Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy - A 5-year cohort study

Background: Although human immunodeficiency virus (HIV)-related morbidity a nd mortality rates in patients with advanced HIV infection who are treated with combination antiretroviral drugs have declined, significant metabolic adverse effects associated with these regimens have been increasingly recog nized. However, since data from patients studied before and after initiatio n of protease inhibitor (PI) therapy are scant, the true effect of PIs on t hese metabolic changes remains unknown. Objectives: To examine temporal trends in serum glucose and lipid levels af ter initiation of PI therapy, to assess whether changes are independent of virological response and improvement in disease severity, and to determine risk factors associated with the development of hyperglycemia, hyperlipidem ia, and lipodystrophy. Methods: A 5-year historical cohort analysis in a population of 221 HIV-inf ected patients observed in the Infectious Diseases Clinic of a tertiary car e center from October 1, 1993, through July 31, 1998. Clinical and laborato ry data were retrieved from medical records and a computerized database. Th e main outcome measure was the incidence of hyperglycemia, hypercholesterol emia, hypertriglyceridemia, and lipodystrophy. Adjusted incidence rate rati os (IRRs) were estimated by means of Poisson regression. In addition, mixed regression analyses were performed to examine effects of PIs on serum lipi d and glucose levels, modeled as continuous outcomes. Results: The cumulative incidence of new-onset hyperglycemia, hypercholeste rolemia, hypertriglyceridemia, and lipodystrophy was 5%, 24%, 19%, and 13%, respectively. Most of these events occurred after initiation of PI therapy . Protease inhibitors were independently associated with hyperglycemia (adj usted IRR, 5.0; 95% confidence interval [CI], 1.3-19.4), hypercholesterolem ia (adjusted IRR, 2.8; 95% CI, 1.5-5.2), hypertriglyceridemia (adjusted IRR , 6.1; 95% CI, 3.1-11.7), and lipodystrophy (adjusted IRR, 5.1; 95% CI, 1.9 -13.9). Anabolic steroids and psychotropic medications were also associated with lipodystrophy. Inclusion of potential intermediate variables (eg, vir ological suppression and increase in body weight) did not reduce the magnit ude of the association with PIs. The association between hypertriglyceridem ia and ritonavir was stronger than for other PIs (Wald test, P=.02). In con trast, the incidence of hyperglycemia, hypercholesterolemia, and lipodystro phy did not vary significantly across different PIs. Longitudinal mixed mod els confirmed that serum lipid levels were more substantially affected by a ntiretroviral therapy, particularly PIs, than serum glucose levels. Similar ly, controlling for surrogate markers did not abolish the strong associatio n between PIs and increase in serum lipid levels. Conclusion: We found an independent association between PI use and hypergly cemia, hyperlipidemia, and lipodystrophy that is not explained by the antiv iral and therapeutic effect of PIs.