Update on Lipodystrophy...Or Is It Just Lipoatrophy?

Donald P. Kotler, MD

Disclosures

August 09, 2002

Editorial Collaboration

Medscape &

The XIV International AIDS Conference will doubtless be best remembered for its emphasis on Tracks F (Interventions and Program Implementation) and G (Advocacy and Policy) rather than Tracks A (Basic Science) and B (Clinical Science and Care), where lipodystrophy usually is discussed. However, many interesting data were presented on the topic of lipodystrophy. There were several breakthroughs in understanding and treatment, as well as a sense that the studies that are under way can provide the definitive answers.

FRAM

The initial presentation of the Fat Redistribution And Metabolism (FRAM) study data by Carl Grunfeld, the principal investigator, dominated the meeting's content regarding lipodystrophy.[1] FRAM is a prospective, multicenter, cross-sectional investigation of HIV-infected subjects and controls. The presentation had been listed in the program as a review of lipodystrophy and not a presentation of original data, and the audience was surprised, to say the least. (I am the principal investigator for one of the research sites and had prior knowledge of the data, meaning that I had previously been stunned.) This study is epidemiologic, and is performed by a clinical investigator who not only is careful in asking research questions, but is also quantitative in his approach to the problem.

FRAM: Background

The FRAM study was performed to address the uncertainties in defining the phenomenon (or phenomena) that we all are seeing. Initial attempts to understand what has come to be known as lipodystrophy linked the various morphologic and metabolic changes into a single entity that was judged to be due solely to the use of protease inhibitors (PIs).[2] This led to arguments between these "lumpers" and other "splitters" who believed many distinct factors might be at work, and a lack of agreement as to how the changes should be categorized and organized. Even when it was shown that PI use was not necessary for the development of the changes, some still acted as though this was a specific syndrome. More recently, nucleoside reverse transcriptase inhibitors (NRTIs) have been implicated as promoting lipoatrophy,[3] and an interaction between NRTIs and PIs has been proposed. The fact that NRTIs and PIs may have independent and interacting effects on the development of lipodystrophy means that the etiology must be multifactorial. It does not mean that they are the sole factors responsible for the observed changes. In fact, this author presented evidence that similar changes in body composition were seen in the pre-HAART (highly active antiretroviral therapy) era, although not in the pre-NRTI era.[4] Anthropometric measurements provided evidence of peripheral fat wasting accompanied by preservation of central fat. Many of the subjects in the pre-HAART era also were malnourished, as evidenced by body cell mass depletion, and many were taking NRTIs. However, those studies suggested that many factors may influence body composition even in the current treatment era.

Similarities between the metabolic syndrome seen in non-HIV-infected individuals and HIV-associated lipodystrophy have been noted repeatedly. While the metabolic syndrome is associated with increased cardiovascular risk, it also is an obvious, but poorly defined, syndrome whose causes are multigenic and multifactorial, and which is present in a proportion of the entire "normal" population. To further complicate the matter, all patients with HIV-associated lipodystrophy started life as HIV-negative members of that "normal" population, so that the factors that influence the development of the metabolic syndrome in anyone may also be present in HIV-infected individuals. Patients with HIV-associated lipodystrophy also all acquired a chronic infection with chronic inflammation, most or all were treated with combinations of medications and other agents, and most or all had some degree of immune reconstitution.

Epidemiologic studies found many factors to be related to the development of lipodystrophy, including host, therapy, and disease-related factors. Clinical features such as nadir CD4+ cell count also influence the development of lipodystrophy.[5] Other studies have found associations between various components of lipodystrophy and the levels of serum inflammatory factors.[6,7] In addition, comorbidities such as hepatitis C infection also affect the development of lipoatrophy, as well as insulin resistance.[8]

Determining cause (as opposed to assigning blame) is a difficult task in clinical medicine. Koch's postulates have been used to determine causation of infectious diseases, since one can isolate the organism in people with the clinical syndrome, prove the absence of the organism in people without the clinical syndrome, and document the occurrence of the clinical syndrome after transmission from one host to another. One also can document the disappearance of the clinical syndrome in response to effective treatment of the "putative" infectious cause. However, Koch's postulates cannot be applied to prove that cigarette smoking causes lung cancer, or that PI use causes lipodystrophy. Instead, one is forced to use a series of statistical associations, such as the Bradford Hill criteria[9] and other techniques, as is being done in FRAM.

