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Lipodystrophy in Human Immunodeficiency Virus-Infected Patients

Division of Nutrition and Metabolic Diseases, Department of Internal Medicine and the Center for Human Nutrition, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Address all correspondence and requests for reprints to: Abhimanyu Garg, M.D., University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9052. E-mail: abhimanyu.garg{at}utsouthwestern.edu.

Abstract

Human immunodeficiency virus (HIV) infection is a major global health problem. Recently, combination therapy including HIV-1 protease inhibitors (PIs) has dramatically improved the long-term survival of HIV-infected patients. However, such therapy is associated with a lipodystrophy syndrome characterized by selective loss of sc fat from the face and extremities and, in some patients, accumulation of fat around the neck, dorsocervical region, abdomen, and trunk. Lipodystrophy in HIV-infected patients (LDHIV) is associated with insulin resistance and its metabolic complications such as impaired glucose tolerance, diabetes, hypertriglyceridemia and low serum high density lipoprotein cholesterol levels. PIs appear to be the strongest link to LDHIV; however, fat loss has been reported in some patients taking non-PI antiretroviral drugs. Other factors, such as duration of HIV infection, age, and gender, may also contribute to the risk of development of LDHIV. The molecular basis of LDHIV remains unknown. There is no specific therapy for LDHIV. Avoiding weight gain by reducing energy intake and increasing physical activity may be beneficial in reducing fat accumulation as well as improving metabolic complications. Antihyperglycemic drugs may be used to treat diabetes. Management of dyslipidemia may require lipid-lowering drugs; however, the safety and efficacy of such intervention require further studies. Substitution of PIs with other antiretroviral drugs can mitigate dyslipidemia and glucose intolerance, but whether reversal of lipodystrophy occurs remains unknown. Future research is needed to discover the biochemical and molecular markers of lipodystrophy in HIV patients and develop PIs or other antiretroviral agents that are free of metabolic toxicity.

RECENTLY, GREAT PROGRESS has been made in the treatment of human immunodeficiency virus (HIV) infection. Highly active antiretroviral therapies (HAARTs) that include HIV-1 protease inhibitors (PIs) in particular result in marked HIV suppression and have dramatically improved the clinical course, prognosis, and survival of patients infected with HIV. In the last few years, however, lipodystrophy, characterized by redistribution of body fat and insulin resistance, has been reported in many HIV-infected patients, and its relationship with antiretroviral drugs and HIV infection per se has become a subject of debate and investigation. This review is intended to discuss the clinical features and possible etiology and pathogenesis of lipodystrophy in HIV-infected patients.

Clinical and metabolic characteristics of lipodystrophy in HIV-infected patients (LDHIV)

The first anecdotal report of body fat redistribution in an HIV-infected patient undergoing antiretroviral therapy including a PI (indinavir) was published in the medical literature in 1997 (1). In early 1998, Carr et al. (2) provided detailed description of a syndrome of peripheral lipodystrophy, dyslipidemia, and insulin resistance related to the use of PIs. Subsequently, many more cases have been reported. Currently, different names are being used to describe this syndrome, such as pseudo-Cushing’s syndrome, fat redistribution or maldistribution syndrome, and PI-associated or HIV-associated lipodystrophy syndrome. We prefer the term lipodystrophy syndrome in HIV-infected patients (LDHIV).

Body fat redistribution

LDHIV is recognized primarily as loss of sc adipose tissue from the facial (sunken cheeks) and peripheral regions, particularly the extremities (2, 3, 4, 5, 6) (Fig. 1 and Table 1). Affected patients appear to be muscular and have prominent superficial veins in the extremities (6). Some patients have concomitant deposition of excess adipose tissue around the neck (double chin), over the dorsocervical spine (buffalo hump) (7, 8, 9, 10, 11, 12, 13, 14), upper torso (1) and intraabdominal region (6, 13, 15, 16, 17). Breast enlargement has been observed in both women (12, 18, 19, 20) and men (21, 22, 23), but whether it is due to excess sc fat, glandular hypertrophy, or both is not clear. Compared with men, peripheral fat loss in women with LDHIV is often more subtle, whereas increased truncal adiposity is the main complaint (24, 25). Women may develop menstrual irregularities (26). Acanthosis nigricans, a feature of other lipodystrophies, has not been reported. Most patients with LDHIV are clinically well and do not have significant weight loss or opportunistic infections. Their peripheral blood CD4 cell counts are relatively high and HIV viral burden low due to effective antiretroviral therapy (3, 8). However, patients affected by severe LDHIV are often troubled by the disfiguring facial and body appearance, altered (stooping) posture, changing size of clothes, and discomfort from buffalo hump when in a supine position. Furthermore, because of disfigurement, many patients may discontinue HAART therapy (27).

View larger version (152K): [in this window] [in a new window]   Figure 1. Anterior and right lateral views of a 49-yr-old HIV-infected male with lipodystrophy. The patient had been receiving a PI-containing antiretroviral drug regimen for 2.5 yr. The marked loss of sc fat is evident from the face, upper and lower extremities, and anterior trunk. A dorsocervical fat pad (buffalo hump) is present. The patient had undergone liposuction for removal of excess fat from the anterior neck and chin area three times. He also had impaired glucose tolerance and hypertriglyceridemia.

Several factors may influence the accuracy of the patient’s self-report and the physician’s determination of body fat loss in affected individuals. First, because fat loss may occur gradually over months or years, early recognition may be difficult, particularly in obese individuals and in women, who have more sc fat than men. Moreover, an individual’s awareness and acceptance of body fat loss or gain may be different. For example, an obese person may not be as concerned with mild peripheral fat loss as with increasing central adiposity.

Although a 98% concordance between the patient’s self-reports and the physician’s diagnosis was claimed according to one study (32), significant discrepancy (50%) was reported more recently by the same investigators (33) and others (34). Therefore, the sensitivity and specificity of subjective criteria currently used for LDHIV are poor.

Objective measurement of body fat with dual energy x-ray absorptiometry has confirmed a significant reduction of fat in the extremities, but preservation of, or increase in, fat in the truncal region in patients with LDHIV (2, 32, 35, 36, 37, 38). Further, computerized tomography (6, 15, 17, 38, 39, 40, 41) or magnetic resonance imaging studies (13, 16) have shown increased intraabdominal fat, but not sc fat, in patients with increased abdominal girth. An increased waist to hip circumference ratio and reduced skinfold thickness in the extremities have also been noted in both men and women with LDHIV (41, 42).

Metabolic abnormalities

Patients with LDHIV often have dyslipidemia, impaired glucose tolerance, and insulin resistance (28, 43, 44) (Table 2). Metabolic abnormalities may precede changes in body fat distribution (45).

Hypertriglyceridemia, hypercholesterolemia, and low serum high density lipoprotein (HDL) cholesterol levels characterize dyslipidemia in LDHIV. In an early case report (46), a 5-fold increase in serum cholesterol and a 15-fold increase in serum triglyceride concentrations were noted in a patient 5 months after initiation of ritonavir therapy, and these values returned toward baseline 5 wk after discontinuing ritonavir. Severe hypertriglyceridemia after starting PI-containing therapy can lead to chylomicronemia, eruptive xanthomas, and acute pancreatitis (47, 48, 49). Carr et al. (32) reported dyslipidemia in 67% of patients receiving PI-containing therapy compared with 26% prevalence in PI-naïve patients. Others have also reported similar prevalence (50–70%) of dyslipidemia in patients treated with PI-containing regimen (14, 50, 51, 52). Ritonavir and, in particular, a combination therapy with two PIs have been reported to increase the risk of hypertriglyceridemia (7.2-fold) and hypercholesterolemia (19.6-fold) (53). Several reports also indicate an increase in the levels of lipoprotein(a) (14, 53, 54).

Dyslipidemia was noted in the pre-PI era in HIV-infected patients, but was characterized by decreased serum levels of total cholesterol, HDL cholesterol, and low density lipoprotein cholesterol and elevated level of triglycerides (55). Dyslipidemia was associated with low blood CD4 counts and increased plasma levels of interferon- and was more common in patients with AIDS (56, 57, 58, 59, 60).

Impaired glucose tolerance and insulin resistance.

Most studies report a prevalence of hyperglycemia ranging from 0–20% (12, 14, 61, 62) during PI-containing HAART therapy. Impaired glucose tolerance was reported in 62% patients taking PIs (50), and a rise in fasting blood glucose levels was reported after initiation of PI-based therapy (63, 64). Worsening of preexisting hyperglycemia or new onset of reversible diabetes mellitus with PI therapy is relatively uncommon (65, 66, 67, 68, 69, 70). However, Vigouroux et al. (71) reported diabetes occurring in 11 of 14 (79%) patients with LDHIV, compared with 4 of 20 (20%) patients taking PI-containing HAART without LDHIV. On nucleoside reverse transcriptase inhibitors (NRTI) treatment, hyperglycemia occurred in only 14% of the patients (72). Increased truncal adiposity and visceral adipose tissue may be related to a higher prevalence of dyslipidemia and insulin resistance (12, 17, 73), but not diabetes (12), in these patients.

Many investigators reported elevation of fasting and/or postprandial serum insulin and C peptide concentrations in patients receiving PI therapies and in those with LDHIV (2, 3, 12, 32, 42, 64). In an 8-wk prospective study of 10 patients receiving indinavir-based therapy, insulin sensitivity, assessed by minimal model, decreased by 30% (63). Walli and co-workers (74) reported a higher prevalence of insulin resistance in patients taking PI-containing HAART compared with those treated with NRTIs alone (55% and 27%, respectively), and this was more prevalent in those receiving prolonged (7–13 months) treatment with PI. Furthermore, a reduction in the insulin sensitivity has been documented using hyperinsulinemic euglycemic clamp in patients with LDHIV (75, 76, 77). Mynarcik et al. (75) further showed that insulin resistance in patients with LDHIV was related to the loss of limb fat and not to the accumulation of truncal fat. Glucose intolerance, hyperinsulinemia, and insulin resistance in patients receiving PI-containing HAART therapy may be early manifestations of lipodystrophy syndrome.

