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subfractions in HIV-1-infected patients receiving
protease inhibitors
Randa Bittar, Élisabeth Aslangul, Philippe Giral, Lambert Assoumou,
Marc-Antoine Valantin, Olga Kalmykova, Marie-Christine Federspiel, Corinne
Cherfils, Dominique Costagliola, Dominique Bonnefont-Rousselot
To cite this version:
Randa Bittar, Élisabeth Aslangul, Philippe Giral, Lambert Assoumou, Marc-Antoine Valantin, et al..
Lack of effects of statins on high-density lipoprotein subfractions in HIV-1-infected patients receiving
protease inhibitors. Comptes Rendus Biologies, Elsevier Masson, 2016, �10.1016/j.crvi.2016.11.004�.
�hal-01421154�
Biochemistry/Biochimie
Lack
of
effects
of
statins
on
high-density
lipoprotein
subfractions
in
HIV-1-infected
patients
receiving
protease
inhibitors
Absence
d’effet
des
statines
sur
les
sous-fractions
des
lipoprote´ines
de
haute
densite´ chez
des
patients
infecte´s
par
le
VIH-1
recevant
des
inhibiteurs
de
prote´ase
Randa
Bittar
a,b,*
,
E´lisabeth
Aslangul
c,d,
Philippe
Giral
b,e,
Lambert
Assoumou
f,g,
Marc-Antoine
Valantin
f,g,h,
Olga
Kalmykova
i,
Marie-Christine
Federspiel
a,
Corinne
Cherfils
a,
Dominique
Costagliola
f,g,h,
Dominique
Bonnefont-Rousselot
i,
the
ANRS
126
study
group
a
Unite´ fonctionnelledebiochimiedesmaladiesme´taboliques,servicedebiochimieme´tabolique,hoˆpitauxuniversitaires Pitie´-Salpeˆtrie`re–Charles-Foix,Assistancepublique–HoˆpitauxdeParis,83,boulevarddel’Hoˆpital,75651Pariscedex13,France
b
UPMCuniversite´ Paris06,UMR_S1166ICAN,75013Paris,France
cServicedeme´decineinterne,HoˆpitalLouis-Mourier,Assistancepublique–HoˆpitauxdeParis,92701Colombes,France dUniversite´ Paris-Descartes,ruedel’E´cole-de-Me´decine,75006Paris,France
e
Unite´ depre´ventioncardiovasculaire,serviced’endocrinologieme´tabolisme,hoˆpitauxuniversitairesPitie´-Salpeˆtrie`re–Charles-Foix, Assistancepublique–HoˆpitauxdeParis,75651Pariscedex13,France
f
Sorbonneuniversite´s,UPMCuniversite´ Paris-6,UMR_S1136,institutPierre-Louisd’e´pide´miologieetdesante´ publique,75013Paris, France
gInserm,UMR_S1136,institutPierre-Louisd’e´pide´miologieetdesante´ publique,75013Paris,France
hServicedesmaladiesinfectieusesettropicales,hoˆpitauxuniversitairesPitie´-Salpeˆtrie`re–Charles-Foix,Assistancepublique–Hoˆpitauxde
Paris,75651Pariscedex13,France
i
InsermU1022CNRSUMR8258,ChimieParisTech,PSLResearchUniversity,unite´ detechnologieschimiquesetbiologiquespourlasante´, faculte´ depharmacie,SorbonneParisCite´,universite´ Paris-Descartes,75006Paris,France
ARTICLE INFO Articlehistory:
Received8February2016
Acceptedafterrevision17November2016 Availableonlinexxx Keywords: HIV-1population Rosuvastatin Pravastatin HDLdistribution Cardiovascularrisk ABSTRACT
Background.–Weevaluatedtheeffectof45daysofrosuvastatinorpravastatintreatment onthedistributionofHDLsubfractionsinHIV-1-infectedindividualsreceivingboosted proteaseinhibitors(PIs)withcardiovascularrisk.
