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Changes in lipids over twelve months after initiating protease inhibitor therapy among persons treated… Levy, Adrian R; McCandless, Lawrence; Harrigan, P R; Hogg, Robert S; Bondy, Greg; Iloeje, Uchenna H; Mukherjee, Jayanti; Montaner, Julio S Feb 10, 2005

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ralssBioMed CentLipids in Health and DiseaseOpen AcceResearchChanges in lipids over twelve months after initiating protease inhibitor therapy among persons treated for HIV/AIDSAdrian R Levy*1,2, Lawrence McCandless2, P Richard Harrigan3, Robert S Hogg1,3, Greg Bondy4, Uchenna H Iloeje5, Jayanti Mukherjee5 and Julio S Montaner3,6Address: 1Department of Health Care and Epidemiology, University of British Columbia (UBC), Vancouver, Canada, 2Centre for Health Evaluation & Outcome Sciences, St. Paul's Hospital, Vancouver, Canada, 3BC Centre for Excellence in HIV/AIDS, St. Paul's Hospital, Vancouver, Canada, 4St. Paul's Hospital HIV Metabolic and Lipid Clinic, Vancouver, Canada, 5Bristol-Myers Squibb, Wallingford, Connecticut, USA and 6Department of Medicine, UBC, Vancouver, CanadaEmail: Adrian R Levy* - alevy@interchange.ubc.ca; Lawrence McCandless - lawrence@stat.ubc.ca; P Richard Harrigan - richard@hivnet.ubc.ca; Robert S Hogg - bobhog@hivnet.ubc.ca; Greg Bondy - gbondy@providencehealth.bc.ca; Uchenna H Iloeje - uchenna.iloeje@bms.com; Jayanti Mukherjee - jayanti.mukherjee@bms.com; Julio S Montaner - julio.montaner@hivnet.ubc.ca* Corresponding author    HIV/AIDSprotease inhibitorscholesteroltriglyceridescardiovascular diseaseAbstractBackground: Protease inhibitors are known to alter the lipid profiles in subjects treated for HIV/AIDS. However, themagnitude of this effect on plasma lipoproteins and lipids has not been adequately quantified.Objective: To estimate the changes in plasma lipoproteins and triglycerides occurring within 12 months of initiating PI-basedantiretroviral therapy among HIV/AIDS afflicted subjects.Methods: We included all antiretroviral naïve HIV-infected persons treated at St-Paul's Hospital, British Columbia, Canada,who initiated therapy with protease inhibitor antiretroviral (ARV) drugs between August 1996 and January 2002 and who hadat least one plasma lipid measurement. Longitudinal associations between medication use and plasma lipids were estimated usingmixed effects models that accounted for repeated measures on the same subjects and were adjusted for age, sex, timedependent CD4+ T-cell count, and time dependent cumulative use of non-nucleoside reverse transcriptase inhibitors andadherence. The cumulative number of prescriptions filled for PIs was considered time dependent. We estimated the changes inthe 12 months following any initiation of a PI based regimen.Results: A total of 679 eligible subjects were dispensed nucleoside analogues and PI at the initiation of therapy. Over a median47 months of follow-up (interquartile range (IQR): 29–62), subjects had a median of 3 (IQR: 1–6) blood lipid measurements.Twelve months after treatment initiation of PI use, there was an estimated 20% (95% confidence interval: 17% – 24%) increasein total cholesterol and 22% (12% – 33%) increase in triglycerides.Conclusions: Twelve months after treatment initiation with PIs, statistically significant increases in total cholesterol andtriglycerides levels were observed in HIV-infected patients under conditions of standard treatment. Our results contribute tothe growing body of evidence implicating PIs in the development of blood lipid abnormalities. In conjunction with thePublished: 10 February 2005Lipids in Health and Disease 2005, 4:4 doi:10.1186/1476-511X-4-4Received: 01 October 2004Accepted: 10 February 2005This article is available from: http://www.lipidworld.com/content/4/1/4© 2005 Levy et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Page 1 of 7(page number not for citation purposes)predominance or men, high rates of smoking, and aging of the treated HIV-positive population, elevated lipoproteins andtriglycerides may mean that patients such as these are at elevated risk for cardiovascular events in the future.Lipids in Health and Disease 2005, 4:4 http://www.lipidworld.com/content/4/1/4IntroductionAbnormalities in the lipid metabolism of persons infectedwith human immunodeficiency virus (HIV), potentiallyinduced by the disease itself and the medications used fortreatment, were first reported in the early 1990s[1].Reductions in high- (HDL) and low-density