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Lipid lowering efficacy and safety of Ezetimibe combined with rosuvastatin compared with titrating rosuvastatin… Saeedi, Ramesh; Johns, Kevin; Frohlich, Jiri; Bennett, Matthew T; Bondy, Gregory Jun 19, 2015

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RESEARCH Open AccessLipid lowering efficacy and safety of Ezetimibecombined with rosuvastatin compared withtitrating rosuvastatin monotherapy in HIV-positivecombination of ezetimibe and rosuvastatin improved TG, AIP and non-HDL cholesterol levels more than a dose increaseSaeedi et al. Lipids in Health and Disease  (2015) 14:57 DOI 10.1186/s12944-015-0054-xBritish Columbia, Vancouver, CanadaFull list of author information is available at the end of the article1Department of Pathology & Laboratory Medicine, University of BritishColumbia, Vancouver, Canada4Departments of Medicine and Pathology, Faculty of Medicine, University of* Correspondence: gbondy@providencehealth.bc.cain rosuvastatin in patients with HIV-associated dyslipidemia.Keywords: HIV, Rosuvastatin, Ezetimibe, Lipid profileConclusions: The addition of ezetimibe to rosuvastatin apppatientsRamesh Saeedi1, Kevin Johns2, Jiri Frohlich1, Matthew T. Bennett3 and Gregory Bondy1,4*AbstractBackground: HIV-infected patients on antiretroviral therapy frequently develop dyslipidemias and, despite therapywith potent lipid-lowering agents, a high percentage does not achieve guideline recommended lipid targets. In thisstudy, we examined the efficacy of combination treatment with a statin and the cholesterol transport blocker,ezetimibe, vs. monotherapy with a statin in HIV-infected patients not achieving lipid goals.Methods: This was a 12-week, prospective, randomized, open-label clinical trial. Patients were eligible if they hadan apolipoprotein B (apoB) >0.80 g/L despite therapy with rosuvastatin 10 mg daily for a minimum of 12 weeks.Patients were randomized to take ezetimibe 10 mg/rosuvastatin 10 mg or rosuvastatin 20 mg for 12 weeks. Percentageand absolute change in apoB (primary outcome), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC),triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), non-HDL-C, apoliporpotein A1 (apoA1), apoB/apoA1, TC/HDL-C, atherogenic index of plasma (API), and high-sensitivity C-reactive protein (hsCRP) were compared. Changes insafety parameters (such as AST, ALT, CK) and clinical symptoms were also assessed.Results: Forty-three patients (23 on ezetimibe 10 mg/rosuvastatin 10 mg and 20 on rosuvastatin 20 mg) completedthe trial. Baseline characteristics did not differ between the groups. Significant improvements in apoB were seen withboth ezetimibe plus rosuvastatin (mean of -0.17 g/L, p < 0.001) and rosuvastatin 20 mg (mean of -0.13 g/L, p = 0.03)treatment groups, but did not differ between groups (p = 0.53). Significant between-group differences were observedfor mean TC (-1.01 mmol/L vs. -0.50 mmol/L, p = 0.03), TG (-0.62 mmol/L vs -0.17 mmol/L, p = 0.03), and non-HDL-C(-0.97 mmol/L vs. -0.53 mmol/L, p = 0.03) all in favour of the ezetimibe plus rosuvastatin group. Two patients, both inthe rosuvastatin 20 mg group, experienced mild myalgias; neither discontinued the study.ears to be safe in patients with HIV. Furthermore, the© 2015 Saeedi et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License(http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium,provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Saeedi et al. Lipids in Health and Disease  (2015) 14:57 Page 2 of 8BackgroundHuman immunodeficiency virus (HIV)-associated dys-lipidemia is becoming more common with the extensiveuse of antiretroviral therapy (ART) resulting in an in-crease in incidence of atherosclerotic cardiovasculardisease (ASCVD) [1–6].Statins have been widely used for prevention of ASCVD[7]. Increasing numbers of individuals with HIV-associateddyslipidemia are receiving statins for secondary preventionof ASCVD [8]; many HIV-infected patients receiving statintherapy do not achieve recommended treatment goals [9].Furthermore, treatment of HIV-associated dyslipidemia isfurther complicated by altered statin metabolism and druginteractions with antiretroviral medications both of whichincrease the risk of statin induced myopathy [9]. Few stud-ies have examined the effect of alternative lipid-loweringagents in HIV-infected patients.Ezetimibe, an inhibitor of intestinal cholesterol absorp-tion, has been used as a second-line therapy for patientswho are unable to tolerate high dose statins or in thosewho do not achieve therapeutic lipid target levels [10].In HIV-dyslipidemia, ezetimibe is safe and can be usedin patients with poor response to statins and those re-ceiving protease inhibitors [10–14].Rosuvastatin is a relatively new statin, which is notmetabolised by the cytochrome P 3A4 (CYP3A4) enzymesystem. As CYP3A4 is often enzyme-inhibited by certainART therapies, rosuvastatin is preferred in the treatmentof ART-associated dyslipidemia. A limited number of trialshave assessed the efficacy of rosuvastatin in patients withHIV with all reporting a favorable decline in some of lipidparameters [8, 15–18]. The aim of the current study wasto assess whether HIV-infected patients treated with acombination of rosuvastatin 10 mg plus ezetimibe 10 mgshow a greater improvement in their lipid profile com-pared to an increased dose of rosuvastatin (from 10 to20 mg). Several studies in non-HIV populations haveshown that co-administration of rosuvastatin plus ezeti-mibe is safe, and achieved significant improvements inlipid profiles in high-risk patients compared to monother-apy [10].MethodsThis prospective, randomized, open-label study was car-ried out in HIV-infected patients seen at the Immunodefi-ciency Clinic (IDC)-HIV metabolic Clinic at St. Paul’sHospital, Vancouver, BC, Canada. We compared the effi-cacy and safety of co-administration of 10 mg rosuvastatinand 10 mg of ezetimibe versus 20 mg of rosuvastatin overa 15 months period. The protocol and informed consentwere approved by the institutional Ethics Board (Univer-sity of British Columbia).Patients included in this study were men and womenage ≥ 19 years with apolipoprotein B (apoB) >0.8 g/L,maintained on stable dose of rosuvastatin 10 mg for thepast 12 weeks and on a stable background of ART forthe 12 weeks prior to study. Patients continued the sameART for the subsequent 12 weeks of study.Main exclusion criteria included serum aspartate ami-notransferase (AST) or alanine aminotransferase (ALT)elevations ≥3-fold upper limit of normal (ULN), serumcreatine kinase (CK) concentration elevation ≥10-foldULN, previous adverse reaction to ezetimibe, recent useof ezetimibe (within 30 days of starting the study), a his-tory of significant myopathy or rhabdomyolysis with anystatin, current use of gemfibrozil (Lopid), niacin/nico-tinic acid, colestipol (Colestid), cholestyramine (Novo-Cholamine), or any agent with a potential drug-druginteraction, pregnant or breastfeeding woman or expect-ing to conceive or donate eggs during the study; malesplanning to impregnate a woman or provide sperm do-nation during the study; use of excessive (more than onedrink a day for a woman and two drinks for a man)amounts of alcohol or recreational drugs; or previous orcurrent liver disease.Patients were randomized in a 1:1 ratio to either an in-creased daily dose of rosuvastatin to 20 mg, or to 10 mgezetimibe added on to their current 10 mg rosuvastatindaily dose. Serum samples were obtained and analyzedat the baseline and after 12 weeks of treatment for lipidprofile, safety and inflammatory parameters. Also, at theend of the study (12 weeks) participants were askedquestions regarding side effects (such as myalgia andgastrointestinal side effects).The primary outcome was the percent change inserum apoB, between participants treated with rosuvas-tatin 20 mg versus participants treated with ezetimibe10 mg plus rosuvastatin 10 mg. Even though, calculatedor measured LDL-C concentration has been known asthe major goal of lipid lowering therapies, many individ-uals may experience progression of atherosclerosis orcardiovascular events despite having ideal LDL-C con-centrations. Barter et al have shown that predicting thefuture CVD is best reflected by apoB concentration [19].ApoB, which measures numbers of atherogenic particlesin plasma, is superior to LDL-C not only as an index ofcardiovascular risk but also as a guide to the adequacyof lipid lowering therapy. Secondary outcomes includedthe percent and absolute change in serum concentra-tions of low-density lipoprotein cholesterol (LDL-C),total cholesterol (TC), triglycerides (TG), high-densitylipoprotein cholesterol (HDL-C), TC/ HDL, non- HDL-C, apolipoprotein A1 (apoAI), apoB/apoAI, atherogenicindex of plasma (AIP), fasting blood glucose (FBG), andhigh-sensitivity C-reactive protein (hsCRP) between par-ticipants treated with rosuvastatin alone versus partici-pants treated with rosuvastatin and ezetimibe. Furthersecondary endpoints included within group changes inthe above endpoints and the assessment of safety param-eters, specifically incidence of complications as mea-sured by an increase in AST and/or ALT ≥3-fold ULNand a CK ≥10-fold ULN in participants treated withrosuvastatin 20 mg versus participants treated with eze-timibe 10 mg plus rosuvastatin10 mg.For the primary outcome, with a sample size of 50 pa-tients planned for randomization, the study was anticipatedto have at least 90 % power to demonstrate a difference be-tween ezetimibe co-administrated with rosuvastatin andthe comparative increased dose rosuvastatin monotherapy,assuming a reduction of apoB of 0.25 g/L, a SD of 0.27 g/L(the type one error of 0.05 and type two error of 0.1).Statistical analysisData are expressed as mean ± SD. Assumptions ofnormality were tested by Shapiro-Wilks tests and reviewof plots. The primary analysis was to compare treatmenteffects between groups. For variables with a symmetricaldistribution, analysis of covariance (ANCOVA) adjustedfor baseline values were used. For variables with skeweddistributions, between-treatment changes from baselinewere compared with Mann-Whitney U tests. The sec-ondary analysis was to compare changes within eachgroup with paired t-tests or Wilcoxon rank-sum tests, asappropriate. Calculations were performed using com-puter software (SPSS/Mac v. 19.0.0).Any patients who did not return for the 12-week visitwere excluded from the analysis except those who hadwithdrawn for reason of intolerance or toxicity. Thesepatients were considered not to have changed frombaseline if they did not appear for their follow-up visit.The proportion of patients who have experienced an in-crease in AST and ALT ≥3-fold ULN or a CK ≥10-foldULN were compared between treatment groups usingthe Fisher’s exact test.ResultsPatient demographics and baseline characteristicsDue to slow enrollment accrual only 46 patients wererandomized and 43 patients (23 rosuvastatin plus ezeti-mibe, 20 rosuvastatin) completed the 12 week study.Three patients out of 46 patients were excluded, 2 dueto elevated liver enzymes and one due to complaints ofmuscle soreness. Baseline characteristics of the studypopulation are summarized in Table 1. There were nodifferences between groups in terms of age or clinicalcharacteristics of HIV. However, despite randomization,there were some observable differences between groupsin terms of cardiovascular risk factors. More patientsd-Saeedi et al. Lipids in Health and Disease  (2015) 14:57 Page 3 of 8Table 1 Baseline characteristics of the study subjects*Characteristic Ezetimibe adAge, years† 56.5 ± 7.4Male sex 22 (95.6)Caucasian 19 (82.6)Duration of ARV therapy (months)† 24 (16–34)CD4+ cell count (cells/mm3)† 580.0 ± 193Undetectable VL‡ 20 (87.0)PI 21 (91.3)NNRTI 6 (26.1)NRTI 23 (100)Fibrate 4 (17.4)Antihypertensive agents 13 (56.5)Current Smoker 6 (26.1)Previous Smoker§ 8 (34.8)Diabetes Mellitus 8 (34.8)Hypertension 13 (56.5)Family History of CVD 10 (43.5)Body Mass Index (kg/m2)† 26.0 ± 4.2Waist Circumference, cm† 98 ± 13.7*Data are frequency (%) unless otherwise indicated†Data are mean (±SD)‡ < 40 copies/mL§ less than one year of smoking cessation prior to study recruitmentARV, antiretroviral; VL, viral load; PI, protease inhibitor; NNRTI, non-nucleosidereverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase; CVD, cardiovaon group (n = 23) Increased rosuvastatin (n = 20)57.0 ± 9.917 (85.0)15 (75.0)25(14-48)508.0 ± 20819 (95.0)17 (85.0)7 (35.0)19 (95.0)6 (30.0)6 (30.0)1 (5.0)14 (70.0)7 (35.0)6 (30.0)10 (55.0)25.3 ± 4.793 ± 15.3scular diseasereceiving ezetimibe had a history of hypertension andmore were current smokers whereas more patients inthe rosuvastatin group self-identified as past smokers(quit within the last 12 months). Baseline lipid andlipoprotein levels were similar between the two groups(Table 2).Effects of adding ezetimibe to rosuvastatin or increasingrosuvastatin dose on metabolic parametersThe primary and secondary endpoints are displayed inTable 3. Twelve weeks of treatment with either rosuvas-tatin 20 mg or rosuvastatin 10 mg plus ezetimibe 10 mgsignificantly decreased TC, LDL, TC/HDL, and apoB.Also, addition of ezetimibe to rosuvastatin resulted insignificant improvements in TG, non-HDL-C, apoB/apoAI, and AIP. The improvement in TC and TG wassignificantly greater with ezetimibe 10 mg plus rosuvas-tatin 10 mg than with rosuvastatin 20 mg alone.Ezetimibe 10 mg plus rosuvastatin 10 mg and rosuvas-tatin 20 mg monotherapy were generally well toleratedduring this 12 week study. Two patients in the rosuvas-Sub-analysis was carried out to determine the propor-tion of patients reaching primary (LDL-C ≤2.0 mmol/L,50 % reduction in LDL-C, ApoB ≤0.80 g/L, or non-HDL-C ≤2.6) or secondary (TG <1.7 mmol/L, ApoB:A-poA1 ratio <0.80, hsCRP <2 mg/L) high cardiovascularrisk targets [20] as well as the high risk limit for AIP(<0.21) [21]. As illustrated in Table 4, both treatmentregimens resulted in an increased proportion of patientsreaching primary and secondary targets with the excep-tion of hsCRP, which showed no improvement in theezetimibe plus rosuvastatin group.DiscussionThe primary findings of this study is that rosuvastatin10mg/ezetimibe 10 mg combination had a greater effect onlowering non-HDL-C, TG, and AIP as compared torosuvastatin 