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Protease inhibitor-containing antiretroviral therapy for the treatment of HIV-1 infection is associated with elevated triglyceride and low-density lipoprotein (LDL)-cholesterol levels which may expose patients to an increased risk of coronary artery disease (CAD). We report the lipid and lipoprotein profiles of a representative subset of treatment-naive patients included in the Atlantic Study. This study compares patients treated with stavudine and didanosine plus the random addition of either the non-nucleoside reverse transcriptase inhibitor nevirapine (NVP), the protease inhibitor indinavir or the nucleoside reverse transcriptase inhibitor lamivudine.Lipids and lipoproteins were quantified from prospectively collected and cryopreserved plasma samples obtained at weeks 0, 6 and 24.We observed a striking increase in high-density lipoprotein (HDL)-cholesterol (49%), apolipoprotein AI (19%), lipoprotein AI (38%) and HDL particle size (3%) in the NVP-treated patients (n = 34) at week 24. Much less pronounced changes in these parameters were seen to a similar extent both in patients receiving lamivudine (n = 39) and indinavir (n = 41). LDL-cholesterol also increased significantly both in the NVP and indinavir arms, but only in the NVP arm was this offset by a significant reduction (14%) in total over HDL-cholesterol ratio. Using a multivariate linear regression model, adjusting for CD4 cell count and plasma HIV RNA both at baseline and during treatment, randomization to the NVP-containing arm remained significant in explaining the observed changes in HDL-cholesterol and other HDL-related parameters.In HIV-1 infected patients treated with a regimen of stavudine, didanosine and NVP we found changes in lipids and lipoproteins which are associated with a sharp decrease in risk for CAD in other settings. If confirmed in larger studies, these findings both may influence the initial choice of therapy for HIV-1 infection, and might lead to novel approaches targeted at raising HDL-cholesterol for CAD prevention.