Abnormalities of body-fat distribution are a recognized complication of HIV infection and of antiretroviral therapy (ART), and they are a common concern of patients. They include central fat accumulation (lipohypertrophy) and subcutaneous fat wasting (lipoatrophy). These morphologic changes are often referred to as lipodystrophy, though that term fails to distinguish between the two phenomena. Abnormalities in fat distribution and body shape have been noted in up to 40-50% of patients treated with ART, but the incidence may be much lower with the use of newer, less lipotoxic, antiretroviral (ARV) medications and with earlier initiation of ART. Lipohypertrophy and lipoatrophy are associated with other metabolic abnormalities, such as dyslipidemia and insulin resistance, and visceral fat accumulation (at least in HIV-uninfected persons) is a risk factor for cardiovascular disease.
Research on fat maldistribution has yielded varying results, in part because there are no standard clinical case definitions of lipodystrophy, lipoatrophy, or lipohypertrophy. The pathogenesis of fat abnormalities in HIV-infected individuals is not well understood, but research to date suggests that it is multifactorial and is associated with HIV-related immune depletion and immune recovery, ARV medications, disregulation of fatty acid metabolism, hormonal influences, individual genetic predispositions, and factors that are not related to HIV such as diet and obesity. Lipodystrophy has been associated with lower nadir CD4 count as well as with gender (central lipohypertrophy may be more common in women) and age (more common in older patients), and longer exposure to ART. Lipohypertrophy has not been definitively proven to be related to specific ARVs or to specific ARV classes, but has been variably associated with protease inhibitors (PIs) and with nucleoside reverse transcriptase inhibitors (NRTIs). However, morphologic changes occasionally develop in ARV-naive individuals. Lipoatrophy is most commonly associated with NRTIs, notably stavudine, as well as didanosine and zidovudine.
The most common morphologic changes seen in lipohypertrophy are a firm enlarged abdomen caused by central or visceral fat accumulation, breast enlargement (gynecomastia) in both men and women, development of a dorsocervical fat pad ("buffalo hump"), and neck enlargement. Lipoatrophy most commonly appears as the loss of subcutaneous fat in the face, arms, legs, and buttocks. Lipoatrophy differs from the generalized wasting seen in advanced AIDS, because lean cell mass generally is preserved. When lipohypertrophy and lipoatrophy occur together, the affected individuals show a mixed picture of abdominal obesity with thinning in the face, arms, and legs.
Severe lipoaccumulation can cause discomfort and, in some cases, impairment of breathing or other bodily functions. It may be associated with other metabolic abnormalities, including dyslipidemia, insulin resistance, and the metabolic syndrome. Both lipoaccumulation and lipoatrophy can be disfiguring, can damage self-image and quality of life, and can negatively influence ARV adherence.
The patient may report any of the following: abdominal fat accumulation with change in waist size, increased neck size, "buffalo hump," enlarged breasts, and reduced range of motion. Women may note an increase in bra size. Alternatively (or in addition), the patient may report sunken cheeks, decreased arm or leg circumference, prominence of veins in the arms or legs, or buttock flattening.
Determine CD4 cell count nadir, ARV medication history with particular attention to past use of thymidine analogues and PIs, and duration of and response to each regimen. Ask about past medical and family history, specifically regarding hyperlipidemia, diabetes or insulin resistance, other metabolic disorders, and cardiovascular disease. Evaluate the effect of body-shape changes on the patient's self-esteem, medication adherence, and interpersonal relationships.
Compare past and current weights. Calculate body mass index (BMI); see chapter Initial Physical Examination for information on BMI.
Measure and document waist and hip circumferences. A waist circumference of >102 cm (39 inches) in men and >88 cm (35 inches) in women is the clinical definition of abdominal obesity and is associated with the metabolic syndrome. Waist-to-hip ratios of >0.95 in men and >0.85 in women are associated with an increased risk of coronary heart disease.
Examine the head, neck, back, breasts, and abdomen for fat accumulation, especially looking for dorsocervical fat pad and facial, neck, or breast enlargement. Examine the face and extremities for subcutaneous fat loss (e.g., in the cheeks, temples, limbs, and buttocks).
Review laboratory history (glucose, lipid panel) to identify other metabolic disorders. (See chapters Dyslipidemia and Insulin Resistance, Hyperglycemia, and Diabetes on Antiretroviral Therapy.)
No uniform standard criteria are available for defining or grading lipohypertrophy or lipoatrophy in clinical practice. Clinicians must base their assessment on patient self-report, physical examination (for characteristic body-shape changes), associated symptoms, and psychological consequences.
In research settings, modalities such as dual-energy X-ray absorptiometry (DEXA), computed tomography (CT), and magnetic resonance imaging (MRI) have been used to characterize and quantify lipoaccumulation and lipoatrophy. Anthropometric measurements may be made in the clinic by trained personnel (e.g., nutritionists), but do not measure visceral fat directly. Although measurements such as waist circumference cannot be used to assess lipohypertrophy, they have been validated (in HIV-uninfected individuals) as an assessment of cardiovascular risk (see chapters Dyslipidemia and Coronary Heart Disease Risk). Bioelectrical impedance analysis (BIA) does not measure regional body composition and thus is not used to measure abnormal body-fat changes.
Differential diagnosis of lipohypertrophy includes obesity or excess weight gain, ascites, and Cushing syndrome.
