In developed countries, the availability of highly active antiretroviral therapy (HAART) has contributed to a dramatic decrease in mortality and opportunistic infections associated with HIV/AIDS. However, as patients have begun to live longer, new complications have emerged. Over the last several years, clinicians have seen perplexing changes in fat distribution and metabolism. These changes manifest in varying combinations as lipoatrophy, lipohypertrophy, or both in localized areas, frequently in association with dyslipidemia and disturbances in glucose homeostasis [1–6] (Table 1).
Often, the alterations are associated with HAART regimens that include protease inhibitors (PI), but both lipoatrophy and lipohypertrophy have been described in patients taking PI-sparing regimens [1,7–10]. Many other contributing factors have been proposed, including duration of antiretroviral therapy, duration of HIV infection, change in viral load, age, gender, and ethnicity [4,10–20].
Consequences for patients include disfiguring alterations in body shape, e.g., increased abdominal girth, enlargement of the dorsocervical fat pad, wasting in the extremities (Table 1), which could discourage adherence to antiretroviral treatment regimens. Furthermore, the mere possibility that such changes may develop could deter treatment initiation. Dyslipidemia, including increased triglycerides, increased total cholesterol and low density lipoprotein (LDL) cholesterol, and decreased high density lipoprotein (HDL) cholesterol (Table 1), has raised concern about increased risk for atherogenesis and atherosclerotic vascular disease . Patients also may develop problems with glucose homeostasis, even in the absence of morphological changes, that may lead to diabetes mellitus and diabetes-associated health problems [22,23].
The prevalence of morphological and metabolic abnormalities among HIV-infected patients is not firmly established. Estimates vary widely, possibly because of variations in study methodology, defining criteria, treatment regimens, and patient populations . Estimates of abnormalities in fat distribution range from as low as 2% to as high as 84% of patients taking a PI (Table 2). Between 15% and 30% of HIV-infected patients have dyslipidemia; estimates approach 60% in patients taking a PI . Impaired glucose tolerance has been reported in 47% of patients on PI treatment . The prevalence of hyperglycemia has been estimated at 3–5% in patients receiving a PI; approximately 1% of these patients have clinical evidence of diabetes. [28–30]. However, systematic studies are needed to determine more accurately the prevalence of hyperinsulinemia, insulin resistance, glucose intolerance, and diabetes among patients with HIV [13,24,31].
It is unclear, and a matter of some controversy, whether the changes in body habitus and metabolic abnormalities represent separate conditions or a single syndrome, referred to variously as lipodystrophy syndrome, fat maldistribution syndrome, PI- or HAART-associated lipodystrophy, or HIV-associated adipose redistribution syndrome (HARS) . What has become clear is that standard approaches are needed for diagnosing and assessing the disorder(s) to facilitate the clinical research necessary for developing treatments and guidelines that can help to improve the health and quality of life of people with HIV .
This review focuses on the most current information available on fat maldistribution and metabolic changes observed in people with HIV infection. We begin with an overview of findings from several cohort investigations underway worldwide. Factors and mechanisms thought to contribute to lipodystrophy syndrome are discussed, and approaches to assessing, managing, and treating the disorder are proposed.
Epidemiology of lipodystrophy syndrome: findings from cohort studies
The Australian Prevalence Survey of Lipodystrophy Syndrome
Clinicians at St Vincent’s Hospital in Sydney, Australia were among the first to notice changes in fat distribution and metabolism among patients with HIV . Since then, a national network of investigators has begun a cross-sectional survey, the Australian Prevalence Survey of Lipodystrophy Syndrome .
Of 1348 predominantly male patients surveyed at 14 centers, fat maldistribution was documented in 54% of patients. Seventy-three percent of all patients were on an antiretroviral regimen that included a PI; of these patients, 63% had lipodystrophy. Fourteen percent of all patients were taking nucleoside reverse transcriptase inhibitors (NRTI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTI) but no PI; of these patients, 32% had lipodystrophy. Twelve percent of all patients had not taken any antiretroviral agents; of these patients, 21% had lipodystrophy. Physicians characterized most patients’ self-reported conditions as mild or moderate. As severity of fat maldistribution increased, so did the incidence of metabolic abnormalities, such as elevated fasting triglyceride, insulin, and C-peptide levels. Preliminary analysis identified increasing age, symptomatic HIV disease, increased duration of NRTI and PI treatment, and lower viral load as risk factors for lipodystrophy syndrome.