lipoprotein(LDL) cholesterol were observed amongst personsinfected with HIV and increases in triglycerides wereobserved among persons with AIDS[1]. Following theintroduction of protease inhibitors (PI), morphologicalchanges in fat distribution were reported. This was fol-lowed by numerous reports of metabolic disturbances,including glucose and lipid abnormalities presenting asinsulin resistance, impaired glucose tolerance, hyperglyc-emia, type 2 diabetes mellitus [2-5], elevated serum trig-lycerides, LDL and very low density lipoproteincholesterol, apolipoprotein B, E, and lipoprotein(a) [2-4,6]. The combination of metabolic disturbances andmorphological changes are now described as the HIV-related "lipodystrophy syndrome"[2,3].Up to one-half of subjects treated with PIs have shown ele-vated levels of triglycerides, total cholesterol (TChol),LDL, insulin, and fasting glucose [7-10]. The onset of met-abolic changes appears to occur soon after initiation oftreatment, often as quickly as within several weeks[11].The high prevalence of disturbances of lipoproteins andtriglycerides, the rapidity of their onset, and large changesthat have been observed in randomized trials have led toconcern regarding the potential impact of PIs on the car-diovascular health of persons with HIV/AIDS. However,the direction and magnitude of changes in plasma lipo-proteins and triglycerides induced by PIs has yet to bequantified in an observational setting. The aim of thisstudy was to quantify the magnitude of change in lipopro-tein and triglyceride levels over twelve months followingany initiation of PI-based treatment in a cohort of subjectstreated for HIV/AIDS in a large tertiary care institution.MethodsWe included all antiretroviral naïve HIV-infected personstreated at St-Paul's Hospital, British Columbia (BC), Can-ada, who initiated use of PIs between August 1996 andJanuary 2002. Plasma lipoprotein and triglyceride levelswere obtained from measurements taken over the courseof regular monitoring. Longitudinal effects of the impactof PIs on lipoproteins and triglycerides were estimatedusing statistical models that accounted for correlation dueto repeated measurements on the same individuals.Study Setting and PopulationIn BC, antiretroviral drugs have been centrally distributedat no cost to eligible HIV-infected individuals sincefor Excellence in HIV/AIDS. Since December 1996, themainstay of treatment for HIV/AIDS has been highlyactive antiretroviral therapy (HAART) including two nucl-eosides and either a PI or a non-nucleoside reverse tran-scriptase inhibitor (NNRTI). Typically, HIV-infectedsubjects receiving antiretroviral therapy are monitored byphysicians at intervals no longer than three months atwhich time prescriptions are renewed or modified basedon clinical and laboratory parameters, and necessary lab-oratory tests are conducted. This research received ethicalapproval from the Institutional Review Board of Provi-dence Health Care in BC.Exposure to antiretroviral therapy for HIV/AIDSAt the BC Centre for Excellence in HIV/AIDS, records ofCD4+ T-cell counts and a profile of dispensed antiretrovi-ral therapy are routinely maintained, including the: pre-scription fill dates, medications prescribed, and amountdispensed. Records of dispensed antiretroviral medica-tions, (including nucleoside analogs, PI and NNRTI) wereused to determine the drugs dispensed and available toeach subject during each month of follow-up. Subjectswere considered unexposed until the first month that a PIwas dispensed. The exposure at the time of the lipid meas-urement was calculated as the cumulative number of con-secutive months of drug exposure up until and includingthe month in which a measurement was taken. As we wereinterested in estimating changes that occur in plasma lipo-proteins and triglycerides within the first year after treat-ment initiation, we included measurements with acumulative PI exposure up to a maximum of twelvemonths. Subjects were considered unexposed thirty daysafter the last PI was dispensed and, at that time, the cumu-lative exposure was set to zero.Plasma lipoproteins and triglyceridesApproximately one-half of HIV-infected patients in BC arefollowed at one treatment centre located at St. Paul's Hos-pital, a large teaching hospital in Vancouver. For thesesubjects, in addition to virological testing, the hospitallaboratory records the results of plasma lipoproteins andtriglycerides. Subjects were routinely instructed to fast for12 hours