Body Habitus Changes Related to Lipodystrophy

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1 SUPPLEMENT ARTICLE Body Habitus Changes Related to Lipodystrophy Fred Sattler Keck School of Medicine, University of Southern California, Los Angeles, California Changes in body fat in persons infected with the human immunodeficiency virus (HIV) have been associated with deleterious changes in blood lipids and insulin resistance, raising concern that these changes will increase the risk for accelerated atherosclerosis. Changes in body fat are often identified in advanced disease but may also occur early after HIV infection is detected. Conflicting evidence suggests that fat maldistribution may be related to use of protease inhibitors, nonnucleoside reverse transcriptase inhibitors, or a combination of these two classes of drugs, but the etiologies of the various changes in body fat remain uncertain. To date there have been no remedies for the loss of subcutaneous fat, but recent evidence has suggested that discontinuation of stavudine or zidovudine therapy may be associated with limited restoration of extremity fat. For fat accumulation, a number of strategies have been attempted, including treatment with human growth hormone, androgens, or metformin, and changes in diet and exercise. As in persons not infected with HIV, it is expected that the cornerstone of management, especially in the presence of central obesity, dyslipidemia, and insulin resistance, will include a diet low in saturated fat, with low glycemic index carbohydrates, and high in fiber. Very limited evidence in persons infected with HIV has suggested that a supervised exercise program may be beneficial. From early in the era of HAART, a spectrum of changes in body fat have been reported to occur in 20% 80% of subjects receiving these therapies (table 1) [1, 2]. In those with abdominal obesity, hypertension, abnormal serum lipids, and evidence of insulin resistance, this constellation simulates features of the dysmetabolic syndrome (syndrome X) [3]. Moreover, there is also evidence that the loss of subcutaneous fat per se in persons with HIV is associated with insulin resistance [4 6]. Thus, there is concern that these disorders will increase the risk for accelerated atherosclerosis (coronary artery disease, stroke, and peripheral vascular complications), as occurs in other populations without HIV [7]. Here, I review the difficulties in ascertaining the incidence of body fat abnormalities, their relation- Financial support: National Institutes of Health (DK-49308; NCRR GCRC MOI RR-43). Reprints or correspondence: Dr. Fred Sattler, Keck School of Medicine, University of Southern California, 1300 N. Mission Rd., Room 351, Los Angeles, CA (fsattler@usc.edu). Clinical Infectious Diseases 2003; 36 (Suppl 2):S by the Infectious Diseases Society of America. All rights reserved /2003/3607S2-0006$15.00 ship to antiretroviral therapies, and management of these complications. INCIDENCE AND PREVALENCE There are few data on the incidence of clinical fat maldistribution. One report describing 84 subjects from the French PRIMO cohort and who were initiating HAART (88% received at least one protease inhibitor [PI]) shortly after acute HIV infection indicated that the incidence of lipodystrophy was 5% at 6 months, 9% at 12 months, and 26% at 24 months [8]. These data suggest that changes in body fat may occur very early after HIV infection and are not limited to advanced disease. In a study of 494 consecutive antiretroviral therapy naive subjects treated with 2 nucleoside reverse transcriptase inhibitors (NRTIs) and at least one PI from October 1996 to September 1999, the incidence of central obesity was 9.2 (95% CI, ) and for lipoatrophy was 7.7 (95% CI, ) per 100 patientyears (table 2) [9]. Most studies have been cross-sectional in design and initially reported disparate occurrence rates (table 1). S84 CID 2003:36 (Suppl 2) Sattler

2 Table 1. therapy. Prevalence of fat loss and fat accumulation in patients with HIV related to PI Fat change Incidence in patients with HIV who received PI therapy No PI therapy Reference Fat loss, lipoatrophy Loss of facial fat 3/372 (1%) Boix et al /63 (3%) 0/42 (0%) Reboli et al /32 (22%) Viraben et al /29 (24%) Wong et al /105 (68%) Carr et al Loss of extremity fat 9/116 (4%) Dong et al /63 (11%) 0/42 (0%) Reboli et al /32 (13%) Viraben et al /105 (64%) Carr et al Any fat wasting 72/368 (20%) 17/179 (9%) Thiebaut et al Fat accumulation Increase in dorsocervical fat 2/95 (2%) 0/32 (0%) Sutinen et al /116 (3%) Dong et al /63 (5%) 0/42 (0%) Reboli et al /13 (38%) Miller et al Breast enlargement 3/372 (1%) Boix et al /63 (6%) 0/42 (0%) Reboli et al /116 (4%) Dong et al /95 (37%) 10/32 (31%) Sutinen et al