The Self-Ascertained Lipodystrophy Syndrome Survey: gender differences in lipodystrophy syndrome
For the Self-Ascertained Lipodystrophy Syndrome (SALSATM) Survey, which is ongoing at 50 sites in the United States, Canada and Australia, patients complete a questionnaire on body morphology, medical history, health habits, and lifestyle; health care providers fill in a corresponding form with medical history, prescribed medications, and data from physical examinations and laboratory tests. Data from SALSATM has revealed gender differences in patients with morphological abnormalities.
Of 526 patients with morphological abnormalities, 99% were taking antiretroviral agents, and only 2% were PI-naive . The most common morphological abnormality reported was fat accumulation in the abdomen, reported in 76% of men and in 93% of women (Fig. 1). The second most common abnormality was fat depletion in the limbs (67%) in men and fat accumulation in the breasts (69%) in women. Most women (59%) also had fat depletion in the limbs.
Survey data also revealed metabolic disturbances, including hypertriglyceridemia, hypercholesterolemia, and hyperglycemia, in many patients. Men were more likely than women to have metabolic abnormalities (Fig. 2).
Multivariate analysis of the data identified fat accumulation as being associated with female gender, low viral load (< 500 copies/ml), and high body mass index (BMI > 28 kg/m2) [34,35]. Fat depletion was associated with low BMI and prior treatment with stavudine .
The HIV Outpatient Study
Data from the HIV Outpatient Study (HOPS), a prospective study of HIV patients from United States private practice, public health, and university clinics, has helped to characterize further morphological abnormalities and associated risk factors in patients with HIV infection. The survey includes 1077 patients, with or without lipodystrophy disorder, who have been followed for over 8000 patient years.
Of these patients, 49% showed some evidence of fat maldistribution. Factors most strongly associated with an increased risk of lipodystrophy were increasing age and the use of one PI or one NRTI; NNRTI treatment was not associated with lipodystrophy. Duration and severity of HIV infection, time since reversal of clinical progression of HIV infection, use of two antiretroviral agents, and extreme changes in BMI were also strongly associated.
The LIPOCO study
The LIPOCO cohort study is an ongoing observational investigation of changes in body fat distribution and metabolism among HIV-infected patients in France . In one recent analysis, patients were divided into four clinical categories: a fat depletion group; a fat accumulation group; a mixed group, including patients with both fat depletion and fat accumulation; and a control group, consisting of patients with no changes in fat distribution.
Of 154 patients in the study, 15 were therapy-naive, 39 had been on NRTI therapy only, and 100 had been taking combination therapy that included at least one PI. Alterations in body fat distribution were observed in 82 (53.3%); of these patients: 34 (22.1%) were classified in the lipoatrophy group, nine (5.9%) in the fat accumulation group, and 39 (25.3%) in the mixed group. Patients in the lipoatrophy group had significant decreases in subcutaneous fat, as measured by computed tomography (CT), and elevations in plasma triglycerides. Patients in the fat accumulation and mixed groups had significant increases in intra-abdominal fat, as measured by CT, and elevated plasma insulin levels. Multivariate regression analyses correlated fat wasting with stavudine treatment. Surprisingly, treatment with a PI was not significantly associated with changes in fat distribution .
These results and additional LIPOCO data suggest that distinct types of fat maldistribution may occur in patients on antiretroviral therapy, including a fat depletion syndrome that may be related to the use of stavudine and a mixed fat redistribution syndrome that may be related to effective virus control . Other French cohort studies have provided similar findings [37–39].
EuroSIDA: a multicohort study
The EuroSIDA study is a large multicohort study that began in 1994 as an epidemiological study of AIDS in Europe. This ongoing prospective study includes more than 8000 subjects from more than 60 sites in 20 European countries . A prospective substudy of EuroSIDA, begun in 1998, is identifying risk factors for fat accumulation and fat depletion. Preliminary results have corroborated findings from other cohort studies that show associations between changes in fat distribution and gender, increasing age, prior AIDS diagnosis, and number of antiretroviral drugs, but have found no association with viral load.