Methods.–ThedistributionofHDLsubclassesbygradientgelelectrophoresiswasblindly assessedin74HIV-1-infectedindividualsreceivingboostedPIsatbaselineandatday45of statintreatment,andcomparedwiththedistributionobtainedin63healthy normoli-pidemicindividualstakenascontrols.
Results.–NosignificantmodificationappearedinHDLdistributionbetweenthetwoarms ofstatinsfortheHIV-1-infectedindividuals.Nevertheless,whencomparedtocontrols, HDLsubfractionsshowedasignificantlylowerHDL2bproportionandsignificantlyhigher proportionsofHDL2aandHDL3b(P<0.001).
* Correspondingauthorat:Unite´ fonctionnelledebiochimiedesmaladiesme´taboliques,servicedebiochimieme´tabolique,hoˆpitauxuniversitaires Pitie´-Salpeˆtrie`re–Charles-Foix,Assistancepublique–HoˆpitauxdeParis,83,boulevarddel’Hoˆpital,75651Pariscedex13,France.
E-mailaddress:randa.bittar@psl.aphp.fr(R.Bittar).
ContentslistsavailableatScienceDirect
Comptes
Rendus
Biologies
w ww . sc i e nce d i re ct . co m
http://dx.doi.org/10.1016/j.crvi.2016.11.004
1631-0691/ C 2016Acade´miedessciences.PublishedbyElsevierMassonSAS.ThisisanopenaccessarticleundertheCCBY-NC-NDlicense(http:// creativecommons.org/licenses/by-nc-nd/4.0/).
1. Abbreviations
cART combinationantiretroviraltherapy
PI proteaseinhibitor
sdLDL small-denselow-densitylipoproteinparticles
LDL low-densitylipoprotein
SR-B1 scavengerreceptorB1
ABCG1 ATP-bindingcassettetransporterA1
D0 baseline
D45 day45
2. Introduction
HIV-1infectionanditstreatmentbyproteaseinhibitors
(PIs),especially whenboostedwithritonavir,havebeen
associatedwithincreasedcardiovascularrisk[1–3].This
increasedriskispartiallyrelatedtometabolicdisorders,
includingdyslipidemia as hypertriglyceridemiaand low
high-density lipoprotein (HDL) level [4], with a high
prevalence of atherogenic lipoprotein phenotype and
endothelialdysfunction [2,4]. Clinical studiessuggested
that cardioprotective properties were more associated
with HDL2 than with HDL3, and low levels of HDL2b
associated withelevated HDL3b wererelated to a high
cardiovascularrisk[5–7].
ManystudiesreportedtheroleoftheHIV-1infectionin
additiontotheroleofPIs-containingcombined
antiretro-viral therapy (cART) in accentuating the atherogenic
profileinHIV-infectedindividuals,whichischaracterized
bya lowlevelofHDL-cholesteroland ahighproportion
of small-dense low-densitylipoproteinparticles (sdLDL)
[8–10]. Mature HDL can be separated by gradient gel
electrophoresis into five distinct subclassesof different
sizes: HDL2b (12.9–9.71nm), HDL2a (9.71–8.77nm),
HDL3a(8.77–8.17nm),HDL3b(8.17–7.76nm),andHDL3c
(7.76–7.21nm)[5,11,12].The largestHDL2band HDL2a
subfractions displayed a superior capacity to mediate
cellularfree-cholesteroleffluxviabothscavengerreceptor
classB1(SR-BI)-andATP-bindingcassettetransporterG1
(ABCG1)-dependentpathwaysthansmallerHDL3
subspe-cies [13].HDL3c may provide potentprotection of LDL
fromoxidativedamageinducedbyoxygenreactivespecies
in the arterialintima, resulting in theinhibition of the
generationofpro-inflammatoryoxidizedlipids[14].
In a substudy of therandomizedmulticenter French
National Agency for AIDS and Viral Hepatitis Research
(ANRS) 126 VIHstatinetrial, we evaluated theeffect of
45 days of rosuvastatin (10mg/day) vs. pravastatin
(40mg/day)ontheLDLsizeandthedistributionof
LDL-subfractions [10]. We concluded that rosuvastatin was
moreeffectivethanpravastatininincreasingthediameter
of the LDL peak, in decreasing the percentage of
Conclusion.–NodifferencewasobservedinHDLdistributionbetweenpravastatinand rosuvastatin after 45 days treatment, in HIV-1-infected individuals under PIs. Nevertheless,whencomparedtohealthynormolipidemicsubjects,HDLdistributionis clearlydifferent,withadistributioninHIV-infectedindividualsunderPIsassociatedwith anincreasedcardiovascularrisk.
