Lipodystrophy, insulin resistance, diabetes mellitus, dyslipidemia, and cardiovascular disease in human immunodeficiency virus infection. (Featured CME Topic: Lipodystrophy Syndrome in HIV Infection).

Abstract

The introduction of highly active antiretroviral therapy has significantly reduced morbidity and mortality in patients infected with the human immunodeficiency virus. Treatment with antiretroviral agents--protease inhibitors in particular--has uncovered a syndrome of abnormal fat redistribution, dyslipidemia, and impaired glucose metabolism, collectively termed lipodystrophy syndrome. The cause of the syndrome seems to be multifactorial; however, its exact mechanisms have yet to be elucidated. Accelerated risk for cardiovascular disease is likely to be a major concern in these patients in the future. At this time, no clinical guidelines are available for the prevention and/or the treatment of lipodystrophy syndrome. The available treatment options range from switching the different antiretroviral drugs and lifestyle modifications to the use of pharmacologic agents to treat patients with dyslipidemia, impaired glucose tolerance and/or diabetes, and changes in body composition. This review emphasizes the clinical features, potential molecular mechanisms, and treatment options for patients infected with human immunodeficiency virus who have lipodystrophy syndrome.

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Human immunocleficiency virus (HIV) infection affects approximately 900,000 individuals in the United States. (1) The development of highly active antiretroviral therapy (HAART) has led to significant reductions in morbidity and mortality rates in HIV-infected patients. (2) Unfortunately, the use of these agents--particularly protease inhibitors (PIs)--has given rise to the metabolic and morphologic abnormalities collectively termed lipodystrophy syndrome. These abnormalities include abnormal fat distribution, dyslipidemia, and abnormal glucose metabolism. (3,4) During the past 2 to 3 years, a number of studies have been performed to discoverthe pathophysiology of these abnormalities and to evaluate methods of prevention and/or treatment. Most of these studies have been published in infectious disease journals. Recently, an increasing number of patients have been referred to endocrinologists for the management of the HAART-associated metabolic abnormalities. Familiarity with this literature and an understandi ng of the potential mechanisms of disease are critical to the endocrinologist in managing these patients. Pertinent literature was identified by performing a MEDLINE search for publications that appeared between 1982 and 2002 as well as in secondary sources such as published conference reports and abstracts. Key terms used in the search included HIV infection, lipodystrophy, metabolic abnormalities, dyslipidemia, insulin resistance, cardiovascular disease, and treatment. In this article, we discuss the prevalence, potential mechanisms, clinical features, and management options for the metabolic and morphologic abnormalities associated with HIV-infected patients who receive HAART.

Lipodystrophy

Despite the existence of an enormous amount of published literature on the subject, a consensus case definition of lipodystrophy has not yet been established. Much of the current understanding of lipodystrophy has been gained from the study of rare congenital lipodystrophies. (5) Lipodystrophy is characterized by the loss of subcutaneous adipose tissue, usually of the limbs, buttocks, and face; increased visceral abdominal fat; increased accumulation of fat in the dorsocervical area (ie, the "buffalo hump") and the breasts; or a combination of these features. (6'7) Several different measures have been used to assess abnormal fat distribution in various studies, including patient-reported fat patterns, findings on clinical examination, laboratory studies, and anthropometric data. A variety of different techniques, such as dual-energy x-ray absorptiometry, bioelectric impedance analysis, computed tomography, magnetic resonance imaging, and sonography have been used for the quantitative assessment of body fat di stribution. The lack of clear diagnostic criteria and assessment techniques makes it difficult to evaluate the true prevalence of this disorder in any population. Lipodystrophy has been reported in patients with HIV infection with or without HAART, but its prevalence has increased greatly since the introduction of P1 therapy. (8,9) Of the PIs, indinavir, ritonavir, and saquinavir have been implicated most often, but abnormalities can occur with the use of any of the PIs. Recently, nucleoside reverse-transcriptase inhibitors (NRTIs) have been reported to be associated with metabolic and morphologic abnormalities.'0 The incidence of lipodystrophy varies widely, and it has been reported that as many as 83% of patients treated with PIs may develop lipodystrophy. (7-9) The lack of uniform criteria, the patient populations studied, the duration of follow-up, the antiretroviral regimens used, and the variety of different tests used to assess the body fat redistribution might explain some of the differences in incide nce reported in the various studies. The onset of lipodystrophy may vary from 7 to 22 months after the initiation of treatment. (4) The changes in body composition vary by sex; women are more likely to experience fat accumulation in the waist and the breasts, whereas the buffalo hump is more common in men. Men are more likely than women to have fat depletion. (11)

