Body shape changes: where are we?

In 1997, people taking the recently introduced protease inhibitors (PIs) reported rapid enlargement of their abdomens. The condition picked up the name "Crix belly," most likely from the large market share of indinavir (Crixivan) at that time. In June 1997, the Food and Drug Administration (FDA) issued an advisory about cases of diabetes and hyperglycemia in patients receiving PIs. (1) A few months later, Cart and colleagues published a paper identifying a syndrome of "lipodystrophy," which they defined as fat wasting of the face, limbs, and upper trunk. (2) This was the first published use of the term "lipodystrophy" in conjunction with HIV-associated metabolic and morphologic disturbances.

Defining Lipodystrophy

Prior to these reports of lipodystrophy in HIV-infected patients, the clinical condition of lipodystrophy was considered to be a cluster of rare genetic or acquired disorders (non-HIV-related) characterized by a near-total absence of body fat, or by fat loss in the extremities (although sometimes not in the legs) and fat deposition around the head and neck areas. HIV-associated lipodystrophy affects many more people and differs from the "non-HIV" lipodystrophies, as many with this condition have increased fat deposition in the abdomen.

Unfortunately, many research studies in HIV rely on clinician-defined lipodystrophy as an endpoint. In some cases, researchers have combined lipid changes with morphologic (body shape) changes as their definition. Fat gain and fat loss are commonly combined, although the processes responsible for each may be quite separate. The inaccurate term "fat redistribution" is often used to describe HIV-associated lipodystrophy, implying a movement of adipose tissue or cells from the periphery to the abdomen or other areas, an idea for which there are no supportive data.

While laboratory abnormalities are objective and easily quantifiable, the same is not true for the morphologic changes associated with lipodystrophy. Patient self-report has been used as an indicator, confirmed in some cases by clinical observations. However, disagreements or discrepancies on the severity of fat loss or accumulation are common. Anthropometric measurements are fraught with both inter- and intra-rater unreliability, despite the availability of detailed instruction manuals. Bioelectric impedance analysis is useful only to measure overall body composition and cannot generate regional body composition data. Dual-energy X-ray absorptiometry (DXA) scans can provide data on regional body composition, and abdominal computed tomography (CT) scan slices provide quantifiable data on subcutaneous and visceral fat. However, these techniques are not widely available largely due to cost, and norms for interpreting their results have yet to be established.

With causative factors still unclear, lipodystrophy remains little more than a collection of symptoms mainly observed in people taking antiretroviral medications for HIV (see Table). As more side effects are identified and associated with antiretroviral therapy, new symptoms or related conditions (including lipodystrophy) are added by various researchers to the list of conditions considered part of HIV and/or its treatment. Because of the confusion about a definition of lipodystrophy, its prevalence has been variably reported from as low as 13% to as high as 84%.

The idea for an overall definition of HIV-associated lipodystrophy is based on the assumption that the various elements of lipodystrophy are in fact interrelated and may have a common etiology. However, clinicians do not need an overall definition to treat their patients. They continue to diagnose and treat individual symptoms, while researchers continue to look for their causes.

Newer Approaches to Understanding Body Shape Changes

In 2002, at the International AIDS Conference in Barcelona, Grunfeld (3) first suggested that in lipodystrophy, peripheral fat loss is actually associated with central fat loss and is clearly greater in HIV-infected patients with lipodystrophy than in HIV-infected patients without lipodystrophy or in HIV-negative controls. Further, he stated that a "mixed" syndrome of peripheral fat loss and central fat gain does not exist and that visceral adipose tissue was lower in HIV-positive patients compared to controls. His comments were based on a preliminary analysis of data on men only from the Fat Redistribution and Metabolic Change in HIV Infection or FRAM study, (4) a cross-sectional comparison of HIV-infected patients with or without lipodystrophy and HIV-negative controls. The FRAM study was the first major research report to suggest that fat loss and fat gain were distinct syndromes, perhaps with independent causes, and that central fat gain should not be considered a feature of lipodystrophy. Later analysis of data on women in the study showed parallel results: lipoatrophy was not related to central fat gain, but rather to central fat loss. This finding went against many researchers' assumptions and called into question the concept of "fat redistribution." Further analysis of FRAM data and additional studies are needed to clarify this controversy.

