Anti-retroviral protease inhibitors--'a two edged sword?'

The use of anti-retroviral protease inhibitors in combination with nucleoside analog or non nucleoside reverse transcriptase inhibitors (HAART) has led to dramatic decreases in the mortality seen with HIV infected patients. In concert with these treatment regimens, especially with the inclusion of the anti-retroviral protease inhibitors (PI), a complex series of metabolic complications occurred. These included alterations of fat and carbohydrate metabolism. In some patients, one could observe either lipoatrophy (fat wasting) as well as lipohypertrophy (fat deposition) or both. The problem is that the lack of a case definition of the altered fat metabolism confuses diagnoses. In vitro, interference with fat cell differentiation has been demonstrated by PI. Further, in vitro studies demonstrate that indinavir, a PI currently used in HIV treatment, can interact with the insulin responsive glucose transporter (GLUT4). The activity of the GLUT4 is inhibited by indinavir and eventual insulin resistance has been shown (i.e. in vivo and in vitro). Also, controversy exists regarding insulin signaling in fat cells. Finally, the relationships between hyperlipidemia and/or lipolysis and altered carbohydrate metabolism (i.e. mild glucose intolerance, insulin resistance) suggest an association with cardiovascular risk in protease treated patients (Metabolic Syndrome X). In short, while multiple problems exist, no one mechanism can account for the changes observed.