Dyslipidemia

Several studies have documented the temporal association of lipid abnormalities with PI therapy. The characteristic lipid abnormality is elevation in triglyceride level. Total cholesterol level is increased, together with a small increase in low-density lipoprotein (LDL) level. The high-density lipoprotein (HDL) level is often reduced. Increased LDL cholesterol oxidation and apolipoprotein B level were also reported. (12) The cumulative incidence of new-onset hypercholesterolemia and hypertriglyceridemia with PI use in a 5-year cohort study were estimated to be 24 and l9%. (8) Age, sex, and baseline serum triglyceride and cholesterol levels were reported to be predictive of elevation in triglyceride level after the initiation of P1 therapy. (13)

Mechanism of Lipodystrophy and Dyslipidemia

Despite extensive research, the molecular mechanisms of preadipocyte differentiation and adipocyte death and/or apoptosis are unclear. A preadipocyte cell line (3T3-L1) was used in vitro to understand these complex molecular mechanisms. The mechanism of adipogenesis involves the activation of several families of transcription factors. These factors include CAAT box enhancer-binding protein [alpha], peroxisome proliferator-activated receptor [gamma]/retinoid X receptor heterodimer (PPAR[gamma]: RXR), and sterol regulatory element-binding protein-1/adipocyte determination and differentiating factor-1. All of these factors--particularly CAAT box enhancer-binding protein [alpha] and PPAR[gamma]:RXR--play important roles in adipogenesis. (14) Lipodystrophy could be a result of decreased preadipocyte differentiation and/or increased adipocyte apoptosis. Several in vitro studies have shown that PIs inhibit the preadipocyte differentiation and increase adipocyte death. With the use of 3T3-L1 cells, Dowell et al (15) showed that a PI (nelfinavir) inhibited a complex network of transcription factors that play a key role in the differentiation of preadipocytes to adipocytes (Fig. 1).

The potential mechanism of increased peripheral adipocyte death and/or apoptosis and altered lipid metabolism that Carr (16) proposed is shown in Figure 1. Cytoplasmic retinoic acid-binding protein-1 (CRABP-1) presents retinoic acid to cytochrome P-450 3A (CYP-3A), which in turn converts retinoic acid to cis-9-retinoic acid. The binding of cis-9-retinoic acid to PPAR[gamma]:RXR regulates adipocyte differentiation and apoptosis. The catalytic region of HIV protease and two human proteins--CRABP-1 and low-density lipoprotein receptor-related protein--that are involved in triglyceride metabolism in the peripheral circulation and in the liver have amino acid sequence homology. Carr et al (17) proposed that the PIs, because of their amino acid sequence homology, may bind to CRABP-1/CYP-3A and impair PPAR[gamma]:RXR heterodimer activity, resulting in increased apoptosis of peripheral adipocytes, decreased adipocyte differentiation, and decreased triglyceride storage in adipose tissue. Protease inhibitors may also i nhibit low-density lipoprotein receptor-related protein/ lipoprotein lipase complex activity, causing impaired chylo-micron and/or triglyceride clearance from the circulation. (17) This hypothesis has yet to be proved, however.

It has been proposed that NRTI-induced metabolic abnormalities are mediated by mitochondrial toxicity. The NRTIs specifically bind to deoxyribonucleic acid (DNA) polymerase [gamma], the only enzyme involved in the mitochondrial DNA replication. By binding to this enzyme, NRTIs inhibit mitochondrial DNA synthesis, which results in the depletion of mitochondrial DNA and subsequent dysfunction. (18)

Glucose Metabolism

The alterations in glucose metabolism in patients with HIV who are receiving PIs range from impaired glucose tolerance to frank diabetes mellitus. Impaired glucose tolerance is the most commonly reported abnormality and develops in approximately 16 to 46% of patients; diabetes mellitus has been reported to occur in 5 to 7% of patients treated with PIs. (8,9) Like Type 2 diabetes mellitus, insulin resistance seems to be a primary defect in the development of abnormal glucose metabolism. Some investigators have suggested the possibility of B-cell dysfunction, however.