C 2016Acade´miedessciences.PublishedbyElsevierMassonSAS.Thisisanopenaccess
articleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/by-nc-nd/ 4.0/). RE´ SUME´
Contexte.–Nousavonse´value´ l’effetde45joursdetraitementparlarosuvastatineoula pravastatinesurladistributiondessous-fractionsdesHDLchezdespersonnesatteintes de VIH-1recevant des inhibiteurs de la prote´ase booste´es (IPs)et ayant unrisque cardiovasculaire.
Me´thodes.– Ladistributiondessous-classesd’HDLeffectue´eparunee´lectrophore`sesur gelengradientae´te´ e´value´eenaveuglesur74personnesinfecte´esparleVIH-1recevant desinhibiteursdelaprote´asebooste´es(IPs),etceaujour0etapre`s45joursdetraitement par les statines. Cette distribution a e´te´ ensuite compare´e a` celle obtenue chez 63personnesenbonnesante´,conside´re´escommete´moins.
Re´sultats.–Aucunemodificationsignificativen’estapparuedansladistributiondesHDL entrelesdeuxbrasdesstatinespourlesindividusinfecte´sparleVIH-1.Ne´anmoins, comparativement aux te´moins,les sous-fractions HDL pre´sentaient une proportion significativementplusfaibledeHDL2betdesproportionssignificativementpluse´leve´es deHDL2aetdeHDL3b(p<0,001).
Conclusion.–Aucunediffe´rencedanslamodificationdeladistributiondesHDLn’ae´te´ observe´eapre`s45joursdetraitemententrelapravastatineetlarosuvastatinechezles personnesinfecte´esparleVIH-1sousIPs.Cependant,ladistributiondesHDLchezdes personnesinfecte´esparleVIHsousIPsestclairementdiffe´rentequandelleestcompare´e a` celleobserve´echezlessujetssains,etestassocie´ea` unrisquecardiovasculairee´leve´.
C 2016Acade´miedessciences.Publie´ parElsevierMassonSAS.Cetarticleestpublie´ en
OpenAccesssouslicenceCCBY-NC-ND(http://creativecommons.org/licenses/by-nc-nd/ 4.0/). Motscle´s: PopulationVIH-1 Rosuvastatine Pravastatine DistributiondesHDL Risquecardiovasculaire
R.Bittaretal./C.R.Biologiesxxx(2016)xxx–xxx 2
atherogenicsmall-denseLDLandincreasingthe percent-ageoflessatherogeniclargeLDL[10].
Inthecurrentsubstudy,ouraimwastoevaluatethe
distributionofHDL subfractionsatbaselineinthesame
population of HIV-1-infected individuals receiving PIs
[1,2,10], to appreciate the effect of a 45-day statin
treatment onthis distribution,andtocomparewiththe
distributionofHDLsubfractionsinacontrolpopulation.
3. Materialsandmethods
Determinationoflipidparametersbyroutine
enzymat-icmethodswasperformedonfreshseraatbaseline(D0)
and day-45 (D45) in a central laboratory [1,2]. HDL
subclasses were determined blindly of sampling time
(D0 versus D45) ortreatment arm (rosuvastatinversus
pravastatin) in serum, as explained previously, after
isolationoflipoproteinsbysequentialultracentrifugation [10,15]. The lipoproteins from D0 and D45 of statin
treatment were run simultaneously on the same gel,
togetherwithlipoproteinsisolatedfromanormolipidemic
subjecttakenascontrol[2,10].
Seventy-four patients of the 83 patients enrolled in
the VIHstatine trial with available frozen samples at
baselineandD45wereeligibleforthissubstudy:36inthe
pravastatin arm and 38 in the rosuvastatin arm with
the same demographic, immunovirological and lipid
parameters,particularlyHDL-cholesterol[1,2,10].
