Effects of protease inhibitors on hyperglycemia, hyperlipidemia, and lipodystrophy: a 5-year cohort study.
BACKGROUND
Although human immunodeficiency virus (HIV)-related morbidity and 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 recognized. However, since data from patients studied before and after initiation of protease inhibitor (PI) therapy are scant, the true effect of PIs on these metabolic changes remains unknown.


OBJECTIVE
To examine temporal trends in serum glucose and lipid levels after 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, hyperlipidemia, and lipodystrophy.


METHODS
A 5-year historical cohort analysis in a population of 221 HIV-infected patients observed in the Infectious Diseases Clinic of a tertiary care center from October 1, 1993, through July 31, 1998. Clinical and laboratory data were retrieved from medical records and a computerized database. The main outcome measure was the incidence of hyperglycemia, hypercholesterolemia, hypertriglyceridemia, and lipodystrophy. Adjusted incidence rate ratios (IRRs) were estimated by means of Poisson regression. In addition, mixed regression analyses were performed to examine effects of PIs on serum lipid and glucose levels, modeled as continuous outcomes.


RESULTS
The cumulative incidence of new-onset hyperglycemia, hypercholesterolemia, 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 (adjusted IRR, 5.0; 95% confidence interval [CI], 1. 3-19.4), hypercholesterolemia (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, virological suppression and increase in body weight) did not reduce the magnitude of the association with PIs. The association between hypertriglyceridemia and ritonavir was stronger than for other PIs (Wald test, P=.02). In contrast, the incidence of hyperglycemia, hypercholesterolemia, and lipodystrophy did not vary significantly across different PIs. Longitudinal mixed models confirmed that serum lipid levels were more substantially affected by antiretroviral therapy, particularly PIs, than serum glucose levels. Similarly, controlling for surrogate markers did not abolish the strong association between PIs and increase in serum lipid levels.


CONCLUSIONS
We found an independent association between PI use and hyperglycemia, hyperlipidemia, and lipodystrophy that is not explained by the antiviral and therapeutic effect of PIs.
Tsiodras
S
S
Division of Infectious Diseases, Beth Israel Deaconess Medical Center, West Campus, One Autumn Street, Kennedy Bldg, Sixth Floor, Boston, MA 02215, USA. stsiodra@caregroup.harvard.edu.
Mantzoros
C
C
Hammer
S
S
Samore
M
M
D000328:Adult; D005260:Female; D017320:HIV Protease Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D006801:Humans; D006937:Hypercholesterolemia / Q000139:chemically induced*; D006943:Hyperglycemia / Q000139:chemically induced*; D015228:Hypertriglyceridemia / Q000139:chemically induced*; D015994:Incidence; D008060:Lipodystrophy / Q000139:chemically induced*; D008297:Male; D016012:Poisson Distribution; D012044:Regression Analysis; D012307:Risk Factors
D017320:HIV Protease Inhibitors