Abnormalities of Body-Fat Distribution

Background

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 older antiretroviral (ARV) medications, but the incidence may be much lower with the use of newer, less lipotoxic ARVs 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.

S: Subjective

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. 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.

O: Objective

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 have been 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.)

A: Assessment

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.

P: Plan

Diagnostic Evaluation

Laboratory

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.

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 are most closely associated with lipoatrophy). All patients who take ARVs should be monitored carefully for the development of fat maldistribution. If abnormalities are noticed, the suspect ARV should be discontinued and a more benign ARV started in its place, 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.

ARV Substitutions

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.

Nonpharmacologic Measures

Diet

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.

Exercise

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.

Pharmacologic Measures

Insulin-sensitizing agents

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, specifically 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.

Growth hormone-releasing factor

Tesamorelin, a synthetic growth hormone-releasing factor analogue, is approved by the U.S. Food and Drug Administration (FDA) for treatment of excess abdominal fat in HIV-infected persons with lipodystrophy. It has been shown to reduce central fat accumulation by about 18% over the course of 12 months, without adverse effects on glucose or lipid parameters. Unfortunately, patients rapidly regain visceral fat when tesamorelin is discontinued. That, along with its expense, has limited the use of tesamorelin. No long-term safety data are available.

Recombinant human growth hormone

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.

Plastic and reconstructive surgery

Various techniques have been investigated, but generally have limited applicability and efficacy. Poly-L-lactic acid (Sculptra, New-Fill) and a calcium hydroxylapatite preparation (Radiesse) are approved by the FDA as treatments for facial lipoatrophy. These injectable materials have shown good cosmetic results and often significantly improve patients' satisfaction with their appearance. 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 may be 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.

Patient Education

  • Instruct patients who are receiving ARV medications to inform their health care provider if they notice changes in the shape or appearance of their bodies.
  • Review the importance and benefits of ART and assess adherence to the regimen.
  • For patients with lipohypertrophy, recommend aerobic and resistance exercise to reduce fat and build muscle. Assess local resources for safe muscle-strengthening.
  • If weight reduction is needed, refer to a dietitian for consultation. Remind the patient that quick weight-loss diets may result in excessive muscle loss.
  • For patients with severe facial lipoatrophy, consider referral to an experienced dermatologist or plastic surgeon for restorative treatment.

References

  • Carr A, Workman C, Carey D, et al. No effect of rosiglitazone for treatment of HIV-1 lipoatrophy: randomised, double-blind, placebo-controlled trial. Lancet. 2004 Feb 7;363(9407):429-38.
  • Chow D, Day L., Souza S, et al. Metabolic Complications of HIV Therapy. In: Coffey S, Volberding PA, eds. HIV InSite Knowledge Base [online textbook]. San Francisco: UCSF Center for HIV Information; 2006. Available at hivinsite.ucsf.edu/InSite?page=kb-03-02-10.
  • Egrifta [prescribing information]. EMD Serono: Rockland, MA. Accessed December 1, 2013.
  • Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. N Engl J Med. 2007 Dec 6;357(23):2359-70.
  • Falutz J, Potvin D, Mamputu JC, et al. Effects of tesamorelin, a growth hormone-releasing factor, in HIV-infected patients with abdominal fat accumulation: a randomized placebo-controlled trial with a safety extension. J Acquir Immune Defic Syndr. 2010 Mar 1;53(3):311-22.
  • Gallant JE, Staszewski S, Pozniak AL, et al.; 903 Study Group. Efficacy and safety of tenofovir DF vs stavudine in combination therapy in antiretroviral-naive patients: a 3-year randomized trial. JAMA. 2004 Jul 14;292(2):191-201.
  • Haubrich RH, Riddler SA, DiRienzo AG, et al.; AIDS Clinical Trials Group (ACTG) A5142 Study Team. Metabolic outcomes in a randomized trial of nucleoside, nonnucleoside and protease inhibitor-sparing regimens for initial HIV treatment. AIDS. 2009 Jun 1;23(9):1109-18.
  • Martin A, Smith DE, Carr A, et al.; Mitochondrial Toxicity Study Group. Reversibility of lipoatrophy in HIV-infected patients 2 years after switching from a thymidine analogue to abacavir: the MITOX Extension Study. AIDS. 2004 Apr 30;18(7):1029-36.
  • Moyle G. Metabolic issues associated with protease inhibitors. J Acquir Immune Defic Syndr. 2007 Jun 1;45 Suppl 1:S19-26.
  • Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Accessed December 1, 2013.
  • Pirmohamed M. Clinical management of HIV-associated lipodystrophy. Curr Opin Lipidol. 2009 Aug;20(4):309-14.
  • Rubenoff R, Schmitz H, Bairos L, et al. 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. 2002 Feb 1;34(3):390-3.
  • Schambelan M, Benson CA, Carr A, et al.; International AIDS Society-USA. Management of metabolic complications associated with antiretroviral therapy for HIV-1 infection: recommendations of International AIDS Society-USA panel. J Acquir Immune Defic Syndr. 2002 Nov 1;31(3):257-75.
  • Wohl DA. Diagnosis and management of body morphology changes and lipid abnormalities associated with HIV Infection and its therapies. Top HIV Med. 2004 Jul-Aug;12(3):89-93.

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Abbreviations for Dosing Terminology

BID
twice daily
BIW
twice weekly
IM
intramuscular (injection), intramuscularly
IV
intravenous (injection), intravenously
PO
oral, orally
Q2H, Q4H, etc.
every 2 hours, every 4 hours, etc.
QAM
every morning
QD
once daily
QH
every hour
QHS
every night at bedtime
QID
four times daily
QOD
every other day
QPM
every evening
TID
three times daily
TIW
three times weekly