Initial efforts to define lipodystrophy were based on the assumption that the syndrome was related to the use of PIs, despite the fact that many symptoms-including half of the cases reported in the first paper on buffalo humps (5)--were seen in patients who had never taken PIs. Brinkman introduced nucleoside reverse transcriptase inhibitor (NRTI)-induced mitochondrial toxicity as a potential cause of lipodystrophy. (6) This hypothesis reinforced the view that lipodystrophy might represent 2 syndromes: fat accumulation (probably caused by PIs) and fat wasting (most likely caused by NRTIs).

Because the PIs were blamed for visceral fat accumulation, a series of "switch" studies examined the impact of changing from PIs to non-nucleoside reverse transcriptase inhibitors (NNRTIs). Although these studies showed improvements in blood lipid levels, the effects on visceral fat were very modest. However, switching away from certain NRTIs--particularly d4T (stavudine or Zerit)--in several studies proved helpful in decreasing the rate of peripheral fat loss, or even in restoring it. Demonstrating any link between specific drugs and body shape changes is complicated because people do not remain on a particular regimen for long, and the effects from various components of each regimen may be difficult to separate.

Alternatively, lipodystrophy may not be significantly related to individual medications. The HIV Outpatient Study (HOPS) has consistently reported that in new cases of lipoatrophy identified during a 21-month study, neither drug class nor individual agents were significantly related to the development of lipoatrophy. (7) Instead, patient characteristics such as White race, a less robust treatment-induced CD4 lymphocyte increase, CD4 lymphocyte count below 100, and lower body mass index (BMI) were found to be significantly associated with fat loss. More recently, a series of analyses has examined the link between patient genetic profiles and the development of fat loss and fat accumulation, with suggestive results that point to the need for larger trials to confirm these findings. (8)

Additionally, there are several reports of gender differences in the manifestations of lipodystrophy. (8) The SALSA study found that male patients started with less body fat and were more likely to report fat loss, while female patients (with greater initial fat) were more likely to report fat gain. Engelson and Kotler's group used magnetic resonance imaging (MRI) and DXA scans to define changes in body composition in HIV-infected men and women compared to uninfected controls. (9) Commenting on this study, Kotler noted that only men had a significant decrease in subcutaneous adipose tissue, while both men and women had increased visceral adipose tissue. Disagreeing with the FRAM study findings, he suggested that visceral fat increase is the primary element of lipodystrophy, while subcutaneous fat loss may be caused by other factors. (10)

Most studies of lipodystrophy have been cross-sectional rather than longitudinal, the former design being unable to capture rates of change for various parameters. An HIV-positive population with several years of experience on antiretroviral medications might appear similar to HIV-negative controls in certain respects, but longitudinal study might show very different patterns of change. The datasets for some longitudinal studies clearly show that cross-sectional analyses at different time points would have yielded very different results. (11)

Questions also have been raised concerning whether the HIV-negative controls used in the FRAM study were selected appropriately. Data were collected at one time point from age-matched patients from the national CARDIA study of cardiovascular disease. Some researchers are concerned that this is a poor comparator for the body shape changes that sometimes occur within a fairly short time frame in people with HIV. Certainly, the experience of patients and clinicians dealing with lipodystrophy suggests that it is characterized by sometimes rapid changes in body shape, particularly in abdominal girth. Fat atrophy and fat hypertrophy may often appear simultaneously, even if they are not both statistically linked to a single cause. Clinicians and patients might be ill-served if the definition of HIV-associated lipodystrophy, far example, were to exclude abdominal fat accumulation as not being statistically linked to HIV disease. Conceivably, such a definition might lead to reduced research attention to the diagnosis and treatment of abdominal fat accumulation, or to reduced third-party reimbursement for related treatments or procedures.

Treatments for Body Shape Changes

As noted earlier, clinicians do not need an overall definition to treat their patients. They diagnose and treat individual symptoms, and much research has focused on this topic. For example, great attention is being paid to central fat accumulation as part of an overall, clinically defined metabolic syndrome that has been observed in the general population (usually associated with aging, development of diabetes, central fat gain, etc). Along that line, medications used to normalize glucose levels such as metformin and pioglitazone have been studied, but with limited benefit in reducing fat accumulation. (12) A difficulty in many such studies is the lack of clear baseline values for study participants. Studies investigating the effects of diet and exercise changes have also been conducted in patients with HIV-associated lipodystrophy (see article on page 20 of this issue).

