Protease Inhibitors PI

The introduction of highly active antiretroviral therapy (HAART) has significantly improved the survival and quality of life of HIV-infected individuals. However, HARRT-regimen, especially those including PIs have also resulted in increased incidence of metabolic syndrome and diabetes. Eleven PIs are now available in US and at least eight of them are clearly associated with disturbance in glucose homeostasis. It is estimated that up to 40% of patients receiving Pi-based regimen show glucose intolerance and 6% to 7% develop new-onset diabetes (92). One of the early reports of Pi-induced diabetes was in 1997 by Visnigarwala et al. (93) when addition of nelfinavir to the patient's regimen resulted in overt diabetes in less than 2 weeks. The duration of PI therapy preceding the onset of hyperglycemia or overt diabetes is still debatable, timing of onset has been seen as early as 2 weeks (94) to as late as up to 24 months (95). Some investigators have shown the biochemical abnormalities with even a single dose of indinavir (96).

Currently, mechanisms responsible for hyperglycemia and onset of overt diabetes with use of PI include onset of insulin resistance (97), presence of beta cell dysfunction (98) and effect of dyslipidemia on both peripheral resistance and beta-cells (99).

Several studies have shown that use of PI results in decreased activity of GLUT4, a major transporter for glucose uptake by the peripheral tissues, especially in skeletal muscle resulting in insulin resistance (100).

Literature is also rife with data showing direct effect of PIs on beta cells resulting in decreased release of insulin in the setting of insulin resistance (101). In addition, recent literature also proposes the role of lipotoxicity in the insulin resistance. A study by Yarasheski et al. (102) presented data from a cross-sectional study of 22 non-obese, HIV-infected individuals in whom insulin sensitivity was assessed with hyperinsulinemic euglycemic clamp. Author found an inverse correlation between insulin sensitivity and hepatic and soleus muscle lipid content.

The newer PIs—atazanavir, tipranavir, mozenavir and amprenavir—do not seem to have any hyperglycemic effects.

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