The Body Covers: The 35th Annual Meeting of the Infectious Diseases Society of America
HIV Protease Inhibitor-Induced Metabolic Disorders Are Influenced by Genetics and Diet
November 19, 1999
The description of metabolic disturbances and fat redistribution in patients receiving combination therapy with nucleoside RT inhibitors and protease inhibitors has heightened concern about the long-term potential toxicities of these regimens. Despite the growing number of clinical reports of hyperlipidemia, insulin resistance, and lipodystrophy, little is understood about the underlying pathogenesis of these disorders. These abnormalities may occur in HIV-uninfected individuals, particularly in patients with a genetic predisposition towards obesity, hypercholesterolemia, or diabetes. The development of these disorders is also strongly influenced by diet.
In order to determine the influence of diet and heredity on susceptibility to metabolic disturbances caused by protease inhibitors, Lenhard et al studied the effects of indinavir (IDV), saquinavir (SQV), nelfinavir (NFV), and amprenavir (APV) on insulin, glucose, triglycerides, lipase, and bilirubin levels in two strains of mice (ritonavir was not tested in this study). One strain, AKR/J, is susceptible to diet-induced obesity, whereas the other strain, SWR/J, is relatively resistant to diet-induced obesity. Diet had a significant influence on the effect of the various drugs. For example, SQV increased serum triglycerides both mice fed a high-fat diet, but reduced SQV levels below control in mice fed a low-fat diet. Some effects were strain-specific, however. For example, SQV, APV, and IDV produced the highest triglyceride levels in mice that were genetically resistant to diet-induced obesity (SWR/J), whereas as IDV, APV, and NFV produced the highest triglyceride levels in diet-susceptible mice (AKR/J).
Diet also influenced the effect of the protease inhibitors on serum glucose and insulin concentrations. No effect was observed in mice fed a high-fat diet, whereas IDV and NFV both increased serum glucose and decreased plasma insulin levels.
It is not certain to what extent these results can be extrapolated to humans. For example, IDV and NFV had similar effects on triglycerides in this study, whereas NFV is less frequently associated with hypertriglyceridemia in patients. Nevertheless, the results of this study show that metabolic effects of protease inhibitors are not necessarily class-specific, and that each drug may have unique effects that can be modulated by genetic and enivronmental factors. These factors will need to be considered when designing studies to explore the pathogenesis of the metabolic disorders associated with antiretroviral therapy.
Authored by: J. Lenhard, J. Weiel, D. Croom, A. Spaltenstein, J. Binz, D. Reynold, P. Wheelan, E. Furfine
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