Complexities of developing a case definition
The past several years have brought a flood of information about HIV/HAART-associated changes in body shape and metabolism. Unfortunately, to date, the available data have not helped to generate a definition or diagnostic criteria for lipodystrophy syndrome. Defining the disorder is complicated by uncertainty as to whether it is a single syndrome with multiple, varying components or involves multiple, distinct conditions. In part, this reflects the scant and sometimes contradictory data on how metabolic and morphological components of the syndrome may be linked. Also, causal relationships among specific antiretroviral agents and metabolic and morphological disturbances remain uncertain. PIs clearly play a role, and NRTIs also may contribute , but many abnormalities have been observed in the absence of antiretroviral treatment  and non-medication risk factors clearly play a role .
The Fat Redistribution and Metabolism (FRAM) study
The FRAM study has been designed to address some of these issues. It is a multicenter, cross-sectional survey of 1200 randomly selected HIV-infected patients from geographically diverse United States sites and 300 healthy, non-HIV-infected subjects from an ongoing study of cardiac disease (CARDIA). The FRAM study has been designed to estimate the prevalence of individual fat distribution and metabolic abnormalities, define associations among these abnormalities, and identify contributing covariates. The use of standardized techniques among multiple sites allows assessment of the role of study site, ethnicity, HIV risk factors, and socioeconomic status as potential contributors to differences in prevalence. Fat distribution will be assessed using head-to-toe wide-slice magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DEXA), with computed readings performed in a central laboratory. The study also will examine relationships between self-reported changes in fat distribution and those detected using quantitative measures. Analysis of the data obtained may help to define HIV-associated lipodystrophy syndrome, characterize associations among its manifestations, and identify etiological factors.
Cardiovascular risk associated with lipodystrophy syndrome
The biological implications of HIV/HAART-associated changes in body composition and metabolism, in terms of increased cardiovascular risk, are uncertain. Most experts agree that this risk is unlikely to outweigh the benefits of antiretroviral therapy. To date, available data suggest that these patients have little or no short-term increase in coronary event rates [42,43]. Examination of structural changes has yielded mixed results. For example, one study has shown no difference in carotid intima thickness (as measured by ultrasound) among HIV-positive patients taking PI compared with age-, sex-, and ethnicity-matched HIV-negative control subjects . However, a similar study demonstrated a higher-than-expected prevalence of premature carotid artery lesions (detected by ultrasound) in PI-treated versus PI-naive patients .
To understand fully the cardiac risk in patients with lipodystrophy syndrome, long-term studies are needed that involve subjects stratified by risk using accepted risk stratification guidelines (such as those set up by the Framingham group  or the National Cholesterol Education Program ). Collection and analysis of multicenter data should provide powerful predictions of the rate of coronary disease in this patient population.
In practice, the risk for heart disease in HIV-positive patients taking HAART needs to be considered in the context of other predisposing factors. Clinicians need to obtain a thorough history on each patient to identify factors that increase patient risk, e.g., hypertension, insufficient physical activity, smoking, family history of heart disease, obesity, and diabetes. Physical examinations should include measurement of blood pressure, a cardiovascular examination, and identification of obesity or adipose accumulation or atrophy. A 12-lead electrocardiograph should be performed for patients who are at moderate or higher risk for coronary artery disease. Laboratory tests should be ordered to determine whether dyslipidemia or diabetes is present. Medical interventions should be initiated to correct dyslipidemia and other treatable risk factors. When relevant, patients should be encouraged to stop smoking, modify their diet, lose weight and increase physical activity.
Etiology of lipodystrophy syndrome
The etiology of HIV-associated lipodystrophy syndrome remains to be elucidated. The changes observed result from direct toxic side effects of antiretroviral treatment, infection-induced alterations in metabolism, or a combination of both.
Understanding what causes the changes seen in patients with HIV-associated lipodystrophy syndrome is hampered by disparity in the methods used to assess various manifestations of the syndrome and the need for studies designed to distinguish causative factors among risk factors. Antiretroviral agents are thought to play a primary role, but so far, most studies implicating these agents show associations rather than causation. Numerous non-drug factors also appear to contribute to HIV-associated lipodystrophy.
Understanding etiology is further complicated by difficulties in determining relationships among different aspects of the syndrome [21,24]. Available evidence shows that metabolic changes precede fat redistribution; it is not clear whether metabolic changes cause fat redistribution or, conversely, whether fat redistribution promotes metabolic changes [48–50].
As mentioned above, PIs have been implicated most strongly in both metabolic and fat distribution abnormalities. However, evidence is accumulating to support a role for NRTI (in particular, stavudine and dideoxyinosine) in lipodystrophy syndrome [18,51]. It is also possible that PI and NRTI drugs act together to produce changes associated with lipodystrophy.