FRAM: Methods

In February 2002, at the 9th Conference on Retroviruses and Opportunistic Infections in Seattle, Washington, Andrew Carr[10] presented data from another study designed to provide a case definition of lipodystrophy, using combinations of clinical signs. In that study, a predictive equation was derived using the results of computed tomography (CT) scans, dual-energy x-ray absorptiometry (DEXA) scans, anthropometry, demographic information, and the results of metabolic measurements. This correctly identified the presence or absence of lipodystrophy only two thirds of the time.

FRAM was conceived without preconceptions as to any linkages among the various components of lipodystrophy, and is being used to evaluate whether there are such linkages. The overall aim of the study is to compare groups of HIV-infected subjects and healthy adults (not tested for HIV, but with an expected seropositivity rate of < 0.4%). There are 3 levels of measurement:

  • First, subject report (perception) was recorded regarding their current body habitus, whether they perceived it to have changed, and if so, whether there had been an increase or a decrease. Subjects were then divided into 2 groups depending on whether lipoatrophy was (LA+) or was not (LA-) self-reported, and these groups were then compared with each other and with controls.

  • Second, the evaluators, all trained centrally, reported the presence or absence of visible lipoatrophy and its degree. (Careful visual inspection of the body is rarely done in clinical medicine today, for a variety of reasons, and we must concede that we modern doctors are not as aware of the variations in body habitus that are present in the general population as were our predecessors.)

  • Third, body composition measurements were made using sophisticated methods, including whole-body MRI scanning with 3-dimensional reconstruction of fat compartments and whole-body DEXA scanning, as well as surrogate methods.

In addition to comparing HIV-infected subjects and controls, the investigators attempted to find a cluster of physical and metabolic changes that could be grouped as a syndrome. Before the data were collected, a set of rules for interpretation were agreed upon. To be considered HIV-related, a finding had to differ statistically between HIV-infected and control subjects. In addition, for any 2 features to be considered as related, they had to have a statistical association.

A total of about 1200 HIV-infected subjects and 300 controls have been studied. This preliminary report only involved a subgroup of these, only looked at men, and only examined body composition measures. The HIV-infected subjects were chosen at random from the databases of 16 different clinics around the United States, and were then approached for inclusion in the study. Although this initial selection process was therefore unbiased, the study was not necessarily unbiased with regard to who agreed to participate between sites, or even within a site. The control subjects were taken from 2 clinical sites in the CARDIA study of the natural history of cardiovascular disease, which has been ongoing for more than 15 years. The controls had exactly the same assessments as the HIV-infected subjects, and the evaluators underwent the same training.

The HIV-infected and control groups were well matched in many ways, such as age and height. However, the HIV-infected group was lighter than the controls. This is a very important consideration in a study such as FRAM, which relies on absolute measurements, and one that confounds all nutritional studies: many of the relevant comparisons will be performed on adjusted data, and one must choose whether to adjust according to weight. Since the development of lipoatrophy often is accompanied by weight loss, correcting for weight loss will introduce a bias in data analysis, and this was not done in the FRAM study. However, completely ignoring body weight might introduce an opposite bias, as discussed below. For the purpose of statistical analysis, choosing not to match subjects and controls by weight is equivalent to assuming that premorbid weight and fat distribution was the same in HIV-infected subjects and controls. The validity of this assumption is impossible to determine in a cross-sectional study.

FRAM: Results

The major finding of the study was that the HIV-infected group had lipoatrophy compared with controls, based upon self-report, physical examination, and quantitative measurements. The lipoatrophy was in the subcutaneous compartment, as shown by many others. However, both the subjects who reported the presence of lipoatrophy and those who did not self-report lipoatrophy had less subcutaneous adipose tissue (SAT) by MRI and less limb fat by DEXA than did the CARDIA controls; thus, both the self-reported LA+ and LA- groups can be considered to have lipoatrophy. However, LA+ subjects had more SAT depletion than LA- patients. The depletion of SAT was not uniform around the body: more fat was lost from the legs than from the arms, more from the arms than from the lower trunk, and more from the lower trunk than from the upper trunk. (However, it should be noted that the analysis does not attempt to distinguish lipoatrophy from wasting.)

Average visceral adipose tissue (VAT) content was slightly lower in HIV-infected subjects than in controls, though the relative amount of VAT per body weight was not reported. The difference in VAT content between subjects and controls was lower than the difference in SAT content. The apparent preservation of central fat was also seen as higher waist-to-hip circumferences in LA+ subjects than in LA- subjects or controls, because their waist circumference was decreased, but to a lesser extent than was their hip circumference. This finding distinguishes HIV-associated lipodystrophy from the metabolic syndrome in which patients also have elevated waist-to-hip ratios, but caused by increased waist circumference and not by decreased hip circumference. Elevated waist-to-hip ratios without an increase in waist circumference also were seen in the pre-HAART era.[4] Of importance, the amount of VAT was not statistically associated with the amount of SAT, in contrast to the general belief that the changes are reciprocal.