Increased abdominal girth 3/272 (1%) Boix et al /72 (7%) Rosenberg et al /116 (16%) Dong et al /63 (21%) 0/42 (0%) Reboli et al /95 (56%) 13/32 (41%) Sutinen et al /105 (65%) Carr et al Any fat accumulation 9/13 (69%) Silva et al /32 (38%) Gervasoni et al /368 (14%) 18/179 (10%) Thiebaut et al Both fat loss and fat accumulation 5/272 (2%) Boix et al /306 (8%) Gervasoni et al /116 (18%) Dong et al /158 (22%) Veny et al /63 (24%) 0/42 (0%) Reboli et al /113 (84%) 1/28 (4%) Carr et al /9 (100%) Madge et al /368 (47%) 44/179 (25%) Thiebaut et al NOTE. PI, protease inhibitor. The wide variability in prevalence is likely related to the following causes: absence of standardized case definitions; inclusion of cases based on patients self-report of changes; variability in the way different physicians clinically assess fat distribution; and extraction of data from chart reviews. Several groups of national and international HIV investigators have assembled and attempted to develop clinically meaningful and relatively easy to apply case definitions for change in body fat that can be used for surveillance purposes. However, the reproducibility of such definitions has not been tested. Prospective longitudinal Body Habitus Changes Related to Lipodystrophy CID 2003:36 (Suppl 2) S85

3 Table 2. Prevalence and incidence of fat loss and fat accumulation in patients with HIV. Cohort No. of subjects Lipodystrophy, % Lipoatrophy, % Fat accumulation, % Both lipoatrophy and fat accumulation, % Aquitaine cohort [11] (95% CI, 32 42) 16 (95% CI, 13 18) 12 (95% CI, 10 15) 10 (95% CI, 8 13) LIMS cohort [12] (750) a 33.7 (253) 25.6 (192) 40.7 (305) Canadian cohort [10] b NA HOPS cohort [13] Spanish cohort [9] c 11.7 (95% CI, ) 9.2 (95% CI, ) 7.7 (95% CI, ) NOTE. LIMS, Lipodystrophy Italian Multicenter Study; HOPS, HIV Outpatient Study; NA, not applicable. a Proportion of 2258 with the abnormality. b Increase in abdominal girth. c Incidence per 100 patient-years. studies with appropriate controls and objective, quantifiable measurements of body fat (e.g., by dual X-ray absorptiometry [DXA] and CT and MRI imaging) will be necessary to validate case definitions, to reliably determine incidence, and to assess the relationship among specific HIV treatments. Four recent, larger studies (totaling nearly 5000 subjects) describe patients experiencing fat maldistribution (table 2) [10 13]. In the Aquitaine cohort from France [11], in which patients fat maldistribution was diagnosed by treating clinicians, the prevalence was 38% among 581 subjects. The prevalence of fat wasting was 16%, fat accumulation 12%, and mixed syndrome 10%. In a provincewide Canadian report of 1035 participants [10], 50% of patients self-reported abnormalities of body fat, with 36% reporting fat wasting, 33% increased abdominal girth, and 6% a buffalo hump. In the Lipodystrophy Italian Multicenter Study (LIMS) of 2258 subjects, fat maldistribution was present in 33.2% of cases [12]. Finally, in the HIV Outpatient Study (HOPS) cohort, 49% of 1077 subjects developed manifestations of fat maldistribution (13% lipoatrophy, 13% fat accumulation, and 23% mixed syndrome) [13]. These rates of lipodystrophy are lower (33% 50%) than those reported earlier by Carr et al. [14] (83%) and emphasize differences in methodologies, potential for selection bias, and the need for reproducible case definitions. PATHOGENESIS AND ASSOCIATED RISK FACTORS Female sex. Trunk obesity rather than subcutaneous fat wasting appears to occur more often in women than in men [5, 12, 15 17]. In the Aquitaine cohort, more than a quarter of the subjects ( n p 156) were women [11]. The prevalence of fat maldistribution in these women was 37%, considerably greater than the 10.5% prevalence in a smaller cohort reported earlier [18]. In these women, fat wasting occurred less often (10%) compared with men (17%), but fat accumulation was similar between the sexes. In the large LIMS cohort, female sex was a risk factor for combined fat loss and accumulation [12]. In the Italian Cohort Naive Antiretrovirals (ICONA) study of antiretroviral therapy naive subjects in which 704 women (27.9%) were followed for a median of 96 weeks, female sex was a risk factor for fat accumulation and for the mixed fat syndrome. Likewise, in the prospective cohort from Spain, fat accumulation was more likely to develop in women than in men [9]. Thus, it is possible that women may be at greater risk for accumulation of fat, although a cross-sectional study evaluating fat by a validated, reproducible methodology (i.e., DXA) in 265 subjects revealed no differences in occurrence of fat accumulation or loss by sex [19]. Prospective studies will be necessary to further evaluate whether there are true differences between the sexes [20]. PIs. Initial reports of fat maldistribution suggested that these changes were related to use of PIs. However, a sizable portion of patients developing lipodystrophy had never received a PI (table 1). In addition, a cross-sectional study involving 102 subjects (89 with and 13 without lipodystrophy) indicated that subjects receiving PIs were no more likely to develop fat loss or accumulation (the latter were assessed by CT scans) than those not receiving a PI [21]. Results of a number of switch studies in which PIs have been changed to non-nrtis have not demonstrated consistent, objective evidence of improvement in fat distribution 6 12 months after discontinuing PIs (reviewed in [22]). It may be that favorable changes in body composition take longer or that lipoatrophy is not reversible in some patients. Finally, the well-documented effects of PIs on lipid and carbohydrate metabolism may be independent of changes in body fat [23]. Indirect evidence in fact did suggest that PIs were involved because the odds of fat wasting were shown to increase with the duration of therapy [14, 24 25]. The use of PIs also increases the probability of intra-abdominal fat accumulation [14, 26]. Some of the most compelling evidence implicating PIs emanates from a study that assessed a subset ( n p 77) of 277 subjects undergoing serial DXA scans at 6-month intervals. In that study, PI-based therapies were associated with a faster rate of fat wasting than in subjects not receiving PIs [25]. In the S86 CID 2003:36 (Suppl 2) Sattler

4 Canadian study [10], the OR for developing lipodystrophy was 2.63 (95% CI, ) for subjects who had ever received a PI [25]. In the Aquitaine cohort [11], the OR for developing lipodystrophy was 3.83 ( P!.001) for subjects who had ever received a PI. In the HOPS cohort, for those identified with moderate to severe lipodystrophy (171 patients), use of indinavir for 12 years was a risk factor for changes in body fat [13]. However, causality cannot be ascribed from prevalence studies. NRTIs. Cross-sectional studies also suggest that the NRTIs may be causally related to changes in body habitus, possibly by causing mutations in the mitochondrial DNA polymerase gamma gene and thus adversely affecting mitochondrial oxidative phosphorylation [27, 28]. The observation that older subjects were more likely to have fat wasting [11, 13] supports this concept because mitochondrial DNA mutations accumulate with aging. Length of therapy with NRTIs may also increase the risk for fat loss [9, 13, 25, 29]. Finally, dual NRTI therapy is more likely to cause fat wasting than is therapy with a single NRTI [25]. There may be differences in the propensity of various NRTIs to cause abnormalities of fat distribution. In the LIPOCO, HOPS, Australian, and Swiss cohorts, treatment with stavudine was a risk factor for lipoatrophy [17, 24, 25, 30 32]. Peripheral fat wasting was also more common in subjects receiving stavudine plus didanosine in the Swiss cohort [31]. Treatment with lamivudine has also been associated with fat maldistribution [21, 24]. These observations may reflect selection bias because stavudine and lamivudine were the last NRTIs licensed before the PIs, and their use may merely reflect previous use of zidovudine or longer treatment with NRTIs. However, when body fat was measured by serial DXA scans, the risk of lipoatrophy was 265% per year greater for patients receiving stavudine than zidovudine after controlling for duration of NRTI usage and age [25]. The criteria for selecting the subset for DXA scanning from the parent cohort were not clear. In a report of 36 patients openly switched from stavudine to abacavir or zidovudine, peripheral fat stores by anthropometric measures improved after a median of 9 months [33]. However, abdominal fat, as assessed by CT scans, also increased. Because there was no control group, these results should be interpreted cautiously: uncontrolled interventions may have contributed to the observed changes. Finally, in the NOVAVIR study, follow-up was available after 30 months for 96 persons randomized to a stavudine- versus zidovudine-based lamivudine-indinavir regimen [34]. The occurrence of lipoatrophy, as determined by skinfold measurement and physician assessment, was significantly less common in subjects randomized to zidovudine. However, this was a multicenter study and thereby required different operators for the anthropometric measurements, which can result in considerable variability in outcomes. By contrast, in the Eurosupport II project, involving 1141 subjects, there was no difference in the occurrence of lipodystrophy between subjects receiving stavudine and those receiving lamivudine [35]. Similarly, in 98 heavily pretreated subjects, stavudine