Numerous studies have shown that patients taking a PI have higher blood levels of triglycerides, total and LDL cholesterol, certain lipoproteins, insulin, and glucose [27,31]. One longitudinal study of patients with HIV has observed increases in serum glucose, insulin, triglycerides, and total and LDL cholesterol levels in the absence of evidence of fat redistribution after initiation of PI therapy . Studies showing reversal or improvements in glucose, insulin, triglyceride, or cholesterol abnormalities when PI are discontinued strengthen the hypothesis of a direct PI effect . These studies are discussed in more detail below. In addition, one recent study has shown that ritonavir treatment can increase blood triglycerides, lipoprotein (a) levels, and apoprotein B levels in HIV-seronegative individuals, thereby implicating drug effects distinct from HIV effects .
Current data suggest that elevated blood levels of glucose or insulin may be a consequence of HIV infection , a result of PI or NRTI treatment [52,23], or an indirect consequence of truncal adiposity or lipoatrophy [54–57]. Insulin resistance has been demonstrated in patients taking antiretroviral agents, most often with PI treatment [22,31] but also with NRTI treatment alone . One study has shown that replacing PI with nevirapine partially reverses insulin resistance 
Studies of PI-naive, HIV-positive patients have shown increased triglycerides; decreased total, LDL, and HDL cholesterol; and increased hepatic lipogenesis [6,58], but not hyperglycemia, insulin resistance, or glucose intolerance . More studies are needed to clarify the mechanisms and causal relationships involved.
Fat loss seen in patients with HIV, typically in subcutaneous regions, may result from cell atrophy, apoptosis, or dedifferentiation of fat cells. Fat gain in visceral regions may result from adipogenesis, lipogenesis, or both. Because visceral fat drains portally into the liver, it may contribute to the elevation in serum triglycerides and insulin resistance seen in patients with HIV. Factors controlling fat loss and accumulation are complex and thought to be influenced by cytokines such as tumor necrosis factor alpha and interleukin 6, by endocrine factors such as cortisol, testosterone, and growth hormone, and by differential expression of receptors for these factors on adipocytes in different fat depots [59–63]
Possible mechanisms for antiretroviral agent effects
The presumed causal role of PI drugs has been challenged by a growing number of observational studies that document body composition changes in the absence of PI treatment, both in antiretroviral treatment-naive patients and in patients on PI-sparing treatment regimens. However, evidence suggests that both PI and NRTI use are involved.
On a cellular and molecular level, PI drugs have been shown to inhibit adipocyte differentiation, [64,65], thereby possibly contributing to morphological changes. In addition, some researchers speculate that toxic effects of NRTIs on mitochondrial function and associated lactic acidosis may be linked to changes in fat distribution .
Mitochondrial toxicity associated with non-nucleoside reverse transcriptase inhibitors
NRTI drugs are known for their toxic effects on mitochondria. In vitro studies have established that NRTIs inhibit HIV RNA reverse transcriptase, an RNA-dependent DNA polymerase, as well as host-cell DNA polymerases. Mitochondrial DNA polymerase gamma, an enzyme that is essential to mitochondrial DNA replication and therefore to mitochondrial viability and function, is particularly sensitive to NRTI inhibition 
All NRTI drugs can cause mitochondrial toxicity, but to differing degrees, [51,67] and their impact may be worsened by interactions with PIs. For example, when indinavir and stavudine are combined, indinavir can increase plasma stavudine concentrations, [51,68,69], thereby potentially increasing or accelerating NRTI-mediated mitochondrial toxicity.
When mitochondria do not function properly, pyruvate is converted to lactic acid in the cytosol, where it may accumulate with toxic consequences for the cell and surrounding tissues. Fatty acids that normally would be metabolized in mitochondria also may accumulate in the cytosol, possibly explaining the lipid accumulation observed within muscle, liver, and nerve cells in vitro and sometimes in biopsies of patients with other mitochondrial disorders [70–78]. Ensuing cellular damage can lead to hepatic steatosis, myopathy, cardiomyopathy, peripheral neuropathy, and, possibly, lipodystrophy.