Based upon these data, the conclusion of the study is that lipoatrophy (ie, depletion of SAT) is an HIV-associated phenomenon, VAT accumulation is not an HIV-associated phenomenon, and that changes in SAT and VAT are not linked (and thus from now on, we should use, "accompanied by" rather than "associated with" in our discussions of morphologic changes). For this reason, VAT accumulation cannot be used as a criterion for the definition of whatever it is that we are seeing in our patients. Dr. Grunfeld did not say that VAT accumulation cannot occur in HIV-infected individuals; he said only that it did not occur more often or to a greater degree, on average, than in controls, so it cannot be used as a diagnostic criterion.

The independence of SAT and VAT change calls into question the whole notion of fat redistribution. Fat distribution usually refers to the relative amounts of fat in subcutaneous and visceral compartments. Based on this loose definition, a relative change in the ratio of VAT to SAT, which occurred in the HIV-infected group and especially in those with self-reported lipoatrophy, can be considered as evidence of redistribution. However, the lack of a relationship between the perceived changes, as well as the measured differences in VAT and SAT, can also be interpreted as a pure loss of SAT rather than redistribution. The distinction is semantic.

Once again, the issue of matching must be raised, since the interpretation of some data is based upon the assumed premorbid equivalence of the HIV-infected subjects and the CARDIA controls. As noted above, the matching procedure implies that the premorbid (ie, before HIV infection) body weights were the same in subjects and controls. While it is appropriate that subjects and controls were matched by height but not by weight, this does not mean than premorbid body weights were indeed the same in the subject and control groups. If premorbid body weights and body fat contents were lower in those who were to become HIV-infected than in CARDIA controls, the depletion of SAT would be accentuated and the accumulation of VAT would be masked. However, differences in premorbid weight would not affect the lack of relationship between SAT and VAT. The uncertainty surrounding premorbid weight and body composition reflects the inadequacies of all cross-sectional studies and emphasizes that prospective studies have the best hope of providing unbiased information. Such studies are under way, in which measurements are taken starting before the initiation of the first HAART regimen, and they contain nested substudies of body composition and fat distribution.

Another surprise was the finding that the presence of a buffalo hump in HIV-infected individuals also cannot be used as a diagnostic criterion because it was not present more often, statistically, than in controls. It should be mentioned that the data presented were subjective only, and the actual sizes and other characteristics of the buffalo humps in HIV-infected subjects and controls were not compared. This physical finding flies directly in the face of clinical experience, and led to some emotional venting by some in the audience. Most would not accept the implied premise that the buffalo hump was previously present and was simply unmasked by the development of lipoatrophy. While it is true that many men with lipodystrophy might begin to resemble controls if one could stuff a large volume of subcutaneous fat all over their bodies, this explanation does not elucidate the cases of previously lean HIV-infected men who suddenly develop big stomachs and buffalo humps. I asked Carl Grunfeld about such patients. He has seen them as well, and doesn't know how it happens, either.

FRAM: Discussion

There are a lot more data to be presented from FRAM, including the results in women and the effects of various cofactors, including specific antiviral agents and their duration of use. (Along those lines, Pribram[11] reported sex differences in central adiposity and its relationship to serum lipid levels, similar to what has been reported previously, particularly the fact that women tend to be heavier, relatively speaking, than men but not to have the same degree of hyperlipidemia.) The metabolic measurements also remain to be presented, and genetic studies have yet to be performed. Relationships between the factors will be dissected. Of note, the relative importance of the various factors and their quantitative effect in producing the end points can be estimated. We should try to be patient and to wait for the data to be delivered in its final form. Undoubtedly, the study will not answer all questions, and will be subject to continued interpretation. Furthermore, one can argue that the importance of fat redistribution and metabolic changes in HIV infection lies not in how the problem is defined, but rather in its consequences and in the ability to forestall adverse outcomes with targeted interventions.

The FRAM study, as well as the topic of lipodystrophy in general, poses other fundamental questions for clinical medicine. Most important is the question of what represents a disease. How abnormal does something have to be before it is considered a separate entity? If we can specify a constellation of signs and symptoms that predictably leads to bad outcomes, is that sufficient to justify the allocation of resources for monitoring, diagnosis, and treatment? A related question is to determine what is worthy of treatment, ie, what is important clinically. For example, depressed HDL cholesterol and elevated total cholesterol may or may not be found to be HIV-specific in their etiology, but they are still worthy of treatment. These questions are especially relevant in the context of whether third-party payors or health departments will cover the costs of disease management. Such conflicts are not new in clinical medicine. The lack of coverage for nutritional education and management in patients with insulin resistance may represent an example of a missed opportunity, while programs for smoking cessation represent the opposite.

