Lipodystrophy in HIV

Updated: Sep 19, 2016
  • Author: David T Robles, MD, PhD; Chief Editor: Dirk M Elston, MD  more...
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Overview

Overview

HIV-associated lipodystrophy is a syndrome that occurs in HIV-infected patients who are being treated with antiretroviral medications. Although the term HIV-associated lipodystrophy refers to abnormal central fat accumulation (lipohypertrophy) and localized loss of fat tissue (lipoatrophy), some patients have only lipohypertrophy, some have only lipoatrophy, and, less commonly, a subset of patients exhibits a mixed clinical presentation.

Because no uniform morphologic changes occur with HIV lipodystrophy, lipohypertrophy and lipoatrophy are considered distinct entities, with different risk factors and metabolic processes underlying their development. This article addresses both lipohypertrophy and lipoatrophy, with a focus on the morphologic changes and underlying pathophysiology of HIV-associated lipodystrophy. Note the image below.

Facial HIV-associated lipodystrophy in a patient r Facial HIV-associated lipodystrophy in a patient receiving highly active antiretroviral therapy.

Lipohypertrophy in this syndrome is characterized by the presence of an enlarged dorsocervical fat pad, circumferential expansion of the neck, breast enlargement, and abdominal visceral fat accumulation. Lipoatrophy is exemplified by peripheral fat wasting with loss of subcutaneous tissue in the face, arms, legs, and buttocks.

Lipodystrophy can be disfiguring cosmetically. Involvement of the face is most common and carries a social stigma that may reduce the quality of life of patients with HIV disease and may pose a barrier to treatment and reduce medical adherence. [1, 2]

The incidence of diabetes mellitus or atherosclerotic cardiovascular disease is increased secondary to hyperglycemia (from insulin resistance) or hyperlipidemia, respectively.

Other features of HIV lipodystrophy syndrome include hyperlipidemia, insulin resistance, hyperinsulinemia, and hyperglycemia. Consequently, patients with HIV lipodystrophy syndrome are at increased risk for the development of atherosclerosis and diabetes mellitus.

The following Medscape articles address other forms of lipodystrophy:

The following Medscape Resource Centers may be helpful as well:

For other discussions on management of HIV infection, see HIV Disease, Pediatric HIV Infection, and Antiretroviral Therapy for HIV Infection.

For patient education information, see the Sexually Transmitted Diseases Center, Cholesterol Center, and Statins Center, as well as HIV/AIDS, High Cholesterol, Cholesterol FAQs, and Atorvastatin (Lipitor).

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Pathophysiology

Although the precise mechanisms underlying HIV lipodystrophy are not well understood, several hypotheses based on in vitro and human studies may explain the pathogenesis of the lipid changes that take place. Most experts currently believe that HIV type 1 (HIV-1) protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine and zidovudine, are implicated. [3, 4, 5, 6, 7] Genetic factors in the patient may confer particular susceptibility. [8, 9] In addition, immunohistochemical components may play a role in the process of lipodystrophy in HIV patients. [10]

One mechanism in which PIs function is by down-regulating PPAR-gamma and C/EBP-alpha, which are key adipogenic transcription factors. Once these factors are down-regulated, there is an interruption with lipogenesis and adipocyte maturation. In addition, they create a large production of reactive oxygen species, which leads to the production of cytokines, macrophage recruitment, and inhibition of glucose transport 4 (GLUT-4), along with a deficiency in insulin signaling and the hormones leptin and adiponectin. [11] If adiponectin is replaced, studies have shown decreased PI toxicity. [12]  PIs have also been shown to activate endoplasmic reticulum stress pathways by depleting the calcium in adipocytes. In addition, they also interfere with the expression of regulator genes, CHOP, ATF4, and XBP, which further alters lipid metabolism and autophagy. [11]

PIs also have a high affinity for the catalytic site of HIV-1 protease, which shares a 60% sequence homology with 2 proteins involved in lipid metabolism, cytoplasmic retinoic acid–binding protein type 1 (CRABP-1), and low-density lipoprotein receptor–related protein (LDLR-RP).