20 mg monotherapy. This trial is the firststudy to evaluate and compare the efficacy and safety ofezetimibe and rosuvastatin 10 mg versus rosuvastatin20 mg in HIV-infected patients.This study showed that both ezetimibe 10 mg plusrosuvastatin 10 mg and rosuvastatin 20 mg significantlyrou000.0Saeedi et al. Lipids in Health and Disease  (2015) 14:57 Page 4 of 8tatin monotherapy group experienced myalgias with oneof them experiencing moderate to severe cramping.Neither of these two patients discontinued the studymedication. A statistically significant increase in ALTwas observed in the ezetimibe plus rosuvastatin groupbut this increase was small and not likely to be clinic-ally relevant.Table 2 Baseline values for primary and secondary outcomesEzetimibe add- on gApoB, g/L 1.06 ± 0.24ApoA1, g/L 1.54 ± 0.27ApoB:ApoA1 0.69 ± 0.21TC, mmol/L 5.23 ± 1.06LDL, mmol/L 2.80 ± 0.93HDL, mmol/L 1.21 ± 0.29TC:HDL 4.92 ± 2.25TG, mmol/L 2.55 ± 1.32AIP 0.29 ± 0.33Non-HDL-C, mmol/L 4.04 ± 1.05Glucose, mmol/L 6.54 ± 1.84hsCRP, mg/L 5.6 ± 10.2Creatinine, μmol/L 91 ± 22.5ALT, U/L 33 ± 13.8AST, U/L 29 ± 11.0CK, U/L 142 ± 100Data are given as mean (±SD)apoB, apolipoprotein B; apoA1,apolipoprotein A1;TC, total cholesterol; LDL-C, low-dtriglycerides; AIP, atherogenic index of plasma; FBG, fasting blood glucose; hsCRP, haminotransferase; CK, creatine kinasereduced LDL-C. Addition of ezetimibe 10 mg to rosu-vastatin 10 mg had a greater impact on lowering LDL-Cthan rosuvastatin 10 mg monotherapy (22.5 % reductionvs. 16.5 % reduction, respectively). The magnitude ofchanges in LDL-C in our study was similar to otherstudies done in HIV populations where eztimibe was co-administrated with statin therapy; these studies reportedp (n = 23) Increased rosuvastatin (n = 20)1.01 ± 0.381.51 ± 0.320.72 ± 0.395.07 ± 0.502.55 ± 0.581.29 ± 0.404.25 ± 1.153.05 ± 1.520.33 ± 0.333.78 ± 0.696.16 ± 2.222.8 ± 3.3798 ± 30.5134 ± 12.7030 ± 11.40177 ± 85.22ensity lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; TG,igh-sensitivity C-reactive protein; AST, aspartate aminotransferase; ALT, alanineTable 3 Effects of adding ezetimibe to rosuvastatin or increasing rosuvastatin dosage on lipid and metabolic outcomesValues after 12 weeks Change after 12 weeks P Value (DifferenceBetween add on vs.increased dose)Ezetimibe add-on group(n = 21)Increased rosuvastatin(n = 18)Ezetimibe add-on group(n = 21)Increased rosuvastatin(n = 18)ApoB, g/L 0.89 ± 0.25 0.88 ± 0.22 −0.17 ± 0.18* −0.13 ± 0.25* 0.53ApoA1, g/L 1.47 ± 0.26 1.56 ± 0.30 −0.07 ± 0.25 −0.05 ± 0.24 0.15ApoB:ApoA1 0.55 ± 0.29 0.60 ± 0.23 −0.15 ± 0.29* −0.12 ± 0.33 0.81Saeedi et al. Lipids in Health and Disease  (2015) 14:57 Page 5 of 8TC, mmol/L 4.23 ± 1.03 4.56 ± 0.75LDL, mmol/L 2.12 ± 0.63 2.07 ± 0.46HDL, mmol/L 1.21 ± 0.27 1.31 ± 0.48TC:HDL 3.29 ± 1.41 3.73 ± 0.92TG, mmol/L 1.92 ± 0.98 2.88 ± 1.42AIP 0.16 ± 0.30 0.30 ± 0.38Non-HDL-C, mmol/L 3.06 ± 0.98 3.25 ± 0.71FBG, mmol/L 6.87 ± 2.49 5.82 ± 1.29hsCRP, mg/L 5.19 ± 7.25 1.72 ± 1.87Creatinine, μmol/L 98 ± 58 151 ± 265ALT, U/L 42 ± 22 34 ± 15AST, U/L 32 ± 21 29 ± 8CK, U/L 126 ± 63 189 ± 103Data are given as mean (±SD)a 12-35 % decrease in LDL-C [11–14]. The wide rangeof changes in LDL-C between studies may be due toother factors such as age of participants, type and doseof statin, type of ART, or other medications. Overall, thepercent reduction in LDL-C in our study and studies in-volving HIV-infected patients is not as high as in studiesinvolving non-HIV infected patients. In non-HIV studieswith ezetimibe added on therapy LDL-C was decreased by25-60 % [10]. This suggests