Insulin resistance and glucose intolerance may help in distinguishing LDHIV from AIDS-associated wasting (Table 2). For example, in contrast to the patients with LDHIV, HIV-infected patients (Centers for Disease Control, group IV) in the pre-PI era were noted to have increased peripheral insulin sensitivity and lower fasting serum insulin and glucose levels (78, 79) (Table 2).

Prevalence of LDHIV

Due to the differences in diagnostic criteria, selection of study populations, and duration of follow-up, considerable differences in the reported prevalence of LDHIV exist, ranging from 8–84% and averaging 42%, in patients treated with PI-containing HAART (Table 3). Average incidence varies from 7.3 (61) to 11.7 (80) per 100 patient-yr. Despite these differences, however, a generally higher prevalence was reported in patients after longer-term therapy. From pooled data, the prevalence of LDHIV is 17% in adults treated with PI-containing therapy for less than 1 yr and 43% in those treated for 1 yr or more (Fig. 2). The prevalence of LDHIV in women has been reported to range from 10.5% (35) to 37% (12), but it is probably underreported. Each additional 6 months of treatment with HAART is associated with a 45% increased risk of lipodystrophy (80). An increase in the prevalence of LDHIV is expected in the future with longer follow-up and continued use of HAART. It is interesting that LDHIV has become the most prevalent type of lipodystrophy, whereas the other types of acquired lipodystrophies as well as familial lipodystrophies are still rare diseases (29).

View larger version (21K): [in this window] [in a new window]   Figure 2. Prevalence of lipodystrophy in HIV-infected patients according to the treatment regimen and duration of therapy. Prevalence is calculated from the data appropriate for analysis.

Risk factors for LDHIV

The direct cause of LDHIV is unknown, but several risk factors have been associated with the occurrence of LDHIV (Table 4). PIs appear to be the strongest link to LDHIV; however, non-PI antiretroviral drugs, duration of HIV infection, age, and gender may contribute to the risk of development of LDHIV.

Many case reports (3, 7, 15, 24) and large observational studies have shown an association between LDHIV and PI-based HAART. During a 21-month follow-up of 39 patients receiving PI therapy, the rate of total body fat loss was 0.4 kg/month during the first year and 0.13 kg/month during the second year (32). The fat loss involved all peripheral regions, but not the abdomen, whereas total and extremity lean body masses remained unchanged (32). In contrast, body fat remained essentially unchanged in PI-naïve patients (32). Similarly, a 15% fat loss/yr from the legs was observed in patients taking PI-containing HAART (84). In addition, PI use is associated with dyslipidemia, impaired glucose tolerance, and insulin resistance (Table 5).

NRTIs

Fat loss and accumulation have also been reported in PI-naïve patients treated with NRTIs alone (Table 3). Lamivudine (3TC) (35) and stavudine (d4T) (41, 84, 86) as well as various combinations of NRTI (72, 87) have been implicated in causing body fat redistribution (Table 1,4). Carr et al. (86) suggested that the features of body fat loss in 14 patients treated with NRTI alone were indistinguishable from those of PI-induced lipodystrophy. However, these patients also presented with recent weight loss, fatigue, nausea, hepatomegaly, hepatic dysfunction, and high plasma concentrations of lactic acid (86).

Data are inconsistent concerning the effects of NRTIs on glucose and lipid metabolism (Table 2). Although some investigators have found dyslipidemia (88) in patients treated with NRTIs alone, no relationship between metabolic abnormalities characteristic of insulin resistance and NRTI therapy has been reported by others (86). In fact, patients with NRTI-associated body fat redistribution had either normal blood lipids, glucose, and insulin levels or lower values compared with those in PI-related LDHIV patients and values similar to those in patients not receiving any antiretroviral treatment (86, 88).

It is possible, therefore, that the fat loss and fat accumulation in patients treated with NRTIs alone represent a different disorder than the lipodystrophy syndrome in patients treated with PI-containing HAART and could be complicated by organ toxicity or failure and AIDS wasting in many of them. Whether a particular NRTI causes more fat loss than others is not yet clear. A long duration of NRTI therapy may be required to observe significant fat loss, as no significant body fat changes were noted in 151 patients participating in a randomized, controlled trial of combination NRTI therapy for a 6-month period (89). It is speculated that NRTIs may cause slow fat loss that is accelerated with the addition of PIs (84).

HIV infection

The development and severity of LDHIV have been positively associated with the duration of HIV infection, negatively associated with previous HIV viral load, and both positively and negatively associated with blood CD4 lymphocyte counts in various studies (Table 4). However, how these factors play a role in determining or modifying the development of LDHIV remains unclear.

Nutritional status, age, and adiposity

Body adiposity before receiving PI-containing HAART may also affect features of LDHIV. For example, a cross-sectional study suggested that overweight men and women (body mass index, >28 kg/m²) had a higher prevalence of buffalo hump and breast enlargement (women), but a lower prevalence of facial and gluteal fat loss compared with underweight subjects (body mass index, <20 kg/m²) (90). Older people tend to have greater body fat mass, particularly intraabdominal fat (91, 92, 93, 94), which may contribute to or modulate the body fat changes seen in LDHIV (95).

A disproportionately higher gain in fat mass relative to lean tissue was observed during refeeding after malnutrition and weight loss, although there is substantial individual variation (96). HIV-infected patients with wasting syndrome (weight loss >10% of baseline body weight) lost more fat than lean body mass (97). Thus, during recovery from wasting, body fat may accumulate disproportionately in certain areas. However, LDHIV can occur in patients without a previous history of wasting.

Pathogenesis of LDHIV

The precise mechanisms by which PIs or NRTIs cause body fat changes are not known. However, various speculations and hypotheses have been proposed.

Mechanisms of PI-induced body fat changes and metabolic abnormalities.

Some similarities in body fat distribution between patients with LDHIV and Cushing’s syndrome prompted examination of the hypothalamic-pituitary-adrenal axis in patients with LDHIV (1, 7, 8, 9, 10, 98, 99). Only a few patients with LDHIV had mildly increased serum cortisol concentration or 24-h urinary excretion of free cortisol, but they all had preserved cortisol circadian rhythm and normal response to dexamethasone. Thus, overt hypercortisolism was essentially ruled out.

However, cortisol may be locally produced in adipose tissue from conversion of biologically inactive cortisone by the enzyme 11ß-hydroxysteroid dehydrogenase type 1. The expression of this enzyme and of glucocorticoid receptors is significantly higher in omental fat than in sc fat (100, 101, 102). Therefore, a locally increased glucocorticoid concentration or action without systemic hypercortisolism may induce regional adiposity, but whether this mechanism contributes to the development of LDHIV has not been assessed.

Carr et al. (103) identified a homology between a 12-amino acid sequence of the catalytic domain of HIV-1 protease and the retinoic acid-binding domain of cytoplasmic retinoic acid-binding protein-1 (CRABP-1) and the lipid-binding domain of low density lipoprotein receptor-like protein (LRP). CRABP-1 carries retinoic acid (104), which, when isomerized to cis-9-retinoic acid, activates nuclear retinoid X receptor- peroxisome proliferator-activated receptor- (PPAR) complex known to regulate adipocyte proliferation and differentiation (105, 106). Thus, PIs, by inhibiting CRABP-1, may inhibit adipocyte differentiation. However, preliminary results of in vitro studies do not support this hypothesis. For instance, three-dimensional crystal analyses of CRABP-1 and HIV-1 protease showed no structural similarity (107). Furthermore, none of the PIs directly binds to retinoid X receptor- or PPAR (108, 109). Inhibition of LRP by PIs may not account for hyperlipidemia, as inactivation of LRP in the livers of wild-type mice did not result in hyperlipidemia (110). Other investigators propose that nonspecific inhibition of human proteins, such as insulin-degrading enzymes or cathepsins (aspartyl proteases), by PIs can cause primary hyperinsulinemia (44, 45, 111, 112). However, this mechanism cannot explain the loss of body fat.

Limited information about the histopathology of fine needle biopsy or surgical specimens of the adipose deposition reveals nonencapsulated mature adipose tissue (7, 9), some with fibrotic changes (113), ruling out dysplastic or neoplastic pathology. Subcutaneous adipocyte apoptosis has also been reported in lipodystrophic areas of patients with LDHIV (114); however, control, PI-naive, HIV-infected subjects were not studied. The same group reported that apoptosis was not reversed on switching from indinavir to nevirapine despite improvement in the metabolic parameters (115). In vitro studies with C3H10T1/2 murine mesenchymal stem cells (108), 3T3-L1 preadipocytes (109), and human preadipocytes (116, 117) showed that several PIs inhibited adipocyte differentiation. Recently, Bastard et al. (118) showed reduced mRNA expression of many transcription factors, including sterol regulatory element-binding protein-1 (SREBP-1) in adipocytes from patients with LDHIV taking PIs compared with healthy subjects; however, SREBP-1 protein levels were increased. A similar increase in the SREBP-1 protein expression has been noted in the liver and adipose tissue of ritonavir-treated mice (119) and after nelfinavir and ritonavir exposure of 3T3-L1 preadipocytes (117, 120), but in 3T3-F442A cells, indinavir reduced SREBP-1 protein expression (121). As SREBP-1c overexpression in adipose tissue of mice causes lipodystrophy (122), PI-induced alterations of SREBP-1 expression may be a plausible mechanism for LDHIV.

Inhibition of insulin-stimulated glucose uptake in 3T3-L1 adipocytes has been produced by indinavir (123) and saquinavir (124), which affect the intrinsic transport activity of glucose transporter-4 (123, 125). These inhibitory effects of PIs on glucose transporter-4 are selective and noncompetitive and may potentially affect insulin sensitivity adversely (126).

When given alone to the healthy volunteers (54) and for the prevention of occupational exposure of the HIV infection to the health care workers, PIs caused hypertriglyceridemia (127). Several mechanisms have been proposed for PI- induced hypertriglyceridemia, including reduction of lipoprotein lipase activity by 81% (124) and protection of apolipoprotein B from degradation by proteasome (128). These mechanisms may pertain to the development of dyslipidemia in patients with LDHIV.

