EZETIMIBE COMBINED WITH LOW DOSE STATIN EFFECTIVELY LOWERS LDL IN PROTEASE INHIBITOR TREATED PATIENTS; Kaletra PK
Reported by Jules Levin
4th IAS Conference, July 2007, Sydney, Australia
Olga M. Klibanov1, John P. Gaughan1, Ellen M. Tedaldi1, Kelly M. Lattanzi1, Anjali N. Parekh1, Katherine A. Gallagher2, Rafael
O. Rivero2, Mary van den Berg-Wolf1
1Temple University, Philadelphia, Pennsylvania, USA
2Abbott Labs, Abbott Park, Illinois, USA
--This pilot study was performed at a single institution, with a limited number of patients
--Our strict inclusion criteria of low-dose statins (due to safety concerns) may have led to a blunted cholesterol-lowering response to combination therapy with statins and EZB
--Adding ezetimibe to statins resulted in a significant reduction of TC and LDL in our cohort of minority HIV-infected patients with multiple risk factors for cardiovascular disease
--Despite these reductions, only 35% of our patients achieved their NCEP III LDL goal at study completion
--Addition of EZB to statins and PI-based HAART was safe and well-tolerated
--No changes in the trough concentrations of LPV or RTV were seen after addition of EZB
Objectives: Ezetimibe (EZB) lowers cholesterol by blocking cholesterol absorption in the intestine. Data regarding its use are limited in HIV-infected patients. Our main objective was to assess LDL reduction 18 weeks after addition of EZB 10mg/day in statin-treated patients on protease inhibitor (PI)-based antiretroviral therapy (ART).
Methods: HIV-infected adults on stable PI-based ART were enrolled in this prospective pilot study if their LDL was not at goal (per National Cholesterol Education Program III guidelines) despite therapy with a statin (pravastatin 20 mg or atorvastatin 10 mg). In a subgroup of patients on lopinavir/ritonavir
(LPV/RTV), trough LPV and RTV concentrations were obtained before and after addition of EZB. Data were analyzed using repeated measures ANOVA on ranks with Bonferroni adjustment.
Results: We enrolled 20 subjects; 12 (60%) men, 18 (90%) African American, 2 (10%) Latino; mean (SD) age was 49.1 (8.5) years. ART included RTV-boosted PIs in 17 (85%) patients, 3 (15%) were on nelfinavir; 19 were on pravastatin, 1 on atorvastatin. Cholesterol changes are described in the table. 13 patients were receiving LPV/RTV; LPV and RTV trough concentrations did not change after addition of EZB. One patient experienced elevated CPK possibly related to study medication; no other laboratory abnormalities or adverse effects were seen.
Conclusions: Addition of EZB to low dose statin effectively lowers LDL and TC and appears to be safe and well-tolerated.
--Lipid abnormalities are common in HIV-infected patients
--Controlling this cardiovascular risk factor is essential in decreasing the risk of myocardial infarction (MI) and other atherosclerotic complications; however, HMG-CoA reductase inhibitor (statin) therapy often fails to meet target lipid goals in this patient population
--Ezetimibe (EZB) inhibits absorption of cholesterol in the intestine, resulting in a reduction of hepatic cholesterol stores and an increase in clearance of cholesterol from the blood1
--Two clinical studies in HIV-infected individuals evaluating EZB monotherapy reported a 10-12% reduction in LDL cholesterol after 6 weeks of treatment.2,3 A 24-wk study in 23 HIV-infected patients evaluated addition EZB to pravastatin 20mg/day and showed an additional 7% decrease in LDL.4
--Our main objective was to assess lipid changes in HIV-infected patients after addition of EZB to stable statin and PI-based HAART
--Prospective pilot study
--HIV-infected adults (> 18 years) on stable PI-based HAART for at least 6 weeks prior to study entry
--Hypercholesterolemia treated with atorvastatin (ATR) 10mg/day or pravastatin (PRA) 20mg/day, and LDL-cholesterol not at goal based on National Cholesterol Education Program III (NCEP)
--Laboratory values within normal limits
--Pregnant or breast-feeding women
--Active alcohol or substance abuse
--Presence of decompensated heart failure, MI within 1year, severe vascular disease, poorly
controlled diabetes mellitus
--To assess LDL reduction at 18 weeks
--To assess TC, LDL, TG, HDL reductions at 6, 12, and 18 weeks of EZB therapy
--To assess safety of the addition of EZB to statin therapy in HIV-infected patients on PIs
--To evaluate lopinavir and ritonavir trough concentrations before and after addition of EZB (baseline and week 6) in a subgroup of patients on LPV/r
--Data were analyzed using repeated measures ANOVA on ranks with Bonferroni adjustment
--Addition of EZB was safe and well tolerated
--4 patients did not complete week 18 study visit
- 1 patient due to asymptomatic elevations in CPK (>5 x ULN) likely related to
concomitant cocaine abuse
- 2 patients due to protocol violation
- 1 patient expired after week 12 visit due to a MI (not considered to be a drug-related adverse event)
--One patient experienced asymptomatic elevations in CPK (>5 x ULN) at week 18 study visit, possibly related to study medication. This patient completed the study and CPKs declined after EZB discontinuation
Demographics (Table 1)
--Our cohort of minority patients had many baseline risk factors for cardiovascular disease
--Based on the NCEP III guidelines, 18 of 20 patients (90%) had a LDL goal <100 mg/dL
Cholesterol changes (Graph 1)
--Addition of EZB resulted in significant reduction of LDL and TC at all study visits (p<0.05), without significant changes in TG or HDL
--7 of 20 patients (35%) achieved their NCEP III LDL goal at study completion
--13 of 20 patients were on LPV/r at study entry and completed the PK substudy. No changes in the trough concentrations of LPV or RTV were observed after addition of EZB.5
1. Merck/Schering-Plough Pharmaceuticals. Zetia (ezetimibe) product information. North Wales, PA;2005.
2. Coll B, Aragones G, Parra S, Alonso-Villaverde C, Masana L. Ezetimibe effectively decreases LDL-cholesterol in HIV-infected patients. AIDS 2006;20:1675-7.
3. Wohl D, Hsue P, Richard S, Schnell A, Napravnik S, Simpson R et al. Ezetimibe’s effects on the LDL cholesterol levels of HIV-infected patients receiving HAART. 14th CROI 2007; Los Angeles, CA. Oral Abstract 39.
4. Negredo E, Rey-Joly C, Puig J, Bonjoch A, Molto J, Blanco A et al. Ezetimibe, a selective inhibitor of cholesterol absorption, as a new strategy for treatment of hypercholesterolemia secondary to antiretroviral therapy. 45th ICAAC, Washington DC 2005, #H-336.
5. Klibanov OM, Gaughan JP, Tedaldi EM, Lattanzi KM, Gallagher KA, van den Berg-Wolf M. The effect of ezetimibe (EZB) on the steady-state trough levels of lopinavir/ritonavir (LPV/r).
8th International Workshop on Clinical Pharmacology of HIV Therapy, Budapest, Hungary, poster #64.