Metabolic disorders among HIV-infected patients treated with protease inhibitors: A review

Currently available protease inhibitors are associated with development of a group of metabolic disorders. These include a peripheral lipodystrophy sy ndrome in which there is fat wasting in the face, arms, and legs; fat accum ulation in the abdomen, dorsocervical region, and/or breasts (women only); as well as hyperlipidemia. hypercholesterolemia. and insulin resistance. A review of 15 observational studies and case reports shows that the incidenc e of the peripheral lipodystrophy syndrome increases with time of exposure to protease inhibitors, with a >60% incidence seen after 1 year of continuo us treatment. Protease inhibitors are hypothesized to cause this syndrome b y impairing conversion of retinoic acid to cis-9-retinoic acid (leading to impaired peripheral fat storage, sequestration of body fat to central adipo cytes, and hyperlipidemia) and by inhibiting low-density lipoprotein recept or-related protein (LRP), thus preventing postprandial chylomicron clearanc e and further contributing to hyperlipidemia. Recent in vitro data suggest that more than one pathway contributes to the lipodystrophy syndrome and th at pathways may differ among protease inhibitors. Although the central fat accumulation, hyperlipidemia, and insulin resistance components of this syn drome may reverse after discontinuation of protease inhibitor therapy, it i s not known whether complete normalization of fast-wasted body regions is p ossible. Prospective controlled studies are needed to define whether protea se inhibitors currently under development are less prone to produce the lip odystrophy syndrome.