NRTI-related mitochondrial toxicity may contribute to the fat redistribution syndrome seen in patients with HIV infection. This relationship is based partly on the resemblance of certain manifestations of the syndrome to other conditions characterized by abnormal fat accumulation and mitochondrial malfunction, such as Madelung’s disease and dorsocervical lipoma in the absence of Cushing’s disease [79,80]. But HIV-infected patients have only certain of the changes seen with either condition, so the association may be unrelated to the pathogenesis of HIV-lipodystrophy syndrome. Furthermore, despite the ability of NRTI to inhibit mitochondrial DNA polymerase gamma in vitro, frank lactic acidosis is a rare occurrence in patients taking these agents. Moreover, there are no data to link the manifestations of HIV-associated lipodystrophy syndrome to lactic acidosis or other signs of mitochondrial dysfunction.
Management of HIV-associated lipodystrophy syndrome
The wide variation in metabolic and fat distribution abnormalities experienced by patients complicates diagnosis and management of patients with HIV-associated lipodystrophy syndrome. Treatments to reverse or reduce metabolic and fat distribution abnormalities must address each patient’s specific changes and health risks.
Management of fat maldistribution
Relationships between body shape (specifically, relative sizes of different adipose tissue compartments) and health risks have been recognized for many years . For example, people with upper-body obesity are more likely to have type 2 diabetes, hypertension, hyperlipidemia, and excess morbidity and mortality than people with lower-body obesity. Such associations may be relevant to the changes seen in HIV-infected individuals.
In addition to the health problems noted above, patients with obvious changes in body habitus may report discomfort or feel stigmatized by the changes in their appearance . Some may seek cosmetic surgery such as liposuction, which presents its own risks and may only partially or temporarily correct fat accumulation. Some patients may even refuse to start or continue antiretroviral therapy for fear of developing health risks and unsightly morphological changes [83,84]. Therefore, for health and cosmetic reasons, patients taking HAART require careful monitoring to detect changes in fat distribution and, if necessary, need interventions to reverse or reduce abnormalities.
Assessment of body fat redistribution
Although little information is available to guide measurement of fat distribution in HIV-infected patients, there is extensive experience for non-HIV conditions.
Various techniques are used to assess body fat distribution, including anthropometric measures, regional DEXA, ultrasound, and whole-body or single-slice MRI or CT. To date, these techniques have been used mainly in epidemiological studies; currently, no technique is generally accepted for clinical practice. Skinfold measurements are potentially useful for monitoring subcutaneous fat stores in patients with lipoatrophy, when performed by trained personnel. Another measure, the waist-to-hip ratio (WHR), is widely accepted as a marker that can be reproducibly correlated with adverse patient outcomes in epidemiological studies . However, many studies have shown that WHR is unreliable compared with other measures in studies of patients with HIV or other conditions [86–88]. Waist circumference alone, as well as sagittal diameter, have been shown to be more sensitive and specific than WHR [89–94].
Additional techniques for assessing changes in body fat, such as DEXA and ultrasound, have been applied in limited fashion, mostly in epidemiological studies. As yet, they have not been applied in the clinic because of the greater need for precision and accuracy in clinical versus epidemiological applications.
DEXA and ultrasound have been used to assess body fat distribution in both in HIV and non-HIV conditions [95–98]. Ultrasound can be used to measure specific adipose tissue reservoirs, even on the face, , whereas DEXA measures total and regional adipose tissue. DEXA is suitable for examining appendicular fat, which consists almost entirely of subcutaneous adipose tissue. However, it cannot distinguish abdominal subcutaneous adipose tissue from visceral adipose tissue.
Cross-sectional imaging techniques, such as CT and MRI, yield more precise information about fat distribution. Multislice CT and MRI scans can provide a three-dimensional reconstruction of normal tissues. CT and MRI measurements of fat and lean mass have been validated against measurements in cadavers  and against each other . Single-slice CT or MRI measurements also correlate strongly with whole body CT or MRI measurements of subcutaneous and visceral adipose tissue (Fig. 3) , yet are much easier to obtain.
However, cross-sectional imaging has some limitations and is expensive and resource-intensive. Single slice measurements may not be valid reflections of whole body composition in the presence of lipodystrophy. In addition, as with whole body imaging, there are no generally accepted ‘normal’ measures. Studies to derive standardized visceral adipose tissue values in patients with HIV infection are underway (E. S. Engelson, D. Agin, D. Gallagher, S. B. Heymsfield and D. P. Kotler, unpublished data). Once practical approaches and measures are established for diagnosing HIV-associated changes in fat distribution, standards will need to be established for men and women by age and ethnicity.