Insulin Resistance

The overall prevalence of insulin resistance has been estimated to be 25 to 60% in PI-treated patients. (9,12) To assess insulin resistance, most studies have used the oral glucose tolerance test (OGTT), the fasting insulin level, the insulin-to-glucose ratio, the homeostatic model assessment, or the proinsulin-to-insulin ratio. The number of euglycemic clamp studies performed to assess the insulin resistance is limited, however. In a recent study of HIV-seronegative men who underwent OGTT and euglycemic clamping, Noor et al (19) showed that insulin resistance develops within 4 weeks of the initiation of indinavir therapy, independent of changes in body composition or lipid profile. The exact mechanism of PI-mediated insulin resistance is unknown. The cause of insulin resistance seems to be multifactorial (Fig. 2). The loss of adipose tissue may result in increased levels of circulating triglycerides and free-fatty acids, with subsequent accumulation of triglycerides and free-fatty acids in the skeletal muscl es and the liver. This in turn can lead to impaired glucose metabolism and increased insulin resistance in muscles and the liver. (20) Studies in animals and patients with congenital lipodystrophy indicate that some signals from fat cells affect insulin sensitivity in muscles and the liver. (21) Therefore, PI-mediated loss of adipose tissue may lead to increased insulin resistance in muscles and the liver. The glucose transporter (GLUT4) mediates insulin-stimulated uptake in adipocytes and muscle. Recently, two in vitro studies demonstrated that PIs cause insulin resistance by selectively decreasing transport activity of GLUT4 and/or GLUT4 translocation without affecting early insulin signaling in adipocytes and skeletal muscle. (22,23) Furthermore, coinfection with hepatitis C virus in HIV-seropositive individuals has been reported to contribute to insulin resistance. (24) Increased production of several cytokines, particularly tumor necrosis factor-[alpha] in patients with HIV, can cause increased insulin r esistance. (25)

B-cell Dysfunction

Studies of the direct measurement of B-cell function and/or insulin secretion are lacking. In a recent prospective study, Dube et al (26) evaluated the effect of indinavir-based therapy on insulin secretion (B-cell function) and insulin sensitivity with the use of OGTT, an intravenous glucose tolerance test, and homeostatic model assessment. During 8 weeks of indinavir-based therapy, patients' fasting glucose levels increased and their insulin sensitivity decreased without compensatory increases in insulin secretion, suggesting B-cell dysfunction. In a prospective study, Behrens et al (12) showed an increased proinsulin-to-insulin ratio during the first phase of OGTT in patients with HIV who underwent PI treatment, suggesting that PIs may interact with the enzymes required for the processing of proinsulin to insulin, resulting in defective insulin secretion. Other investigators have shown that PIs do not interfere with insulin processing. (27) Another potential mechanism of impaired insulin secretion and decr eased B-cell mass is the increased availability of fatty acids and increased triglyceride content in islet cells. In animal studies, accumulation of triglycerides in islet cells beyond a certain level has been shown to cause impaired insulin secretion and increased islet cell apoptosis by increasing cellular ceramide and nitric oxide levels. (28) Studies of islet cell morphology in humans are lacking, however, because of the unavailability of tissues. In addition, genetic predisposition and progressive loss of islet cells because of increasing demand as a result of insulin resistance may contribute to the development of impaired glucose tolerance and diabetes mellitus.

