Hyperlipidemia and Insulin Resistance Are Induced by Protease Inhibitors Independent of Changes in Body Composition in Patients With HIV Infection

Abstract

Although protease inhibitor (PI) therapy has improved the clinical status of patients with HIV infection, concerns have arisen that such treatment may have deleterious effects on glucose control, lipid metabolism, and body fat distribution. To determine whether initiation of PI therapy uniquely affects glucose and lipid metabolism, we analyzed paired data in HIV-infected patients before and after beginning antiretroviral therapy that included a PI (PI; N = 20) or lamivudine (3TC) but no PI (3TC; N = 9); and a control group on stable regimens that included neither of these agents (CONT: N = 12). Measurements included fasting glucose; insulin; triglycerides; total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol; HIV RNA; CD4+ lymphocytes; weight; and total and regional body composition. Neither weight nor total or regional fat content changed significantly in any group during the period of observation. Nonetheless, in patients beginning PI therapy, there were significant increases in glucose (+9+/-3 mg/dl; p = .0136), insulin (+12.2+/-4.9 U/ml; p = .023), triglycerides (+53+/-17 mg/dl; p = .0069), and total and LDL cholesterol (+32+/-11 and +18+/-5 mg/dl; p = .0082 and .0026, respectively). None of these parameters changed significantly in the 3TC or CONT groups. The PI and 3TC groups experienced comparable increases in CD4+ lymphocytes, suggesting that the observed metabolic effects may be associated with PIs uniquely, rather than improvement in clinical status. However, it is also possible that the metabolic effects of PIs are associated with more effective viral suppression, because a greater proportion of patients in the PI group achieved undetectable levels of virus. We conclude that changes in glucose and lipid metabolism are induced by PI therapy in the absence of significant changes in weight or fat distribution. Longer periods of follow-up will be required to determine the clinical significance of these changes. However, at the moment, the risks associated with these metabolic effects do not appear to outweigh improvements in survival seen with PI therapy.

The effects of protease inhibitors on basal and insulin-stimulated lipid metabolism, insulin binding, and signaling

“…In concert with this, the lack of effect on lipolysis have further demonstrated the complexity of the effects of PI on the adipose tissue mass (25,26). Peripheral fat and visceral fat have been shown to behave differently in vivo (25,26). We feel that the data presented herein show key events on TG synthesis and breakdown that may help explain the effects of treatment with HAART.…”

“…Our data indicate that the effects of PI while elevating basal TG synthesis are not manifested by increased insulin-stimulated TG synthesis. In concert with this, the lack of effect on lipolysis have further demonstrated the complexity of the effects of PI on the adipose tissue mass (25,26). Peripheral fat and visceral fat have been shown to behave differently in vivo (25,26).…”

Longitudinal changes in serum lipids among HIV‐infected men on highly active antiretroviral therapy

“…Use of single or dual nucleoside reverse transcriptase inhibitors (NRTIs) was not associated with significant changes in serum lipid levels. However, within 2 years of the widespread availability of potent protease inhibitor (PI)-based highly active antiretroviral therapy (HAART), there were numerous reports of moderate to severe changes in serum lipids as well as other metabolic alterations [4][5][6][7][8][9][10][11][12]. These observations were initially anecdotal or based on limited case series, but in recent years large randomized clinical trials of HAART have routinely included prospective measurement of serum lipids [13,14].…”

The long-term effects of anti-retroviral protease inhibitors on sugar transport in L6 cells

“…While this combined anti-retroviral therapy (i.e. highly active anti-retroviral therapy or HAART) has represented a significant advance in the treatments of HIV infection, side-effects of different degrees of severity have been reported such as fat wasting, insulin resistance, central adiposity, hypertriglyceridemia and hyperglycemia (Hammer et al 1997, Mouton et al 1997, Carr et al 1998, Lo et al 1998, Virabin & Aquilina 1998, Gervasoni et al 1999, Mulligan et al 2000. Further, the removal of these drugs can reverse the metabolic disturbances; however, such an action results in a dramatic reappearance of circulating virus in the bloodstream after up to 2 years of combination drug treatment.…”