Facial Lipoatrophy in HIV-infected Patients
Facial Lipoatrophy in HIV-infected Patients |
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Key words: HIV infection, lipoatrophy, lipodystrophy, body image, anti-retrovirals, management.
Introduction
Facial wasting is rapidly becoming an important issue in the lives of those living with HIV. Facial lipoatrophy is often seen as part of a complex metabolic and morphologic change seen in HIV infected patients treated with antiretroviral therapy. Lipoatrophy has multiple characteristics, depending on the affected part of the body. The most problematic for patients is buccal fat pad thinning, which results in the appearance of facial wasting. Other sites of lipoatrophy include the buttocks and the extremities.
A person's HIV status sometimes becomes apparent just looking at their face. Quality of life and not vanity, is the central issue for patients with the most severe degree of facial lipoatrophy. The stigma associated with facial wasting frequently result in poor self-image, social isolation and depression. These characteristic changes of facial lipoatrophy may lead to consideration of delayed initiation of antiretroviral therapy, modification of established therapy to alternative regimens, or discontinuation of therapy to prevent or attempt to manage the problems.
Aetiology and Pathogenesis
Prevalence rates for fat redistribution syndromes have varied in published studies. The lack of standardized case definitions limits the ability to compare data across studies. The topics of aetiology and pathogenesis of facial lipoatrophy is confusing because of their extreme complexity.
Similar metabolic disturbances was seen in a study of HIV-uninfected individuals who had undergone bone marrow transplant but were now mostly off immunosuppressants (1). A range of host and disease factors as well as antiretroviral treatments have been associated with an increased risk of HIV lipodystrophy. Factors related to HIV disease and/or immune recovery may interact with antiretroviral medication (2). Some observational studies have found an association between lipodystrophy and either complete viral suppression, a history of a low CD4+ cell count or, in particular, the change in CD4+ cells count during therapy. Protease inhibitors (PIs) and the nucleoside reverse transcriptase inhibitors (NRTIs) have been associated with these changes (3,4,5). However, there have been reports of patients who have never received PIs (6,7) or have never received or have developed the syndrome while not receiving NRTIs, (8,9). This indicates that these agents alone do not exclusively cause the problem. The highest cumulative prevalence of morphologic abnormalities in these studies appears to be in persons receiving both PIs and NRTIs compared with other combinations.
The mechanism by which NRTIs contribute to the syndrome is not known. There is some evidence to support mitochondrial toxicity (9) however; some data have accumulated to refute this hypothesis (10). Fat biopsy studies demonstrate modest reduction in mitochondrial DNA (mtDNA) in samples from lipoatrophic patients. A possible mechanism by which PIs may contribute to this syndrome includes diminishing fat-cell replacement, (11) blocking fat-cell insulin-dependent glucose uptake via the GLUT4 transporter, (12) and altering liver processing and release of fat (13). Inhibition of the GLUT4 adipocyte- and myocyte-based insulin-dependent transporter may be an important mechanism by which PIs contribute to the morphologic syndrome, since GLUT4-deleted mice have reduced amounts of subcutaneous fat (12). Although the role of PIs in metabolic disturbances appears clear, differences may exist between drugs.
Fat biopsy samples have shown higher levels of tumour necrosis factor alpha (TNF-a) in individuals with clinical lipoatrophy on therapy than on those treatment-matched controls without lipoatrophy (14). TNF-a is a known inducer of apoptosis in adipocytes, and may be produced by adipocytes or by T cells located in adipose tissue. Dysregulation of TNF-a production may occur in persons on highly active antiretroviral therapy (HAART), and an association between lipoatrophy and the proportion of TNF-a-producing CD8+ cells was noted in one study (15). Raised levels of serum TNF-a receptor are associated with insulin resistance and lipoatrophy (16) and, individuals with specific TNF-a polymorphisms appear more prone to develop lipodystrophy. These data highlight the concept that genetic and cytokine markers may explain why some individuals rapidly
develop the lipodystrophy syndrome, while others remain unaffected during many years of the same therapy.
