Fat Loss, Fat Gain and Related Metabolic Abnormalities in HIV-Infected Patients Receiving Highly Active Antiretroviral Therapy (HAART)

S. Grinspoon<sup>1

1</sup> Neuroendocrine Unit, Massachusetts General Hospital, Bulfinch 457B, Fruit St. Boston MA 02114

E-mail: sgrinspoon@partners.org

Keywords: Adipocyte, Visceral Fat, Subcutaneous Fat, HIV, Insulin, Cholesterol, Cardiovascular Risk

Q: What are the anthropometric abnormalities seen in HIV-infected patients receiving highly active antiretroviral therapy?

Recent studies using detailed body composition assessments, including dual energy X-ray absorptiometry, cross-sectional CT and whole body MRI, demonstrate reduced subcutaneous fat (face, arms, legs, abdomen) and increased abdominal visceral fat in a large subset of HIV-infected patients receiving highly active antiretroviral therapy (1-3). The estimates of prevalence vary widely, depending on definition, but range upward from one quarter to half of all such patients in the US (4). An even larger number of patients may be affected with subclinical changes in fat distribution. Discrete subcutaneous fat deposits, particularly in the dorsocervical area have been described (5). The phenotypic expression of these changes is not uniform, and a minority of patients exhibit pure fat atrophy, a second group demonstrates increased abdominal visceral adiposity alone, and a third, larger, group demonstrates both abnormalities (6). Although, increased visceral fat has been described in patients investigated prior to the current era of HAART (7), most studies suggest that the changes in body composition are associated with use of the two major classes of antiretroviral drugs, nucleoside reverse transcriptase inhibitors (NRTI's) and protease inhibitors (PI's) (8). Use of both such agents simultaneously may result in the most severe changes in body composition.

Q: What is the mechanism for the abnormalities in fat distribution among HIV-infected patients?

The mechanism for fat loss and gain in HIV-infected patients remains unknown. In vitro studies to date suggest potential effects of PI's to decrease adipogenesis, but no unifying hypothesis has thus far emerged. Furthermore, sequence homology of the PI's to lipoprotein-related protein (LRP) suggests a potential effect of the PI's on lipid clearance, but the clinical importance of this observation remains unknown (9). Alternatively, NRTI's may inhibit DNA polymerase gamma, decreasing oxidative phosphorylation. However, no specific link between any effects of NRTI therapy on DNA polymerase gamma and clinical fat loss has thus far been demonstrated. Of note, some studies suggest that drug exposure alone is not sufficient to result in changes in fat distribution (10). Potential interactions with immune function, cytokines and other mediators have been postulated. For example, increased soluble Type 2 TNF-alpha receptor levels were seen in one study of HIV-infected men, and related to the severity of extremity fat loss (11). It remains unknown whether subcutaneous fat loss is linked physiologically to excess visceral fat among affected patients. Research is now ongoing to determine the mechanisms of subcutaneous fat loss and visceral fat gain in HIV-infected patients.

Q: What metabolic abnormalities and complications are seen among HIV-infected patients with fat redistribution, and what is the relationship of metabolic changes to fat redistribution in this population?

An emerging body of evidence suggests significant abnormalities in lipid metabolism and glucose homeostasis among HIV-infected patients with fat redistribution (6). Lipid disorders are seen frequently among HIV-infected patients. Prior to the era of HAART, hypertriglyceridemia was commonly seen among HIV infected patients (12). Increased hepatic VLDL synthesis and decreased triglyceride clearance were seen (13). More recently, severe hypertriglyceridemia has been demonstrated, particularly among patients receiving protease inhibitors. The unique effects of PI to increase serum triglyceride concentrations has also been shown among non HIV-infected patients (14). Individual PI's may have varying effect on triglyceride synthesis. Among HIV-infected patients with fat redistribution, defined based on loss of extremity fat or increased truncal fat, increased triglyceride, low HDL and increased cholesterol to HDL ratio are seen (6).