Inhibition of CRABP-1 impairs the production of retinoic acid, leading to decreased fat storage and adipocyte apoptosis, with the subsequent release of lipids into the circulation. Inhibition of LDLR-RP results in hyperlipidemia secondary to the failure of hepatic and endothelial removal of chylomicrons and triglycerides from the circulation.

NRTIs inhibit mitochondrial DNA (mtDNA) polymerase gamma, leading to mtDNA depletion, respiratory chain dysfunction, and reduced energy production, which, in turn, causes insulin resistance and secondary dyslipidemia. [13, 14] Interestingly, mtDNA is depleted only at normal oxygen levels; hypoxic adipocytes do not take up triglycerides and are resistant to mtDNA-induced damage, except after treatment with NRTIs. [15]

Some PIs, particularly ritonavir, inhibit cytochrome P450 3A, a key enzyme in lipid metabolism. Ritonavir has also been shown to cause an extreme amount of apoptosis. On the other hand, atazanavir has been shown to cause apoptosis and autophagy. The PIs saquinavir, ritonavir, and nelfinavir directly inhibit the development of adipocytes from stem cells and increase the metabolic destruction of fat in existing adipocytes.

Taking genetics into account, a missense mutation in the resistin gene has been shown to have an association with hyperlipidemia, insulin resistance, and limb fat loss when combined with highly active antiretroviral therapy (HAART). [11] Other studies have shown that resistin can function as a useful biomarker for peripheral adipose tissue loss and may be the future of therapeutic strategies. [16]

A 2016 study done on rats has shown that PIs reduce the activity of paraoxonase 1 (PON1), which is an HDL-bound esterase that inhibits the decomposing lipid peroxidation products, which further inhibits atherosclerosis. Therefore, there is a higher risk of atherosclerosis and a greater chance of experiencing lipodystrophy. [17]

In observation of immunohistochemical components, a 2014 cross-analytical study analyzed the cytokine expression from adipose tissue obtained in biopsies in 19 HIV patients experiencing lipodystrophy. As a result, tissue necrosis factor (TNF)–alpha and caspase-3 were more prominent in men than in women. In addition, the patients with lipodystrophy had less TNF-beta when being compared with the control group. Lastly, the group of individuals that experienced longer exposure to HIV and HAART had a positive association with levels of TNF-alpha. [10] As shown, sex differences lead toward different pathophysiologic outcomes, but more so, the elevation in cytokine production elevates the likelihood of developing lipodystrophy in HIV patients.

In another 2014 study focused on HIV patients with lipodystrophy, 21% of women and 37% of men were found to have growth hormone deficiencies (GHDs). Men who had GHD had higher amounts of visceral adipose tissue, subcutaneous adipose tissue, and trunk fat. Women who had GHD had significantly lower insulinlike growth factor-1 (IGF-1). Overall, adipose tissue distribution accounts for growth hormone sex differences; those with deficiencies have more problems with lipodystrophy. [18]

Evidence also suggests decreased insulin sensitivity and beta-cell dysfunction in patients with HIV-associated lipodystrophy. [19] Additionally, researchers have found that estrogen receptor expression is down-regulated in the subcutaneous adipose tissue of these patients. This is due to the effects of HAART regimens that include PIs. Stavudine has been particularly implicated in the apoptosis of adipocytes, affecting both dividing and differentiating cells. [20, 21]

In addition, HIV-1 may cause dyslipidemia and lipodystrophy in the absence of HAART, via impaired cholesterol efflux from macrophages and increased tumor necrosis factor–alpha, which modulates free fatty acid metabolism and lipid oxidation and attenuates insulin-mediated suppression of lipolysis. [13, 22]  Tumor necrosis factor‒like weak inducer of apoptosis (TWEAK) is a multifocal cytokine that is decreased in patients with HIV-associated lipodystrophy. [23]

A 2006 study in HIV-positive patients on HAART found that resting energy expenditure and lipid oxidation were significantly higher in those with lipodystrophy than in those without lipodystrophy. [24]  

More recent research has found an association with genetic variants in plasma levels, specifically an increased RBP4 and a decreased level of omenti in patients with HIV-associated lipodystrophy. [25] Associations with circulating fibroblast growth factor 23 (FGF23) levels are also increased. [26] Further studies are needed to examine how these updated associations can be incorporated in advancing treatments and early detection of lipodystrophy.