Compa-risonsbetweenthetwostatinarmsorbetweenthetwo
statinarm combinedversus63 healthy normolipidemic
controlswereanalysedusingthenon-parametricMann–
Whitney test, while comparisons between D45 and D0
wereanalysedusingthepairedWilcoxontest.
4. Results
After45 days,no significantdifferencewasobserved
betweenthetwoarmsofstatintreatmentregardingthe
distribution of different HDL subclasses percentage,
respectively:HDL2a,HDL2b,HDL3a,andHDL3b.
Furtheranalyses werethus performed consideringa
global statin group (Table 1). After 45 days of statin
treatment, onlyHDL3b subfractionwasdecreased
com-paredtobaseline(P=0.003).TheD45HDLsubfractionsin
theHIV-infectedindividuals,comparedtothoseinhealthy
controls,showedasignificantlylowerHDL2bproportion
(P<0.001)andsignificantlyhigherproportionsofHDL2a
and HDL3b, while no difference wasevidenced for the
HDL3asubfraction(Fig.1).
5. Discussion
ThelowlevelsofHDL2bassociatedwithhighlevelsof
HDL3bobservedinourstudyareassociatedwithcardiac
Table1
DistributionofHDLsubfractionproportionsinthestatin-treatedHIV-infectedpatients(n=74)andinhealthynormolipidemiccontrols(n=63). % Day0 (n=74) Day45 (n=74) D(D45 D0) P Healthycontrols n=63 P* HDL2a 26.905.51 27.305.45 0.493.74 0.159 23.873.99 <0.001 HDL2b 13.306.15 13.506.10 0.193.63 0.446 23.683.62 <0.001 HDL3a 31.503.70 32.204.35 0.693.22 0.070 33.144.22 0.164 HDL3b 20.856.80 19.506.65 1.364.75 0.003 15.053.40 <0.001 Thesignificantresultsarepresentedinbold.HDL:high-densitylipoprotein;D45:day45;D0:baseline;P:comparisonD0vs.D45inthepooledstatin treatmentgroupusingthepairedWilcoxontest;P*:comparisonD45vs.healthysubjectsusingtheMann–Whitneytest.
Fig.1. Percentagesofhigh-densitylipoprotein(HDL)subfractionsintheglobalstatin-treatedHIV-infectedgroupofpatientsatD45comparedtohealthy normolipidemicsubjects.*P<0.001.
heart diseasein the general population [5,15].
Further-more,HDL2bsubclassisstronglyinverselycorrelatedwith
thecoronarydiseaserisk[16].
DyslipidemiaisafrequentsideeffectofcART,especially whenboostedPIsareused[1].Thelipiddisordersaremore
severe than before cART including PIs use, and usually
consist of hypercholesterolemia, hypertriglyceridemia,
elevatedlevels ofsmall-dense LDL particles.Stein etal.
[9]reportedhighproportionofsmall,lessprotectiveHDL
particles associated with endothelial dysfunction in a
groupof22HIV-1patientsreceivingARTunderPIswith
stabledosesformorethan6months.UseofPIsinHIV-1
populationhasbeenassociatedwithendothelial
dysfunc-tion,anearlystepinatherosclerosisthatpredictsfuture
adverse cardiovascular events [17] and cardiovascular
diseaseremainedincreasedwhencomparedtothegeneral
population[18].
StatinscanreducetotalcholesterolandLDL-cholesterol
in patients with HIV-1 infection under PIs, improve
endothelialfunctionanddelaytheprogressionof
cardio-vasculardisease, whilemore sideeffects wereobserved
duringstatintreatment[18].Selectionofstatintreatment andthepotentialfordruginteractionswithantiretroviral
therapy must beconsidered in this infected population
[18,19].
