HIV-associated lipodystrophy or lipoatrophy, unreported before the introduction of
highly active antiretroviral therapy (
HAART), was first described in 1998, and has a prevalence ranging from 18% to 83%. As in genetic
lipodystrophy syndromes, fat redistribution may precede the development of metabolic complications (
dyslipidemia,
insulin resistance) in HIV-infected patients receiving
HAART. The pathogenesis of
HAART-associated
lipodystrophy and
metabolic syndrome is complex and a number of factors are involved, including direct effects of
HAART on lipid metabolism, endothelial and adipocyte cell function, and mitochondria.
Protease inhibitors are responsible for a decrease in cytoplasmic
retinoic-acid protein-1, in
low density lipoprotein-receptor-related
protein and in
peroxisome proliferator activated receptor type-gamma.
Nucleoside reverse transcriptase inhibitors, and
thymidine analogues, are responsible for
mitochondrial dysfunction as demonstrated by a decrease in subcutaneous adipose tissue
mitochondrial DNA content. Both phenomena are responsible for a decreased differentiation of adipocytes, increased levels of
free fatty acids and lipoatrophy. The increased levels of proinflammatory
cytokines, such as
tumor necrosis factor (
TNF)-alpha and
interleukin-6 may further contribute in development of
lipodystrophy. TNF-alfa activates 11-beta-hydroxysteroid
dehydrogenase type-1, which converts inactive
cortisone to active
cortisol, resulting in increased
lipid accumulation in adipocytes and
insulin resistance.
HAART drugs and inflammatory
cytokines are associated with a decrease in
adiponectin. The levels of
adiponectin and
adiponectin-to-
leptin ratio correlate positively with
insulin resistance in HIV-infected patients with
lipodystrophy.
HAART-associated
metabolic syndrome is an increasingly recognized clinical entity. The atherogenic profile of this syndrome may increase the risk of
cardiovascular disease even in young HIV-infected patients. A better understanding of the molecular mechanisms responsible for this syndrome will lead to the discovery of new drugs that will reduce the incidence of
lipodystrophy and related metabolic complications in HIV-infected patients receiving
HAART.