prior to the sample being drawn. Blood sampleswere collected in 10-1 EDTA-coated vacutainer tubes.Plasma was separated by centrifugation for 10 minutes at2,000 revolutions per minute. TChol in the plasma wasdetermined using an enzymatic method[14] and plasmatriglyceride was determined as previously described[15].HDL cholesterol was determined using a heparin manga-nese precipitation of apo B-containing lipoproteins[16]and LDL cholesterol was calculated using the Friedewaldformula[17,18].Page 2 of 7(page number not for citation purposes)1986[12,13]. In October 1992, the HIV/AIDS Drug Treat-ment Program became the responsibility of the BC CentreFor some subjects, the first lipid measurement was takenprior to the dispensation of any antiretroviral drugLipids in Health and Disease 2005, 4:4 http://www.lipidworld.com/content/4/1/4("treatment naïve" baseline lipid measurements). Othersubjects had their first recorded plasma lipoproteins andtriglycerides after HAART was initiated (initiation lipidlevels).Statistical analysisWe used linear mixed effects models[19] to estimate theeffect of PI-based HAART on changes in plasma lipopro-teins and triglycerides over twelve months. As blood lipidlevels were always greater than 0, the responses were logtransformed prior to model fitting. Effect estimates wereobtained via restricted maximum likelihood estimationusing the R© function lme(.). An analysis of variance indi-cated that simple parallel-line models, where the exposureeffect was assumed to be constant over subjects, couldadequately explain variation in the data compared tomore complex models with random slopes. To accountfor correlated responses due to repeated measurements onthe same individual, the correlation structure of themodel was specified to include only a random interceptfor each subject.The following explanatory variables were included in themodels: age, sex, and CD4+ T- cell count at PI initiation,concomitant use of NNRTI, and a measure of adherenceto antiretroviral therapy. Exposure to NNRTI was consid-ered time-dependent and quantified using the same algo-rithm that was used to calculate time dependent PIexposure. Adherence was calculated by dividing thenumber of months of antiretroviral medications dis-pensed by the number of months of follow-up in the firsttwelve months after treatment initiation. Incompleteadherence represents the gap between the time that theprevious medication supply ran out until the next refilldate, and/or until the last contact date with the program.This method is reliably associated with both clinical out-comes and un-timed drug level monitoring[20,21].For each outcome and associated regression coefficient β,the quantity exp(β)-1 represented the adjusted monthlypercent change in that plasma lipid fraction. These valueswere annualized using the formula exp(12 × β)-1. Ninetyfive percent confidence intervals (95% CI) for the effectestimates were obtained using the standard error for eachregression coefficient.Two sensitivity analyses were conducted. The first analysisinvolved restricting the analysis to lipid measurementswhich were taken on subjects prior to any change frombaseline antiretroviral therapy. The second sensitivityanalysis included only subjects who had lipid measure-ments taken prior to initiation of therapy.ResultsThere were 679 subjects who were eligible for analysis,91% of whom were male (Table 1). The median age was38 years at initiation of therapy and the median baselineCD4+ T-CELL COUNT was 210 cells/mm3. All subjectsinitiated therapy that included a nucleoside analog and aPI.Subjects were followed for a median of 47 months (Table2). During that follow-up time, subjects had a mean of73% of months in which a PI had been dispensed, with amean of 31 prescription refills. The mean adherence in thefirst year was 89%, and the median adherence was 100%indicating that more than one-half of subjects were dis-pensed all their medications.A total of 3,010 lipid measurements were used in the anal-ysis, with 400 subjects having had two or more lipidmeasurements during the course of follow-up. There werea median of 3 (IQR 1–6) measurements per subject. Themedian time between lipid measurements was 3 (IQR 2–5) months for all subjects.Table 3 shows the percentage change in plasma lipopro-tein and triglyceride levels after 12 months of PI use, afteradjustment for age, sex, and CD4+ T- cell count atinitiation, concomitant use of NNRTI, and adherence. Sta-tistically significant increases of