When he presented the results of the initial analyses to his coinvestigators, Dr. Grunfeld was well aware that the findings might not be received warmly. In fact, he prefaced his presentation to us with a quote from George Bernard Shaw: "If you are going to tell people the truth make them laugh, or they will kill you." A more appropriate quote can be found in Bye Bye Birdie, when Mrs. Peterson, a Jewish lady probably from the Bronx, New York, has just returned from her physician. She tells her son, "And by the way, Albert darling, I got some good news for you. I just got a report from the hospital and it's absolutely definite. I got a condition. Never mind what condition. A condition! And the one thing doctors can't cure is a condition."

Other Studies of Etiology

Two posters[12,13] presented updated information from a study first presented at the 3rd International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV in Athens, Greece, in October 2001.[14] In these studies, the metabolism of subcutaneous adipose tissue, as obtained by aspiration, was examined in HIV-infected subjects with and without lipodystrophy and in healthy controls. The rationale was that body fat redistribution must represent a change in the metabolism of the affected adipose tissue depots, which can be examined on a variety of levels. On a tissue level, fat loss or gain can be shown as a change in cell production or cell death (see below). On a cellular level, fat accumulation or depletion could represent a change in either triglyceride synthesis or in lipolysis.

In addition to examining aspects of fat deposition (lipoprotein lipase activity) and lipolysis (glycerol release) during short-term incubations of adipose tissue samples, cytokine release and systemic cytokine activities also were determined. Several prior studies had suggested a link between immune or inflammatory factors and fat redistribution. Proinflammatory cytokines are known to stimulate lipolysis and inhibit adipose tissue lipogenesis. Studies of HIV-infected subjects have found associations between the development of lipodystrophy and nadir CD4+ cell count as well as the rise in CD4+ cell count during HAART, independent of specific antiretroviral agents. Ledru and colleagues[6] found evidence of immune dysregulation in HAART-treated subjects: they had higher numbers of CD8+ lymphocytes containing tumor necrosis factor (TNF), a finding that was associated with dyslipidemia. Mynarcik and colleagues[7] noted associations among insulin resistance, lipoatrophy, and serum concentrations of soluble TNF receptors in HIV-infected subjects. A study of cytokine levels in cervicovaginal lavage specimens from women initiating a dual-PI regimen also noted persistence of proinflammatory cytokine activities (interleukin-6, interleukin-1 beta) indicating persistent defects in immunity despite effective antiretroviral therapy and immune reconstitution.[15]

Albu and colleagues[12] (including this author) reported the results of studies in 56 subjects who underwent whole-body MRI scanning, fat aspiration from the lower abdominal subcutaneous compartment, and blood tests. In this study, lipodystrophy was judged by self-report. The patients with lipodystrophy had more VAT than did HIV-infected subjects without self-reported lipodystrophy or controls, but had no lipoatrophy. Since this was a cross-sectional study, there was no objective information about recent changes in fat compartments. Glycerol and lactate release from adipose tissue samples during incubation were elevated in both HIV-infected groups compared with controls, indicating increased lipolysis. The release of glycerol and lactate were statistically associated. Serum lactate levels also were significantly elevated in HIV-lipodystrophy subjects compared with controls; a lesser rise in subjects without lipodystrophy was not significant. Elevated serum lactate concentrations and lactate release during adipose tissue incubations were statistically associated with NRTI use but not with self-reported lipodystrophy. The release of TNF from SAT was significantly higher in HIV-lipodystrophy than in the nonlipodystrophy group or controls, as were serum interleukin-6 and serum soluble TNF receptor 2 concentrations. Statistical associations among these measures were noted. There were no associations among proinflammatory cytokine activities and antiretroviral agents.

These results suggest the presence of at least 2 pathogenic mechanisms, which could promote fat redistribution. The finding of increased lipolysis, as determined by a whole-body stable isotope technique, was reported recently[16] and is consistent with the current data. The association of increased lipolysis with NRTI use and the associations with elevated serum lactate and lactate release during incubation of adipose tissue suggest that the cause might be related to mitochondrial dysfunction. Of importance, there were no associations with proinflammatory cytokines. In any event, an increase in lipolysis in a steady-state manner would lead to a degree of lipoatrophy.