Recently, autosomal dominant familial partial lipodystrophies were reported to be due to defects in lamin A/C (LMNA) (31, 129, 130) and PPARG (131) genes, and autosomal recessive congenital generalized lipodystrophy (CGL) to be due to mutations in 1-acylglycerol-3-phosphate O-acyltransferase-2 (AGPAT2) (132) and Berardinelli-Seip congenital lipodystrophy-2 (BSCL2) genes (133). There are phenotypic similarities among LDHIV and familial partial lipodystrophies. Therefore, whether lipodystrophy in HIV-infected patients occurs due to PI-induced changes in the expression of these genes or other homologous genes, particularly those involved in the triglyceride or phospholipid biosynthetic pathways or adipocyte differentiation, remains to be ascertained.

Lipodystrophies, including LDHIV, present unique opportunities to study regional heterogeneity among adipose tissue and skeletal muscles, particularly their differentiation, regulation, and metabolism in relation to the insulin sensitivity. For example, an increased proportion of type II skeletal muscle fibers (134) and an increase in intramyocellular lipids (135) may contribute to insulin resistance in CGL patients. Whether such alterations occur in patients with LDHIV remains to be investigated.

Mechanisms of NRTI-induced body fat changes.

Recently, Brinkmann et al. (136) emphasized the similarity in body fat distribution in patients with LDHIV and multiple symmetric lipomatosis (MSL), which is characterized by marked accumulation of nonencapsulated adipose tissue around the neck (horse collar and buffalo hump), shoulders, and upper torso regions (137). Although heavy ethanol intake causes MSL in most patients, point mutations in mitochondrial DNA (138, 139, 140, 141) and mitochondrial dysfunction (142) have been identified in some nonalcoholic patients with familial MSL.

Interestingly, NRTIs inhibit DNA polymerase- and thus replication of mitochondrial DNA (143, 144). Mitochondrial toxicity, including reduced cytochrome c oxidase activity and impaired ß-oxidation of fatty acids, is a recognized side-effect of NRTIs and is implicated in hepatotoxicity, myopathy, and neuropathy. NRTIs increase lactate production and can cause lactic acidemia (86, 136) and, in a few cases, severe lactic acidosis (145, 146, 147, 148, 149). Some investigators speculate that, as in familial MSL, mitochondrial dysfunction by NRTIs can induce body fat changes (136, 150). However, patients with MSL do not have facial fat loss, and reduction in sc fat distal to the mid-arms and mid-thighs is relatively mild. Furthermore, most MSL patients with mitochondrial DNA mutations had multiple, discrete, and encapsulated lipomas in the neck and trunk. It should also be noted that patients with MSL usually do not develop metabolic abnormalities associated with insulin resistance, and they have high levels of serum HDL cholesterol (137, 151, 152, 153, 154, 155). Therefore, whether the mitochondrial toxicity of NRTIs is related to body fat changes remains controversial. Whether lactic acidemia is an integral component of NRTI-induced body fat changes is also unclear.

Differential diagnosis

Several disorders that cause loss or redistribution of body fat need to be differentiated from LDHIV. First of all, generalized body fat loss is commonly seen in HIV-infected patients with AIDS wasting syndrome (Tables 1 and 2). These individuals often are clinically ill due to a high viral burden. Such patients lose significant weight, including body fat and lean body mass, as opposed to LDHIV in which lean body mass is preserved. Furthermore, patients with AIDS wasting syndrome do not have impaired glucose tolerance or hyperinsulinemia, although they may have hypertriglyceridemia (47). Poorly controlled diabetes can also present with severe weight loss. MSL should be considered if there is a history of heavy ethanol intake. A history of steroid or megesterol use should be determined, as Cushing’s syndrome is associated with central obesity and dorsocervical fat deposition. Testosterone therapy can cause muscular appearance of the limbs, requiring differentiation from lipodystrophy.

Management

Observation.

Most patients with LDHIV have only mild symptoms. It is unclear how frequent and to what extent LDHIV is reversible, either spontaneously or with intervention. As PIs provide superior HIV suppression and, at present, are the most effective treatment for long-term survival of HIV-infected patients, the benefits from continued use of PIs probably outweigh the side-effects in many patients.

Diet and exercise.

Increased physical activity, particularly aerobic exercise, should be encouraged to improve dyslipidemia and insulin resistance. Resistance exercise has been shown to be beneficial in reducing truncal fat as well as total body fat in a 16-wk pilot study (156). Exercise training can lower serum triglycerides (157, 158) by as much as 25% (157) and along with dietary restriction can reduce total abdominal and visceral fat as well (159).

Severely hypertriglyceridemic patients should be advised to consume very low fat diets and avoid ethanol consumption to prevent chylomicronemia and acute pancreatitis (160). Low fat, high carbohydrate diets, however, exacerbate hypertriglyceridemia and hyperinsulinemia in nondiabetic subjects and in patients with type 2 diabetes (161, 162). Increased doses of -3 polyunsaturated fatty acids (5–10 g/d) from concentrated fish oil preparations may effectively lower plasma triglyceride concentrations.

Cessation and alteration of antiretroviral therapies.

In patients with severe LDHIV syndrome who were unable to continue current therapy, improvement in fat loss after cessation of PI therapy has been observed by some investigators (163), but not by others (3, 9). PI withdrawal may also improve dyslipidemia, insulin resistance, or hyperglycemia in such patients (46, 48, 66, 67). As the severity of dyslipidemia induced by different PIs alone or in combination may differ (2, 164, 165), switching PIs (such as from the ritonavir/saquinavir combination to indinavir or nelfinavir) may also result in an improvement in lipid profile in certain patients.

Although substituting PI with an NRTI may improve insulin sensitivity (74), a non-NRTI class of antiretroviral drugs may be another alternative. Replacing PI with nevirapine in combination antiretroviral therapy for 6–12 months has been reported to improve and even normalize dyslipidemia, glycemia, and insulin resistance, whereas HIV suppression was maintained (166). Quality of life and subjective perception of lipodystrophy were also improved after switching PI to nevirapine during a 3- to 6-month follow-up (23, 166, 167). However, lipodystrophy associated with nevirapine (168) and failure of HIV suppression after switching PI to nevirapine in some patients (169) has been reported. The incidence of developing lipodystrophy was reported to be lower in patients treated with efavirenz than in those given indinavir-containing regimens during a 24- to 88-wk follow-up (170). However, conflicting effects of efavirenz on dyslipidemia are reported (40, 171). Substitution of stavudine with other NRTIs for 6 months was reported to increase total body fat in patients receiving PI-containing and other regimens (172). Switching to abacavir has been reported to improve lipid levels and decrease insulin resistance (173). Recently, switching from PIs to abacavir, nevirapine, adefovir, and hydroxyurea led to an improvement in dyslipidemia, but not in loss of limb fat, over a period of 6 months. Interestingly, fasting plasma glucose and insulin remained unchanged. A reduction in the intraabdominal fat was also noted (174). Further prospective controlled studies are needed before definite recommendations can be made regarding substitution of PIs with other therapies.

Recombinant human GH (rhGH) and anabolic steroids.

Therapy with rhGH for 3–6 months caused noticeable reduction in the size of buffalo hump and truncal adiposity in a small number of patients with LDHIV, but there was no improvement in peripheral lipodystrophy and dyslipidemia. The studies, however, were not placebo controlled (175, 176, 177). In other studies rhGH therapy decreased visceral fat and fasting serum triglyceride concentrations, but worsened insulin sensitivity (77, 177). Nandrolone therapy for 8 wk had no significant effect on body fat redistribution (178). The effects of testosterone therapy on LDHIV have not been studied, but it may reduce intraabdominal fat accumulation (179).

Surgical correction.

Liposuction has been used to remove excess cervical and truncal fat (180, 181). However, excess fat deposition may recur if patients continue to take PI-containing HAART (7, 9).

Drug therapy for dyslipidemia and diabetes.

Fibric acids (gemfibrozil, benzafibrate, and fenofibrate) lower serum triglycerides by approximately 40% (182, 183, 184). Hydroxymethylglutaryl coenzyme A reductase inhibitors (statins) have also been used effectively (182). However, because many statins (simvastatin, lovastatin, and atorvastatin) are metabolized by cytochrome P4503A4, which is inhibited by PIs, simultaneous use of PIs and statins can elevate plasma levels of statins and increase the risk of myopathy. Pravastatin is not metabolized by P4503A4 and should be used with caution (185). Fibrates are also metabolized through cytochrome P450, but the predominant pathway is CYP4A (186); thus, PIs are less likely to interfere with their metabolism. The long-term safety and efficacy of lipid-lowering drugs in LDHIV patients remain to be investigated. Extreme hypertriglyceridemia leading to pancreatitis may require plasmapheresis (49).

Treatment of diabetes with common antihyperglycemic medications is reported to be effective (66, 68, 69). Metformin is beneficial (187, 188), improves insulin sensitivity, and reduces visceral fat (188). However, lactic acidosis remains a concern, particularly when metformin is used with NRTIs. Further, metformin can cause fat loss (188). In a pilot study of six patients with PI-associated diabetes, treatment with troglitazone, a PPAR activator, improved insulin sensitivity, glucose homeostasis, and dyslipidemia (189, 190). However, in a double-blind, randomized, placebo-controlled trial, rosiglitazone exacerbated hypertriglyceridemia in patients with LDHIV (191). Estrogen therapy should be avoided in women with LDHIV and hypertriglyceridemia either as oral contraceptives or as postmenopausal hormone replacement therapy because it can accentuate hypertriglyceridemia.

Future directions

The first step in studying LDHIV is to establish reliable diagnostic criteria. Large-scale epidemiological studies and, ultimately, prospective, randomized, and controlled clinical trials are needed to establish risk factors for LDHIV. The underlying molecular basis of LDHIV needs to be elucidated. This knowledge may lead to the discovery of new antiretroviral agents that are a low risk for lipodystrophy and hyperlipidemia and may provide insight into the mechanisms of insulin resistance in other adipose tissue disorders.

