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W2023480288 abstract "Introduction 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).Table 1: Physical and metabolic changes associated with HIV-associated adipose redistribution syndrome. 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 [21]. 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 [24]. Estimates of abnormalities in fat distribution range from as low as 2%[25] to as high as 84%[13] 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 [26]. Impaired glucose tolerance has been reported in 47% of patients on PI treatment [27]. 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].Table 2: Prevalence estimates of body composition changes in patients with HIV infection. 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) [21]. 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 [32]. 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 [11]. Since then, a national network of investigators has begun a cross-sectional survey, the Australian Prevalence Survey of Lipodystrophy Syndrome [33]. 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 [34]. 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.Fig. 1.: Fat depletion (FD) and fat accumulation (FA) in HIV-infected men (dark columns; n = 445) and women (light columns; n = 81) with morphological abnormalities in the SALSATM survey.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).Fig. 2.: Metabolic abnormalities in HIV-infected men (dark columns) and women (light columns) with morphological abnormalities in the SALSATM survey.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 [34]. 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 [36]. 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 [36]. 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 [36]. 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 [40]. 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. Case definition 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 [36], but many abnormalities have been observed in the absence of antiretroviral treatment [41] and non-medication risk factors clearly play a role [24]. 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 [44]. 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 [45]. 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 [46] or the National Cholesterol Education Program [47]). 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. Metabolic changes 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 [52]. Studies showing reversal or improvements in glucose, insulin, triglyceride, or cholesterol abnormalities when PI are discontinued strengthen the hypothesis of a direct PI effect [53]. 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 [50]. Current data suggest that elevated blood levels of glucose or insulin may be a consequence of HIV infection [31], 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 [23]. One study has shown that replacing PI with nevirapine partially reverses insulin resistance [53] Studies of PI-naive, HIV-positive patients have shown increased triglycerides; decreased total, LDL, and HDL cholesterol;[41] and increased hepatic lipogenesis [6,58], but not hyperglycemia, insulin resistance, or glucose intolerance [54]. More studies are needed to clarify the mechanisms and causal relationships involved. Morphological changes 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 [51]. 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 [66] 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 [81]. 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 [82]. 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 [85]. 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, [98], 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 [99] and against each other [100]. Single-slice CT or MRI measurements also correlate strongly with whole body CT or MRI measurements of subcutaneous and visceral adipose tissue (Fig. 3) [101], yet are much easier to obtain.Fig. 3.: Correlation between single-slice and whole-body computed tomographic scans in measuring visceral adipose tissue.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 [102]. Available fibrates include clofibrate, fenofibrate, and gemfibrozil. Gemfibrozil and clofibrate are metabolized by CYP3A4, whereas fenofibrate is not metabolized by the cytochrome P450 system [103] 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 [102]. 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 [102]. 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" @default.
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W2023480288 date "2001-10-01" @default.
W2023480288 modified "2023-10-16" @default.
W2023480288 title "Clinical perspectives on HIV-associated lipodystrophy syndrome: an update" @default.
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