title: Antiretroviral Drug Levels and Interactions Affect Lipid, Lipoprotein, and Glucose Metabolism in HIV-1 Seronegative Subjects: A Pharmacokinetic-Pharmacodynamic Analysis.
abstract: BACKGROUND
  HIV-infected patients treated with antiretroviral medications (ARVs) develop undesirable changes in lipid and glucose metabolism that mimic the metabolic syndrome and may be proatherogenic. Antiretroviral drug levels and their interactions may contribute to these metabolic alterations.
  
  
  METHODS
  Fifty six HIV-seronegative adults were enrolled in an open-label, randomized, pharmacokinetic interaction study, and received a nonnucleoside reverse transcriptase inhibitor (efavirenz on days 1-21) plus a protease inhibitor (PI; amprenavir on days 11-21), with a second PI on days 15-21 (saquinavir, nelfinavir, indinavir, or ritonavir). Fasting triglycerides, total LDL-and HDL-cholesterol, glucose, insulin, and C-peptide levels were measured on days 0, 14, 21, and 2-3 weeks after discontinuing drugs. Regression models were used to estimate changes in these parameters and associations between these changes and circulating levels of study drugs.
  
  
  RESULTS
  Short-term efavirenz and amprenavir administration significantly increased cholesterol, triglycerides, and glucose levels. Addition of a second protease inhibitor further increased triglycerides, total and LDL-cholesterol levels. Higher amprenavir levels predicted larger increases in triglycerides, total, and LDL-cholesterol. Two weeks after all study drugs were stopped, total, LDL-, and HDL-cholesterol remained elevated above baseline.
  
  
  CONCLUSIONS
  ARV regimens that include a nonnucleoside reverse transcriptase inhibitor plus single or boosted PIs are becoming more common, but the pharmacodynamic interactions associated with these regimens can result in persistent, undesirable alterations in serum lipid/lipoprotein levels. Additional pharmacodynamic studies are needed to examine the metabolic effects of ritonavir-boosted regimens, with and without efavirenz.
authors.affiliation: Harvard School of Public Health, Boston, MA.
authors.forename: Susan L
authors.initials: SL
authors.lastname: Rosenkranz
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Yarasheski
authors.forename: Michael F
authors.initials: MF
authors.lastname: Para
authors.forename: Richard C
authors.initials: RC
authors.lastname: Reichman
authors.forename: Gene D
authors.initials: GD
authors.lastname: Morse