Acknowledgments

We acknowledge Dolores Peterson, M.D., Ph.D., and Claudia Quittner, R.N., for referring HIV-infected patients with lipodystrophy to us, and Angela Osborn for technical assistance.

Footnotes

This work was supported by NIH Grants DK-56583 and MO1-RR-00633.

Abbreviations: CRABP-1, Cytoplasmic retinoic acid-binding protein-1; HAART, highly active antiretroviral therapy; HDL, high density lipoprotein; HIV, human immunodeficiency virus; LDHIV, lipodystrophy in HIV-infected patients; LRP, low density lipoprotein receptor-like protein; MSL, multiple symmetric lipomatosis; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; PPAR, peroxisome proliferator-activated receptor-; rhGH, recombinant human GH; SREBP-1, sterol regulatory element-binding protein-1.

Received May 23, 2002.

Accepted August 8, 2002.

References

1. Hengel RL, Watts NB, Lennox JL 1997 Benign symmetric lipomatosis associated with protease inhibitors. Lancet 350:1596
2. Carr A, Samaras K, Burton S, Law M, Freund J, Chisholm DJ, Cooper DA 1998 A syndrome of peripheral lipodystrophy, hyperlipidaemia and insulin resistance in patients receiving HIV protease inhibitors. AIDS 12:F51–F18
3. Viraben R, Aquilina C 1998 Indinavir-associated lipodystrophy. AIDS 12:F37–F39
4. Shaw AJ, McLean KA, Evans BA 1998 Disorders of fat distribution in HIV infection. Int J STD AIDS 9:595–599[Abstract/Free Full Text]
5. Kotler DP, Rosenbaum K, Wang J, Pierson RN 1999 Studies of body composition and fat distribution in HIV-infected and control subjects. J Acquired Immune Defic Syndr Hum Retrovirol 20:228–237[Medline]
6. Panse I, Vasseur E, Raffin-Sanson ML, Staroz F, Rouveix E, Saiag P 2000 Lipodystrophy associated with protease inhibitors. Br J Dermatol 142:496–500[CrossRef][Medline]
7. Lo JC, Mulligan K, Tai VW, Algren H, Schambelan M 1998 "Buffalo hump" in men with HIV-1 infection. Lancet 351:867–870[CrossRef][Medline]
8. Miller KK, Daly PA, Sentochnik D, Doweiko J, Samore M, Basgoz NO, Grinspoon SK 1998 Pseudo-Cushing’s syndrome in human immunodeficiency virus-infected patients. Clin Infect Dis 27:68–72[Medline]
9. Roth VR, Kravcik S, Angel JB 1998 Development of cervical fat pads following therapy with human immunodeficiency virus type 1 protease inhibitors. Clin Infect Dis 27:65–67[Medline]
10. Striker R, Conlin D, Marx M, Wiviott L 1998 Localized adipose tissue hypertrophy in patients receiving human immunodeficiency virus protease inhibitors. Clin Infect Dis 27:218–220[Medline]
11. Saint-Marc T, Touraine JL 1998 "Buffalo hump" in HIV-1 infection. Lancet 352:319–320[Medline]
12. Thiebaut R, Daucourt V, Mercie P, Ekouevi DK, Malvy D, Morlat P, Dupon M, Neau D, Farbos S, Marimoutou C, Dabis F 2000 Lipodystrophy, metabolic disorders, and human immunodeficiency virus infection: Aquitaine Cohort, France, 1999. Clin Infect Dis 31:1482–1487[CrossRef][Medline]
13. Ionescu G, Kotler DP, Engelson ES, Agin D, Inada Y 2000 Serum complement components in HIV-infected individuals with and without fat redistribution (lipodystrophy). J Acquired Immune Defic Syndr 25:370–371
14. Mercie P, Tchamgoue S, Thiebaut R, Viallard J, Faure II, Dancourt VV, Marimoutou C, Dabis F, Rispal P, Darmon Y, Leng B, Pellegrin J 2000 Atherogen lipid profile in HIV-1-infected patients with lipodystrophy syndrome. Eur J Intern Med 11:11
15. Miller KD, Jones E, Yanovski JA, Shankar R, Feuerstein I, Falloon J 1998 Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 351:871–875[CrossRef][Medline]
16. Engelson ES, Kotler DP, Tan YX, Agin D, Wang J, Pierson RN, Heymsfield SB 1999 Fat distribution in HIV-infected patients reporting truncal enlargement quantified by whole-body magnetic resonance imaging. Am J Clin Nutr 69:1162–1169[Abstract/Free Full Text]
17. Saint-Marc T, Partisani M, Poizot-Martin I, Rouviere O, Bruno F, Avellaneda R, Lang JM, Gastaut JA, Touraine JL 2000 Fat distribution evaluated by computed tomography and metabolic abnormalities in patients undergoing antiretroviral therapy: preliminary results of the LIPOCO study. AIDS 14:37–49[CrossRef][Medline]
18. Herry I, Bernard L, de Truchis P, Perronne C 1997 Hypertrophy of the breasts in a patient treated with indinavir. Clin Infect Dis 25:937–938[Medline]
19. Lui A, Karter D, Turett G 1998 Another case of breast hypertrophy in a patient treated with indinavir. Clin Infect Dis 26:1482
20. Madge S, Kinloch-de-Loes S, Mercey D, Johnson MA, Weller IVD 1999 Lipodystrophy in patients naive to HIV protease inhibitors. AIDS 13:735–737[CrossRef][Medline]
21. Schurmann D, Bergmann F, Ehrenstein T, Padberg J 1998 Gynaecomastia in a male patient during protease inhibitor treatment for acute HIV disease. AIDS 12:2232–2233[Medline]
22. Toma E, Therrien R 1998 Gynecomastia during indinavir antiretroviral therapy in HIV infection. AIDS 12:681–682[Medline]
23. Donovan B, Bodsworth NJ, Mulhall BP, Allen D 1999 Gynaecomastia associated with saquinavir therapy. Int J STD AIDS 10:49–50[Abstract/Free Full Text]
24. Dong KL, Bausserman LL, Flynn MM, Dickinson BP, Flanigan TP, Mileno MD, Tashima KT, Carpenter CCJ 1999 Changes in body habitus and serum lipid abnormalities in HIV-positive women on highly active antiretroviral therapy (HAART). J Acquired Immune Defic Syndr Hum Retrovirol 21: 107–113
25. Falutz J, Turcot D, Considerations in the development of a case definition for HIV/HAART-associated lipodystrophy syndrome [Abstract 21]. 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego, CA, 1999; p. 29
26. Hadigan C, Miller K, Corcoran C, Anderson E, Basgoz N, Grinspoon S 1999 Fasting hyperinsulinemia and changes in regional body composition in human immunodeficiency virus-infected women. J Clin Endocrinol Metab 84:1932–1937[Abstract/Free Full Text]
27. Duran S, Saves M, Spire B, Cailleton V, Sobel A, Carrieri P, Salmon D, Moatti JP, Leport C 2001 Failure to maintain long-term adherence to highly active antiretroviral therapy: the role of lipodystrophy. AIDS 15:2441–2444[CrossRef][Medline]
28. Rozenbaum W, Gharakhanian S, Salhi Y, Adda N, Nguyen T, Vigouroux C, Capeau J Clinical and laboratory characteristics of lipodystrophy in a French cohort of HIV-infected patients treated with protease inhibitors [Abstract 12]. First International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego, CA, 1999; p. 20
29. Garg A 2000 Lipodystrophies. Am J Med 108:143–152[CrossRef][Medline]
30. Garg A, Peshock RM, Fleckenstein JL 1999 Adipose tissue distribution pattern in patients with familial partial lipodystrophy (Dunnigan variety). J Clin Endocrinol Metab 84:170–174[Abstract/Free Full Text]
31. Garg A, Vinaitheerthan M, Weatherall PT, Bowcock AM 2001 Phenotypic heterogeneity in patients with familial partial lipodystrophy (Dunnigan variety) related to the site of mis-sense mutations in Lamin A/C (LMNA) gene. J Clin Endocrinol Metab 85:59–65
32. Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA 1999 Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 353:2093–2099[CrossRef][Medline]
33. Miller J, Carr A, Smith D, Emery S, Law MG, Grey P, Cooper DA 2000 Lipodystrophy following antiretroviral therapy of primary HIV infection. AIDS 14:2406–2407[CrossRef][Medline]
34. Lo JC, Mulligan K, Tai VW, Algren H, Schambelan M 1998 Body shape changes in HIV-infected patients. J Acquired Immune Defic Syndr Hum Retrovirol 19:307–308[Medline]
35. Gervasoni C, Ridolfo AL, Trifiro G, Santambrogio S, Norbiato G, Musicco M, Clerici M, Galli M, Moroni M 1999 Redistribution of body fat in HIV-infected women undergoing combined antiretroviral therapy. AIDS 13: 465–471
36. McDermott AY, Shevitz A, Knox T, Roubenoff R, Kehayias J, Gorbach S 2001 Effect of highly active antiretroviral therapy on fat, lean, and bone mass in HIV-seropositive men and women. Am J Clin Nutr 74:679–686[Abstract/Free Full Text]
37. Brambilla P, Bricalli D, Sala N, Renzetti F, Manzoni P, Vanzulli A, Chiumello G, di Natale B, Vigano A 2001 Highly active antiretroviral-treated HIV-infected children show fat distribution changes even in absence of lipodystrophy. AIDS 15:2415–2422[CrossRef][Medline]
38. Huang JS, Rietschel P, Hadigan CM, Rosenthal DI, Grinspoon S 2001 Increased abdominal visceral fat is associated with reduced bone density in HIV-infected men with lipodystrophy. AIDS 15:975–982[CrossRef][Medline]
39. Stricker RB, Goldberg B 1999 "Buffalo humps" associated with protease inhibitors. Ann Intern Med 130:241–242[Free Full Text]
