Clinical Institute of Infections and Immunology, Institu d'Investigacions Biomédiques August Pi i Sunyer, Hospital Clínic, 08036Barcelona, Spain
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Abstract |
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Keywords: definition , treatment , body fat changes , metabolic abnormalities , structured treatment interruptions
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Introduction |
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HIV-associated lipodystrophy may affect up to half or even more HIV-infected patients receiving antiretroviral therapy.1,2 Antiretroviral drugs, which have a variety of effects, may play a role in the pathogenesis of body fat changes. However, at present it is not known whether lipodystrophy is a unique syndrome or several different overlapping syndromes. Several metabolic features (such as dyslipidaemia and insulin resistance, and body fat abnormalities consisting of a generalized decrease in subcutaneous fat with or without intra-abdominal, breast or dorsocervical accumulation) have been commonly reported, although the intensity and the associations of those changes have been highly variable. Other derangements such as hyperlactataemia, decreased bone mineral density, avascular necrosis, hypogonadism and hypertension have been described, although their relationship with the lipodystrophy syndrome has not been clearly established. The consequence of body fat changes is social stigmatization that may lead to poorer adherence and the failure of antiretroviral therapy. Moreover, metabolic abnormalities may increase the risk of cardiovascular disease.3 The knowledge of some aspects of this problem has increased in recent years, but many important questions still remain to be answered.
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Definition of lipodystrophy |
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Measurement |
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Another important issue is whether it is necessary to incorporate objective measurements of regional body fat into clinical practice, beyond investigational purposes. The availability and cost of current objective techniques are certainly important obstacles. However, the evolution of even minimal changes of body fat need to be detected and measured objectively, in order to prevent or diminish further evolution and also in order to evaluate accurately any possible intervention. We strongly believe that clinicians and healthcare providers should try to incorporate a readily available objective technique, to be performed as a part of standard procedures in the care of HIV-infected patients.
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Managing HIV lipodystrophy |
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The use of recombinant human growth hormone (rhGH) can be beneficial in patients with increased visceral abdominal fat and/or buffalo hump, but it is not recommended for the treatment of lipoatrophic aspects of lipodystrophy syndrome, as it may lead to a decrease in peripheral fat. The safety of this drug and its long-term efficacy are of concern due to a high rate of dropout and adverse reactions in several trials using high doses of rhGH.1719
Epidemiological data show an increased risk of HIV-associated lipodystrophy in women, older patients, lower nadir CD4 cell count, lower body mass index and/or AIDS diagnosis, as well as hepatitis C virus co-infection.2022 Patients with higher risk require closer follow-up, and since it is so difficult to obtain lipodystrophy reversion, it is important to try to prevent it by choosing an optimal treatment with a lower incidence of lipodystrophy.2326
The impact of switching antiretroviral drugs that are supposed to be involved in lipodystrophy has been commonly assessed in different studies. The majority of these studies and the first performed historically were those concerned with discontinuing protease inhibitors.27,28 In general, switching protease inhibitors may improve metabolic abnormalities, particularly those induced or increased by protease inhibitor therapy, but the impact on body fat is very small or nil. Switching thymidine analogues (most data coming from stavudine discontinuation or dose reduction) has been the only intervention to improve lipoatrophy in different independent studies.2934
The effect of discontinuing all antiretroviral therapy on the evolution of lipid abnormalities and body fat is poorly known. There are some preliminary data obtained from a group of well-controlled patients with primary HIV infection that have shown gain of total and regional fat during consecutive cycles of structured treatment interruptions (STIs).35 This issue will be addressed in the now ongoing large scale studies, such as the SMART study. Although STIs can be an attractive strategy to prevent or treat lipodystrophy they may also have unfavourable consequences, such as HIV drug resistance emergence, and immunological and virological disease progression. Because of this, patients have had to be closely monitored and chosen from the group of immunologically preserved HIV-infected patients in which even prolonged STIs have been shown to be generally safe.36
Treatment with thiazolidinediones and leptin has shown good results in the group of non-HIV-infected patients with familial and autoimmune lipodystrophy.3739
Moreover, two small uncontrolled studies suggested that rosiglitazone might contribute to fat gain regardless of ongoing antiretroviral therapy.40 However, randomized, placebo-controlled studies have shown that rosiglitazone does not improve fat mass in HIV lipoatrophy, and may even worsen dyslipidaemia despite the improvement of insulin sensitivity.41,42
The lack of the effect of rosiglitazone seems to be related to the continued exposure to thymidine analogue therapy.43
Data from randomized studies comparing the effects of metformin, gemfibrozil and placebo in the group of patients receiving highly active antiretroviral therapy (HAART) found less fat loss with gemfibrozil than with placebo, and no effect of metformin, but all patients lost fat over time, which, although it may reduce cardiovascular risk parameters, leads to aggravation of peripheral lipoatrophy.4446 Therefore, there are too few reasons to support widespread therapeutic interventions with metabolic drugs, except on an individual basis.47
Since there is no effective and quick solution for lipodystrophy, there is a growing demand for interventions with immediate results. This explains why the advances in the field of plastic and reparatory surgery are such attractive treatment options. Liposuction performed in some patients with severe buffalo hump as well as increased subcutaneous fat depots gave good results in the short-term, but some patients re-accumulated fat in the following months.48,49 Unfortunately, excision or liposuction is not a treatment option in patients with visceral fat accumulation.
Implant surgery for lipoatrophy can be performed using permanent or biodegradable implants such as poly-L-lactic acid50,51 (the first filler approved by the US Food and Drug Administration for the treatment of HAART-associated facial lipoatrophy),52 hyaluronic acid,53 Bio-Alcamide54,55 or autologous fat from the dorsocervical or subcutaneous abdominal area.56 The treatment of facial lipoatrophy by injecting autologous adipose tissue (Coleman's lipostructure) seems to be a satisfactory and cost-effective option to treat facial lipoatrophy if there is a source of fat graft existing.57 Prospective studies are ongoing to assess the durability, complications58 and potential differences among surgical procedures.51
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Conclusions |
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The only intervention that has been shown to revert lipoatrophy is the discontinuation of thymidine analogues, but the results obtained are partial and slow at best. Structured therapy interruption has become an increasingly popular strategy aimed at preventing antiretroviral drug toxicity, but few objective data exist on its impact on the body composition of HIV-infected patients. At present, the only available solution is plastic surgery, which may at least give satisfactory aesthetic results in the absence of other definitive options.
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References |
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