about 20% were observedin TChol, the lipoprotein fractions, and triglycerides.The sensitivity analyses indicated that the models wererobust to changes in the sub-population studied and theexposures that were included. In the analysis thatincluded subjects who had a baseline measurement priorto start of HAART, a plasma profile prior to antiretroviraltherapy initiation showed a similar pattern but with widerconfidence intervals. In the analysis which was restrictedto lipid measurements taken on subjects prior to switch-Table 1: Demographic and clinical characteristics at treatment program enrollement among 679 subjects treated with PI-based HAART initiation for HIV/AIDS at St Paul's Hospital, Vancouver, BC, August 1996 – January 2002Characteristic*Age (y)Mean (SD) Median 39 (8.9) 38Sex (% male) 91Status (% alive) at end of follow-up 93CD4 (cells/mm3)Mean (SD) Median 255 (222) 210Abbreviations: SD = Standard deviation; PI protease inhibitor.Page 3 of 7(page number not for citation purposes)ing from baseline therapy, the effect estimates were simi-lar to those in Table 3.Lipids in Health and Disease 2005, 4:4 http://www.lipidworld.com/content/4/1/4DiscussionIn patients treated for HIV infection with HAART in a nat-uralistic setting, we observed that treatment with PIs wasestimated to result in 20% increases in the levels of totalcholesterol, HDL- and LDL-cholesterol and triglyceridestwelve months after treatment initiation. Our results con-tribute to the growing body of evidence implicating PIs inthe development of blood lipid abnormalities[22] and arein keeping with findings of randomized trials where achange from PI-based HAART to NRTI- or NNRTI-basedHAART was associated with improvements in the lipidprofile[23]. The observed increases in LDL-cholesteroland triglycerides were expected based on results reportedfrom randomized trials. The finding of an increase inHDL-cholesterol has been reported only in some[24] butnot all randomized trials.Low HDL levels and other forms of dyslipidemia, and dis-for cardiovascular morbidity and mortality in the generalpopulation[25,26]. Furthermore, the clustering of risk fac-tors leads to greater cardiovascular morbidity and mortal-ity than would be expected to occur in relation to eachcomponent alone[25]. These factors, when consideredtogether, provide grounds to suspect that persons beingtreated for HIV infection with PI are at an increased risk ofcardiovascular disease[8]. The increases in triglyceridescaused by use of PI is of concern because there is growingevidence that these lipids are an independent risk factorfor cardiovascular disease[27,28].Two large observational cohort studies, published in2003, showed discrepant results regarding the risks of car-diovascular disease among persons treated withHAART[29,30]. A retrospective administrative claimsdatabase study from the US Veteran's Affairs indicatedthat there was no relation between the use of antiretroviralTable 2: Use of PIs among 679 subjects initiating PI-based HAART for HIV/AIDS at St Paul's Hospital, Vancouver, BC, August 1996 – January 2002Characteristic*Number of months between initiation of PI and end of observation, median (IQR)** 47 (29–62)% of follow-up time with dispensed therapy mean (SD), median for PI 73 (30) 84Mean (SD) number prescriptions for***PI 31 (19)% adherence in first yearmean (SD) 89 (21)median (IQR) 100 (92 – 100)Abbreviations: SD = Standard deviation; IQR = Interquartile range; NRTI = nucleoside reverse transcriptase inhibitors; PI protease inhibitor; NNRTI = non-nucleoside reverse transcriptase inhibitor* PIs available during follow-up included: indinavir, nelfinavir, saquinavir, and ritonavir. All data taken from time of first therapy initiation (treatment program enrollement).** Time between first dispensation of HAART (enrollment) and last date of follow-up.