Differential diagnosis of lipoatrophy includes weight loss and wasting.
Check for other metabolic abnormalities associated with the use of ARVs, such as dyslipidemia and impaired glucose metabolism (check fasting lipids and random or fasting glucose). See chapters Dyslipidemia and Insulin Resistance, Hyperglycemia, and Diabetes on Antiretroviral Therapy, for further information about workup and treatment.
Treatments for lipohypertrophy and lipoatrophy have not reliably reversed body shape changes once these changes have occurred. In general, treatment interventions have shown poor results in patients with marked or severe fat maldistribution and inconsistent or limited responses in those with milder conditions. The best approaches to managing lipodystrophy are prevention and early intervention.
Clinicians can help to prevent body fat abnormalities by avoiding, whenever possible, ARV agents known to confer a greater risk of this disorder (particularly stavudine, didanosine, and zidovudine, which particularly are associated with lipoatrophy). All patients who take ARVs should be monitored carefully for the development of fat maldistribution. If abnormalities are noticed, intervention should be initiated, if possible.
The optimal management strategy for established lipoaccumulation or lipoatrophy is not known, although the following approaches can be considered (see below). Also consider referring the patient to clinical studies of lipodystrophy treatment, and for psychological or adherence support and counseling, if indicated. If the patient is distressed enough to consider discontinuing or interrupting ART, review with the patient any gains he or she has made on ART and discuss treatment options (see below). In some cases the patient may insist on discontinuing ARV medications; in this situation, carefully review the risks of treatment interruption as well as the alternatives to discontinuing treatment.
Avoiding thymidine analogue NRTIs, particularly stavudine, and avoiding the NRTI combination stavudine + didanosine have been shown to reduce the risk of lipoatrophy.
In patients with lipoatrophy, modest slow improvement in limb fat has been demonstrated after switching from thymidine analogues (stavudine, zidovudine) to nonthymidine NRTIs (such as abacavir or tenofovir) or to NRTI-sparing regimens. In patients with lipohypertrophy, similar NRTI switch strategies have had little effect on visceral or trunk fat. Studies in which PIs were eliminated from the ART regimen generally have not shown significant effects on body fat measures.
Before switching therapies, carefully assess the potential risk to the patient's long-term HIV management.
The effects of diet on lipohypertrophy have not been evaluated thoroughly. If overall weight reduction is needed, recommend dietary changes and exercise. Avoid rapid weight loss plans, as lean body mass often is lost disproportionately. Refer to a dietitian to help the patient decrease intake of saturated fat, simple sugars, and alcohol.
Regular, vigorous cardiovascular exercise may help control central fat accumulation, whereas resistance exercises (strength training) will improve the ratio of muscle to fat. Some studies of exercise (done alone or in combination with diet) have shown a reduction in visceral fat accumulation with minimal or no changes in peripheral lipoatrophy. Moderate aerobic exercise should be encouraged for all patients.
In diabetic and non-HIV lipodystrophy, treatment with thiazolidinediones may decrease visceral fat, increase peripheral fat, and improve glycemic control. In HIV-infected patients with lipoatrophy, studies of thiazolidinediones, pecifically rosiglitazone and pioglitazone, have shown mixed results. Some patients have reported improvement in limb fat, particularly those with insulin resistance; however, a larger, 48-week randomized trial of rosiglitazone found no significant increase in limb-fat mass. In patients with visceral fat accumulation, thiazolidinediones have not been found to be effective.
In clinical studies, metformin has been modestly effective in treating visceral adiposity in patients with insulin resistance, but may cause worsening of lipoatrophy. Metformin should be used with caution in patients with chronic liver or renal disease.
Treatment with recombinant human growth hormone (rHGH), 3-6 mg/day for 12 weeks followed by maintenance therapy with lower doses of 1-2 mg/day, has been shown to reduce visceral fat in many patients with minimal impact on peripheral fat wasting; other studies suggest efficacy (and improved tolerability) of lower dosages of rHGH. However, the high cost of rHGH, the high rate of adverse effects (including insulin resistance), and the frequent recurrence of visceral fat accumulation once rHGH is discontinued have resulted in a limited role for this treatment.
Tesamoralin, a synthetic growth hormone-releasing factor analogue, has been shown in Phase 3 clinical studies to reduce central fat accumulation by about 18% over the course of 12 months, without adverse effects on glucose or lipid parameters. As with rHGH, patients regain visceral fat when tesamoralin is discontinued. Tesamoralin currently is under review for approval by the U.S. Food and Drug Administration (FDA).
Various techniques have been investigated, but generally have limited applicability and efficacy. Poly-L-lactic acid (Sculptra, New-Fill) is approved by the FDA as a treatment for facial lipoatrophy. This injectable material has shown good cosmetic results and often significantly improves patients' satisfaction with their appearance. Calcium hydroxylapatite (Radiesse) also has FDA approval for HIV-associated facial lipoatrophy. Treatment effects of both agents typically wane with time and the procedures often must be repeated. Other facial fillers, as well as cheek implants and autologous fat transfer, have been used successfully in some cases. For lipoaccumulation, treatments such as liposuction for focal areas of fat deposition (e.g., dorsocervical) and breast reduction may be effective in the short term, though fat often reaccumulates.
These interventions increasingly are covered by private- and public-payer sources, but still often are deemed to be the financial responsibility of the patient. In some cases, they may be only a temporary solution, because abnormalities may reappear after treatment.