Cardiovascular Disease

The major concern of HIV-infected patients who undergo HAART is the potential risk of developing accelerated atherosclerosis and/or coronary artery disease. Several case reports of premature coronary artery disease in HIV-infected patients who underwent HAART have been published in the literature. (29,30) In the Frankfurt cohort study, (31) a retrospective analysis of 4,993 HIV-infected patients who underwent HAART showed that the incidence of myocardial infarction per 1,000 patient-years increased from 0.86 in the period from 1983 to 1986 to 3.41 in the period from 1995 to 1998 after the introduction of HAART. The increased risk of coronary artery disease may be related to multiple metabolic and morphologic abnormalities (eg, insulin resistance, dyslipidemia, fat redistribution) associated with HAART. These abnormalities are similar to those seen in syndrome X. (32) The association of syndrome X with increased risk of cardiovascular disease is well established. In addition, elevated plasminogen activator inh ibitor (PAI) level, tissue plasminogen activator (tPA) antigen level, cytokines (tumor necrosis factor [alpha]), and endothelial dysfunction may predispose patients to accelerated atherosclerosis. (33)

Treatment Options

The proper treatment for patients with lipodystrophy syndrome is uncertain. The available treatment options range from switching from one type of antiretroviral drug therapy to another and making changes in diet and exercise to the use of pharmacologic agents to improve lipid profile, insulin sensitivity, and body composition (Fig. 3). Several treatment approaches are under investigation.

Switching Antiretroviral Drug Therapy

Some studies have demonstrated that switching from one PI to another or from PI to non-NRTI therapy improves the patient's metabolic profile, whereas others have shown no change in or worsening of the metabolic profile. No change in body composition has been observed, however. (34,35)

Diet and Exercise

Limited data suggest that diet and exercise may improve the patient's metabolic profile and affect changes in body fat redistribution. A pilot study of 10 HIV-positive men with truncal obesity showed that a 16-week exercise program decreased total body fat and truncal body fat. (36) Recently, Roubenoff et a1 (37) tested the efficacy of a combination of exercise and a low-fat diet and a high-fiber diet as a treatment for patients with HIV-associated lipodystrophy. In a brief report of the first patient who completed an ongoing, 4-month clinical trial, the authors demonstrated a dramatic improvement in several aspects of lipodystrophy syndrome, including body weight, fat redistribution, and lipid parameters. Whether the same changes will be observed in other patients in the study remains to be determined. Further long-term clinical trials are required to assess the efficacy of lifestyle modification in the prevention and/or reversal of HIV-associated lipodystrophy.

Lipid-lowering Therapy

There are no specific guidelines for the management of lipid abnormalities associated with lipodystrophy syndrome. A few studies have examined the effect of statins (3-hydroxy3-methyglutaryl coenzyme A [HMG-CoA] reductase inhibitors) and/or fibrates .on lipid profile. No long-term, controlled studies are available. In a small cohort of patients with PI-related hyperlipidemia, treatment with atorvastatin (10-20 mgld) alone for 12 weeks reduced total cholesterol and triglyceride levels by 25 and 35%. (38) Recently, in a randomized, open-label, comparative trial, Moyle et al (39) evaluated the effect of diet alone versus a combination of diet and pravastatin therapy on lipid level in men with PI-associated dyslipidemia. During the 24-week study, LDL levels decreased significantly (19%) in the pravastatin treatment group as compared with those in the dietary advice-only group (5.5%). In another small, 8-week pilot study, pravastatin therapy reduced triglyceride levels by 19% and total cholesterol levels by 37% in patients with PI-associated dyslipidemia. Normal levels were observed for cholesterol in 5 (26%) of 19 patients and for triglyceride in 1 (5%) of 19 patients. (40)

Henry et al (41) evaluated the effect of combination therapy with statins and fibrates using National Cholesterol Education Program guidelines in 44 patients with PI-related hyperlipidemia. After 5 to 7 months of treatment, the patients treated with diet alone showed a reduction of 9 to 11% in total cholesterol level and 15 to 30% in triglyceride level. The group treated with gemfibrozil only had reductions in total cholesterol level of 27 to 34% and of 23 to 61% in triglyceride level. Patients treated with atorvastatin alone had a 19% decrease in total cholesterol level and a 21% decrease in triglyceride level. The combination therapy of atorvastatin and gemfibrozil was the most effective, reducing total cholesterol level by 60% and triglyceride level by 30%. (41) Cerivastatin has been shown to be effective and equivalent to other statins in reducing LDL cholesterol and triglyceride levels in non-HIV-infected patients with hyperlipidemia. (42) The drug was recently taken off the market because of an increase in the reported mortality rate when used in combination with fibric acid derivatives. Fenofibrate, a fibric acid derivative, is similar to gemfibrozil in reducing triglyceride level; however, it also has been shown to reduce LDL cholesterol level. Case reports of patients who underwent fenofibrate therapy have yielded results similar to those of patients with HIV-associated dyslipidemia who were administered gemfibrozil therapy. (43) The clinical trials in non-HIV-infected patients have shown that fenofibrate therapy is safe and effective in combination with small doses of statins. (44) Because of its LDL cholesterol-lowering effect, therefore, fenofibrate may be the fibrate of choice for combination therapy with statins in the treatment of patients with HIV-associated dyslipidemia.