The presence of excess proinflammatory cytokine activity could lead to lipoatrophy by a number of mechanisms. In a substudy of the study just described, Ionescu and colleagues[13] examined the associations among fat redistribution, proinflammatory cytokine activities, and the production of acylation-stimulating protein (ASP). This protein upregulates the pathways for glucose uptake and fat deposition in adipocytes and has homologies to a product of the alternative pathway of complement, specifically the C3a anaphylotoxin, which has been deactivated by removal of a terminal arginine residue. The alternative pathway of complement is a key component of innate immunity and is highly conserved evolutionarily. Many of the proteins of the alternative pathway of complement are produced in adipose tissue, and most have uncertain functions. ASP would appear to have an inverse relationship to inflammation.

The hypothesis underlying this study was that lipoatrophy may be related, at least in part, to a decrease in ASP production, and that ASP production is inhibited by proinflammatory cytokines. Three-day incubations of SAT aspirates were performed in 24 subjects. Those with lipodystrophy had lower levels of SAT and more VAT compared with those without lipodystrophy or controls. The production of complement factor 3, the precursor of ASP, was similar in the 3 groups, while the production of ASP and the conversion of C3 to ASP were significantly lower in the lipodystrophy group. By regression analysis, lipoatrophy of the lower limbs was found to be statistically associated with ASP conversion rate, while serum levels of soluble TNF receptor 2 were inversely related to ASP conversion. The conclusion of this study is that lipoatrophy may be promoted by a decrease in fat deposition due to subnormal ASP production, related in some way to a persistent inflammatory response.

Domingo and colleagues[17] examined a different potential mechanism for lipoatrophy, apoptosis of adipocytes. This group previously had reported increased apoptosis of adipocytes in areas of lipoatrophy, using the technique of terminal labeling of DNA fragments that form during apoptosis.[18] In the present study of 53 subjects, they documented statistical associations between the levels of apoptosis and soluble TNF receptors 1 and 2.

Clinical Outcomes

The potential clinical outcomes of lipodystrophy include cardiovascular disease and quality of life. Two studies reported the effects on quality of life,[19,20] both of which concluded that the presence of lipodystrophy significantly affected quality of life, as reported previously in research meetings. The effects were experienced in role and social functioning plus stigmatization, as opposed to physical functioning, which was more affected by malnutrition.

Cardiovascular Risk

Interesting information was presented on the topic of cardiovascular disease. As background, case reports first identified young HIV-infected subjects with symptomatic cardiovascular disease in 1998.[21] The results of broad-based epidemiologic studies were reported at previous meetings and gave discrepant results. Mary-Krause and colleagues[22] examined the French Hospital Database on HIV and noted an increase in myocardial disease in patients taking PIs, especially those who had been treated with PIs for longer than 30 months. Klein and colleagues[23] used the Northern California Kaiser Permanente database to show an increase in cardiovascular risk in HIV-infected subjects both taking and not taking PIs. Currier and colleagues[24] used the Southern California MediCal database to find a small increase in cardiovascular risk. In contrast, Bozzette and colleagues[25] presented the results of a large Veterans Administration study in which there was a decrease in all-cause mortality in HIV-infected subjects and no evidence of an increase in cardiovascular mortality.

Barbaro and colleagues[26] performed a randomized, open-label comparison of cardiac end points in antiretroviral-naive patients starting PI-based HAART vs non-PI-based HAART. After studying about 1200 evaluable patients for 3 years, the investigators showed a rate of angina or myocardial infarction of almost 1 per 100 patient-years of follow-up among patients receiving PI-based therapy, which was 10-fold greater than in the subjects taking non-PI-based HAART, and about 3 times more frequent than in other studies. Several of the patients were quite young. By multiple regression, the factors predisposing to end points were typical for cardiovascular disease, ie, hyperlipidemia, lipodystrophy, cigarette smoking, hyperfibrinogenemia, and so forth. Almost 90% of the study group smoked more than 15 cigarettes per day. Of note, most of the end points occurred during the third year of follow-up.

In an invited lecture, Jens Lundgren[27] put the issue of cardiovascular disease in HIV infection in perspective when he noted that cardiovascular disease is a late-onset adverse event and, as such, has a lag phase. As an example, he cited a major study of statin use in a non-HIV-infected cohort which showed no benefit for about 4 years, before beginning to demonstrate highly significant benefits. He reviewed the studies in HIV infection mentioned above, noting that the onset of symptomatic cardiovascular disease only began to appear after 20 months of follow-up in Barbaro's study.[26] The study presented by Mary-Krause[22] demonstrated a 3-fold increase in the incidence of myocardial infarction in patients on PI-containing HAART for more than 30 months. The HOPS cohort also noted a lag time of about 3 years before beginning to note an increase in myocardial infarction.[28] The one discordant study was that presented by Bozzette[25]; however, follow-up is short so this cohort may still be in its lag phase.

