Clinical perspectives on HIV-associated lipodystrophy syndrome: an update (2001)

Introduction In developed countries, the availability of highly active antiretroviral therapy (HAART) has contributed to a dramatic decrease in mortality and opportunistic infections associated with HIV/AIDS. However, as patients have begun to live longer, new complications have emerged. Over the last several years, clinicians have seen perplexing changes in fat distribution and metabolism. These changes manifest in varying combinations as lipoatrophy, lipohypertrophy, or both in localized areas, frequently in association with dyslipidemia and disturbances in glucose homeostasis [1–6] (Table 1).Table 1: Physical and metabolic changes associated with HIV-associated adipose redistribution syndrome. Often, the alterations are associated with HAART regimens that include protease inhibitors (PI), but both lipoatrophy and lipohypertrophy have been described in patients taking PI-sparing regimens [1,7–10]. Many other contributing factors have been proposed, including duration of antiretroviral therapy, duration of HIV infection, change in viral load, age, gender, and ethnicity [4,10–20]. Consequences for patients include disfiguring alterations in body shape, e.g., increased abdominal girth, enlargement of the dorsocervical fat pad, wasting in the extremities (Table 1), which could discourage adherence to antiretroviral treatment regimens. Furthermore, the mere possibility that such changes may develop could deter treatment initiation. Dyslipidemia, including increased triglycerides, increased total cholesterol and low density lipoprotein (LDL) cholesterol, and decreased high density lipoprotein (HDL) cholesterol (Table 1), has raised concern about increased risk for atherogenesis and atherosclerotic vascular disease [21]. Patients also may develop problems with glucose homeostasis, even in the absence of morphological changes, that may lead to diabetes mellitus and diabetes-associated health problems [22,23]. The prevalence of morphological and metabolic abnormalities among HIV-infected patients is not firmly established. Estimates vary widely, possibly because of variations in study methodology, defining criteria, treatment regimens, and patient populations [24]. Estimates of abnormalities in fat distribution range from as low as 2%[25] to as high as 84%[13] of patients taking a PI (Table 2). Between 15% and 30% of HIV-infected patients have dyslipidemia; estimates approach 60% in patients taking a PI [26]. Impaired glucose tolerance has been reported in 47% of patients on PI treatment [27]. The prevalence of hyperglycemia has been estimated at 3–5% in patients receiving a PI; approximately 1% of these patients have clinical evidence of diabetes. [28–30]. However, systematic studies are needed to determine more accurately the prevalence of hyperinsulinemia, insulin resistance, glucose intolerance, and diabetes among patients with HIV [13,24,31].Table 2: Prevalence estimates of body composition changes in patients with HIV infection. It is unclear, and a matter of some controversy, whether the changes in body habitus and metabolic abnormalities represent separate conditions or a single syndrome, referred to variously as lipodystrophy syndrome, fat maldistribution syndrome, PI- or HAART-associated lipodystrophy, or HIV-associated adipose redistribution syndrome (HARS) [21]. What has become clear is that standard approaches are needed for diagnosing and assessing the disorder(s) to facilitate the clinical research necessary for developing treatments and guidelines that can help to improve the health and quality of life of people with HIV [32]. This review focuses on the most current information available on fat maldistribution and metabolic changes observed in people with HIV infection. We begin with an overview of findings from several cohort investigations underway worldwide. Factors and mechanisms thought to contribute to lipodystrophy syndrome are discussed, and approaches to assessing, managing, and treating the disorder are proposed. Epidemiology of lipodystrophy syndrome: findings from cohort studies The Australian Prevalence Survey of Lipodystrophy Syndrome Clinicians at St Vincent’s Hospital in Sydney, Australia were among the first to notice changes in fat distribution and metabolism among patients with HIV [11]. Since then, a national network of investigators has begun a cross-sectional survey, the Australian Prevalence Survey of Lipodystrophy Syndrome [33]. Of 1348 predominantly male patients surveyed at 14 centers, fat maldistribution was documented in 54% of patients. Seventy-three percent of all patients were on an antiretroviral regimen that included a PI; of these patients, 63% had lipodystrophy. Fourteen percent of all patients were taking nucleoside reverse transcriptase inhibitors (NRTI) and/or non-nucleoside reverse transcriptase inhibitors (NNRTI) but no PI; of these patients, 32% had lipodystrophy. Twelve percent of all patients had not taken any antiretroviral agents; of these patients, 21% had lipodystrophy. Physicians characterized most patients’ self-reported conditions as mild or moderate. As severity of fat maldistribution increased, so did the incidence of metabolic abnormalities, such as elevated fasting triglyceride, insulin, and C-peptide levels. Preliminary analysis identified increasing age, symptomatic HIV disease, increased duration of NRTI and PI treatment, and lower viral load as risk factors for lipodystrophy syndrome. The Self-Ascertained Lipodystrophy Syndrome Survey: gender differences in lipodystrophy syndrome For the Self-Ascertained Lipodystrophy Syndrome (SALSATM) Survey, which is ongoing at 50 sites in the United States, Canada and Australia, patients complete a questionnaire on body morphology, medical history, health habits, and lifestyle; health care providers fill in a corresponding form with medical history, prescribed medications, and data from physical examinations