A significant drug interaction may occur between HMG-CoA inhibitors and PIs. Simvastatin, lovastatin, and, to a lesser extent, atorvastatin are metabolized to different degrees by CYP-3A4, an enzyme that is inhibited by PIs. On the other hand, fluvastatin and pravastatin are not metabolized by GYP-3A4. As a consequence, levels of some HMG-CoA inhibitors may increase in the circulation by 5- to 30-fold with the coadministration of PIs. The greatest risk of drug interaction occurs in patients who are taking simvastatin or lovastatin, and those who are taking pravastatin and fluvastatin may be least affected by PI coadministration. (13) The use of HMG-CoA inhibitors causes liver function test abnormalities. It is generally recommended that liver function tests be performed before and at least 12 weeks after the initiation of therapy, at the time of any dose increase, and periodically (approximately every 6 months) thereafter.

No single agent is available to treat HIV-associated dyslipidemia effectively. Most patients are likely to need combination therapy with HMG-CoA inhibitor and a fibrate. The literature suggests that treatment with a combination of HMG-CoA inhibitor and a fibrate is safe, effective, and well tolerated; however, small increases in the risk of myopathy (incidence approximately 0.12%) and hepatotoxicity have been reported. (45,46) Patients who are treated with the combination of HMG-CoA inhibitor and fibrate should be advised to report any flulike symptoms such as myalgia, malaise, or severe back pain. It is recommended that if the creatinine phosphokinase level is elevated to 10 times the upper limit of normal, the drugs should be discontinued. In short, all individuals with PI-associated dyslipidemia who are treated with a combination of HMG-CoA inhibitor and fibrate should be started on the lowest recommended dose, and the dose should gradually be titrated upward. Additional large studies are needed to determi ne the safest, most effective way to use the available lipid-lowering drugs and to monitor the adverse effects in PI-associated dyslipidemia.

Nicotinic acid is available in immediate-release and sustained-release form. Niacin is a potent lipid-lowering agent that may be beneficial in the treatment of HIV-associated dyslipidemia. In clinical trials of non-HIV-infected patients with hyperlipidemia, niacin therapy reduced triglyceride levels by 23 to 28% and LDL cholesterol levels by 8 to 9%, and it increased HDL cholesterol levels by approximately 30%. It is also effective in reducing the level of lipoprotein(a). It has been reported to be safe and more effective when administered in combination with statins. (47,48) Niacin use is limited because of its side effect profile, however. Niacin causes flushing, gastrointestinal toxicity, and hepatotoxicity. In addition, niacin has been reported to cause an increase in blood glucose levels. In a prospective, randomized, placebo-controlled study called the Arterial Disease Multiple Intervention Trial (ADMIT), Elam et al (47) demonstrated that in patients who were taking niacin, there was a modest increase i n blood glucose levels in patients with diabetes mellitus as compared with patients who did not have diabetes mellitus. Hemoglobin A1c (HbA1c) levels remained unchanged from baseline to follow-up (60 wk) in patients with diabetes mellitus who were treated with niacin. The study suggests that niacin therapy is safe and effective in patients with well-controlled diabetes (HbA1c level, <7.0).

The major adverse effects of sustained-release niacin therapy include flushing and gastrointestinal irritability, and elevation of transaminase levels has been reported with the use of high doses (>2,000 mg/d). Overall, in clinical studies, tolerance of sustained-release niacin has been better than that of immediate-release niacin, with flushing and relatively mild hepatic effects. (49) No clinical study reported to date has evaluated the effect of immediate- or sustained-release niacin therapy in individuals with dyslipidemia induced by antiretroviral medications. Elevation of liver function test values and increase in blood glucose levels would be the major concerns in these individuals. Blood glucose levels and liver function tests should be monitored closely in patients who are taking immediate- or sustained-release niacin in this setting. Further studies are warranted to determine the most effective and safest way to use niacin and to monitor its adverse effects in patients with PI-associated dyslipidemi a.