that HIV-infected patients areless affected by this therapy. The 2012 Canadian Cardio-vascular Society (CCS) guidelines for the general popula-tion have recommended a 50 % reduction in LDL-C frombaseline or LDL < 2.0 mmol/L as the target levels for thetreatment of moderate and high risk patients [20]. In ourcenter, we treat HIV- positive patients at the moderate risklipid profile targets. While ezetimibe administration was*Significant change from their baseline (p < 0.05)apoB, apolipoprotein B; apoA1,apolipoprotein A1;TC, total cholesterol; LDL-C, low-dtriglycerides; API, atherogenic index of plasma; FBG, fasting blood glucose; hsCRP, haminotransferase; CK, creatine kinaseTable 4 Primary and secondary targets 12 weeks after treatment wiPrimary TargetsLDL-C ≤2.0 mmol/L 50 % reductionin LDLApoB ≤0.80Rosuvastatin 20 mg 2.07 19 % reduction 0.88Rosuvastatin 10 mg +Ezetimibe 10 mg2.12 24 % reduction 0.89LDL-C, low-density lipoprotein cholesterol; apoB, apolipoprotein B;; non-HDL-C, nonA1; hsCRP, high-sensitivity C-reactive protein−1.01 ± 0.79* −0.50 ± 0.63* 0.03−0.68 ± 0.54* −0.48 ± 0.55* 0.37−0.00 ± 0.29 0.03 ± 015 0.72−1.63 ± 2.86* −0.52 ± 0.65* 0.09−0.62 ± 0.58* −0.17 ± 0.57 0.03−0.12 ± 0.20* −0.03 ± 0.12 0.13−0.97 ± 0.68* −0.53 ± 0.13 0.030.34 ± 1.28 −0.34 ± 1.75 0.15−0.60 ± 12.5 −1.06 ± 3.48 0.878 ± 48 53 ± 258 0.439 ± 17* 1.28 ± 16.6* 0.184 ± 14 −0.10 ± 8 0.30−20 ± 90 12 ± 69 0.23more effective in reducing LDL-C, neither of the twogroups reached therapeutic targets.The 2012 CCS guidelines also recommend alterna-tive targets including apoB ≤ 0.8 g/L or non-HDL-C ≤2.6 mmol/L for the treatment of moderate and highrisk patients [20]. Growing evidence indicates that dur-ing treatment of dyslipidemia, CVD events correlatemore strongly with levels of apoB and non-HDL-C[22]. ApoB has been suggested as an alternative pri-mary treatment target in the 2012 CCS guidelines forindividuals with moderate-high CVD [20]. Recently,Piconi et al have suggested that apoB may predictASCVD in HIV-infected populations [23]. In terms ofpatients reaching the CCS target of apoB ≤0.80 g/L theresults were similar between groups following 12 weeks oftreatment. When ezetimibe was added to rosuvastatin,ensity lipoprotein cholesterol; HDL, high-density lipoprotein cholesterol; TG,igh-sensitivity C-reactive protein; AST, aspartate aminotransferase; ALT, alanineth rosuvastatin or rosuvastatin plus ezetimibeSecondary Targetsg/L non-HDL-C ≤2.6 TG <1.7 mmol/L ApoB:ApoA1ratio <0.80hsCRP <2 mg/L3.25 2.88 0.60 1.723.06 1.92 0.55 5.19- high-density lipoprotein cholesterol; TG, triglycerides; apoA1, apolipoproteinSaeedi et al. Lipids in Health and Disease  (2015) 14:57 Page 6 of 845 % (from 15.0 % at baseline) of patients reached targetcompared to 50 % (from 27.8 % at baseline) in patientstreated with rosuvastatin alone. These improvements inapoB are similar to those reported in a large trial in non-HIV patients on ezetimibe monotherapy [24]. In addition,only the ezetimibe treated group had a significant reduc-tion in non-HDL-C (24 %) as compared to baseline. Inkeeping with our findings, others have shown that in HIV-infected patients combination of statin with ezetimibe wasmore effective in lowering non-HDL-C than statin alone[25]. Borrato et al have shown that treatment of HIV-infected patients with rosuvastatin 10 mg alone for16 weeks resulted in a significant reduction of LDL-C aswell as non-HDL-C with 65 % of them achieving thera-peutic targets [26]. In rosuvastatin monotherapy, we didnot see any significant changes in non-HDL-C. The dif-ferences between their