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Etiology

Part of the early difficulty in establishing the risk factors for HIV-associated lipodystrophy has been agreement on a case definition. Fat accumulation and lipoatrophy are clinically distinct and appear to have separate risk factors. Because most patients are taking a regimen of combined antiretroviral medications, identifying a specific class of antiretroviral associated with lipodystrophy has proved difficult. Despite this, the most common culprits of HIV-associated lipodystrophy appear to be those regimens containing PIs and thymidine analogue NRTIs.

Lipodystrophy associated with PIs occurs 2-12 months after starting PI therapy. Previous reports have shown that ritonavir-saquinavir combinations have a stronger association with abnormal fat accumulation than indinavir or nelfinavir. One study revealed that switching from other PIs to nelfinavir led to an improvement in lipodystrophy symptoms. The association between ritonavir and hypertriglyceridemia is stronger than that with other PIs.

An increased risk of lipodystrophy is reported with the addition of NRTIs (eg, stavudine) to PI treatment compared with treatment with only PIs. Of the NRTIs, the thymidine analogues stavudine (d4T) and zidovudine (ZDV, previously known as AZT) are mostly directly implicated in lipodystrophy, particularly lipoatrophy; switching to a different NRTI such as tenofovir or abacavir can produce demonstrable increases in limb fat and can improve lipid profiles. [27, 28]

In children with HIV, both thymidine analogue NRTIs and PIs are implicated in the development of lipodystrophy. [29] Lipodystrophy has been reported in individuals with HIV infection who have never been treated with PIs; possible mechanisms are noted in Pathophysiology.

Other reported risk factors associated with HIV-associated lipohypertrophy are as follows:

  • Duration of antiretroviral therapy
  • Female sex
  • Higher body fat at onset of HAART
  • Higher triglyceride levels

Other reported risk factors associated with HIV-associated lipoatrophy are as follows:

  • Therapy with thymidine analogue NRTIs (eg, stavudine, zidovudine)
  • Lower pretreatment body mass index at onset of HAART
  • Longer duration of HIV infection
  • White race

Other reported risk factors associated with both lipohypertrophy and lipoatrophy are as follows [30] :

  • Duration of HAART therapy
  • Older age
  • Low CD4 count
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Epidemiology

United States statistics

Wide variation exists in the literature regarding the prevalence of HIV lipodystrophy. Various studies show the prevalence rate of this syndrome is 2-60% in all patients who are HIV positive [31, 32] ; a 2007 meta-analysis found a prevalence rate of 14-40% in HIV-positive patients on highly active antiretroviral therapy (HAART). [33] In untreated patients with HIV infection, a 4% prevalence rate is reported. The incidence of associated new-onset hypercholesterolemia, hypertriglyceridemia, and hyperglycemia is 24%, 19%, and 5%, respectively.

International statistics

Rates of HIV-associated lipodystrophy vary according to country. [6, 34, 35] A prospective cohort study in England demonstrated a 17% prevalence rate after an 18-month follow-up. Variations in the reported prevalence rates are related to a variety of many factors, including age, genetics, HIV medications, and case definition.

In 2014, among all people living with HIV worldwide, the prevalence of lipodystrophy ranges from 10-80%. [36]

Racial, sexual, and age-related differences in incidence

The risk of lipoatrophy is higher in whites (5.4 odds ratio) than in blacks. Women are at a higher risk of lipodystrophy than men (1.9 relative risk). Women are more likely to report fat accumulation in the abdomen and breasts and hypertriglyceridemia, whereas men are more likely to describe fat depletion from the face and extremities, along with hypertension and hypercholesterolemia. [37] Increasing age is a risk factor in the development of this syndrome.