and laboratory tests. Data from SALSATM has revealed gender differences in patients with morphological abnormalities. Of 526 patients with morphological abnormalities, 99% were taking antiretroviral agents, and only 2% were PI-naive [34]. The most common morphological abnormality reported was fat accumulation in the abdomen, reported in 76% of men and in 93% of women (Fig. 1). The second most common abnormality was fat depletion in the limbs (67%) in men and fat accumulation in the breasts (69%) in women. Most women (59%) also had fat depletion in the limbs.Fig. 1.: Fat depletion (FD) and fat accumulation (FA) in HIV-infected men (dark columns; n = 445) and women (light columns; n = 81) with morphological abnormalities in the SALSATM survey.Survey data also revealed metabolic disturbances, including hypertriglyceridemia, hypercholesterolemia, and hyperglycemia, in many patients. Men were more likely than women to have metabolic abnormalities (Fig. 2).Fig. 2.: Metabolic abnormalities in HIV-infected men (dark columns) and women (light columns) with morphological abnormalities in the SALSATM survey.Multivariate analysis of the data identified fat accumulation as being associated with female gender, low viral load (< 500 copies/ml), and high body mass index (BMI > 28 kg/m2) [34,35]. Fat depletion was associated with low BMI and prior treatment with stavudine [34]. The HIV Outpatient Study Data from the HIV Outpatient Study (HOPS), a prospective study of HIV patients from United States private practice, public health, and university clinics, has helped to characterize further morphological abnormalities and associated risk factors in patients with HIV infection. The survey includes 1077 patients, with or without lipodystrophy disorder, who have been followed for over 8000 patient years. Of these patients, 49% showed some evidence of fat maldistribution. Factors most strongly associated with an increased risk of lipodystrophy were increasing age and the use of one PI or one NRTI; NNRTI treatment was not associated with lipodystrophy. Duration and severity of HIV infection, time since reversal of clinical progression of HIV infection, use of two antiretroviral agents, and extreme changes in BMI were also strongly associated. The LIPOCO study The LIPOCO cohort study is an ongoing observational investigation of changes in body fat distribution and metabolism among HIV-infected patients in France [36]. In one recent analysis, patients were divided into four clinical categories: a fat depletion group; a fat accumulation group; a mixed group, including patients with both fat depletion and fat accumulation; and a control group, consisting of patients with no changes in fat distribution. Of 154 patients in the study, 15 were therapy-naive, 39 had been on NRTI therapy only, and 100 had been taking combination therapy that included at least one PI. Alterations in body fat distribution were observed in 82 (53.3%); of these patients: 34 (22.1%) were classified in the lipoatrophy group, nine (5.9%) in the fat accumulation group, and 39 (25.3%) in the mixed group. Patients in the lipoatrophy group had significant decreases in subcutaneous fat, as measured by computed tomography (CT), and elevations in plasma triglycerides. Patients in the fat accumulation and mixed groups had significant increases in intra-abdominal fat, as measured by CT, and elevated plasma insulin levels. Multivariate regression analyses correlated fat wasting with stavudine treatment. Surprisingly, treatment with a PI was not significantly associated with changes in fat distribution [36]. These results and additional LIPOCO data suggest that distinct types of fat maldistribution may occur in patients on antiretroviral therapy, including a fat depletion syndrome that may be related to the use of stavudine and a mixed fat redistribution syndrome that may be related to effective virus control [36]. Other French cohort studies have provided similar findings [37–39]. EuroSIDA: a multicohort study The EuroSIDA study is a large multicohort study that began in 1994 as an epidemiological study of AIDS in Europe. This ongoing prospective study includes more than 8000 subjects from more than 60 sites in 20 European countries [40]. A prospective substudy of EuroSIDA, begun in 1998, is identifying risk factors for fat accumulation and fat depletion. Preliminary results have corroborated findings from other cohort studies that show associations between changes in fat distribution and gender, increasing age, prior AIDS diagnosis, and number of antiretroviral drugs, but have found no association with viral load. Case definition Complexities of developing a case definition The past several years have brought a flood of information about HIV/HAART-associated changes in body shape and metabolism. Unfortunately, to date, the available data have not helped to generate a definition or diagnostic criteria for lipodystrophy syndrome. Defining the disorder is complicated by uncertainty as to whether it is a single syndrome with multiple, varying components or involves multiple, distinct conditions. In part, this reflects the scant and sometimes contradictory data on how metabolic and morphological components of the syndrome may be linked. Also, causal relationships among specific antiretroviral agents and metabolic and morphological disturbances remain uncertain. PIs clearly play a role, and NRTIs also may contribute [36], but many abnormalities have been observed in the absence of antiretroviral treatment [41] and non-medication risk factors clearly play a role [24]. The Fat Redistribution and Metabolism (FRAM) study The FRAM study has been designed to address some of these issues. It is a multicenter, cross-sectional survey of 1200 randomly selected HIV-infected patients from geographically diverse United States sites and 300 healthy, non-HIV-infected subjects from an ongoing study of cardiac disease (CARDIA). 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