and our study could be due tothe type of ART, or other confounding factors. In ourstudy, more patients in the combination group reachedTG <1.7 mmol/L (53.3 %) than the increased dosegroup (15 %).Another marker for cardiovascular risk that has yet tobe thoroughly assessed in the HIV-infected patients isthe apoB/apoA1 ratio. Several studies in the non-HIVpopulation have shown that increase in this ratio is asso-ciated with an increased risk of CVD [27, 28]. It hasbeen suggested that apoB/apoA 1 ratio can be consid-ered a tool to fine-tune the risk assessment and thus thetargets of therapy [5]. This ratio may be valuable in de-termining the risk or response to treatment in the HIV-infected individuals. Our study showed that both treat-ments resulted in a reduction in apoB/apoA1, albeitthis reduction was statistically significant only in theezetimibe-treated patients. However, it should be notedthat among our study patients, an elevated apoB/apoA1ratio (>0.80) was not prevalent (38 % of patients). Thismay be due to the fact that at baseline all these patientswere on 10 mg of rosuvastatin. Accordingly, nearlyevery patient reached the apoB/apoA1 target following12 weeks of treatment. This could suggest that CVDrisk is not greatly elevated in the HIV-infected popula-tion but as our sample size is small and further investi-gation into prevalence of elevated apoB/apoA1 ratio inthis population is warranted.The reported effects of ezetimibe on other lipidparameters and hsCRP have been variable. Our study re-sults showed a significant decrease in TC by 19 % in theezetimibe plus rosuvastatin group and 10 % in rosuvasta-tin monotherapy group which is similar to the 10-32 %reduction previously reported [11, 12, 29]. Also, hsCRPwas lowered by 38 % in rosuvastatin 20 mg group and10 % in combination of ezetimibe and rosuvastatingroup. In neither group reached statistical significance.The hsCRP is an inflammatory biomarker, levels ofwhich are associated with risk of CVD. The EmergingRisk Factors Collaboration has shown an stepwise in-crease in risk of CVD for hsCRP levels between 0.5 and20 mg/L with hsCRP > 2.0 mg/L associated with a haz-ard ratio of CVD of 1.5 [30]. However, this was attenu-ated after correction for age, sex, diabetes, TG, andHDL-C. Also, Mendelian randomization studies havedemonstrated that hsCRP is not related to risk of CVDand not a target of therapy [31, 32]. For HIV-infectedpatients, the role of hsCRP may be less clear because theresults could be confounded by other factors such asother comorbidities and risk factors [5]. We did not seeany significant changes in HDL-C in either group whichis consistent with some studies [12, 14].Here we showed that the combination of ezetimibeand rosuvastatin decreased TG (0.62 mmol/L, 24.0 %)and AIP (0.12, 42.6 %) whereas no such improvementwas seen in the rosuvastatin 20 mg group following12 weeks of treatment. A novel and not fully investigatedmarker of CVD risk in the HIV-infected population isAIP. The AIP, calculated as logarithm (TG/HDL-C), cor-relates with size of LDL-C particles, rate of esterificationof plasma cholesterol independent of apoB concentra-tion [33]. It is used as a predictive marker for atherogenicrisk and cardiovascular risk and is a useful measure ofresponse to pharmacological intervention [33, 34]. Thus,AIP may prove to be a useful predictor of risk in thispopulation given its predictive utility in non-HIV studies[20] and the fact that it combines two parameters that areoften adversely affected by HIV and ART. At baseline,60 % of our study cohort were above the