HIV-associated lipodystrophy: a review of underlying mechanisms and therapeutic options
Journal of Antimicrobial Chemotherapy (2008) 62, 648– 660
doi:10.1093/jac/dkn251
Advance Access publication 18 June 2008
HIV-associated lipodystrophy: a review of underlying mechanisms
and therapeutic options
Jane E. Mallewa1*, Edmund Wilkins1, Javier Vilar1, Macpherson Mallewa2, Dominic Doran3,
David Back4 and Munir Pirmohamed5
Department of Infectious Diseases, North Manchester General Hospital, Delaunays Road, Manchester M8 5RB,
UK; 2Division of Child Health, Royal Liverpool Children’s Hospital, University of Liverpool, Eaton Road,
Liverpool L12 2AP, UK; 3Department of Sports Science, Liverpool John Moores University, Henry Cotton
Campus, 15–21 Webster Street, Liverpool L3 2ET, UK; 4Department of Pharmacology and Therapeutics,
University of Liverpool, 70 Pembroke Place, Liverpool L69 3GF, UK; 5Department of Pharmacology and
Therapeutics, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK
Lipodystrophy (LD) is a common adverse effect of HIV treatment with highly active antiretroviral
therapy, which comprises morphological and metabolic changes. The underlying mechanisms for LD
are thought to be due to mitochondrial toxicity and insulin resistance, which results from derangements in levels of adipose tissue-derived proteins (adipocytokines) that are actively involved in energy
homeostasis. Several management strategies for combating this syndrome are available, but they all
have limitations. They include: switching from thymidine analogues to tenofovir or abacavir in lipoatrophy, or switching from protease inhibitors associated with hyperlipidaemia to a protease-sparing
option; injection into the face with either biodegradable fillers such as poly-L-lactic acid and hyaluronic
acid (a temporary measure requiring re-treatment) or permanent fillers such as bio-alcamid (with the
risk of foreign body reaction or granuloma formation); and structured treatment interruption with the
risk of loss of virological control and disease progression. There is therefore a need to explore alternative therapeutic options. Some new approaches including adipocytokines, uridine supplementation,
glitazones, growth hormone (or growth hormone-releasing hormone analogues), metformin and statins
(used alone or in combination) merit further investigation.
Keywords: adipocytokines, antiretroviral therapy, protease inhibitors, nucleoside reverse transcriptase inhibitors
Introduction
The success of controlling HIV infection with antiretroviral
drugs (ARVs) and the resultant reduction in morbidity and mortality has been marred somewhat by the development of significant adverse effects in some patients, which include metabolic
and morphological changes. Lipodystrophy (LD) is a term used
to embrace these changes that comprise peripheral lipoatrophy,
localized fat accumulation (visceral, back of neck and lipomata),
hyperlipidaemia, insulin resistance and hyperglycaemia.1 The
prevalence rate of LD in patients on highly active antiretroviral
therapy (HAART) is reported to be up to 40%.1,2 The frequency
of LD, not unexpectedly varies with the drugs used. Nucleoside
reverse transcriptase inhibitors (NRTIs), particularly thymidine
analogues (zidovudine and stavudine), have been associated with
morphological changes, particularly extremity fat loss,3 while
protease inhibitors (PIs) have been associated with biochemical
derangements of glucose and lipids as well as with localized
accumulation of fat.4 NRTIs such as stavudine have also been
shown to be associated with dyslipidaemia.5 Since the drugs are
often used together as part of HAART, clinical data suggest that
they act synergistically in causing LD. The body changes of LD
are distressing and can be stigmatizing for sufferers. The metabolic effects have been associated with an increased risk of
cardiovascular disease.6 – 9 Mitochondrial toxicity, insulin resistance, adipose gene expression derangements, genetic polymorphisms and cellular dysfunction are thought to be important
pathophysiological mechanisms underlying the development of
LD.8,10 – 16
.....................................................................................................................................................................................................................................................................................................................................................................................................................................
*Corresponding author. Tel: þ44-1516410099/7841203427; Fax: þ44-1617202562; E-mail:
.....................................................................................................................................................................................................................................................................................................................................................................................................................................
648
# The Author 2008. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved.
For Permissions, please e-mail:
1
Review
The mechanisms of HIV LD
Mitochondrial toxicity
Insulin resistance and adipose tissue-derived cytokines
Derangement in the function of adipocytes in adipose tissue is
thought to result in insulin resistance. Studies have shown that the
insulin resistance associated with obesity and type II diabetes is
mediated at the level of the adipocyte and adipose tissue. The
adipocyte has been shown to be actively involved in energy
homeostasis by secreting hormones or proteins that have collectively been termed adipocytokines (adiponectin, leptin, resistin
and visfatin).21 – 23 Adipocytes also secrete pro-inflammatory cytokines such as tumour necrosis factor-a (TNF-a) and interleukin-6
(IL-6).21,24 These cytokines are known to affect glucose and lipid
metabolism and may also alter body habitus.8,21,23 Obese and type
II diabetic patients have raised levels of TNF-a, IL-6 and leptin;
they also show reduced levels of adiponectin while levels of resistin have been variable.24
Altered levels of adipocytokines and pro-inflammatory
markers have also been demonstrated in in vitro (in murine and
human adipocytes cell lines) and in vivo studies with the use of
NRTIs ( particularly zidovudine and stavudine) and PIs in HIV
patients.25 – 29 PIs led to the following changes in these studies:
(i) A reduction in lipid accumulation in adipocytes.
(ii) Increase in adipocyte apoptosis leading to a reduction in
cell numbers.
(iii) Induction of insulin resistance by:
(a) Inhibition of insulin-stimulated glucose uptake via inhibition of the glucose transporter (GLUT-4).
(b) Induction of IL-6 and TNF-a.
(c) Reduction in gene expression and secretion of
adiponectin.
(d) Increased lipolysis.
The ability of PIs to induce these changes varies between
the individual drugs, with lopinavir, ritonavir, saquinavir and
Adipose gene (...truncated)