*** All prescriptions are of 30 day durationTable 3: Baseline plasma cholesterol and triglycerides and estimated percent changes after 12 months when using PI among 679 subjects treated for HIV/AIDS at St Paul's Hospital, Vancouver, BC, August 1996 – January 2002Number of measurements (subjects)Mean lipid baseline measurements (SD)% change* (95% CI)TChol 1620 (529) 4.2 (1.0) 20 (17, 24)HDL 1250 (419) 1.0 (0.3) 22 (15, 29)LDL 677 (295) 2.5 (0.8) 12 (5, 20)N-HDL 1247 (419) 3.1 (1.2) 20 (15, 26)TRG 1743 (556) 1.9 (1.2) 22 (12, 33)Abbreviations: PI protease inhibitor; TChol = total cholesterol; HDL = high-density lipoprotein cholesterol; LDL = low- density lipoprotein cholesterol; N-HDL = Non-HDL Cholesterol; TRG = triglycerides* Adjusted for age, sex, and CD4+ cell count at first prescription for HAART, concomitant use of non-nucleoside reverse transcriptase inhibitor and adherence to antiretroviral therapy in the first year of treatmentPage 4 of 7(page number not for citation purposes)turbances in glucose metabolism, as well as central obes-ity, have been shown to be strong independent risk factorstherapy and the risk of cardiovascular or cerebrovascularhospitalizations [29]. A prospective multi-country collab-Lipids in Health and Disease 2005, 4:4 http://www.lipidworld.com/content/4/1/4orative study, with clinical events validation from elevencohorts of HIV-infected persons showed that the inci-dence of myocardial infarction increased with longerexposure to combination antiretroviral therapy[30].This study has a number of features that add credence tothe results. First, while only based at one hospital, thestudy population comprised about one-half of the treatedpopulation in BC. The study sample had similar demo-graphic composition (age and sex) and CD4+ T-cell countat initiation of therapy as other treated subjects in theprovince. We believe that these results are therefore gener-alizable to PI-regimen treated HIV-infected patients in BC,as well as to other target populations with similar demo-graphic characteristics. Second, as all dispensed PIs andother antiretroviral medications are paid for and recordedcentrally, there was complete information on all HAARTmedications available to all study subjects. We adjustedfor adherence using each subjects' refill compliance in thefirst year of treatment. Third, data on the plasma lipid pro-file, including both lipoproteins and triglycerides, were ofhigh quality. The measurements, while lacking the featureof being taken at uniformly spaced intervals as in closelymonitored system such as randomized trial, represent theactual experience in an observational setting. Fourth, theenrollment period lasted over five years, allowing a largesample size. We employed repeated measures analyses toaccount for the correlated structure of the data.This study was also subject to several limitations. First,lipid measurements were not collected in a predeterminedmanner as is typical in a prospective research study. Con-sequently, the timing of measurements was irregular andnot all lipid fractions were measured when blood wasdrawn. Second, despite instructions some subjects maynot have fasted for the full 12 hour period prior to blooddraws. Non-fasting triglyceride measurements are stilluseful for predicting cardiovascular disease anddeath[31]. Third, other potent risk factors for changes inlipid profiles such as family history and diet were not con-sidered. It is possible but unlikely that the type of tripletherapy prescribed by physicians could have been influ-enced by the belief that PIs may negatively impact lipidlevels, likely leading to an attenuation of the estimates.Fourth, a number of factors contributed to a bias towardsunderestimating the true changes: for some subjects base-line values were not obtained prior to treatment initia-tion; it was not possible to adjust for concomitant use oflipid modifying agents such as statins because these datawere not available; subjects with large changes in theirlipid profiles may have been switched to another class;and treatment interruptions would also have affectedexposure estimates. As a result of these limitations, theassumed that patients who stop therapy or skip a monthof therapy can be modelled as treatment naïve withrespect to any subsequent therapy. More sophisticated sta-tistical techniques are available[32] for handling this lim-itation, but appropriate software and resolution oftechnical issues are still in the developmental stages.Lastly, it is possible that the PI effect on lipids and triglyc-eride levels is not a class effect. The recently introduced PI,atazanavir sulfate, has been shown in several randomizedclinical trials not to adversely affect lipid levels [33-38].Due to changes in the HAART regimen that occurredbecause of resistance, non-compliance, or other reasons, itwas not possible to isolate the effect of individual PIs.Over the period under study, most subjects initiating PI-based HAART were prescribed either indinavir ornelfinavir.Treating PI-induced dyslipidemiaAs PI-based HAART is very effective in increasing survivalin HIV-infected patients[39], discontinuing PI is