was not more likely than zidovudine to be associated with lipodystrophy [36]. Finally, in a German cohort of patients who began HAART after 1 January 1996 and continued therapy with either stavudine or zidovudine for a median follow-up of 23.8 months, there was no difference in the occurrence of lipodystrophy after correction for confounding variables [37]. In the prospective cohort study from Spain, no individual NRTI was associated with increased risk [9]. Thus, it remains to be established whether stavudine increases the risk of fat maldistribution more than other NRTIs. Combination antiretroviral therapy. It is also possible that NRTI and PIs together contribute to abnormalities in fat distribution. Indeed, PI therapy combined with dual NRTIs resulted in faster lipoatrophy than therapy with dual NRTIs, whereas PI therapy per se did not exert a strong independent risk for fat loss [25], although the predominance of data reviewed above suggests that PIs are causally related to lipodystrophy. Moreover, in the Canadian study of 1035 subjects in which PIs were associated with a nearly 3-fold increased risk for lipodystrophy, stavudine and lamivudine were independently associated with risk of lipodystrophy (OR, 1.35 and 1.32, respectively) after adjustment for PI use [10]. Finally, in the LIMS cohort of 2258 subjects, the risk was greater in subjects treated with a combined regimen of NRTIs and PIs (OR, 2.1 [95% CI, ]) compared with patients treated only with NRTIs (OR, 1.0) [12]. MANAGEMENT OF LIPOATROPHY Little is known about options for management of lipoatrophy. Anecdotal reports suggest that implants with collagen or fascia in the buccal area improve facial appearance, but further loss of fat may occur in some cases. Polylactic acid, a bioabsorbable material that stimulates collagen formation, was injected in the cheeks of 26 HIV-positive men who experienced fat wasting [38]. Echography found that the mean dermal thickness increased by 4.1 mm (151%) and 5.3 mm (196%) at weeks 12 and 24, respectively, with cosmetic improvements. However, in the absence of controlled studies showing long-term demonstrable benefits and safety, such strategies cannot be recommended. Anabolic steroids have been tried without clinical evidence to suggest that they would augment peripheral fat. There is also evidence to suggest that this class of agents might actually reduce peripheral fat [39, 40]. Thus, these therapies cannot be recommended at this time. Insulin sensitizing agents. Because both fat atrophy and fat accumulation are associated with insulin resistance, which Body Habitus Changes Related to Lipodystrophy CID 2003:36 (Suppl 2) S87

5 predisposes non HIV-infected persons to coronary artery disease [41, 42], insulin-sensitizing agents are attractive therapies for investigation. Experimental data suggest that the thiazolidinediones, which are ligands for nuclear peroxisome proliferator-activated receptor-g in adipose tissue, might be beneficial for repleting subcutaneous fat. These agents increased preadipocyte differentiation and lipid accumulation in cultures of subcutaneous adipose tissue but not abdominal fat cells from clinical biopsy specimens [43]. In subjects with congenital or acquired lipoatrophy, those who received at least 6 months of troglitazone had a 2.4% increase in body fat ( P p.044) by DXA. MRI revealed an increase in subcutaneous fat but no change in visceral adipose tissue [44]. Because of the potential for liver toxicity and potential for drug interactions, controlled studies of thiazolidinediones in persons with HIV are needed before they can be recommended for treatment of lipodystrophy. Treatment switching strategies. Although a number of switch studies in which PIs were changed to regimens without this class of drugs failed to demonstrate consistent, objective improvements in body composition, 3 recent reports indicated that changing stavudine to either zidovudine or abacavir resulted in small but statistically significant increases in subcutaneous fat, as assessed by DXA or CT scan [45 47]. Although these studies had limitations in design, they suggest that lipoatrophy may not be as irreversible as previously feared. Peer review will be important in understanding the validity and implications of these results. MANAGEMENT OF FAT ACCUMULATION Human growth hormone. Human growth hormone has potent fat-oxidizing properties and has decreased dorsocervical fat in persons with HIV [48 50] and reduced abdominal fat in HIV-negative men with abdominal obesity [51]. In 14 HIVpositive subjects with fat maldistribution treated with recombinant human growth hormone (rhgh; 6 mg/kg/d), body fat was significantly reduced after 24 and 36 weeks [52]. However, reaccumulation of central