Of note, Woolley and colleagues[29] from the Multicenter AIDS Cohort Study (MACS) also reported on the incidence of cardiovascular disease. MACS is a long-term, prospective follow-up of HIV-infected and HIV-negative gay and bisexual men. This study tested the hypothesis that macrolide antibiotic use decreases the risk of cardiovascular disease, as an example of a possible infectious link to atherosclerosis. Although this hypothesis was not proven, the investigators were able to examine the incidence of cardiovascular disease, performing a case-control study that compared 87 cases of cardiovascular disease with a total of 827 controls. After much data adjustment for possibly relevant variables, the results appeared to show a short-term decrease in cardiovascular disease incidence, followed by a later increase. These data are fully consistent with Dr. Lundgren's thesis of a lag phase. The data further suggest that, initially, HAART is cardioprotective, presumably by decreasing the inflammatory response, which is strongly linked to atherogenesis.

Several small studies evaluated surrogate markers for cardiovascular disease. De Larranaga and colleagues[30,31] documented increased serum contents of prothrombotic proteins in association with either lipodystrophy or insulin resistance. While not unexpected, these observations imply that the excess cardiovascular risk is mediated via known mechanisms. Such knowledge would allow for monitoring using standard techniques. Studies of endothelial function via flow-mediated dilatation were reported by Cotter and colleagues.[32] In a previous report, Stein and coworkers[33] reported that endothelial dysfunction as assessed by flow-mediated dilatation was associated with PI use, and it could be predicted by serum lipid values; however, Cotter and associates found a much weaker relationship between flow-mediated dilatation and PI use. The study group also had relatively few cardiac risk factors and relatively normal measurements. These data also support the contention that cardiac risk in HIV is mediated via known pathways.

Treatment of Visceral Obesity

Kotler and colleagues[34] presented the results of a multicenter trial of growth hormone (GH) for the treatment of the pathological accumulation of VAT. The rationale for this study was that visceral fat accumulation is linked to adverse outcomes in non-HIV syndromes, it can be objectively quantitated, and it may be affected by targeted interventions.

Background

Several presentations, including some at this meeting, have associated body fat redistribution with physical discomfort and psychological distress. Evidence from the non-HIV literature indicates that excess VAT has independent, adverse effects on intermediary metabolism, including hepatic insulin resistance and delayed postprandial clearance of circulating fats. VAT accumulation may contribute independently to cardiovascular risk, though much of the increased risk is mediated by recognized surrogate markers of atherogenesis, such as serum lipoprotein concentrations and insulin resistance.

There is a complex, mutually inhibitory relationship between VAT and GH secretion in both HIV and non-HIV models. Adult and pediatric GH deficiency (as a result of surgery, tumor, or trauma) is associated with increased VAT, a condition that is reversed by GH therapy. GH secretion is blunted in HIV-infected[35] and HIV-negative men with truncal obesity. Furthermore, GH deficiency itself is associated with increased cardiovascular risk, and such patients demonstrate insulin resistance, elevated serum triglycerides, low HDL cholesterol, hypertension, and elevated fibrinogen and PAI-1 levels.

Initial anecdotal observations by Torres and colleagues[36] and subsequently by others suggested that growth hormone administration for wasting led to a decrease in the size of the trunk, buffalo humps, and breasts. Several pilot studies have shown that GH therapy at 3-6 mg/day significantly reduces truncal and visceral fat in HIV-infected men and women. However, side effects were frequent in those studies. In addition, visceral fat promptly reaccumulated once therapy was discontinued. Consequently, lower doses of GH and longer periods of treatment have been recommended. The optimal therapeutic dose is unknown and it is possible that the use of different doses for induction and maintenance therapy may be effective.

The STARS Trial

The Serostim in the Treatment of Adipose Redistribution Syndrome (STARS) trial is a phase 2/3 multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study. A total of 239 subjects were randomized to receive GH at 4 mg/day administered by subcutaneous injection either daily or on alternate days, or placebo, for 12 weeks; the data from this induction phase were presented. Subjects enrolled in the study are also being monitored for up to 1 year on various maintenance regimens. The primary end points were changes in visceral fat as estimated by single-slice CT and by DEXA scans (trunk:limb fat). Secondary end points included other DEXA measurements, anthropometry, serial medical photography, fasting serum triglycerides, total, HDL, and non-HDL cholesterol, fasting glucose and insulin, oral glucose tolerance tests, quality of life, plasma HIV-1 RNA levels, CD4+ cell counts, and other safety analyses.