Predisposing Factors
An important study of predictors and risk factors has been the HIV Outpatient Study (HOPS) (17) carried out in USA. This study looked at 1077 patients who visited eight clinics in seven cities in the United States of America and identified host factors, drug factors, and disease state as important determinants of body shape changes. One or more signs of fat redistribution were reported in 49% of patients. Signs of lipoatrophy seen in 13% of patients, 13% had fat accumulation and 23% had a mixed syndrome. The univariate predictors for body shape changes included older age, use of stavudine, use of indinavir for more than 2 years, body mass index (BMI) decrease, and longer duration and more advanced stage of HIV infection. In terms of individual agents, stavudine was associated with increased fat loss, while indinavir was associated with increased central obesity.
Multivariate analyses indicated that HIV Infection and host factors were more critical to the development of new lipodystrophy than were drug factors. Specifically, white race was associated with a 5-fold increase in the relative odds of developing lipodystrophy. The CD4 cell count nadir and the magnitude of change in the CD4 cell count were also associated with increased risk: Individuals with a history of a CD4 cell count less than 100 cells/mm3 and those whose CD4 cell count had not risen by more than 100 cells/mm3 were more likely to develop lipodystrophy. This suggests a role for immune reconstitution in the pathogenesis of metabolic abnormalities (17). Individuals with BMI less than 24 had 2.4-fold greater odds of developing lipodystrophy (18). There was no association between the onset of lipoatrophy, duration, initiation, continuation, and discontinuation of any antiretroviral medication.
Women are more likely than in men to be affected, however, this may vary by the type of morphologic changes. Men tend to experience more fat loss, particularly from the extremities. Women, on the other hand, are more likely to have lipohypertrophy, such as increased intra-abdominal fat and breast enlargement.
Clinical presentation
Patients may have a mixed syndrome consisting of both lipohypertrophy and lipoatrophy.
Loss of subcutaneous fat, or lipoatrophy, has multiple characteristics, depending on the affected part of the body. The most problematic for patients is buccal fat pad thinning, which results in the appearance of facial wasting. Fat may also be lost from the temple and under the zygoma. Other sites of lipoatrophy include the buttocks and the extremities. Such fat loss in the arms and legs may result in abnormal protrusion of veins, which is also stigmatizing. Lipoatrophy should be distinguished from HIV-associated wasting. A patient with wasting experiences progressive decreases in body weight in the form of decreases in both lean body mass (LBM) and fat mass. In addition, wasting is characterized by decreases in cross-sectional muscle area (CMA) and waist girth. In contrast, patients with fat redistribution generally have a stable body weight.
Diagnosis
The prevalence and incidence rates of lipodystrophy vary widely and frequently rely upon self- and or clinician reports. Currently no validated assessment tool for facial lipoatrophy is available. CT and MRI scans are valuable in patients with morphologic changes. Whole-body MRI can be used to compare whole-body and regional skeletal muscle and adipose tissue contents. Multiscan, single-slice CT is accurate at measuring total body skeletal muscle mass in patients with HIV infection. It also is able to characterize the extent of lipoatrophy. Measuring skin-fold thickness (Anthropometry), dual-energy x-ray absorptiometry (DEXA) are not suitable for assessing facial lipoatrophy. Since many of the standard body composition measurement techniques are limited in their ability to detect facial wasting, the clinician may need to rely on more simple procedures, such as patient reporting and photographs.
Management
Since the treatment of established lipoatrophy is limited, interventions that diminish the chance of lipodystrophy occurring may be crucial. Possible strategies includes, choosing regimens that avoid combining PIs and NRTIs, avoiding stavudine containing combinations or Commencing therapy before the CD4+ cell count reaches 200 cells/mm3. Avoidance of a low CD4+ cell count may be a critical issue in reducing the risk of lipoatrophy, which may have implications for the debate regarding when to start antiretroviral therapy. The use of immune modulators may also have a role, because achieving a rapid increase in CD4+ cell count may reduce the risk of lipoatrophy. Equally important may be dietary interventions to aggressively manage weight loss before it becomes substantial.
Once established, consideration should be given for early intervention. The management of facial lipodystrophy falls into 3 categories:
1. Modifications of the treatment regimen
2. Specific drug therapies
3. Cosmetic surgery.
Therapy Modifications
Individuals considering changing their treatment regimen because of lipodystrophy must keep in mind that they may put at risk their long-term HIV management in exchange for an uncertain outcome with regard to their lipodystrophy. Beneficial effects of treatment modifications on lipoatrophy have not been consistently observed in clinical trials. In light of the fact that morphologic changes can occur with any current drug combination, it is not surprising that the strategy of switching therapy away from specific drugs or drug classes has not led to resolution of the syndrome.