Fish Oil

Fish oils are rich in eicosapentaenoic acid and docosahexaenoic acid. Clinical studies suggest that ingesting fish oil (2-4 g/d) reduces triglyceride levels significantly (20-25%). Moreover, the Diet and Reinfarction Trial and the Indian Experiment of Infarct Survival have demonstrated a reduction in rates of cardiac arrhythmia and sudden cardiac death.50 Adverse effects include fishy taste, bad breath, and abdominal cramps. Slight increases in LDL cholesterol level have been observed in individuals who are administered fish oil supplements. The data on the deleterious effects of fish oil consumption on glycemic controls are controversial. These studies suggest that fish oil's effect on decreasing triglyceride levels seems to persist as long as the supplementation is continued and that the slight increase in LDL cholesterol level seems to diminish with time. The use of fish oil may be beneficial in decreasing triglyceride levels in patients with HIV infection; however, no study data are available. Future clin ical studies are required to assess the effectiveness of fish oil supplementation in patients with HIV-associated dyslipidemia.

Insulin-sensitizing Agents

In three clinical trials, metformin therapy has shown promising results in reducing insulin resistance and related cardiovascular risk factors in HIV-related lipodystrophy syndrome. In a randomized, double-blind, placebo-controlled study of 26 patients, patients who were administered metformin had a significant reduction in fasting insulin level, body weight, diastolic blood pressure, and visceral abdominal fat. (51) A separate study of metformin use in 27 patients demonstrated similar results and also showed significant reduction in triglyceride levels. (52) More recently, Hadigan et al (53) investigated the effect of metformin therapy (500 mg bid) on PAI and tPA levels in a double-blind, randomized, controlled study. The group treated with metformin showed a significant decrease in PAI and tPA levels after 3 months of therapy. Because NRTIs may cause lactic acidosis, metformin should be used with caution in patients who are administered NRTIs.

The thiazolidinediones (TZDs) are a relatively new class of insulin-sensitizing agent. In addition to enhancing the sensitivity of adipose tissue to insulin action, these agents have been shown to play an important role in the differentiation of adipocytes by activating PPAR[gamma], which is highly expressed in adipose tissue. This effect is markedly enhanced in subcutaneous fat, whereas visceral fat seems to be refractory to the action of TZDs. Several studies have assessed the effect of TZDs on preadipocyte differentiation and body fat distribution with the use of a variety of techniques, such as computed tomography, magnetic resonance imaging, and dual-energy x-ray absorptiometry. These studies have demonstrated that TZDs have a tendency to significantly increase subcutaneous fat, decrease or have no effect on visceral fat, and significantly decrease the visceral-to-subcutaneous fat ratio. (54,55) Additional studies in animal models have shown that TZDs play a key role in the remodeling of adipose tissue. Thiazolidinediones have been shown to increase the number of small adipocytes and decrease the number of large adipocytes in fat depots. The new, small, insulin-sensitive adipocytes may decrease circulating plasma free-fatty acid and triglyceride levels as well as skeletal muscle triglyceride content, which, in part, may improve skeletal muscle insulin resistance. (56)

In a clinical trial of non-HLV-infected lipoatrophic patients, troglitazone therapy reduced HbA1c and triglyceride levels and increased subcutaneous body fat. (57) In a pilot study of six patients with metabolic and morphologic abnormalities associated with antiretroviral therapy, treatment with troglitazone improved or reversed insulin resistance, decreased triglyceride levels, decreased visceral fat, and increased subcutaneous fat. (58) Unfortunately, troglitazone is no longer available for clinical use, owing to its side effect of serious liver toxicity. Two agents of the same class--rosiglitazone and pioglitazone--are available, however, and have been shown be safe and more effective in non-HIV-infected patients with Type 2 diabetes mellitus, either alone or in combination with other hypoglycemic agents. (59) In addition, these agents have been shown to have beneficial effects on the lipid profile. Limited data suggest that treatment with pioglitazone results in a trend toward improvement in all lipid var iables, and rosiglitazone therapy has shown an increase in total cholesterol, triglyceride, and LDL cholesterol levels as well as a trend toward a decrease in HDL cholesterol level.

