HIV lipodystrophy and its metabolic consequences: implications for clinical practice.
ABSTRACT The introduction of highly active antiretroviral therapy (HAART) around 1996 markedly reduced mortality and morbidity from human immunodeficiency virus (HIV) infection. As life expectancy has improved, the chronic complications of HIV and HAART have become increasingly relevant.
This article provides an overview of the HIV-associated lipodystrophy, its pathogenesis and its clinical consequences (based on a search strategy in PubMed including literature published to November 2007).
Lipodystrophy syndrome is characterized by abnormal fat distribution syndrome associated with metabolic disturbances and includes insulin resistance, deranged glucose and lipid metabolism. It is associated with increased risks of progression to type 2 diabetes and cardiovascular disease. Robust diagnostic criteria are required for lipodystrophy, and subsequent prospective cohort studies and randomized controlled trials are then required to determine the etiology and prognosis of lipodystrophy, and to evaluate therapeutic interventions for this consequence of HAART. Therapies to improve insulin resistance have been tried but they are frequently ineffective, and are limited by potential toxicity in this population. Hence, current management options for HIV associated lipodystrophy are limited and are mostly based on avoidance of risk factors and switching of antiretroviral drugs.
As the '3 by 5 strategy' of providing HIV drugs to the developing world is implemented worldwide, the numbers of patients adhering to antiretroviral medicines is dramatically increasing. One must be aware that in reducing the burden of acute retroviral disease, the treatments proposed might lead to significant rates of metabolic complications and further exacerbation of the epidemic of diabetes and cardiovascular disease.
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ABSTRACT: HIV therapy with nucleoside analogue reverse transcriptase inhibitors (NRTI) such as stavudine remains in widespread use in resource-limited nations due to potent efficacy, convenience of formulation and lack of practical alternatives. However, it remains unclear whether adverse side effects with NRTI include reduced mitochondrial respiratory function, particularly in peripheral blood lymphocytes (PBLs). The aim of this study was to determine whether stavudine-based highly active antiretroviral therapy (HAART) is associated with impaired mitochondrial respiratory transport chain function in patient derived CD4+PBLs. CD4+PBLs were isolated from asymptomatic HIV-infected patients treated with stavudine-HAART for 3 months (n=10), HIV-infected patients not on treatment (n=9) and uninfected controls (n=18). The basal mitochondrial oxygen consumption of CD4+PBLs from stavudine-treated patients was reduced relative to that of untreated HIV-infected patients and controls (stavudine treated group, 4.22 (25% 2.16, 75% 8.84); control uninfected, 11.2 (25% 3.95, 75% 16.6); untreated 18.1 (25% 11.8, 75% 37.9)ng oxygen atoms/min/ml). Maximal oxygen consumption (stimulated with the proton ionophore FCCP) in cells from stavudine treated patients was also reduced relative to that of untreated patients and controls (stavudine treated, 24.4+/-10.5; control uninfected, 50.6+/-39.5; untreated, 68.8+/-41.1 ng oxygen atoms/min/ml). Citrate synthase activities, relative mitochondrial volume (by electron microscopy) and mtDNA copy numbers per cell were not different between groups. Therapy with stavudine results in impaired mitochondrial function in CD4+PBLs that does not appear to be due to reduced mitochondrial volume or DNA content and cannot be attributed to infection with HIV.Mitochondrion 08/2010; 10(5):534-9. DOI:10.1016/j.mito.2010.05.010 · 3.52 Impact Factor
Article: Tesamorelin[Show abstract] [Hide abstract]
ABSTRACT: Tesamorelin (Egrifta™) is a synthetic analogue of human growth hormone-releasing hormone (also known as growth hormone-releasing factor) that stimulates the synthesis and release of endogenous growth hormone. It is the first and, so far, only treatment indicated for the reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. This article reviews the pharmacological properties, clinical efficacy and tolerability of tesamorelin in patients with HIV-associated central fat accumulation. Subcutaneous tesamorelin was effective in reducing visceral adipose tissue (VAT), but did not affect subcutaneous adipose tissue to a clinically significant extent in two 26-week, well designed, clinical trials in patients with HIV-associated central fat accumulation. This reduction in VAT was maintained in the longer term in patients who continued to receive tesamorelin until week 52 in the extension phases of the two trials. However, discontinuation of therapy during this period resulted in the reaccumulation of VAT. Tesamorelin therapy was also associated with significant improvements in other body composition measures (e.g. trunk fat and waist circumference) and improvements were generally seen in some body image parameters (e.g. belly image distress). Tesamorelin was generally well tolerated, with treatment-emergent serious adverse events occurring in <4% of patients during 26 weeks of therapy. Most of these events were injection-site reactions or events known to be associated with growth hormone therapy (e.g. arthralgia, headache and peripheral oedema). Although long-term clinical experience is needed to further assess the benefits and risks of therapy, current evidence suggests that tesamorelin may be useful for reducing visceral adiposity in patients with HIV-associated lipodystrophy, thereby potentially improving self image.Drugs 01/2011; 71(8). DOI:10.2165/11202240-000000000-00000 · 4.13 Impact Factor
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ABSTRACT: Chronic complications of human immunodeficiency virus (HIV) and highly active retroviral therapy have become increasingly relevant as life expectancy for HIV patients has improved and the affected population ages. HIV-associated lipodystrophy syndrome is characterised by an abnormal fat distribution syndrome associated with metabolic disturbances including insulin resistance, and deranged glucose and lipid metabolism. It is associated with increased risks of progression to type 2 diabetes and cardiovascular disease.Lipodystrophy is a clinical diagnosis and mostly subjective as standardised diagnostic criteria have not yet been defined. Several therapeutic interventions have been investigated including lifestyle therapy, vitamin supplements, switching antiretroviral therapy and specific therapies for insulin resistance and hyperlipidaemia. Current management options for HIV associated lipodystrophy are limited and are mostly based on avoidance of risk factors and switching of antiretroviral drugs. Therapies to improve insulin resistance have been tried but they are frequently ineffective as are lipid-lowering drugs. Interest in anabolic agents has been resurrected and new clinical data suggest that HIV-associated lipodystrophy growth hormone releasing factor therapy may have a beneficial role in the treatment of HIV-associated lipodystrophy. However, there still remains a need for robust prospective cohort studies and well designed intervention trials to resolve the aetiology and define the best treatment for this complication of HIV disease and its treatment.The British Journal of Diabetes & Vascular Disease 05/2008; 8(3):113-119. DOI:10.1177/14746514080080030201