40. Moyle G, Baldwin C, Mandalia S, Comitis S, Burn P, Gazzard B 2001 Changes in metabolic parameters and body shape after replacement of protease inhibitor with efavirenz in virologically controlled HIV-1-positive persons: single-arm observational cohort. J Acquired Immune Defic Syndr 28:399–401
41. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, Gastaut JA, Touraine JL 1999 A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 13:1659–1667[CrossRef][Medline]
42. Hadigan C, Meigs JB, Corcoran C, Rietschel P, Piecuch S, Basgoz N, Davis B, Sax P, Stanley T, Wilson PW, D’Agostino RB, Grinspoon S 2001 Metabolic abnormalities and cardiovascular disease risk factors in adults with human immunodeficiency virus infection and lipodystrophy. Clin Infect Dis 32: 130–139
43. Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA 1999 Diagnosis, prediction, and natural course of HIV-1 protease-inhibitor-associated lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 353:2093–2099
44. Martinez E, Casamitjana R, Conget I, Gatell JM 1998 Protease inhibitor-associated hyperinsulinaemia. AIDS 12:2077–2079[Medline]
45. Martinez E, Gatell JM 1999 Metabolic abnormalities and body fat redistribution in HIV-1 infected patients: the lipodystrophy syndrome. Curr Opin Infect Dis 12:13–19
46. Sullivan AK, Feher MD, Nelson MR, Gazzard BG 1998 Marked hypertriglyceridaemia associated with ritonavir therapy. AIDS 12:1393–1394[Medline]
47. Di Perri G, Del Bravo P, Concia E 1998 HIV-protease inhibitors. N Engl J Med 339:773–774[Free Full Text]
48. Perry RC, Cushing HE, Deeg MA, Prince MJ 1999 Ritonavir, triglycerides, and pancreatitis. Clin Infect Dis 28:161–162[Medline]
49. Routy JP, Smith GHR, Blank DW, Gilfix BM 2001 Plasmapheresis in the treatment of an acute pancreatitis due to protease inhibitor-induced hypertriglyceridemia. J Clin Apheresis 16:157–159[CrossRef][Medline]
50. Behrens G, Dejam A, Schmidt H, Balks HJ, Brabant G, Korner T, Stoll M, Schmidt RE 1999 Impaired glucose tolerance, ß cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS 13:F63–F70
51. Domingo P, Perez A, Torres OH, Montiel JA, Vazquez G 1999 Lipodystrophy in HIV-1-infected patients. Lancet 354:868[CrossRef][Medline]
52. Thiebaut R, Dabis F, Malvy F, Jacqmin-Gadda H, Mercie P, Valentin VD 2000 Serum triglycerides, HIV infection, and highly active antiretroviral therapy. J Acquired Immune Defic Syndr 23:261–265
53. Periard D, Telenti A, Sudre P, Cheseaux JJ, Halfon P, Reymond MJ, Marcovina SM, Glauser MP, Nicod P, Darioli R, Mooser V 1999 Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation 100:700–705[Abstract/Free Full Text]
54. Purnell JQ, Zambon A, Knopp RH, Pizzuti DJ, Achari R, Leonard JM, Locke C, Brunzell JD 2000 Effect of ritonavir on lipids and post-heparin lipase activities in normal subjects. AIDS 14:51–57[CrossRef][Medline]
55. Sellmeyer DE, Grunfeld C 1996 Endocrine and metabolic disturbances in human immunodeficiency virus infection and the acquired immune deficiency syndrome. Endocr Rev 17:518–532[Abstract/Free Full Text]
56. Grunfeld C, Kotler DP, Hamadeh R, Tierney A, Wang J, Pierson RN 1989 Hypertriglyceridemia in the acquired immunodeficiency syndrome. Am J Med 86:27–31[Medline]
57. Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR 1992 Lipids, lipoproteins, triglyceride clearance, and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. J Clin Endocrinol Metab 74:1045–1052[Abstract]
58. Shor-Posner G, Basit A, Lu Y, Cabrejos C, Chang J, Fletcher M, Mantero-Atienza E, Baum MK 1993 Hypocholesterolemia is associated with immune dysfunction in early human immunodeficiency virus-1 infection. Am J Med 94:515–519[CrossRef][Medline]
59. Constans J, Pellegrin JL, Peuchant E, Dumon MF, Pellegrin I, Sergeant C, Simonoff M, Brossard G, Barbeau P, Fleury H, et al 1994 Plasma lipids in HIV-infected patients: a prospective study in 95 patients. Eur J Clin Invest 24:416–420[Medline]
60. Zangerle R, Sarcletti M, Gallati H, Reibnegger G, Wachter H, Fuchs D 1994 Decreased plasma concentrations of HDL cholesterol in HIV-infected individuals are associated with immune activation. J Acquired Immune Defic Syndr 7:1149–1156
61. Narciso P, Tozzi V, D’Offizi G, De Carli G, Orchi N, Galati V, Vincenzi L, Bellagamba R, Carvelli C, Puro V 2001 Metabolic and morphologic disorders in patients treated with highly active antiretroviral therapy since primary HIV infection. Ann NY Acad Sci 946:214–222[Medline]
62. Dever LL, Oruwari PA, Figueroa WE, O’Donovan CA, Eng RHK 2000 Hyperglycemia associated with protease inhibitors in an urban HIV-infected minority patient population. Ann Pharmacother 34:580–584[Abstract]
63. Dube MP, Edmondson-Melancon H, Qian D, Aqeel R, Johnson D, Buchanan TA 2001 Prospective evaluation of the effect of initiating indinavir-based therapy on insulin sensitivity and B-cell function in HIV-infected patients. J Acquired Immune Defic Syndr 27:130–134
64. Mulligan K, Grunfeld C, Tai VW, Algren H, Pang MY, Chernoff DN, Lo JC, Schambelan M 2000 Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquired Immune Defic Syndr 23:35–43
65. Lumpkin M 1997 Protease inhibitors may raise blood glucose levels. Am J Health Syst Pharm 54:1575[Free Full Text]
66. Eastone JA, Decker CF 1997 New-onset diabetes mellitus associated with use of protease inhibitor. Ann Intern Med 127:948[Free Full Text]
67. Dube MP, Johnson DL, Currier JS, Leedom JM 1997 Protease inhibitor-associated hyperglycaemia. Lancet 350:713–714[Medline]
68. Visnegarwala F, Krause KL, Musher DM 1997 Severe diabetes associated with protease inhibitor therapy. Ann Intern Med 127:947[Free Full Text]
69. Paterson DL, Singh N 1998 Exacerbated hyperglycemia associated with nelfinavir. Ann Pharmacother 32:609–610[CrossRef][Medline]
70. Rakotoambinina B, Medioni J, Rabian C, Jubault V, Jais JP, Viard JP 2001 Lipodystrophic syndromes and hyperlipidemia in a cohort of HIV-1-infected patients receiving triple combination antiretroviral therapy with a protease inhibitor. J Acquired Immune Defic Syndr 27:443–449
71. Vigouroux C, Gharakhanian S, Salhi Y, Nguyen TH, Chevenne D, Capeau J, Rozenbaum W 1999 Diabetes, insulin resistance and dyslipidaemia in lipodystrophic HIV-infected patients on highly active antiretroviral therapy (HAART). Diabetes Metab 25:225–232[Medline]
72. Galli M, Ridolfo AL, Adorni F, Gervasoni C, Ravasio L, Corsico L, Gianelli E, Piazza M, Vaccarezza M, Monforte AD, Moroni M 2002 Body habitus changes and metabolic alterations in protease inhibitor-naive HIV-1-infected patients treated with two nucleoside reverse transcriptase inhibitors. J Acquired Immune Defic Syndr 29:21–31
73. Kosmiski LA, Kuritzkes DR, Lichtenstein KA, Glueck DH, Gourley PJ, Stamm ER, Scherzinger AL, Eckel RH 2001 Fat distribution and metabolic changes are strongly correlated and energy expenditure is increased in the HIV lipodystrophy syndrome. AIDS 15:1993–2000[CrossRef][Medline]
74. Walli R, Herfort O, Michl GM, Demant T, Jager H, Dieterle C, Bogner JR, Landgraf R, Goebel FD 1998 Treatment with protease inhibitors associated with peripheral insulin resistance and impaired oral glucose tolerance in HIV-1-infected patients. AIDS 12:F167–F173
75. Mynarcik DC, McNurlan MA, Steigbigel RT, Fuhrer J, Gelato MC 2000 Association of severe insulin resistance with both loss of limb fat and elevated serum tumor necrosis factor receptor levels in HIV lipodystrophy. J Acquired Immune Defic Syndr 25:312–321
76. van der Valk M, Gisolf EH, Reiss P, Wit F, Japour A, Weverling GJ, Danner SA 2001 Increased risk of lipodystrophy when nucleoside analogue reverse transcriptase inhibitors are included with protease inhibitors in the treatment of HIV-1 infection. AIDS 15:847–855[CrossRef][Medline]
77. Schwarz JM, Mulligan K, Lee J, Lo JC, Wen M, Nook MA, Grunfeld C, Schambelan M 2002 Effects of recombinant human growth hormone on hepatic lipid and carbohydrate metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 87:942–945[Abstract/Free Full Text]
78. Hommes MJ, Romijn JA, Endert E, Eeftinck Schattenkerk JK, Sauerwein HP 1991 Insulin sensitivity and insulin clearance in human immunodeficiency virus-infected men. Metabolism 40:651–656[CrossRef][Medline]
79. Heyligenberg R, Romijn JA, Hommes MJ, Endert E, Eeftinck Schattenkerk JK, Sauerwein HP 1993 Non-insulin-mediated glucose uptake in human immunodeficiency virus-infected men. Clin Sci 84:209–216[Medline]
80. Martinez E, Mocroft A, Garcia-Viejo MA, Perez-Cuevas JB, Blanco JL, Mallolas J, Bianchi L, Conget I, Blanch J, Phillips A, Gatell JM 2001 Risk of lipodystrophy in HIV-1-infected patients treated with protease inhibitors: a prospective cohort study. Lancet 357:592–598[CrossRef][Medline]