Recently, Khan et al (60) compared-the impact of the use of pioglitazone and rosiglitazone on lipid levels in a cohort of 127 patients with Type 2 diabetes who previously were treated with troglitazone. During the 4-month study period, significant improvement in lipid profile values--specifically in total cholesterol level (decrease of 20 mg/dl)--was noted in the group that was administered pioglitazone compared with the group taking rosiglitazone. There was no significant change in HDL cholesterol level. Gegick and Altheimer, (61) in a 3-month observational study, showed that mean total cholesterol, triglyceride, and LDL cholesterol levels decreased by 4.7, 11.3, and 7.3%, respectively, with pioglitazone treatment but increased by 8.4, 38.4, and 8.1%, respectively, in patients who were administered rosiglitazone. Mean HDL cholesterol level increased by 2.6% in patients taking pioglitazone and decreased by 6.3% in those who were administered rosiglitazone. Another observational study demonstrated similar resu lts. (62) Whether these effects on lipid profile will have any impact on cardiovascular outcome needs to be established in long-term, randomized clinical trials. Whether similar results will be observed in patients with PI-associated dyslipidemia remains unknown. In short, TZDs have the potential to improve or reverse P1-associated morphologic and metabolic abnormalities (Fig. 1) and might be considered for use in the management of these patients. Liver function should be monitored closely while these agents are administered in patients who are receiving HAART.

Recombinant Human Growth Hormone 

Several small studies have shown changes in body composition but not in metabolic profile in patients who were administered recombinant human growth hormone (rhGH) and had the wasting syndrome associated with HIV infection or lipodystrophy syndrome. A 12-week, randomized, double-blind, placebo-controlled, multicenter study showed that treatment with rhGH (0.1 mg/kg/d) in patients with HIV-associated wasting resulted in a sustained and statistically significant increase in weight and lean body mass as well as a decrease in total body fat. (63) In HIV-positive men with lipodystrophy, treatment with pharmacologic doses of growth hormone (3-6 mg/d) was shown to reduce buffalo hump size, excess visceral adipose tissue, total body fat, and waist-to-hip ratio as well as an increase in lean body mass. (64,65) When used in such supraphysiologic doses, rhGH has been reported to be associated with edema, arthralgia, elevated insulin-like growth factor level, impaired glucose tolerance, and hyperglycemia. In addition, hi gh doses may predispose patients to an increased risk for developing malignancies. Patients with HIV-associated lipodystrophy should be screened for impaired glucose metabolism before rhGH therapy is initiated, and they should be monitored closely for adverse consequences associated with long-term growth hormone therapy.

Cosmetic Therapy

Limited data show that suction-assisted lipectomy may be beneficial in the treatment of abnormal fat deposits in the abdomen or buffalo hump, but that it has no effect on metabolic profile. (66)

Accepted My 24, 2002.

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RELATED ARTICLE: Key Points

* Lipodystrophy syndrome, which is characterized by abnormal fat distribution, insulin resistance, and dyslipidemia, is an increasing concern in patients infected with the human immunodeficiency virus who are receiving highly active antiretroviral therapy.

* Several possible mechanisms involved in the pathogenesis of the syndrome have been proposed, but its exact mechanisms need to be elucidated.

* Either alone or in combination with a fibrate, 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors significantly improve the lipid profile but do not normalize cholesterol and triglyceride levels.

* Potential drug interactions between protease inhibitors and some 3-hydroxy-3-methyglutaryl coenzyme A inhibitors may occur; therefore, these patients need to be monitored closely for adverse effects, such as liver toxicity and myopathy.

* Thiazolidinediones have the potential to improve and/or reverse the morphologic and metabolic abnormalities in patients with lipodystrophy syndrome.

From the University of Louisville and the Veterans Affairs Medical Center, Louisville, KY.

Address reprint requests to Lal K. Tanwani, MD, 425 S. Hubbards Lane #t to, Louisville, KY 40207. Email: [e-mail]

Copyright [c] 2003 by The Southern Medical Association 0038-4348/03/9602-0180