Eligibility was determined using both waist-to-hip ratio (WHR) and waist circumference (WC), a methodology that was successful in detecting men and women with increased VAT in previous studies. In men, WC had to be > 35 inches and WHR > 0.95; in women, WC had to be > 30 inches and WHR > 0.9. Despite having elevated waist circumferences and WHR, they were not, on average, obese: mean body mass index (BMI) was 27 and mean body fat was 21% of weight. (The Centers for Disease Control and Prevention define obesity as a BMI of 30 or more.) The eligibility criteria were strict with respect to glucose tolerance, but not to hyperlipidemia. Despite the fact that 30% of subjects were taking statins or fibrates, mean fasting serum cholesterol and triglyceride concentrations were elevated. All subjects were receiving antiretroviral therapy, including 55% on PIs.

In a substudy, Kotler and colleagues[37] compared VAT contents in 53 subjects from this study with matched subjects from a database of whole-body MRI scans from St. Luke's-Roosevelt Hospital Center in New York, NY. Mean VAT in the current study subjects was more than 4 times higher than in healthy adult controls, as well as about twice the average reported in FRAM.

At 12 weeks, there was a significant decrease in VAT among patients receiving daily GH, as well as a strong trend to a decrease in VAT among those receiving alternate-day GH. Both GH treatment regimens significantly reduced DEXA trunk:limb fat ratio. Of the total fat lost in both treated groups (as assessed by DEXA), 84% was lost from the truncal region. The absolute losses of total and trunk fat by DEXA were highly significant in both GH arms. In contrast, there were no statistically significant changes in limb fat at either dose of GH, by DEXA. In contrast to fat loss, weight and lean body mass increased significantly at both doses.

Mean serum fasting total and atherogenic, non-HDL cholesterol concentrations decreased significantly in both GH arms compared with placebo therapy. Decreases were seen both in subjects taking and not taking antihyperlipidemic agents. Serum HDL concentrations rose during therapy with daily GH (P = .06). Serum triglycerides did not change significantly. Both mean fasting and postprandial glucose concentrations rose significantly on GH therapy, and the number of subjects who required dose reduction for hyperglycemia was higher in the daily GH arm than in the alternate-day GH arm, and both were higher than in the placebo arm. In general, complaints were more frequent on daily GH therapy, although only 6.3% discontinued the study before the week-12 visit. In data not presented, GH also improved quality of life significantly. The conclusion of the study was that "induction" therapy with growth hormone, 4 mg daily for 12 weeks, was effective at achieving the primary end point of a reduction in visceral fat accumulation. Continuing investigation will assess the ability of long-term, lower-dose GH therapy to sustain the beneficial effects.

Discussion

The results of the FRAM study confound the interpretation of this trial, whether or not VAT accumulation is found to be related in some way to HIV infection, its treatment, or other factors. The finding that healthy controls may have as much VAT as HIV-infected individuals is not terribly reassuring, since some healthy controls drop dead of heart attacks in their early 50s. The relevant point is that some HIV-infected patients develop morphologic alterations, often accompanied by metabolic alterations, that are likely to leave to adverse outcomes, notably accelerated atherogenesis. Under those circumstances, who cares about a definition?

Like the data from the FRAM study, the findings of this study again highlight that a debate is needed over the question of what makes a condition worthy of prevention, monitoring, and treatment. Is it a strict case definition, the potential for successful intervention, or the price? This is not the first time that such questions have been raised in HIV infection: In the late 1980s, patients had to fit a clinical definition of AIDS if they were to access specific services. The debate is relevant not only to the issue of showing efficacy and safety in order to gain Food and Drug Administration approval for therapies -- not only GH but also others such as glitazones for insulin resistance and for lipoatrophy -- but also to ensuring access to such therapies to those who would benefit.

Perhaps I should have spent more time in Tracks F and G.

Other Therapies

Moyle and colleagues[38] presented data that corroborated studies presented at the 9th Conference on Retroviruses and Opportunistic Infections by groups from the United States and Australia, which demonstrated reversal of lipoatrophy after modifying NRTI therapy. While the changes were statistically significant in those studies, the clinical change was relatively small. In the present study, subjects receiving a first-line stavudine-based PI or NNRTI regimen were randomized to (1) replace stavudine with abacavir, or (2) continue stavudine but replace their PI or efavirenz with abacavir, or (3) to replace both stavudine and their PI or efavirenz with zidovudine and abacavir. Increases in limb fat were seen after 48 weeks, but not after 24 weeks, in the subjects who switched from stavudine to abacavir, but the other 2 strategies (remaining on stavudine or replacing stavudine with zidovudine) had no effect. The increases in limb fat were greater, quantitatively, than the changes reported by others in Seattle. However, it is not clear that the repletion is complete, in part because no measurements were done in controls. Obtaining a normal control group would be helpful, ultimately, for interpreting the data on this point. It is quite possible that partial repletion will occur based upon the relative contribution of NRTIs to the underlying problem. Nonetheless, these data are welcome and support the contention that NRTI use promotes lipoatrophy.