81. Arpadi SM, Cuff PA, Horlick M, Wang J, Kotler DP 2001 Lipodystrophy in HIV-infected children is associated with high viral load and low CD4⁺- lymphocyte count and CD4⁺-lymphocyte percentage at baseline and use of protease inhibitors and stavudine. J Acquir Immune Defic Syndr 27:30–34
82. Babl FE, Regan AM, Pelton SI 1999 Abnormal body-fat distribution in HIV-1-infected children on antiretrovirals. Lancet 353:1243–1244
83. Jaquet D, Levine M, Ortega-Rodriguez E, Faye A, Polak M, Vilmer E, Levy-Marchal C 2000 Clinical and metabolic presentation of the lipodystrophic syndrome in HIV-infected children. AIDS 14:2123–2128[CrossRef][Medline]
84. Mallal SA, John M, Moore CB, James IR, McKinnon EJ 2000 Contribution of nucleoside analogue reverse transcriptase inhibitors to subcutaneous fat wasting in patients with HIV infection. AIDS 14:1309–1316[CrossRef][Medline]
85. Flexner C 1998 HIV-protease inhibitors. N Engl J Med 338:1281–1292[Free Full Text]
86. Carr A, Miller J, Law M, Cooper DA 2000 A syndrome of lipoatrophy, lactic acidaemia and liver dysfunction associated with HIV nucleoside analogue therapy: contribution to protease inhibitor-related lipodystrophy syndrome. AIDS 14:F25–F32
87. Chene G, Angelini E, Cotte L, Lang JM, Morlat P, Rancinan C, May T, Journot V, Raffi F, Jarrousse B, Grappin M, Lepeu G, Molina JM 2002 Role of long-term nucleoside-analogue therapy in lipodystrophy and metabolic disorders in human immunodeficiency virus-infected patients. Clin Infect Dis 34:649–657[CrossRef][Medline]
88. Saint-Marc T, Partisani M, Poizot-Martin I, Bruno F, Rouviere O, Lang JM, Gastaut JA, Touraine JL 1999 A syndrome of peripheral fat wasting (lipodystrophy) in patients receiving long-term nucleoside analogue therapy. AIDS 13:1659–1667
89. Molina JM, Chene G, Ferchal F, Journot V, Pellegrin I, Sombardier MN, Rancinan C, Cotte L, Madelaine I, Debord T, Decazes JM 1999 The ALBI trial: a randomized controlled trial comparing stavudine plus didanosine with zidovudine plus lamivudine and a regimen alternating both combinations in previously untreated patients infected with human immunodeficiency virus. J Infect Dis 180:351–358[CrossRef][Medline]
90. Muurahainen N, Pettit R, Kotler D, Falutz J, Santos G, Kleintop M, Glesby M, Abnormalities in HIV-associated lipodystrophy syndrome that vary by weight status [Abstract 63]. 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego, CA, 1999; p. 53
91. Shimokata H, Tobin JD, Muller DC, Elahi D, Coon PJ, Andres R 1989 Studies in the distribution of body fat. I. Effects of age, sex, and obesity. J Gerontol 44:M66–M73
92. Kehayias JJ, Fiatarone MA, Zhuang H, Roubenoff R 1997 Total body potassium and body fat: relevance to aging. Am J Clin Nutr 66:904–910[Abstract/Free Full Text]
93. Borkan GA, Hults DE, Gerzof SG, Robbins AH 1985 Comparison of body composition in middle-aged and elderly males using computed tomography. Am J Phys Anthropol 66:289–295[CrossRef][Medline]
94. Zamboni M, Armellini F, Harris T, Turcato E, Micciolo R, Bergamo-Andreis IA, Bosello O 1997 Effects of age on body fat distribution and cardiovascular risk factors in women. Am J Clin Nutr 66:111–115[Abstract/Free Full Text]
95. Mercie P, Tchamgoue S, Dabis F, Pellegrin JL 1999 Lipodystrophy in HIV-1-infected patients. Lancet 354:867–868[CrossRef]
96. Dulloo AG, Jacquet J, Girardier L 1996 Autoregulation of body composition during weight recovery in human: the Minnesota Experiment revisited. Int J Obes Relat Metab Disord 20:393–405[Medline]
97. Mulligan K, Tai VW, Schambelan M 1997 Cross-sectional and longitudinal evaluation of body composition in men with HIV infection. J Acquired Immune Defic Syndr Hum Retrovirol 15:43–48[Medline]
98. Williamson K, Reboli AC, Manders SM 1999 Protease inhibitor-induced lipodystrophy. J Am Acad Dermatol 40:635–636[CrossRef][Medline]
99. Yanovski JA, Miller KD, Kino T, Friedman TC, Chrousos GP, Tsigos C, Falloon J 1999 Endocrine and metabolic evaluation of human immunodeficiency virus-infected patients with evidence of protease inhibitor-associated lipodystrophy. J Clin Endocrinol Metab 84:1925–1931[Abstract/Free Full Text]
100. Bujalska IJ, Kumar S, Stewart PM 1997 Does central obesity reflect "Cushing’s disease of the omentum?" Lancet 349:1210–1213[CrossRef][Medline]
101. Bujalska IJ, Kumar S, Hewison M, Stewart PM 1999 Differentiation of adipose stromal cells: the roles of glucocorticoids and 11ß-hydroxysteroid dehydrogenase. Endocrinology 140:3188–3196[Abstract/Free Full Text]
102. Rebuffe-Scrive M, Bronnegard M, Nilsson A, Eldh J, Gustafsson JA, Bjorntorp P 1990 Steroid hormone receptors in human adipose tissues. J Clin Endocrinol Metab 71:1215–1219[Abstract/Free Full Text]
103. Carr A, Samaras K, Chisholm DJ, Cooper DA 1998 Pathogenesis of HIV-1-protease inhibitor-associated peripheral lipodystrophy, hyperlipidaemia, and insulin resistance. Lancet 351:1881–1883[CrossRef][Medline]
104. Li E, Norris AW 1996 Structure/function of cytoplasmic vitamin A-binding proteins. Annu Rev Nutr 16:205–234[CrossRef][Medline]
105. Chambon P 1996 A decade of molecular biology of retinoic acid receptors. FASEB J 10:940–954[Abstract]
106. Tontonoz P, Hu E, Spiegelman BM 1995 Regulation of adipocyte gene expression and differentiation by peroxisome proliferator activated receptor gamma. Curr Opin Genet Dev 5:571–576[CrossRef][Medline]
107. Stevens GJ, Chen M, Grecko R, Lankford A, Lee C, Harr J, Rose PW, Investigations into proposed mechanisms of HIV-associated peripheral lipodystrophy, hyperlipidemia and insulin resistance [Abstract 29]. 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego, CA, 1999; p. 34
108. Lenhard JM, Furfine ES, Jain RG, Ittoop O, Orband-Miller LA, Blanchard SG, Paulik MA, Weiel JE 2000 HIV protease inhibitors block adipogenesis and increase lipolysis in vitro. Antiviral Res 47:121–129[CrossRef][Medline]
109. Zhang B, MacNaul K, Szalkowski D, Li Z, Berger J, Moller DE 1999 Inhibition of adipocyte differentiation by HIV protease inhibitors. J Clin Endocrinol Metab 84:4274–4277[Abstract/Free Full Text]
110. Rohlmann A, Gotthardt M, Hammer RE, Herz J 1998 Inducible inactivation of hepatic LRP gene by cre-mediated recombination confirms role of LRP in clearance of chylomicron remnants. J Clin Invest 101:689–695[Medline]
111. Martinez E, Gatell J 1998 Metabolic abnormalities and use of HIV-1 protease inhibitors. Lancet 352:821–822[Medline]
112. Stricker RB, Goldberg B 1998 Fat accumulation and HIV-1 protease inhibitors. Lancet 352:1392[Medline]
113. Schindler JT, Spooner KM, Decker CF 1998 "Buffalo humps" associated with protease inhibitors. Ann Intern Med 129:164[Free Full Text]
114. Domingo P, Matias-Guiu X, Pujol RM, Francia E, Lagarda E, Sambeat MA, Vazquez G 1999 Subcutaneous adipocyte apoptosis in HIV-1 protease inhibitor-associated lipodystrophy. AIDS 13:2261–2267[CrossRef][Medline]
115. Domingo P, Matias-Guiu X, Pujol RM, Domingo JC, Arroyo JA, Sambeat MA, G V 2001 Switching to nevirapine decreases insulin levels but does not improve subcutaneous adipocyte apoptosis in patients with highly active antiretroviral therapy-associated lipodystrophy. J Infect Dis 184:1197–1201[CrossRef][Medline]
116. Wentworth JM, Burris TP, Chatterjee VK 2000 HIV protease inhibitors block human preadipocyte differentiation, but not via the PPAR/RXR heterodimer. J Endocrinol 164:R7–R10
117. Dowell P, Flexner C, Kwiterovich PO, Lanes MD 2000 Suppression of preadipocyte differentiation and promotion of adipocyte death by HIV protease inhibitors. J Biol Chem 275:41325–41332[Abstract/Free Full Text]
118. Bastard JP, Caron M, Vidal H, Jan V, Auclair M, Vigouroux C, Luboinski J, Laville M, Malachi M, Girard PM, Rozenbaum W, Levan P, Capeau J 2002 Association between altered expression of adipogenic factor SREBP1 in lipoatrophic adipose tissue from HIV-1-infected patients and abnormal adipocyte differentiation and insulin resistance. Lancet 359:1026–1031[CrossRef][Medline]
119. Riddle TM, Kuhel DG, Woollett LA, Fichtenbaum CJ, Hui DY 2001 HIV protease inhibitor induces fatty acid and sterol biosynthesis in liver and adipose tissues due to the accumulation of activated sterol regulatory element-binding proteins in the nucleus. J Biol Chem 276:37514–37519[Abstract/Free Full Text]
120. Nguyen AT, Gagnon A, Angel JB, Sorisky A 2000 Ritonavir increases the level of active ADD-1/SREBP-1 protein during adipogenesis. AIDS 14:2467–2473[CrossRef][Medline]