Specific drug therapies
With regard to specific drug therapies for individual manifestations of lipodystrophy, there is interest in the use of metformin (20), glitazones, and growth hormone. Metformin may have beneficial effects on fat accumulations and insulin resistance and may improve some lipid and coagulability factors. Benefits for patients with peripheral lipoatrophy have not been reported. A retrospective analysis of rosiglitazone identified nine normoglycemic individuals who had received this drug. Rosiglitazone was increased from 4 mg to 8 mg in five individuals during the course of therapy. After a median twenty-four weeks of therapy, four patients had reported an improvement in facial fat wasting and thinning of the extremities. Growth hormone may improve fat metabolism and lead to improvements in appearance of both fat accumulation and lipoatrophy, including facial changes. Unfortunately the improvements reverted when growth hormone therapy was discontinued.
Cosmetic therapy
At present, no therapies are available that reverse the metabolic disturbances that cause lipoatrophy. As a result, the focus has shifted to treatments that directly compensate for the loss of facial fat. A number of different approaches have been proposed to reconstruct normal facial contours. Cosmetic approaches such as fat transfer, collagen, and implants are expensive. Fat transfer is only feasible if fat is available to harvest from other body areas and injected into spaces where fat has been lost. Unfortunately the transferred fat usually resorbs within months. Facial implants may also be used but there is a risk that fat loss may occur around the implant, resulting in a lumpy appearance.
"Filler" materials can be injected to restore the appearance of subcutaneous fat. Some are biodegradable and therefore give temporary relief. Bovine collagen is an example of a biodegradable material. It is expensive, can cause allergic reactions, and does not last very long. Other synthetic materials (Silicone), which are non-biodegradable and provide a more permanent effect but could lead to chronic infection or glaucomatous reaction.
The use of polylactic acid injections (New-fill) for treating facial lipoatrophy has attracted considerable interest. Polylactic acid is a biocompatible, bioabsorbable synthetic polymer belonging to the family of aliphatic polyesters. Polylactic acid implants have been used safely in a variety of clinical applications since the mid-1990s in a range of medical and surgical applications (rheumatology, reconstructive traumatology). It stimulates fibroblasts to produce collagen and thus is not really a "filler”. It is hypoallergenic and biodegradable over the course of about 2 years, so it does not trigger the chronic inflammatory reactions that may accompany silicone injections. It takes 3-5 sessions for moderate facial wasting, and 6-7 for severe facial wasting. A significant increase in the median total cutaneous thickness of greater than 10 mm has been observed with this treatment in the majority of patients. Bruising and local skin infections are the main adverse effects. Some patients may develop non-visible subcutaneous
micronodules.
Conclusion
The impact of facial lipoatrophy on self-image and self-esteem is devastating for the HIV infected patient. The aetiology of fat redistribution is multifactorial and overlapping and cannot be ascribed to any single agent. Antiretroviral agents are only part of the problem. Factors related to HIV disease, immune reconstitution, and direct effect of antiretrovirals may all play a role. As morphologic changes can occur on any regimen, it is not surprising that attempts to manage lipodystrophy by modifying the antiretroviral regimen have had only limited success. Lipodystrophy and lipoatrophy can occur in the absence of NRTIs or in the absence of PIs, thus, neither class of agent is necessary for or exclusively causative of the syndrome. Switching from a PI-based regimen may improve metabolic parameters, but effects on fat maldistribution are less clear. Given the current state of knowledge, a major question is whether the specter of lipodystrophy should affect our prescribing
practices. In fact, it has played a role in the development of diverse strategies, including PI-sparing therapies, NRTI-sparing therapies, switching therapies, interrupting treatment, and treating intermittently. But hard data is not available to show that these interventions are effective.
The efficacy, safety profile, and the simplicity of the injection schedule associated with the use of polylactic acid (New-fill) make this filling material a potentially attractive treatment that may help alleviate the psychological and social consequences of facial lipoatrophy in affected HIV-infected patients.
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