adipose tissue was nearly complete by 12 weeks after rhgh had been discontinued. Significant decreases in extremity fat also occurred during treatment, suggesting that rhgh may aggravate peripheral fat wasting. In a different study, 8 subjects with fat accumulation received rhgh (3 mg/d) for 6 months, which resulted in significant decreases in total fat, buffalo hump size, and visceral adipose tissue [53]. However, endogenous production of hepatic glucose (signifying insulin resistance) increased significantly and remained elevated at the end of the 6 months [54]. In HIV-negative subjects with abdominal obesity, growth hormone caused insulin resistance early in the course of therapy [51]. Because persons with HIV are prone to insulin resistance from several different causes, rhgh cannot be routinely recommended at the pharmacologic doses studied to date. Androgens. In men without HIV who have had abdominal obesity, low or replacement doses with testosterone or similar synthetic analogues have reduced intra-abdominal fat, as assessed by CT scan [55]. The greatest beneficial effects occurred in men with lower levels of serum testosterone, as often occurs in men with HIV. Special care is needed in administering testosterone and its analogues to women, who appear to be more sensitive to developing insulin resistance in the setting of excess androgen. Moreover, as indicated above, treatment with androgens may also reduce peripheral fat [39, 40]. Thus, testosterone (or similar analogs) cannot be recommended at this time except in men who are overtly hypogonadal, with testosterone levels!250 ng/dl. Metformin. Metformin is an insulin-sensitizing agent that reduces hepatic glucose production. In an open-label study in which metformin (850 mg) was administered 3 times a day to HIV-infected subjects with central obesity, fasting insulin levels and insulin response to oral glucose tolerance testing improved and visceral adipose tissue decreased [56]. In a placebo-controlled study of HIV subjects with lipodystrophy and impaired glucose tolerance, 26 subjects were randomized to placebo or 500 mg of metformin twice daily [57]. After 3 months, indirect measures of insulin sensitivity and glucose tolerance improved significantly, and there was a trend toward decreased visceral adipose tissue (change of 6%, P p.08). However, metformin, which may be complicated by lactic acidosis, cannot be recommended until additional controlled studies establish its relative efficacy and safety and the appropriate dose is determined for persons with HIV. Diet and exercise. Until the efficacy and safety of pharmacological interventions are rigorously studied in persons with HIV, the cornerstone of management for central fat accumulation should be diet and exercise, as extrapolated from populations not infected with HIV [58]. For central fat accumulation, the goal should be to decrease intake of saturated fat and excess caloric energy. Aerobic exercise is expected to augment the effects of dietary change because intra-abdominal fat (mesenteric and omental adipose tissue) is metabolically more active than peripheral fat in responding to lipolytic stimuli, such as increases in epinephrine with exercise. In persons without HIV, intensive aerobic exercise can decrease intra-abdominal adipose tissue by 17% 20% [59]. In addition, aerobic exercise increases peripheral glucose disposal in obese persons, even in the absence of weight loss [60, 61], and should be beneficial for subjects with insulin resistance. A recent report suggests that an aerobic exercise program with a moderate-fat, low glycemic-index, high-fiber diet can reverse aspects of lipodystrophy [62]. Supervised resistance (strength) training modestly decreased truncal fat as assessed by DXA scanning in 2 S88 CID 2003:36 (Suppl 2) Sattler

6 preliminary studies [63, 65], but resistance exercise is not expected to be as efficient in reducing fat as aerobic exercise. However, it remains to be determined whether vigorous aerobic exercise negatively affects peripheral fat stores in persons with HIV. Although the general goal for diet is caloric energy restriction to reduce central fat, the prescribing of specific changes for intake of macronutrients (fats and carbohydrates) should be based on serum lipid levels and glucose intolerance [64]. References 1. Wanke CA. Epidemiological and clinical aspects of the metabolic complications of HIV infection the fat redistribution syndrome. AIDS 1999; 13: Safrin S, Grunfeld C. Fat distribution and metabolic changes in patients with HIV infection. AIDS 1999; 13: Reaven GM. Syndrome X: 6 years later. J Intern Med Suppl 1994; 736: Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC. 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