Ezetimibe (Zetia) è un farmaco che abbassa i livelli di colesterolo LDL, riducendo l’assorbimento intestinale di colesterolo e dei fitosteroli associati. Nei pazienti con ipercolesterolemia, due studi clinici controllati con placebo hanno mostrato che Ezetimibe riduce la concentrazione di colesterolo totale di circa il 13% e di colesterolo LDL di circa il 18%. Al CROI è stato presentato uno studio controllato con placebo su persone con HIV. Sicuro, ben tollerato ed efficace: un importante opzione per i pazienti che non possono assumere statine.

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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. Ezetimibe decreases absorption of cholesterol by 50% resulting in ~ 10-20% reduction in LDL cholesterol when used alone and up to 55% when combined with a statin. Negredo et al. previously presented data on 19 subjects on HAART treated with Ezetimibe with a 15% reduction in LDL cholesterol.

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 subjects had to have a CD4+ count > 100 cells/cu mm and HIV viral load < 10,000 copies/mL. All were randomized to ezetimibe 10 mg daily (N=25) or placebo (N=23) 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 (101, 152) 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. 5 additional patients had non-treatment limiting grade 2 or higher AEs (2 with headache, one in each arm); 1 diarrhea (EZT arm); and 1 with chest pain (EZT).

Conclusions: Ezetimibe alone led to significant and clinically meaningful declines in LDL-C (12%; 2-22% 95 CI) 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.

Ezetimibe’s Effects on the LDL Cholesterol Levels of HIV-infected Patients Receiving HAART
David Wohl*1, P Hsue2, S Richard1, A Schnell2, S Napravnik1, R Simpson1, J Keys1, and D Waters2
1Univ of North Carolina at Chapel Hill, US and 2Univ of California, San Francisco, US