Treatment of dyslipidemia
Treatment of lipid disorders in patients with HIV is an area of active investigation. Fortunately, a number of effective lipid-lowering agents are available. These include 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins), which reduce triglycerides and cholesterol, and fibrates, which reduce triglycerides but not cholesterol. Unfortunately, antiretroviral agents may interact with lipid-lowering agents, enhancing toxicities of these agents and potentially leading to severe adverse consequences, such as the rhabdomyolysis sometimes seen with high serum levels of statins.
Recent pharmacokinetic studies have shown that the metabolism of most statins and fibrates is influenced by PIs, probably via effects on cytochrome CYP3A4 . Available fibrates include clofibrate, fenofibrate, and gemfibrozil. Gemfibrozil and clofibrate are metabolized by CYP3A4, whereas fenofibrate is not metabolized by the cytochrome P450 system 
Statins, including atorvastatin, cerivastatin, fluvastatin, lovastatin, pravastatin, and simvastatin, may vary considerably in metabolism, potency, and drug interaction. These differences may be important for patients taking antiretroviral therapy. Fluvastatin, lovastatin, and simvastatin have significant interactions with other drugs that affect the metabolic activity of cytochrome P450 enzymes. Cerivastatin and atorvastatin may interact with other drugs as well, but to a lesser extent. Pravastatin is metabolized by sulfation and not by any of the cytochrome P450 enzymes; it, therefore, has a much lower potential to interact with antiretroviral agents .
The Adult AIDS Clinical Trials Group (ACTG), a network of 32 university-affiliated clinical research sites across the United States, has initiated a series of studies focused on metabolic complications of HIV disease. Among them, ACTG 5047 and ACTG 5087 will examine the safety and efficacy of lipid-lowering agents. ACTG 5047 was designed to identify and characterize interactions between PIs (specifically, ritonavir and saquinavir or nelfinavir) and statins (atorvastatin, pravastatin, and simvastatin) in healthy, HIV-seronegative subjects . Preliminary results from this study show that, with both PI regimens, atorvastatin and simvastatin levels increased significantly while pravastatin levels decreased slightly. In the presence of ritonavir plus saquinavir, atorvastatin acid levels increased by 343%, total active atorvastatin levels increased by 74%, simvastatin levels increased by 2676%, and pravastatin levels decreased by 47%. Pravastatin does not affect concentrations of nelfinavir or its active metabolite, and none of the three statins has a significant effect on ritonavir or saquinavir concentrations. Therefore, pravastatin appears to be safe for patients taking ritonavir and saquinavir. Atorvastatin should be used with caution, and simvastatin should be avoided.
Further study is needed to expand these findings and examine the potential for drug interaction when statins or fibrates are given with other antiretroviral agents, and to assess the effectiveness of statins and fibrates in lowering triglyceride levels in patients with HIV-associated dyslipidemia. Recently, study ACTG 5087 has begun to compare the efficacy of pravastatin and fenofibrate in a randomized, open-label, 48-week clinical trial involving patients on potent antiretroviral treatment. In addition to these research efforts, the ACTG Cardiovascular Focus Group has recently published recommendations managing HIV-associated dyslipidemia . Their recommendations are based on guidelines established by the National Cholesterol Education Program .
Treatment of abnormalities in glucose and insulin metabolism
To detect glucose and insulin abnormalities in patients with HIV-associated lipodystrophy syndrome, a fasting insulin level or a 2 h, 75 g oral glucose tolerance test is often needed because fasting glucose levels are frequently normal in these patients. Optimal management approaches are as yet unknown, but diet and exercise are a reasonable first-line strategy. Oral insulin-sensitizing agents such as metformin and the glitazones may increase insulin sensitivity; they also may reduce visceral fat accumulation. Insulin therapy is most appropriate for patients with diabetes or hyperglycemia who have not responded to oral therapy.
Metformin decreases hepatic glucose production and increases peripheral glucose uptake [105,106]. Metformin may also reduce triglyceride levels and promote modest weight loss in patients with diabetes and can reduce insulin levels and promote weight loss in obese women with polycystic ovary syndrome [107–109]. Risks associated with metformin treatment include gastrointestinal intolerance at therapy initiation and, rarely, lactic acidosis. One study of HIV-infected patients on PIs found that metformin (850 mg given three times daily) reduced insulin resistance as well as visceral adipose tissue; the patients also lost weight . A second study examined the effect of metformin in a group of HIV-infected, non-diabetic patients with fat redistribution and abnormal oral glucose tolerance test results, hyperinsulinemia, or both . Results showed that a relatively low dose of metformin (500 mg twice daily) produced significant reductions in oral glucose tolerance test insulin (but not glucose) levels, weight, waist circumference, and diastolic blood pressure (Table 3). Non-significant reductions in visceral adipose tissue were also observed (mean change, −1115 mm2 in patients taking metformin and +1191 mm2 in placebo-treated patients. In both studies, diarrhea was the most common adverse effect [110,111].