Over the last 12 years, the prevalence of lipodystrophy in HIV-infected men has decreased, yet the prevalence of metabolic syndrome and cardiovascular disease risk has increased. [38]

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Prognosis

HIV-associated lipodystrophy progressively worsens as PI therapy is continued, and the discontinuation of PI therapy may result in regression. [39]

To the authors’ knowledge, no studies have been conducted to determine the morbidity and mortality from the body morphologic changes of HIV-associated lipodystrophy per se. However, the insulin resistance and hyperlipidemia is associated with excess morbidity and mortality. The incidences of diabetes mellitus and atherosclerotic cardiovascular disease are increased secondary to hyperglycemia (from insulin resistance) and hyperlipidemia, respectively.

Osteopenia of the lumbar spine may be present in patients with increased visceral fat accumulation.

Dorsocervical fat pad accumulation may result in neck pain and sleep apnea.

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Clinical Presentation

HIV-associated lipodystrophy is a progressive disease; its severity is directly proportional to age, duration of disease, and length of protease inhibitor (PI) and/or nucleoside reverse transcriptase inhibitor (NRTI) treatment. On physical examination, abnormal fat accumulation (lipohypertrophy) findings are as follows:

  • The dorsocervical fat pad (commonly called "buffalo hump") becomes variably enlarged [40, 41, 42]
  • The circumference of the neck expands by 5-10 cm
  • Breast hypertrophy occurs
  • Central truncal adiposity results from abdominal visceral fat accumulation ("Crix belly" [referring to Crixivan, the trade name for indinavir, a PI] or "protease paunch")
  • Symmetric and asymmetric lipomatoses may occur; a rare pattern of lipoaccumulation involving bandlike lipomatosis tissue symmetrically from the breasts, laterally to the axillae, has been reported [43]
  • Suprapubic fat pads (pubic lipomas) occur in nearly 10% of patients with lipodystrophy [44]
  • The development of multiple angiolipomas is associated with PI therapy [45]

Lipoatrophy findings are as follows:

  • Temporal wasting and loss of subcutaneous fat from the cheeks (buccal fat pad) produces an emaciated appearance with prominent nasolabial creases (see image below)
    Facial HIV-associated lipodystrophy in a patient r Facial HIV-associated lipodystrophy in a patient receiving highly active antiretroviral therapy.
  • Subcutaneous tissue is depleted from the arms, shoulders, thighs, and buttocks (peripheral wasting), with prominence of the superficial veins in these sites
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Differential

Diagnostic considerations

Other problems to be considered in patients with lipodystrophy are as follows:

  • Seip-Berardinelli syndrome
  • Lawrence syndrome
  • Dunnigan syndrome
  • Kobberling syndrome
  • Barraquer-Simons syndrome
  • Abdominal carcinoma
  • Malnutrition

Other problems to be considered in patients with lipohypertrophy are as follows:

  • Cushing disease
  • Glucocorticoid therapy
  • Scleredema of diabetes mellitus
  • Launois-Bensaude syndrome

Other problems to be considered in patients with lipoatrophy are as follows:

  • HIV wasting syndrome [46]
  • Localized lipodystrophy
  • Malnutrition
  • Anorexia nervosa
  • Hyperthyroidism
  • Cancer cachexia
  • Severe chronic infection
  • Adrenal insufficiency

Differentials

Generalized Lipodystrophy

Acquired Partial Lipodystrophy

Progressive Lipodystrophy

Localized Lipodystrophy

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Workup

HIV-associated lipodystrophy is a clinical diagnosis. Although there is not a specific clinical protocol to make the diagnosis, advancements have been made that can aid in the assessment of lipodystrophy. A 2014 cross-sectional European study showed that anthropometric ratios (fat-mass ratio, waist-to-thigh ratio, waist-to-calf ratio, and arm-to-trunk ratio) are useful in making the diagnosis of lipodystrophy. Incorporating this method can lead to an accurate and earlier diagnosis. [47]

