf reducfion... 

In combination with other antiretroviral agents, stavudine has caused fatal lactic acidosis in some patients. It is also associated with motor weakness in which case it should be discontinued. Peripheral neuropathy is the most common toxicity associated with stavudine, which is more prevalent at high doses (4mg/kg per day). Neuropathy in these patients generally is associated with numbness, tingling or pain in feet or hands. Patients treated with the combination of stavudine and didanosine may also exhibit liver function abnormalities (hepatic steatosis) and pancreatitis. It may also be associated with the etiology of HIV lipodystrophy syndrome. 

Some patients receiving indinavir exhibit nephrolithiasis/urolithiasis including flank pain that may be accompanied by hematuria. The frequency of nephrolithiasis is dependent on the period of treatment with indinavir. Other side effects associated with indinavir include insulin resistance, hyperglycemia, asymptomatic hyperbilirubinemia, HIV lipodystrophy syndrome and skin abnormalities. Indinavir should not be coadministered with drugs that affect the cytochrome P-450 system (CYP3A4). Antacids are not recommended within 2 h of its administration, specifically didano-sine containing an antacid buffer. 

Calmy A, Hirschel B, Hans D, Karsegard VL, Meier CA. Glitazones in lipodystrophy syndrome induced by highly active antiretroviral therapy. AIDS 2003 17 770-2. 

Dyslipidemia is a common accompaniment of the lipodystrophy syndrome observed in HIV-infected patients. This syndrome presents as a combination of peripheral lipoatrophy and the metabolic syndrome (central adiposity, insulin resistance, and dyslipidemia). The term lipodystrophy syndrome was first used in two case reports to describe a clinical picture of subcutaneous fat wasting in the face and limbs of HIV infected patients treated with indinavir, reminiscent of the rare congenital lipodystrophy syndromes (138,139). In addition, benign symmetric lipomatoses on the trunk and neck were described. A systematic study of this syndrome in the Australian HIV cohort showed co-existence of peripheral lipoatrophy with abdominal visceral obesity, dyslipidemia, and insulin resistance in HIV-infected patients with or without treatment with protease inhibitors (140). 

Combination antiretroviral therapy is associated with redistribution of body fat in some patients ( lipodystrophy syndrome ), and protease inhibitors may disturb lipid and glucose metabolism. Appropriate laboratory tests to monitor these effects should be performed. 

Caso JA, Prieto Jde M, Casas E, Sanz J. Gynecomastia without lipodystrophy syndrome in HIV-infected men treated with efavirenz. AIDS 2001 15(ll) 1447-8. 

Insulin, administered subcutaneously, may cause either lipoatrophy or lipohypertrophy. Lipoatrophy is the breakdown of adipose tissue at the insulin injection site causing a depression in the skin at the injection site and occasionally at distant sites also. It may be the result of an immune response or the use of less than pure insulin. Some findings suggest that total lipodystrophy syndrome results from the inflammatory destructive process of adipose tissue (Yanagawa et al., 1990). Injection of human or purified porcine insulin into the site over a 2-4-week period may result in subcutaneous fat accumulation. 

Adverse effects of protease inhibitors are similar to those seen with reverse transcriptase inhibitors. In addition, this group of drugs causes metabolic disturbances, particularly insulin resistance and hyperglycaemia, and fat redistribution leading to raised plasma lipid levels, which increases the risk of heart disease. These effects are collectively known as lipodystrophy syndrome, which appears to be similar to what happens with long-term corticosteroid use. 

Lipodystrophy syndrome - insulin resistance, hyperglycaemia, fat redistribution and raised lipid levels as adverse effect of antiretroviral therapy Lipolysis - break down of lipid LOCA - low osmolar contrast agent... 