Insulin resistance and impaired glucose tolerance are commonly seen among HIV-infected patients with fat redistribution, receiving highly active antiretroviral therapy (6,11,15). A number of studies suggest that HIV-infected patients with fat redistribution demonstrate fasting hyperinsulinemia, with normal fasting glucose levels. Decreased glucose uptake has been shown on clamp studies, indicating insulin resistance. Compared to age and BMI-matched patients in the Framingham Offspring Study, the relative risks of impaired glucose tolerance and diabetes mellitus were 10.0 and 16.1, respectively (6). A number of potential mechanisms may contribute to insulin resistance in HIV-infected patients. Recently completed in vitro studies suggest that protease inhibitors inhibit Glut-4 mediated glucose transport, by an as yet unknown mechanism (16). Glut-4 translocation to the cell surface and insulin receptor and post receptor phosphorylation were not disturbed with exposure to PI. Similarly, recent in vivo studies conducted in non HIV-infected patients demonstrated that exposure to Indinavir over 4 weeks increased insulin resistance as assessed by euglycemic, hyperinsulinemic clamp (17). In addition, changes in body composition may also contribute to insulin resistance. Fasting insulin levels are most increased among patients with significant peripheral fat loss and increased abdominal visceral adiposity, whereas patients with either fat loss or increased visceral adiposity alone, demonstrate lesser degrees of hyperinsulinemia (6). Potential mediators of insulin resistance among such patients include increased fatty acid levels and increased cytokines, such as TNF-alpha. The percentage of HIV-infected patients with significant insulin resistance and impaired glucose tolerance that will develop overt diabetes mellitus remains unknown.

Q: Is there evidence for increased cardiovascular risk among patients with fat redistribution receiving highly active antiretroviral therapy?

Longitudinal studies have not yet been performed to firmly establish whether such patients are at increased risk for cardiovascular disease. Cross-sectional studies demonstrate marked increases in triglyceride levels, and thrombotic markers such as tissue plasminogen activator (tPA) and plasminogen activator inhibitor I (PAI-1), reduced HDL as well as modest increases in LDL and diastolic blood pressure (6,18). In cross-sectional studies, increased carotid intimal-medial thickness has been shown among HIV-infected men exposed to PI's (19). Recent data from France demonstrated a substantially increased risk of myocardial infarction among French HIV-infected patients receiving a PI for > 30 months compared to < 18 months (20). In contrast, among 4541 persons followed from 1996 to 2000 in the Kaiser Permanente system, coronary heart disease event rates were not significantly different among PI vs. non-PI users (5.8 vs. 5.2 event rates/1000 PY, but overall CHD event rates were higher in the HIV-infected patients compared to the control subjects (event rate: 2.8/1000 PY of follow-up) (21). Further longitudinal studies with larger numbers of patients are needed to determine whether HIV-infected patients in the era of HAART are at increased risk for MI or CHD secondary to increased risk factors.

Q: What strategies can be used to reverse the body composition changes and associated metabolic abnormalities in HIV-infected patients.

Antiretroviral switching strategies designed to substitute an NNRTI or NRTI for a PI may be useful among patients with severe hypertriglyceridemia (22), but effects on insulin resistance and body composition have not been adequately investigated. As PI's may contribute directly to insulin resistance, use of this class of agent among patients with severe glucose intolerance should be individualized, and glucose checked frequently in such patients. Insulin sensitizing agents, such as metformin, may be of use in the large population of patients with severe insulin resistance. Metformin has been shown to significantly decrease insulin, waist circumference, diastolic blood pressure and tPA and PAI, thereby improving the cardiovascular risk profile in such patients (23). The thiazolidinediones (TZD's) have been shown to increase subcutaneous fat and reduce visceral fat among non HIV-infected patients with congenital lipodystrophy (24), and similarly, use of the TZD's is also under investigation in HIV-infected patients with fat redistribution and insulin resistance. Growth hormone (GH) has also been proposed for such patients because of it's lipolytic effects on visceral fat, but GH administration promotes further insulin resistance (25). Additional studies are necessary to determine the safety and efficacy of lower doses of GH in HIV-infected patients with fat redistribution.

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