More work is also underway in treating lipoatrophy. Switching away from d4T has shown benefits, although often slow and modest. Newer studies are trying to correct mitochondrial depletion through the use of the supplement uridine, which has been shown effective in treating mitochondrial toxicity caused by d4T and AZT (zidovudine or Retrovir).

Non-drug treatments include the use of liposuction to remove fatty accumulations behind the neck (dorsocervical fat pads). Liposuction, however, cannot be used to reduce visceral fat accumulations, which are deep in the body and surround internal organs. A more dramatic treatment is the use of facial fillers or implants to correct fat loss. Much work continues to be done to investigate the safety and effectiveness of such interventions. Sculptra, an injectable form of poly-L-lactic acid that is a biodegradable and biocompatible synthetic polymer, was FDA-approved in 2004 for facial use and has been used as extensively as patient financial resources allow.

There is little doubt that research will continue into both drug and cosmetic treatments for the body shape changes associated with HIV disease and its treatment. However, these efforts are hampered by a continuing lack of clarity on the pathogenesis of these morphologic changes.

References

(1.) US Food and Drug Administration. FDA Public Health Advisory: Reports of Diabetes and Hyperglycemia in Patients Receiving Protease Inhibitors for the Treatment of Human Immunodeficiency Virus (HIV), June 11, 1997.

(2.) Carr A, Samaras K, Burton S, et al. AIDS. 1998;12:F51-F58.

(3.) Grunfeld C. [Invited lecture]. XIV International AIDS Conference. July 7-12, 2002; Barcelona.

(4.) Bacchetti P, Gripshover B, Grunfeld C, et al. J Acquir Immune Defic Syndr. 2005;40(2):121-131.

(5.) Lo JC, Mulligan K, Tai VW, Algren H, Schambelan M. Lancet. 1998;351:867-870.

(6.) Brinkman K, Smeitink JA, Romijn JA, Reiss P. Lancet. 1999;354:1112-1115.

(7.) Lichtenstein K, Delaney K, Ward D, Moorman A, Wood K, Holmberg S. 9th Conference on Retroviruses and Opportunistic Infections. February 24-28, 2002; Seattle. Abstract 684.

(8.) De Luca A, Di Giambenedetto S, Schwarz J, et al. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006; Denver. Abstract 766.

(9.) Muurahainen N, Falutz J, Pettit R, et al. 39th Interscience Conference on Antimicrobial Agents and Chemotherapy. September 26-29, 1999; San Francisco. Abstract 1301.

(10.) Engelson ES, Kotler DP, Tan Y, et al. Am J Clin Nutr. 1999;69:1162-1169.

(11.) Dube MP, Zackin R, Tebas, P, et al. 4th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV. September 22-25, 2002; San Diego. Abstract 27

(12.) Mulligan K, Yang Y, Koletar S, et al. 13th Conference on Retroviruses and Opportunistic Infections. February 5-8, 2006; Denver. Abstract 147.

By Robert Munk, PhD

Robert Munk, PhD, is the Coordinator of AIDS InfoNet (aidsinfonet.org) and a Research Assistant Professor at the University of New Mexico Health Sciences Center.

TABLE: Symptoms often associated with lipodystrophy

Fat accumulation                     Fat wasting
(hypertrophy)                        (atrophy)

[up arrow] visceral fat              [up arrow] subcutaneous fat
[up arrow] abdominal girth                      in legs and arms
[up arrow] dorsocervical fat pad     [up arrow] gluteal fat
           (buffalo hump and/or      [up arrow] buccal fat pad
           horse collar)             [up arrow] fat at temples
[up arrow] breast hypertrophy
           (gynecomastia)
[up arrow] lipomas

Lipid and glucose                    Other symptoms
metabolism

[up arrow] triglycerides             * hypertension
[up arrow] LDL cholesterol           * dry skin
[up arrow] HDL cholesterol           * brittle hair and nails
[up arrow] blood glucose             * sexual dysfunction
[up arrow] insulin resistance        * loss of bone
                                       mineral density
                                       (osteoporosis and
                                       osteonecrosis)

                                     [up arrow] serum lactate
                                     [up arrow] lactic acidosis