Summary: 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.
Therapy with protease inhibitors (PIs) decreases plasma HIV RNA levels, increases CD4+ lymphocyte counts, reduces the rates of opportunistic infections, and prolongs survival in patients with HIV infection (1-7). However, results of cross-sectional studies and case reports suggest that this class of agents may also have potentially deleterious metabolic effects, such as hyperglycemia (8-11), insulin resistance (12-14), and hyperlipidemia (12,15-17). Additionally, a number of HIV-infected patients have developed alterations in body composition, including increased abdominal girth (16,18), buffalo hump (19), total or peripheral lipodystrophy (12,18,20), lipomatosis (21), and breast enlargement (22,23), that some clinicians and patients are attributing to the use of PIs. Because hyperglycemia, insulin resistance, hypertriglyceridemia, hypercholesterolemia, and central obesity are associated with increased risk of cardiovascular disease, these effects, if substantiated, may impact on the long-term prognosis in patients whose life expectancies are now significantly extended because of effective viral suppression by PIs.
Although insulin resistance, hypercholesterolemia, and hypertriglyceridemia have been observed in HIV-infected patients with increased abdominal girth (16) and lipodystrophy (12), it is not yet known whether the metabolic changes and abnormal fat distribution represent one or more syndromes. Moreover, in patients with fat redistribution and metabolic abnormalities, it is not known whether the metabolic abnormalities precede or result from the changes in body composition. Likewise, it is not clear whether these effects are unique to PI therapy or simply manifestations of improving overall health. We report herein longitudinal data, obtained under fasting conditions, suggesting that initiation of PI therapy may, indeed, have unique metabolic effects that occur relatively early in the course of treatment and precede significant changes in body fat content or distribution.