Onlyafewstudiescomparedtheeffectofstatinson
thedistributionofHDLsubfractionsindyslipidemicand
incontrolsubjects,andtheirresultsarecontradictory.No
data is currently available in HIV-1 patients. Schaefer
etal.[16]foundthatatorvastatinincreasedthe
percent-ageofHDL2bby25%,whereasthoseofmediumandsmall
HDL3 (i.e. HDL3b and HDL3c) did not significantly
change. Harangi et al. [20] reported that atorvastatin
significantlyincreasedtheproportionofHDL3,whereas
HDL2aandHDL2bweredecreasedinpatientsreceiving
20mg per day during three months. Lower doses of
atorvastatin used in this study could not restore the
physiologic proportions of the HDL subclasses. The
importantanti-atherogenicfunctionsofHDLsubclasses
include removal of excess cholesterol from peripheral
tissuesandreversecholesteroltransporttotheliverfor
excretionintobile[5,14].
Inconclusion,ourstudyshowsnodifferenceinHDL
distributionchangebetweenpravastatinand
rosuvasta-tinafter45daystreatment,inHIV-1-infected
individu-als under PIs and only HDL3b subfraction decreased
comparedtobaseline.Nevertheless,whencomparedto
healthy subjects, HDL distribution is clearly different,
withadistribution in HIV-1-infectedindividualsunder
PIs associated with an increased cardiovascular risk.
Reducingatherogeniclipoproteinchangesand
endothe-lialdysfunctioninHIVunderPIs,byoptimalstatinsand
management of cardiovascular risk, is needed in this
population. However, the lack of power of our study
(respectivepowerfor each ofthe fourtested variables
i.e. HDL2a, HDL2b, HDL3a, and HDL3b: 20%, 7%, 45%,
and65%,respectively)couldexplainthenegativeresults
and constitutes a limitation. Interactions with cART
shouldalsobeconsidered.Finally,theseresultsneedto
be confirmed on a large number of HIV-1-infected
patients.
Authors’contributions
Recruitment of patients was carried out by: E.A.,
M.-A.V.,P.G.,O.K.,andtheANRS126studygroup.
Statisticalanalysiswasperformedby:L.A.,D.C.,P.G.
Measurementoflipidparameters,andHDLdistribution
wasdoneby:M.-C.F.,C.C.,R.B.,D.B-R.
Interpretationofbiologicaldatawasperformedby:R.B., D.B-R.
Draftingofthearticlewasperformedby:R.B.,D.B-R.,
E.A,P.G.,D.C.
Studydesign,analysisand interpretationof thedata,
andcriticalrevisionofthearticleforimportantintellectual contentandfinalapprovalofthearticlewasdoneby:R.B., D.B-R.,E.A.,P.G.,D.C.,L.A.,M.-A.V.,O.K.
Disclosureofinterest
Lambert Assoumou, Dominique Bonnefont-Rousselot
andOlgaKalmykovadeclarethattheyhavenocompeting
interest. Randa Bittar has received travelling grants,
paymentofregistrationfeesandlecturefeesfromGilead
Sciences and Solvay. Philippe Giralhasreceived lecture
feesfromPfizer,AstraZenecaandSolvayandtravelgrants
fromMerck.E´lisabethAslangulhasreceivedtravelgrants
from Sanofi Aventis, Pfizer and Bristol-Myers-Squibb.
Marc-AntoineValantinhasreceivedlecturefees,traveling
expenses and payment of registrationfees from Roche,
Tibotec (Johnson& Johnson), Gilead, Glaxo-Smith-Kline,
Bristol-Meyers Squibb, MSD, and Boehringer-Ingelheim.
DominiqueCostagliolahasreceivedtravelgrants,
consul-tancy fees, honoraria or study grants from various
pharmaceutical companies, including Abbott,
Boehrin-ger-Ingelheim, Bristol-Myers-Squibb, Gilead Sciences,
Glaxo-Smith-Kline,Janssen,Merck,Roche.
Acknowledgements
TheFrenchNationalAgencyforAIDSandViralHepatitis
Research(ANRS)sponsoredthetrialandwasinvolvedin
thestudydesign.
This work was presented at the 82nd European
Atherosclerosis Society Congress, 31 May–3 June 2014,
Madrid, Spain, as a poster presentation (Abstract
EAS-1175). References
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