121. Caron M, Auclair M, Vigouroux C, Glorian M, Forest C, Capeau J 2001 The HIV protease inhibitor indinavir impairs sterol regulatory element-binding protein-1 intranuclear localization, inhibits preadipocyte differentiation, and induces insulin resistance. Diabetes 50:1378–1388[Abstract/Free Full Text]
122. Shimomura I, Hammer RE, Richardson JA, Ikemoto S, Bashmakov Y, Goldstein JL, Brown MS 1998 Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev 12:3182–3194[Abstract/Free Full Text]
123. Murata H, Hruz PW, Mueckler M 2000 The mechanism of insulin resistance caused by HIV protease inhibitor therapy. J Biol Chem 275:20251–20254[Abstract/Free Full Text]
124. Ranganathan S, Kern PA 2002 The HIV protease inhibitor saquinavir impairs lipid metabolism and glucose transport in cultured adipocytes. J Endocrinol 172:155–162[Abstract]
125. Nolte LA, Yarasheski KE, Kawanaka K, Fisher J, Le N, Holloszy JO 2001 The HIV protease inhibitor indinavir decreases insulin- and contraction-stimulated glucose transport in skeletal muscle. Diabetes 50:1397–1401[Abstract/Free Full Text]
126. Murata H, Hruz PW, Mueckler M 2002 Indinavir inhibits the glucose transporter isoform Glut4 at physiologic concentrations. AIDS 16:859–863[CrossRef][Medline]
127. Puro V, Ippolito C 2000 Effect of antiretroviral agents on T-lymphocyte subset counts in healthy HIV-negative individuals. AIDS 24:440–443
128. Liang JS, Distler O, Cooper DA, Jamil H, Deckelbaum RJ, Ginsberg HN, Sturley SL 2001 HIV protease inhibitors protect apolipoprotein B from degradation by the proteasome: a potential mechanism for protease inhibitor-induced hyperlipidemia. Nat Med 12:1327–1331
129. Cao H, Hegele RA 2000 Nuclear lamin A/C R482Q mutation in Canadian kindreds with Dunnigan-type familial partial lipodystrophy. Hum Mol Genet 9:109–112[Abstract/Free Full Text]
130. Speckman RA, Garg A, Du F, Bennett L, Veile R, Arioglu E, Taylor SI, Lovett M, Bowcock AM 2000 Mutational and haplotype analyses of families with familial partial lipodystrophy (Dunnigan variety) reveal recurrent missense mutations in the globular C-terminal domain of lamin A/C. Am J Hum Genet 66:1192–1198[CrossRef][Medline]
131. Agarwal AK, Garg A 2002 A novel heterozygous mutation in peroxisome proliferator-activated receptor-gamma gene in a patient with familial partial lipodystrophy. J Clin Endocrinol Metab 87:408–411[Abstract/Free Full Text]
132. Agarwal AK, Arioglu E, de Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A 2002 AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 31:21–23[CrossRef][Medline]
133. Magre J, Delepine M, Khallouf E, Gedde-Dahl Jr T, Van Maldergem L, Sobel E, Papp J, Meier M, Megarbane A, Bachy A, Verloes A, d’Abronzo FH, Seemanova E, Assan R, Baudic N, Bourut C, Czernichow P, Huet F, Grigorescu F, de Kerdanet M, Lacombe D, Labrune P, Lanza M, Loret H, Matsuda F, Navarro J, Nivelon-Chevalier A, Polak M, Robert JJ, Tric P, Tubiana-Rufi N, Vigouroux C, Weissenbach J, Savasta S, Maassen JA, Trygstad O, Bogalho P, Freitas P, Medina JL, Bonnicci F, Joffe BI, Loyson G, Panz VR, Raal FJ, O’Rahilly S, Stephenson T, Kahn CR, Lathrop M, Capeau J 2001 Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat Genet 28:365–370[CrossRef][Medline]
134. Garg A, Stray-Gundersen J, Parsons D, Bertocci LA 2000 Skeletal muscle morphology and exercise response in congenital generalized lipodystrophy. Diabetes Care 23:1545–1550[Abstract]
135. Szczepaniak LS, Babcock EE, Schick F, Dobbins RL, Garg A, Burns DK, McGarry JD, Stein DT 1999 Measurement of intracellular triglyceride stores by H-1 spectroscopy: validation in vivo. Am J Physiol 276:E977–E989
136. Brinkman K, Smeitink JA, Reiss P 1999 Mitochondria toxicity induced by nucleoside-analogue reverse-transcriptase inhibitors is a key factor in the pathogenesis of antiretroviral-therapy-related lipodystrophy. Lancet 354:1112–1115[CrossRef][Medline]
137. Enzi G 1984 Multiple symmetric lipomatosis: an updated clinical report. Medicine 63:56–64[CrossRef][Medline]
138. Klopstock T, Naumann M, Seibel P, Shalke B, Reiners K, Reichmann H 1997 Mitochondrial DNA mutations in multiple symmetric lipomatosis. Mol Cell Biochem 174:271–275[CrossRef][Medline]
139. Campos Y, Martin MA, Navarro C, Gordo P, Arenas J 1996 Single large-scale mitochondrial DNA deletion in a patient with mitochondrial myopathy associated with multiple symmetric lipomatosis. Neurology 47:1012–1014[Abstract/Free Full Text]
140. Naumann M, Kiefer R, Toyka KV, Sommer C, Seibel P, Reichmann H 1997 Mitochondrial dysfunction with myoclonus epilepsy and ragged-red fibers point mutation in nerve, muscle, and adipose tissue of a patient with multiple symmetric lipomatosis. Muscle Nerve 20:833–839[CrossRef][Medline]
141. Gamez J, Playan A, Andreu AL, Bruno C, Navarro C, Cervera C, Arbos MA, Schwartz S, Enriquez JA, Montoya J 1998 Familial multiple symmetric lipomatosis associated with the A8344G mutation of mitochondrial DNA. Neurology 51:258–260[Abstract/Free Full Text]
142. Klopstock T, Naumann M, Schalke B, Bischof F, Seibel P, Kottlors M, Eckert P, Reiners K, Toyka KV, Reichmann H 1994 Multiple symmetric lipomatosis: abnormalities in complex IV and multiple deletions in mitochondrial DNA. Neurology 44:862–866[Abstract/Free Full Text]
143. Dalakas MC, Illa I, Pezeshkpour GH, Laukaitis JP, Cohen B, Griffin JL 1990 Mitochondrial myopathy caused by long-term zidovudine therapy. N Engl J Med 322:1098–1105[Abstract]
144. Chen CH, Vazquez-Padua M, Cheng YC 1991 Effect of anti-human immunodeficiency virus nucleoside analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol 39:625–628[Abstract]
145. Mhiri C, Baudrimont M, Bonne G, Geny C, Degoul F, Marsac C, Roullet E, Gherardi R 1991 Zidovudine myopathy: a distinctive disorder associated with mitochondrial dysfunction. Ann Neurol 29:606–614[CrossRef][Medline]
146. Gopinath R, Hutcheon M, Cheema-Dhadli S, Halperin M 1992 Chronic lactic acidosis in a patient with acquired immunodeficiency syndrome and mitochondrial myopathy: biochemical studies. J Am Soc Nephrol 3:1212–1219[Abstract]
147. Bissuel F, Bruneel F, Habersetzer F, Chassard D, Cotte L, Chevallier M, Bernuau J, Lucet JC, Trepo C 1994 Fulminant hepatitis with severe lactate acidosis in HIV-infected patients on didanosine therapy. J Intern Med 235:367–371[Medline]
148. Sundar K, Suarez M, Banogon PE, Shapiro JM 1997 Zidovudine-induced fatal lactic acidosis and hepatic failure in patients with acquired immunodeficiency syndrome: report of two patients and review of the literature. Crit Care Med 25:1425–1430[CrossRef][Medline]
149. Roy PM, Gouello JP, Pennison-Besnier I, Chennebault JM 1999 Severe lactic acidosis induced by nucleoside analogues in an HIV-infected man. Ann Emerg Med 34:282–284[CrossRef][Medline]
150. Kakuda TN, Brundage RC, Anderson PL, Fletcher CV 1999 Nucleoside reverse transcriptase inhibitor-induced mitochondrial toxicity as an etiology for lipodystrophy. AIDS 13:2311–2312[CrossRef][Medline]
151. Ruzicka T, Vieluf D, Landthaler M, Braun-Falco O 1987 Benign symmetric lipomatosis Launois-Bensaude. Report of ten cases and review of the literature. J Am Acad Dermatol 17:663–674[Medline]
152. Greene ML, Glueck CJ, Fujimoto WY, Seegmiller JE 1970 Benign symmetric lipomatosis (Launois-Bensaude adenolipomatosis) with gout and hyperlipoproteinemia. Am J Med 48:239–246[CrossRef][Medline]
153. Enzi G, Favaretto L, Martini S, Fellin R, Baritussio A, Baggio G, Crepaldi G 1983 Metabolic abnormalities in multiple symmetric lipomatosis: elevated lipoprotein lipase activity in adipose tissue with hyperalphalipoproteinemia. J Lipid Res 24:566–574[Abstract]
154. Deiana L, Pes GM, Carru C, Campus GV, Tidore MG, Cherchi GM 1993 Extremely high HDL levels in a patient with multiple symmetric lipomatosis. Clin Chim Acta 223:143–147[CrossRef][Medline]
155. Enzi G, Angelini C, Negrin P, Armani M, Pierobon S, Fedele D 1985 Sensory, motor, and autonomic neuropathy in patients with multiple symmetric lipomatosis. Medicine 64:388–393[Medline]
156. Roubenoff R, Weiss L, McDermott A, Heflin T, Cloutier GJ, Wood M, Gorbach S 1999 A pilot study of exercise training to reduce trunk fat in adults with HIV-associated fat redistribution. AIDS 13:1373–1375[CrossRef][Medline]
157. Jones SP, Doran DA, Leat PB, Maher B, Pirmohamed M 2001 Short-term exercise training improves body composition and hyperlipidaemia in HIV-positive individuals with lipodystrophy. AIDS 15:2049–2051[CrossRef][Medline]
158. Yarasheski KE, Tebas P, Stanerson E, Claxton S, Marin D, Bae K, Kennedy M, Tantisiriwat W, Powderly WG 2001 Resistance exercise training reduces hypertriglyceridemia in HIV-infected men treated with antiviral therapy. J Appl Physiol 90:133–138[Abstract/Free Full Text]