A poster by Laueroth-Mai and coworkers,[39] using clinical criteria to evaluate a closed cohort of subjects, also did not find a difference in the incidence or prevalence of lipodystrophy in patients on stavudine- and zidovudine-containing regimens.

Engelson and colleagues[40] (including this author) presented the results of a diet-plus-exercise weight loss program in obese HIV-infected women with varying degrees of visceral fat content. This was a labor-intensive study, involving 12 weeks of thrice-weekly supervised exercise sessions (both resistance and aerobic) plus nutritional education and a 1200-kcal diet. Weight loss averaging about 6 kg was documented in the 15 women who have completed the study. Almost all of the weight lost was fat, so the exercise program successfully preserved skeletal muscle mass. Both VAT and SAT were lost. However, despite the loss of weight, body fat, and SAT, insulin resistance changed little. Such findings are different from those reported in obese, HIV-uninfected subjects. In another analysis of these data, Albu and colleagues[41] examined the relationships between body fat compartments and insulin resistance, as determined by fasting insulin and by the frequently sampled IV glucose tolerance test, comparing the results in the obese HIV-infected women with those from similar studies in obese HIV-negative female controls. The relationships between insulin resistance and body fat compartments differed between the groups. While insulin resistance was directly related to SAT mass in controls, it was inversely related to SAT in the HIV-infected subjects, similar to the results reported by Mynarcik and associates[7] in predominantly lipoatrophic HIV-infected men. In addition, at any level of VAT, insulin resistance was greater in the HIV-infected subjects than in the controls. Thus, the factors controlling insulin resistance in HIV-infected subjects differ from those acting in HIV-negative individuals, and probably include antiretroviral effects, and possibly effects of proinflammatory cytokines. It would appear that insulin resistance in HIV infection may be more refractory to treatment than it is in HIV-negative subjects, although this must be tested directly.

Several other posters described treatment studies for various aspects of HIV-lipodystrophy.[42,43,44,45] In general, the treatments described here and in other meetings and publications -- such as diet, omega-3-fatty acids, metformin, gemfibrozil, and others -- had only modest effects. While therapies may produce statistically significant effects, the abnormalities rarely are completely reversed. It would appear that HIV-infected individuals do not appear to respond as well to therapy as do HIV-negative subjects with similar alterations, though the data are hard to interpret because there are no control groups of treated, non-HIV-infected subjects. It will be important to carefully examine treatment studies and to be sure that the treatments applied to lipodystrophy have clinically meaningful, as opposed to merely statistically significant, effects.

Conclusions

The field of lipodystrophy has undergone a great evolution in the 4 years since its initial description, and further data -- especially from the FRAM study -- will continue to refine our understanding. The major body composition changes (ie, changes in VAT and SAT) appear not to be related, so patients with the so-called "combined syndrome" may really have 2 syndromes rather than 1. There will be a lot of debate regarding the relationship of VAT change with some aspect of HIV infection. The etiologic factors and pathogenic mechanisms are likely multifactorial, and include host-, disease-, and treatment-associated causes.

The association of the body composition and metabolic changes with adverse cardiovascular outcomes is gaining acceptance. The evidence presented at this and prior meetings leads this author to propose that the atherosclerotic risk may be greater in HIV-infected individuals than in non-HIV-infected subjects with the metabolic syndrome. Positive interactions between genetic risk, inflammatory responses, and drug-induced changes in glucose and lipid metabolism may lead to augmented atherogenesis in some HIV-infected patients. Individual risk can be estimated by standard methods, implying that the pathogenic mechanisms act via known pathways. The concept of a lag phase is ominous: we may be in the lag phase of what might prove to be a serious and common problem of symptomatic cardiovascular disease. The response to interventions also may be less in patients with lipodystrophy than in non-HIV-infected individuals with similar metabolic alterations.

Attention should be placed on the clinical relevance and adequacy of treatment responses as opposed to the statistical significance of an end point. We should consider the possibility that what we see as lipodystrophy may be undefinable, at least in clinical terms, and recognize that proper patient care does not require a defined syndrome. Access to appropriate care to prevent cardiovascular disease also must not be subject to a definition of a specific HIV-associated syndrome.

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