Glitazones increase insulin sensitivity by increasing glucose transport and adipogenesis, ultimately increasing peripheral glucose uptake. Rosiglitazone and pioglitazone are currently available in the United States. Unlike troglitazone, which was recently withdrawn from the United States market, rosiglitazone and pioglitazone do not seem to contribute to liver toxicity. They may be used in combination with metformin, but the combinations have not been tested extensively in patients with HIV. An ACTG study, 5082, will examine the effect of metformin and rosiglitazone, alone or in combination, on hyperinsulinemia in patients with lipodystrophy syndrome.
Diet and exercise therapy
It is well established that diet and exercise can affect both total and regional fat mass in the general population . In addition, both dietary and exercise therapy have an impact in controlling insulin resistance and diabetes and in lowering cholesterol levels [112–115]
The impact of diet in reversing these manifestations in patients with HIV is less clear, as there are very few data in this area. Furthermore, the very-low-fat, high-carbohydrate diet often prescribed for weight loss and modification of serum lipids in patients with cardiovascular disease has been called into question. New research suggests that this diet may decrease HDL cholesterol levels, increase triglyceride levels, and contribute to postprandial lipidemia, hyperglycemia, and hyperinsulinemia [113,116]. A very-low-fat diet may also accelerate carbohydrate absorption 
A diet that includes a moderate amount of fat and substitutes omega-3 and omega-6 fatty acids for saturated fatty acids may work better to reduce lipogenesis and decrease insulin resistance. In addition, the inclusion of high-fiber foods and carbohydrates with a low glycemic index can be of benefit [117–119]. This diet may help to reduce insulin resistance, minimize insulin secretion, decrease fat biosynthesis, decrease blood triglycerides, and reduce both weight and central fat accumulation. Research is needed not only to determine whether the diet can correct fat maldistribution and associated metabolic disorders, but also whether it can prevent these complications if initiated early with antiretroviral therapy.
The benefits of exercise in the general population are well known and include improved cardiovascular fitness, improved HDL and LDL cholesterol levels, increased insulin-dependent glucose uptake, and reductions in abdominal fat. Studies in HIV-positive patients show that an exercise program consisting of resistance training with an aerobic component, is safe and can reduce abdominal adiposity as measured by DEXA scanning [120,121]. Additional studies are warranted to investigate the impact of exercise on cardiovascular fitness, peripheral fat stores, lipid levels, and insulin resistance in these patients.
Antiretroviral switch studies
Numerous studies have examined the effectiveness of switching antiretroviral therapies in managing fat redistribution and metabolic complications [53,122–138]. Most studies have involved switching from PI-based antiretroviral regimens to NNRTI-based regimens; some have examined the effect of changing a PI to abacavir, and a few have studied the impact of discontinuing stavudine.
Overall, studies conducted to date have shown that switching from a PI-based HAART to an NNRTI-based HAART, with no change in NRTI, maintains viral suppression and has some favorable effects on dyslipidemia and insulin resistance. However, data from two studies have suggested improvements in fat distribution. Most of these studies are uncontrolled, and methodological issues limit interpretation of the data. One published study has examined the effects of switching from a PI to nevirapine in 23 patients with fat redistribution and metabolic changes . Six months after PI withdrawal, significant improvements were detected in serum cholesterol levels, triglyceride levels, glucose levels, and fasting insulin resistance indices. Weight and BMI did not change, but WHR decreased significantly. In addition, 91% of patients reported partial improvement in body changes . In another study, when abacavir was substituted for PI, investigators observed resolution of abdominal hypertrophy, lower-limb atrophy, and gynecomastia within 12 weeks . Saint-Marc and colleagues have examined the effect of replacing stavudine with other NRTI drugs or with a combination of NRTI and an NNRTI in male patients who had peripheral fat wasting without central adiposity. Results suggested that discontinuing stavudine produced an increase in subcutaneous adipose tissue but no changes in visceral adipose tissue as detected by CT .