high-risk AIP tar-get of >0.21 [21]. This was significantly improved in thecombination therapy group. The 20 mg rosuvastatinmonotherapy improved AIP by 8 % but this did not reachstatistical significant.Addition of ezetimibe to rosuvastatin was found to bewell tolerated with an improvement in clinical and bio-chemical safety profile. As it does not interfere withCYP450 system and there is low probability of drug-drug interaction between ezetimibe and HIV drugs.LimitationsThere are several limitations to this study. First this wasa single center study with a small sample size. A 12 weekstudy duration may be considered short and was not de-signed to evaluate possible the long-term adverse effectsof ezetimibe. Furthermore, it is not clear whether theimproved reductions in lipid endpoints with ezetimibeadd on therapy will correlate with cardiovascular end-points when compared to increased statin therapy in thispopulation. In addition, despite randomization, therewere differences between the groups, especially withrespect to smoking and hypertension.Saeedi et al. Lipids in Health and Disease  (2015) 14:57 Page 7 of 8ConclusionsWe have demonstrated that addition of ezetimibe 10 mgto rosuvastatin 10 mg is a more effective treatment fordyslipidemia in HIV-infected population than increasingdose to 20 mg. Despite lowering of apoB within groups,there was no statistically significant difference in apoB be-tween the treatment groups. Ezetimibe was well-toleratedand no serious adverse events were identified. Trials inHIV-infected populations are required to assess the ef-fectiveness of ezetimibe and/or statins on cardiovascu-lar outcome.Competing interestsThere is a conflict of interest. This study was funded by Merck Frosst-ScheringPharma Company which makes the drug.Authors’ contributionsRS carried out data analysis and drafted the manuscript. KJ enrolled thepatients, collected data, performed data analysis, and edited the manuscript.JF edited the manuscript. MTB edited the manuscript. GB is the correspondingauthor. He also edited the manuscript. All authors read and approved the finalmanuscript.AcknowledgementWe would like to acknowledge Merck Frosst-Schering Pharma, G.P. for theirfinancial support for this study.Author details1Department of Pathology & Laboratory Medicine, University of BritishColumbia, Vancouver, Canada. 2Experimental Medicine Program, Faculty ofMedicine, University of British Columbia, Vancouver, Canada. 3Division ofCardiology, Department of Medicine, University of British Columbia,Vancouver, Canada. 4Departments of Medicine and Pathology, Faculty ofMedicine, University of British Columbia, Vancouver, Canada.Received: 28 November 2014 Accepted: 2 June 2015References1. Law MG, Friis-Moller N, El-Sadr WM, Weber R, Reiss P, D'Arminio MonforteetA, et al. 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Executive Summary of The Third Report of TheNational Cholesterol Education Program (NCEP) Expert Panel on Detection,Evaluation, And Treatment of High Blood Cholesterol In Adults (AdultTreatment Panel III). JAMA. 2001;285(19):2486–97.Submit your next manuscript to BioMed Centraland take full advantage of: • Convenient online submission• Thorough peer review• No space constraints or color figure charges• Immediate publication on acceptance• Inclusion in PubMed, CAS, Scopus and Google Scholar• Research which is freely available for redistributionSaeedi et al. Lipids in Health and Disease  (2015) 14:57 Page 8 of 8Submit your manuscript at www.biomedcentral.com/submit


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