159. Roubenoff R, Schmitz H, Bairos L, Layne J, Potts E, Cloutier GJ, Denry F 2002 Reduction of abdominal obesity in lipodystrophy associated with human immunodeficiency virus infection by means of diet and exercise: case report and proof of principle. Clin Infect Dis 34:390–393[CrossRef][Medline]
160. Brunzell JD 2001 Deficiencies of lipoprotein lipase, Apo C-II, and hepatic lipase. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular basis of inherited diseases, 8th Ed. New York, Toronto: McGraw-Hill; 2789–2816
161. Garg A, Bonanome A, Grundy SM, Zhang ZJ, Unger RH 1988 Comparison of a high-carbohydrate diet with a high-monounsaturated-fat diet in patients with non-insulin-dependent diabetes mellitus. N Engl J Med 391:829–834
162. Garg A, Bantle JP, Henry RR, Coulston AM, Griver KA, Raatz SK, Brinkley L, Chen Y-DI, Grundy SM, Huet BA, Reaven GM 1994 Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus. JAMA 271:1421–1428[Abstract/Free Full Text]
163. O’Mahony C, Price LM, Nelson M 1998 Lipodystrophy despite anabolic steroids. Int J STD AIDS 9:619[Free Full Text]
164. Stocker DN, Meier PJ, Stoller R, Fattinger KE 1998 "Buffalo hump" in HIV-1 infection. Lancet 352:320–321
165. Roge BT, Katzenstein TL, Gerstoft J 2001 Comparison of p-triglyceride levels among patients with human immunodeficiency virus on randomized treatment with ritonavir, indinavir or ritonavir/saquinavir. Scand J Infect Dis 33:306–311[CrossRef][Medline]
166. Martinez E, Conget I, Lozano L, Casamitjana R, Gatell JM 1999 Reversion of metabolic abnormalities after switching from HIV-1 protease inhibitors to nevirapine. AIDS 13:805–810[CrossRef][Medline]
167. Ruiz L, Negredo E, Domingo P, Paredes R, Francia E, Balague M, Gel S, Bonjoch A, Fumaz CR, Johnston S, Romeu J, Lange J, Clotet B 2001 Antiretroviral treatment simplification with nevirapine in protease inhibitor-experienced patients with HIV-associated lipodystrophy. J Acquir Immune Defic Syndr 27:229–236
168. Aldeen T, Wells C, Hay P, Davidson F, Lau R 1999 Lipodystrophy associated with nevirapine-containing antiretroviral therapies. AIDS 13:865–867[CrossRef][Medline]
169. Carr A, Thorisdottir A, Samaras K, R. KG, Chisholm DJ, Cooper DA 1999 Reversibility of protease inhibitor (PI) lipodystrophy syndrome on stopping PIs or switching to nelfinavir [Abstract 668]. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, IL, 1999; p. 193
170. Stryker R, Skiest D, Tashima K, Staszewski S, Villano SA, Labriola DF, Ruiz NM, Lack of clinical lipodystrophy in patients receiving efavirenz plus NRTIs in study 006 [Abstract 39]. First International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego, CA, 1999; p. 40
171. Martinez E, Garcia-Viejo MA, Blanco JL, Bianchi L, Buira E, Conget I, Casamitjana R, Mallolas J, Gatell JM 2000 Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy. Clin Infect Dis 31:1266–1273[CrossRef][Medline]
172. Saint-Marc T, Touraine JL 1999 The effects of discontinuing stavudine therapy on clinical and metabolic abnormalities in patients suffering from lipodystrophy. AIDS 13:2188–2189[CrossRef][Medline]
173. Walli R, Michl GM, Bogner JR, Goebel FD 2001 Improvement of HAART-associated insulin resistance and dyslipidemia after replacement of protease inhibitors with abacavir. Eur J Med Res 6:413–421[Medline]
174. Carr A, Hudson J, Chuah J, Mallal S, Law M, Hoy J, Doong N, French M, Smith D, Cooper DA 2001 HIV protease inhibitor substitution in patients with lipodystrophy: a randomized, controlled, open-label, multicentre study. AIDS 15:1811–1822[CrossRef][Medline]
175. Torres RA, Unger KW, Cadman JA, Kassous JY 1999 Recombinant human growth hormone improves truncal adiposity and ’buffalo humps’ in HIV-positive patients on HAART. AIDS 13:2479–2481
176. Wanke C, Gerrior J, Kantaros J, Coakley E, Albrecht M 1999 Recombinant human growth hormone improves the fat redistribution syndrome (lipodystrophy) in patients with HIV. AIDS 13:2099–2103[CrossRef][Medline]
177. Lo JC, Mulligan K, Noor MA, Schwarz JM, Halvorsen RA, Grunfeld C, Schambelan M 2001 The effects of recombinant human growth hormone on body composition and glucose metabolism in HIV-infected patients with fat accumulation. J Clin Endocrinol Metab 86:3480–3487[Abstract/Free Full Text]
178. Gold J, Batterham M 1999 Nandrolone decanoate; use in HIV-associated lipodystrophy syndrome: a pilot study. Int J STD, AIDS 10:558[CrossRef][Medline]
179. Marin P 1995 Testosterone and regional fat distribution. Obes Res 3:S609–S612
180. Rohrich RJ, Kenkel JM 1999 Suction-assisted lipectomy for lipodystrophy syndromes attributed to HIV-protease inhibitor use: discussion. Plast Reconstr Surg 104:1821–1822[CrossRef]
181. Wolfort FG, Cetrulo CL, Nevarre DR 1999 Suction-assisted lipectomy for lipodystrophy syndromes attributed to HIV-protease inhibitor use. Plast Reconstr Surg 104:1814–1820[Medline]
182. Henry K, Melroe H, Huebesch J, Hermundson J, Simpson J 1998 Atorvastatin and gemfibrozil for protease-inhibitor-related lipid abnormalities. Lancet 352:1031–1032[CrossRef][Medline]
183. Hewitt RG, Shelton MJ, Esch LD 1999 Gemfibrozil effectively lowers protease inhibitor-associated hypertriglyceridemia in HIV-1-positive patients. AIDS 13:868–869[CrossRef][Medline]
184. Calza L, Manfredi R, Chiodo F 2002 Use of fibrates in the management of hyperlipidemia in HIV-infected patients receiving HAART. Infection 30:26–31[CrossRef][Medline]
185. Fichtenbaum CJ, Gerber JG, Rosenkranz SL, Segal Y, Aberg JA, Blaschke T, Alston B, Fang F, Kosel B, Aweeka F 2002 Pharmacokinetic interactions between protease inhibitors and statins in HIV seronegative volunteers. AIDS 16:569–577[CrossRef][Medline]
186. Amacher DE, Beck R, Schomaker SJ, Kenny CV 1997 Hepatic microsomal enzyme induction, ß-oxidation, and cell proliferation following administration of clofibrate, gemfibrozil, or bezafibrate in the Cd rat. Toxicol Appl Pharmacol 142:143–150[CrossRef][Medline]
187. Saint-Marc T, Touraine JL 1999 Effects of metformin on insulin resistance and central adiposity in patients receiving effective protease inhibitor therapy. AIDS 13:1000–1002[CrossRef][Medline]
188. Hadigan C, Corcoran C, Basgoz N, Davis B, Sax P, Grinspoon S 2000 Metformin in the treatment of HIV lipodystrophy syndrome: a randomized controlled trial. JAMA 84:472–477
189. Goebel FD, Walli R, ART-associated insulin resistance: frequency, potential cause and possible therapeutic interventions [Abstract 5]. 1st International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV, San Diego, CA, 1999; p. 7
190. Walli R, Michl GM, Muhlbayer D, Brinkmann L, Goebel FD 2000 Effects of troglitazone on insulin sensitivity in HIV-infected patients with protease inhibitor-associated diabetes mellitus. Res Exp Med 199:253–262[CrossRef][Medline]
191. Sutinen J, Hakkinen AM, Westerbacka J, Vehkavaara S, Halavaara J, Jarvinen A, Ristola M, Yki-Jarvinen H, Rosiglitazone in the treatment of HAART-associated lipodystrophy (HAL): randomized, double-blind, placebo-controlled study. 9th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, 2002, p 101
192. Lichtenstein KA, Ward DJ, Moorman AC, Delaney KM, Young B, Palella Jr FJ, Rhodes PH, Wood KC, Holmberg SD, Investigators HIVOS 2001 Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS 15:1389–1398[CrossRef][Medline]
193. Wurtz R, Ceaser S 2000 Adipose redistribution in human immunodeficiency virus-seropositive patients: association with CD4 response. Clin Infect Dis 31:1497–1498[CrossRef][Medline]
194. Capiluppi B, Ciuffreda D, Sciandra M, Marroni M, Tambussi G, Lazzarin A 2000 Metabolic disorders in a cohort of patients treated with highly aggressive antiretroviral therapies during primary HIV-1 infection. AIDS 14:1861–1862[CrossRef][Medline]
195. Lichtenstein KA, Ward DJ, Moorman AC, Delaney KM, Young B, Palella FJ, Rhodes PH, Wood KC, Holmberg SD 2001 Clinical assessment of HIV-associated lipodystrophy in an ambulatory population. AIDS 15:1389–1398
196. Thiebaut R, Dequae-Merchadou L, Ekouevi DK M, P., Malvy D, Neau D, Dabis F 2001 Incidence and risk factors of severe hypertriglyceridaemia in the era of highly active antiretroviral therapy: the Aquitaine Cohort, France, 1996–99. HIV Med 2:84–88[CrossRef][Medline]
197. Tsiodras S, Mantzoros C, Hammer S, Samore M 2000 Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study. Arch Intern Med 160:2050–2056[Abstract/Free Full Text]

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