Pharmacological therapies under investigation
As mentioned above, insulin-sensitizing agents such as metformin and the glitazones may reduce fat accumulation. In one study, metformin (500 mg twice daily) not only improved glucose tolerance but may have reduced visceral adipose tissue as well, although the difference was not statistically significant . An ACTG randomized clinical trial will examine the effects of two oral antidiabetic medications, metformin and rosiglitazone, in patients with HIV infection who have fasting hyperinsulinemia and elevated WHR.
Another ACTG study, 5079, has been designed to explore the effect of testosterone supplementation in men with abdominal obesity and mild-to-moderate reductions in serum testosterone. This randomized, placebo-controlled trial will examine the effects of 24 weeks of testosterone treatment on visceral abdominal fat, insulin sensitivity, lipid metabolism, and total and regional body composition.
Growth hormone is known to increase lipolysis and lipid oxidation,  and these processes inhibit growth hormone secretion . Clinically, growth hormone-deficient adults are often obese and have visceral adiposity. They can lose body fat with growth hormone replacement [140,142]. In children with growth hormone deficiency, chronic growth hormone supplementation has been shown to reduce subcutaneous abdominal fat 
Several reports show that treatment with growth hormone can reduce abnormal fat accumulation in patients with HIV infection [144–149]. One study of HIV-positive patients with fat redistribution syndrome  has associated growth hormone treatment with reductions in percentage of body fat (assessed using bioelectric impedence analysis), decreases in WHR, and increases in mid-thigh circumference; all of these changes were statistically significant. Others have shown that growth hormone can reduce truncal adiposity as well as buffalo hump [144,145] in HIV-positive patients taking antiretroviral agents.
An ongoing study is examining the safety and efficacy of growth hormone (6 mg/day for 24 weeks) for the treatment of excess visceral adipose tissue, as determined by whole-body MRI, in 24 HIV-positive patients taking HAART [147,148]. The trial includes a 12-week follow-up off growth hormone therapy to examine the impact of discontinuing treatment. Preliminary MRI findings have shown statistically significant decreases in subcutaneous and visceral adipose tissue at 12 and 24 weeks – effects that reversed 12 weeks after growth hormone treatment stopped. Growth hormone also improved lipid profiles. However, fasting glucose and insulin levels increased; these are known side effects of growth hormone treatment. At this dose, joint stiffness and pain were common adverse events.
Researchers in Switzerland have conducted a small placebo-controlled randomized clinical trial of growth hormone (6 mg/day) for HAART-associated fat accumulation . The study involved eight people, with crossover after 12 weeks. Results showed that trunk fat decreased by a mean 2.4 kg (assessed by DEXA) during treatment. Trunk fat increased by a mean 1.8 kg during placebo treatment, an effect that may partially reflect rebound fat accumulation in the group that received growth hormone initially. Adverse effects that occurred during growth hormone treatment included foot swelling and dysesthesia in one patient, and diabetes and hypertriglyceridemia in another.
A blinded, randomized controlled trial is being planned to examine the effect of growth hormone in reducing visceral adipose tissue and buffalo hump, improving metabolic complications of HAART, and improving the quality of life among patients with lipodystrophy. The study will include lower doses of growth hormone and a maintenance phase, with results expected to clarify whether growth hormone is effective and safe for long-term treatment.
Our familiarity with HIV-associated lipodystrophy syndrome has increased substantially since the first observations of central adiposity and peripheral wasting just a few years ago. Still, there is much to learn. The debate continues as to whether lipodystrophy syndrome represents a single disorder or multiple distinct but interrelated disorders. There remains a need for international consensus on methods of assessment and on a case definition (or definitions) to facilitate the collection of consistent, more easily comparable data on prevalence, risk factors, cardiovascular outcomes, and effective safe management strategies.
The authors thank Judith A. Aberg, Ben Cheng, David A. Cooper, Ellen S. Engelson, Susan K. Fried, Joseph M. Gertner, Marshall J. Glesby, Steven K. Grinspoon, Carl Grunfeld, Thomas N. Kakuda, Kenneth Lichtenstein, Ariane Marelli, Kathleen Mulligan, Norma Muurahainen, and Cecilia Shikuma for their research contributions and invaluable comments on the manuscript. Much of the information included in this manuscript was presented at a meeting on clinical perspectives on lipodystrophy, which was held on May 4, 2000 in Scottsdale, Arizona, USA.
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