The only relevant laboratory studies are serum lipid assays. A skin or subcutaneous fat biopsy is not routinely performed to make a diagnosis of HIV lipodystrophy. Imaging studies are not generally necessary in the workup of HIV lipodystrophy. Dual energy x-ray absorptiometry scanning, CT scanning, and MRI are limited to research studies to objectively quantify fat abnormalities. [48]

MRI demonstrates the accumulation of visceral fat in the abdomen compared with subcutaneous fat. CT scanning demonstrates abnormal fat proliferation throughout the abdomen in a perivisceral distribution and little subcutaneous fat. Intra-abdominal organs are normal, and no ascites is seen. Dual-energy x-ray absorptiometry may demonstrate lumbar spine bone density reduction in association with increased visceral fat accumulation. [49]

Lipid panel

Because abnormal glucose and/or lipid metabolism may accompany HIV lipodystrophy, checking the lipid panel and assessing for glucose intolerance is important prior to initiating antiretroviral therapy. Some experts suggest checking these values again at 6 months and then, if the results are normal, yearly.

Hyperlipidemia findings are as follows:

  • Fasting cholesterol level – Greater than 200 mg/dL
  • Fasting triglyceride level - Greater than 150 mg/dL
  • Increased apolipoprotein c-III and apolipoprotein E levels

Hyperglycemia and/or hyperinsulinemia findings are as follows:

  • Diabetes - Fasting plasma glucose level of greater than 126 mg/dL or a 2-hour oral glucose tolerance test result of greater than 200 mg/dL
  • Impaired fasting glucose - Fasting plasma glucose level of 100-125 mg/dL
  • Impaired glucose tolerance - Two-hour oral glucose tolerance test result of 140-199 mg/dL
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Treatment & Management

Lipodystrophy is often progressive and, in limited cases, may regress after the withdrawal of PI therapy. Withdrawal of thymidine analogues (eg, switching from protease inhibitors to efavirenz) has shown to be effective for reversing lipoatrophy. [29, 50]

Treatment of the underlying metabolic derangements of glucose and lipid metabolism is necessary. The evaluation and management of glucose intolerance, diabetes, and hyperlipidemia are discussed elsewhere (see Type 1 Diabetes Mellitus, Type 2 Diabetes Mellitus, Polygenic Hypercholesterolemia, and Hypertriglyceridemia).

Tesamorelin, a growth hormone–releasing factor analog, was approved by the US Food and Drug Administration (FDA) for treatment of HIV-associated lipodystrophy in November 2010. Approval was based on 2 studies that showed that visceral adipose tissue was significantly decreased from baseline at 26 weeks and sustained at 52 weeks. [51, 52, 53] These were multicenter, randomized, double-blind, placebo-controlled, phase 3 studies in 816 HIV-infected patients with excess abdominal fat associated with lipodystrophy.

In 2015, the FDA approved metreleptin, a synthetic leptin analog for the treatment of non-HIV lipodystrophy. [54] Currently, clinical trials are pending for the use of metreleptin in patients with HIV lipodystrophy.

For the treatment of hyperlipidemia, fibrates and/or statins, as well as dehydroepiandrosterone (DHEA) alone, improve the lipid profile. [55]

For treatment of hyperglycemia, metformin, [56] insulinlike growth factor–1, [57, 58] and DHEA improve glycemic control.

Studies of thiazolidinedione treatment for HIV lipodystrophy have yielded conflicting results. One randomized controlled trial demonstrated positive effects of rosiglitazone on lipoatrophy, insulin sensitivity, and metabolic indices [59] ; another randomized, controlled trial of rosiglitazone did not show a benefit for lipoatrophy or metabolic parameters. [60]

A meta-analysis of six placebo-controlled trials found that pioglitazone therapy was more effective than placebo for increasing limb fat mass in HIV lipoatrophy, but rosiglitazone was not significantly more effective. [61] A meta-analysis of 16 trials concluded that rosiglitazone should not be used in HIV-associated lipodystrophy; that pioglitazone may be safer, but any benefits appear small; and that metformin was the only insulin-sensitizer to demonstrate beneficial effects on insulin resistance, lipids, and body fat redistribution. [62]

An improvement in lipohypertrophy and/or lipoatrophy in individuals treated with human growth hormone, [63, 64] anabolic steroids, naltrexone, and a combination of DHEA and a cyclo-oxygenase inhibitor (eg, (indomethacin 100 mg/day, naprosyn 1000 mg/day) has been reported in some cases.