undesir-able, even in patients with dyslipidemia. However, as PI-induced dyslipidemia is often asymptomatic and typicallyoccurs in younger patients whose baseline risk of cardio-vascular disease is low, the need for primary prevention isoften under-appreciated in clinical practice[40]. When itis recognized, rather than discontinuing or switching PItherapy, one response is to initiate pharmacologic therapywith statins and/or fibrates[41].Statins have been shown to be effective drugs to preventcardiovascular disease in non-HIV patients[26]. While therole of statins in preventing cardiovascular disease in HIVpatients remains to be demonstrated definitively, severalsmaller randomized controlled trials that have shown thatthese medications have beneficial effects on PI-induceddyslipidemia [42]. Until recently, pravastatin was the pre-ferred statin for treating PI-induced dyslipidemia becauseit does not require metabolism by the cyp 3A4 system.However, recent studies have shown that moderate lipidlowering with pravastatin was less effective than intensivelipid lowering with atorvastatin in reducing: progressionof atherosclerotic lesions [43] in patients requiring coro-nary angiography; and death or major cardiovascularevents in patients with an acute coronary syndrome[44].Atorvastatin is a powerful and effective statin, thoughthere are still only limited published studies with thisagent in HIV patients[45]. Because of metabolism by cyp3A4, the dose of atorvastatin should be reduced one-halfin patients receiving PIs. Lovastatin and simvastatinrequire metabolic activation by cyp 3A4 and should beavoided in patients receiving PIs. Rosusvastatin, a recentlyintroduced statin has features that make it attractive forPage 5 of 7(page number not for citation purposes)actual changes in plasma lipoprotein and triglyceridesmay be greater than reported in this study. Fifth, wetreating patients with PI-induced dyslipidemias: it doesnot require metabolism by the cyp 3A4 system and itLipids in Health and Disease 2005, 4:4 http://www.lipidworld.com/content/4/1/4effectively reduces LDL cholesterol. The safety and effec-tiveness of rosuvastatin in reducing clinical outcomes inHIV patients remain to be demonstrated.Fibrates are effective in lowering triglycerides and increas-ing HDL and have been shown to be effective in HIVpatients[42]. Despite the impact on plasma lipids andtriglycerides, only one trial has shown fibrates to reduceclinical outcomes[46,47]. Therefore, the role of fibrates inreducing cardiovascular disease outcomes remains to befully elucidated. The main role of fibrates is to reduce therisk of pancreatitis associated with hypertriglyceridemia.In HIV patients, gemfibrozil should be limited to mono-therapy because of the risk for myopathy. Fenofibrate isthe preferred drug if combination therapy with a statin iscontemplated. The efficacy of other lipid lowering drugssuch as niacin and cholesterol transport blockers(ezetimibe) remains to be demonstrated. Bile acid seques-trants are contraindicated in patients receiving HAART.We conclude that there was an estimated 20% increase inlipoproteins and triglycerides in the first year after initiat-ing PI-based antiretroviral therapy in HIV-infectedpatients under conditions of standard treatment. Whetherthese increases continue beyond one year is of considera-ble interest because lipoproteins and triglycerides areknown risk factors for cardiovascular disease. In conjunc-tion with the predominance or men, high rates of smok-ing, and aging of the treated HIV-positive population,elevated lipoproteins and triglycerides may mean thatpatients such as these are at elevated risk for cardiovascu-lar events in the future.AcknowledgementsThe authors gratefully acknowledge the following persons: Dr. Frances Rosenberg, Ms. Linda Row and Ms. Angie Lim from Department of Pathol-ogy at St Paul's Hospital for providing access to blood lipid measurements; to Ms. Benita Yip and Mr. Keith Chan for preliminary data analysis, and to Anne Drummond PhD for editorial support.Financial support: Partial funding for this study was provided by an unre-stricted grant from the Bristol-Myers Squibb Company.References1. Grunfeld C, Pang M, Doerrler W, Shigenaga JK, Jensen P, Feingold KR:Lipids, lipoproteins, triglyceride clearance, and cytokines inhuman immunodeficiency virus infection and the acquiredimmunodeficiency syndrome. J Clin Endocrinol Metab 1992,74:1045-1052.2. 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