The most common adverse effect with stavudine is peripheral neuropathy which occurs in -12% of patients. Combining stavudine with zidovudine leads to increased risk and severity of peripheral neuropathy and potentially fatal pancreatitis, and these drugs shorrld not be used together under most circumstances. Lactic acidosis and hepatic steatosis also have been seen and are more common with stavudine than with zidovudine or abacavir. Of aU the nucleoside analogs, stavudine is most strongly linked to the HIV lipodystrophy syndrome, perhaps due to toxic effects on adipocytes. 

Domingo P, Cabeza MC, Pruvost A, Salazar J, Gutierrez Mdel M, Mateo MG, Domingo JC, Fernandez I, Villarroya F, Munoz J, Vidal F, Baiget M. Relationship between HIV/highly active antiretroviral therapy (HAART)-associated lipodystrophy syndrome and stavudine-triphosphate intracellular levels in patients with stavudine-based antiretroviral regimens. Clin Infect Dis 2010 50(7) 1033. ... 

Six patients with pre-existing HIV-lipodystrophy developed symptomatic Cushing s syndrome when treated with... 

Soon after the introduction of highly active antiretroviral combination treatments (HAART), lipodystrophy was associated with the use of protease inhibitors, and several reports have confirmed that a syndrome of peripheral lipodystrophy, central adiposity, breast hypertrophy in women, hyperlipidemia, and insulin resistance with hyperglycemia is an adverse event associated with the use of potent combination antiretroviral therapy, particularly including HIV-1 protease inhibitors (982-987). 

Lipodystrophy is not limited to patients taking protease inhibitors (992,993). Nevertheless, protease inhibitors are strongly associated with metabolic alterations and with lipodystrophy, while NRTIs are associated with low-grade lactic acidosis and less markedly with lipodystrophy. Some reports have speculated a link between mitochondrial dysfunction and lipodystrophy. It is clear, however, that the syndrome is related to total duration of antiviral therapy and inversely related to viral load. 

Lipodystrophy, a syndrome characterized by fat redistribution, hyperglycemia/insulin resistance, and dyslipidemia, can be associated with long-term HIV infection or with highly active antiretroviral therapy (HAART). In 1035 patients, those who took stavudine were 1.35 times more likely to report lipodystrophy (1076). However, the study was retrospective, and other factors unrelated to specific drug therapy may have had a greater effect on the adjusted odds ratio. 

Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, Cooper DA. A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 1998 12 F51-8. 

Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, Gastaut JA, Touraine JL. A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 1999 13(13) 1659-67. 

D. Effects on Carbohydrate and Lipid Metaboiism The use of protease inhibitors in HAART drug combinations has led to the development of disorders in carbohydrate and lipid metabolism. It has been suggested that this is due to the inhibition of lipid-regulating proteins which have active sites with structural homology to that of HIV protease. The syndrome includes hyperglycemia and insulin resistance or hyperlipidemia, with altered body fat distribution. Buffalo hump, gynecomastia, and truncal obesity may occur with facial and peripheral lipodystrophy. The syndrome has been observed with protease inhibitors used in HAART regimens, with an incidence of 30-50% and a median onset time of approximately 1 year s duration of treatment. 

Gupta SK, Dube MP. Exogenous Cushii syndrome mimicking human immunodeficiency virus lipodystrophy. Clin Infect DisQ.002) 35, e69-e71. 

In addition to reducing adipose tissue mass, the tl0cl2 CLA isomer has been linked to increased insuhn resistance in men who have symptoms of the metabolic syndrome. A CLA mixture also appeared to cause hyperinsulinemia in C57BL/6J mice that was accompanied by severe adipose tissue ablation and decreased leptin levels. The effects of the CLA mixture on adipose tissue depletion were reversed by continuous leptin infusion. In a follow-up study, decreasing the amount of a CLA mixture from 1 to 0.1 g/100 g diet, while increasing the amoimt of total fat in the diet from 4 to 34 g/100 g diet, did not lead to lipodystrophy, while fat mass was modestly reduced. Insuhn resistance was present in the group fed the 1 g CLA/100 g diet, but not present in the 0.1 g CLA/100 g diet group. 

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