Lastly, a case report has shown that the use of oral contraceptive pills worsens hypertriglyceridemia; therefore, this is not the recommended method of birth control while dealing with lipodystrophy. [65]

Surgical procedures for lipodystrophy

A variety of plastic surgery procedures have been studied for the treatment of HIV-associated lipodystrophy. [66] For lipohypertrophy, the effects of treatment with liposuction or lipectomy are variable, and recurrence is common. Fat harvested during liposuction of the dorsocervical fat pad can be used for autologous fat transfer to facial areas exhibiting lipoatrophy. [67] Facial fat grafting is further addressed in Facial Fat Grafting. Additional treatment for lipohypertrophy, classically the buffalo hump, can be accomplished with adipocitolitic aqueous microgelatinous solution. [68]

For lipoatrophy, free flaps, lipotransfer, or commercial fillers or implants can be used to replace adipose tissue. Poly-L-lactic acid (Sculptra) has been used as a semipermanent injectable filler in these patients. [69] Sculptra is approved by the FDA for the treatment of facial lipoatrophy in HIV-positive patients. In addition, the use of polymethylmethacrylate (PMMA) has been proven to benefit those patients experiencing lipoatrophy. Individuals who experience the benefits of PMMA have improved quality of life and body image, which has been shown to aid in reducing depression and increasing the compliance of antiretroviral therapy. [70, 71]

Calcium hydroxylapatite (Radiesse) is a soft-tissue filler consisting of 30% calcium hydroxylapatite microspheres and 30% carboxylmethylcellulose. It is also FDA-approved for the treatment of facial lipoatrophy in HIV-positive patients.

A 5-year study has also shown that a polyacrylamide hydrogel‒based filler is a safe and effective treatment for facial wasting. [72]

Other filler options include injectable bovine and human collagens, hyaluronic acid, [73, 74] and autologous free fat transfer. See Soft Tissue Implants for more information.

Rare cases of persistent granulomatous inflammatory reactions to some fillers have been reported [75] ; thus, patients undergoing such treatment should understand possible risks.

Diet and activity

No specific dietary regimen is used in the management of HIV-associated lipodystrophy. Adequate nutrition and exercise may result in modest improvement in lipodystrophy and improve central obesity. A balanced low-fat, low-carbohydrate diet is preferable when hypertriglyceridemia is present. [76]

Exercise has been proven to improve insulin sensitivity. One study showed that progressive resistance training with an aerobic component may reduce trunk fat mass. [77] Physical activity has also been shown to yield metabolic improvements and a decreased risk of cardiovascular disease and mortality. [78]

Consultations

Dermatologist consultation can be useful for an evaluation of the underlying causes of lipodystrophy and for consideration of surgical options. Plastic surgeons also may be considered for fillers, fat transfers, and liposuction.

Internal medicine or endocrinology specialist consultations help for an evaluation of the underlying causes of lipodystrophy and for the management of hyperlipidemia and hyperglycemia.

Infectious diseases specialist consultation is useful for the management of HIV infection.

Psychiatrist or psychologist consultation may be necessary because of the psychological impact of body shape changes.

Long-term monitoring

Follow-up laboratory testing should include assessments of the following:

  • Viral load and/or CD4+ T-cell counts to evaluate HIV-disease progression
  • Fasting lipid profile to evaluate hyperlipidemia
  • Fasting blood glucose and/or glucose tolerance test to evaluate hyperglycemia and insulin resistance

Patients should receive follow-up care every 3-6 months, and the aforementioned laboratory examinations should be performed as necessary.

Patients with HIV lipodystrophy may report feelings of anxiety, depression, loss of self-esteem, poor body image, and social and sexual dysfunction. It is important to ask about these issues and consider referral to a psychiatrist when appropriate.

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