Background:  Ezetimibe, a novel agent that inhibits the intestinal absorption of dietary and biliary cholesterol, is approved for use with statins for LDL cholesterol (LDL-C) reduction.  Its safety and efficacy in HIV⁺ patients is not known.

Methods:  Randomized, double-blind, placebo-controlled, 2-period cross-over trial to study the safety and effect of ezetimibe in lowering LDL-C in HIV⁺ patients on stable HAART but no lipid-lowering therapy with LDL-C ≥75 mg/dL and triglycerides (TG) <800 mg/dL.  All were randomized to ezetimibe 10 mg daily or placebo for 6 weeks followed by a 2-week washout and then 6 weeks of treatment with the alternative study assignment. Fasting lipid panel (8 hours) including direct LDL-C and chemistries were evaluated at entry and weeks 6, 8, and 14. Differences in percent change of LDL-C cholesterol (%∆ LDL-C) from pre- to post-intervention between ezetimibe and placebo were compared using generalized linear models with a normal probability distribution fit with generalized estimation equations to account for repeated measures. We used an ITT - LOCF analysis.

Results:  We enrolled 48 subjects, of whom 23% were women, 48% African American, median age = 46 years (IQR 43, 51), median CD4 = 555/mm³ (IQR 447, 783), and all but 1 subject had HIV RNA <400 copies/mL. We randomized 25 to ezetimibe followed by placebo and 23 to placebo followed by ezetimibe. At pre-intervention and following washout the median LDL-C was 121 mg/dL and 123 mg/dL, p = 0.70. The median %∆ LDL-C after ezetimibe treatment was –12% (IQR –23%, 1%), and after placebo was 3% (IQR –6%, 17%), p = 0.03. 35% of patients had at least a 17% drop in LDL-C after 6 weeks of ezetimibe. The difference in %∆ LDL-C comparing ezetimibe to placebo was –12% (95%CI –22%, –2%), p = 0.02. Treatment period did not affect these results (p = 0.85). There were no significant changes in HDL-C or TG observed. Of the 5 subjects who discontinued the study drug prematurely, 2 were on ezetimibe (1 grade-3 LFT in subject with grade-1 LFT at entry, 1 epigastric pain) vs 3 on placebo (1 grade-2 LFT, 1 headache and nausea, 1 neuropathy); 2 other subjects had new LFT increases (grade 2), both while on placebo.

Conclusions:  Ezetimibe alone led to significant and clinically meaningful declines in LDL-C and was well-tolerated. This trial, the first placebo-controlled study of ezetimibe in HIV⁺ patients, suggests a role for ezetimibe in the management of elevated LDL-C in patients with HIV. Further, for patients unable to take a statin, monotherapy with ezetimibe may be an option.